"Stage IV Breast Cancer at Diagnosis: To operate or not: Swinging the Pendulum" and "WHO 2021 Classification of CNS Tumors - THE FIFTH - an update"

October 07, 2021

Information

Yale Cancer Center Grand Rounds | October 5, 2021

Presentations by: Drs. Mehra Golshan and Anita Huttner

ID6966

To CiteDCA Citation Guide

00:00So I think we can get started.
00:03So hello everyone,
00:04welcome to one more YCC green Browns.
00:08I am Antonio Mora,
00:10chief of neurology and today is my
00:12pleasure to introduce our wonderful speakers,
00:15both of whom from our very own Cancer Center.
00:20The first speaker is Doctor Merrick,
00:22Goshen, who is a professor of
00:25surgery within oncology and Deputy
00:27Chief Medical Officer for surgical
00:29services at Smilow Cancer Hospital.
00:31Doctor Goshen earned his medical
00:33degree from Case Western Reserve
00:35University School of Medicine.
00:37And he also pursued an MBA at MIT.
00:42As well as a fellowship in breast surgical
00:44ecology at Northwestern Memorial Hospital,
00:47doctor Goshen is an innovator in
00:49tailoring surgery and therapy for
00:50women with early stage breast cancer.
00:52With funding support from the
00:54breast Cancer Research Foundation
00:56and National Institutes of Health.
00:58He is the principal investigator.
00:59Several phase two trials aiming to reduce
01:02the need for second surgeries or re
01:04excisions in women with breast cancer,
01:06one of which uses innovative image
01:09guided operating room capabilities to
01:11capture and remove all residual tumor
01:13utilizing MRI and mass spectrometry,
01:16which is used at Yale's hybrid
01:18operating room.
01:19Prior to joining nail,
01:21doctor Gosh spent 17 years in Boston
01:24at the Dana Farber Cancer Institute,
01:26where he was the inaugural and
01:29incumbent Dr Abdul Mohsin and Susannah
01:31out to hearing the distinguished
01:33chair in Surg conchology.
01:36He also served as the director
01:38of the Breast Surgical Quality
01:39Fellowship at the Dana Farber.
01:41And was an associate professor of
01:43surgery at Harvard Medical School.
01:45So without further ado.
01:47Doctor Goshen, the foresters.
01:50Thank
01:50you so much for that kind introduction
01:54and I'm excited to be here.
01:56I know we have one hour and we're
01:58going to try to go through two talks,
02:01so I will do my best to stay on time.
02:04And although you know in the
02:06introduction you talk about,
02:07you know, reducing the need for
02:09surgery and minimizing surgery.
02:11One interest of mine early on when
02:14I finished or was in training and
02:17fellowship was the role of surgery
02:19in stage four breast cancer.
02:21I'll kind of go through how the pendulum
02:24has really swung in actually two directions,
02:28so historically stage four breast
02:30cancer as a medium survival.
02:31This is really older data before more modern,
02:34targeted therapies of less than two years,
02:36and really treatment has been
02:38chemotherapy endocrine therapy more
02:40recently targeted or molecular therapy.
02:42There has been some radiation
02:44to sites of metastatic disease,
02:45and you know, interestingly,
02:47when people started looking at
02:49whether local regional therapy.
02:51Was being done.
02:52That number was actually fairly high,
02:5535 to 60% of women were undergoing
02:58local regional therapy in the United
03:00States when really it should have been
03:02reserved for palliation at the time.
03:04And then there was a question of whether
03:06there is any survival benefit in doing this.
03:08This is United States data,
03:10certainly most women fortunately present with
03:13localized or regional disease on stage four,
03:16breast cancer in the United States
03:18and this is very different when
03:19you look outside of EU.
03:21S.
03:21Is only about four to 6% of the population.
03:25You know,
03:26when I was taking my surgery boards,
03:28I would have really I I would have
03:30failed the room if I had suggested that
03:32we should do surgery in this stage.
03:34Four setting outside of palliation.
03:37It was generally accepted that local
03:39therapy did not prolong survival
03:41and there was some earlier data
03:43suggesting that there may be some
03:45stimulation of metastatic growth.
03:46However,
03:47we know that there are diseases
03:48in the stage for setting where
03:50resection of the primary and or
03:52metastatic tumor site could improve
03:54survival or does improve survival.
03:56For example, in colorectal disease,
03:58potentially with metastatic disease to
04:00the liver or in renal cell carcinoma,
04:03and there are good reasons
04:04to leave the primary alone,
04:06and there may be reasons to
04:07resect the primary tumor.
04:08For example,
04:09it is very easy to measure disease
04:11as opposed to getting scans when
04:14you leave the primary tumor alone.
04:16There is morbidity associated
04:18with resection in with even in
04:21a breast cancer surgery,
04:22certainly with mastectomy and more
04:25complex closures and reconstructions.
04:26With sometimes are required,
04:28there was some early data suggesting
04:31sources of cytokines or angiogenesis.
04:33Inhibitors which restrain growth
04:35could be released with metastasis.
04:37And really you know a question
04:39on whether there is a survival
04:41benefit in this setting or not.
04:43We did use surgery in the
04:45palliation of symptoms.
04:46Certainly fear of uncontrolled local disease.
04:49There was suggestion of reducing
04:51the shedding of metastatic cells
04:54and you know could it.
04:55Potentially if you respect the
04:57site provide more effective.
04:59Systemic therapy. Again,
05:01there was data and ovarian cancer,
05:04renal cell cancer and colorectal
05:06cancer setting about surgical debulking
05:09and surgical removal of disease,
05:11and again, this was work that I started
05:15about 2/2 and a half decades ago.
05:18So I say challenging the
05:19standard so Seema Khan,
05:21who was one of my attendings
05:23when I was a fellow,
05:25presented in 2002 in a in in a
05:29not a major surgical society or.
05:31On Koleji society was called
05:34Central Surgical Society,
05:35looking at the National Cancer Database
05:38for women with stage four disease.
05:41You know about 4% of patients in EU?
05:43S presented with stage four breast cancer.
05:45This is again in the 1990s median
05:47age or mean age of 62,
05:50which is really in line with our
05:52average age of breast cancer in
05:54the United States and you know,
05:55she looked at 16,000 women over a.
05:59I think it was a two or three
06:00year cohort period of time.
06:02And first you know the thing that
06:04was surprising to us and to her
06:05and to others was that almost 60%
06:07of women underwent local therapy.
06:10About 60% underwent mastectomy,
06:13about 40% underwent breast
06:15conservation and and you know,
06:18you can see what the negative
06:20margin rates were at the time.
06:23Not surprisingly,
06:24those that either did not undergo
06:26surgery or underwent mastectomy had
06:29larger burden of disease in terms of.
06:32Tumor size and you know she was
06:34the first to really present that.
06:36You know, if you didn't do surgery,
06:38Sir survival was twenty months.
06:40If he did,
06:41breast conservation was 27 months
06:43and if you did a mastectomy,
06:4532 months and again suggesting that
06:48potentially there is a survival
06:50benefit in the surgical cohort.
06:52You know those that had bone or soft
06:55tissue disease tended to do better.
06:57Certainly if you had fewer
06:58sites of metastatic disease,
06:59your outcomes were better giving chemo
07:03and or endocrine or combination of
07:06therapy ended up being of benefit and
07:08this is something that seem Doctor
07:10Khan has spent a lot of time on as
07:13well and we'll get to the modern
07:15era is on margin positive ITI and
07:18whether that would influence outcome.
07:21So independent predictors of survival.
07:23Or the use of systemic therapy?
07:24Certainly the location of metastatic disease.
07:26The burden of disease and the type
07:29of surgical resection that was done.
07:31And really for four or five years,
07:33this presented as central Surgical
07:35and published in surgery really didn't
07:38get much attention until 2006 to 2009.
07:41So guilty barbiere at MD Anderson decided
07:44to look at their stage four breast cancers.
07:47The mean Age was a little bit
07:49younger in their cohort.
07:50They were, you know,
07:52somewhat surprised at about.
07:5340% of their patients underwent surgery,
07:56have had breast conservation,
07:57have had mastectomies, and you know what?
08:00We would probably expect is
08:02that the patients were younger,
08:04less likely to have nodal involvement,
08:06fewer sites of metastatic disease
08:09in their cohort.
08:12And when they looked at their
08:14follow-up for 32 months,
08:16there was a trend towards better
08:18overall survival in the surgery group.
08:21And there was a benefit in terms of
08:25metastatic progression free survival.
08:27Then in the GPIO and there
08:29was an accompanying editorial
08:31by Monica Morrow and 2006,
08:34and I think it was something about this.
08:36The horse out of the barn.
08:37There were 300 patients
08:39with metastatic disease,
08:40with the Geneva Tumor Cancer
08:42Registry on the use of local
08:44therapy and again little over half
08:47the patients didn't have surgery,
08:49but 127 patients did.
08:51Most were mastectomies.
08:53They describe breast conservation as tumor,
08:55ectomy's negative margins and about half and.
08:59Nodal surgery in about 1/4 of patients,
09:02and this is just kind of a the diagram
09:05breaking that down in a schematic
09:08or graph form those that ended up
09:11undergoing surgery versus not were younger.
09:13Lower burden of disease in terms of
09:16the size of tumor and nodal disease,
09:19more likely again to have a single
09:21site of metastatic disease or less
09:24likely to have visceral metastasis
09:26more likely to undergo radiation.
09:29And then you can see what the
09:31use of chemotherapy and endocrine
09:32therapy was the same.
09:34And again, this is,
09:35you know,
09:35leads the thought of potential
09:37selection bias.
09:38If you were able to resect the
09:40tumor and get clear margins,
09:41there was a survival benefit as
09:44opposed to those that did not undergo
09:46surgery or that have positive margins.
09:49And then Fields Group looked at the
09:51wash U data over almost a decade,
09:54again about half of patients
09:56underwent surgery.
09:57This is a much longer median.
10:00Follow up of 142 months and again there was
10:03a survival benefit for surgery versus not.
10:06And there there is a theme in in.
10:08In all this there was a 250
10:10institution review over almost
10:13a two decade period of time.
10:15This was published in the Annals of Surgery,
10:17but Blanchard again.
10:19About 60% had surgery in the
10:22stage four setting and survival
10:25was 27 months versus 17 months.
10:28So, as I alluded to,
10:29there is selection bias, potentially
10:32younger woman with smaller tumors,
10:34less knodel involvement,
10:35fewer sites of metastatic disease,
10:37and this is kind of the differences
10:40between the studies from Seema Khan
10:42and Repeate and guilty Barbie era.
10:44And from the wash you and
10:46the the other data again.
10:48Younger women with smaller tumors,
10:50less nodal involvement,
10:51and fewer sites of metastatic
10:53disease had surgery.
10:55And certainly there have been a lot of
10:58attempts statistically and in terms
10:59of matching to be able to look at
11:02whether that difference continued or not.
11:06So this was a work that a
11:08previous resident of mine decided.
11:09Well,
11:10let's look at the Brigham and Farber and
11:12Mass general data and you know again,
11:14very similar to what everyone else did.
11:16You know we had a pretty small
11:18cohort of patients a little
11:20bit more modern era treatment.
11:21About 40% of our patients had
11:23surgery in the stage for setting,
11:25and I found that actually pretty
11:27surprising to see it was that high.
11:29But we were actually the first
11:31group to look at whether the
11:34timing of diagnosis or surgery.
11:36In relationship to the
11:37diagnosis of stage four,
11:39disease made a difference or not.
11:41About 25 out of those 61 patients had
11:45that surgery before stage 4 diagnosis.
11:47I'll go over why this is probably
11:50potentially important and 36
11:51after stage 4 diagnosis this is
11:53kind of hard to read, but again,
11:55those in the surgery group in terms
11:58of sites of metastatic disease
12:01very similar to previous studies
12:03with the surgery group having
12:05fewer sites of metastatic disease.
12:07Versus those that did not undergo surgery.
12:11And again, if you underwent surgery,
12:13you're more likely to get radiation therapy.
12:16So our median survival from the
12:19surgery group was 3.52 years
12:21and in the nose surgery group,
12:23just like everyone else.
12:242.36 years.
12:25However, the timing of diagnosis of
12:28stage four disease before after surgery,
12:31if it was done afterwards,
12:33that survival was four years
12:36versus before a 2.4 years.
12:38So you know,
12:39we you know our group looked into
12:41this and could this be an example
12:43of the Will Rogers phenomenon?
12:45Honestly two decades ago, if you ask me.
12:47But that was I didn't know the
12:50example that that Will Rogers uses,
12:52that when the Okies left the state of
12:54Oklahoma for the state of California,
12:56they raised the average IQ of both states.
12:59So I'll let you guys ponder
13:01that as we as we move on.
13:03So this was the first paper to suggest
13:06that the maybe it's there is no survival
13:08benefit in surgery and it's really the
13:10timing of surgery in relationship to
13:12the diagnosis of stage four disease.
13:15This shows the difference
13:16between surgery and not.
13:18But when we looked at the timing,
13:20that difference went away.
13:21So then I asked another colleague of
13:24mine that we recruited Laura Dominici.
13:26We looked at the NCCN database
13:28of stage four breast cancer.
13:29Again a little bit more modern,
13:31era 1000 patients,
13:33a much larger group.
13:35And then we did a match analysis
13:37of 236 non surgery patients to
13:4054 patients with that had surgery
13:42followed by drug therapy and again
13:45that survival benefit that was being
13:47seen in the surgery group versus
13:50non surgery actually disappeared.
13:52Survival is 3 1/2 versus 3.4 years.
13:55We matched her age,
13:56number of sites of metastatic disease,
13:58ER, her two sites of metastatic disease,
14:01and again I and my there was a very few
14:04of us who actually came out strongly
14:07against surgery in the stage for setting.
14:10And all I've been talking about is
14:13retrospective data, and obviously,
14:14you know with this you know
14:16anything in the world of oncology.
14:18Want prospective data?
14:19So the world of prospective data came
14:22from really a couple of brilliant folks.
14:25One is Raj Way bad way.
14:27Who's runs the breast service
14:30at Tata Memorial in Mumbai,
14:33India?
14:33They ran the first randomized trial of
14:37surgical removal of primary
14:40tumor with lymph node.
14:43Surgery in the metastatic setting there.
14:47Endpoints where primary endpoint was
14:49looking at removal of the primary
14:51tumor and actually nodes on overall
14:53survival and progression survival,
14:55and we're going to go over a couple of the
14:57randomized trials that have been done.
14:59That again, the Tata Group
15:01and Roger Roger Broadway,
15:02where there's a first looked at 350 patients.
15:05They were randomizing early to surgery,
15:09will go over to next to the
15:11the Turkish Medical Federation,
15:14which did drug therapy first,
15:15followed by surgery and finally.
15:17We're going to get to the E kog
15:19trial in the United States that
15:20I helped with with semakan drug
15:22therapy first followed by surgery.
15:24So the group in India looked at
15:26randomizing woman with stage four breast
15:29cancer to local regional therapy to none.
15:31They underwent local regional therapy
15:34and then if indicated anti estrogen
15:37therapy in the no local regional therapy,
15:39they were followed by when
15:41indicated anti estrogen therapy.
15:43Note it's important to know that there
15:45were in the time of her two positive.
15:48Breast cancer.
15:48None of the patients receive
15:50anti her two therapy,
15:52so that's a criticism of the trial.
15:54But again this was done.
15:55You know,
15:56deck started decades ago where you
15:58know anti her two therapy was just.
16:01You know getting approved in
16:02the United States and certainly
16:04in resource limited countries.
16:06It's not something that was,
16:08you know,
16:08automatically approved and paid for.
16:11This is the matching.
16:12They matched the you know their
16:14patient population very well and
16:16looking at overall survival.
16:18There was actually no difference
16:20between the two groups.
16:22They tried breaking it down
16:24by menopausal status numbers,
16:26the sites of metastatic disease,
16:27a number of sites of metastatic disease,
16:29like with that were done like
16:31the previous trials,
16:31and you can see really no difference.
16:35Interestingly,
16:35distant progression free survival
16:37was actually lower in the local
16:40regional therapy group as opposed
16:42to those that did not.
16:44And again,
16:45this is different than what will get to this.
16:47The Turkish and the US trial they
16:50were diagnosed with stage four breast
16:52cancer underwent surgery first,
16:54then followed by Agilent therapy.
16:58So Attila Saran,
16:59who's add Pittsburgh but helped run
17:01on behalf of the Turkish Federation
17:04of Society of Breast Disease.
17:06On randomized trial of evaluating
17:08resection of primary breast
17:09tumor with women with stage four,
17:12breast cancer,
17:13and these were actually simultaneous
17:15same day presentations at the
17:17San Antonio Breast Conference.
17:19Their early presentation in 2013
17:21is actually ends up being different
17:23than what they ended up publishing.
17:25Will spend a moment or two on that.
17:27Their primary goal is assessive.
17:29Early surgical treatment of the
17:31primary tumor and stage four
17:32disease effects overall survival.
17:33They also looked at progression
17:35free survival, quality, life,
17:37and morbidity different than the
17:39Tata group stage four breast cancer.
17:42That presentation was randomized
17:44as systemic therapy.
17:46Then local therapy for local progression
17:49versus initial local therapy.
17:51Uh,
17:52then a systemic therapy
17:54and then looking at overall survival
17:57chemotherapy was given to all patients
17:59either immediately or after randomization.
18:01All hormone receptor positive patients
18:04received anti estrogen therapy
18:06different than the Tata Group.
18:08The her two positive,
18:11overexpressed received trastuzumab therapy.
18:15Most patients if they underwent
18:18local therapy, underwent mastectomy.
18:20Radiation was given to some patients
18:23with with sites of metastatic disease.
18:26And early on, looking at the
18:28difference between surgery and those
18:30that just received systemic therapy,
18:32there was no statistical difference.
18:35Overall, when they broke it down by
18:39numbers of sites of metastatic disease,
18:41and if there was just a single site
18:44versus multiple sites in the Solitaire
18:46E or oligo metastatic setting,
18:48there was a suggestion,
18:50potentially of survival benefit
18:52and this is what they ended up
18:54presenting at San Antonio in 2013.
18:58This wasn't actually published
19:00until five or six years later,
19:02and we'll go over that.
19:03While the Tata group,
19:04you know,
19:05pretty rapidly published in Lancet on Koleji,
19:08so they had suggested the Atilius
19:10Group surrounds group in the Turkish
19:13Federation that there was no statistically
19:15difference or difference in overall
19:17survival survival in early follow-up.
19:20Potentially those with limited numbers
19:23of sites of metastatic disease,
19:25and I know that's of interest
19:27of people here at Yale and.
19:29Around the country of maybe not.
19:31Group behaves differently than
19:34others with metastatic breast cancer.
19:38These are the randomized trials
19:40that were or were underway,
19:43and their primary endpoints are either
19:45survival or time to progression.
19:47So we've seen what happened in India,
19:49what happened in Turkey?
19:50We're going to talk about the COG
19:53in the next one that will actually
19:55report out will be the Japanese
19:57jade COG 10710 seventeen trial.
20:00So this kind of circles back to you know.
20:03I think maybe if there's anyone who's in
20:05training that's watching is that you know,
20:07two decades ago I started as a
20:09fellow of SEMA Konzum and watched
20:11the work that she did in the central
20:13surgical challenging the standards
20:15of and providing local therapy.
20:17A suggestion that local therapy
20:19would be of survival.
20:20But then watching the retrospective data
20:23come out, then the prospective data,
20:25and then the usdata.
20:27So I was the KVB rap,
20:30which is now part of alliance.
20:32For E card 22108,
20:35this was presented at 2020 in San Antonio.
20:38The publication honestly will be coming out,
20:40hopefully in the next month,
20:41but until then you know it
20:45isn't published presented,
20:46but it will be published very soon,
20:49so we know that from the Tata Group
20:51that there was no survival with early
20:54local regional recurrence and then
20:56again I said that Alisa ran in 2018,
20:59presented that there was no
21:01difference also in.
21:03Come in local regional therapy in terms
21:06of survival but with longer follow-up.
21:09Their group actually suggested that
21:11there was an overall survival benefit.
21:13There is a lot of issues with
21:15this paper and publication and I,
21:18II and others wrote an editorial that
21:20was simultaneously published with this,
21:23but and we can discuss this in the
21:25in in the question answer session.
21:28But there was a suggestion that
21:29there was a survival benefit,
21:31so there's conflicting data equals 2108.
21:34Started in 2011 with its last
21:37patients enrolled in 2015 and
21:392013 because of slow accrual,
21:42they did amend their their overall
21:45goal and the and the randomization,
21:47but basically in EU,
21:49S or North America stage,
21:51four denovo breast cancer.
21:53Optimal systemic therapy including
21:55obviously anti her two therapy
21:57if there was no progression of
21:59distant disease followed by 4 to 8
22:02months of optimal systemic therapy.
22:03They either continued down
22:05the route of systemic.
22:06Therapy versus local early
22:08local regional therapy.
22:10And again, this is something that
22:12Doctor Khan focuses a lot on.
22:14Is the complete resection with free margins.
22:18Overall survival, just like I showed
22:20you with all the randomized trials.
22:22This is the breakdown in
22:25terms of the patient cohorts.
22:27For those that were registered,
22:29not randomized and randomized,
22:31again anti her two therapy was given
22:34when they were her two positive,
22:36certainly anti estrogen therapy
22:38when he R and or PR positive.
22:41Uhm, the dropout,
22:43which is really not surprising
22:45as those that had more,
22:47you know,
22:48advanced local disease was ended up
22:51being higher in the initial systemic
22:54therapy as opposed to or the group
22:57that was stable or responding.
22:59Uhm, median age a little bit
23:02younger than CMAS earlier study.
23:04Looking at,
23:05you know the NCDB database
23:07by about six or seven years.
23:09And then when you looked at
23:10those that were randomized,
23:11early local therapy 109 received surgery,
23:1687 achieved surgical free margins
23:19and and and local regional therapy
23:22was at 74 of those patients.
23:25The reasons why no surgery,
23:27some ended up refusing some progress,
23:30some was made by MD decision.
23:33Finally,
23:33we were able in the US to go back
23:36to what SEMA started in saying
23:38that there was a survival benefit.
23:40Now we come to the point of
23:42having randomized data from the
23:44US and suggested that there is no
23:46overall survival benefit for women
23:48with stage four breast cancer.
23:49This is with a median follow-up of
23:545353 months progression free survival.
23:57Similarly, no difference,
23:59something that you know we saw a
24:02suggestion of in the Tata Group.
24:05Is that potentially and there are
24:08certain subtypes of breast cancer that
24:10actually operating may actually be
24:12a more of a detriment to not operating,
24:15so it's not necessarily been equivalent,
24:16but potentially worse,
24:18and maybe that's seen in the
24:20triple negative breast cancer.
24:23One thing again that you know
24:25will be focused on a little bit
24:27in the paper is that there is
24:29some benefit in terms of local
24:31regional progression free survival.
24:33That's how useful that is of an
24:37endpoint is worth discussing.
24:40So kind of coming to conclusion is
24:42that early local therapy does not
24:45improve survival in patients with
24:47denovo metastatic breast cancer
24:49that there was actually a higher
24:52local regional progression when
24:54local regional therapy was used,
24:56the primary site. Again,
24:58there is a suggestion of progression free,
25:02you know, some local regional
25:05therapy response in the stage.
25:07Four breast cancer setting,
25:09and again the JAYCOB trial.
25:11Is still pending and at least in my,
25:14in my conclusions were that like in in
25:17almost two and a half decades, we went.
25:19The pendulum was swung from, you know,
25:22no surgery to surgery to maybe surgery or
25:25no surgery to hopefully now no surgery.
25:29You know, outside of palliation,
25:31although there is interest in,
25:34you know in the those with
25:36limited numbers of metastatic
25:37site or oligo metastatic disease.
25:39I don't think the randomized data from
25:41Tata or the Turkish group supports this
25:44and the card data that was presented
25:47ASCO doesn't support this either.
25:49Over the publication is still
25:50pending and once that's out then you
25:52guys can make your own judgment.
25:53So with that,
25:54I'd like to thank you for the provision
25:56of the podium and look forward to talking.
26:01Thank you very much, Mary.
26:03Uh, we have a few questions here,
26:07so for everyone, if you have questions,
26:09please post them in the chat.
26:11So let me read some of the questions here.
26:14A question from Doctor Caring, Addison.
26:19She points out that there is a
26:21national trend toward doing more
26:22local therapy for metastatic disease,
26:24which is calling a metastasis
26:27sectomy I guess.
26:29So, does this data provide some
26:30warning for adoption of this
26:32trend outside of research studies?
26:35Honestly, I think it it does,
26:37at least in breast cancer, that we really,
26:40you know, we may have an idea.
26:42We may have antidotes of when it works,
26:45and you know when you we looked
26:47at our data institutionally.
26:49Or many others did as well.
26:51You know you have to really be, you know.
26:55Careful for selection bias is
26:57that you know are unintended,
27:00but certainly part of this and I am really
27:02outside of the clinical trial or research.
27:05Sending as Doctor Edelson suggested.
27:08Really not a big fan of even
27:10certainly not local therapy,
27:12but even metastatic disease
27:14in that setting as well.
27:16And I know this is different than
27:18some other solid tumor types,
27:20but in the world of breast cancer,
27:23yeah, there was retrospective data.
27:25There was conflict on that,
27:26then we waited for prospective data.
27:28There was conflict on that on.
27:30Well it's not U S data or European data.
27:33Finally we get the usdata and we're,
27:35you know,
27:36on the border of getting the
27:39publication out on that as well.
27:41And then I thought.
27:43Another question from Doctor Peters.
27:46So did the EKACH trial allow
27:49any number of metastasis?
27:51It seems like the general
27:52thought was that this may be
27:54helpful in low volume disease, so
27:57it did allow for multiple
27:59sites of metastatic disease.
28:01I think the only real from what I
28:04remember and I actually enrolled a
28:06couple of patients to this trial.
28:09Patients that couldn't wear those with
28:12like leptomeningeal disease that were
28:14excluded and maybe a handful of others.
28:17And again, I think this points to the,
28:19you know is low volume or oligo metastatic
28:22disease different than those with
28:24higher volumes or burden of disease.
28:26And again a lot of people try to
28:28address those selection biases
28:30of like you know you know,
28:32is visceral Mets or lung Mets going to be
28:34different than soft tissue or bone Mets?
28:36I again outside of the research setting I am.
28:39Really cautious of this.
28:41I'm glad that in my two decades
28:44I've seen a a trend,
28:46hopefully away from from
28:47from local regional therapy.
28:50Thank you and Doctor David Rim.
28:54It's asking is it even possible to
28:57study cancer presented stage four,
28:59since in this modern era discovery
29:01of the cancer at stage 4 classifieds
29:03the patients as having received
29:05below is the standard of care.
29:09Any comment meaning
29:11maybe. I don't understand the question 100,
29:15so the. Bing diagnosis stage four is
29:19below the standard of care. Well, I mean,
29:21we're obviously in the United States I.
29:23I would say that you know,
29:24because we have such a well screened
29:26population that that number is
29:28relatively low, but it still is about,
29:30you know again, 4 to 6% depending
29:32on whether you look at Sierra,
29:33NCDB or whatever data set.
29:35But I really like thinking of things
29:38well outside of EU S borders and
29:40certainly in Sub Saharan Africa or
29:43Asia and many other parts of the world.
29:46You know there are a lot of women who
29:48are presenting with stage four breast
29:49cancer and are a lot more patients
29:52presenting with stage four breast cancer.
29:54And you know, should different
29:56options be considered in that setting?
29:59You know it was nice that at least and
30:01you know in the work on stage four,
30:03breast cancer and local regional therapy
30:06that we had counterparts in India in Turkey,
30:08in Japan and others that
30:10were looking at this.
30:11And it wasn't just run by EU
30:14S and Europeans in terms of.
30:16Helping us answer those questions.
30:19OK, and that well, how about the?
30:23Role of the Disney Cetera Ginnetti and
30:27the different phenotypes and molecular
30:30phenotypes and treatment available and how
30:33what does that do to despair? Diamond?
30:35In other words, I was wondering if you
30:38know if you have a great treatment,
30:40is it good to have surgery or not?
30:42Or maybe if you guys have a great
30:44treatment it doesn't matter? Yeah,
30:46so that's that's such a great question
30:48and you know you get those you know.
30:50You know, there's this young patient,
30:52you know she's got like.
30:54A couple of sites that maybe liver disease.
30:55You get anti her two therapy.
30:57Everything disappears.
30:58You know maybe she has a little bit
31:01of a lump or mass in the breast but
31:03you know you know you get the story.
31:05You know she has young kids
31:06and a family and you know,
31:07let's just, you know it's easy.
31:09Just take it out, you know I,
31:11I really think that's you know the you
31:14know she's going to likely do well anyways,
31:16whether I do the lumpectomy or mastectomy,
31:19remove the lymph nodes, yes or no.
31:21And again, there's this, you know, making.
31:24US or the patient feel better
31:27versus are we actually, you know,
31:30doing a benefit in terms of
31:31keeping them alive longer.
31:33And certainly you know,
31:34breast surgery may not be,
31:36you know, as morbid as you know,
31:37very large thoracic and
31:39intra abdominal surgeries,
31:40but you know in this society
31:42we put a lot of emphasis on on
31:44breasts in the breast cancer.
31:46And, you know, removal of the breast.
31:48And then the question becomes in the
31:50stage for setting if you do a mastectomy.
31:51How about doing reconstruction
31:52yes or no and kind of where?
31:54Where does that end?
31:55Or why don't you move the opposite?
31:57The rest as well, and you know,
31:58I've had those discussions
31:59time and time again,
32:00and you know,
32:01I would hope we're making some of these
32:03decisions based on data and the science,
32:05and not what like you know,
32:07feels good or or maybe the right
32:09thing to say at that moment.
32:11So I do think heterogeneity does
32:13make a difference,
32:14but I think it's probably
32:15going to do well regardless of
32:17what I do with my scalpel.
32:19Thank you and Doctor Lustberg is pointing
32:21out that they are very aggressive
32:23tumors that present biological stage
32:25for particularly in younger women.
32:27So it's not necessarily substandard care.
32:30This bad biology rim.
32:33That's great, that's a great comment.
32:35Yes, wonderful thank you so much.
32:37So I mean there's interest of time.
32:39We're going to move on to the
32:41next talk for the next talk.
32:44We have our very own doctor
32:47Anita Hutner Dr Hutner is an
32:49associate professor of pathology,
32:51who specialize in identifying
32:53diseases and cancers in the brain.
32:55She has received her medical degree from the
32:59University of Ehrlinger Nurburg in Germany.
33:01And a completely fellowship at Harvard
33:04Medical School at the Brig and and her
33:07residency here at the Ionia Haven Hospital.
33:09So in addition to her
33:12specialty in neuropathology,
33:13Dr Hutton has stated molecular
33:16diagnostic pathology,
33:17so in her research,
33:18Dr Hutner uses stem cells to try
33:20to recreate the brain disorders
33:22founding diseases like epilepsy and
33:24Alzheimer's disease and hopes to find
33:27better treatments for brain tumors.
33:28So today,
33:29Doctor Hutner will talk to
33:31us about a very important.
33:33Update in the WHL classification of
33:35brain tumors that will pretty much
33:38append the way we are calling these
33:40diseases and classifying disease and
33:42enrolling the patients in clinical trials.
33:45So we're very fortunate to have her
33:47here to educate us on that hardener.
33:52Thank you, Antonio.
33:53Thank you for this kind introduction.
33:56Thank you. It's a it's a real
33:58pleasure to be here and have the
34:00opportunity to share with you some
34:02insights into the upcoming 2021 W
34:062 classification of CNS tumors.
34:09It's now the 5th and I'll
34:12talk more about that.
34:15Uhm, in general, you might wonder, well,
34:18why shall we even deal with brain tumors?
34:21Yeah, they're relatively rare
34:23compared to other cancers,
34:26and when you look at the numbers in in
34:28a bit more detail, you realize that.
34:30Yes, well they are relatively
34:32rare compared to let's say breast,
34:35lung and other entities.
34:38UM, the outcome is rather devastating,
34:41so roughly estimated.
34:43We will find about 24,000
34:46patients with malignant glioma.
34:50The 85 year survival rate is rather low,
34:55it's 36% anti survivability
34:57rate for those two suffer.
35:00With a clear blastoma is really low,
35:03so it's it begs for innovation
35:06this entire field.
35:08The costs of treating patients
35:10with brain tumors or tremendous
35:13in in in simplified terms.
35:17But also we are illustrative,
35:18is this graph here.
35:20When you look at the survival rates,
35:23the five years or survival rates
35:25of children with leukemia.
35:27Right now, nine out of 10 surviving.
35:30Patients with breast cancer.
35:32Similarly,
35:32nine out of 10 survive when you
35:35look at patients with brain cancer.
35:37Now you're down to two per ten surviving.
35:41And then with glioblastoma,
35:43you're down to one pretend so you
35:46can see even in 2021 the field
35:50is begging for innovation and
35:53new approaches to handle this
35:56absolutely devastating disease.
35:59And so we this year there is a new W
36:02classification of brain tumors coming out,
36:07which is dramatically significantly
36:09different from before,
36:11and so I felt.
36:13Since we have a very large and active
36:15neuro clinical neuroscience community here,
36:17it would be good to discuss a few of
36:21those new changes because they will
36:24affect how we all practice and interact,
36:27and so for today I thought
36:29I'll show you a few.
36:31Some of the general changes
36:33and recommendations,
36:34then go into tumor specific
36:36changes and at the end I'd like
36:38to conclude with one of our own
36:41cases and methadone analysis.
36:43For brain tumors,
36:44which is now also recommended.
36:47And so.
36:47Why is it overall so important to
36:50accurately classify tumor samples well?
36:53The multiple aspects personalized,
36:57individualized patient care.
36:59It contributes to prognosis
37:02AIDS in therapeutic guidance.
37:04It's click current critical for
37:07clinical trial enrollment and
37:08also then we sent it for the
37:11interpretation of clinical trials data.
37:13The enrollment in experimental studies
37:15and here also data and analysis
37:19interpretation the evaluation of
37:22population based disease trends.
37:24Are aided by accurate classification
37:26system and also you know affected
37:29is allocation of resources by
37:31governments and health insurers
37:33to support health care and so.
37:36UW now publishes periodic revisions
37:40of tumor classifications,
37:42and these have therefore very diverse
37:44and important effects on many aspects
37:47actually of individual and population health,
37:50however,
37:51and David Luiz emphasize
37:52this at the last meeting.
37:54All classifications are somewhat imperfect.
37:59They are imperfect representations,
38:02and represent of.
38:04Come off in this state and
38:06the representative state of
38:08understanding at a particular time.
38:10And the interpretations.
38:12Of a limited number of experts and so.
38:17You see their limitations,
38:18their works in progress,
38:20yet they're still extremely needed.
38:26Just to shed light on the 5th.
38:28So the when you look at how
38:31the classification emerged,
38:32the first one was published in 17-9.
38:36The first edition then evolved over
38:38the years that the time gaps are
38:41at times quite considerable from
38:44the from 20 from 2007 to 2016 there
38:49was an almost 10 year time span,
38:52however the 2016.
38:54In addition, was a more or less a
38:58revised edition of the 4th edition,
39:01which received 2007 version,
39:03and here for the first time.
39:07Definitions were now based on
39:09the combination of morphologic
39:11and genetic characteristics.
39:13This was a huge shift in the field.
39:17And I feel that was celebrated by one.
39:21By some there's a paper in Kansas, L.
39:25Which caused the fall of the optical
39:28wall freedom from the tyranny of
39:30the microscope and the molecular
39:33changes stand could demonstrate this
39:37improves humor risk stratification.
39:41Uhm, the from 2016 to now to 2021.
39:46Again,
39:47you know time passed and but now with
39:52the advents in molecular technology.
39:55Information is gathered as lightspeed
39:58and so in order to bridge these gaps
40:03between WTO classifications, the.
40:07Consortium was formed.
40:09They see impact now consortium,
40:11which is a consortium to inform
40:14molecular and practical approaches
40:16to CNS tumor taxonomy.
40:18The goal here is to.
40:21Publish new developments in
40:24molecular diagnostics and inform
40:26the clinical world so this could
40:29be implemented along the way and
40:32there wouldn't be a long gap until
40:35new changes were implemented.
40:37If you wonder what the now stands for,
40:40it means not officially who,
40:42because this consortium was
40:44established in 2016 and basically
40:46the authors of all these C impact
40:48papers are also authors and editors
40:51of the new double classification.
40:53So it's a very.
40:54It's a very homogeneous group that works
40:56on this the the expert editorial group
41:00is composed of international group.
41:03Unfortunately the Blue Book
41:05is not yet published there.
41:07I was told by David Lewis there are
41:11production issues related to the pandemic.
41:14However,
41:15in the meantime I review paper,
41:19came out in neuro Oncology
41:21which is available and can be.
41:23Teen and so I quickly would like to go
41:26through a few general changes before I
41:28go into too much specific changes and.
41:33The significant change is really
41:37related to the report structure,
41:41and here we have now a so-called integrated
41:45histo molecular classification system.
41:49It's already in place at Yale,
41:51and this is what one of our reports looks
41:53like and so you have four layers there.
41:56Two is the histopathological diagnosis,
41:58which would be here.
41:59For example,
41:59glioblastoma layers 3 then defines the
42:04grade would be here for and then layer
42:084 forms the molecular information,
42:11which would be a list of molecular
42:14data here and in order to make sense
42:17out of this different components.
42:20A layer one is added which forms
42:24the integrated diagnosis and this
42:26is the combined tissue based
42:29histological and molecular diagnosis.
42:31And so this is continuously
42:33expanding with the addition of
42:35additional newer markers and the
42:37integrated diagnosis is really a
42:39collaborative, team based effort where we,
42:42as neuropathologists from surface as
42:45central role for the integration component.
42:49We closely work with neurosurgery,
42:51neurology, neuro oncology,
42:54genetics, and new radiology,
42:57and then integrate from
43:00this integrated diagnosis.
43:02Which then is used by neurooncology in
43:05radiation oncology foot for treatment.
43:08So it's a very intimately integrated process.
43:13A few words to just a few nomenclature
43:17issues, so when a diagnosis cannot
43:20be made and the term Nos is used,
43:25meaning non not otherwise specified,
43:27this just means that molecular
43:29information is not available and
43:31there could be multiple reasons
43:33it's either not available or not.
43:34The test was not performed or simply was
43:37not successful, whereas the NEC term.
43:42Not elsewhere classified,
43:44just indicates that the test
43:47was successfully performed.
43:48However, the test results simply
43:51do not fit into a known category,
43:55so further on.
43:57Now, in this new version,
43:59we're now distinguishing our
44:02grading from other classifications
44:04by adding the Hoos TNS grade,
44:07because this is meant to emphasize
44:10that the way the neuro Neuro.
44:13Who grades tumors is different from
44:15how it's done and you and your breast,
44:18for example.
44:20Further from the now we research,
44:24this might sound trivial using Arabic
44:27numerals instead of Roman numerals.
44:30And lastly,
44:31now is also grading within tumor types,
44:34and this is a bit more substantial.
44:36This is meant to provide more flexibility
44:39in using grade relative to tumor type.
44:42It should emphasize biological
44:44similarities within tumor types rather
44:47than just approximate clinical behavior,
44:49and it should.
44:50It conforms with who grading
44:52in non CNS tumor types.
44:53For example,
44:54we used to say astrocytoma IDH
44:58Mutant who's seen as great.
45:00Two or three or form when you have before,
45:05you could say, for example,
45:06I had a trim anaplastic
45:09astrocytoma who creates three.
45:11This is now obsolete.
45:13Now it's replaced and the
45:16nomenclature now would indicate
45:17that you have to say astrocytoma,
45:19IDH Mutant,
45:20who CNS great three.
45:23I think it will take a bit of time
45:25to get used to this overtime and the
45:28term glioblastoma now is exclusively.
45:31Served for the adult IDH wild type tumors,
45:35so the the stratification is really
45:39based on IDH status and so on.
45:43The humerus specific changes
45:44now go into this,
45:46so when you look at the 2016 WO list of
45:50tumors it has a wide range of entities.
45:53Terms like Mr Citic astrocytoma or here
45:56to use sarcoma epithelioid, do you blastoma?
46:00All these have been removed.
46:02Everything has been streamlined
46:05and reduced to three main groups,
46:08and these are the adult type diffuse gliomas,
46:11pediatric type diffuse, low grade glioma,
46:14Sandy Patrick type diffuse,
46:16high grade lumas.
46:18The pediatric type does not mean these
46:20are exclusively present in pediatric
46:22patients but they're often or more
46:25more readily seen in pediatric patients.
46:27We now when we look at this more
46:30closely so the astrocytoma now.
46:32We're talking now specifically
46:35about diffuse gliomas.
46:37There now is, it is the idea.
46:40Mutant status matters most,
46:42and the certification is based on
46:46astrocytoma IDH mutant and then the
46:49grading is based on grade 2-3 and
46:52four for the OLIGODENDROGLIOMAS.
46:54Again, IDH mutant status is very relevant.
46:58In addition to that,
47:00the 1P19 Q correlation status again,
47:04he DCNS grade goes up to two to three.
47:08And a glass stoma is exclusively
47:11reserved for IDH wild type tumors.
47:14And these are automatically
47:16who create 4 tumors.
47:17D pediatric type diffuse Low
47:20Bradley almost are now in.
47:23Now include diffuse astrocytomas
47:26with milk and milk LA mutations
47:30the angiocentric Luma.
47:33The polymorphous low grade
47:35neuroepithelial tumor of the young
47:37and then diffuse low grade lumas
47:39with MAP kinase alterations so you
47:41see it's very different group of
47:43tumors that's now front and center
47:45stage within a diffuse cleoma group,
47:48and then lastly high.
47:49Correctly,
47:50Omar Group includes H3K27 and altered 2 must,
47:56a new entity DH3G34 Mutant
47:59Group is now included.
48:02And also a new group deep diffuse
48:07pediatric type hydrate guma.
48:10Which is H3 wild type in wild type.
48:13Now with a high great great forward and
48:16nomenclature is part of it and then the
48:19last city infant type hemispherically
48:22Omaha for the adult type tumor tumors.
48:25There were also significant changes,
48:27so the diffusely infiltrative Astro
48:30City humor with an IDH mutation
48:34is morphologically in general well
48:37differentiated, lacks features of anaplasia.
48:39My target of activity is not detected
48:43or very low and what is absent and
48:46this is diagnostically relevant.
48:48Is microvascular proliferation and necrosis,
48:52and also there cannot be a city
48:55into a homozygous deletion?
48:57For the intermediate type here,
48:59formally called anaplastic as just cytoma,
49:02this is now the astrocytoma IDH
49:05mutant and now who CNS grade three.
49:09You have similar features except
49:11that now you find focalor dispersed.
49:14Anaplasia significant mitotic activity
49:17but still no faster proliferation,
49:20only crosses and no city can to a
49:24deletion rest for the highest grade now.
49:28Which is no longer called glioblastoma,
49:30but this is the astrocytoma IDH mutant.
49:35Suppose CNS great for you have features
49:39of a diffusely infiltrative Astro,
49:41static new class and with.
49:44And IDH mutation that exhibits
49:47also microvascular proliferation,
49:50necrosis,
49:50and in this case also sitting case
49:53IDK and to a homozygous deletion or
49:57any combination of these features.
49:59So overall. Do they drive home?
50:03Point is the diagnosis anaplastic
50:06astrocytoma IDH mutant and glioblastoma
50:09IDH mutant are no longer recommended
50:12and the city KN 2A and B homozygous
50:16deletions are molecular markers of whose
50:19in S grade 4 in an idea mutant astrocytoma.
50:25Uhm, the criteria for Clyde Blastoma now are
50:29limited to exclusively IDH wild type tumors.
50:34And here you find diffuse associated
50:38tumors with microvascular proliferation
50:40or in the past it used to be an end.
50:42Now it's just or you need
50:44one of those features,
50:45or you have a molecular defined tumor.
50:49Third promoter mutation,
50:51EGFR gene F receptor gene,
50:54and if.
50:55Amplification or plus 7 -- 10
50:58chromosome copy number changes.
51:02DIDID H1 type diffuse kioma with any of
51:05these features is called a glioblastoma.
51:07Who CNS Grade 4.
51:11So the question arises, how do you,
51:14you know, handle you plus two more now.
51:16So there are two options.
51:20And this is not necessarily trivial,
51:22so the case with diffuse kiyama without
51:26microvascular proliferation or necrosis.
51:28So without anaplastic features it is
51:31logically not really a hit glioblastoma,
51:35but it is a glioblastoma when it is IDH,
51:39wild type and displays each Fr amplification.
51:44Third promote imitation or plus 7 -- 10 E 10.
51:48Whereas when you have a true histological
51:51glioblastoma where you see morphologic
51:54features of anaplasia like Vasco preparation.
51:59Only crosses,
52:00it's not ugly blastoma.
52:02It's then a he still logically blows,
52:05not clear plus stoma with IDH
52:08mutation would then be an astrocytoma
52:11IDH mutant grade four so the
52:14term glioblastoma is not used its
52:17astrocytoma IDH mutant who created for.
52:22For the pediatric group, then we have
52:25the entities I already mentioned.
52:27I just wanted to point out the diffuse low
52:31grade leoma with the map kinase pathway
52:34alterations where you have several entities.
52:37Now within the FGF receptor category,
52:41where you have duplications mutations,
52:44be roughest involved or again into a D pad.
52:49Pediatric type diffuse tactically.
52:51Almost this is a relatively.
52:53Unusual entity in here.
52:55You have some involvement of
52:57PDGF receptor amplifications,
53:00or EGFR amplifications or milk.
53:05Others, when you then go beyond the
53:07diffuse gliomas, you look at Leo,
53:09neuronal, and neuronal tumors.
53:11I just want to point out there
53:13were few additional tumors added,
53:15like the high grade astrocytoma with
53:18pilot features within the glue,
53:20neuronal and neuronal tumors,
53:22and unusual tumor diffuse clonal
53:24tumor with oligo dentro cleoma like
53:26features and nuclear clusters.
53:28Myxoid Cleo neuronal tumors and the
53:32multinodular backlighting neuronal tumor.
53:34Uhm?
53:36Major changes were also seen
53:38added to the EPENDYMAL tumors.
53:40Appendable tumors are those with a
53:43relatively isomorphic appearance which
53:47form pseudorosettes around vasculature.
53:51They're linked to the ventricular
53:53system mostly,
53:54and so this was the original
53:57classification in 2016.
53:59Now this is abolished and the
54:02classification is now based on location
54:05Histology and genetic alterations.
54:08And here we have location based
54:12Supratentorial intro tutorial spinal and
54:15then lastly a few added two additional
54:18entities to MC so popular in Panama.
54:20And these soccer pending normal.
54:22And when we look at those.
54:24In in greater detail,
54:27the supratentorial ependymoma's used to
54:30be known with a real or fusion partner.
54:33This has been changed now the C 11 open
54:37reading frame 95 now is dedicated as
54:40CFTA and has multiple fusion partners.
54:43These are usually hemispheric extra
54:47ventricular tumors in adults and children,
54:51and another option is also.
54:54Yup, one fused to positive tumor.
54:58The interesting to introspect the
55:01info tutorial appending moments.
55:04Are the posterior fossa pantomima
55:06a Group A or B,
55:08and these are primarily in infants.
55:11Have an extremely poor prognosis.
55:13Unknown to have H3K27M metalation.
55:17Loss whereas here you have our attention
55:22of the HTK 27 M in the B once and
55:25they have a bit better prognosis.
55:27This panel Panama must show
55:30often mxi amplification.
55:32They are they're very malignant now.
55:36The mix of popular Panama was upgraded
55:38now to Grade 2 used to be grade one.
55:41There's no additional molecular
55:44data to change anything,
55:47and similarly for this update
55:49pending more marks stays the same,
55:51the embryonal tumors.
55:54I have seen also significant changes.
55:58These are as you can see in the image,
56:02very aggressive appearing blue cell
56:05tumors with high mitotic rate and here
56:09we have now molecular defined and
56:12histologically defined tumors in 2016.
56:15There were four.
56:17Subgroups and demolished the middle
56:21stomachs were stratified according
56:24to pathways which involved wind
56:27pathway Sonic hedgehog pathway and
56:30then non wind non Sonic hedgehog.
56:34The wind pathway.
56:37Middle of last time I had a
56:39relatively good prognosis,
56:40whereas the Sonic hedgehog
56:42activated ones with up TP with a
56:45P53 mutation in addition,
56:46had a very poor prognosis.
56:48Now in in 2021 the Sonic Hedgehog
56:53Pathway Group went from 2
56:55subgroups to four subgroups,
56:57so those on the editorial board that were
57:02splitters one rather than the lumpers,
57:05and so we have now more subgroups.
57:08Lastly, whenever you have MC involved or P53,
57:13these survival goes down the.
57:18The non wind non the groups
57:22three and four now went from.
57:26You know, to eight subgroups,
57:29which is now a significant
57:31almost hairsplitting.
57:35Attempt and you also have C or
57:37wherever you have mic involved.
57:39You have lower survival time.
57:41We will see whether this.
57:44Splitting major plus Thomas
57:46UP will hold over time.
57:49The molecular defined middle class Thomas,
57:53however, demonstrate distinct
57:55associations with morphologic patterns,
57:58and here for all wind tumors
58:00you see the classic type,
58:01which is a blue cell tumor.
58:04The Sonic Hedgehog group shows this
58:07decimal plastic nodular arrangement.
58:10And also you have a similar
58:13feature called in middle class.
58:15Tomorrow is extensive nodularity
58:17and the the group three and
58:20four are usually large cell,
58:22very anaplastic appearing middle blastomas.
58:26So for the middle class stoma.
58:27Overall it's more complex.
58:29Now it's more split.
58:33The tumor types I'm just pointing
58:36out a change in red in grading.
58:39Uhm, their overall to just
58:42summarize the 222 new entities.
58:46Within different subtypes,
58:47clue Mas que neuronal and ependymal.
58:50UM Brian has seen 4 sarcomas,
58:54so he added and there are several changes.
58:58I will not go through those just to see
59:02there is quite a bit of modification.
59:05Last feed I just wanted to make close with
59:08the case we had and we are out of time.
59:10Almost the methylome analysis
59:12for brain tumors.
59:14In 2018, this paper came out by
59:17the German group on David Capper,
59:20where Metalation based classification of
59:23central nervous system team was really dumb.
59:27Breakthrough in certain ways.
59:30The cancer methylome is really
59:32a combination of SOMATICALLY
59:34acquired in a metalation changes.
59:36And characteristics that reflect
59:38this cell of origin so you can
59:41trace the cell back to its origin.
59:44It also has been shown that this
59:46technology is highly robust and
59:48reproducible even when you use very
59:50small samples and you have only poor
59:53quality material and this profiles
59:55have been widely used to classify
59:57CNS tumors and this Disney plot here
01:00:00shows that there has been really a
01:00:03discovery of several new tumor entities.
01:00:06Secondly,
01:00:06it's very straightforward to use where
01:00:10you use a paraffin embedded section,
01:00:14microdissected,
01:00:14run the array,
01:00:16and then generate a report which
01:00:19is then based on this.
01:00:22And pattern here and the these
01:00:26new classification recommends
01:00:28DNA metalation studies done
01:00:32explicitly for several tumor types.
01:00:35For example,
01:00:35the pediatric high grade gliomas,
01:00:39the extra ventricular neurosci,
01:00:41Thomas Appending Momus,
01:00:42and also embryonal tumors.
01:00:44It's mandatory now for high grade
01:00:48astrocytomas with highlighted features,
01:00:50it's the only way to really
01:00:52diagnose this tumor.
01:00:53And for the diffuse general tumors with
01:00:56liquid entropy human like features,
01:00:58UM case election should follow cases
01:01:03with ambiguous tumor classification.
01:01:05Which are some I mentioned already.
01:01:08For example,
01:01:09in a young adult with a malignant
01:01:12IDH wild type glioma is suspicious.
01:01:15That should be looked at by methylome
01:01:19analysis diffuse wildtype lumas
01:01:21without necrosis and so forth.
01:01:24And brown tumors in general.
01:01:26Ependymoma as the higher grade
01:01:28many tumors will benefit from it,
01:01:30and patients with putative tumor syndromes.
01:01:33It also it aids in additional
01:01:36testing in complex cases,
01:01:38and there I wanted to briefly show
01:01:39one of the cases we had at Yale.
01:01:41We are metal lumen.
01:01:43Alesis actually resolved this case.
01:01:45So it was a 9 year old female
01:01:47with a very complex heterogeneous
01:01:50tumor with enhancement,
01:01:52cystic degeneration, midline shift.
01:01:56No one was sure was that this
01:01:58is on the benign side of things,
01:02:00or somewhat malignant and so
01:02:02biopsied and or a resection shows
01:02:05a very peculiar picture.
01:02:07Also,
01:02:07where we have fields with embryonal type
01:02:11morphology areas with pseudo rosette forming,
01:02:14this is almost Astro Astro blastoma
01:02:17like fields with sclerosis and there's
01:02:20more pleasure there is nothing.
01:02:22In our current WTO that would
01:02:26fit this features and so the the
01:02:30immunohistochemistry was not helpful
01:02:32at all. We ran I enormously wide
01:02:36piano or without any conclusion.
01:02:38UM, lastly sent it to end to end
01:02:44value for DNA metalation studies and
01:02:48here it came back to our surprise
01:02:52as a tumor which matches a neural
01:02:55epithelial tumor with Eminem,
01:02:58Eminem, one alteration.
01:02:59This was confirmed with a fish he choose.
01:03:04Helped us out and here we have
01:03:07now a probe that confirmed that
01:03:09the emanon arrangement is really,
01:03:13truly the driving factor here,
01:03:17and so the high grade new rapidly tumors
01:03:21M1 is defined as one rearrangement
01:03:24is a very new or relatively
01:03:27new entity recently described.
01:03:29It has several bank binding partners,
01:03:32including Band 2.
01:03:34Uhm it be metalation profiling shows it
01:03:38really splits off as a separate entity
01:03:43is distinctly different from others,
01:03:47so most of this high grades CNS.
01:03:50Peanuts are grouped clusters
01:03:52within the reference group.
01:03:55Here, 24% form 4 clusters,
01:03:58and the I mean one is one of them.
01:04:02And so in in general this.
01:04:05Worked a sort of false between Astroplus
01:04:09stoma, but also somewhat high grade.
01:04:12He was unsure morphologically
01:04:14what to do with it,
01:04:16but this now really helped us.
01:04:20You know,
01:04:21stratified this tumor,
01:04:22and so it was initially reported
01:04:25in in a minute you mop.
01:04:27In other tumors it has been seen in AML.
01:04:29It's actually it's improved survival,
01:04:33but I think there's not enough data to
01:04:37properly judge this rearrangement here.
01:04:39And so where do we go from here?
01:04:44Uhm,
01:04:44the goal is to build and expand
01:04:46on a molecular neuropathology
01:04:48service here at Yale.
01:04:50Embrace new developments.
01:04:54Embrace state of the art technology
01:04:57molecular markers and so forth
01:05:00to improve on the statistics.
01:05:02The image I showed you at the beginning
01:05:05of the talk and continue to work very
01:05:07closely with all our clinical partners.
01:05:09And here we are.
01:05:11I'd like to acknowledge and thank a wide
01:05:14range of colleagues from neurosurgery.
01:05:17Neurooncology my own group is
01:05:20fantastic group of neuropathologists
01:05:22Neuro radiology medical genetics.
01:05:24Molecular genetic pathology also again
01:05:27in my department radiation oncology
01:05:29and then many who work behind the
01:05:32scenes and help us along the way.
01:05:36And with that,
01:05:36thank you,
01:05:37I'm sorry I'll reign over.
01:05:41Thank you very much.
01:05:44Thank you very much. I need to.
01:05:46So I think we are running over time.
01:05:48So I think questions will need to
01:05:50be addressed through email to you.
01:05:52So I think this is fantastic and
01:05:56I think it is one more example of
01:05:58where the oncology field is heading.
01:06:00Usually bring tumors,
01:06:01lead the way in terms of
01:06:04incorporating molecular studies
01:06:06and then other diseases follow.
01:06:08So it seems like we're getting more
01:06:11complex and more sliced and if even.
01:06:14Rarer diseases so big challenges ahead,
01:06:19so thank everyone for attending and
01:06:21once again thank you for our wonderful
01:06:24speakers and I hope to see you next week.
01:06:27Our next grand rounds.
01:06:28Thank you very much.
01:06:30Bye bye.