Understanding Melanoma: Treatment Advances & Patient Care
October 13, 2021Information
Smilow Shares in partnership with Melanoma Research Foundation | October 12, 2021
Presentations by:
Jonathan Leventhal, MD, Assistant Professor of Dermatology
Thuy Tran, MD, PhD, Instructor of Medicine (Medical Oncology)
Kelly Olino, MD, Assistant Professor of Surgery (Surgical Oncology)
James Clune, MD, Assistant Professor of Surgery (Plastic)
Jeffrey Ishizuka, MD, DPhil, Assistant Professor of Medicine (Medical Oncology)
ID7035
To CiteDCA Citation Guide
- 00:00To introduce Amy Marble from
- 00:02the Melanoma Research Foundation,
- 00:04we'd like to thank Amy for Co.
- 00:06Sponsoring this event with us and I'm
- 00:08going to let me take the floor for
- 00:10a couple of minutes to talk about
- 00:12the Melanoma Research Foundation,
- 00:13which is something that's very
- 00:15dear to all of our hearts.
- 00:17They support a lot of the work that we do,
- 00:19and we love partnering with them.
- 00:21So thank you Amy,
- 00:22for being with us this evening.
- 00:24Thanks after Cougar and Doctor Small
- 00:26for hosting this event and for
- 00:28all of the physicians who will be
- 00:30presenting as Doctor Krueger said.
- 00:32My name is Amy Marva.
- 00:33I am the education officer here at
- 00:36the Melanoma Research Foundation,
- 00:37the Melanoma Research Foundation.
- 00:39We are celebrating our 25th
- 00:41anniversary this year.
- 00:42The foundation was started
- 00:44by a patient when in 1996,
- 00:47which seems not that long ago,
- 00:49but it's been 25 years and she was
- 00:53on her third recurrence of Melanoma.
- 00:55And was told she had no
- 00:57additional treatment options.
- 00:59She did not like that answer and
- 01:00so she wanted to make a difference
- 01:02with her with her cancer journey and
- 01:05decided to start the foundation to
- 01:07provide research to opportunities.
- 01:10Funding to both researchers and
- 01:13clinicians to find new treatment
- 01:14options as well as to hopefully
- 01:16one day find a cure for Melanoma.
- 01:18Unfortunately,
- 01:19she passed
- 01:19away before the MRF was able to provide
- 01:22their first research grants, but
- 01:23obviously her legacy lives on because.
- 01:26We are celebrating our 25th anniversary.
- 01:28Obviously, as the name implies,
- 01:30Melanoma Research Foundation.
- 01:31We focus a lot on research grants,
- 01:33but we also focus on two other areas,
- 01:36advocacy as well as education.
- 01:39We have a lot of educational opportunities
- 01:40such as these patients, symposia,
- 01:42events as well as education materials,
- 01:46webinars, animated patient videos
- 01:48kind of helped to explain the Melanoma
- 01:51diagnosis and treatment options
- 01:52a little bit clearer in a visual way.
- 01:54We have a lot of opportunities.
- 01:56And I really encourage you to
- 01:58visit our website at melanoma.org
- 02:00to learn more to find out, find
- 02:02more resources, more information,
- 02:04and to find the support that you might need.
- 02:06So again, I'm really happy to be
- 02:08here and to the MRF to help Co.
- 02:10Sponsor this event and Doctor Kluger.
- 02:12I'll turn it back over to you to to
- 02:14start to kick off the speakers right?
- 02:17Thank you so much Amy.
- 02:18We really appreciate everything that you
- 02:20do for us as a as a research community.
- 02:23So our first speaker this evening is Doctor
- 02:26Jonathan Leventhal. He is an assistant
- 02:28professor of dermatology.
- 02:29We call him live for short.
- 02:32He's going to talk to us
- 02:34about diagnosis of Melanoma,
- 02:35so take it away, John.
- 02:38Thank you so much Harriet.
- 02:39Let's just share my screen.
- 02:40I'm John Leventhal on the
- 02:42dermatologist in the Melanoma team
- 02:44it's a pleasure to be here and today
- 02:46I'm going to discuss diagnosis,
- 02:48risk factors, prevention and
- 02:49screening in Melanoma in advance.
- 02:52So I wanted to start by going over
- 02:54some key facts and that is that skin
- 02:56cancer is the most common cancer in
- 02:58the United States and there are three
- 03:00main types that you may have heard of.
- 03:02Basal cell,
- 03:03squamous cell and Melanoma.
- 03:04And although Melanoma only accounts
- 03:06for approximately 1% of all skin cancers,
- 03:09it is the deadliest and is more
- 03:10than one million people living
- 03:12with Melanoma in the United States.
- 03:17And so I wanted to start by
- 03:19going over what is Melanoma?
- 03:20So Melanoma is a malignant
- 03:22tumor of melanocytes,
- 03:24so these are the cells that
- 03:25produce pigment in our body.
- 03:27Most of them are located on the skin.
- 03:29However, they can also be
- 03:31present in mucosal surfaces,
- 03:33such as on the eyes or inside the map.
- 03:36And many cases of Melanoma,
- 03:39most I should say,
- 03:40arises new lesions on the skin.
- 03:41However, some can develop
- 03:42from an atypical mole or
- 03:44birthmark that then transforms.
- 03:48Next flight. And so who develops Melanoma?
- 03:51Well, anybody can, all ages,
- 03:53genders and ethnicities.
- 03:55However, the majority of people with
- 03:57Melanoma are white men over the age of 50.
- 04:00Interestingly, under the age of 50,
- 04:02women are more likely than
- 04:04men to develop Melanoma.
- 04:05This is likely due to certain tanning habits.
- 04:08However, by 865,
- 04:09most people with Melanoma are men.
- 04:12Next fight.
- 04:15And if you look at this table,
- 04:16you'll see that the lifetime risk
- 04:18of developing Melanoma is increased
- 04:20over the past several decades,
- 04:22decades, and currently approximately
- 04:23one in 40 individuals in the United
- 04:27States will develop Melanoma.
- 04:29This is likely due to many factors,
- 04:30but possibly because we're picking
- 04:32up melanomas at earlier stages,
- 04:34so one of the things get started by
- 04:36going over. How do we diagnose Melanoma?
- 04:40And so the first step of diagnosing Melanoma
- 04:43is to identify a concerning skin lesion.
- 04:47In advance this slide.
- 04:50You can advance again,
- 04:51and so it's important for us to have
- 04:53an idea of what Melanoma looks like.
- 04:55You may be familiar with the ABC DES,
- 04:58which stands for asymmetrical lesion,
- 05:00a border that's irregular color
- 05:02that's varied and then D is diameter
- 05:05greater than 6 millimeters,
- 05:06or a pencil tip eraser.
- 05:08I don't love diameter because you can have
- 05:10melanomas that are smaller than that,
- 05:12and so I prefer dark for D as most of
- 05:14the melanomas are pigmented lesions and I
- 05:17think perhaps the most important one is.
- 05:20He which is evolution.
- 05:21So we're looking for a lesion that
- 05:23seems to be changing either in size,
- 05:25shape, or becomes symptomatic.
- 05:27Next slide please.
- 05:29And I think it's also helpful to have
- 05:31an idea what the different types
- 05:33of melanomas look like, and so on.
- 05:35The top left you'll see the
- 05:37superficial spreading type,
- 05:38which is the most common.
- 05:39But there can also be nodular types,
- 05:42lentigo maligna,
- 05:42which develops in sun exposed areas.
- 05:45Some melanomas can actually have no pigment,
- 05:48and they can appear as pink papules.
- 05:51And then there's the April and Hyginus
- 05:52type which can occur on the palms and soles,
- 05:55or even under the nails,
- 05:56as seen here as a pigment did band.
- 05:59Next slide, please.
- 06:02So once you've identified a
- 06:04concerning lesion,
- 06:04a physician performs a skin biopsy.
- 06:07This can be done either by shave punch
- 06:10biopsy, or an excision of the lesion.
- 06:12Now,
- 06:12the type of biopsy is not that important
- 06:15as long as the lesion is sampled in
- 06:18its entire T so that an accurate
- 06:20diagnosis can be made and accurate.
- 06:23Evaluation of the depth of the lesion
- 06:25and that takes us to the final step.
- 06:27Step three in advance,
- 06:28which is where a pathologist
- 06:30will look under the microscope.
- 06:32To confirm the diagnosis and provide
- 06:34an initial stage which is based on
- 06:37how deep the Melanoma goes in the low
- 06:39into the lower layers of the skin.
- 06:41Next slide.
- 06:43So now that we know what Melanoma
- 06:45is and how to diagnose it,
- 06:47I wanted to briefly review some
- 06:48of the risk factors and what we
- 06:50can do to prevent it.
- 06:53And so when it comes to
- 06:54risk factors for cancer,
- 06:55there really two types.
- 06:56Those that are environmental and
- 06:58in those that we can't control,
- 06:59which are hereditary.
- 07:00So I wanted to start by going
- 07:02over those that are environmental.
- 07:06Next slide, please.
- 07:09And so the modifiable risk factors here.
- 07:11If you look at these figures all involve
- 07:14ultraviolet radiation, next slide.
- 07:18And so ultraviolet radiation reaches the
- 07:20earth surface primarily is ultraviolet.
- 07:22A in ultraviolet feet.
- 07:23And as you can see in the
- 07:25figure on the top left,
- 07:26these penetrates the layers of the skin.
- 07:29And what happens is these ultraviolet
- 07:32penetration results and DNA damage and
- 07:35changes in our DNA called mutations.
- 07:38These accumulate and can result in
- 07:40the development of skin cancers,
- 07:42including Melanoma.
- 07:42I also wanted to point out that you
- 07:45ultraviolet a can penetrate car windows,
- 07:47which is something that.
- 07:49Patients often ask me about
- 07:50next slide please.
- 07:53And the type of ultraviolet
- 07:55exposure that contributes the
- 07:56most to Melanoma is unfortunately
- 07:58the type that we love the most.
- 08:00So intermittent short bursts of
- 08:02outdoor activity, beach vacations,
- 08:04and the majority of melanomas can be
- 08:07attributed to ultraviolet exposure.
- 08:10You do not want to look like
- 08:11Will Ferrell in that picture.
- 08:12There's also. Evidence thank you
- 08:14can progress the next slide.
- 08:16There's also evidence that
- 08:18sunburns contribute to Melanoma.
- 08:20Now we're not just talking
- 08:22about sunburns in childhood,
- 08:23which is a bit of a misconception,
- 08:26as some patients will say, well,
- 08:27I already had a lot of numbers in
- 08:29child that I might as well enjoy
- 08:31myself on the golf course now,
- 08:32but we know that it's actually
- 08:34cumulative sunburns over the course of
- 08:36a lifetime that contributes to Melanoma,
- 08:39and indeed,
- 08:39sunburns during childhood can increase
- 08:41the odds of developing Melanoma.
- 08:44As you can see in these tables here,
- 08:46next slide.
- 08:49And. Tanning beds is one of the
- 08:52most important carcinogens that we
- 08:54know increase the risk of Melanoma.
- 08:57So studies have shown that young women,
- 08:58for example, under age of 30,
- 09:00had a six times increase
- 09:02odds of developing Melanoma.
- 09:04If they had a history of tanning bed use,
- 09:06so tanning bed should really
- 09:08come equipped with that sign.
- 09:09A question that I guess sometimes
- 09:11for patients is weather spray tanning
- 09:13is OK and the short answer is yes,
- 09:16spray tanning is perfectly safe and does
- 09:18not contribute to development of skin cancer.
- 09:20You may remember Ross.
- 09:22Friends, you can progress to the next slide.
- 09:24You just don't want to overdo
- 09:25it or you look like a carrot.
- 09:27Next slide, please.
- 09:30And for next,
- 09:30we're going to discuss the risk
- 09:32factors that we can't control those
- 09:35that are hereditary or genetic.
- 09:36We can progress slide.
- 09:40And so having nevi a large number of
- 09:43nevi over 100 atypical moles and having
- 09:47solar lentago's or sunspots all can
- 09:49increase your risk of skin cancer as you
- 09:51see on the photo on the lower right,
- 09:53you'll see the development of these
- 09:55solar lentago's occur in areas
- 09:56that are sun exposed,
- 09:58whereas skin that is not seen chronic
- 10:01ultraviolet radiation looks far
- 10:03healthier without these solar lentago's.
- 10:06Next slide please.
- 10:09And we also know that having light hair,
- 10:11light skin, blue eyes,
- 10:13and freckles are characteristics that
- 10:15are all increased with higher chance
- 10:18of developing Melanoma compared to
- 10:20individuals that have darker hair,
- 10:23darker skin and darker eyes. Next slide.
- 10:29In addition, having a personal history,
- 10:31Melanoma increases your risk of
- 10:33getting subsequent melanomas and
- 10:35having a first degree relative with
- 10:37Melanoma also doubles your risk.
- 10:39In addition to a personal and family history,
- 10:41we know that there are certain
- 10:43types of genetic syndromes that
- 10:45increase your risk of Melanoma.
- 10:47The most important one is the familial
- 10:50atypical multiple Melanoma syndrome,
- 10:52where mutations in genes that the CDKN 2
- 10:54a result in having hundreds of atypical
- 10:57looking nevi as seen in the picture.
- 10:59Here, but also highly increased
- 11:01risk of Melanoma as well as other
- 11:04cancers such as pancreatic cancer.
- 11:06Next slide, please.
- 11:10And perhaps this is the most important slide.
- 11:12So what can we do to prevent
- 11:14the development of Melanoma?
- 11:15So first and foremost,
- 11:17avoid indoor tanning beds.
- 11:19Also, protect yourself
- 11:20from the sun at all times,
- 11:22so by seeking shade,
- 11:24wearing some protective clothing,
- 11:25there actually is clothing with
- 11:27ultraviolet protective factors
- 11:28which are made especially to help
- 11:31prevent UV damage to the skin.
- 11:33It's important to wear a wide brimmed
- 11:34hat and sunglasses with UV protection.
- 11:36In addition, applying broad spectrum
- 11:38sunscreen with an SPF 30 or above.
- 11:41To all exposed areas and reapplying will
- 11:43help reduce the chance of getting Melanoma.
- 11:46Next slide, please.
- 11:49And then in the final moments,
- 11:50I just wanted to briefly review how
- 11:52do we screen patients for Melanoma?
- 11:56In advance this slide.
- 11:58I wanted to start by saying that
- 12:00there are no national screening
- 12:02guidelines for Melanoma and the United
- 12:04States Preventive Services Task
- 12:06Force does not recommend screening
- 12:08all adults that are asymptomatic
- 12:09and don't have concerning lesions.
- 12:11However, there are important
- 12:13exceptions for at risk individuals,
- 12:16meaning those that have a
- 12:17concerning lesion on their skin.
- 12:19A history of skin cancer
- 12:21or strong family history.
- 12:22These individuals should see a
- 12:24dermatologist and dermatologists would
- 12:26conduct a full body skin examination,
- 12:28which we're going to review.
- 12:29In addition,
- 12:30educating the youth about Sun
- 12:32protective behavior is also
- 12:34recommended next slide.
- 12:38And we know that there are
- 12:40benefits to a screening program.
- 12:42One example is the American
- 12:43Academy of Dermatology,
- 12:44conducted a study and they found that
- 12:47dermatologists at a higher percentage
- 12:49of finding thinner melanomas than those
- 12:51compared to a general population registry.
- 12:54Interestingly, another study showed
- 12:56that patients and their spouses can
- 12:59be trained to look for Melanoma,
- 13:01and they were able to identify melanomas
- 13:04on themselves or their spouse,
- 13:06and they were able to find them
- 13:07at low as low stages.
- 13:09Next slide.
- 13:12So some tips that I think are
- 13:14helpful is the ugly duckling sign.
- 13:16So when you take a look at the
- 13:18moles on your body or those of
- 13:20a significant another friend,
- 13:21you'll see that many most often look alike.
- 13:24Those are called signature nevi.
- 13:26It look like they belong in the same family.
- 13:28When you see him all that looks like
- 13:29it doesn't belong with the rest,
- 13:30that's the ugly duckling.
- 13:31I find that this sign is very helpful,
- 13:34especially when I educate my
- 13:36patients next slide.
- 13:39And dermatologists are able to use
- 13:41specialized lens with magnifying glass,
- 13:44called a Mattis, built to more precisely
- 13:47inspect skin lesions and identify Melanoma.
- 13:49Digital photography is also helpful to
- 13:52take photographs of lesions and monitor
- 13:55them overtime for change next slide.
- 13:58So in closing, I wanted to briefly
- 13:59review how to screen yourself,
- 14:01but I think a video is far better than
- 14:04looking at this at these pictures.
- 14:06So next slide.
- 14:07And Doctor Lee know if you don't
- 14:09mind clicking the play button,
- 14:10you'll see a demonstration of how to
- 14:12perform a total body skin examination.
- 14:28So some important points are to make
- 14:30sure you check areas of the skin,
- 14:32such as behind the ears.
- 14:34Look through the hair in the scalp.
- 14:36Make sure you look at bodily
- 14:37folds such as the underarms,
- 14:39under their breasts.
- 14:41Dermatologist check everywhere
- 14:43including between the toes.
- 14:45Palms and soles and even
- 14:47the groin area as well.
- 14:51By doing a thorough photo body skin exam,
- 14:54you're more likely to detect
- 14:56something on your skin next slide.
- 14:58So I wanted to thank you all
- 14:59for your time and I'll gladly
- 15:01take any questions, thanks.
- 15:05No, thank you so much, John.
- 15:06So I guess I didn't realize that
- 15:08there are two possibilities
- 15:09for typing in questions.
- 15:12You can put questions in
- 15:13the chat or in the Q&A.
- 15:15It might be better to
- 15:16put them all in the Q&A,
- 15:18but certainly there's one
- 15:20question here about your opinion
- 15:22regarding recommending the
- 15:24catena meter nacina made for
- 15:27patients who have Melanoma.
- 15:29Even if you haven't
- 15:29upgraded so, so that's a great question.
- 15:32So there are certain medications
- 15:35such as nicotinamide,
- 15:36which is a vitamin B derivative as well
- 15:38as acid Trident of vitamin A derivative,
- 15:41which have been shown to reduce the the
- 15:44possibility of getting skin cancers.
- 15:46These have mostly been studied
- 15:48though in squamous cell carcinoma
- 15:50and basal cell carcinomas,
- 15:51so I don't routinely recommend
- 15:53these medications for reducing
- 15:55the risk of Melanoma.
- 15:57Thank you and then another question
- 15:59about when you use Doppler ultrasound
- 16:02to assess the depth and aggression
- 16:04via two minier vascularity there's
- 16:07a reference there for image guided
- 16:10dermatology in spring of 2020.
- 16:13So that's a good question, and one
- 16:15that it had to look at that reference.
- 16:17The surgical oncologist might be able
- 16:18to talk about the use of ultrasounds,
- 16:20which sometimes are done to look for lymph
- 16:23nodes we don't routinely do that though,
- 16:25so I would say in in standard practice
- 16:28the diagnosis is made based on biopsy,
- 16:31which which is the gold standard.
- 16:34Thank you so much for that and I guess
- 16:36if there are any additional questions
- 16:38for Doctor Leventhal if you wouldn't
- 16:40mind putting them into the Q&A.
- 16:43Area that would be great and
- 16:45I guess without further ado,
- 16:47we'll go ahead and introduce our second
- 16:49speaker who is the wonderful Doctor,
- 16:52Jim Clune. He's a plastic surgeon who's
- 16:55an assistant professor of surgery.
- 16:57He's been with the group for a while already,
- 16:59and he's going to talk to us about
- 17:02surgery for primary Melanoma.
- 17:04So thank you, Jim.
- 17:08Great, thanks very much.
- 17:09Glad to follow Doctor Leventhal here
- 17:11because he is touched on a few things that
- 17:14will make my talk a little bit easier.
- 17:16You know surgery is a large
- 17:19conversation regarding Melanoma,
- 17:20but I'm going to kind of start as if
- 17:22you were coming to the office with a
- 17:25biopsy that's already being completed
- 17:26and a diagnosis of Melanoma and kind
- 17:28of where we go from there so you know,
- 17:31once ducked 11th,
- 17:32all or your dermatologist has done the biopsy
- 17:35and you have a diagnosis of a Melanoma.
- 17:37It could be a Melanoma insight 2.
- 17:39Or an invasive Melanoma.
- 17:40You'll also have a path report with you,
- 17:43so I usually go over the path report
- 17:45with our patient and then we talk
- 17:47about the surgical options usually,
- 17:49which involves removing the Melanoma and
- 17:52then in certain situations we also remove
- 17:55some lymph nodes for testing purposes.
- 17:58So, briefly, talking a little bit about
- 18:00Doctor Leventhal already talked about,
- 18:02but there's really there's
- 18:03two layers to your skin,
- 18:05the epidermis and the dermis,
- 18:06and then underneath the dermis,
- 18:08which is the thick layer skin, is the dermis.
- 18:10Here there's a fat and subcutaneous layer,
- 18:12and the Melanoma resides in the
- 18:14in the epidermis and the dermis.
- 18:17And when it's invasive,
- 18:18so it's important that the
- 18:19biopsy include the epidermis,
- 18:21and as much of the dermis as possible,
- 18:23so we can really determine
- 18:24the depth of the Melanoma.
- 18:25So sometimes when a patient
- 18:27comes into the office.
- 18:28We re biopsy the area that they've
- 18:30already had a thinner biopsy to
- 18:32confirm the diagnosis and to really
- 18:35understand the depth of the Melanoma.
- 18:38And a lot of people always ask me.
- 18:39You know, I've had other skin cancers before.
- 18:42Is this similar?
- 18:43Well,
- 18:44they come from the same place
- 18:46they are in the skin,
- 18:47but the ones that most people are
- 18:49referring to are squamous cell
- 18:50carcinoma and basal cell carcinoma.
- 18:52These are much more common skin
- 18:54cancers and they come from the
- 18:55squamous cells and the basil layer
- 18:57at the bottom of the epidermis.
- 18:59Your melanocytes are in here as
- 19:00Doctor Leventhal mentioned that
- 19:01give you the pigment to your skin
- 19:03and they're scattered throughout
- 19:04the basement membrane here in
- 19:05your in your skin as well.
- 19:09So the first thing we look at when you
- 19:11come to the office is your pathology
- 19:13report and really the thing that
- 19:15we look at the most is the depth.
- 19:17So this is an actual pathology report
- 19:18and it shows the tumor thickness is
- 19:206 millimeters in this case and we
- 19:22also look for a few other features
- 19:24such as ulceration, mitotic rate,
- 19:25and these are all things that will go
- 19:27through in detail with you to talk about
- 19:29your pathology report and determine
- 19:31what type of surgery you might need.
- 19:35And this is sort of a busy chart,
- 19:36but this is sort of the the
- 19:39the standard discussion.
- 19:40When you have surgery is you want
- 19:43to know how thick your Melanoma is.
- 19:45You want to know the margin when when
- 19:47I say margin it's the amount of normal
- 19:50skin that we're taking out around the
- 19:52Melanoma site and then a Sentinel
- 19:53node which is a testing of a lymph node.
- 19:57It's kind of near the Melanoma
- 19:59site and not everybody needs to
- 20:01have a lymph node tested and I
- 20:03have a criteria here that we use.
- 20:05You can look at this later on.
- 20:06I think this is being recorded so
- 20:07you can refer back to this if you
- 20:09want to understand it in more detail,
- 20:10but this is something that we talked
- 20:12to you about in quite a bit of
- 20:13detail when you come to the office.
- 20:17So what is a margin?
- 20:18So the amount of normal skin that we
- 20:21removed from around the Melanoma.
- 20:22So here's a Melanoma on the heel of a
- 20:24patient, and it was a thin Melanoma,
- 20:26but it was relatively broad,
- 20:28but we took about a 1 centimeter margin of
- 20:30normal skin all the way around the Melanoma.
- 20:32So that's the first thing
- 20:33we're going to talk about.
- 20:34Is how much do we need to take out then?
- 20:36The next question is,
- 20:37do I need a lymph node biopsy?
- 20:39Well, what is a lymph node?
- 20:41Well, lymph nodes are sort of
- 20:43like the coffee filter paper,
- 20:45and they sit up in your axilla,
- 20:46your neck, your groin.
- 20:47If you prick your finger
- 20:49while you're gardening,
- 20:50and you get an infection in your finger,
- 20:52your lymph nodes in your armpit
- 20:53may expand and enlarge as they're
- 20:55fighting off the bacteria.
- 20:57The same thing happens with Melanoma.
- 20:59Your body may recognize that as a
- 21:02foreign entity and the lymph node
- 21:04will have Melanoma in the lymph node,
- 21:07may enlarge overtime and as you
- 21:09produce an immune response,
- 21:11or if the Melanoma becomes filled
- 21:13with the lymph node becomes.
- 21:14Filled with Melanoma,
- 21:15so one of the first places that a
- 21:18Melanoma may travel is the lymph node,
- 21:20so we often will test these to
- 21:23see if there's.
- 21:24It's basically the best predictor
- 21:26of whether or not the Melanoma
- 21:28has metastasized and we can sort
- 21:30of predict how the patient May
- 21:32is going to do in the future,
- 21:34and whether or not they may
- 21:35need further treatment.
- 21:36So this is how I'm depicting
- 21:38how it would happen.
- 21:39But here's the blue Melanoma cells
- 21:41and they drop down into the lymphatic
- 21:43channels and then they can travel to
- 21:45the lymph nodes wherever that may be.
- 21:47So if you have a Melanoma on your arm
- 21:49then the lymph lymphatic channels
- 21:51which are depicted here is these.
- 21:54Green tubules will lead to the
- 21:57lymph nodes and the Melanoma
- 21:59cells may migrate there.
- 22:01So what we do in the operating
- 22:03room was a lymph node biopsy.
- 22:05But you have about.
- 22:06You know 3040 lymph nodes in your armpit.
- 22:09We don't want to take them all out.
- 22:10We only want to take out the lymph
- 22:12node that has the highest chance
- 22:14of having Melanoma at first.
- 22:16So that's what we call the
- 22:18Sentinel lymph node.
- 22:19So we get a map made ahead of time.
- 22:22They go down to nuclear medicine,
- 22:23they inject some dye into your arm,
- 22:25and it has a radioactive isotope tag to it,
- 22:28and it they inject the dye here and it
- 22:30goes up the tubules into the lymph nodes.
- 22:32And the first lymph node that gets
- 22:34the die is the one that we have to
- 22:36take out in the operating room.
- 22:37And we often will take out a
- 22:39few others around it,
- 22:40but we don't need to take all the lymph
- 22:42nodes out for the testing purposes.
- 22:44So this is an example of what
- 22:46a lymph node
- 22:47map looks like, so this is a patient.
- 22:48This is the head and their arms are up
- 22:51behind their head like this and the injection
- 22:53site looks like a tear in the chest.
- 22:55They inject the dye here and then it maps
- 22:58to a lymph node in the armpit and also two
- 23:00lymph nodes down here just above the hip.
- 23:03So this will give us some information
- 23:04about what we need to do in the operating
- 23:06room so when we go to the operating room
- 23:08we inject the dye again and we use a
- 23:11special counter called a Geiger counter.
- 23:14And this allows us to detect that radioactive
- 23:16isotope and identify where the lymph node is.
- 23:19'cause we only want to take out
- 23:20as few lymph nodes as possible.
- 23:21We want to make sure we take out the lymph
- 23:23node that is in charge of cleaning that
- 23:25piece of skin that where the Melanoma was.
- 23:29So, continuing on our surgical options,
- 23:32now we know our margin.
- 23:33We base that on our depth and a
- 23:35few other things that I talked
- 23:36about in the pathology report,
- 23:37and we also know if we need
- 23:39a lymph node biopsy or not.
- 23:41And we also got a map to show
- 23:42us where that lymph node is.
- 23:44If you need a lymph node biopsy.
- 23:46So now we can go to the operating
- 23:48room so the surgical steps are to
- 23:50remove the Melanoma and then to
- 23:51identify and remove the intended
- 23:53lymph nodes for testing and then
- 23:55reconstruct the surgical site.
- 23:58As I said before,
- 23:59we remove the Melanoma we take about
- 24:00one to two centimeters of normal skin.
- 24:02With the Melanoma now there's
- 24:04also a Melanoma insight two,
- 24:05which I mentioned briefly earlier and
- 24:07that's in the upper layer of skin.
- 24:08In that case,
- 24:09we usually only take about a
- 24:11half a centimeter.
- 24:13And the reason we take a margin
- 24:15is that you know the Melanoma
- 24:17is is the central focus.
- 24:19But we also worry that there may
- 24:20be some small Melanoma cells
- 24:22that may be slightly outside
- 24:23of the main focus of Melanoma,
- 24:25and that's why we take
- 24:26this additional margin,
- 24:27and this decreases the chances of
- 24:29it coming back in the same place.
- 24:31And you know,
- 24:31I,
- 24:32I always try and explain to the
- 24:33patients how much we have to take out,
- 24:35but it's a little bit hard to
- 24:36understand our picture.
- 24:37What it looks like when we take out
- 24:39one to two centimeters for normal skin.
- 24:41So I'm going to show a few pictures.
- 24:43You know the images are blocked
- 24:45out enough that you know,
- 24:47but it's a surgical procedure,
- 24:49so this is a Melanoma on the scalp and
- 24:51this is about a 1 centimeter margin
- 24:53of normal skin that's been removed.
- 24:55This is a near where we take out
- 24:57about a centimeter of normal skin
- 24:59around where the Melanoma was,
- 25:00and this is a foot with about a
- 25:02centimeter of normal skin has
- 25:04been removed around the Melanoma.
- 25:07So this is a brief depiction of the lymph
- 25:10node portion of this of the procedure.
- 25:12So we've taken the Melanoma out, right?
- 25:14So we've taken our margin and
- 25:15now we have to do the lymph node.
- 25:16So we this is the Melanoma site on this
- 25:19patient, we inject the dye right in here
- 25:22and then we use this little silver thing.
- 25:24It's a Geiger counter and we listen to where
- 25:27the lymph node is because the technetium,
- 25:30the isotope that we've injected,
- 25:32is going to be picked up by this
- 25:33Geiger counter and then we make
- 25:35our incision in that lymph node.
- 25:36Face and it could be in the neck,
- 25:37the gland and the cheek.
- 25:38The armpit of the groin.
- 25:40And then we remove that lymph node.
- 25:42And this is what a lymph node
- 25:44looks like when it's removed.
- 25:46They're pretty small.
- 25:46Maybe the size of a nickel.
- 25:48Some are even smaller and
- 25:49somewhere slightly bigger,
- 25:50and that's what we send to the lab,
- 25:52and so the Melanoma that we took
- 25:53out and the lymph node are sent
- 25:55to the lab and they look under the
- 25:57microscope and it takes them about
- 25:58a week or so to let us know if we
- 26:00removed all of the Melanoma and
- 26:02also whether there's any Melanoma
- 26:04in the lymph node that we took out.
- 26:06So now we've removed the Melanoma.
- 26:08We've tested the lymph node.
- 26:10We've closed up where the lymph
- 26:11node was taken out,
- 26:12and now we have to repair
- 26:14the Melanoma excision site.
- 26:16So I'll briefly show what
- 26:17reconstruction looks like for the
- 26:19vast majority of our patients,
- 26:21the reconstruction will happen at the
- 26:22same time as the removal of the Melanoma,
- 26:24so you only have to have one surgery.
- 26:26In some instances,
- 26:27it is better to wait to make
- 26:29sure all the Melanoma is gone
- 26:30before we do the reconstruction,
- 26:32but that's that's the exception.
- 26:35So this is the scalp Melanoma
- 26:37that we just showed.
- 26:38Remove the Melanoma and then we
- 26:40do what's called flaps to put it
- 26:42back together so this entire seas
- 26:44of skin that we remove we are able
- 26:46to rotate in and you know it seems
- 26:48like a large surgery which it is
- 26:49at the time but within a few weeks
- 26:51the hair is growing back and the
- 26:53scars look quite good.
- 26:54Once the hair is growing back.
- 26:56This is an example of a patient
- 26:58that had a similar scalp flap to
- 27:00the patient you just saw.
- 27:01You can sort of see this car in the hairline,
- 27:03but the good thing about flaps rather
- 27:05than graphs is that the hair does.
- 27:06Throwback nicely.
- 27:08And this is a flap for the
- 27:10foot for after resection,
- 27:11so the Melanoma has been removed
- 27:13and then we design A flap of skin.
- 27:15They became rotated in to fill the defect.
- 27:18We always try and put flaps,
- 27:19which is a piece of skin that
- 27:21has the Fed on it still.
- 27:22So especially on a weight
- 27:24bearing surface like on the
- 27:25heel of the foot.
- 27:26And then this isn't here, so again,
- 27:28the melanomas been removed and we're
- 27:30able to to use what's left of the ear
- 27:32to reconstruct and make a new ear.
- 27:34So in decisions can be made down here.
- 27:36The rest of the ear can be
- 27:37brought up to fill the defect,
- 27:38and it's interesting when you
- 27:40compare it to the contralateral ear.
- 27:41And really, the main difference is the size.
- 27:43But the interesting thing with ears is
- 27:45when you look at somebody you really
- 27:47don't see both ears at the same time,
- 27:49so a size difference is not that big
- 27:51of a deal, but asymmetry would be.
- 27:54And this is an example of a
- 27:57another ear Melanoma.
- 27:58This is the main site a centimeter
- 28:00of normal skin on each side.
- 28:01The ear Melanoma has been removed
- 28:02and then the ear reconstructed.
- 28:06So and I'll briefly talk
- 28:08about this last topic,
- 28:09and this is completion lymphadenectomy.
- 28:11We used to do this for every patient
- 28:13that had a positive Sentinel lymph node.
- 28:15Meaning if we found Melanoma in
- 28:17the lymph node, we would remove
- 28:18all the lymph nodes around it.
- 28:20We for the most part have
- 28:22slowed down on doing these.
- 28:23Based on our research over
- 28:25the last number of years.
- 28:27But we do do this in certain cases still.
- 28:30So if this is the case with you,
- 28:31it's a conversation will have.
- 28:33But for the vast majority of patients.
- 28:35We're no longer doing this.
- 28:39So thanks very much and I will take a
- 28:40look and see what the questions are.
- 28:45Alright, thank you so much, Jim.
- 28:47I think you have one question.
- 28:50Uhm, can you please talk about
- 28:53Melanoma in the interior organs?
- 28:55Perfect actually, so Doctor Alina,
- 28:57our surgical oncologist is here and
- 28:59I think I will defer the internal
- 29:02organs questions to her when she when
- 29:04she comes back and there you are.
- 29:07But maybe you can comment
- 29:09on your coastal melanomas a little bit.
- 29:12It's a slightly different question, but
- 29:14sure, yeah, so mucosa, Melanoma,
- 29:17you know this is the the.
- 29:20Any surface of the body, the vagina,
- 29:22the oral mucosa, nasal mucosa.
- 29:25These melanomas can occur there.
- 29:27They're obviously not the sun bearing skin
- 29:29that you might expect to find a Melanoma.
- 29:32So the genetics of this
- 29:33is a little bit different,
- 29:34but the surgical option still remains.
- 29:38Usually there's some upfront imaging that
- 29:39is done before an operation will happen
- 29:41on that maybe a pet scan or a CAT scan,
- 29:44but the surgical procedure
- 29:46itself is very similar.
- 29:47We can still remove the mucosal
- 29:49Melanoma and a lymph node.
- 29:51Biopsy can actually still be.
- 29:53Performed as well.
- 29:54The mapping is slightly different,
- 29:56but the genetics of this is different.
- 30:00Time. Thank you so much Jim.
- 30:02That was a terrific talk.
- 30:04Wonderful work that you're doing and
- 30:06our next speaker is Doctor Kelly Alina,
- 30:10who's an assistant professor of surgery,
- 30:12and she's going to be talking to us
- 30:16about various approaches to treat
- 30:18the to treat patients with systemic
- 30:21therapy prior to the surgery.
- 30:24So thank you so much, Kelly.
- 30:27Floor is yours.
- 30:29So this is a usually II.
- 30:31It's much better when Doctor Kuhn and
- 30:33I are in person because Doctor Koon
- 30:35is a plastic surgeon by by train.
- 30:36So I don't know if you can see,
- 30:38but I'm actually 90 years old
- 30:39and Doctor Clune is done.
- 30:40Beautiful reconstruction work on me,
- 30:43but you kind of miss or are running
- 30:45side jokes on zoom a little bit.
- 30:47So this nicely summarized with
- 30:49Doctor Koenig spoke about which
- 30:52is removing our primary tumor
- 30:54and checking the lymph nodes.
- 30:56But there's other situations and and again.
- 30:59Thank you to the plant in the audience
- 31:01for asking the question where the
- 31:02Melanoma is spread and we can feel it
- 31:04in the lymph nodes or it's traveled
- 31:06to other locations like the brain
- 31:09distally in the soft tissue or the
- 31:12skin in the bow can travel to liver lungs.
- 31:16And there's still a role for surgery,
- 31:18but more and more of this is being
- 31:20combined with a lot of the systemic
- 31:23immunotherapy and targeted therapies
- 31:24that my colleagues will talk a
- 31:26little bit more about this later.
- 31:28Give to patients.
- 31:29So back when we didn't have effective
- 31:31therapies that we could get through an Ivy,
- 31:34the checkpoint blockade and some of the
- 31:37targeted therapies that some Members
- 31:39joining us today may actually be been
- 31:41in the clinical trials and currently
- 31:43getting treatment with was that we
- 31:45still had a role for surgery and
- 31:48that role was really limited towards
- 31:50patients who had very limited disease.
- 31:53So if someone had one or two sites,
- 31:56it was reasonable and people would actually
- 31:58live longer just with an operation.
- 32:01But it really wasn't ideal.
- 32:04You could see here it depending
- 32:06upon where those locations,
- 32:08which many times would be internally
- 32:10people who had lymph node or places
- 32:12that were deep in the tissue.
- 32:14The skin they did well with surgeries,
- 32:17people who had spread to the
- 32:19lung or to other sites.
- 32:20They didn't fare as well.
- 32:23And Doctor Krueger and Doctor Schnall,
- 32:25who are with us today, were part of
- 32:28a revolution and that revolution,
- 32:30and they were pioneers,
- 32:31and many members in the audience may
- 32:33have been the immunotherapy astronauts,
- 32:35as I like to refer to them as that were
- 32:38believed in different types of treatment.
- 32:40And really,
- 32:41the revolution came with immune
- 32:43therapy with a class of agents called
- 32:46Checkpoint blockade and it belimumab,
- 32:48and, you know.
- 32:51The research was recently awarded
- 32:53a Nobel Prize for this work and
- 32:55later the development of anti PD.
- 32:57One blockade really were game changers
- 32:59in the history of treatment of Melanoma.
- 33:02When it's spread,
- 33:04the other thing that was really
- 33:06important was the recognition that
- 33:08about half of melanomas also had
- 33:10an Achilles heel and that's called
- 33:12the B reputation which can actually
- 33:14be targeted by a dual treatment
- 33:16with oral therapies and we call
- 33:19these targeted therapies and again.
- 33:21This allowed to have immune therapy and
- 33:24again targeted therapy and surgery.
- 33:26Now in the armamentarium that
- 33:29we can combine in new
- 33:32and novel ways for patients.
- 33:35So many people would think with all of these
- 33:38developments that we actually operate less.
- 33:40And I actually think that we have a whole
- 33:42host of new opportunities and patients
- 33:45whom sometimes we would begin with
- 33:47treatments that were given through the Ivy,
- 33:50the systemic treatments and now have
- 33:52opened up new opportunities for surgery.
- 33:55Now there's other more special circumstances
- 33:57that I want to touch on when patients
- 33:59come in with more advanced disease.
- 34:01So for example, a person who comes
- 34:03in with a Melanoma and we can.
- 34:05Actually feel it in the lymph
- 34:07nodes during a clinic visit.
- 34:09When we had some patients who
- 34:11come in with multiple spots of
- 34:13Melanoma that we can see and feel,
- 34:15or those that have spread to an organ.
- 34:19So. Are typical.
- 34:20Way that things had been used was that
- 34:24we would do an operation at Doctor Clone,
- 34:27describe,
- 34:27get a lot of information,
- 34:29and then afterwards we would
- 34:31be giving treatment with immune
- 34:34therapy or a targeted agent, but.
- 34:36More people started to question to say,
- 34:39well if we have people who have a
- 34:42little bit more of a risky disease,
- 34:44does it make sense to give them
- 34:46treatment first to see what happens?
- 34:48While we can still have the tumors in
- 34:50place and then follow that by surgery
- 34:53and there was a move over the last
- 34:56few years towards this and Melanoma
- 34:58was a little bit later to the game.
- 35:00But again,
- 35:01there's other cancers like breast cancer
- 35:03where this is actually quite common.
- 35:05So again,
- 35:06what would be the advantage is one
- 35:07you can determine responses to therapy
- 35:09while the tumor is still in place,
- 35:12potentially reduce the size of the
- 35:14tumor before it becomes an operation.
- 35:17There's again,
- 35:17this is a little controversial
- 35:19about whether or not the responses
- 35:21that we see to the immune system to
- 35:23recognize the tumor may be better.
- 35:25Again,
- 35:25I think that's still a little
- 35:27bit subject to debate.
- 35:28The other thing that it does is it allows us.
- 35:31As for research,
- 35:32in order to really study these responses.
- 35:35More in a real time setting,
- 35:38and there's again a little
- 35:40controversial about whether or not
- 35:42this actually leads to a decrease
- 35:44in early recurrences in patients
- 35:46who are deemed to be higher risk.
- 35:49So beginning in 2019,
- 35:50one of the first what we call a neoadjuvant,
- 35:54which means that you'd give the
- 35:56treatment before the surgery
- 35:58was with the targeted agents.
- 35:59Again,
- 36:00people who had the B RAF mutation
- 36:03and what they did was.
- 36:04They gave patients and these are given.
- 36:08Daily,
- 36:08so the Dubrovnik has given actually
- 36:10usually 150 milligrams twice a day,
- 36:12so a total of 300 milligrams and then
- 36:14the train Aetna 2 milligrams daily.
- 36:16They gave it to the patients for 12 weeks.
- 36:19They took about a week off,
- 36:20had surgery and then about two
- 36:22weeks later than they finished
- 36:23off the course of a year,
- 36:25then receiving the agent and they said,
- 36:26well,
- 36:27how do these patients do
- 36:28so? They noted that in about 86% of
- 36:32the patients what they had removed and
- 36:33in this case these were just people
- 36:36who presented with large lymph nodes,
- 36:38they shrunk. And when they looked
- 36:40underneath the microscope to say,
- 36:41did all of the Melanoma resolved would
- 36:44that's called a pathologic complete response
- 36:46that happened in almost half of the patients,
- 36:50but with everything in life
- 36:51there's always a tradeoff, right?
- 36:53So again, we many of our patients will
- 36:55be the first one to tell you is that you
- 36:58know what are the costs of treatment,
- 37:00and we usually measure that in not
- 37:02necessarily just financial costs,
- 37:04but the toxicity that can be
- 37:06associated with that.
- 37:07So in this case there was about 30.
- 37:09Percent of patients who had toxicity,
- 37:11which we call grade 3,
- 37:12which is enough that you have to go.
- 37:14The doctor sometimes be brought into
- 37:16the hospital and what they did is when
- 37:18they looked at patients over two years,
- 37:20about 43% or so.
- 37:23Actually had some recurrences
- 37:27when we look at.
- 37:29Immune therapy again,
- 37:31very small studies.
- 37:32Again,
- 37:33we're still getting more of this information.
- 37:34The first one used a combination of two
- 37:37different types of checkpoint blockade and
- 37:40compare that to a single agent and again.
- 37:43Again, looked and said,
- 37:44did we see a response when people looked
- 37:47at X rays and CAT scans and so forth?
- 37:49What did it look like underneath
- 37:51the microscope and the combination
- 37:53actually had more complete responses.
- 37:55So where where you looked you
- 37:57didn't see alive Melanoma cells
- 37:58underneath the microscope?
- 37:59But again,
- 38:00this is really stark in that three
- 38:03out of four people got serious
- 38:06toxicity and when one looks at again
- 38:08over a two year period of time,
- 38:1180% of those and again these
- 38:13these data keep getting.
- 38:14Updated as we as we learn more and more.
- 38:17Didn't have any of the Melanoma
- 38:19progress or comeback compared
- 38:21to when we just gave a single
- 38:23one of the checkpoint blockades.
- 38:25This is the anti PD one.
- 38:26Agent were again much less toxicity
- 38:29but you know people did not have as as
- 38:33long of a recurrence free survival.
- 38:38Again, now people have looked at this with.
- 38:42Different combinations,
- 38:43again,
- 38:43trying to find a combination
- 38:45for which things work well where
- 38:48we get really great responses,
- 38:50but we have more minimal toxicity and
- 38:53this dose here in highlighted here
- 38:56at B which is the PD one agent giving
- 38:58that at a higher dose in a lower
- 39:01dose of the implement which is a CTA
- 39:04for agent translates over to here,
- 39:06which is the best response with
- 39:08the least amount of toxicity and
- 39:11this combination.
- 39:12Is actually now being actively
- 39:14looked at in ongoing clinical trials.
- 39:17Again,
- 39:18trying to get the most amount
- 39:21of benefit again,
- 39:22we could probably debate for hours,
- 39:24the utility and where we
- 39:26think the field is going.
- 39:27But again,
- 39:28I think it's really important to
- 39:30talk about these things as some
- 39:32clinical trials will also be opening
- 39:35up. Now this is a more recently published.
- 39:39Compilation, so there's been six of these.
- 39:41What we call neoadjuvant trials.
- 39:43Two have used the targeted agents and four
- 39:45have used the immune therapy and one of the
- 39:48things that people are starting to look at.
- 39:51And again, this is combining all those trials
- 39:54together is when we look after we remove
- 39:57the tumor underneath the microscope does.
- 39:59What we see that pathologic response,
- 40:02whether or not the tumor looks
- 40:03like that it's been killed by the
- 40:06therapies underneath the microscope,
- 40:08does that translate into
- 40:09how people are doing,
- 40:11and particularly for the targeted therapy,
- 40:15if you did not have one of
- 40:17these very strong responses,
- 40:18people did not do well with the same
- 40:21thing here, with the immunotherapy.
- 40:22So all of these ones over here,
- 40:24these are people who had what we
- 40:25called a path out pathologic response
- 40:27compared to those people who did not.
- 40:30And again,
- 40:30you can see these curves
- 40:32different from across the room.
- 40:36So. The role of surgery
- 40:39in these combinations.
- 40:40Getting the timing right for the right
- 40:42people at the right time and the right order.
- 40:45That's going to be continuing to expand.
- 40:48And again, we always need to be cautious.
- 40:51As I showed you really balancing
- 40:53this with the real side effects that
- 40:55can happen with these treatments.
- 40:57So again, a tremendous amount of
- 40:59research and novel combination
- 41:01therapies are also being used,
- 41:03so I I think that this is going to
- 41:06be an opportunity for ongoing growth.
- 41:08To benefit patients in the future and not
- 41:11to be outdone by Doctor Leventhal's cartoons,
- 41:13here you're smart to see me.
- 41:16Doctor Lewis,
- 41:17I should make this doctor Leventhal
- 41:19these moles in your backs.
- 41:20Definitely look suspicious.
- 41:22So and with that I'll take any questions.
- 41:30Thank you so much, Kelly.
- 41:32I think you have three questions, OK?
- 41:37Two left OK. We talked about the melon
- 41:40on the other organs desmoplastic
- 41:42Melanoma compared to other forms
- 41:45of Melanoma. So on that sure.
- 41:48So desmoplastic Melanoma there,
- 41:50there's actually two varieties,
- 41:52one we call a pure form and when
- 41:54we call them mixed form and what
- 41:56their what they do is they look very
- 41:59differently underneath the microscope.
- 42:00Generally they're thicker and there's more
- 42:03fibrotic tissue in association with those.
- 42:05Now what's interesting is that
- 42:07depending upon which variety you have,
- 42:09one is equally likely to go to lymph
- 42:12nodes much with Doctor Clune has
- 42:14described the other one, really.
- 42:16Doesn't like to go to the lymph nodes?
- 42:19Both of them have the risk of spreading,
- 42:21but interestingly seemed to be
- 42:23more sensitive even to single
- 42:25therapy with immune therapy,
- 42:27so I don't know if that
- 42:29answered your question,
- 42:30but that's a general overview of
- 42:32the world of Desmoplastic Melanoma.
- 42:35Thank you.
- 42:41Train.
- 42:44Hey so, welcome back everyone.
- 42:48We're going to finish off
- 42:49with two additional talks.
- 42:51The first one is from Doctor Tran,
- 42:55who is a medical oncologist and
- 42:57assistant professor of medicine who just
- 42:59joined our group and she's going to be
- 43:01talking to us about systemic therapy.
- 43:03In other words, therapy that's
- 43:05given by Ivy or by mouth.
- 43:08Uhm, for patients who've had this,
- 43:10their their melanomas resected,
- 43:12so take it away, tweet.
- 43:16Thank you so much,
- 43:17Doctor Kluger and my colleague Dr Alino.
- 43:19Perfectly set me up for this logical
- 43:21progression here so the doctor Alina
- 43:23focused a lot of neoadjuvant therapies
- 43:25in Melanoma and I'm gonna have the
- 43:27pleasure to talk to you about sort
- 43:29of what we think of as clinicians
- 43:31when we see a patient with high
- 43:34risk disease of recurrence and what
- 43:36we can do to minimize that risk.
- 43:38So, just in terms of defining
- 43:41exactly what Advent therapy is,
- 43:43we throw a lot of jargon around in
- 43:45our clinic. But just to be clear.
- 43:47We kind of lump sum high risk
- 43:49melanomas into two buckets,
- 43:51meaning either their resectable or their
- 43:54unrespectable in terms of their disease.
- 43:56UM, when you talk about
- 43:59receptable before surgery,
- 44:01any treatment that we use before
- 44:02surgery is considered new adjutant.
- 44:04Any treatment that we've used after
- 44:06surgery we consider atrovent and really,
- 44:08the goals of these treatments
- 44:10either before or after surgery,
- 44:12are a little bit different.
- 44:13So as doctor Alino perfectly laid out,
- 44:16the goals of New Advent.
- 44:17Therapy basically to shrink the tumor,
- 44:20and hopefully if the tumor is smaller,
- 44:22that makes the surgery a little easier.
- 44:24You'll have a higher chance
- 44:26of getting clean margins.
- 44:27We also you get an opportunity to
- 44:30assess the response to therapy.
- 44:31So if your therapies potentially affected,
- 44:33there might be a lot of immune
- 44:36infiltration into any residual tumor,
- 44:38or there might be a complete response.
- 44:39And there's a pathologic response where
- 44:42the tumor is almost obliterated by the
- 44:45effectiveness of there are treatments.
- 44:47They're also one of the additional
- 44:50unique things about treating UM
- 44:52a patient with a tumor already
- 44:54in places that you can help,
- 44:55stimulate or educate the immune system,
- 44:57particularly with RF very
- 45:00effective immune therapies,
- 45:01because they will have access
- 45:04to these tumor neoantigens.
- 45:06In terms of management therapy,
- 45:07though after surgery,
- 45:09potentially all gross or visible
- 45:11tumor is removed and so really
- 45:14we're talking about not treating
- 45:16the actual primary tumor itself,
- 45:18but treating micrometastatic disease
- 45:20that those few clusters of cells that
- 45:23might have hitched along the lymphatic
- 45:25vessels or into the blood that might
- 45:27be hiding out in other areas of the
- 45:29body just waiting for their chance to
- 45:32repair and so active in therapy was
- 45:34really targeted trying to eradicate.
- 45:36Completely,
- 45:37these remaining residual clusters
- 45:38of cells and the whole goal of agile
- 45:42in therapy is to prevent relapse
- 45:44or recurrence and ultimately to
- 45:47improve survival in our patients.
- 45:49This is a little bit different from
- 45:52unresectable or metastatic disease,
- 45:53where it's kind of more of
- 45:57a salvage approach.
- 45:58Trying to control the growth of the tumor,
- 46:00trying to delay progression,
- 46:01trying to improve survival,
- 46:03and maybe with our more effective
- 46:05therapies these days in a small subset.
- 46:07Patients potentially still
- 46:09provide accurate if option.
- 46:12When you focus on your budget in
- 46:14adamant therapy long there are certain
- 46:15limitations that we have to be aware of.
- 46:18So in terms of neoadjuvant therapy,
- 46:20if we give these tumors upfront
- 46:23and delay surgery or
- 46:25curative resection by
- 46:26potentially up to three months.
- 46:29If the tumors don't respond,
- 46:30that could mean that the tumor is
- 46:33growing that entire interval and
- 46:34making the surgery even more difficult
- 46:37to provide a complete resection for.
- 46:39In addition to that,
- 46:41any treatments that we provide.
- 46:42Systemically, have their own side
- 46:44effects and toxicities and so when
- 46:47we have to consider side effects,
- 46:49potentially those side effects
- 46:51may delay the curative surgery.
- 46:54The limitations in the atrovent setting,
- 46:56though, is that you know we're
- 46:58treating a lot of patients,
- 47:00some of whom may never have
- 47:02recurred to begin with,
- 47:03and so you are subjecting a large
- 47:06group of patients to potentially a
- 47:08treatment without the added benefit.
- 47:10Overall,
- 47:11in terms of decreasing relapse or recurrence.
- 47:14These side effects may also significantly
- 47:17impact their quality of life,
- 47:20particularly with immune therapies.
- 47:21Some of these side effects may be permanent.
- 47:25Also,
- 47:25even with the best effective
- 47:27agement therapies that we have,
- 47:29it's not an absolute guarantee that
- 47:31this tumor will not come back.
- 47:33There's also a financial toxicity
- 47:35for these drugs as well.
- 47:37They're not cheap,
- 47:39and ultimately you know it,
- 47:41it ultimately comes down to
- 47:44what insurance will provide,
- 47:46what the patient will put
- 47:47up with opportunity costs,
- 47:49all the visits to the clinic,
- 47:51even beyond just the financial toxicity.
- 47:54There's a lot of time commitment
- 47:56for these patients to come back
- 47:58for agile in therapy for a year,
- 48:00so when we consider effective therapies,
- 48:03you know.
- 48:03What are the drugs that we are
- 48:05using in the adjutant setting?
- 48:07We've applied a lot of the drugs
- 48:09that we know are effective
- 48:10in the metastatic setting.
- 48:12Our question is ultimately if they work
- 48:14so well in the metastatic setting,
- 48:16can they be moved up earlier
- 48:19in higher risk disease,
- 48:20particularly stage three?
- 48:21Disease in in used in that setting
- 48:24so that they can decrease recurrence
- 48:27breast in improves survival and overall
- 48:29the you have to consider sort of
- 48:31the side effects versus the quality.
- 48:34Life from the years gained.
- 48:36When we take a look at stage three disease,
- 48:38we like to subset or sub stage
- 48:41stage three disease into various
- 48:43sub categories as well.
- 48:45Stage 3A where you had the five
- 48:48year Melanoma specific survival,
- 48:50so meaning survival as it just relates
- 48:53to Melanoma as being the cause of death.
- 48:56So five year survival for stage
- 48:593A Melanoma is really good.
- 49:01It's 93% when we consider that over 10
- 49:03years a little bit a lot longer interval,
- 49:06it's.
- 49:0688% if you were taking a quiz.
- 49:09These are passing spores and so you
- 49:12can really see that stage 3A melanomas
- 49:15overall have really good outcomes
- 49:17regardless of adding any additional
- 49:20ajibon therapy in that setting.
- 49:22However,
- 49:22when we move down this list to stage 3B,
- 49:25stage 3C or stage 3D,
- 49:28this drops particularly in stage
- 49:303D disease to a five year Melanoma.
- 49:33Specific survival of 32% in a 10 year.
- 49:36Melanoma specific survival of 24%.
- 49:39These are bismal numbers and
- 49:41so really the objective in
- 49:44Advent therapy is trying
- 49:46to improve these outcomes.
- 49:48When I see a patient in our in our
- 49:50Melanoma medical oncology clinic,
- 49:52you know it's really the stage three
- 49:55Melanoma patients that we focus on.
- 49:57Because this is the cohort of
- 49:59individuals who we think there is
- 50:01an active role for adjutant therapy
- 50:03in improving patient outcomes.
- 50:05So what we take into consideration
- 50:08is the biology, so the pathology
- 50:10that was taken from the biopsy,
- 50:11the wide localists excision,
- 50:13the lymph node assessments that
- 50:15are done by doctors Cloonan dolino.
- 50:18Really, we're looking at the tumor thickness,
- 50:20the number of lymph nodes involved,
- 50:21and overall the stage 3 subtype.
- 50:25In addition to that,
- 50:26we do our standard radio graphic staging,
- 50:29which includes either CT of the chest,
- 50:31abdomen, pelvis, or whole body pet,
- 50:33as well as in brain MRI.
- 50:35And that's really just to make sure
- 50:37that we're dealing with exactly stage
- 50:39three disease and we're not accidentally
- 50:41missing early stage four disease.
- 50:43Now we have a lot of different
- 50:45opportunities and advancements
- 50:47in next generation sequencing
- 50:49for tumor molecular profiling,
- 50:52so this is when we take the tumor
- 50:54that is respected on and you know in
- 50:57the OR and send it for sequencing of
- 51:00various mutations gene amplifications,
- 51:02things that could be potentially
- 51:05targeted in the future.
- 51:07In the most relevant setting in our clinic,
- 51:09though,
- 51:10the most important question for deciding
- 51:12about which adamant therapy to offer
- 51:15individuals is there beer at status,
- 51:17so B rap is a gene typically be wrapped.
- 51:21This specific mutations the V600E or V600K.
- 51:27Indicate that these melanomas
- 51:28are success susceptible to what
- 51:30we consider targeted therapies,
- 51:32so these are actual oral drug
- 51:36treatments that specifically inhibit
- 51:38tumors with harboring this mutation,
- 51:41the one that's FDA approved in this
- 51:43realm is to Bracknell traumatized
- 51:45after we know alluded to.
- 51:47So this is an oral pill that
- 51:49you take for one year.
- 51:50All of these adjectives therapies
- 51:52typically have a duration of
- 51:55one year after the surgery.
- 51:57If you don't have a beer at mutation,
- 51:59so we consider this be rack wildtype,
- 52:01regardless of tumor biomarker,
- 52:03that we look at to assess sensitivity
- 52:06to immunotherapy this PDL.
- 52:09One positive ITI if you're wild
- 52:11type to be raft then the other
- 52:14alternative options are immune therapy.
- 52:16The first one that gained FDA approval
- 52:18was at the gym after your boy.
- 52:20All these immune therapies are
- 52:22intravenous and they're also given
- 52:24over the course of a year too.
- 52:27It blew my map.
- 52:28Interestingly,
- 52:29fell out of favor though because
- 52:31it's highly toxic.
- 52:32About 50% of patients develop
- 52:35serious toxicity to this drug,
- 52:37and it also was later shown that the
- 52:41volume after Opdivo was superior to
- 52:43epulu map in terms of decreasing relapse.
- 52:47Free survival.
- 52:48So really, when we see individuals in clinic,
- 52:52it's really a discussion about new volume
- 52:56app versus pembrolizumab or KEYTRUDA.
- 52:58These are both anti PD one inhibitors,
- 53:01meaning they target the PD one pathway
- 53:04to stimulate the immune system.
- 53:06So these are drugs that activate
- 53:09our own immune system
- 53:10to try to increase cytotoxic T
- 53:13cell activity to basically find
- 53:15and destroy the cancer cells.
- 53:18Uhm, the other alternative option
- 53:20that will talk about a little bit
- 53:23too is clinical trial opportunities
- 53:25in the advanced setting as well.
- 53:27So when we talk about relapse free survival,
- 53:30we're gonna make you guys all experts and
- 53:32looking at these curves in a little bit.
- 53:35But what we're looking for is
- 53:37separation of the curves and the higher,
- 53:40the greater the degree of separation,
- 53:42the higher the clinical potential,
- 53:43clinical impact in differences
- 53:46in those treatment arms.
- 53:48So in the first iteration
- 53:50of these immune therapies,
- 53:51so it believe map was compared to placebo,
- 53:54and you can see in terms of
- 53:56decreasing recurrence, free survival.
- 53:58It blew my map,
- 53:59was superior to just a miss placebo
- 54:03care later on and I tell you,
- 54:05This is why if aluminum at fell
- 54:08out of favor when the volume at was
- 54:10compared to Apple map new volume at
- 54:13out be out competed at Blue Man.
- 54:15Additionally the one additional added
- 54:17benefit was that with new volume
- 54:20app the serious grade toxicities
- 54:23decreased to about 1415% versus 50%
- 54:26of patients in the clinical trials.
- 54:28Later on,
- 54:29Campbellism ever was also compared
- 54:31to standard of care,
- 54:32and so pembrolizumab also did trade
- 54:35and increase benefit in terms of
- 54:38decreasing relapse. Free survival.
- 54:40Now this is for those individuals who
- 54:44have a beer at least 600 E or V600K mutation.
- 54:48They were eligible to receive
- 54:50treatment with these oral drugs
- 54:51called graph Neb and Trim Aetna,
- 54:53and what's striking here is that
- 54:56these curves really do separate
- 54:58out and we see a robust improvement
- 55:00and we left pretty survival with
- 55:03these B RAF MEK inhibitors.
- 55:06When we look at overall survival though,
- 55:08it's not so much of a clear picture.
- 55:12With these immune therapies,
- 55:13there's a lot of crossover
- 55:15in terms of these curves,
- 55:17indicating that the benefit in terms
- 55:20of these immune therapy drugs in
- 55:23reducing or improving overall survival
- 55:25is very minimal, and so with the volume up,
- 55:28and it blew my map.
- 55:30Basically these curves overlap with
- 55:32pembrolizumab versus standard of care.
- 55:34These curves also basically overlap.
- 55:36It's really what their brand new band Trim,
- 55:38Aetna,
- 55:38again with these patients who Harbor B RAF.
- 55:42Mutations that have a ongoing improvement
- 55:45in overall survival years out this data.
- 55:49You know the best as as these
- 55:53data mature for on and on.
- 55:55Who knows, it may be a separation.
- 55:57In our clinic.
- 55:59We don't really think that these
- 56:01there is a significant impact or
- 56:04in improving overall survival with
- 56:06immune targeted therapies like there
- 56:08is with B raft targeting therapies.
- 56:11So when we have an individual patient
- 56:13and their family in front of us,
- 56:15you know what are the basic
- 56:17considerations that we have to
- 56:18take into account when deciding on
- 56:20a personalized regimen for them.
- 56:22We really have to take into account
- 56:24the individual, you know what are there.
- 56:25Priorities, what are there you know?
- 56:29What is the emphasis on their
- 56:30current quality of life
- 56:32and how to maintain that?
- 56:33What are there other medical corner Bilitis?
- 56:36Do they have a history of autoimmune disease
- 56:38that we could potentially exacerbate
- 56:40with these immune activating drugs?
- 56:42You know what their comfort
- 56:44is with surveillance versus a
- 56:46desire to be aggressive up front.
- 56:48And overall again, going back to cost
- 56:50and this is not just financial costs.
- 56:52This is, you know, time off of work
- 56:55time is spent in the clinic with us.
- 56:57Uhm, I know you guys like us.
- 56:59There are no substitute for, you know,
- 57:01you're awesome families and spending
- 57:03time out on the doing your hobbies and
- 57:06living your life and so this is a this
- 57:08is quite a considerable cost to spend
- 57:10an additional year in and out of our clinic.
- 57:13Getting ongoing treatments and
- 57:15again the the question is,
- 57:17you know, not all patients.
- 57:19Uhm, derive the same exact
- 57:21benefit from these medications.
- 57:23So in addition to factors on the individual,
- 57:26there are also two more factors
- 57:28that we take into account,
- 57:29such as B raft status,
- 57:31what other aggressive,
- 57:32pathological features that might
- 57:33be in the tumor,
- 57:35such as you know,
- 57:36the number of mitotic cells that
- 57:38don't really get into factored
- 57:40into our current staging criteria.
- 57:42And really our emphasis on trying
- 57:43to focus on the individuals who have
- 57:46the higher stage stage three disease.
- 57:48Those that are really.
- 57:50Higher risk of having a great parents
- 57:53and decreased overall survival
- 57:55due to recurrence.
- 57:56So going back to our original diagram here,
- 57:59you know it's pretty clear that with
- 58:01the B raft targeting drugs you know
- 58:04these are effective in decreasing
- 58:06recurrence and improving survival.
- 58:09Plus the side effects here if they
- 58:11do occur are pretty reversible.
- 58:14You know these are all drugs,
- 58:15they tend to side effects,
- 58:17tend to improve after withdrawal
- 58:19of the drugs if needed,
- 58:21whereas with immune therapy were
- 58:23really edgy reeducating the
- 58:25immune system to go after these.
- 58:27Tumors,
- 58:27and so sometimes when they when
- 58:29we push the immune system to the
- 58:31opposite end of the spectrum and
- 58:33cause a lot of side effects in
- 58:35terms of autoimmune toxicities,
- 58:37potentially these side effects
- 58:39are irreversible.
- 58:41They all tend to show that there
- 58:43is a decrease in recurrence,
- 58:44but still the data is not very
- 58:47indicative that it really long term
- 58:49improves survival for these folks,
- 58:52so really kind of the next step
- 58:53way and what you know.
- 58:54Dot my colleague Dr Issues UK
- 58:56is going to focus on is.
- 58:57How can we check all of these
- 59:00boxes here where you know they
- 59:02will with newer drug targets,
- 59:06we can potentially have something
- 59:08that doesn't have prolonged or
- 59:10irreversible side effects that it
- 59:12will decrease recurrence that it
- 59:14will improve survival, you know?
- 59:16So we're always developing our
- 59:18clinical trial program at Yale.
- 59:19Most recently we did have a phase.
- 59:23And an Advent clinical trial with Madonna.
- 59:28And yes,
- 59:28this is the same order that came
- 59:29up with the code.
- 59:30One of the COVID vaccines that's
- 59:33been really effective
- 59:34using the same exact technology.
- 59:36Basically an M RNA vaccine that
- 59:39is engineered specifically
- 59:40to NEO antigens or epitopes.
- 59:43These sophistic to protein tags that are
- 59:45present in the tumor patient tumor samples.
- 59:48And really using that as a target
- 59:51in combination with pembrolizumab,
- 59:52one of the immune.
- 59:53Therapies to try to stimulate the immune
- 59:57system against individual specific Melanoma.
- 59:59So really interesting client,
- 01:00:01typically, unfortunately,
- 01:00:02that trial is now closed to additional
- 01:00:05accrual accrual at our site, but,
- 01:00:08uhm, you know one of the ongoing
- 01:00:10things is how can we make our
- 01:00:12clinical program more robust?
- 01:00:13Do you know encouraging these
- 01:00:15clinical trials which are really
- 01:00:18scientifically interesting?
- 01:00:23Thank you so much we.
- 01:00:25I think there are two questions for
- 01:00:26you before we move on to the last talk.
- 01:00:28One is if you could just elaborate a
- 01:00:31little bit about the permanent toxicities
- 01:00:33and whether all people are tested
- 01:00:35for beer at the time of diagnosis.
- 01:00:39Sure, so the immune related toxicities,
- 01:00:42UM it. Interestingly,
- 01:00:43on some of these clinical trials
- 01:00:45is particularly with the pendulum,
- 01:00:47have active in therapy,
- 01:00:48and if aluminum app treatment,
- 01:00:51some of those patients who had curative
- 01:00:53resections and were technically disease
- 01:00:56free did have irreversible toxicities.
- 01:00:59And there were some deaths reported
- 01:01:01on these adjutants studies.
- 01:01:02So one death on an Advent
- 01:01:04study is one death too many.
- 01:01:06These are patients who potentially cured.
- 01:01:09Of their disease and we really just
- 01:01:11trying to focus on decreasing relapse.
- 01:01:14And again,
- 01:01:14this kind of goes back to the point
- 01:01:16of what we're trying to emphasize is
- 01:01:18really trying to figure out who would
- 01:01:20benefit the most from these therapies
- 01:01:23and maybe develop future better
- 01:01:27predictive algorithms or biomarkers
- 01:01:29to really identify individuals
- 01:01:31at most most at risk for relapse.
- 01:01:34Come in addition. So the other question.
- 01:01:38Dr.
- 01:01:38Cleaver was.
- 01:01:40Does everyone get tested for? BRF yes,
- 01:01:43thank you reminder.
- 01:01:44So at our institution with anyone
- 01:01:47with the phase three or even the
- 01:01:50high risk stage stage two or in
- 01:01:53all stage three Melanoma really,
- 01:01:55yet uhm molecular profiling
- 01:01:57done on their tumor in advance.
- 01:02:00And so this molecular profiling.
- 01:02:01Depending on the panel that your
- 01:02:04medical oncologist orders typically
- 01:02:06will also include byref testing
- 01:02:08and so that is very routinely.
- 01:02:10Donna understood institution.
- 01:02:11It's good to have that information
- 01:02:13up front in our back pocket in
- 01:02:15case we need to fall back on it,
- 01:02:17and particularly in in folks
- 01:02:19with stage three disease.
- 01:02:21UM, really byref targeting his
- 01:02:23sort of demonstrated the best in
- 01:02:26terms of decreasing relapse and
- 01:02:29improving overall overall survival.
- 01:02:33Thank you so much. Tweet.
- 01:02:35It was a great talk.
- 01:02:36Thanks for everything and I'm going
- 01:02:37to introduce our last speaker,
- 01:02:39but certainly not least not least,
- 01:02:42Doctor Jeff Ishizuka is going to
- 01:02:44be talking to us about research,
- 01:02:47clinical trials, and what we're
- 01:02:49planning to do for advanced Melanoma.
- 01:02:51Some Melanoma that's already spread, so.
- 01:02:53Jeff is an assistant professor of medicine.
- 01:02:56He's in medical oncologist and
- 01:02:58a physician scientist Jeff.
- 01:02:59The floor is yours.
- 01:03:03Thank you so much, I'm happy to be
- 01:03:05here tonight talking a little bit
- 01:03:07about research and clinical trials,
- 01:03:09and you know some of these topics
- 01:03:11have come up a little bit through
- 01:03:13Doctor Lena or Doctor Trans talks.
- 01:03:15And and we'll revisit those
- 01:03:16and try and go one cut deeper.
- 01:03:22So I think there are three major
- 01:03:24points that I want to cover tonight.
- 01:03:26The first is the kind of Melanoma
- 01:03:28research we do at Yale to try to kind of
- 01:03:31pull back the curtain a little bit and
- 01:03:33let you know the research activities.
- 01:03:34The breadth of research activities
- 01:03:37that are going on here.
- 01:03:39The second is to think about clinical trials.
- 01:03:40Think about why, why you might participate.
- 01:03:43You know what some of the factors
- 01:03:45that go into the decision to
- 01:03:46bring a clinical trial to Yale,
- 01:03:48and you know the factors that might.
- 01:03:51Induce somebody to want to
- 01:03:53participate in clinical research.
- 01:03:54And then finally just briefly to touch
- 01:03:57upon some of the clinical opportunities
- 01:04:00that are either available or coming
- 01:04:02soon into the clinical trial portfolio.
- 01:04:05Things that we're particularly
- 01:04:06excited about for the future and
- 01:04:08to give you a sense of where we
- 01:04:10might be going as an institution.
- 01:04:13So, so first, what kind of Melanoma
- 01:04:15research is happening at Yale?
- 01:04:17And I would say that there
- 01:04:18are three basic kinds,
- 01:04:20starting with basic research.
- 01:04:21Basic research is research that that
- 01:04:24really ask questions about fundamental
- 01:04:26mechanisms and cancer and related biology.
- 01:04:28So how does cancer development spread?
- 01:04:31How does the immune system
- 01:04:32recognize and eliminate tumors?
- 01:04:34What is the genetic basis for cancer?
- 01:04:36There are a lot of questions,
- 01:04:37but they're they're really on this
- 01:04:38kind of fundamental end of things,
- 01:04:40and you know, they there may be some some.
- 01:04:42Aspects that are applied,
- 01:04:44but it's potentially a little
- 01:04:45bit further back from the most
- 01:04:47applied research that would be
- 01:04:49the most immediately beneficial
- 01:04:51on the other end of the spectrum.
- 01:04:52There's clinical research,
- 01:04:54so that's that's collaboration with
- 01:04:56you with patients and this directly
- 01:04:58tries to advance the development
- 01:05:00of new treatments or understand or
- 01:05:03improve experiences and and understand
- 01:05:05patterns of incidents and outcome
- 01:05:07so you know is a new therapy better
- 01:05:09than current standard of care.
- 01:05:10How can our care of patients here at.
- 01:05:12That's my little be improved.
- 01:05:14Those are the types of questions
- 01:05:15that one might ask you in clinical
- 01:05:17research and between the two you
- 01:05:18have translational research and
- 01:05:19the goal of translational research
- 01:05:21is is really everything in between
- 01:05:23is to bridge the gap between basic
- 01:05:25research and clinical research.
- 01:05:26You know,
- 01:05:27can we predict from patient two
- 01:05:28more blood samples who will benefit
- 01:05:30from a given treatment.
- 01:05:31Some aspects of basic questions,
- 01:05:33basic biology,
- 01:05:34but also things that we might be
- 01:05:36able to apply readily in the clinic.
- 01:05:39So as a case study for this and
- 01:05:41for how research works at Yale,
- 01:05:43I did want to return to the idea of
- 01:05:45these immuno therapies and these
- 01:05:47have come up in in both Doctor
- 01:05:49Trans and Doctorale knows talks and
- 01:05:51and I believe Dr Alino actually
- 01:05:52mentioned you know called him a sort
- 01:05:54of a revolution and I don't think
- 01:05:56that's exaggerated because I think
- 01:05:58compared to some of the therapies
- 01:05:59that that came before you know it
- 01:06:02was such a seachange and
- 01:06:04what we're able to offer when
- 01:06:07these therapies were approved.
- 01:06:09And you know, I'm not going to go
- 01:06:10deep into the basic biology here,
- 01:06:12but as was previously mentioned,
- 01:06:14the big breakthrough, I think,
- 01:06:16was that the immune system was capable
- 01:06:18of recognizing and eliminating tumors,
- 01:06:20and in particular T cells in
- 01:06:22the little blue BLOB here,
- 01:06:24you know, had the potential to
- 01:06:27attack and destroy tumor cells,
- 01:06:29and that what was going on was
- 01:06:31that in many cases the brakes
- 01:06:32were on the immune system.
- 01:06:34There were inhibitory pathways like
- 01:06:36the little red arrow points out
- 01:06:37that we're stopping the T cells.
- 01:06:39From expanding and attacking cancer
- 01:06:41and and so the breakthrough came when
- 01:06:43people realize that you can use antibodies,
- 01:06:45drugs, that you give in the veins
- 01:06:47to block these inhibitory pathways,
- 01:06:49to kind of unleash the T cells,
- 01:06:50allow them to proliferate and
- 01:06:53to attack the tumor cells.
- 01:06:55And this was a massive improvement
- 01:06:57over over many of the prior therapies.
- 01:06:59Overall less toxic and more effective
- 01:07:02and I have to say I was still
- 01:07:05in training when some of these
- 01:07:07therapies were first developed.
- 01:07:09And approved and you could really
- 01:07:11see the changes.
- 01:07:12And in clinical practice and
- 01:07:14what we're able to offer.
- 01:07:16Ultimately,
- 01:07:16this was an advance that started in Melanoma,
- 01:07:18but has spread to many other tumor types.
- 01:07:22But but a lot of the key components
- 01:07:24to this advance were actually
- 01:07:26occurred at Yale or with the help of
- 01:07:29Yale scientists and physicians and
- 01:07:31patients treated at yellow as well.
- 01:07:33And so I'll take you through that
- 01:07:36a little bit,
- 01:07:37but but even as I talk about it,
- 01:07:39you know openly acknowledged that
- 01:07:41although you know although these
- 01:07:43drugs are were in our are great in
- 01:07:45some regards we've talked about,
- 01:07:47there's there's still too toxic and
- 01:07:48they're still not affected for everybody.
- 01:07:50And so everybody on this team goes
- 01:07:51to bed at night and wakes up in the
- 01:07:53morning most days thinking about this
- 01:07:55and thinking about how we can make it better.
- 01:07:57And that's really at the heart
- 01:07:59of what research is here.
- 01:08:01And,
- 01:08:01you know,
- 01:08:02I think what research should be a Melanoma.
- 01:08:05So you know just to go to just to
- 01:08:07talk you through the human side of this.
- 01:08:09I mentioned basic research,
- 01:08:10translational research and clinical research
- 01:08:12and and how important these drugs were.
- 01:08:14Well,
- 01:08:15you know a lot of the people who are at
- 01:08:17Yale made critical contributions to this.
- 01:08:19So so Liping Chen is is,
- 01:08:22uh,
- 01:08:22you know,
- 01:08:22works on more on the basic side,
- 01:08:24but did some of the fundamental
- 01:08:26research that helped identify the
- 01:08:28basic pathway and immune cells
- 01:08:30recognize in the very early days,
- 01:08:32decades ago that it could be important for.
- 01:08:35Cancer Marcus Bosenberg helped
- 01:08:36to define some of the genetics,
- 01:08:38and was built preclinical models
- 01:08:41and and research infrastructure
- 01:08:42here that has provided a basis for
- 01:08:45studying a lot of these therapies
- 01:08:46and moving them forward.
- 01:08:47The animal models David Rim
- 01:08:49is one of the most
- 01:08:50kind of prominent people.
- 01:08:52The field also here at Yale
- 01:08:54as a pathologist to you know,
- 01:08:56has been leading the search for
- 01:08:57biomarkers in patient populations,
- 01:08:59who who will benefit is, you know,
- 01:09:01one of the most world renowned people
- 01:09:02at this and then Harriet and Mario.
- 01:09:05Who are hosting tonight really played
- 01:09:07a leadership role in the clinical
- 01:09:10development of these drugs and you know,
- 01:09:12did so really in collaboration,
- 01:09:15collaboration with yellow patients,
- 01:09:17and so you know just to talk a little
- 01:09:21bit more about clinical research and
- 01:09:23the role that it has played in can play.
- 01:09:26You know, I wanted to address this
- 01:09:28issue of why you might participate
- 01:09:30in clinical research, and you know,
- 01:09:32as already mentioned,
- 01:09:33a lot of you don't need this answered.
- 01:09:34Many people actually have participated
- 01:09:36here already and played this
- 01:09:38important role in moving it forward.
- 01:09:40But I think it's worth going
- 01:09:42through because it's important and
- 01:09:43I would say that there were there
- 01:09:45are kind of three big reasons.
- 01:09:46The first one is is the team and I've
- 01:09:48talked about some of that team already,
- 01:09:50but I I can expand on that a little
- 01:09:51bit 'cause I think we have a great
- 01:09:53team here that's able to provide
- 01:09:54support and and do this the right way.
- 01:09:58A really importantly because it
- 01:10:00increases options for treatment and it
- 01:10:02it hopefully puts an option that makes
- 01:10:04an option available that is a better
- 01:10:06option than any other that we have.
- 01:10:08And then finally because it can help to
- 01:10:10speed the development of new treatments.
- 01:10:12And so I'll talk about each
- 01:10:14of these a little bit.
- 01:10:15So regarding team,
- 01:10:16I've already mentioned a lot of
- 01:10:18the people on the top row here,
- 01:10:20so you know these are some of
- 01:10:22the senior people who have have
- 01:10:24laid the foundation for a lot of
- 01:10:26the therapies that we have today.
- 01:10:28Provided a research infrastructure for
- 01:10:30understanding what trials might be
- 01:10:33the most beneficial for patients and
- 01:10:35and and might be the most helpful and
- 01:10:38and I have to say that the experience
- 01:10:40and expertise that that this group brings,
- 01:10:43you know is, I think,
- 01:10:45a really important part of why
- 01:10:46doing clinical trials here.
- 01:10:47It may make sense.
- 01:10:49I will say that you know,
- 01:10:52for myself or my family,
- 01:10:54I would want people like the leadership
- 01:10:56of this clinical research team,
- 01:10:58sort of.
- 01:10:58Helping to select the trials and
- 01:11:00decide which ones are the most
- 01:11:02likely to lead to benefit.
- 01:11:04We you met some of us tonight.
- 01:11:06Some of the other.
- 01:11:07Some of the folks who are also or are
- 01:11:09active in participating clinical research,
- 01:11:11bringing trials forward or
- 01:11:12helping to enact them.
- 01:11:13But usually it's not just the
- 01:11:15people on this side either,
- 01:11:17it's it's an entire research staff,
- 01:11:19and any of you have participated
- 01:11:21in clinical trials.
- 01:11:21Know this, but research nurses,
- 01:11:24you know,
- 01:11:25dedicated research staff that helped
- 01:11:27the trials to to open the tracks.
- 01:11:29Safety that are,
- 01:11:30you know,
- 01:11:31patient facing that may provide
- 01:11:33additional care or do safety
- 01:11:35labs and make sure that we can do this
- 01:11:38in a way that that maximizes safety and
- 01:11:41the chance of having a good outcome.
- 01:11:44So I think the team here is one reason,
- 01:11:46but ultimately I think you
- 01:11:48know as you think about this.
- 01:11:51Participation in clinical trials is
- 01:11:53always just a choice and a personal
- 01:11:55choice that has to be made with
- 01:11:57input from from your physician.
- 01:11:59But and also your family,
- 01:12:00and every trial isn't right for everyone.
- 01:12:03It's true that not all trials
- 01:12:04succeed in that new drugs can have
- 01:12:06new toxicities and side effects.
- 01:12:07That's always a risk and a reason that we
- 01:12:10do extra lab tests and have extra visits,
- 01:12:12which is again a potential challenge
- 01:12:14in participating even the best drugs
- 01:12:17don't always benefit every patient.
- 01:12:19In fact, they don't generally benefit all.
- 01:12:21Patients, but you know, I think.
- 01:12:24I think as you think about this
- 01:12:27with your physician.
- 01:12:28Your physician will only put in front
- 01:12:30of you trial options that they think are
- 01:12:32at least as good and hopefully better
- 01:12:35than the alternative options that you
- 01:12:37may consider and and you know as an example,
- 01:12:41I'd return to the development of
- 01:12:43immunotherapy for Melanoma patients
- 01:12:45at Yale were receiving these drugs
- 01:12:47and had access to them years before
- 01:12:48they were approved for general use.
- 01:12:50So you know potentially had an option in
- 01:12:52front of them that that could be valuable,
- 01:12:55and it's one of the major reasons to
- 01:12:57pursue care at a tertiary care center.
- 01:13:00The larger care center likes Milo,
- 01:13:03so increasing options is an important
- 01:13:05reason to think about clinical trials.
- 01:13:07And then finally that we think this
- 01:13:10can help dispute the development
- 01:13:12of new treatments.
- 01:13:13And I know that in some ways
- 01:13:14that's a lot to to think about.
- 01:13:16For you know you're facing a cancer
- 01:13:18diagnosis and now all of a sudden
- 01:13:20you're fighting that cancer for everyone
- 01:13:22else who has or may one day get it.
- 01:13:24And yet many, many patients.
- 01:13:26Many of you do,
- 01:13:28and I guess the the way that I think
- 01:13:30about it is that this thing we're
- 01:13:32trying to move cancer and Melanoma,
- 01:13:35so it's so big and implacable
- 01:13:37that that none of the you know
- 01:13:39people I've presented to you.
- 01:13:40None of us could do it alone, but.
- 01:13:42You know everyone is sort of
- 01:13:44shoulder up to it and pushing,
- 01:13:46and it's not good enough or
- 01:13:48fast enough by half, but it is.
- 01:13:50It is moving and it's moving
- 01:13:52because because of you,
- 01:13:53and because everyone pushes together
- 01:13:56so you know always has to be the right
- 01:13:58choice in that you know personal decision.
- 01:14:01Depending on the clinical context
- 01:14:03and the availability of an option,
- 01:14:05that is the best option available.
- 01:14:07But you know,
- 01:14:08I think collectively also moves forward.
- 01:14:12And and I wanted to just wrap up a
- 01:14:14little bit by by talking about some
- 01:14:16of the clinical trials that were
- 01:14:18particularly excited about some of
- 01:14:20the areas of focus that are either
- 01:14:22active trials or you know,
- 01:14:24areas that we are are have studies
- 01:14:27opening up in in the near future,
- 01:14:30and the first is this idea of CD40,
- 01:14:32agonism and and, you know,
- 01:14:34Doctor Krueger and Doctor Lino and others
- 01:14:37have done really interesting work here,
- 01:14:39and the basic question here is.
- 01:14:41OK, so I told you that T cells are
- 01:14:43important cells for attacking tumors and
- 01:14:45that you can block receptors and kind of
- 01:14:47get them fired up to attack the tumor.
- 01:14:49But what about the rest of
- 01:14:51the immune system, right?
- 01:14:52And so CD 40 is sort of a receptor that
- 01:14:55is present on a number of a number of cell
- 01:14:57types at a number of other immune cells,
- 01:15:00and it was found that actually by stimulating
- 01:15:02rather than blocking this receptor,
- 01:15:04that you can kind of get the rest
- 01:15:06of the immune system fired up and
- 01:15:08so one of the hopes is that by
- 01:15:10adding this type of drug to the.
- 01:15:12Drugs that are currently available to
- 01:15:14take the brakes off the immune system
- 01:15:16that you may get a better effect.
- 01:15:18So that's an area of active study here.
- 01:15:20Another one.
- 01:15:21Are there other ways the Union system
- 01:15:23is controlled and suppressed in tumors,
- 01:15:26and so this is another discovery that's
- 01:15:28really taken place here at Yale,
- 01:15:29and this is Erin Ring,
- 01:15:31who is a scientist here.
- 01:15:32Also a physician, although not practicing,
- 01:15:34but a scientist who really made this
- 01:15:36discovery and and really what he
- 01:15:38found out is there are are are kind
- 01:15:41of molecules that are secreted by
- 01:15:42immune cells that have the potential
- 01:15:44to activate the immune system and make
- 01:15:47it more effective against cancer.
- 01:15:48However,
- 01:15:49there are also mechanisms that are
- 01:15:51built into those molecules that
- 01:15:52shut them down so that and I think
- 01:15:55probably you know if you're trying
- 01:15:57to provide an explanation for that.
- 01:15:59The reason is to avoid kind of over
- 01:16:01activation of the immune system
- 01:16:03and different types of situations,
- 01:16:05but what what Aaron did is he found
- 01:16:08out that if you get rid of those
- 01:16:11kind of inhibitory interactions
- 01:16:12on these secreted molecules,
- 01:16:14that you actually get a better
- 01:16:16immune response against cancer,
- 01:16:17and actually in the preclinical models.
- 01:16:19That you don't get a lot of toxicity
- 01:16:21that it appears to be safe,
- 01:16:23and so this is some another kind
- 01:16:25of approach that looks incredibly
- 01:16:26promising for stimulating immune
- 01:16:28system to fight cancer.
- 01:16:30That is kind of being developed
- 01:16:32into clinical trials here.
- 01:16:35And then the last one
- 01:16:35I'll highlight is is this,
- 01:16:37which is a tumor infiltrating lymphocytes.
- 01:16:40And so this is a little bit more complicated
- 01:16:43as a therapeutic paradigm for the others.
- 01:16:45We might just give something through an Ivy.
- 01:16:47And even if the immunology and the
- 01:16:49science is a little bit complicated,
- 01:16:51the delivery is pretty straightforward.
- 01:16:53In this case the delivery is actually
- 01:16:55a little bit complicated too,
- 01:16:56but what it all aims at is this question
- 01:16:58of what if we don't have enough activated
- 01:17:01immune cells to attack the tumor?
- 01:17:02And in this case, one of the potential.
- 01:17:05Approaches that looks very promising.
- 01:17:07This actually take out the tumor,
- 01:17:09and we've realized that if you take
- 01:17:11the immune cells from that tumor and
- 01:17:13you stimulate them the right way,
- 01:17:14you give them,
- 01:17:15you know you bathe them in substances
- 01:17:17that help them to grow and get activated,
- 01:17:19that they they multiply and you
- 01:17:21get a whole lot of that.
- 01:17:22And then what you can do is actually
- 01:17:25infuse these back into the patient, right?
- 01:17:27So to give these cells back
- 01:17:29once they're more multitudinous,
- 01:17:30they're they've expanded,
- 01:17:32and they're more activated,
- 01:17:33and by doing so, you may increase
- 01:17:36the chance of controlling cancers.
- 01:17:38And I, you know,
- 01:17:39yeah was one of the the early centers
- 01:17:40to be involved in this type of trial.
- 01:17:42It still remains very active here.
- 01:17:44It's a.
- 01:17:45It's a kind of a another exciting
- 01:17:47approach that's being developed here.
- 01:17:50So for the last two slides,
- 01:17:52I promise I won't go go on and on.
- 01:17:54I do want to share just one vignette.
- 01:17:56This is recent research from our
- 01:17:58laboratory in which we've been able
- 01:18:01to take small samples from surgically
- 01:18:03resected tumors and directly study
- 01:18:05the effects of drugs on the tumor and
- 01:18:07immune cells. Within these small pieces.
- 01:18:09This approach allows us to actually
- 01:18:12study single cells and measure the
- 01:18:14expression of all the genes within them
- 01:18:17and the cellular behavior following
- 01:18:19treatment with drugs outside of the body.
- 01:18:21Uhm?
- 01:18:21And So what do you get when you
- 01:18:23do these experiments?
- 01:18:25So so you get back what looked like
- 01:18:27pointless paintings on the left
- 01:18:28and starry nights on the right.
- 01:18:30But but what each?
- 01:18:31What these represent are really all of
- 01:18:33thousands of immune cells and tumor
- 01:18:35cells that each can be studied individually,
- 01:18:37and each of the kind of stars in
- 01:18:39the kind of right hand side here
- 01:18:41represents a cell with its position
- 01:18:43kind of determined by the average
- 01:18:45of all of its cellular behaviors.
- 01:18:47The gene expression that's
- 01:18:49occurring within the cell.
- 01:18:50And because of this,
- 01:18:51we can perform kind of analysis.
- 01:18:53And understand some of the deepest
- 01:18:55aspects of cellular behavior.
- 01:18:56Identify new pathways of response
- 01:18:58and resistance to therapy and
- 01:18:59and that's that's our hope.
- 01:19:01Our hope is to one day be able to
- 01:19:02use approaches like this as a guy.
- 01:19:04If not, you know individual therapy choice,
- 01:19:07at least for the development of
- 01:19:09therapies that are most likely
- 01:19:11to work and to reprogram the
- 01:19:13interactions of immune
- 01:19:14and tumor cells in a fruitful
- 01:19:16way to understand the mechanisms
- 01:19:17by which the drugs we are using
- 01:19:19and testing fundamentally act.
- 01:19:21So with that, I want to thank everybody
- 01:19:25for staying all the way through
- 01:19:27and for listening to to all of us,
- 01:19:29and I want to thank the MRF for hosting
- 01:19:32tonight if you want to hear more
- 01:19:34about our work or the Melanoma program
- 01:19:36at Yale Cancer Center or the work.
- 01:19:39The kind of web links in Twitter
- 01:19:41handles are there and I'm also
- 01:19:43happy to take any questions.
- 01:19:46Thank you so much, Jeff.
- 01:19:48I think we're running two minutes over.
- 01:19:50Uhm, I think this.
- 01:19:53Maybe we can put this question to
- 01:19:57Jonathan 'cause it's about us automated
- 01:20:00scanning tools to avoid biopsies,
- 01:20:02so it's a German question, John,
- 01:20:04if you wouldn't mind responding in
- 01:20:06the chat while we while we wrap up,
- 01:20:08and I'm going to actually turn to
- 01:20:09Doctor Schnoll for some closing remarks.
- 01:20:20Jonathan's on mute.
- 01:20:21I believe you know he's gonna respond
- 01:20:24in the in the chat 'cause it's late,
- 01:20:25so yeah, if you wanna just
- 01:20:27make some closing remarks.
- 01:20:29Of course, I thought he was
- 01:20:31gonna respond by I was.
- 01:20:32So first of all,
- 01:20:33I want to thank first thank you
- 01:20:35Harriet for leading the meeting
- 01:20:37and and I want to thank all
- 01:20:39the speakers are teammates for
- 01:20:41providing this wonderful update
- 01:20:43on on the treatment of management
- 01:20:45of Melanoma all the way from
- 01:20:47the additional diagnosis from
- 01:20:49the dermatologist.
- 01:20:50Other way to surgical management
- 01:20:52all the way to oncology treatment
- 01:20:55and and to research as you've heard.
- 01:20:59Uhm, we've been involved in the
- 01:21:01management treatment research
- 01:21:02of Eleanor for many years.
- 01:21:04We we are very committed to
- 01:21:07improving the standard of care this
- 01:21:09disease and providing the best
- 01:21:10possible care that we can for our
- 01:21:13patients. I think there's a
- 01:21:15great deal of opportunity for further
- 01:21:17advancement here and for further
- 01:21:20advancement in the field altogether.
- 01:21:24We appreciate our patients.
- 01:21:25We appreciate your attention
- 01:21:27and your willingness to join
- 01:21:29the chat and we hope that we can
- 01:21:31provide answers to your questions.
- 01:21:34Either during this meeting
- 01:21:35or we see you in in clinic.
- 01:21:37I also want to thank the Melanoma
- 01:21:40Research Foundation for their sponsorship
- 01:21:42of of this and their cooperation
- 01:21:46with setting up this this meeting.
- 01:21:49Let me turn this back over to you Harriet.
- 01:21:51It's always a pleasure to be involved
- 01:21:54in these. Educational activities.
- 01:21:56Yeah, thank you so much Mario.
- 01:21:59And actually I just wanted to thank
- 01:22:01everybody for calling in and staying
- 01:22:03with us for for such a long time.
- 01:22:05And before all your attention we've I
- 01:22:08think have a huge number of attendees
- 01:22:11for a video event and all we can
- 01:22:14hope for is that the next one is
- 01:22:16in person in that tech auditorium.
- 01:22:18We've had some good times there in the past,
- 01:22:20so stay healthy and stay safe.
- 01:22:23Everyone and thank you so much
- 01:22:24for staying with us, goodnight.
- 01:22:28Thank you.