00:00welcome and thank you all for joining
00:03this educational activity
00:09different expertise specializing in
00:14and our plan is to sort of walk you
00:16through a few cases a couple rare cases
00:20a couple a little more common to try to
00:22emphasize the Multiverse disciplinary
00:24nature of this tumor
00:26and the management especially with some
00:29advances in the management that have
00:31happened more recently I'm shreyas Patel
00:34I'm a medical oncologist I treat
00:36sarcomas at the University of Texas MD
00:38Anderson Cancer Center
00:40I have two other colleagues joining me
00:42yes I am Brian Rubin and I am a
00:45pathologist who specializes in the
00:47diagnosis of sarcoma I'm also the
00:49chairman of pathology at the Cleveland
00:51Clinic in Cleveland Ohio and I am
00:53delighted to be part of this wonderful
00:57hi I'm Kathleen Poulson I'm a nurse
00:59practitioner I work at the Dana forever
01:01Cancer Institute in Boston Massachusetts
01:06um I'm also very excited to be part of
01:11wonderful with the Preamble then let's
01:16and here are our disclosures
01:19so our objectives for this session uh
01:22basically involves emphasizing the
01:24multidisciplinary nature of this disease
01:27I think we're going to highlight some
01:28patient and tumor characteristics
01:30sort of walk you through how they inform
01:34diagnostic procedures that would then
01:37lead to some personalized therapeutic
01:39approaches in soft tissue sarcomas the
01:42emphasis obviously will be on some newer
01:44therapies that have come to the market
01:46over the last few years it's all of you
01:49or many of you may be aware of these
01:52epidemiologic facts soft tissue sarcomas
01:55as you have all heard is an extremely
01:57rare group of heterogeneous tumors the
02:00incidence appears to be about 13 400
02:03compared to the one million 600 000 plus
02:07new cancers diagnosed in 2023
02:10uh you'll see several numbers in the
02:12literature more than 50 subtypes more
02:15than 70 subtypes and I think this
02:17becomes a matter of semantics and
02:20several different ways of classifying
02:22these tumors the most popular one is
02:24based on tissue of origin and that's
02:26what's listed out here whether it's
02:28fibroblasty fibro hysterectomatus
02:32uh somewhere between 30 to 35 percent of
02:37these soft tissue tumors do show a
02:41translocation and a fusion transcript
02:43that goes along with it so another
02:45classification that's out there and is
02:47popular is translocation positive versus
02:50translocation negative sarcomas and I
02:56shows is that it is a very heterogeneous
02:59group of tumors with a very
03:01heterogeneous biology sometimes even
03:03their clinical Behavior metastatic
03:06and they likewise have differential
03:08sensitivity to various available
03:10systemic therapeutic agents there is
03:12some commonality but then there are some
03:15specific unique associations that we
03:17will kind of outline in a little bit
03:20the unmet need that popular phrase right
03:23I think there's always going to be an
03:24unmet need as long as we don't cure
03:27everybody with this type of cancer this
03:30is certainly not acupromyolacytic
03:31leukemia by a long shot
03:33so that being the primary and met need
03:36what are some of the lower hanging
03:38fruits if you will I think it would be
03:40nice if we had therapeutic options with
03:42an improved therapeutic index better
03:44efficacy better tolerability
03:48from a translocation Fusion standpoint
03:51as Brian will outline throughout the
03:52talk there have been a tremendous
03:54diagnostic value they've allowed us to
03:56Define entities a little better so at
03:58least we can compartmentalize them in a
04:01little more unique way but the
04:04therapeutic implications of these
04:06translocations have not necessarily kept
04:08up to the promise right the classic
04:10examples are viewing sarcoma synovial
04:12sarcoma we've known these translocations
04:14for a long time but capitalizing on them
04:17from a therapeutic standpoint has not
04:20been very successful there are attempts
04:22going on as many of you who treat these
04:25uh drugs sort of inhibiting enzymes
04:28Downstream of the fusion to shut off the
04:30pathway or even nuclear degraders of
04:33some critical components of the fusion
04:35transcript but none of these have
04:38necessarily made it to the Shelf in the
04:40pharmacy yet it's just to interview for
04:42one second I I totally view what you're
04:44saying because I think we know the
04:46Targets in many cases these Gene fusions
04:48are fantastic targets Unfortunately they
04:51are not enzymes they're mostly chimeric
04:54transcription factors very difficult to
04:56Target so it's been a big struggle
04:58however as you are mentioning I think
05:00we're getting a foothold in this area
05:02and you're going to see some really
05:03interesting therapies coming out over
05:04the next I would say five to ten years
05:06in this area right right so that that is
05:09the promise Brian and that's correct and
05:12uh for lack of a better term
05:14disappointment if I can label it as such
05:16is that when the gist story developed in
05:18the late 90s and early 2000s I think
05:21clearly everyone got excited that you
05:23know this will follow now and eventually
05:25we will take this whole group of tumors
05:27and turn it into smaller just
05:29compartments and that clearly has not
05:31has not quite happened but
05:34on a positive note there are several
05:36areas where we have made an impact and
05:38some of those cases are the topic of
05:40this educational session so I'm not
05:43going to go through each one of these
05:44but there are two slides this one and
05:46the next one and I think if you were to
05:48look at success stories if you will
05:51uh dfsp that has a known 1722
05:55translocation collagen 1a1 Gene that's
05:58next to the pdgf beta Gene upregulates
06:01pdgf beta enema inhibits it nicely and
06:04beautifully and with a handful of
06:06patients the drug data secondary
06:08indication right so this is a fairy tale
06:10not not everything is that simple and
06:13straightforward I think uh the nosumab
06:16in Giants are tumor of bone is another
06:20but then there are others that have sort
06:23of lingered the Met inhibitor story in
06:26clear cell sarcoma for example while
06:29showed some promise early on has not
06:32quite panned out that well
06:34again along the same team the success
06:37story here may well be the ALK
06:39Inhibitors in the inflammatory
06:41myofibroplastic tumors right about half
06:44who have Alpha regulation will show a
06:48nice response to one of the alkyl
06:49Inhibitors and that has been helpful in
06:52this particular uh particular entity
06:54another success story would be the
06:56pacoma story where the tsc-12 mutations
06:59and activation of the mtor pathway can
07:02be fairly effectively addressed uh with
07:05with an mtor inhibitor and there is a
07:07drug napsterolamus that is on the market
07:09in this particular indication
07:12but the other end of that example the
07:14mdm2 and the cdk4 inhibition strategies
07:17in the far more common well-defined if
07:19liposarcoma subset is a still developing
07:23story right and we keep running into
07:25some stumbling blocks uh so I think in
07:28some ways it is promising that we are
07:30identifying some of these targets there
07:32are different ways of addressing them
07:34but the true success in terms of therapy
07:40to the Shelf in the pharmacy those are
07:43fewer examples so with that
07:47introduction I think let's get into some
07:51cases this would represent one of the
07:54rare tumors so Tino synovial giant cell
07:57tumor this used to be called pigmented
08:00villanodular synovitis I think now the
08:03preferred terminology is tgcd as I'm
08:05sure Brian will will educate us in a few
08:09the case I'm going to present is a 33
08:12year old female who originally presented
08:15in 2012 with some right hip pain
08:18MRI suggested some synovial thickening
08:22that's fairly typical and almost
08:24diagnostic if you will in expert hands
08:27uh suggested that this is a tgct it was
08:31felt to be localized based on the
08:33appearance and what happens frequently
08:37in these situations is that they see a
08:39community orthopedic surgeon either that
08:42surgeon will send them to a joints
08:44person or a sports person or some
08:48specialty like that and an arthroscopic
08:52reception is undertaken
08:54unfortunately in less experienced and
08:57it's almost never a gross total or a
09:00complete resection so this patient went
09:03through their first arthroscopic
09:04reception in 2012. not so surprisingly a
09:08year later there was some growth whether
09:11it was growth of persistent tumor or
09:13true local recurrence is open to debate
09:16but then the patient undergoes through
09:18another arthroscopic reception to do a
09:21more optimal debulking and Brian's gonna
09:24walk us through the pathology here right
09:25yeah so just I'm taking a look at the
09:28pathology here and this is just the
09:29typical pathology of this tumor which we
09:31call Tina synovial Giants ultimate
09:33shreyas mentioned this is kind of just
09:35by a variety of other names so
09:37if it occurs in the fingers we call them
09:39giant cell tumor of tendon sheath where
09:41they're localized and really don't cause
09:43a lot of problems but the ones in the
09:44big joints the hips and knees tend to
09:46call Tina synovial giant cell tumor and
09:48then we think of them as whether they're
09:49localized again the localized variants
09:51are readily easily acceptable or
09:54resectable and don't um recur or they're
09:57diffuse type the diffuse types are the
09:59ones that recur over and over and over
10:01again and medical therapy has shown some
10:03promise so what we're looking at here if
10:05you look at the h e you can see there's
10:06a sheet of epithelioid cells and then
10:10that pink stuff is some fibrous stroma
10:12and so you usually get these sheets of
10:13epithelioid cells with the pink fibrous
10:16stroma and then there's other cell types
10:19like lymphocyte-like cells there's
10:20osteoclast type giant cells frequently
10:22associated with these tumors
10:24um and then there's also some um
10:27different kinds of macrophages foamy
10:30histiocytes and so forth now the typical
10:32stains that we um use to make this
10:35diagnosis one is Desmond and actually
10:36Desmond's interesting because Desmond
10:39positivity is often associated with
10:41things like rhabdo myosarcoma and in
10:43fact some cases of penis synovial Giants
10:45Ultima have been my misdiagnosed as
10:47rhabdomyosarcoma so if you see a joint
10:49tumor being called rhabdo you might
10:51think about the possibility that it's
10:53latinosynovial giant cell tumor for
10:54instance but another more recent um
10:56marker is clustering and clustering is
10:58not specific for the diagnosis of
11:00penosynovial giant cell tumor but it is
11:01positive and it stains a variety of cell
11:03types so typical histology here
11:05Florentino synovial giant cell tumor
11:10and I just wanted to make up you know a
11:12few points here so again this is a group
11:14of lesions or most often from the
11:15synovium of joints Bursa tendon cheese
11:18and um they do show what we think of as
11:20synovial differentiation the localized
11:23fingers uh are the most common and then
11:25there's diffuse types that affect the
11:28um diffuse type giant cell tumors are
11:32infiltrative and again they're they're
11:33characterized by repeated local
11:34occurrences these are the ones that
11:36we're talking about treating with
11:37medical therapy however most of these
11:39cases are treated by surgery and surgery
11:42is really useful in treating this
11:43disease it's the occasional or almost
11:46rarer case that requires medical therapy
11:49and I can remember cases in the ankle
11:51for instance uh Tempo mandibular joint
11:54is a really unusual site that's one
11:55that's going to require medical therapy
11:57and then when you get multiple multiple
11:59recurrences in either hip or knees these
12:00can be treated by medical therapy and
12:03um generally useful and in the class of
12:05Inhibitors that we use
12:07or csf1 Inhibitors so the molecular
12:09pathway which is activated in this case
12:12is to a csf1r translocation so that's
12:15receptor for csf1 and so blockading csf1
12:18makes a lot of sense in this disease
12:20they're characterized by simple
12:22cytogenic changes most commonly the csf1
12:25Gene rearrangements and I will just go
12:28on to say that there is a malignant
12:29variant it is extraordinarily rare to
12:31the point of being case reportable
12:36back to you so back to the case uh
12:41so now after two arthroscopic debulking
12:44surgeries and again I want to emphasize
12:45the point that Brian made I think
12:48this is by definition a benign locally
12:52aggressive neoplasm uh metastatic
12:55potential is extremely extremely low
12:58there are anecdotes again like Brian
13:00said to Portable cases uh so this is
13:03managed locally it's just I think the
13:05emphasis always has to be in the right
13:08person doing the right surgery right off
13:10the bat as opposed to multiple attempts
13:13at just trying to nibble at it so after
13:17the two nibblings now the Natural
13:19History stands out over about a
13:21four-year period so between 2014 and
13:25she develops progressively worsening
13:27pain the MRI from February or the
13:31MRI not shown here but the Pet City
13:34shown here from February 2020
13:37shows now a more diffused pattern as you
13:40can see some brightness and ftg ability
13:42diffusely within the right hip joint and
13:46almost encasing that neck of the femur
13:48so at this time uh the patient starts a
13:51matineb which is a poor csf1r inhibitor
13:55we will look at some of the data in a
13:57few minutes but she starts imagining
14:00about the standard dose of 400
14:01milligrams po daily and I think a point
14:04of emphasis with all these tkis in
14:07general no matter how well tolerated
14:13supportive care and and in this
14:16particular disease especially adequate
14:19pain management and adequate Physical
14:22Therapy can make a world of difference
14:25so the patient was seen by a supportive
14:27care specialist going through physical
14:29therapy and a magnet so now by
14:33August 2020 unfortunately just six
14:40the tumor shows some worsening symptoms
14:42worse than Pet City as you can see on
14:44the right hand side now shows again
14:46diffuse uptake with some increased ftg
14:50uh at this time now pexy Darkness was
14:54available and on the market for almost a
14:56year I think it got approved in August
14:582019 if my memory serves me right uh it
15:02is a more specific csf1 receptor
15:04inhibitor clearly the data from The
15:06randomized Trial looked like it was very
15:08encouraging so she starts texted art at
15:12the then prescribed dose and we'll come
15:14back to this a little bit later in the
15:16conversation uh our 400 milligram twice
15:21four months later by December 2020 her
15:24symptoms have improved performance
15:25status and range of motion improved but
15:28she needed dose reduction because of
15:30constitutional symptoms in general and
15:32some transaminitis so the dose was then
15:34reduced to 200 milligram twice daily
15:37and then here comes some points that
15:40Kathleen will make about how do you
15:43maximize the compliance on oral therapy
15:47so some of these newer therapies are
15:49oral therapies that our patients will be
15:51taking at home so it's important to
15:54have good communication with your
15:56patient up front and to talk with them
15:59about potential side effects that they
16:01might experience as well as things they
16:04may be able to do proactively to prevent
16:07things from happening as well as knowing
16:10who to call should they run into any
16:14so we have a variety of providers in our
16:17practice who do the teaching from The
16:19Physician to the nurse practitioner
16:21mid-level provider to the nurse
16:24Navigator and sometimes the clinical
16:28um so you want to be sure that the
16:29patient knows how to reach you and
16:31contact team members during the weekdays
16:33as well as nights and weekends we like
16:38um you have enough people and are able
16:39to do so have a follow-up phone call
16:41with patients typically like a weekend
16:43maybe a follow-up visit in person or
16:46virtually two weeks on drug we highly
16:49suggest patients keep a diary because
16:51sometimes it's hard to remember exactly
16:53how they're feeling on any particular
16:54day but it will jog their memory to talk
16:57to you about side effects that they
16:59might be experiencing
17:00we found in our practice I'm sure the
17:03same with you and your cancer
17:05institutions that early intervention
17:08makes a big difference ideally you can
17:10modify the dose or make adjustments so
17:12that the patient's able to stay on
17:14treatment and not need to hold treatment
17:17for an extended period of time
17:20um we also are very fortunate at our
17:23institution to have a broad
17:26multi-disciplinary team where we can
17:28refer to numerous people from nutrition
17:31to Dermatology to Cardiology
17:34Etc but it's nice to broaden your team
17:35and work together with the goals of
17:37improving the patient's quality of life
17:40and being able to keep them on their
17:42So speaking specifically about hexadard
17:47um because of some trans ammonitus or
17:50elevated liver function tests that were
17:52significant the drug is now available
17:56only through a Rems program where the
17:58provider has to do some education and
18:02enroll in the program up front the
18:04patient has to be enrolled and we
18:07learned early on it's important when you
18:09see the patient in clinic to get both
18:10your signature and their signature on
18:12the form to not have any sort of delays
18:15Baseline liver function tests including
18:19astlt ggt total bilirubin direct
18:22bilirubin and alkaline phosphatase and
18:25then you need to set up a monitoring
18:28plan with the patients very defined like
18:30how frequently you need to monitor the
18:33the guidelines have recently changed in
18:36dosing as highlighted by Dr Patel it was
18:39initially 400 milligrams twice daily on
18:42an empty stomach it's now 250 milligrams
18:46twice daily with a low-fat Meal which is
18:48considered 11 to 14 grams of total fat
18:54um the company has worked with numerous
18:57providers and nutritionists to help
19:01develop some materials to kind of help
19:03patients understand what's 11 to 14
19:07um some teaching materials are available
19:10for the patients there's online websites
19:13as well as some apps that are available
19:15to kind of help patients I know our
19:18nutritionists have identified some
19:20specific granola or protein bars that
19:23make it a little bit easier they can
19:24just eat one of those and take their
19:25dose I don't know how that's been at
19:27your site Dr Patel and Ruben but um and
19:31patients I think we're a little bit
19:32overwhelmed at first for people who were
19:34on it and then had to switch
19:37even the providers right I mean the
19:39first thing came out it's kind of like
19:41gee I don't carry the app on my iPhone
19:43all the time to figure out how many
19:45grams of total fat is in there right so
19:47and then what happens Christmas time and
19:49Thanksgiving time versus other times I
19:51guess but no I I think that information
19:53is now becoming more accessible uh so
19:57that it's not as complicated you're
19:59right exactly and then they've
20:04as they've had gastric bypass or they
20:07are diabetic or whatever
20:09um that may be referring them to a
20:11nutritionist if that's available to you
20:13in the community and it's someone who
20:15can help the patient understand
20:17uh the best choices of foods
20:21again just in recap um the drug is
20:23available only through the Rems program
20:25it's important to monitor liver toxicity
20:29um the monitoring is initially frequent
20:32at first and it spreads out for the
20:34patient it's very important to highlight
20:37hair depigmentation the hair will turn
20:39white and it can be very
20:41striking and hard for young adults for
20:44example to suddenly have white hair
20:47um periorbital edema swelling with some
20:50sometimes just generalized fluid
20:52retention which can also be hard for a
20:55number of young adult patients and well
20:57anyone in general really
20:59patients can experience fatigue rash
21:02taste alterations and it's just
21:05important to monitor in addition to the
21:08liver other laboratory values such as
21:10the you know white blood cell red blood
21:15all right that's that was very good I
21:17think those helpful tidbits are what
21:19helps us maintain those intensity and
21:24so the patient Now by February 2021 had
21:29a maintained response maintained
21:31Improvement in her right hip symptoms
21:33things got derailed by summer of 2021
21:36when she had a covet infection lost her
21:39insurance lost follow-up and she went
21:42off Taxidermy so another factor to take
21:45into account with these oral therapy
21:53depending upon their insurance they may
21:55have excessive co-pays for these
21:58medications a lot of these medications
22:00also require prior authorization and so
22:03depending upon the structure at your
22:05institution and support staff it can
22:07sometimes take a while we're blessed to
22:10have a prior authorization team that
22:12helps us some of these prescriptions
22:15that require mail order pharmacy so that
22:17can be an additional delay specifically
22:19when patients haven't already
22:22with that mail order pharmacy so we like
22:25to discuss this with patients when we
22:28talk with them to say that we have a
22:30multi-disciplinary team to kind of help
22:31us work through this but and let them
22:33know that there may be some delays that
22:35will work together as a unit to get them
22:37the drug as quickly as possible and then
22:39be sure we know when they receive the
22:41drug and then can set up their follow-up
22:45um there are numerous drug Assistance
22:47programs available through the drug
22:49companies often and other co-pay
22:53um companies out in the community that
22:55can sometimes be tapped into but these
22:57delays obviously can result in patients
22:59being off drug and can be very
23:02um anxiety inducing for patients who
23:06have progression of their disease and
23:07need to get on their treatment or as Dr
23:09Patel highlighted if they lose their
23:12insurance or have some sort of change in
23:14that regard it can be it can
23:16it can be a challenge
23:20all of those wonderful suggestions to
23:22try to avoid what ends up happening to
23:25this patient so she then off therapy
23:29comes back in October 22 with some
23:32worsening symptoms clearly Progressive
23:34disease on the PET CT scan that you see
23:36on the right hand side
23:42prove the supportive care and analgesic
23:44support and try to enroll her on an
23:46ongoing phase to study but she somehow
23:50had a screen failure and could not get
23:52onto it another couple of months later
23:54then uh I think this is what we dread
23:58happens right that this benign soft
24:00tissue process will then start eating up
24:03the Bony structures in the surrounding
24:05area to be very generic uh her plain
24:09film started showing some uh subchondral
24:12cysts erosions that sort of stuff that
24:15then for symptom management required a
24:18right total hip arthroplasty at least
24:20that allowed some gross tumor debulking
24:22at that time and as of the last
24:24follow-up from this spring she has no
24:27evidence of imageable disease and her
24:30symptoms are well managed but what
24:32happens in the longer run I think
24:34remains to be seen and then the
24:37consequences of an artificial hip in a
24:40young person present their own
24:42challenges so quickly running through
24:44the data that supports the management in
24:47in this particular tumor type I think
24:49nccm guidelines as many of you may be
24:52aware the category one recommendation is
24:54for taxider nip based on the enlivion
24:57study that I'll show you in a few
25:00seconds imagine about a week csf1
25:03receptor Inhibitors both have been
25:05tested in either retrospective reviews
25:07or prospective clinical trials uh the
25:11level of benefit is a little lower but
25:14likewise the tolerability is much better
25:16so this is the retrospective review from
25:18the Netherlands group of a magnib in
25:20about 62 patients most of them had a
25:22median of two prior surgeries they saw a
25:26response rate of 31 percent I think
25:28honest disclosure my personal experience
25:30is that it's not that high you do see
25:34stabilization you do see some reduction
25:36in size but good volumetric reduction is
25:38rare never the less it does have some
25:41stabilizing effect as you can see from
25:43the PFS rates at one year two years and
25:45five years this was the registrational
25:48study that got hexaduct nib
25:51approved for commercial use
25:55patients were randomized to plexadertane
26:00and the three different columns that you
26:02see are timed events if you will that
26:05the first look week 25 at the March 17
26:09data cut off as you can see from the
26:11waterfall plot the response rate was 39
26:13if you fast forward and go all the way
26:16to the right now to June 2021 almost 40
26:21years later that response rate kind of
26:24matures at about 60 percent so patients
26:27may have slow continued benefit where
26:29the reduction may continue on safety and
26:33and toxicity profile I think the biggest
26:35area of concern early on was with the
26:38liver toxicity that's why the Rams
26:40program it is a sensitivity phenomenon
26:43you see it early on and if it doesn't
26:45happen in the first three months it is
26:47unlikely to be severe that's why the
26:50ramps monitoring is programmed that way
26:52that it is far more frequent in the
26:54first month and then eases up for the
26:56next two and the first three months
26:58pretty much give you an indication as to
27:00how well this patient's going to to
27:02tolerate at least you avoid uh grade
27:06four or higher liver toxicity so the
27:09points that I wanted or we wanted I
27:11should say to convey is that here is a
27:13rare tumor we know what molecularly
27:16drives these tumors that are effective
27:19Inhibitors of this so this would sort of
27:20count as one of the examples of targeted
27:24therapy that has brought clinical
27:26success in terms of outcomes to patients
27:28and there are several molecules that are
27:30in clinical testing along the same lines
27:33that will eventually sort of tell us or
27:37allow clinicians to pick the safest
27:39molecules with the best activity but
27:42moving on to case study two here we
27:44decided that we would sort of highlight
27:47one of the more common sarcomas if you
27:49will gastrointestinal stromal tumor so
27:52this is a patient of mine a 52 year old
27:54white female presented in February 2002
27:57as is very typical for this disease many
28:00of you have seen this near Singapore
28:02episode ER visit hemoglobin is 5.4
28:05clearly some signs of upper GI bleed a
28:09CT gets done of the abdomen and pelvis
28:11it shows about a 12 centimeter gastric
28:13mass and there were no metastases goes
28:17through an EGD and a biopsy
28:19and the diagnosis is confirmed as
28:22gastrointestinal stromal tumor of the
28:24stomach it was seek it positive and
28:27there were 12 mitosis per 50 high power
28:30field for those of you are looking for
28:31some additional markers I think Brian's
28:33going to educate us on that but I remind
28:35you that this was 2002 and we were just
28:38sort of in the very early part of the
28:41learning curve of of this disease driven
28:47patient undergo surgical resection
28:51and Brian's going to take us through the
28:54yeah so you've got a typical histology
28:56here of a spindle cell gastrointestinal
28:59stromal tumor they do actually come in
29:01epithelioid variant as well but the
29:04spindle cell the variant is more common
29:05you can see on the left here with the h
29:07e that you've got bundles fascicles of
29:10spindle cells you know just typically
29:12has monotonous cells just not a lot of
29:14poliomorphism uh typically just have a
29:17low mitotic activity in this particular
29:19case they have 12 it has 12 per 50 which
29:21is actually on the high side and we'll
29:23get that to that in a minute now
29:25good markers for the diagnosis just used
29:27to be a difficult thing to diagnose when
29:30I first started in pathology 25 years
29:32ago but now it's a very straightforward
29:33diagnosis because 95 percent of the
29:36cases are positive for kit and 99 are
29:39positive for dog one uh kit and dog one
29:42are not entirely specific for the
29:44diagnosis of Jess but in this clinical
29:46context with this histology and these
29:48markers this is virtually 100 diagnostic
29:51for gastrointestinal stromal tumor or
29:59we've developed this pretty
30:00sophisticated algorithm I'm not really
30:02to talk about this yet but um the reason
30:04that we developed this is because of the
30:06existence of different genetic subtypes
30:09of gist and so when we make the
30:10diagnosis of just we have a primary
30:12immunity chemical workup where we look
30:14at kit and dog one those are markers of
30:17gist and then the things in the
30:18differential diagnosis Desmond and S100
30:20in this case Desmond for smooth muscle
30:22tumors and S100 for schwannomas one on
30:25where the stomach is not that rare and
30:27I've seen lots of cases over the years
30:29so for a gastric gist the one thing we
30:32want to rule out and it's a bit of an
30:33unusual thing we don't see it very often
30:37um one to three percent of just in total
30:40about seven percent of gastric gists
30:44um and so we do an sdhb stain because
30:47there are rare cases of gist which are
30:50caused by loss of succinate
30:52dehydrogenase sdhp covers actually all
30:54the different mutants and we looked to
30:57see whether it's lost or not it's a
30:59tumor suppressor so if it's retained
31:01then we move down to um talk about
31:04prognosis and stuff however if sdh is
31:06lost then we actually move that patient
31:09into an sdh deficient just pathway and
31:12the reason that's important because
31:14these patients get other tumors too this
31:16is a germline loss of sdh and it's
31:19frequently accompanied by law by
31:21perigangliomas and pheochromocytomas and
31:24actually other tumors as well so
31:26essentially those patients need to be
31:27put into the sdh pathway and it's an
31:29important consideration we actually do
31:31these stains we use this exact protocol
31:33here at the Cleveland clinic now however
31:35if the sdh is retained then we move down
31:38we assess prognosis we look at tumor
31:41um we look at tumor location and I'll
31:43get to this in a section and we look at
31:45mitosis per five millimeter squared this
31:47is sufficient essentially to grade each
31:50tumor and we want to do that because we
31:52want to know whether or not to use
31:54adjuvant matte and we could talk about
31:55this I think most people would say if
31:58it's an intermediate or high risk just
31:59that it's probably worth using adjuvant
32:05um like it's low if it's low risk then
32:07in fact most people don't use adjuvant
32:10and I will say that if you're going to
32:12use adjuvanimatinib you've got to do
32:14molecular testing and the reason you
32:16want to do molecular testing is not all
32:18kiss not all of the genotypes associated
32:20with just respond to a matinee Kid X on
32:2411 mutations respond
32:29pdgfra mutations do not respond as I
32:32mentioned sdh mutations are not going to
32:34respond there's a variety of genetics
32:36that we'll talk about in a second that
32:37don't respond to a magnet and so you'll
32:39want a genotype to know whether or not
32:41the tumors can respond because these
32:42patients will be on imagined it for
32:44quite a while and we want to make sure
32:48all right so now let's look at molecular
32:50testing for a gist so essentially when I
32:52look at whether or not to test or not
32:56I asked myself the question is the
32:58patient going to be treated with
32:59systemic therapy if they are you want a
33:01genotype and the reason you want a
33:03genotype is you want to direct therapy
33:04and we'll get to that in a second if you
33:06don't intend to treat with medical
33:07therapy of a low risk gist there's no
33:09reason to do genotyping you can do a
33:13variety of different things most people
33:14use a single gene or a panel-based
33:16testing and you essentially want to look
33:18at kit exons 8 9 11 13 and 17 and pgfra
33:23exons 12 14 18. if it turns out to not
33:26have a kid or pdgfri mutation you'll
33:29need to move into a different kind of
33:30testing however this captures the
33:32majority of just and it's a really good
33:37it's got a kit or a pdgi party mutation
33:39except kit Exon 9 or pdgfra d842v gonna
33:44give a matin and 400 mix's first line
33:46second line is significant if third
33:48Line's regular affidav and there's even
33:51fourth line therapy now this race will
33:52probably talk about so um a kit X on 9
33:57it's always an ay 502 503 duplication
34:00requires essentially a double dose of a
34:02mat and if we do want to know that up
34:04front before we treat the patient a
34:06pdgfra d842v is going to require
34:09repetitive or a clinical trial if they
34:12have no kit or pdgfri mutation then
34:14you're going to go into that Paradigm of
34:16doing additional mutations looking for
34:17things like B reputations NF1 mutation
34:20and track Gene fusions and loss of sdh
34:24for instance and you want to know that
34:26because each of those therapies or each
34:28of those genotypes would be a company
34:30with either no particular therapy or in
34:33the case of for instance B reputation
34:34you could be with a B ref inhibitor and
34:36that has shown some success at least
34:38temporarily in um in some of those cases
34:43now in terms of um prognostic
34:46prognostication and wrist stratification
34:51table essentially that was set up by
34:53Markham yet and his colleagues at the
34:55afip many many years ago and essentially
34:58um they broke it down into different
34:59site size and mitotic index and if you
35:05stratification mitotic index is by far
35:08and away the most powerful thing in this
35:11table and in fact you can have a wrist
35:12stratification scheme that's totally
35:14based on mitotic index it had actually
35:17um works really well and essentially
35:19since gists aren't very mitotically
35:21active we count 50 high-powered fields
35:23and if it's less than five it falls into
35:25the first category greater than or
35:27greater than five it falls into the
35:29second category remember in this case we
35:32had a patient who had
35:3312 mitotic figures and it was a 12
35:36centimeter gastric gist if you follow
35:38into the table there you kind of get
35:39into the middle we're in the third
35:41column looking down now and it's the
35:43bottom of the table and so this this
35:45particular patient would have a very
35:46high risk and that risk is for local
35:48recurrence and and distant metastasis
35:51just tend not to recur locally they tend
35:53to metastasize mostly to liver and
35:55within the abdomen and so this one has
35:56about an 86 percent chance of recurrence
36:00metastasis and so this is one that I
36:03think most of us would recommend
36:06um getting adjuvant therapy and I think
36:07that's what was done in this case
36:12now again molecular testing was sent for
36:15this case it was kid Exxon 11 557 to 559
36:19deletion that's a a relatively common
36:21kit mutation we know that this one is
36:24susceptible to a matte nib
36:27and the patient would typically get 400
36:29migs every day again I want to make the
36:32point that if it has a kid acts on 9
36:33mutation requires a double dose of a map
36:35nib the pdgfr8 d842 V mutation should be
36:39treated with a for print nib they fail
36:41there they could certainly go into a
36:42clinical trial and then the other just
36:45genotypes including NF1 sdh deficiency B
36:49reputations track egfr and then a
36:52subclass that we call Wild type where we
36:54can't really find any genetic mutations
36:56these don't respond to a Madness they
36:58don't really have a distinct therapy in
37:00most cases however B reputations can be
37:02treated with brap Inhibitors track
37:04Newtons can be treated with track
37:06Inhibitors and of course egfr mutants
37:08can be treated with egfr inhibitors
37:14back to stress all right yes so back to
37:17the patient says Brian mentioned this
37:19patient was deemed to have high risk
37:22so she was enrolled on the ecosox z9001
37:24protocol randomizing patients to one
37:27year of adjuvant therapy imaginative
37:31so she got a Year's worth of treatment
37:33and unfortunately three months later
37:35presents with neck pain paresthesias
37:39Mr of the spine reveals possible
37:42cervical thoracic spine metastases CD
37:45abdomen pelvis shows a liver metastasis
37:48that was biopsy confirmed
37:50in hindsight clearly the patient very
37:52likely was on Placebo but we don't know
37:58so in April when the metastatic disease
38:00was documented she now
38:04restarts or or starts iMat nib at 400
38:07milligrams po daily the standard dose
38:09for this mutational makeup Kathleen's
38:12going to walk us through the management
38:13of side effects Kevin
38:16um so imaginative tense for most
38:18patients to be reasonably well tolerated
38:20with some potential side effects and
38:22again side effects can vary greatly from
38:27um patients can experience fatigue fluid
38:31retention can be quite common sometimes
38:33requiring a diuretic or decreased sodium
38:37in the diet a variety of things you can
38:40try muscle cramping that can be severe
38:43in the hands of feet calves
38:46um sometimes diarrhea nausea vomiting
38:50this medication is to be taken with food
38:53and a big glass of water so sometimes
38:55being sure that the patient is taking it
38:58with a good sized meal and can make a
39:02difference sometimes changing it from
39:04breakfast to dinner can make a
39:06some patients will experience a rash
39:09I've seen that commonly with patients
39:12who go out in the sun and get exposed to
39:14the Sun and suddenly develop a pretty
39:17significant rash early on in dosing
39:20and again important Labs including the
39:23white blood cells red blood cells kidney
39:25function liver functions it can lower
39:27the calcium over time in patients
39:29important to keep in mind
39:31so interestingly enough just a reminder
39:33patients started iMat neb in April 2004
39:38so she almost gets seven plus years
39:41out of this initial stint with him at
39:44nib then I think this is one relevant
39:46point that the kinase Inhibitors
39:49primarily iMat nib and of course the
39:51subsequent ones that have been approved
39:54have obviously changed this landscape
39:56right they've made patients with
39:58metastatic disease live longer the
40:00extension of lifespan endpoint has been
40:03accomplished median survivors before
40:05were just here a year and a half but
40:07here she is uh gets almost seven years
40:10out of it with eventually there is slow
40:13steady progression uh the liver lesion
40:16has grown significantly
40:18bone lesions interestingly enough
40:22so at that time the initial
40:24recommendation was well double the dose
40:27of a matte nib to see if you can get
40:28some mileage out of it on an average
40:30patients may get about six months out of
40:33it with the right mutational makeup
40:36she was one of those who didn't like to
40:38take medications and sure so she chose
40:41not to do it comes in about three months
40:46re-staging and has continued progression
40:48now she does go on to 800 milligrams a
40:52day and basically buys a year out of it
40:55I guess you know by February 2013 then
40:58there is that slow steady progression
41:00that accumulates to a significant uh
41:05so this was the time when the second
41:07line therapy approved second line
41:09therapy was the netanab I think from a
41:12dosing standpoint you know 37 and a half
41:14milligrams continuously daily has been
41:17the general standard of care worldwide
41:19uh despite the pi saying 50 milligrams
41:23four weeks on two weeks off
41:26that's one not good for sustained kinase
41:29inhibition and to certainly the
41:30tolerance becomes more of an issue and
41:33the management of synergenic
41:36so as soon as you know many patients do
41:38a lot of reading so they often think of
41:40this one as more more side effects
41:42compared to imatinib however again I've
41:45seen it Go the complete opposite so it's
41:47just really important as I highlighted
41:49in the first slide that we talked about
41:51that we do a lot of Education up front
41:54um for the patients starting student nib
41:57um the medication can cause high blood
41:59pressure some patients end up requiring
42:02multiple agents to manage their blood
42:04pressure so it's important they have a
42:06blood pressure cuff or a means to get
42:07their blood pressure checked and call
42:09when the number is elevated
42:11patients can experience fatigue Palmar
42:15plantar erythritesia can be of
42:18significant factor for these patients
42:20some patients can experience oral pain
42:23or discomfort without actual visible
42:27hair depigmentation sometimes skin skin
42:31changes some hair thinning can happen I
42:35personally do not think I've seen anyone
42:38with complete hair loss on this on
42:41diarrhea can be another significant
42:43factor that limits patients I've had
42:47patients not want to leave their house
42:48because they don't know where there's
42:50going to be a bathroom between their
42:52home even coming into our institution
42:55some nausea vomiting can happen and
42:58similar to Prior Labs including
43:02uh hypothyroidism it can impact the
43:04thyroid so people um if they're
43:06expressing significant fatigue it's
43:08important that you're monitoring that's
43:10um part of your lab panel every so often
43:14Palmer Point Georgia
43:16so I like to um start with a baseline
43:19skin assessment with patients if they
43:21have significant calluses on their hands
43:25friction wear and tear work what have
43:28you we suggest they buff those calluses
43:31down with like a pause Stone and good
43:33use good moisturizing creams
43:36urea based creams can be effective at
43:40preventing callus formation you can
43:43write prescriptions for these or they
43:45can even buy them online 40 area based
43:48cream is pretty inexpensive
43:49um we encourage patients to reach out
43:51early with these symptoms because this
43:53is definitely one that you can go down
43:55on the dose and make it better refer
43:58them to Dermatology if you're really
44:01running into problems for additional
44:04Epsom salt soaks followed by putting the
44:06creams on can help with um cotton gloves
44:09or socks to keep this creams where you
44:13um and you know I think um the
44:16Dermatology folks that we work with have
44:17been um working hard and have used some
44:20retinoid-based creams that can be
44:21effective for some patients
44:24um and then obviously he has a size that
44:30side effects for managing diarrhea
44:32obviously can start with dietary changes
44:35following a more bland diet can be
44:37helpful but that's obviously very
44:38challenging for patients who are on this
44:40potentially for extended period of time
44:42and maybe used to more healthful eating
44:46um you said Imodium and
44:49lomodo can be effective
44:52um GI consult sometimes I've had
44:54patients with bacterial overgrowth that
44:56can be managed with antibiotics I've had
44:58patients have success with bile acids
45:01the questions like cholestyramine and
45:03managing the diarrhea can make a big
45:07um nausea and vomiting they can
45:09sometimes take a nausea med kind of as
45:11needed throughout the course of the day
45:13if needed for people who have it every
45:15day sometimes taking in nausea
45:16medication say 30 to 60 minutes before
45:19the dose can make a big difference
45:22um a lot of times with in general with
45:24these medications if it's something that
45:26can be taken with food then obviously
45:28making sure they're eating enough if
45:29it's something that has to be on an
45:31empty stomach sometimes shifting to
45:33night time so that they can sleep it off
45:35can make a difference and dose
45:38modification and referrals to nutrition
45:41and or um GI can be effective
45:46fatigue as a um highlighted in one of
45:50the earlier slides you obviously you
45:52want to make sure they're not anemic
45:53make sure that their thyroid's
45:54functioning think about taking it at
45:57night and maybe waking up in the morning
45:58and feeling rejuvenated
46:00make sure that they're not like
46:02sleeping all day and then up all night
46:04sometimes adding a medication like
46:07methylphenidate can help as a stimulant
46:10for some of these medications can help
46:11people feel more awake and it's
46:13something that they can take
46:15when they feel like they need it but
46:16don't have to necessarily take it every
46:19and again dose modification early can
46:25so to recap she started sunitnib in
46:31by November 2013 again her tolerance was
46:34poor and as Kathleen just mentioned I
46:37think the hand foot syndrome was her
46:42disabling toxicity if you will we
46:44decrease the dose to 25 milligrams a day
46:48she hung in there for a few more months
46:50but by that time I think even the
46:51disease was starting to break through
46:54uh so we moved on to regular FNB
46:57choosing a lower continuous dosing but
47:01that was even poorly tolerated compared
47:04to sunitime she didn't last more than a
47:06couple of months on that uh the disease
47:09was relatively stable hadn't quite
47:11started Galloping yet but we were forced
47:15to sort of give her a treatment break
47:17for uh the side effects to resolve
47:25and then with side effects profile
47:28um there can obviously be some
47:29differences from Patient to Patient
47:31where one is better than the other so
47:33they they have hypertension but the
47:34first they may likely continue to have
47:36hypertension um fatigue again and the
47:39Palmar plantar arithia tends to be
47:43pretty pretty similar they can develop a
47:47um which for the average patient isn't a
47:49huge ordeal but I've had patients who
47:50speak routinely that are very bothered
47:54um care deep pigmentation can happen I
47:56did have one female patient lose all of
48:00um although I think it's usually not
48:01overly visible hair thinning that's
48:05um I've actually had more commonly
48:07constipation than diarrhea with this one
48:10but it can go both ways
48:12nausea vomiting is I don't know that
48:15it's that common with this one but it
48:16certainly can happen
48:18um muscle or joint aches or pains and
48:21like similar lab functions are important
48:23to monitor particularly in the beginning
48:27um with the liver kidney function
48:29thyroid throughout and um
48:37right so I think it's the cumulative
48:40fatigue diarrhea and and the vegoff
48:43related side effects that tend to become
48:45sort of the limiting factor for both
48:48sunit nib and ragoraphanip that do have
48:51a more promiscuous kinase inhibition
48:54so we try to resume but again I think
48:58our severe arthralgias and the same
49:02symptoms recurring prevented her from
49:05continuing to trade uh take the drug
49:08not surprisingly another six months
49:11later the disease starts progressing uh
49:14it was liver dominant disease the bone
49:16stuff was relatively stable so she went
49:19through some embolizations we did two of
49:21them January and February for some
49:29it was clear that that more local
49:32therapy to the liver was not going to be
49:35and I think this brings up an important
49:38you know even when a patient with
49:40metastatic just runs out of therapeutic
49:43options whether it's clinical trial or
49:46one of the conventional wisdoms that has
49:48sort of been in practice for a while is
49:50to not leave them off of any kinase
49:53inhibitor right even if she had a
49:55disease had progressed on a matinee
49:57before if that's what she tolerated the
50:00best the idea is to sort of keep her on
50:04some kinase inhibition hoping some cells
50:06are still sort of addicted to that
50:08pathway and therefore that drug will
50:10work to try to make symptom management a
50:15interestingly enough as we were sort of
50:17starting to think about you know going
50:19to nilotnib and soraphaneb and those
50:22sorts of things uh Paz open if for
50:25example that was already commercial by
50:27that time beginning 2012
50:29uh there was a phase one study of a drug
50:32then called DCC 2618 that was starting
50:36to to be investigated
50:38so I sent her to our phase one group she
50:41got enrolled on that trial
50:44began the study drug later in 2016
50:48clearly had some control of her symptoms
50:51control of the disease and just not to
50:53belabor the point but to sort of put it
50:55into perspective but another four years
50:59and I think this is the punch line that
51:01I'm these kinase Inhibitors each one can
51:04sort of in a stepwise fashion add a
51:06little to the patient's lifespan if you
51:09will and then cumulatively they all
51:11collectively have made this at least in
51:14a good fraction of patients more to
51:16chronic disease than it used to be back
51:19in the days prior to the tkis
51:22so she buys four years out of it by
51:24November 2020 she becomes symptomatic
51:27she could not go on the doubling dose
51:29arm of the DCC 2618 now called
51:33representative she eventually comes off
51:36study uh was not interested in any other
51:39clinical trials or anything was just
51:41tired of this thing by this time
51:43remember she started in 2003.
51:46so here she is about 17 years later or
51:5017 plus years later uh with all of these
51:53things happening to her in between so in
51:55January 2021 I sort of had to recommend
51:58just resume imagine about a tolerable
52:00dose and be recommended home hospice and
52:03last I know she was still alive with
52:06disease in December 2021 so I chose this
52:10case to emphasize the point
52:12that just metastatic just can become a
52:16chronic disease in a fraction of
52:18patients now not all of them behave in
52:20this way but at least this is a good
52:22example to keep in mind that continuing
52:25to actively manage disease-related
52:27symptoms treatment related symptoms and
52:30trying to maintain them on a kinase
52:32inhibitor can kind of keep kicking the
52:35can down the road like Congress and
52:36Senate does all the time and allows the
52:39patient to to continue to to manage
52:45Invictus trial randomizing patients with
52:48metastatic gist three prior lines of
52:51failure of therapy randomized to either
52:54represent or Placebo as you can see the
52:58depths of response may not be that great
53:00that is resist PRS are relatively rare
53:03but you do see disease stabilization and
53:06I think this is a disease where we don't
53:08all of a sudden feel compelled to make
53:10it go away or disappear as long as you
53:13can control it and strike a balance
53:15between if controlling the disease and
53:17manageable toxicity patients can go on
53:20for quite some time the durability of
53:23the response and the benefit is also
53:25fairly fairly good too and here is the
53:27median PFS right the placebo or median
53:29PFS was one month the repressed
53:31mid-median PFS is just a little over six
53:34months and to sort of put it into
53:36perspective first line of median PFS is
53:38about 20 24 months second line so net
53:41nib now in the more recent trials uh
53:44comes in around 8 months regular F and
53:47it was right around five months or
53:49thereabouts and it's not a matter of
53:52attrition anymore the fourth line
53:54therapy does bring in about a six-month
53:56median survival it doesn't sound like
53:57it's a home run by a long shot but it
54:00does tend to help Kick the Can down the
54:02road like I described earlier and as you
54:04can see the PFS at 6 12 and 18 months on
54:06the right hand side there are uh
54:10diminishing fractions but nevertheless a
54:13group of patients who continue to
54:15benefit from the appropriate judicious
54:18use of this kindness and overall
54:20survival also gets impacted this is not
54:22just some of those transient responses
54:24the median overall survival for the
54:26representative arm was 18.2 months in
54:29the longer follow-up data set compared
54:31to only six months for placebo
54:33and that this is drug effect is
54:36reflected in the fact that those who
54:37were randomized to Placebo when they
54:39crossed over to representative there's a
54:41gray line in the middle
54:42even they benefited somewhere their
54:44median overall survival was 10 months
54:46now so I think the drug definitely has a
54:50great place if you will in the
54:52management of patients with gist it is a
54:55drug that does not have all the veg up
54:58related side effects
54:59as you can see I think the
55:02Constitutional effects can be there but
55:05the wedge of related side effects the
55:07diarrhea is not as bad the fatigue may
55:10or may not be but they certainly don't
55:12get enough hand foot syndrome or the
55:13Palmer planter editor this is easier and
55:16that's what gives both providers and
55:19patients the impression that this is
55:22better tolerated right and that's the
55:24argument that was made before the mccm
55:27committee to sort of try to introduce
55:30this in the second line as many of you
55:33may be aware the Intrigue study in the
55:35second line setting comparing
55:36representative did not show any
55:39superiority in terms of median PFS
55:42except for a specific molecular
55:44signature of primary ketox on 11
55:47secondary 17 18 mutant subset the
55:52read out exactly at the same level but
55:55the tolerability of this drug is clearly
55:57Superior if you will too either sunitnib
56:00or regular afternoon and so the
56:02guidelines are now modified to reflect
56:05that in a patient in the second line
56:06setting who is truly intolerantine
56:10uh representative would be a very
56:12reasonable alternative and that may be
56:14an argument to take it back to the
56:16payers to try to make the patients
56:18quality of life better because in
56:20general those who don't tolerate
56:22sunithmet well may not tolerate regular
56:24F and if greatly I guess like Kathleen
56:27mentioned earlier it's not a show-in all
56:29the time it doesn't correlate every time
56:32that if they don't tolerate one they
56:33won't tolerate the other but there is
56:36some correlations so as Dr Patel
56:39um for the majority of patients the
56:42stroke tends to be well tolerated with
56:44good quality of life so it is as you
56:47mentioned a good choice for many
56:48patients and for some a relief in side
56:53um some patients can experience muscle
56:54and joint pains that's maybe a little
56:56more prominent for them on on this one
57:00thinning and our hair quality change
57:02some patients develop this frizzy-ish
57:04kind of like hair that is we call it
57:10um nausea vomiting not that common but
57:13can can be present I've had a few Palmar
57:16plantar Earth Register but nowhere near
57:19what we experience with student never
57:21regret kind of across the board
57:24um fluid retention can happen stomach
57:28this one can have rare potential skin
57:31cancer so Baseline skin assessment and
57:33making sure patients are seen routinely
57:35for skin assessment and having them seen
57:37for any concerning changes
57:40potential heart related issues so
57:42Baseline heart studies if needed if
57:44patients at high risk you know I don't
57:46know that people do that globally but if
57:48they have a high risk they want some
57:51studies up front and then follow-up as
57:54needed with a lot of these drugs delayed
57:57wound healing this one just got listed
57:58higher on the list than others and Sun
58:01sensitivity but generally speaking
58:04people tend to do quite well without a
58:06lot of requirement for dose reduction in
58:13um for fluid retention
58:15um sometimes changing to a low sodium
58:17diet can make a difference if it's
58:19periorbital swelling that people are
58:20experiencing elevating their head on the
58:22pillow can be helpful sometimes
58:24diuretics can be helpful both for
58:27managing blood pressure who people
58:28develop high blood pressure and or fluid
58:31retention can be useful having them
58:33check their blood pressure and doing
58:37um in general I have not found the fluid
58:39retention to be like a significant
58:43um Quality of Life issue for most
58:50very good so take home messages again I
58:53think molecular genotyping is important
58:56for appropriate selection of therapy I
58:58think that area is going to become even
59:01more relevant as we go along the uh
59:04uh immediate future I think
59:06there are resistant mutations where
59:09certain drugs have selective activity
59:11and there may well be an indication for
59:13certain drugs for a certain molecular
59:16subtype so I think that's an important
59:18part the other thing is is multiple
59:20kinase Inhibitors are available they're
59:23all efficacious active management of
59:25side effects would allow maintenance of
59:28those intensity and avoid those
59:31interruptions and prolongation of
59:33survival certainly has and can be
59:36improved upon as time goes on Brian
59:39Kathleen any other comments before we
59:41move on to the next case
59:44well I mean I've been working on just
59:45ever since I was a postdoc back at Dana
59:48Farber about 25 years ago and I'm just
59:51blown away by the progress that's been
59:53made with this tumor I think we see it
59:54here we've got four lines of therapy
59:57which is pretty unusual to have four
59:59effective lines of therapy in a solid
01:00:02team where I think just remains one of
01:00:03the greatest success stories in targeted
01:00:05therapy and personalized cancer medicine
01:00:07I think things we didn't talk about
01:00:09today that might be coming down are like
01:00:11liquid biopsies perhaps to look at
01:00:13genotypes to manage these patients and
01:00:15we can maybe do another seminar in the
01:00:17future on that but um we just continue
01:00:19to involve in our understanding of the
01:00:23biology of just as well as the treatment
01:00:24of just and I think it's a fantastic
01:00:29so moving on to case three we chose this
01:00:32as a malignant peripheral nerve sea
01:00:36so this is a patient of ours 26 year old
01:00:41presents with about a three-month
01:00:43history of neck pain and an enlarging
01:00:47December 2019 MRI shows a fairly large
01:00:50mass at least cranial quarterly
01:00:53measuring almost close to 14 centimeters
01:00:57uh Superior and plate all the way to T4
01:01:00if you will wrapping around the tecal
01:01:03sac significant you know no narrowing
01:01:05but certainly wrapping around obviously
01:01:07a lot of ugliness in this large mass
01:01:10bone scan did not show any uh obvious
01:01:13osseous metastasis at that local site
01:01:15just to saw tissue Mass around the nerve
01:01:18Roots uh biopsy in January 2018 reported
01:01:22a spindle cell tumor extensive necrosis
01:01:26immunase stain showed some epithelials
01:01:28kind of markers as 100 the mesenchymal
01:01:32markers were negative and the suggestion
01:01:36was that this is a nerve sheath tumor
01:01:39so in February 2018
01:01:42the patient was treated at a different
01:01:45and got the concomitant or concurrent Dr
01:01:50rubison radiation therapy protocol
01:01:54This Was Then followed by about seven
01:01:57cycles of iphostomide and the topocide
01:01:59systemic therapy so basically that
01:02:01doctor would listen just as a radio
01:02:03sensitizer if you will and then the
01:02:06systemic doses where I phosphide and the
01:02:08topicide uh reports were that he had a
01:02:11positive response he had some sort of
01:02:12reduction of the mass and then in
01:02:16goes through a front back two-stage
01:02:19total resection that was a gross total
01:02:22unfortunately just a few months later
01:02:25by April 2019 there is a new right side
01:02:29at 1.6 centimeter lung nodule biopsy of
01:02:33the nodule certainly confirms metastatic
01:02:36sarcoma it has window and epithelioid
01:02:39features remember patient had Dr
01:02:42Roberson as a radio sensitizer so not
01:02:44quite full therapeutic dose but
01:02:46ifosomide bp16 War Therapeutics so in
01:02:49April 2019 we got forced into sort of
01:02:52that's when he came to see us to be
01:02:53honest uh we put him on doxorubicin into
01:02:56curba scene unfortunately two cycles and
01:02:59Progressive disease
01:03:01so given that the disease burden was
01:03:04relatively small we chose to sort of
01:03:07just treat the oligom metastatic disease
01:03:09with local directed therapies so patient
01:03:12got some stereotactic body radiotherapy
01:03:15to that right lung nodule
01:03:17again you know another six months or so
01:03:20later uh off therapy he presents to the
01:03:23emergency room now with
01:03:24right leg and hip pain uh pet CD shows a
01:03:28fairly large right pelvic metastatic
01:03:31lesion involving acetabulum and the
01:03:35uh there's a separate discontiguous
01:03:38metastatic lesion in the tail of the
01:03:41so at this time he moves on to the quote
01:03:44default second line regimen for soft
01:03:46tissue sarcomas in the United States at
01:03:49least Jim cider being those attacks
01:03:51along a day one day age schedule but
01:03:53unfortunately again no success two
01:03:56cycles later Progressive disease so this
01:03:59was becoming uh obviously far more
01:04:03difficult at this stage he gets goes
01:04:07through a re-biopsy this was sent for
01:04:09for NGS and lo and behold a track fusion
01:04:14uh comes up yeah so
01:04:17there's a whole new area essentially of
01:04:21um mesenchymal tumor pathology now that
01:04:23we're starting to diagnose and a lot of
01:04:25this is being discovered with the you
01:04:27know Newfound ability to do next
01:04:29Generation sequencing on a whole Variety
01:04:31in depth of tumors and so we've recently
01:04:33realized uh there's a n-track rearranged
01:04:37spindle cell neoplasm and I'm just
01:04:39showing you a case from my files here
01:04:41this isn't really the case we're talking
01:04:43about but typically these have a
01:04:45low-grade appearing appearance their
01:04:47spindle cell lesions you can see the h e
01:04:49on the left and essentially it's just
01:04:51fascicles and spindles there's a lot of
01:04:53pink in this picture because these
01:04:54things don't really have a high
01:04:56nucleocytoplasmic ratio typically
01:04:59and they resemble benign nerve tea
01:05:01tumors such as schwannomas although they
01:05:03don't look exactly like schwannomas
01:05:05they're reminiscent of schwannoma this
01:05:08case was positive for S 100
01:05:10cd34 in pan track and you can see those
01:05:13in the figures here the the photos that
01:05:16I've taken now I do want to say that
01:05:18hand track which is an antibody that a
01:05:20lot of us use as a screening tool
01:05:23essentially is not really specific for
01:05:25this diagnosis and so just because it's
01:05:27positive for the pantry antibody does
01:05:29not mean that it has a pan track Gene
01:05:31fusion and what I really want to
01:05:33emphasize is that the diagnosis here
01:05:36needs to be made with a genetic
01:05:37conformation demonstrating in some way
01:05:40that this has a gene fusion and
01:05:43immunistochemistry does not achieve that
01:05:46so essentially these n-track rearrange
01:05:49spindle cell neoplasms are an emerging
01:05:51group of molecularly defined rare soft
01:05:53tissue tumors and they span a wide
01:05:55spectrum of mortal morphologies and
01:05:57histologic grades I showed you a low
01:05:58grade one but in my experience they can
01:06:00have a variety of histologies most cases
01:06:03arise in patients within the first two
01:06:05decades of Life they have frequent
01:06:07co-expression of S100 and cd34 and when
01:06:09I teach Pathologists that's something
01:06:11that's unusual and I like to highlight
01:06:13as part of this diagnosis includes
01:06:16lipofibromatosis like neural tumors
01:06:18that's one of the subtypes of tumor that
01:06:21was originally described that's now
01:06:22included in this group of n-track
01:06:24rearranged spindle cell tumors and also
01:06:26the tumors that closely resemble
01:06:27peripheral nerve sheet tumors most cases
01:06:30Harbor and end track one gene fusion and
01:06:33typical partners are lmna tpr and tpm-3
01:06:36however in track two and in track three
01:06:39Gene fusions can be involved and they're
01:06:45so patient enrolls on an ongoing
01:06:47interactive trial most of you have
01:06:50experience with this or know about this
01:06:52track uh inhibitor that's been around
01:06:56now for quite some time and it may be
01:06:58hard to see but in the hilum of the
01:07:00spleen is that lesion sitting in what
01:07:04was described earlier is the tail of the
01:07:06pancreas if you will on the left hand
01:07:08panel at the February 2020 Baseline that
01:07:11steadily decreased and literally
01:07:13disappeared by about I want to say
01:07:188 to 10 months and then these tend to be
01:07:22durable so the latest follow-up scans
01:07:25that we have on this patient are from
01:07:27just uh a month ago if you will June
01:07:312023 at which time you can see right
01:07:33next to the Celiac axis that soft tissue
01:07:36mass does not exist right so the patient
01:07:38had a complete response and now 40
01:07:40months going on uh on on therapy so as
01:07:45Brian already outlined I think the
01:07:47centrac aberrations in sarcomas these
01:07:50are agnostic to histology or or
01:07:53epithelial mesenchymal tumors as you can
01:07:56see on the left hand side and the adults
01:07:58and the right hand side in the Pediatric
01:07:59population you can see them in a variety
01:08:03carcinomas and sarcomas the evidence of
01:08:08activity is pretty impressive I think
01:08:10this may be one of the latest uh
01:08:15uh great examples of of targeted therapy
01:08:18if you will and as you can see even the
01:08:22responses to the track Inhibitors
01:08:24happens to be agnostic to tumor type age
01:08:28uh or even the histology very nice
01:08:32looking waterfall plots very few
01:08:34Progressive disease a lot of attempts
01:08:37going on trying to study resistance to
01:08:40these first generation track Inhibitors
01:08:43that are second and even third
01:08:44generation track Inhibitors that are in
01:08:46clinical trials and that this area
01:08:49continues to develop and generate more
01:08:51and more excitement and enthusiasm I
01:08:53think this is the list for relevant to
01:08:55sarcomas I guess and Brian I left off
01:08:57the tongue twister that was on your
01:08:59slide earlier lipo fibromatosis like
01:09:02neural tumor off of this one but the
01:09:04classic one is infantile fibrosarcoma
01:09:08I think this is like worse than finding
01:09:11a needle in the haystack though right I
01:09:13think looking for n-track Fusion in a
01:09:17is generally not very rewarding so I
01:09:21think what will sort of what we the
01:09:23community has tried to do is to see but
01:09:25can you narrow it down somehow
01:09:27and there seems to be a suggestion this
01:09:29is by no means a biomarker of proven
01:09:33but if a uterine sarcoma shows an
01:09:36undifferentiated spindle cell pattern
01:09:37that's not the classic
01:09:40lyomyosarcoma or pachoma or endometrial
01:09:42stromal sarcoma then at least that may
01:09:44be one to think about that the quadruple
01:09:46negative just uh malignant peripheral
01:09:49nerve sheets tumors have some
01:09:51preponderance of it although again it's
01:09:53not very very common and myopericytoma
01:09:56and inflammatory myofibroblastic tumors
01:09:59would be other ones so if you run into
01:10:00any one of these entities then I think
01:10:03it's certainly worthwhile uh considering
01:10:06NGS early on I think a debate that
01:10:09continues on in the field of sarcoma
01:10:12medical oncology when should one do ngis
01:10:15is it a mandatory thing or a recommended
01:10:18thing at diagnosis do you do it later uh
01:10:23and I think part of the problem is that
01:10:25actionable targets are few and
01:10:27far-fetched to come by right so there
01:10:29are arguments on both sides I'm
01:10:30personally very conflicted here and I
01:10:32think a lot of of us are because these
01:10:34n-track Gene fusions really respond well
01:10:37many of these patients will have a
01:10:38Lazarus effect they can be have a lot of
01:10:40tumor burden the response is tremendous
01:10:43and so it does really raise this
01:10:46question of whether or not to do NGS on
01:10:48all for instance stage four sarcomas
01:10:50that are not responding to current
01:10:51therapy I don't have the answer I think
01:10:53it's a legitimately
01:10:55um good discussion you know can we
01:10:57afford to do this for all of our
01:10:58patients I don't know but I think we'll
01:11:00keep discussing it and hopefully
01:11:02hopefully we figure out a better way to
01:11:04do it better way to predict which one
01:11:06which of these are going to have n-track
01:11:07fusions in a less expensive way maybe
01:11:10just sequencing will get cheaper or
01:11:12bioinformatics product lines will get
01:11:14cheaper and that'll solve the problem
01:11:15exactly I mean I think the research will
01:11:17help address some of those things right
01:11:19if you keep doing it then I think there
01:11:22sort of that like this list up here on
01:11:24the slide that may be sort of the
01:11:26surrogate marker until other things sort
01:11:28of meet it halfway where uh you know the
01:11:31convenience and cost goes down and then
01:11:33maybe it's not that big a debate as to
01:11:35should we or should we not kind of thing
01:11:37so um the most common and checking
01:11:40converters we've used in our practice
01:11:41anyway they are attracting Ebony and
01:11:44um we like both of you have had very few
01:11:47patients with these
01:11:49um uh tumor types that we were able to
01:11:52use these medications but in the
01:11:54patients who have had them they've had
01:11:56very dramatic responses for very long
01:11:58periods of time and I've had patients
01:12:02um on one for a while and progressed and
01:12:04went to another and were on it still on
01:12:07it for an extensive period of time
01:12:10um in my experience these drugs have
01:12:12been very which is pretty limited
01:12:14um have been very well tolerated with
01:12:16minor symptoms of fatigue potential
01:12:19diarrhea constipation taste changes
01:12:22fluid retention dizziness nausea
01:12:26um shortness of breath I personally have
01:12:29not seen but it made the list
01:12:31um muscle joint experience
01:12:33some cognitive impairment maybe some
01:12:35mild confusion is potentially an issue
01:12:37weight gain cough fevers
01:12:41joint aches and pains vision changes
01:12:43again these are all kind of mild
01:12:45symptoms my experience with patients on
01:12:47this medication has been that um
01:12:51it's been very well tolerated with a few
01:12:53side effects and not a lot of Need for
01:12:55dose modifications I don't know about
01:12:57you Dr Patel I don't know how much of
01:13:00the drugs you give Dr Ruben Reuben
01:13:03so no you're correct Kathy I I think the
01:13:05major difference between these two drugs
01:13:07from a clinical perspective from a side
01:13:10effects standpoint is the cognitive
01:13:11impairment that seems to be maybe a
01:13:13little higher with and cracked in it
01:13:15than lateral tract in it but I think the
01:13:17way the field is moving I think
01:13:19eventually we're going to have these
01:13:20subsequent generation molecules that
01:13:24will hopefully be much better tolerated
01:13:33all right so we'll move on to the last
01:13:35case this is one that describes a
01:13:39patient with an epithelioid sarcoma so
01:13:41this is a 26 year old Arabic male who
01:13:46Emirates October 2019
01:13:50presents with a gradually increasing
01:13:52right perineal Mass over the previous
01:13:54six months Mr initially showed a five by
01:13:57four three four point three centimeter
01:13:59solid Mass eventually this got even
01:14:02larger uh as is not atypical for this
01:14:06histology is eventually we'll talk about
01:14:12lymph nodes in the draining basins that
01:14:16were enlarged and very suspicious for
01:14:19pathologic involvement so just as a side
01:14:23educational Point sarcomas have a
01:14:26tendency to generally spare lymph nodes
01:14:28right majority of the common histologies
01:14:31do not go to lymph nodes as commonly as
01:14:34epithelial tumors would but there are a
01:14:37few histologies that are an exception
01:14:39right uh clear cell sarcoma can go to it
01:14:42epithelioids will do it
01:14:44angiosarcomas can do it the small cell
01:14:46ones can do it so there are a few of
01:14:49them that clearly have a predilection if
01:14:52you will for for lymph node metastases
01:14:54this just happens to be one that one
01:14:57should keep in mind so that's why the
01:14:59lymph nodes were looked at and and
01:15:02certainly were very suspicious
01:15:04ultrasounded guided ultrasound guided
01:15:06biopsy of the lesion pathology confirms
01:15:08an epithelioid sarcoma proximal variant
01:15:11uh the immunohistochemistry is listed
01:15:14here but I'll let Brian describe it to
01:15:17yeah so here's an example of an
01:15:19epithelioid sarcoma of the proximal type
01:15:21and it points out there are two types of
01:15:23epithelioid sarcoma we recognize now
01:15:25there's the classic type that's the one
01:15:27that forms basically on the hands and
01:15:29feet typically but it can occur in a
01:15:33um likes to go to lymph nodes as shreyas
01:15:35mentioned and then there's the proximal
01:15:37type of epithelial sarcoma and I'll get
01:15:40to it in a minute but this tends to
01:15:42um arise typically on the limb girdle
01:15:45here we can see the H and E and it
01:15:47essentially looks almost like breast
01:15:48cancer it's a not very non-specific
01:15:50histology where you've got essentially a
01:15:53sheet of epithelioid cells and in the
01:15:55center of that rounded sheet you can see
01:15:57there's necrosis we call that Camino
01:15:59type necrosis these are typically very
01:16:02positive for keratin and EMA and other
01:16:04epithelial markers and importantly
01:16:07um they stain they have loss of ini1 and
01:16:11so ini1 is part of the bath complex and
01:16:15it's essentially a tumor suppressor so
01:16:17when it's left it can cause cancer and
01:16:19ini1 is not absolutely specific for
01:16:21epithelial there's a variety of
01:16:23carcinomas and sarcomas now that are
01:16:25known to lose ion i1 but it is
01:16:27absolutely typical the point here is
01:16:30um I don't have I don't show this but um
01:16:32epithelioid sarcomas also stain
01:16:34positively for cd34 and the combination
01:16:37actually of keratin and cd34 is is kind
01:16:40of unusual so when you do see that it
01:16:42might point to an epithelioid sarcoma
01:16:44and since these have a non-specific
01:16:45histology they can actually be diagnosed
01:16:47as cars or misdiagnosed as carcinoma
01:16:53so again I mentioned there's two
01:16:54subtypes of the UI sarcoma the classic
01:16:56type and the proximal type the proximal
01:16:58type classically involves the Deep soft
01:17:00tissues frequently arises in these
01:17:02truncal locations buttock or hip they do
01:17:06affect predominantly young to
01:17:08middle-aged adults and they're
01:17:09characterized as we showed by loss of
01:17:12smart B1 which is also called ini1
01:17:15that's the immune histochemical name for
01:17:16it also called bath 47 sniff 5.
01:17:20importantly these are extremely
01:17:22aggressive cancers they can have
01:17:24metastasis the lymph nodes lung Etc
01:17:27and they've got a poor prognosis
01:17:30so the patient comes to us in February
01:17:322020 with progression of the primary
01:17:34tumor the lymphadenopathy was pretty
01:17:36impressive by that time not necessarily
01:17:39large volume but fairly diffused along
01:17:42the inguinal and and
01:17:48non-specific pulmonary nodule to be
01:17:51followed but nothing definite in the
01:17:53lungs at the time of presentation
01:17:55so we chose to put him on gym side of
01:17:57being endocytaxel and we'll talk about
01:17:59this in a few minutes the standard 900
01:18:02100 day one day age schedule he does get
01:18:05a partial response lymph nodes all
01:18:08normalize uh primary tumor is reduced in
01:18:11size uh he then gets pre-operative
01:18:14radiation therapy
01:18:1650.4 grain 28 fractions this was
01:18:19completed in August 2020
01:18:24traditional chemotherapies I don't need
01:18:27to go into this in a huge extent but
01:18:30um typically day one jump side of being
01:18:32only patients tend to do generally
01:18:33pretty well with mild fatigue maybe
01:18:35flu-like syndrome
01:18:38um they take steroids dexamethasone
01:18:40before the treatment with the dose of
01:18:43taxol the day of and the day after to
01:18:45prevent fluid retention and can also
01:18:48help for potential allergic reaction
01:18:50they may experience
01:18:52um diarrhea constipation fluid retention
01:18:55pneumonitis with the gym cited being
01:18:57growth factor support which can cause
01:18:59aches and pains in traditional
01:19:04so back to the patient uh after
01:19:06pre-operative radiation younger goes
01:19:08radical resection of that perineal Mass
01:19:12confirmed diagnosis of proximal type
01:19:15epithelioid sarcoma tumor sizes listed
01:19:18there there was therapy effect a
01:19:21combination of both chemo and radiation
01:19:23of course mitotic activity in this
01:19:25setting does not help us a whole lot but
01:19:28there was gross total resection and the
01:19:30margins were clear and as of January
01:19:322022 he was free of any gross evidence
01:19:35of disease and that's the last follow-up
01:19:39so the choice of therapy for epithelial
01:19:41sarcomas I think the classic or
01:19:44conventional epithelioid sarcomas which
01:19:46typically present in distal extremities
01:19:50can be indolent creeps up along the
01:19:53lymph node chain if you will the classic
01:19:55story would be there's a distal upper
01:19:57extremity lesion epitrochlear node
01:19:59eventually axillary nerves and
01:20:02eventually they'll get multiple tiny
01:20:04pulmonary metastases with some pleural
01:20:05involvement so that Natural History can
01:20:08be uh extended if you will but the
01:20:12majority of the proximal type as Brian
01:20:14mentioned earlier tend to behave very
01:20:19there's some evidence and small series
01:20:22if you will that suggests the gym side
01:20:24of indocitaxel is selectively more
01:20:27active uh Sylvia stacioti and Anna Maria
01:20:30freza from Milano sort of put a series
01:20:34together worldwide experience if you
01:20:36will of all chemotherapy or systemic
01:20:39therapy regimens and the punch line is
01:20:41that after cycling based regiments had
01:20:43about a 25 response rate Jim started
01:20:46Windows to taxol had about a 25 response
01:20:49rate and unfortunately there was no
01:20:51activity of Paz open if at least in that
01:20:53collected uh series of cases so clearly
01:20:57from a toxicity standpoint if not
01:20:59efficacy standpoint the gym side windows
01:21:01attacks all sort of wins out so if you
01:21:03have a patient with epithelial sarcoma
01:21:06certainly these are the choices that you
01:21:08would want to keep in mind and primarily
01:21:11pay attention to what the objective is
01:21:14that you're trying to achieve in a
01:21:16patient this is a patient who had
01:21:17primary tumor and Regional disease
01:21:19disease meaning there was some surgical
01:21:22Salvage provided the lymphadenopathy
01:21:24behaved right I think if the lymph
01:21:26adenopathy did not respond clearly that
01:21:28would have become a much more difficult
01:21:30situation but in a potential
01:21:32uh surgical Salvage you want to use your
01:21:36regimen that may give you the best
01:21:38cytoreductive probability than just
01:21:41stability yeah empathyroid sarcoma is
01:21:43characterized by loss of ini1 as
01:21:45mentioned earlier and it turns out the
01:21:47smart B1 is a core subunit in this
01:21:49chromatin remodeling complex so when you
01:21:52have deletion irritation leads to loss
01:21:55of ini 1 expression by immunistic
01:21:57chemistry and um that loss at the
01:22:00protein level results in chromatin
01:22:01remodeling which affects transcription
01:22:03remember that the um remodeling complex
01:22:09um leads to all sorts of transcriptional
01:22:11changes both both up and down actually
01:22:14um cyclin D1 cdk4 regulation is
01:22:17important here also um one of the
01:22:21downstream Pathways that's been
01:22:22identified is the Sonic Hedgehog pathway
01:22:25and so again when you lose the swap by
01:22:29sniff complex and it's caused by
01:22:31destruction essentially loss of one of
01:22:33the components i91 in this case it tilts
01:22:35that balance of transcription and can
01:22:37affect transcription as I mentioned it
01:22:39can result in some transcription going
01:22:42up some going down but essentially it
01:22:44remodels the entire transcriptional
01:22:47complex resulting in you know loss of
01:22:49Regulation or changes in regulation in
01:22:52various Downstream Pathways such as I
01:22:54mentioned in cyclin D1 and Sonic
01:22:59the reason for the excitement in this
01:23:02area is that there is now a targeted
01:23:05treatment towards that ini one loss
01:23:07right this course sort of activates the
01:23:09easy H2 pathway through the prc1 prc2
01:23:12complex if you will uh and inhibition of
01:23:16the ezh2 pathway certainly can
01:23:18theoretically induce some benefits so
01:23:21there was a trial looking at ezh2
01:23:24inhibitor tazomatostat in patients with
01:23:27epithelial sarcoma and incidentally
01:23:29interestingly enough in synovial
01:23:31sarcomas and and uh some kidney tumors
01:23:36at the same time the response rate for
01:23:40the epithelial sarcoma cohort is
01:23:42relatively low at about 11 to 15 percent
01:23:45the Disease Control rate is what the
01:23:48predominant effect of this drug is and
01:23:51then add to it the fact that it is
01:23:53generally very well tolerated with minor
01:23:56AES that allows patients to stay on the
01:23:58drug for while in a disease that does
01:24:02not have too many great other options is
01:24:06the combination of things that sort of
01:24:07led to the approval of this drug so it
01:24:10has a better set now is approved for
01:24:13patients with metastatic epithelioid
01:24:15sarcoma where the intent may be to sort
01:24:18of just stabilize the tumor and maintain
01:24:24here is the spider plot if you will as
01:24:26you can see the depth of responses are
01:24:29relative is is relatively less but as
01:24:31you can see most of the patients have
01:24:34continued stabilization of the tumor so
01:24:37as Dr Patel highlighted um
01:24:39for the most part
01:24:41um overly well tolerated
01:24:43the dose is 800 milligrams twice daily
01:24:46in my experience weight loss decrease
01:24:49appetite was pretty common
01:24:52um bringing in nutrition can be helpful
01:24:54if patients are losing weight
01:24:57um specifically additional labs to pay
01:24:59attention to include triglycerides and
01:25:04fatigue is obviously a possibility not
01:25:07as vomiting some patients experience
01:25:09headaches and a slight increased risk of
01:25:12secondary malignancies
01:25:14um is a potential but generally speaking
01:25:16patients who have been on the strike
01:25:19it's been well tolerated and no
01:25:21significant major side effects in our
01:25:23patient population
01:25:26so in conclusion then I think what we
01:25:29are trying to convey here is the
01:25:32importance of the multidisciplinary team
01:25:34right you need all the arms and the
01:25:36significant components that help us take
01:25:38care of these patients in the clinic
01:25:40that we need a diagnostic team you need
01:25:43the surgical team to extirpate the tumor
01:25:45where it's feasible the medical teams
01:25:48and radiation oncology teams certainly
01:25:51need to play their role as an adjunct
01:25:53and nothing would be complete and the
01:25:57care is never optimal without the other
01:26:00supporting mechanisms or supporting
01:26:03Specialties that are listed on the right
01:26:04hand slide so it does take a whole
01:26:10a tag team if you will and present the
01:26:14same story and I'm sure that your
01:26:16experience for those of you who have
01:26:18experience with these tumors in your
01:26:22so key takeaways I think some of these
01:26:24we've been emphasizing uh
01:26:27uh throughout the case presentations but
01:26:29for just again as I mentioned earlier
01:26:31prolongation of survival and metastatic
01:26:33disease has been accomplished ProActive
01:26:36Management of side effects is very
01:26:37critical uh continuing some tolerable
01:26:41tyrosine kinase inhibitor even when the
01:26:43patient runs out of options is
01:26:47and then the future is more towards
01:26:50precise targeting based on molecular
01:26:53profiles even in the resistance setting
01:26:55for a long time we've been sort of
01:26:57saying that resistance is very
01:26:59heterogeneous and there is no way to
01:27:01sort of try to make a therapeutic
01:27:04decision I think they're starting to
01:27:06sort of make some headways in that area
01:27:08to at least pick the dominant clones
01:27:11where there may be drugs that are
01:27:13effective uh against those resistant
01:27:16clones as for other soft tissue tumors I
01:27:20think the example of just like Success
01:27:22is Not rampant and common
01:27:25but we've tried to highlight a few
01:27:27subsets where there is progress as Brian
01:27:31outlined during the talks there is hope
01:27:34that with continued research we may keep
01:27:36nibbling away at this large complex
01:27:39group of diseases
01:27:41uh we also mentioned routine versus
01:27:44directed use of NGS continues to be
01:27:48debated but this may evolve as time goes
01:27:51on uh there clearly are examples like
01:27:54the intract fused case that we talked
01:27:57about had we known that the patient had
01:27:59a track inhibitor earlier and had the
01:28:02track Inhibitors been available earlier
01:28:04the patient's life would have been a lot
01:28:06simpler hopefully right so that's the
01:28:08would have could have should have kind
01:28:10of story but at least moving forward
01:28:12those are the kinds of examples that
01:28:14will educate Us in terms of fine-tuning
01:28:16a pathway or a recommendation for
01:28:19broader use uh I think
01:28:22patient characteristics tumor
01:28:23characteristics clearly are important
01:28:26and they inform the personalized
01:28:28therapeutic approaches and as always I
01:28:31think continued research and enrollment
01:28:33on clinical trials is of absolute
01:28:35Paramount importance if we are to make
01:28:38continued progress in these groups of
01:28:40diseases so I'm going to stop my
01:28:42Preamble I'll let Brian and Kathleen add
01:28:45anything to it but thank you very much
01:28:48for those of you who have joined in for
01:28:50the entire four cases I hope you found
01:28:57I think this was a wonderful experience
01:28:58I enjoyed working with both of you and
01:29:00thank you to everybody watching
01:29:03yeah likewise I've enjoyed this
01:29:04afternoon discussing these cases with
01:29:06you and I just would really want to
01:29:08emphasize the treatment of sarcomas is a
01:29:11team sport it really takes a lot of
01:29:13people to treat these patients they are
01:29:15complicated but we are learning every
01:29:18day and I feel like there's been so much
01:29:19progress made I look forward to giving
01:29:21future presentations where we can
01:29:23discuss the continued progress in this
01:29:25really super interesting area thanks