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INFORMATION FOR

"Liver Cancer Clinical Care and Research at Yale" and "Dermatologic Toxicities in Cancer Patients: Updates from the Yale Onco-dermatology Clinic"

May 25, 2021
  • 00:00To this week's character center Grand rounds,
  • 00:03we have two speakers today,
  • 00:04both from Yale will give us
  • 00:07some exciting discussion of some
  • 00:08of the work we're doing here.
  • 00:10Our first speaker is Mario Strozza busco.
  • 00:13He's a professor of medicine, director
  • 00:15of the liver Cancer program here in Co.
  • 00:18Director of the liver center.
  • 00:20He received his medical and PhD degrees
  • 00:22in Italy and then had a number of
  • 00:25leadership positions at the University
  • 00:26of Milan before joining our faculty.
  • 00:28He's an expert on the care of
  • 00:30patients with liver cancer,
  • 00:32is internationally known for
  • 00:33his work and hepatology.
  • 00:34Liver transplantation is a member
  • 00:36of several scientific societies
  • 00:37in Europe in the United States.
  • 00:39His current research relates to
  • 00:41the pathophysiology of biliary
  • 00:43tract disease is repaired.
  • 00:45Biology of liver repair,
  • 00:46liver transplantation,
  • 00:47liver cancer in healthcare management,
  • 00:49and so today we're going to hear from
  • 00:52Mario and tell of his talk is liver cancer,
  • 00:56clinical care and research at Yale.
  • 00:58So Mario, you're
  • 01:00up. Thank you very much, Dan,
  • 01:02for the introduction and thanks for the
  • 01:05Cancer Center for the Invitation Ann.
  • 01:07And thanks a lot for this Milo.
  • 01:12Cancel. After the program has
  • 01:15received during this year,
  • 01:17I'm really only as a as a spokesperson
  • 01:20for for a group of colleagues that are
  • 01:24interested in India in the in liver
  • 01:27cancer and treating liver cancer.
  • 01:29So I'm just the messenger.
  • 01:31So what do we do in the liver
  • 01:35cancer program we take?
  • 01:36We take care of patients with liver
  • 01:39masses either benign or malignant are,
  • 01:42and the two most frequent.
  • 01:44Primary liver cancer are able to sell cash.
  • 01:49You know my also called HTC and
  • 01:53Intraparticle Angela carcinoma and I
  • 01:56focus my talk today mostly on ATC,
  • 01:59which is the most important primary.
  • 02:04Cancer of the liver.
  • 02:05The liver is is an organ which
  • 02:09is located in the abdomen,
  • 02:11but really here it is.
  • 02:13The main regulator of the whole body,
  • 02:16metabolic coma stasis,
  • 02:18and in fact if the liver fails we actually,
  • 02:22the patient suffered of a
  • 02:24syndrome which is very bad.
  • 02:26Absolutely Poly systemic syndrome.
  • 02:28As you can see here.
  • 02:30And the important thing
  • 02:32to understand is that 85%.
  • 02:3490% of the patient with able to sell casino.
  • 02:38They are also cirrhotic in
  • 02:40the liver and not only that,
  • 02:43but if we follow a cohort of patients
  • 02:46with viral induced liver disease
  • 02:48either B or C for enough time,
  • 02:51we see that the main the.
  • 02:55When they die,
  • 02:56most of them they died with the in a
  • 03:00particular casting armor as shown here.
  • 03:03So why what the about the circus
  • 03:06number is actually only rise
  • 03:08worldwide and the estimate are there.
  • 03:11There are 830,000 cases recorded every year,
  • 03:15with the mortality that almost
  • 03:17approached the incidents.
  • 03:18And why is that? Well, this is the.
  • 03:22A result of a number of worldwide the
  • 03:26epidemics that are also risk factor
  • 03:29for chronic liver disease and among
  • 03:33them we can mention viral appetite is B&C.
  • 03:37You see that they the infection
  • 03:40from viral potatis is hundreds
  • 03:43of millions of people I call is
  • 03:47another important work by the.
  • 03:49What is factor as it is obesity,
  • 03:52diabetes?
  • 03:53And more and more,
  • 03:55we realize that if 50 important risk
  • 03:58factor is due to inequality's an patient
  • 04:02population that are underserved and
  • 04:05they have difficulties in reaching
  • 04:07and being reached by the best care,
  • 04:11other risk factors,
  • 04:12smoking alpha toxin and and an other as well.
  • 04:17And this is important to understand that
  • 04:20the combination of risk factor increases.
  • 04:23And actually the risk.
  • 04:24So in every patient that we see,
  • 04:26we need to look for all of them.
  • 04:33This risk factor are distributed
  • 04:37unequally in the world wide.
  • 04:41For example, aflatoxin is more frequent
  • 04:43as it goes in in the African continent,
  • 04:46but if we go to the US, All told,
  • 04:49this publication shows Nash is a main factor.
  • 04:52It is actually we have all the
  • 04:54respect or combining here because
  • 04:56we have Nash with alcohol,
  • 04:58we have appetite is C.
  • 05:00And so on. And in fact,
  • 05:02if we look at the distribution of
  • 05:06the incidents of ATC in the US.
  • 05:09We see that is actually particularly
  • 05:13hygge about 8. Per 100,000 in the.
  • 05:19Massachusetts, Connecticut and New York.
  • 05:22So if we look back more.
  • 05:26In depth into it,
  • 05:27we see that in the US the liver
  • 05:30cancer incidence has increased almost
  • 05:32three times in the last 30 years,
  • 05:35and the mortality is increased
  • 05:37almost two times as shown.
  • 05:39Also in this graph on the right,
  • 05:41if we look at the numbers and
  • 05:44compare the number with two big.
  • 05:47GI killers in their adjustive system,
  • 05:50like bankers and call,
  • 05:52and we see that in Connecticut
  • 05:55we have a record of 480 cases per
  • 05:58year and this is a combination
  • 06:00between HCC an intra Patrick.
  • 06:05Cinema also the interparticle
  • 06:07answer carcinoma is really minority,
  • 06:09so we have 480 new cases and $320
  • 06:13unfortunately and this is a figure
  • 06:16which is similar to another big
  • 06:18killer like the pancreatic cancer.
  • 06:21730 and 520. So what?
  • 06:27How does the molecular
  • 06:29pathogenesis of apples for casino?
  • 06:31We have said it.
  • 06:35Most of the patients have cirrhosis
  • 06:38and in fact the main theory is
  • 06:41that in the cirrhotic nodule
  • 06:43there are Even so happens that
  • 06:45brings to Korando casino man.
  • 06:48I'm in one of these is the.
  • 06:52Alter the.
  • 06:55TRT promoter that basically.
  • 07:01Blocks the ability of the liver
  • 07:04cell under information to undergo
  • 07:06senescence and an among them.
  • 07:09There are other possible.
  • 07:12But the genetic event like P53,
  • 07:15which is basically associated with aflatoxin,
  • 07:17better cotton imitation,
  • 07:18and so on and so forth.
  • 07:21But this is a scenario that
  • 07:22is not very well understood.
  • 07:25All we can say for now is as
  • 07:27there are two different classes,
  • 07:30one name proliferation,
  • 07:31the other non proliferation that are
  • 07:33different in terms of their prognosis
  • 07:35and in terms of their ability to
  • 07:38respond eventually to immunotherapy.
  • 07:42So I put the cell carcinoma is
  • 07:45a very peculiar cancer because
  • 07:47he has a 2 dual personality.
  • 07:50It's a cancer in a failing
  • 07:52vital organ and it can be seen
  • 07:55from a biological perspective.
  • 07:57There are inflammation induced phenomenon,
  • 07:59oncogenic viruses,
  • 08:00literally natural general mutational
  • 08:02landscape and this brings to a complex
  • 08:05tumor fenotype with the witches aggressive.
  • 08:07It is a terror generals with
  • 08:10a high recurrence rate.
  • 08:12When is Sonic Liquor point of view?
  • 08:15We have any plastic disease
  • 08:17and the liver disease,
  • 08:18and so the street.
  • 08:19The treatment strategy has to
  • 08:21be tailored according both to
  • 08:23the tumor stage and the function
  • 08:26of stage liver disease,
  • 08:27and this creates some of the peculiar
  • 08:30things in that management of this disease.
  • 08:33So we don't have one single way to
  • 08:35manage it that you have resection
  • 08:37ablation came embolization value
  • 08:39or addition therapy.
  • 08:41Systemic therapy still has a.
  • 08:43At growing Bastille small role,
  • 08:45we have the possibility to
  • 08:47transport the patient.
  • 08:48The only solid organ that can be
  • 08:51transplanted and most of these
  • 08:53patients actually die because
  • 08:54of liver failure and in fact one
  • 08:58professional figure that is involved in this.
  • 09:00It is the hepatologist.
  • 09:04What, because of all this,
  • 09:07different professionals involved
  • 09:09in in this in the treatment,
  • 09:12the entry points usually are multiple
  • 09:15Ann and this multiple entry points
  • 09:18in the system creates different
  • 09:21trajectory for the patient with way.
  • 09:25Dispassion of resource is an an can
  • 09:27impact on the outcome because there is a
  • 09:30confusion and you don't really know what
  • 09:33the part where the patient should follow.
  • 09:35And this is one of the reason why it
  • 09:38is important to have a team work.
  • 09:41So to give an example,
  • 09:43probably will take the whole day to this
  • 09:46guy to figure out how to change the tires,
  • 09:49whereas the Formula One team can
  • 09:51do it exactly in 2.5 seconds.
  • 09:54Which is amazing and is this love?
  • 09:57Is this out of their coordination of care?
  • 09:59So treatment of Apple Circus nominees,
  • 10:01coordination of care,
  • 10:02and this is the trajectory that the
  • 10:05program has followed through the year.
  • 10:07So we started as a conference and I
  • 10:10remember this few people with me wrong.
  • 10:12Salom Jeff Pollack.
  • 10:14Jeff Wayne Rubber Dam part starting
  • 10:16this little room and then he
  • 10:18grew to a tumor board.
  • 10:19Thanks to Tamar Daddy and then
  • 10:21now it's becoming a program.
  • 10:23And maybe it's really it's
  • 10:25it's ready for the next step.
  • 10:28So when it became a program
  • 10:30we designed in IDL structure,
  • 10:33which is the patient can come into
  • 10:35the system through a single point.
  • 10:38Still working on that aspect,
  • 10:40and then it's actually discussing the
  • 10:43tumor board where they treat him,
  • 10:45allocation happens and is allocated
  • 10:48to the different specialty according
  • 10:50to the best treatment are an.
  • 10:52After that it gets follow-up be 'cause
  • 10:55we need to treat the risk factor.
  • 10:58We need to mind the liver.
  • 11:01Help us some chemo prevention protocols
  • 11:04and mirroring this clinical operation.
  • 11:06There is also research component
  • 11:09which is again a team effort.
  • 11:13So where are we? So we begin with the.
  • 11:16This is a map of the Smiler Care center
  • 11:20OK and this is the two main site for
  • 11:23liver care here at again you have in
  • 11:26hospital and the VA off without but
  • 11:29through the recent year there was
  • 11:31open a site in in Bridgeville with
  • 11:34magnetic so insight in the ambari
  • 11:37came to stand for my shift key.
  • 11:39James Mattis T is,
  • 11:41you know,
  • 11:42the westerly side and soon Alan
  • 11:44Jaffe will go to West for now.
  • 11:47This is in combination with with
  • 11:49the with the transplant team
  • 11:51with which we have a very good
  • 11:53long standing collaboration.
  • 11:55Now it really takes a village to treat
  • 11:58this cancer and here you can see.
  • 12:01Not all of their colleagues that
  • 12:04participates and I have to say it's
  • 12:06it's a real privilege to be able
  • 12:08to work with these individuals,
  • 12:11and they are extremely skilled.
  • 12:13All of them are leaders in their
  • 12:15own right are in their own field,
  • 12:18and so the discussion that we have
  • 12:20are so enlightening and we follow a
  • 12:23like a structure of discussion going
  • 12:25through and analyze the reception,
  • 12:27the transplant candidacy,
  • 12:28the OR whether we need to use local
  • 12:31regional treatment like ablation,
  • 12:33criminalization, radiation.
  • 12:34It's I don't have the time to go into this,
  • 12:38but it's it's every single all of this
  • 12:41possible treatment is very complex
  • 12:43and the decision making is a is
  • 12:45even more complex because it depends
  • 12:48from systemic and local factors,
  • 12:50and in fact we really an.
  • 12:52We basically follow the Barcelona
  • 12:54Liver cancer treatment, which is a.
  • 12:58Used by master Lever Societies an
  • 13:01but it really has a lot of troubles.
  • 13:04OK, there are changes.
  • 13:06This is the latest version and
  • 13:08takes into account liver function,
  • 13:11performance status and and then
  • 13:13atomic location of the cancer.
  • 13:15But really there are lot of
  • 13:17troubles and we cannot be so
  • 13:20strict with the categories and for
  • 13:22example this was written in 2019.
  • 13:25Now the first line treatment
  • 13:27is that is above but.
  • 13:29Cannot be only confined to
  • 13:31patient at about to die,
  • 13:33as in this staging system,
  • 13:34so a lot of things have changed
  • 13:36and that made difficult by the
  • 13:38fact that we have multiple theology
  • 13:41at the underlying liver disease.
  • 13:43The frequent comma abilities in fact,
  • 13:45this is a cancer.
  • 13:47That picture above 65 years of age.
  • 13:50Multiple treatment option and
  • 13:5170% of them have a recurrence of
  • 13:54the cancer in the next 20 months.
  • 13:57We have liver transplantation
  • 13:59and other actors,
  • 14:00so the only way to maintain a.
  • 14:04Structure approach this is to is
  • 14:07to that room and board with four
  • 14:09hours is not a way where we present
  • 14:12strange cases is really the machine
  • 14:14Ann and the credit for this goes to
  • 14:17my colleague and friend to Mark Addy,
  • 14:20who set it up and now we we
  • 14:22discussed 13 cases each week.
  • 14:25Last year we even with the kovit
  • 14:27we discuss 520 cases and one of the
  • 14:30busiest actually tumor Board 2 of
  • 14:33200 of them with new cases we have.
  • 14:35300 patient and follow up.
  • 14:37150 new cases and these actually
  • 14:40treated in several different ways,
  • 14:42but this is not the venue to to go
  • 14:46through the volumes or to their substantial.
  • 14:50The tumor board is also where we
  • 14:52got ideas for research and ideas
  • 14:55for for improvement and innovation.
  • 14:57This is that list of items that we
  • 15:00discussed at the last steering committee.
  • 15:03For example,
  • 15:04several of this question that I'm
  • 15:06not going to read all of them, but.
  • 15:11Generate. Recent opportunities.
  • 15:13Anne Anne, Anne,
  • 15:16Anne and also great care I I wanna
  • 15:18go briefly through this case.
  • 15:20This was a patient. Refer to doctor.
  • 15:23She's key for transfer evaluation
  • 15:25Mike so the patient realized that
  • 15:27he had actually liver cancer.
  • 15:29And Moran had infiltrative
  • 15:31hepatocellular carcinoma with with
  • 15:33the tumour portal vein thrombosis.
  • 15:35So we discussed the case at the
  • 15:38tumor board and it was decided that
  • 15:41there was no other option rather than
  • 15:45medical treatment or offering a trial.
  • 15:48Stacy did try to give him
  • 15:50softening by the beginning I,
  • 15:52but this was denied by the insurance
  • 15:55and so it happened at Stacy
  • 15:57adjust open atrial at the initial
  • 16:00trial with a diesel Bev,
  • 16:01which is now you know,
  • 16:03the first line treatment for back
  • 16:06in that time was actually we were
  • 16:09very lucky that we could offer
  • 16:12him and as you see here.
  • 16:14In the graph of plotting
  • 16:16the alpha fetoprotein,
  • 16:18he had a complete response.
  • 16:22But in the next two years,
  • 16:24this patient was completely and the
  • 16:26quality of life of this patient,
  • 16:28which was completely altered
  • 16:30by recurrent severe episodes of
  • 16:32portosystemic several opathy.
  • 16:33As you can see here from the ammonia
  • 16:35and actually in during one of
  • 16:38these emission it also discussion
  • 16:39about goals of care was initiated,
  • 16:42so we had a patient who was treated by
  • 16:45with you from this malignant tumor.
  • 16:47But he was dying because I believe
  • 16:50this is an act.
  • 16:51.2 very bright hepatologist wanagas
  • 16:54intervals with system are in,
  • 16:57another is stalled.
  • 16:58Slacker, which is an interventional
  • 17:01hepatology calling,
  • 17:02decided to embolize his plane arena.
  • 17:05Shanta and now the patient is
  • 17:08functional cancer free, happy.
  • 17:10And when he refers to what
  • 17:13happened with the insurance,
  • 17:15he quotes wisdom churches saying pessimist
  • 17:17sees difficulty in every opportunity,
  • 17:19an optimist sees opportunity
  • 17:21in every difficulty.
  • 17:22So this is a case which we learn
  • 17:25a lot about it an an in fact.
  • 17:28Now particularly,
  • 17:29you know,
  • 17:30one of the things that was interesting
  • 17:33in the Gary case was that he
  • 17:35never had a recurrence an will.
  • 17:37I said occurrences,
  • 17:39something that playing sour
  • 17:40patient 6070% of them in there.
  • 17:43In their first two years,
  • 17:45so that prompted the opening of a
  • 17:48try again by Stacy and D'istria
  • 17:51will actually try to address
  • 17:53the role of adjuvant treatment
  • 17:56after surgery or ablation.
  • 17:59Another tria is being brought
  • 18:01here by David Madore.
  • 18:03Fu actually addresses and
  • 18:04other nuances of this,
  • 18:06so he his aim is to understand
  • 18:09whether there is a benefit in what
  • 18:12we call combination treatment.
  • 18:14So the idea to combine came
  • 18:16embolization with the.
  • 18:20Even on Koleji, in combination with a PKI.
  • 18:23And another important aspect of the
  • 18:26program is the fact that we really tried
  • 18:29to record and measure the outcomes.
  • 18:32Ariel's affair with John awfully.
  • 18:38My tarantula Shapiro at there are curating
  • 18:41a database of 1000 patients in India
  • 18:44and the survival code divided by BCSC
  • 18:47states that you see, here are our own.
  • 18:51Outcomes so we can really.
  • 18:55Make the termination letter based on.
  • 18:57Now our environment in expertise
  • 18:59and is simple example that the
  • 19:01outcome is outstanding up to more
  • 19:03than three years for this campaign
  • 19:06patient with initial cancer,
  • 19:07things are changing after this an and
  • 19:10there's a lot to be discussed in among
  • 19:13these patients and I I don't have it here,
  • 19:16but if anybody has a doubt
  • 19:18about transplantation,
  • 19:19I can tell you that the code was transfer
  • 19:22stations like this so outstanding long term.
  • 19:25Result for the few patient again get it,
  • 19:29but this is a very,
  • 19:30very important aspect of what we do
  • 19:33an an it's going to be so complex
  • 19:36that in fact Julius with Jim Duncan
  • 19:38Manderly and John actually very much
  • 19:41involved in trying to understand
  • 19:43the use that we can have artificial
  • 19:46intelligence in the diagonal.
  • 19:47This characterization treatment of this
  • 19:50Council and we expect that this would
  • 19:53be a great aid to our decision making
  • 19:56and also discovery of new approaches.
  • 19:59So what the liver cancer program
  • 20:03doesn't have a formalized?
  • 20:08Visas program but is actually
  • 20:10the assembly of of several
  • 20:13different interrested people.
  • 20:15What have we done to.
  • 20:19Put together these people so the
  • 20:21first thing that we have been doing
  • 20:24with Julius De Mar is is these liver
  • 20:27cancer talks their monthly in the
  • 20:30late late afternoon on Thursday.
  • 20:32Each of them with two or three percent
  • 20:35Asia and this has to be ongoing.
  • 20:38Research are now published work.
  • 20:40It covers all the aspects, clinical,
  • 20:42translation and healthcare and and this
  • 20:44actually this approach Spark collaboration.
  • 20:46There were paper grant application
  • 20:48and also a big step.
  • 20:50Forward was at last October when again
  • 20:53with the help of the Miami Justice Ann,
  • 20:57and thanks to the help of Gary Honeycutt's
  • 21:00and his team in the Cancer Center,
  • 21:03we put forward the first liver cancer
  • 21:06Super Summit which is called pre
  • 21:09Lude because he was not in person.
  • 21:11Where was Virtu are,
  • 21:13but the mission was to address the
  • 21:16Uncle logic challenges or liver cancer
  • 21:19to the collaboration amount of abide.
  • 21:22Spectrum will be a faculty.
  • 21:24And I'm I'm gonna really run through
  • 21:27some of this visa suspect and what
  • 21:30in what I call the Commonwealth to
  • 21:33liver cancer is at yeah OK because
  • 21:36it's not again formalized structure,
  • 21:38but is the gathering of of interested
  • 21:41people coming from the medical school,
  • 21:43the School of Public Health?
  • 21:45the VA system involving departments
  • 21:47like surgery, internal medicine,
  • 21:49the Cancer Center, the year,
  • 21:51liver cancer,
  • 21:52the Department of Pathology and
  • 21:54so on and so forth.
  • 21:56But all these people actually.
  • 21:58In a 2019-2020 publish it 72 papers,
  • 22:02an 38 of them original article 7R
  • 22:05position paper 14 reviews and 14 of them
  • 22:09are actually publishing in journals
  • 22:12with an impact factor around or above 20,
  • 22:16which I think is pretty remarkable.
  • 22:19So just a very quickly glancing through it.
  • 22:23The number of our faculties
  • 22:26are actually involved.
  • 22:28In studying the different risk
  • 22:31factors that I mentioned before,
  • 22:33so we have outstanding work
  • 22:35performing virally theology,
  • 22:37interaction with aging,
  • 22:38the HIV.
  • 22:39We have food program that addresses
  • 22:42the obesity,
  • 22:43diabetes and affolder alcoholic liver
  • 22:46diseases in other regions branch
  • 22:49which is which is growing an Ann
  • 22:51and also health care disparities.
  • 22:54An for example.
  • 22:57Razor,
  • 22:57osean and other faculties are addressing.
  • 23:03Some of the. Differences that
  • 23:05we see even in connecticu.
  • 23:07So for example, as you can see here.
  • 23:11The incidence of HCC is clearly
  • 23:13higher in this panic and black
  • 23:16population and hopefully will will
  • 23:18try to nail down what the causes are.
  • 23:21So outstanding results in outcome research,
  • 23:26mostly addressing the role of
  • 23:30surveillance and and all of.
  • 23:37Antiviral treatment and the
  • 23:38growing group of faculties are
  • 23:40also interested in concert cost,
  • 23:42effectiveness and care delivery.
  • 23:44We do a lot of things,
  • 23:46but we don't really know their value
  • 23:49in terms of cost effectiveness,
  • 23:51so this is another growing area.
  • 23:54Translation studies that also growing and
  • 23:57just to mention several faculties in Basic,
  • 24:01more basic studies are interested
  • 24:03in the transition between Nashville,
  • 24:06roses and and cancer and in human
  • 24:10Hansa ran and a lot of people
  • 24:14is actually interesting in the.
  • 24:18Role of the tumor micro environment.
  • 24:22Which this is, I think,
  • 24:24is very interesting.
  • 24:25This is staining for Alpha,
  • 24:27SMA, identifying fiber,
  • 24:28ask cancer,
  • 24:29associated fibroblasts in
  • 24:31cholangiocarcinoma and in hepatoma
  • 24:32you see two very different.
  • 24:38Pathology Ann and these are correlated
  • 24:40to two very different aggressiveness.
  • 24:43Also the tumor let me very briefly
  • 24:45mention some of our work in the macro
  • 24:48environment or the calendar carcinoma
  • 24:51showing the central role of calf or
  • 24:53the Cancer Society fiberglassed in
  • 24:55determining several of the aspects
  • 24:58of the two Moran now our Co other
  • 25:01colleagues are addressing this
  • 25:03using single cell transcriptomics.
  • 25:05This is also an interest of
  • 25:07our colleagues in radiology.
  • 25:09They're trying to use.
  • 25:12The tools of radiology to generate reliable
  • 25:15imaging biomarkers for immunotherapy.
  • 25:17This is I, I think,
  • 25:20it's granted or or or proposed for
  • 25:23the NIH by David matter of MGM Duncan
  • 25:28interest on the metabolic aspect is also.
  • 25:32Followed by by Michael Nathanson,
  • 25:34lab, and here is work from Emma
  • 25:37tells where I'm like nothing.
  • 25:39So I'm looking at the IP3 receptor and
  • 25:43mitochondrial functionality in 80C and CCA,
  • 25:46and they're all in in the in chronic
  • 25:49affect like like existence of up doses
  • 25:52or generating up talking factor of
  • 25:55this was published very well last
  • 25:58year and and finally mentioning.
  • 26:01Tell you who,
  • 26:03just join and the chair of pathology is,
  • 26:06you know, a very well renowned liver cancer
  • 26:10researcher and is doing several things.
  • 26:13Among this he explaining to
  • 26:15detect circulating metallated
  • 26:16DNA as an early diagnosis.
  • 26:19Wait, you see,
  • 26:20and we're really looking forward very
  • 26:23much to this study is an an also.
  • 26:26He is trying to is using
  • 26:29Kartiana Glypican 3 as a target.
  • 26:32Hopefully not that big of a TC
  • 26:34and and I'm I'm gonna finish
  • 26:37now because the time is over.
  • 26:39But you know this is just an example of the
  • 26:43richness of the research that that we have.
  • 26:46And really this is and I have to
  • 26:49thank all the department that are
  • 26:52involved in this enterprise and.
  • 26:55You know each of these department.
  • 26:58There are some hepatologist hiding
  • 27:00there and and this is what what
  • 27:03will I call your liver,
  • 27:05which is a very old tradition.
  • 27:08Here is going to celebrate
  • 27:11the Diamond Jubilee.
  • 27:12Next year and I thank you for your attention.
  • 27:17Thank you very much, Mario.
  • 27:19Very interesting talk. Are there
  • 27:20any questions from the audience?
  • 27:29I can start with one.
  • 27:30So recently drugs have been developed
  • 27:33that will cure hepatitis C virus.
  • 27:36What fraction of people in
  • 27:38this country are affected?
  • 27:39People are being treated by these drugs.
  • 27:41And what's the effect on liver cancer?
  • 27:44Tell the the the strategy would be
  • 27:47worldwide application of of HPV and
  • 27:50therefore I would say that a growing
  • 27:52amount of patients she is being
  • 27:55treated should be treated that has had
  • 27:58like a slowing down during the COVID
  • 28:01crisis but should resume full time.
  • 28:04The question of the effect on liver
  • 28:06cancer is a very good question
  • 28:09because there has been a great
  • 28:12controversy becauses a lot of patient.
  • 28:14After eradication of the virus,
  • 28:16have the path surprised that
  • 28:18delivered Carson happens.
  • 28:19Anyway, this is happening in patients
  • 28:21that were treated already with
  • 28:24significant fibers in their liver.
  • 28:26And it was initially proposed
  • 28:27that actually the allocation of
  • 28:29the virus would get rid of some
  • 28:31kind of beneficial information,
  • 28:33but further studies have shown that
  • 28:35actually the the risk is decreased,
  • 28:37but it's not zero.
  • 28:39So why is not zero is something
  • 28:41that we need to understand.
  • 28:43My personal opinion is that we are simply
  • 28:46eliminating one of the many risk factors.
  • 28:48You know the the regular guy is
  • 28:51a guy that didn't know to have
  • 28:53actitis is a little overweight,
  • 28:55has smoked.
  • 28:56Is drinking, you know,
  • 28:58not drunk but enjoying the wine Ann.
  • 29:03It just doesn't know it an an therefore yeah,
  • 29:06will you ever you have four risk
  • 29:08factor of which you eliminate one?
  • 29:10This is why this is a internal medicine.
  • 29:13This is right because you really
  • 29:15have to address all the risk
  • 29:17factor in every single patient.
  • 29:19Otherwise,
  • 29:19you may fail like like the
  • 29:22eradication of appetite is C shows
  • 29:24in certain patients and so the
  • 29:26basic clinical recommendation is
  • 29:27that the patient that you were ever
  • 29:30advocated while he was erotica still
  • 29:33needs to undergo the six months.
  • 29:36Screening and surveillance for ACC.
  • 29:41Are there other other questions?
  • 29:49OK, with that I I do see the vineyard
  • 29:52behind your folder there in moderation.
  • 29:56Yeah moderation, OK thank you.
  • 29:57Thank you very much.
  • 29:59Mario, thank you, thank you.
  • 30:01So our next speaker today
  • 30:04is is Jonathan Levinthal.
  • 30:06Who is, I'm sorry, just lossed.
  • 30:10My CHEAT SHEET here.
  • 30:13So Jonathan is assistant professor
  • 30:15of Dermatology and the director of
  • 30:17the Yale Uncle Dermatology Clinic.
  • 30:19He received his MD degree from New York
  • 30:22University and is residency here at Yale.
  • 30:25He specializes in caring for
  • 30:27patients with skin cancer,
  • 30:28beginning with skin screening programs
  • 30:30to detect cancers and sun damage and
  • 30:33optimize prevention and therapy.
  • 30:35The clinic serves a dermatologic
  • 30:37needs of cancer patients dealing
  • 30:39with a variety of skin issues,
  • 30:41including skin changes due to
  • 30:43chemo therapies, can infections.
  • 30:44Cancer involvement in the scan,
  • 30:46radiation, dermatitis,
  • 30:47and other changes due to radiation,
  • 30:49so we'll hear that today.
  • 30:50So Jonathan I'm looking forward
  • 30:52hearing you talk. Thank you.
  • 30:54Thank you so much and it's a
  • 30:56real pleasure to be here today.
  • 30:58So today I'm going to talk about
  • 30:59dermatologic conditions in cancer patients,
  • 31:01and I'm going to provide updates
  • 31:02from the ankle dermatology program.
  • 31:05So here is a list of my disclosures,
  • 31:08mostly from serving on advisory
  • 31:10councils with fellow Aqua dermatologist
  • 31:12throughout the country looking at
  • 31:14skin toxicities as well as some
  • 31:16clinical trial research funding.
  • 31:17So the objectives of the talks I
  • 31:19wanted to start by introducing you
  • 31:21to the Aqua dermatology program.
  • 31:22Then I wanted to discuss the importance
  • 31:24of cutaneous toxicities and how they
  • 31:26can impact patients quality of life
  • 31:27as well as their cancer therapies.
  • 31:29When severe, I wanted to highlight
  • 31:30some of the most common toxicities
  • 31:32that I see from select targeted
  • 31:33and immune checkpoint inhibitors
  • 31:34and also traditional chemotherapy
  • 31:36as well and discuss the role that
  • 31:38aren't with their mythology.
  • 31:39Plays at a Cancer Center.
  • 31:41So for some background,
  • 31:43the Uncle Dermatology program was
  • 31:44established by my great mentor and friend,
  • 31:46Jennifer Choi.
  • 31:47Shortly after she graduated residency
  • 31:49and then I had a great opportunity
  • 31:51when she got recruited to Northwestern
  • 31:53as a chief resident to start seeing
  • 31:55patients in the clinic for which
  • 31:57I've led the clinic ever since.
  • 31:59And we've really seen a tremendous
  • 32:00outgrow of support from so many
  • 32:02colleagues in Metanx terjung Radon,
  • 32:04an anthology,
  • 32:05and the clinic has really grown
  • 32:06dramatically over the years.
  • 32:08It's a very robust, busy clinic.
  • 32:10Some days we see up to 50 patients.
  • 32:12And I just have a great team of
  • 32:15nurses residents as well as research
  • 32:17fellows and and support from the Yale
  • 32:19Center for Clinical Investigation.
  • 32:21So the field of supportive Uncle
  • 32:23Dermatology really blossomed in
  • 32:24the 1990s with the advent of many
  • 32:26different targeted kinase inhibitors,
  • 32:28which skin toxicities were so common
  • 32:30in almost the majority of patients
  • 32:32and it really encompasses many
  • 32:33different things that we service,
  • 32:35so there's definitely all the toxicities
  • 32:37that we see from the systemic therapies,
  • 32:39radiation therapies,
  • 32:40graft versus host disease as well
  • 32:42as complications from cancer.
  • 32:43Going to the skin with metastases,
  • 32:45but there's really a lot of other
  • 32:48indirect complications that we treat
  • 32:49in clinic and that includes paranoia.
  • 32:51Plastic disease, infectious complications,
  • 32:53especially in patients who are
  • 32:55immuno suppressed as well as being
  • 32:56part of the survivorship program.
  • 32:58For many patients who have
  • 32:59survived cancer now,
  • 33:00an increased risk for developing
  • 33:02cutaneous carcinogenesis and then
  • 33:04also part of the umbrella is that
  • 33:06the Melanoma program I'm part of.
  • 33:07It falls under the umbrella of
  • 33:09Uncle Dermatology and so a lot of
  • 33:11what I do is also high risk in
  • 33:13cancer screening to diagnose and
  • 33:15treat many different types of skin
  • 33:18cancers and also collaborate with
  • 33:20the cancer genetics program to
  • 33:22obtain tissue for genetics.
  • 33:23So wanted to start by discussing the
  • 33:26cutaneous toxicities are not just cosmetic.
  • 33:28These are really important issues
  • 33:29that impact patients quality
  • 33:31of life and there's been many
  • 33:32studies over the years looking at
  • 33:34validated quality of life surveys.
  • 33:36Anan.
  • 33:36It's just so so common for these
  • 33:39toxicities to to impact in both
  • 33:41physical as well as emotional domains
  • 33:43and so one interesting concept is that
  • 33:45women seem to be affected greater
  • 33:47than men in terms of their quality
  • 33:49of life and it's probably because
  • 33:51of the types of regiments they
  • 33:53did receive for breast and.
  • 33:55Other gynecological cancers which
  • 33:56frequently impact the here in the nails,
  • 33:58and so this can affect women's self image,
  • 34:01cultural identity,
  • 34:02sexuality as well as mental health.
  • 34:04Feelings of depression, anxiety,
  • 34:06and a loss of control over their body.
  • 34:09The hallmark examples
  • 34:10chemotherapy induced alopecia,
  • 34:11which we see from the cytotoxic agents,
  • 34:13in particular an one homework study,
  • 34:15showed that almost 60% of women with
  • 34:17breast cancer preparing for chemo
  • 34:18considered this to be the worst
  • 34:20possible associated side effect
  • 34:21and almost 10% even considered
  • 34:23declining treatment in fear of it.
  • 34:25So these are real,
  • 34:26very real and important issues,
  • 34:27and there's been so many other studies
  • 34:29looking at the acne acne reform,
  • 34:31ranch hand, foot rashes,
  • 34:32nail changes in mucus, itis,
  • 34:34all of which I'm going to discuss
  • 34:36in which can impact quality of life.
  • 34:39So the study on the left kind of
  • 34:41highlights an important concept that
  • 34:43it's not just those main toxicities that
  • 34:46can impact patients quality of life.
  • 34:48In this study of targeted agents
  • 34:50in breast and colorectal cancers,
  • 34:52you'll see that things like itching,
  • 34:54dryness of the skin, easy bruise ability,
  • 34:56pigmentary changes,
  • 34:57they can all be associated with
  • 34:59with poor quality of life and the
  • 35:02study on the right looked at the
  • 35:04different types of chemotherapy and
  • 35:06how they impact quality of life.
  • 35:08And not surprisingly.
  • 35:09A lot of the more novel,
  • 35:11targeted therapies,
  • 35:12especially the EGFR inhibitors,
  • 35:13were associated with an increased
  • 35:15number of skin toxicities,
  • 35:16but also those which impact quality
  • 35:19of life greater than some of the
  • 35:22traditional chemotherapeutic agents.
  • 35:23Unfortunately,
  • 35:24there's mounting data showing that
  • 35:26early dermatologic intervention
  • 35:27can really make a difference,
  • 35:29and so Uncle dermatology programs
  • 35:31have been showing up at most of
  • 35:34the premier cancer centers in
  • 35:36the States and abroad,
  • 35:37and one study from MSK show that with
  • 35:40outpatient Uncle dermatologic involvement,
  • 35:42patients on immunotherapy were less
  • 35:44likely to have interrupted treatment
  • 35:465% versus 30% to those managed
  • 35:48without dermatologic intervention.
  • 35:50In a recent study by the
  • 35:52Harvard Group similarly showed.
  • 35:54The inpatient konsult can also
  • 35:55decrease the chance of patients
  • 35:56receiving systemic immune suppression
  • 35:58and immune therapy discontinuation.
  • 36:00Now,
  • 36:00we haven't performed a comparative study.
  • 36:02We did perform a very large
  • 36:04study recently that was published
  • 36:06of over 100 immunotherapy.
  • 36:07Rash is 1/4 of which presented to my clinic,
  • 36:11often with disruption of immunotherapy.
  • 36:12But with early dermatologic intervention,
  • 36:14over 90% of these patients were
  • 36:16able to remain on their treatment,
  • 36:18so I think these numbers are compelling.
  • 36:21So wanted to start by focusing
  • 36:23on some of the toxicities that
  • 36:25I see from targeted therapy.
  • 36:27I mean there's so many different
  • 36:28types of agents to discuss,
  • 36:30I think I'm just going to
  • 36:32review some of the main ones.
  • 36:34In the interest of time so the EGFR
  • 36:36inhibitors are a class that are commonly
  • 36:38associated with cutaneous toxicities.
  • 36:39Not surprisingly,
  • 36:40as the epidermal growth factor
  • 36:42receptor is expressed in the skin,
  • 36:43hair and nails, and really important
  • 36:45for homeostasis and some of the
  • 36:47monoclonal antibodies likes to talk
  • 36:49some mad panitumumab as well as
  • 36:51the 1st and 2nd generation drugs.
  • 36:53Presents with cutaneous toxicities
  • 36:54in the majority of cases.
  • 36:55Fortunately, the third generation
  • 36:57drugs like OC murdered him
  • 36:58for a lung cancer patients.
  • 37:00They don't seem to get the rest,
  • 37:02the rest nearly as often,
  • 37:03probably less than 30%,
  • 37:04and so the most common toxicity
  • 37:06that we see is the papulopustular
  • 37:08for the acne or form rash,
  • 37:10and this usually manifests on patients face,
  • 37:12scalp, chest and back.
  • 37:13Although it could be widespread
  • 37:14and one common misconception is
  • 37:16that it's just a sterile technique.
  • 37:18Reform drug eruption, which is true.
  • 37:19However,
  • 37:20I find a large percentage of these patients.
  • 37:22Especially when they get to higher grades
  • 37:24often have coinfection with staff.
  • 37:26Both M RSA an MSA,
  • 37:28so that's a good therapeutic Pearl
  • 37:30to obtain wound cultures and hear
  • 37:32examples of the Packers and pustules.
  • 37:34Note all this year is crusting.
  • 37:36It was all in petition eyes with staff.
  • 37:38Oreius is a more typical scenario
  • 37:40in one of the more robust severe
  • 37:42toxicities that might require
  • 37:44more aggressive treatment,
  • 37:45which I'll discuss.
  • 37:46We see lots of nail infections
  • 37:48paronychium and because of the
  • 37:49piercing of the nail plate into
  • 37:51the hyponychium patients can get
  • 37:53this friable granulation tissue
  • 37:54known as pyogenic granulomas.
  • 37:56These can be exquisitely tender
  • 37:57and painful and definitely impacts
  • 37:59patients quality of lights.
  • 38:00It's not uncommon to see her
  • 38:02growth abnormalities,
  • 38:03including elongated eyelashes.
  • 38:04Some patients have a hard time
  • 38:06trimming their eyelashes,
  • 38:07which are curving inward
  • 38:08and irritating their eyes,
  • 38:10so they'll just see me analysis
  • 38:12them with with cutting their
  • 38:13eyelashes we see lots of dryness and
  • 38:16painful cracks and fissures too.
  • 38:18There is an example of,
  • 38:19you know a patient who presented
  • 38:21with a neck near former option which
  • 38:23was in petition eyes with staff.
  • 38:25She responded quite well to Doxie,
  • 38:27cyclin topical steroid ointments,
  • 38:28antibiotic ointments.
  • 38:29And I'm a big fan of antiseptic
  • 38:31soaks like aluminum acetate removed
  • 38:33a serious crusting.
  • 38:34Here's another example of a patient.
  • 38:36Also recently from the Lung Cancer
  • 38:37Group who also had quite a severe
  • 38:39acne deformed mesh occasionally in
  • 38:41very severe circumstances there can
  • 38:43actually be associated alopecia as well.
  • 38:45She responded very well to
  • 38:47dermatologic intervention.
  • 38:47I wanted to highlight that.
  • 38:49While the acne reformers typically
  • 38:50presents during the first few
  • 38:52weeks on the head, chest and back,
  • 38:54we have seen uncommon presentations as well,
  • 38:56which are described in the literature
  • 38:58and those are prepared drug eruptions
  • 39:00which likely fall into the category
  • 39:01of the late acne reform toxicity.
  • 39:03In these cases usually present
  • 39:05many months into treatment,
  • 39:06and they often present on the
  • 39:07lower extremities in the buttocks,
  • 39:09and as you can see with these
  • 39:11perperek looking lesions,
  • 39:12and they're also frequently Co
  • 39:14infected with staff on Moon culture.
  • 39:17Here's an example of a patient with
  • 39:19head and neck cancer who responded
  • 39:21to dermatologic intervention.
  • 39:23And here's an example of a patient
  • 39:25who has pretty
  • 39:25typical pyogenic granuloma with Paronychium,
  • 39:28who responded to the topical
  • 39:30beta blocker timolol gel.
  • 39:31Many of these cases are non responsive
  • 39:33to conservative approaches and sometimes
  • 39:35procedural intervention may be required,
  • 39:37like using silver nitrate to court arise
  • 39:40these granulomas or even nail avulsion
  • 39:43for the really recalcitrant cases will do.
  • 39:46So there's many hot topics around EGFR
  • 39:48inhibitors one over the years has been
  • 39:50looking at pre emptive versus reactive
  • 39:51therapy and there's various phase two
  • 39:53trials which have shown that doc see
  • 39:55cycling Minocycline with with topical
  • 39:57steroids and moisturizers can actually
  • 39:58reduce the severity of the rash.
  • 40:00The overall incidence is probably not
  • 40:02affected and I think the approach towards
  • 40:04the rest differs depending on the program.
  • 40:06Here they've been looking at lots of new
  • 40:08novel approaches for treating the rash,
  • 40:10none of which are really
  • 40:11gained widespread use.
  • 40:12Some of the data is very mixed with
  • 40:15these drugs and so we definitely need.
  • 40:17New approaches and then I just wanted
  • 40:19to briefly mention that there's a few
  • 40:21clinical trials which we're doing here.
  • 40:23Studying the rash one is currently
  • 40:24recruiting and I really appreciate
  • 40:25my awesome collaborators in the head
  • 40:27and neck and thoracic group which
  • 40:29are helping to recruit patients.
  • 40:30And that's to better understand the
  • 40:32microbiome of the populations or option
  • 40:34and see how changes in the microflora
  • 40:36can be associated with the severity of
  • 40:38the rash and response to rash treatment.
  • 40:40And then there's a company that we're
  • 40:42working with that's developing a
  • 40:44novel probiotic with staff epidermal
  • 40:46disappointment to look to see if
  • 40:48this is going to reduce secondary
  • 40:50infections with staff wareus,
  • 40:51which are commonly associated
  • 40:52with severe rashes.
  • 40:53And so this is in development
  • 40:56hoping to do this trial next year.
  • 40:59So shifting gears,
  • 41:00I wanted to briefly discuss
  • 41:01other targeted agents,
  • 41:02which we see a lot of toxicities
  • 41:04from in the breast group.
  • 41:06They heard two inhibitors as well
  • 41:08as American hitters used for various
  • 41:10cancers can actually share some of
  • 41:12the properties of the EGFR inhibitor.
  • 41:14Reactions will often see folliculitis,
  • 41:16eruptions and acne or form rashes.
  • 41:17However,
  • 41:18they usually less severe and less frequent.
  • 41:22I wanted to talk about another very
  • 41:24important toxicity which comes to
  • 41:26clinic and that's the hand foot
  • 41:27skin reaction.
  • 41:28So these usually develop from
  • 41:29the anti angiogenesis agents,
  • 41:31some of which we just heard about
  • 41:33which are used in the paddle cellular
  • 41:35carcinoma such as the anti veg F agents.
  • 41:37And here's a list of the FDA approved
  • 41:39ones and so this seems to be one
  • 41:42of those toxicities which just so
  • 41:44frequently impacts patients quality of life.
  • 41:46They have a hard time being able
  • 41:48to work to do their daily routine.
  • 41:50It very often impacts their activities
  • 41:52of daily living.
  • 41:53Patients usually present early on.
  • 41:55We just kind of thickening or hyper
  • 41:57keratosis of the palms and soles,
  • 41:59but then over time they get these
  • 42:01very painful.
  • 42:01Callous is,
  • 42:02sometimes they are inflamed and
  • 42:04then in the severe cases we even
  • 42:06see blisters develop as well.
  • 42:08This rash can be associated with very
  • 42:11painful dysaesthesia with sometimes
  • 42:12will use gabapentinoids like pre
  • 42:15gabelein or gabapentin to help
  • 42:17assist with at this stage as well.
  • 42:19These drugs also are associated
  • 42:21with genital eruptions as well as
  • 42:23splinter hemorrhages on the nails.
  • 42:25So we don't really have great treatments
  • 42:27for the hand foot skin reaction right now.
  • 42:30Unfortunately, many patients don't
  • 42:31respond to moisturizers and karata lytic,
  • 42:33or topical steroid ointments and
  • 42:35so dose reduction is often needed.
  • 42:37So we're doing a study looking at a
  • 42:39novel topical nitroglycerin ointment
  • 42:41to treat grade two or grade three
  • 42:43hand foot skin rash and the first
  • 42:45phase is going to be comparing it to
  • 42:48vehicle and then the second phase.
  • 42:50Comparing pyren lower percentages
  • 42:51and so if you have any patients
  • 42:53who present with hand foot skin.
  • 42:56On these approved drugs on the left
  • 42:58who have great to her Grade 3 and
  • 43:00really most patients eventually get
  • 43:02to grade 2 because it's almost always
  • 43:04interfering with her activities
  • 43:05of daily living.
  • 43:06Please please I'll refer them to our study.
  • 43:09We definitely need to do better
  • 43:12in managing this toxicity.
  • 43:14In interest of time,
  • 43:15I'm just gonna I'm just just briefly
  • 43:17highlight that we could spend all day
  • 43:19talking about the different targeted
  • 43:21agents in the toxicities I see.
  • 43:23Here are some examples just to illustrate
  • 43:25that really many different classes can do it.
  • 43:27Since you were on or Brewton if for
  • 43:29CLL often get perperek eruptions,
  • 43:31folliculitis patients with breast
  • 43:33cancer on PR, 3 kinase inhibitors,
  • 43:34and get really terrible.
  • 43:36Morbilliform exanthems some requiring
  • 43:37the use of Prednisone so wanted to turn
  • 43:39now to immune checkpoint inhibitors.
  • 43:41Because I think you pennis
  • 43:43toxicities are really important.
  • 43:44To discuss with this class
  • 43:46of cancer cancer therapy.
  • 43:48And so all great rash,
  • 43:49plus parictis it kind of tally.
  • 43:51It all can occur in up to 50% of
  • 43:54patients on checkpoint inhibitors at one
  • 43:56point in time during their treatment.
  • 43:58This is especially true of patients
  • 44:00who are on combination CTL,
  • 44:02a foreign PD one therapy and the way
  • 44:04that I think about the toxicities
  • 44:06from the checkpoint inhibitors is
  • 44:07a categorized them into those that
  • 44:10are the most frequent that we see
  • 44:12which are the morbilliform rashes,
  • 44:14the lichenoid rash,
  • 44:15which I'll discuss a bit more about the
  • 44:18exame and the parictis as well as psoriasis.
  • 44:20And then there's the whole category
  • 44:22of autoimmune disorders which occur
  • 44:24as immune related adverse events such
  • 44:26as diddle I go and bullous pemphigoid
  • 44:28which I'll discuss more about as well.
  • 44:30Fortunately, the severe rashes,
  • 44:31the life threatening Stevens Johnson
  • 44:32ones we've seen them,
  • 44:34but they're not.
  • 44:34They're not common,
  • 44:35and then there's kind of the
  • 44:37miscellaneous category of those that
  • 44:39are granulomatis like sarcoid for those
  • 44:42involving the panniculus or the fassia.
  • 44:44So this is actually one of the
  • 44:46largest studies out there.
  • 44:47Looking at the different branches
  • 44:48from in therapy that we published
  • 44:50a couple of years ago and it was a
  • 44:52retrospective retrospective study
  • 44:53of over 100 rashes that we saw
  • 44:55in the ankle during clinic and we
  • 44:57found is that they really have many
  • 44:59different clinical and histopathologic
  • 45:00morphologies here and a lot of them
  • 45:02resembled idiopathic dermatosis
  • 45:03that that we treat in dermatology.
  • 45:05For patients who are not
  • 45:06on checkpoint inhibitors.
  • 45:08If you take a look at the yellow box I
  • 45:10highlighted kind of the top five and
  • 45:12what's interesting about this is that
  • 45:14a lot of these common rashes actually
  • 45:16develop many months into therapy.
  • 45:18The most common one can be sometimes
  • 45:20six months into treatment,
  • 45:21and I think that's important because
  • 45:23patients don't always realize or
  • 45:24put together that their new rashes
  • 45:26because of their immune therapy,
  • 45:27and in some of the oncologist who are
  • 45:29less familiar with these toxicities,
  • 45:31also may not.
  • 45:32And so I I think that's important to
  • 45:34keep in mind that you can definitely
  • 45:36get late toxicities to write.
  • 45:37This is a very prominent feature.
  • 45:39In most of these containers,
  • 45:41toxicities fortunately were able
  • 45:42to manage these patients in the
  • 45:44vast majority of time,
  • 45:45topically by 20% of patients required
  • 45:48Prednisone because of the severity
  • 45:49of the rash and 25% had disruption
  • 45:51of immune therapy at some point,
  • 45:53sometimes before they saw me in clinic,
  • 45:56or sometimes because the rash progressed.
  • 45:58But really,
  • 45:58the vast majority can remain
  • 46:00on immune therapy.
  • 46:01It was just the cases of Stevens Johnson,
  • 46:04a really bad bullous pemphigoid where
  • 46:06immune therapy was discontinued and another
  • 46:08important concept here is for the rashes.
  • 46:10That do recur after
  • 46:11Prednisone or or that persist.
  • 46:13Targeting the dermatosis in a more
  • 46:15efficient way is probably going to
  • 46:17be the future of how these rashes
  • 46:19are treated and so we've had a great
  • 46:21deal of success using things like
  • 46:23asset reading for the psoriasis
  • 46:24or lichenoid rash Om Alisme after
  • 46:26methotrexate for the Bulls tend
  • 46:28to glide and the TNF inhibitors
  • 46:30for Stevens Johnson,
  • 46:31which is how we treat it typically.
  • 46:33More recently for for the cases that
  • 46:35are not associated with checkpoint,
  • 46:36I wanted to take a moment
  • 46:39to discuss that the.
  • 46:40What what the lichenoid dermatitis
  • 46:41is we throw around the term lichenoid
  • 46:44alot in dermatology and I'm not
  • 46:45sure if the if our colleagues in
  • 46:47meddock or familiar with it and
  • 46:49so like in what looks like like in
  • 46:51which an Organism that grows on
  • 46:53trees kind of scaly and crusty looks
  • 46:55kind of like the rash does.
  • 46:57And then there's the histologic term
  • 46:58of lichenoid dermatitis which is an
  • 47:00interface dermatitis with the bandlike
  • 47:01infiltrate of lymphocytes ANAN.
  • 47:03This is the most common histopathologic
  • 47:05finding that we see in the skin.
  • 47:07And so the lichenoid rash can occur
  • 47:09in up to a third quarter to 1/3 of
  • 47:12patients on PD one and PD Wagon one agents.
  • 47:15And this is kind of a more severe
  • 47:17example highlighting the pink
  • 47:19violaceous scaly patches and plaques.
  • 47:21Here's a patient who responded to
  • 47:23Acitretin were very persistent Palmer
  • 47:25planter involvement and he did not
  • 47:27do as well with topical steroids or
  • 47:29even a short course of Prednisone.
  • 47:31I also wanted to highlight that this
  • 47:33lichenoid rash can involve the mucosa,
  • 47:35and when that occurs,
  • 47:36it can really be quite severe
  • 47:38with ulcerations on the genitals
  • 47:40as well as the oral mucosa.
  • 47:42Anan this this this clearly is very
  • 47:44painful and we were very low threshold
  • 47:46for Prednisone in these cases.
  • 47:48Sometimes we try things like
  • 47:50hydroxychloroquine in those that persist.
  • 47:52So in addition to the lichenoid
  • 47:54rash from checkpoint inhibitors,
  • 47:55we can also see eczematous presentations.
  • 47:57Sorry, acid form presentations.
  • 47:59And then there's patients that
  • 48:00just have terrible parictis even
  • 48:02without an associated rash.
  • 48:03So here's a typical scenario
  • 48:05of a patient with psoriasis,
  • 48:06then goes on checkpoint
  • 48:08inhibitor therapy and flares,
  • 48:09and she responded very well to phototherapy,
  • 48:11which is a really nice non
  • 48:13systemic option for these patients.
  • 48:15Here's an example of widespread eczema,
  • 48:17and here's a patient that I share with
  • 48:19Doctor Goldberg who just developed just
  • 48:21severe itch and she comes to clinic,
  • 48:23covered in bandages and
  • 48:25explorations and she eventually.
  • 48:26Did somewhat better with pre
  • 48:28gabelein and phototherapy,
  • 48:29so just highlighting that the different
  • 48:31the spectrum of these papulosquamous
  • 48:33rash as we call them from dermatology.
  • 48:36So both paperboy is one of those
  • 48:38rashes which is not common,
  • 48:39but it's a very important one because
  • 48:41it has a great deal of associated
  • 48:43morbidity with it and so for those
  • 48:46who aren't familiar with it,
  • 48:47it's an autoimmune blistering
  • 48:49disease with deposition of IG G and
  • 48:51compliment at the dermal epidermal
  • 48:52junction is seen here in my patients
  • 48:54tissue sample and patients also
  • 48:56make autoantibodies against BP 180,
  • 48:58so we conducted a study a few years
  • 49:00ago at our uncle during clinic
  • 49:02and we found that about 1% of the
  • 49:04patients on checkpoint inhibitors
  • 49:06with PD one or PD wagon one.
  • 49:08Based on our pharmacy develop
  • 49:10this rash so it's not common,
  • 49:12but but it definitely can be quite
  • 49:14extensive and the latency is
  • 49:16also usually four to six months.
  • 49:18Clinically,
  • 49:19patients will often present with
  • 49:20just worsening queritis even before
  • 49:22the onset of rash.
  • 49:23Then they get these urticaria lesions
  • 49:25with tense vesicles and bullae,
  • 49:27which can become eroded,
  • 49:28and you can also get mucosal
  • 49:30involvement as well.
  • 49:31Think about the bullous pemphigoid
  • 49:33rash is unlike a lot of the more
  • 49:36common exanthems and lichenoid rash.
  • 49:37These typically require Prednisone due
  • 49:39to the severity of the presentation
  • 49:41with blisters.
  • 49:42We've also had cases which have
  • 49:44persisted even after immunotherapy
  • 49:45has been stopped,
  • 49:46and even after a Prednisone taper
  • 49:48likely do too.
  • 49:49I'm just immune activation and so
  • 49:51for those cases things like Rituxan,
  • 49:53MAB formalism,
  • 49:53Maverick dupilumab which are biologics,
  • 49:55I'll discuss later might be very helpful.
  • 49:59And the one one question about that
  • 50:01comes up a lot is when to worry about
  • 50:04a typical macular papular example,
  • 50:06when should you worry about progression
  • 50:08of Stevens, Johnson, and so?
  • 50:10My advice with these cases is obviously,
  • 50:12you know,
  • 50:13you can grade it based on the
  • 50:15body surface area,
  • 50:16but when the rash is pink and pure Riddick.
  • 50:20It's very reassuring when the rash
  • 50:22starts to become this more dusky color.
  • 50:25And painful. That's when you really
  • 50:27have to worry about a progression to
  • 50:29a more severe cutaneous reaction,
  • 50:31especially if there is any coastal
  • 50:33involvement or blisters or any systemic signs
  • 50:35or symptoms really have a low threshold
  • 50:37for Prednisone and watching carefully,
  • 50:39we've definitely seen these very
  • 50:41atypical scenarios where an example
  • 50:43just progressed and slowly over the
  • 50:45course of several weeks progressed to
  • 50:47a Stevens Johnson type of scenario.
  • 50:49And that's been that's been
  • 50:50published with checkpoint inhibitors,
  • 50:52which is actually very different
  • 50:53than classical Stevens.
  • 50:54Johnson would just takes off.
  • 50:56At a very rapid tempo nears examples
  • 50:58of examples that we've seen,
  • 50:59as well as Stevens Johnson from
  • 51:01Hippie Niveau.
  • 51:04An I think the future direction
  • 51:06for it for treating these cutaneous
  • 51:08toxicities is is looking at a more
  • 51:10efficient way to shut them down.
  • 51:12Basically treating the dermatosis
  • 51:13in the most targeted approach.
  • 51:15There's definitely a good amount
  • 51:16of data suggesting that the
  • 51:18use of systemic steroids is,
  • 51:19in general, fine, inappropriate,
  • 51:21and it has has not been shown
  • 51:23to impair tumor response when
  • 51:24treating cutaneous toxicities,
  • 51:26but for those cases that
  • 51:27are just recalcitrant,
  • 51:28I think we're going to find
  • 51:30the use of anti aisle 413 drugs
  • 51:32like the pillow mab or anti Ige.
  • 51:35He antibodies like oh Melissa
  • 51:36Matthews more frequently.
  • 51:37We already have plenty of biologics
  • 51:39used in psoriasis and I think there
  • 51:42is mounting data in case series of
  • 51:44these being used for checkpoint rash
  • 51:46as well as TNS for Stevens Johnson.
  • 51:48Here's an example of a patient I
  • 51:50share with Sarah Weiss who had bullous
  • 51:53pemphigoid which kept flaring when
  • 51:54we slowly taper the Prednisone.
  • 51:56Eventually,
  • 51:57with the concomitant administration
  • 51:58of Melissa Map were able to get
  • 52:01the patient off criticism.
  • 52:03And so in the final moments,
  • 52:05I just wanted to highlight it's
  • 52:07not the forgotten child,
  • 52:08because we see lots of toxicities
  • 52:10from the cytotoxic drugs.
  • 52:11But these I think you're probably
  • 52:13more familiar with because they've
  • 52:15been around for a long time,
  • 52:17but definitely,
  • 52:17alopecia mucositis are kind of
  • 52:19your hallmark toxicities.
  • 52:20Nail changes are really important
  • 52:21and he's come up a lot to my clinic,
  • 52:24specially young women with breast
  • 52:26and gynecological cancers on
  • 52:27taxanes or anthracyclines.
  • 52:28They get very painful
  • 52:29paronychia subungual hemorrhage.
  • 52:30They can lose the nail plate they can become.
  • 52:33Co infected,
  • 52:34and so I think these toxicities are
  • 52:36really important and then there's
  • 52:38the toxic rash of chemotherapy
  • 52:39which can be hand foot syndrome
  • 52:42or malignant intertrigo flow under
  • 52:43the umbrella of toxic erythema of
  • 52:46chemo and these reactions occur
  • 52:48through the ecrivain excretion of
  • 52:50chemo in the skin of echoing glands.
  • 52:53And we just wanted to do a brief
  • 52:55shout out to my awesome research
  • 52:57fellow who just matched into
  • 52:59dermatology at Cornell.
  • 53:00Rihanna and she was very interested
  • 53:02in looking at the cutaneous toxicities
  • 53:04in patients we've seen with skin
  • 53:07of color which really make up a
  • 53:09large proportion of our clinic.
  • 53:11And while the diagnosis in general or
  • 53:13similar to patients without skin of color,
  • 53:15there's clearly a very prominent
  • 53:17finding of hyperpigmentation,
  • 53:18which is very bothersome and very,
  • 53:20very prevalent after a rash
  • 53:22are examples of that.
  • 53:24Patients who get fatal,
  • 53:25I go with darker skin.
  • 53:26It's obviously a lot more noticeable,
  • 53:28and then there's definitely a propensity
  • 53:30for starring starring alopecia,
  • 53:31but also just keloid scarring.
  • 53:33Here's an example of a patient with a
  • 53:35keloid overport site which responded
  • 53:37well to injection of triamcinolone,
  • 53:38so I think it's important to look
  • 53:41at how these toxicities differ
  • 53:43and in various populations.
  • 53:45And in closing went to refer
  • 53:47patients to our clinic.
  • 53:48I think the short answer is anytime
  • 53:50you need a hand, we're really,
  • 53:52really happy to see these patients.
  • 53:53It is a privilege definitely for rashes
  • 53:55that are higher grade that are impacting
  • 53:57quality of life or that are recalcitrant
  • 53:59to kind of conservative management.
  • 54:01And definitely anytime there's a red
  • 54:03flag that I mentioned like skin pain,
  • 54:05duskiness, blisters or plus definitely
  • 54:07send those patients our way.
  • 54:09So in conclusion, I hope you'll you'll
  • 54:11see from this talk that cutaneous
  • 54:13toxicities are not just common,
  • 54:15but they're also really important in the
  • 54:17overall management of cancer patients.
  • 54:19Ann Ann.
  • 54:20I hope that Dermot Earley dermatologic
  • 54:22intervention can make a difference.
  • 54:23Remember that the EGFR acne
  • 54:25reform rash often starts.
  • 54:26It is a sterile rash,
  • 54:28but it can often be secondarily
  • 54:30infected and you can get these unusual
  • 54:32late perperek eruptions as well.
  • 54:34Hand foot skin from the anti angiogenesis
  • 54:37drugs and definitely have associated pain.
  • 54:39We don't have great treatments yet,
  • 54:41so please consider referring patients
  • 54:42to the study using a novel nitroglycerin
  • 54:44ointment to treat it and then turning
  • 54:46to the checkpoint inhibitor rash.
  • 54:48I think the lichenoid one is
  • 54:50the important one to know about.
  • 54:52It's common it can have associated
  • 54:54parictis and mucosal involvement
  • 54:55as well as bullous pemphigoid,
  • 54:56which frequently requires systemic therapy.
  • 54:58And if there's any red flag,
  • 55:00signs or symptoms,
  • 55:01obviously you know you have to
  • 55:02treat these patients aggressively.
  • 55:04So I just wanted to thank really all
  • 55:06of my colleagues Ann and Metang.
  • 55:09Sir John Cradoc,
  • 55:10everyone at Smilow who's supported
  • 55:11our clinic over the years.
  • 55:13I have a really great team from the
  • 55:15admins to the nurses to my chief residents,
  • 55:18many of which have chosen Uncle Dharmas.
  • 55:20Akarere Anatomy very proud and as well
  • 55:22as my my research fellows, an NYCC I.
  • 55:25So if you ever have any patients,
  • 55:27I'm very I'm always available.
  • 55:28You can text me call me.
  • 55:30Contact us and we'll gladly see them.
  • 55:33So thank you and I'll take any questions.
  • 55:39It's terrific, thank you, Jonathan.
  • 55:41Do you have questions from the audience?
  • 55:54My recollection is that with the the
  • 55:57B RAF inhibitors there was a serious
  • 56:00problem with squamous cell carcinoma's is
  • 56:02that yeah so
  • 56:03actually had a.
  • 56:04I had a picture of that slide.
  • 56:07I didn't go into it too much but but we had.
  • 56:11We saw a lot of toxicities over the
  • 56:13years with the beer at inhibitors,
  • 56:15but with the concomitant administration
  • 56:17of the American hitters we've actually
  • 56:19seen that basically drop down to
  • 56:21near near 0 and so you can still get
  • 56:23phototoxic rash is another odd things,
  • 56:25like everything and awesome,
  • 56:26we've not seen squamous cells
  • 56:27develop in patients on be right
  • 56:29contributors to the American hitter.
  • 56:31Coadministration
  • 56:31perfect thank you.
  • 56:40Any other questions?
  • 56:49If not, thank you Jonathan.
  • 56:50Very interesting. Looks like
  • 56:51you're making a lot of progress in
  • 56:53managing these these disorders.
  • 56:56Thanks for having me.