Pathology Grand Rounds, Dec. 7, 2023 - Liang Cheng, MD, MS

December 13, 2023

Information

Liang Cheng, M.D., M.S., Professor, Vice Chair for Translational Research, Director of Anatomic Pathology, Director of Molecular Pathology, Department of Pathology and Laboratory Medicine at Warren Alpert Medical School of Brown University, presents on "Bladder Cancer: State of the Field and Future Directions."

ID11080

To CiteDCA Citation Guide

00:00It's about time. So let's start it.
00:05It's my great honor and the privilege to
00:09introduce today's ground run speakers.
00:11And Doctor Ling Chen.
00:14He's currently a Professor and Vice Chair
00:18for Translational Research Director,
00:21or Anatomic Passage,
00:22Director of Molecular Passage in the
00:25Department Passage and Laboratory
00:28Medicine at the Brown University
00:31Warren Alpert Medical School.
00:35So Doctor Chang also is associate
00:39director for the shared resources at
00:42the Brown University Cancer Center.
00:49He got his medical education from
00:53Beijing Uni Medical University.
00:56Now it's part of baking universities,
00:59and he received passage to residency
01:04training at KC Western Reserve
01:07University University Hospital,
01:09Cleveland Medical Center.
01:10So he did his fellow passage fellowship
01:15training at the Mayo Clinic Rochester,
01:18MN, before he joined the Bron.
01:23Almost lived there almost two
01:26year now and he was long been in
01:30Indiana University he's they are
01:32he's endowed professor and the
01:36director of molecular passage.
01:40So over the course his professional
01:43career he published numerous papers.
01:46So he's CVI even not try to read
01:49through his CVI only read his
01:52summary or his CV which is a packed
01:55with words and it's 3 pages long.
01:58So he published over 1200,
02:04you know, peer reviewed articles
02:07which I counted probably you know,
02:09think about 20 years career and almost
02:13every month he had to write 4 papers.
02:16So I don't know how he can do this.
02:18So all this publication generated
02:22about 63,000 citations.
02:26His age index is
02:29125. So he also is very
02:34productive published numerous
02:36textbook and the numerous book
02:39chapters and some of his textbook
02:44including Molecular Surgical Passage,
02:47Urological Surgical Passage and
02:49The Essential of Anatomic Passage.
02:53This is the one of his textbook.
02:56You know I you know during my training
02:58and my practice I still I read a lot
03:02of his book so he going to donate this
03:05book to our passage residents so after
03:09meeting you take it the book so he
03:14also is a contributor authors for The
03:19Who 2004 2016 and
03:232022 blue Book which is WHO
03:27classification of tumor urinary and
03:30genital and Male genital tumors.
03:33So in the most recent edition WHO Blue Book,
03:37he contributed 21 chapters.
03:44So he's a research focus on the translational
03:46study of genital urinary cancers,
03:50especially bladder cancers and
03:54molecular diagnostics of solid tumors.
03:57So he has been principal and Co
04:01investigator for many grants.
04:04I counted over 40 grants
04:06and he also served on many.
04:11Review board is A50 review
04:14board for the Federal Funding
04:18Agency including NIHNCI and DoD.
04:22And he's served as a panelist for
04:27the NCI Sport program since 2000.
04:31Every years he was sitting
04:33in the as a panelist.
04:35I don't know that after I reveal his CV.
04:40So, I mean,
04:42he's a renowned geopathologist
04:44and was ranked number one among
04:48the world expert in Euro genital
04:51neopath and top three expert in
04:55the field of bladder cancers.
04:58And he's the president-elect of
05:02International Society of Zoological
05:06Passage, so I said.
05:09So he received numerous prestigious
05:14award including the Stilwell
05:18Orbison Award from the United States
05:21and the Canadian Academy of Passage,
05:24the Cross Medical Medal award from the
05:29International Society of Urological Passage.
05:32So ASAP and the thing also Pudi
05:37Stewart Price from the Osprey
05:39Society of Surgical Passage.
05:42So so it's without further ado I think he
05:47I can go on you know to to to read all his
05:51CVI think you know today his presentation.
05:54So I I will not do more presentation.
05:58I will leave the floor to Doctor Dan.
06:02So, Doctor Chen,
06:05thank you so much.
06:08Thank you Doctor, for being in chat.
06:11I was really great privilege and honoured
06:13to be here and to see many friends.
06:17Peter he's also one of my mentor and
06:20and Johnson Ma you know Doctor Liu and
06:24yeah so very happy to hear and this
06:28this this morning and I get a chance to
06:31show some interesting cases and we're
06:33going to talk about it in a little bit.
06:35You know there's a the resin the
06:37fellow it's just amazing of course
06:39you know you don't treat them the
06:41best so so this really yeah and talk
06:44talking about that and I think you
06:47know they also you know I'm also very
06:50lucky that I was able to work one
06:55really two of the best geopolitics
06:59jump in the field in the West.
07:01After finishing my fellowship training
07:04at the mayor clinic I will update
07:07Oswick and John Indiana work with
07:10John Abelay until I moved to Brown.
07:14And so I'm really very fortunate
07:16I get a chance and to work with
07:19them and learn from them And so.
07:23So today I'm going to be you know
07:26you know so in my lab talk you know
07:30very next next half hour also try
07:33to kind of try to you know bridging
07:36some gaps and kind of explain you
07:39know that you know some new entity
07:41or some old entity know where we
07:44standing and it's in the last decade.
07:47You know it's really we truly
07:50see remarkable progress in the,
07:52in the,
07:53in the,
07:53in our field not just Gu here but
07:56I think Gu is very,
07:58very good example if you look at
08:00the timelines you know the the 1st,
08:02the 3rd edition of the publisher
08:04was published in 2002 and it's
08:07long lag for it's almost 14 years
08:11you know but people hunt for it
08:14is one of the chief editor of the
08:172016 edition and and now it's only
08:19takes 6-6 years for new edition.
08:22I was told that the next edition will be
08:25come out in three years or maybe 2025.
08:28So that's how things expanded
08:31and so this truly amazing.
08:35But for Bladder,
08:38I guess it's the framework
08:41that has been laid out,
08:42you know from previous edition Peter
08:45Humphrey and it's remain the same intact,
08:49it's largely very,
08:52very small.
08:53You know funality changes we're
08:56going to go into go into that.
08:59And in the in the W-2 202 classifications
09:04you'll probably notice that it's
09:05kind of one of a few exceptions
09:07that we always have to list two.
09:10I don't know why there's only two
09:12Banana tumour was listed so many
09:14banana other tumours you know there's
09:16only two has been listed and under
09:19banana category Lamb there's a pang
09:22lamp which is somewhat controversial
09:24entity I will not talk about in
09:26this lecture and in a molecular
09:28tumour and invasive customer.
09:30So this is a framework you know
09:32so it's just you can pretty much
09:34fit in and all the leachings
09:37you know both malignant
09:38leaching in those category.
09:41So that's beauty about that's so
09:43how about so what's pump you Lucilia
09:46Papilloma and this study was was done
09:49was well as a fellow and I think
09:52this truly you know kind of set up
09:54a theme that in the in the analysis
09:57we've done back in the 20 years
10:0022 years ago we analyzed you know
10:0352 cases of the eucilia papilloma
10:06using the strict W2 criteria people
10:10at the Mayo Clinic in the lodges
10:13they it's the unique advantage to
10:17study there is the population here
10:19the 1st in our stable they don't
10:22move so more than 58 years follow
10:24up we found this issue that really
10:27you know occur and also they never
10:30develop you know see a customer so.
10:32So by default you know and boys I think
10:35there's several other studies came out
10:37later years and that's it's been an issue.
10:39And so what's the molecular magnitude,
10:42what's new about this,
10:44you know what's the,
10:45what's the,
10:46what's the driver you know for this tumor.
10:49And I was I think you know there's a
10:51study with publishing a couple years
10:53ago in the European your knowledge and
10:56we found that interestingly we're going
10:58to talk about this tut new tissue again.
11:00You know this is very you know
11:02kind of a a very,
11:04very hard prevalence of a tut promoter
11:07mutation in the UCLA Papilloma and
11:10also it's fair common you know
11:12that you know this is 1/3 promoter
11:15mutation is probably the major
11:17you know breakthrough findings in
11:20terms of our understanding.
11:22You know funding molecular drafters
11:25like molecules only was recently
11:27described in the 2013 ten almost
11:2910 years ago 1st paper pubs in
11:32the science that talking about
11:34funding could promoting the tissue
11:37in Melanoma and bladder cancer.
11:39Since that explosion of knowledge
11:41and the publications and this is
11:45a few papers we just published
11:47this a couple months ago in human
11:50massage and we summarize you know
11:53the findings that that's done.
11:56You know in the cumulatively there's this
12:00over 7000 patients blood cancer patient,
12:04blood tumor patient has been analyzed
12:07for 3rd mutation as 2023 and 3rd
12:10mutation you know will lead to teramus
12:13reactivation will eventually OK good
12:17leading to the genetic instability
12:20stem cellness and stem cellness and
12:23prolification and tumor progression
12:25And and it's interesting you know
12:27that you know we found you know
12:30this is just say you know in this
12:32systemic meta analysis you know
12:34could promote mutation is kind of
12:38across board it's most common it's
12:41up to 80% of Uricilia tumor will
12:44have third promote mutation.
12:46It's regardless low grade highway
12:49or tumor stage it's a fair stable.
12:52So this is really great bar Mark
12:56go back you know to another banana
12:59lesion it's called inverted uricilia
13:02type and input ulucilia papadoma.
13:05The lesion is first almost identical
13:08to what we've seen in the head
13:11neck organ and the tumors,
13:13you know that they're characterized
13:14you know by you know they have
13:17a polypod architecture and
13:18a cuff by normal ulucilium
13:19with the and the most in cause.
13:22And again this is complete benign lesion
13:25if you strictly follow W criteria
13:28that not say it's been on tumor.
13:31And so why we talk about invert
13:35Papilloma here because this is going
13:37to be leading to one of the key
13:39degradation diagnosis it's called
13:41Eurocilia carcinoma of will invert
13:44growth or invert Eurocilia customer
13:46less terminology we're not we're not
13:49using so it's but again so it's kind
13:52of important you know from surgical.
13:54Yeah yeah OK OK so from a yeah good day.
13:59So from surgical passage point of view
14:01it's important that you know distinguish
14:03you know that's a let me let me ask
14:06the audience you know not not Peter.
14:08So who can who can tell which
14:10one which one should be which
14:12one should be the bladder out.
14:13Which one the bladder should stay.
14:15Which one's been on which one malignant
14:19We have a any senior resident Gu fellow.
14:24OK let what's your fault you
14:26know which one's benign.
14:27Which one's malignant
14:31It's the A, A's, A's A's benign malignant
14:38B is benign. B for benign good.
14:49OK. So I cannot tell and I'm, I'm,
14:55I'm, I'm, I'm sure you know that this
14:57is kind of saying even nowadays with
14:59all the knowledge in the bladder tumor
15:01is still challenging and difficult.
15:05And in this case, the,
15:09the inferred papilloma, you know,
15:11first thing for your customer,
15:12I think, I think you know even for
15:14expert maybe have some hesitation.
15:16And so what's the key molecular
15:19features that you know if you,
15:21I want 100% rely on morphology.
15:24So what's the key molecular features
15:26LAD can tell them in my experience,
15:28you know that really it's a,
15:32this is probably 2 most useful features
15:36that I can help me to distinguish those two,
15:39especially in small biopsies
15:41in my limited materials.
15:42And it's that first is that invert
15:46Eurociliac customer cancer they will
15:49typically have associated the typical
15:52exophytic pepper component this one.
15:55The second truly I think
15:56it's really the Tribecca,
15:58the thick Tribeca that we're seeing
16:00and the certainly you can see
16:02other other features like frequent
16:04hematotic figure PFS three KR,
16:07second seven CT 20 and and will be helpful.
16:11And again, so go back to this case,
16:12you can see here that not even
16:16to go back to further,
16:17you know,
16:17you see this is typical in Word papilloma.
16:20They have thin trabecular.
16:23But in contrast with bladder cancer you see
16:27the segment significantly thickened tobacco
16:30unlike you know here the top ones benign.
16:33You know here the bottom line you see fair,
16:35fair, fair, you know,
16:37thickened tremendous second so.
16:39So those are morphologic crew.
16:40Not sure not if you have difficult case,
16:43you're not sure you can show it.
16:46They will tell you right away no problem.
16:49And if you have more trouble,
16:52you can ask her.
16:54I'm not sure he's here now, you know.
16:57So, OK, yeah, OK.
17:00Do the Euro fishing test fast.
17:06So, so that's another case that
17:08you can just not running the
17:10fish now that's it could be,
17:12it could be helpful but most cases not
17:14helpful and nowadays even even better.
17:17We have another one marker called Tut,
17:19just mention that it can be you know
17:22unlike you know the the you know
17:24Cilia pipeline was just discussed.
17:26Tut is cannot help euciliate type
17:29of Lomas versus other Euciliation
17:31but could promote her mutation is
17:35almost you know always present 80%
17:39time in inverted Eucilia customer,
17:41but it's always almost always negative,
17:45you know Eucilia inverted type of Lomas.
17:48So that's something that could be
17:50potentially helpful if you really have
17:52difficult cases inverter you will
17:54see the platform is really firefight
17:57interesting machine and though it is you
17:59know it's a good negative to promoter
18:01mutation negative but it is very,
18:04very high preference of FGFR stream mutation.
18:07So again you know some you know I
18:09think you'll have to kind of reap it's
18:12not it's not one one shoe fit all.
18:16So you have to kind of think about,
18:18you know this intimate different mutation
18:20or the understanding the context.
18:22And also with you know that apparently
18:24you know it's definitely that you
18:26will see the carcinoma in in for the
18:29growth will in for the growth and
18:30in for the you know sleep papilloma.
18:31They have different pathogenesis
18:34in molecular pathways.
18:35And this is the view article.
18:37Let's not say tutorial let written by
18:40Doctor MO MO Acue and so a former fellow
18:44he's the one who will be artist Geo
18:47pathology fellows we have in back in Indiana.
18:51He's not at the Ebony Medical College.
18:55Brilliant geopathologist and so what's new?
19:01So what's new,
19:02what's upcoming?
19:03You know there's in a 2022
19:07September actually yeah,
19:09it's in the September 2222,
19:11you know ASUP gather and I have a
19:14meeting in the Consensus conference
19:16at the Basel in Switzerland and the
19:19the result is going to be released
19:22published in general issue of the AGSP.
19:27So next next month that all the
19:30working for working group funding
19:32is going to be published.
19:34So I'm not going to spend much of
19:38time to talk about each working
19:41groups funding but I want I one
19:43thing I want to say is that still
19:45you know that's the grading,
19:47you know think about grading,
19:49you know that you know it's I think you
19:52know that's you know count grading is
19:55built upon the one we have back in 1998,
19:58ladder grading,
19:59the low grade, high grade.
20:02And so that's the fundamentals framework
20:05we have established back to 1998,
20:09almost 30 years ago.
20:11Nothing has changed,
20:12but if you look at Prostate,
20:14how many revision had gone through?
20:16We can renal cell customer
20:17how many are fishing.
20:19So we felt that you know it's the
20:23work farewell maybe we need to some
20:27refinement and and get additional you
20:30know so this is you know we have to
20:34understand you know breeding especially
20:36in the bladder it's it's spectrum disease.
20:38It's not always black white you know low
20:42grade heart rate positive, negative.
20:44It's really spectrum disease in
20:47the 1997 three W2 grading system
20:49that many old generation passage
20:51probably more familiar with that
20:53it's grade 123 and in the 2004 and
20:59after that was considered low grade
21:01heart grade # lump is another vanishing
21:06cancer that with the increasing incidence
21:11of being called and and services so
21:14so but in general I think this is a
21:18kind of the current those are two most
21:22commonly used grading system since
21:24in the especially in the European
21:27side in the 1973 W grade sipping used
21:30and this is a Eau prognostic factor
21:35risk group that's been most popular
21:39widely used in the European countries
21:42and this is you know this you know
21:45this paper was published you know the
21:47guideline was published in the 2021
21:49and one one thing one change they have
21:53made is that they have a kind of a
21:57stratified you know in the previous
21:59edition they only use 1973 W 2 grading
22:03123 but in this new flushing they have
22:08incorporate so they have proposed that
22:11combination so reporting both W 2/19/73
22:17and current low grade heart rate.
22:20So very nicely using this combined hybrid
22:24system they can further nicely stratify
22:27patient into different prognosis group.
22:30So that's really you know that's
22:32kind of why you know the very nice
22:35contribution and this is in the in
22:39the paper published in the European
22:41your large focus and that also have
22:44issued it's kind of its own opinion
22:49and and here's in another survey
22:52we did was publishing the European
22:55urology as well and and in the this
22:59is the surveys conduct among both
23:01US and European pathologists and
23:03we can see here still in almost you
23:07know there's a 40% of pathologists
23:09you know institutions you know they
23:12still using this combined system 1973
23:16and at the 2004 grading system.
23:20So I think let's this is some newly
23:23proposed you know we feel that you
23:26know that maybe less the Poundland
23:29probably can be completely gone because
23:32treatment and prognosis everything is
23:34almost identical guidelines you know
23:37same as a low grade so so that entity
23:39probably can be gone and again it's
23:42a you know it's on the proposal and
23:44and so this is a four tiered grading.
23:46So I think the main thing is that we
23:48all know this tumor grade especially
23:50in the in the current double chip in
23:52the current classification not all
23:54hardware have a same you know some
23:56you can almost definitely you can
23:58feel that you know some morphology
24:01we don't have a trouble to tell you
24:04know very very low rate or # lump and
24:07or hardware end and but we really we
24:10have something you know in between you
24:11know there's a grade zone area it's a
24:14grade 2 low grade hard grade or hard grade.
24:18So I think that's really you have to think
24:21about you know there's a again the grading,
24:23you know that's a,
24:24you know it's a spectrum of disease,
24:26it's not you know so.
24:28So I think that would be what we'll
24:30see hopefully in in the coming years
24:33there will be more study conducted and
24:35more have more defined criterias into
24:38how you know help out the clinicians
24:41to further strictify patients for
24:44for additional treatment. All right.
24:47So let's switch gear talk about flat
24:52leverage and I'm not sure you know
24:56I think now that's you know that you
24:58know that you know so one thing keep
25:00in mind is that you know the you know
25:02Doubletrol is constantly evolving.
25:04It's not static to you know this this
25:07is news in the in this newest published
25:10old classification and the the non all
25:14the in in the flat leash only you Lucila
25:18carcinoma in such has been included.
25:21It's kind of a much simplified version.
25:24So the only one issue they talk about
25:26it there's only the issue that we have
25:29abundant knowledge we know what it
25:32is and for many years for decades and
25:34you'll see the customs and satchel is
25:37one for the worst CRS in the human body.
25:40It killed the patient.
25:41So if you want to choose between
25:44Prost cancer or kidney cancer versus
25:49CRM T1 kidney cancer,
25:50I would rather prefer to have those you
25:53know cancer by CISCIS in this study
25:58we conducted over at the male and with
26:01over 10 years follow up in a patient,
26:04the 15 year cancer specific survival for
26:08bladder cancer that's only 79% or 80%.
26:12So really you know this is a it's
26:15not you know innocuous you know that.
26:18So again you can of course you
26:20can argue about other things.
26:22So let's go back you know for personally
26:25I know I still laugh like the framework
26:28you know that has been laid out in the
26:312016 double ship classification in
26:33terms of especially in this flat leaching,
26:36I think you know that's in the WCO 2016
26:41classification for that leaching. Well,
26:43you know there's a you will see the pepperon,
26:45you will see this picture,
26:46you will see the customings are true.
26:48We all feel familiar.
26:50But they also introduced a very you know,
26:53somewhat controversial leasing at that time.
26:56It's called Euro Celia profession
26:59of uncertainment potential.
27:01In the 2022 those two leachings
27:04pretty much gone.
27:05It's only CRS being left in the current
27:09classification and from a you know in
27:14terms of the carcinogenetics it's a long
27:17standing theory not theory anymore.
27:20We we all know from knowledge of
27:23human almost 100 years that you know
27:26Brad the tumor you know silicosis
27:29genetics is prime example of a field
27:33of fact and and it's a it's not you
27:35know it is multiple it's still the
27:39fact it's not involving different
27:41lesions different pathways and this
27:43kind of well established at least
27:46it's from the basic science point of
27:48view we know that you know there's
27:51a hyperpay sure display sure you
27:53know it's it's well much more well
27:56established in animal models that you
27:59know there's CRS you know different
28:01molecular pathway genetic mutation
28:03that has been involved in terms of
28:06the you know also we know if you
28:08look at the supplied cases there's
28:10always you know ways on areas that
28:12you know some squeezing bordering
28:14between CRS and complete normal.
28:16And this paper will have partially
28:18numbers are probably one of the fair
28:21few paper that we did you know able
28:23to follow up the patient long term
28:25and you'll see that this patient
28:28in the using we found that.
28:30So it's not as bad as the CRS but
28:33indeed about 16% of patient will have
28:37progressed into CRS or other lesions.
28:40So it's not complete benign it does
28:43exist and if you look in the cell you
28:46know that's you can you can you know
28:48you can argue you know this cell is
28:50you know I was maybe you know it's
28:53it's it's CIS maybe not but it's not
28:56probably not complete reach to the
28:58left of the logical tape here you
29:01know in common diagnosis CIS how
29:03many cells you need.
29:05You don't you only need one cell to
29:06make that I'm I'm not psychologist
29:08but there's criteria you only need
29:10one cell unlike cervical CRS you need
29:12the full thickness in in the bladder
29:14you only need one cell called the CRS.
29:17So the cell, you know,
29:18again you can look at the cells here and
29:20well you can argue some cell may be reaching,
29:22yeah, but but it said, you know,
29:24it's kind of embodiment between
29:25you something, you know,
29:26it's not complete normal and it's
29:28it's a fully approved immune staining,
29:32P53 immune staining or C20 staining.
29:35So this is a lesion that it does exist.
29:38And how about this controversial
29:41lesion called Euro Celia provision
29:44of uncertainment potential.
29:46This is the machine that has
29:48been proposed in the W-2 2016,
29:50including actually including two leash.
29:52One is a type of you city have a patient,
29:55the other one is flat,
29:57you will city have a patient.
29:58And those are, I think by the name implied,
30:01you know that you know this is leaching.
30:03That is kind of, you see there's a,
30:06you know, incipient
30:10almost like, you know,
30:11there's a pity structure but
30:12it's not fair well formed.
30:14You also see if rich, fast school
30:16chair on the underneath and the flat,
30:18you'll see you have a patient.
30:19It's very simple.
30:21It is very, very tremendous.
30:23Second that you'll see them so.
30:25And the jewellery,
30:26I think that you know,
30:27the jewellery is still up.
30:28It's not complete that yet,
30:31and at least you know in this paper
30:33we're publishing this year in the
30:36modern pathology we analyzing,
30:37you know over 52 cases of pepper.
30:40You will still have a pay share
30:41you know at least with fun.
30:43You know we compare this leaching
30:45with the norful leaching and MP
30:47machine code is a single user
30:50customer low grade and we found in
30:52a significant number of patients
30:54we'll have to the mutation again
30:56to the mutation along doesn't
30:57tell you it's cancer not cancer
30:59and at least you know this is not
31:02complete reactive normal process.
31:03You can argue you know this is a
31:06true precursor not true because
31:08but at least I think this should be
31:11bringing to the our community again
31:13really deserve fuller investigation
31:16so and for the bladder I think you
31:20know it's really you know that's
31:21a it's you know if you're looking
31:24at the virtual classification
31:25in CIS it's super simplified.
31:27So when you again special for for
31:30the Chinese you know that yes that's
31:32our battle that's how we follow
31:34guidelines but it's you have to
31:36understand the you know molecular
31:38mechanism the pathway go beyond that
31:40looking through and understand the
31:42you know that you know it's just
31:44some you know some some difficult
31:47entities you know it's completely
31:50ignored will not will not make
31:52things go away you know so I just
31:54I think it's a we should always
31:56tactically challenge you know just
31:58you know to look in things deeper
32:01at the deeper level that's how we
32:04at the France our field and so go
32:08back and to the W 222 classification
32:10income of in base USA customer.
32:13I think the only things that has
32:15been changed it's really it's a
32:17terminology you know we call them the
32:19the ferrant you know it used to be
32:21we call it histological ferrant of
32:23you know plasma subtle you invasive
32:26you will see customer so now we have
32:29kind of calling them you know just a
32:31histologic subtype so that's not to
32:33not afford confusing with the gene
32:36or teaching that was called and in
32:38terms of a number of parent we've
32:41seen it's you know the terminology
32:43is remain the same and and they are
32:46very you know kind of largely has
32:49not been changed let me let me give
32:54our resident a quiz you know that
32:56we we we have a a slide conference
33:00and this so we talk about you know
33:04this so-called prolific lesions
33:05that you know we have all those
33:08different differential diagnosis in
33:10this case and let's see who attended
33:14this morning's conference you know
33:16so so if you remember anything OK good.
33:19So what's your diagnosis.
33:30Well OK let's let's the diagnosis so
33:35so why why is why you think about that
33:56glance small fuse gland no
33:59big open looming so and good.
34:03So you don't need molecular you can make
34:05diamonds purely based on morphology.
34:08Very good. OK. So that's indeed
34:10that's the case of nest variant,
34:12you will see the carcinoma and and
34:15also if you want to do molecular
34:17study and certainly you can the
34:20truth promoter is really fantastic.
34:22That's a paper punch from my my friends,
34:27you know and abdomen and histopathology
34:30you know that more than 62% patient
34:33with the next family you will see
34:35the customer will be positive for
34:37the term mutation and also you know
34:40kind of interestingly but a few
34:41patients will have FC past three
34:44mutation and the tumor belong to
34:46this luminal molecular subtypes.
34:48And indeed third nutrition computation
34:50is very helpful bar marker,
34:52it's negative for in all the denomination
34:55so far we have analysed and so it's good,
34:59it's great bar markers and so go back
35:01to the fair and it's logic fair.
35:04And one particular fair and I want to
35:07point out is the macro Papri your city
35:10customer of bladder Leslie Lee Shing.
35:13But Peter Humphrey has started 20 years ago,
35:16I guess you know published paper.
35:18I was I'm not sure if people don't
35:20think you remember it's a it's a
35:23it's one of the classic study that
35:25Peter Humphrey had published and
35:27and it was you know in terms of our
35:30understanding morphology not much
35:31there's not much change you know but
35:34it's really very aggressive friend
35:37one unique features could be in
35:39your board exam is that this tumor
35:41also have fair fair high preference
35:44of a her to you know mutation or
35:48her to you know old expression.
35:51This one fair few tumor in the that's really
35:54fair for her instance of her to expression.
36:00Jessica Possible is our former
36:02surgical prosology fellow.
36:04He did the study last year.
36:06Brown and we compared genome profiling of
36:15220 patients and all have the two mutations,
36:2011 will have the macro peppery morphology,
36:24one will not macro peppery morphology.
36:27What we keep the take home message is
36:30that you know this is just you know
36:33the KMT two RB One and TAB this key
36:37molecular driver for morphologic.
36:40So not when they really kind of
36:42morphological molecular correlation.
36:43So this is something we found
36:46in the study the KMT two,
36:48RB One and TAB the key molecular
36:51driver of this issue.
36:52All right. So let's
36:59take a another quiz to see what you
37:01have learned from this morning's
37:05lecture or slide seminar. OK.
37:07And let's pick up another resident. OK.
37:11So this is a 65 years old man presented
37:14with him two years, 3 centimeters,
37:173 centum mass and and also look at
37:21three is positive and that's tumor.
37:24So what's your diagnosis?
37:27I mean, the senior resident who
37:30have attended today's SLA seminar,
37:35You want to What's your
37:37diagnosis? What diagnosis? You said
37:48that paragraph was 3 positive.
37:53So
37:59exactly let's let's let's let you know.
38:03Let's let bladder para gangloma,
38:06you know this is a leaching that right you
38:09know have a fair peculiar you know that
38:12you know they have anthropilic cytoplasma,
38:14they have a very vascular structure but
38:17there's also could be you know they're
38:20all get the street positive so so
38:22that's that's good very unusual tumor.
38:24So you have to keep in mind wide
38:27open differential diagnosis.
38:29Yeah, paragraph Gangloma is a fair,
38:31fair you know kind of a rare tumor that
38:34you know this is the prognosis wise you
38:38know that's the pathologic stage is only
38:41saying that can predict patient outcome.
38:44So in terms of the in terms of the neural
38:48endocrine tumor and classification
38:49in for bladder this remain the same.
38:52Now it says with more,
38:54more or less mirror what's we're seeing in
38:57the in the lung with small cell carcinomer,
38:59large cell neuronic customer word,
39:01the French neuronic customer
39:03and the perigangioma.
39:05But the small set customer is probably
39:07not really it's a terrible terrible,
39:09this terrible disease.
39:11The prognosis is,
39:13is is one of the worst five years
39:17above or 10 years above it's almost
39:20zero and and the multi modality mostly
39:24including actrophone chemotherapy
39:26is the key is all for the best
39:30hope for the patient chair.
39:32So,
39:33so that's the you know kind of it's
39:35fair you know kind of bad disease
39:38and in terms of the pathogenesis
39:40you know so one of the questions
39:42we have is that you know a small
39:45cell carcinomer colonial related
39:47to Eurociliac carcinoma or not are
39:50they independent you know separate
39:52from some new land Chrome cells.
39:54And in the study we found that and
39:58are using Modic genetic F approach,
40:00we found both your Cilic customer
40:02and small cell customer component.
40:03They are originally from same stem
40:06cells in the uricilium and now
40:09we have to promote mutation.
40:11So we also analyzing could promote
40:14mutation in both small cell customer
40:18and coexisting your customer and also
40:21analyzing control 26 patients with
40:24a prosthetic small cell customer.
40:27What we found it's not surprisingly the
40:30Kurd mutation is also very prevalent.
40:33It's present more than half of
40:35that is small set customer and
40:37interestingly you know it's negative.
40:39We don't see any function Kurd permutation
40:42in blood prospect small set customer.
40:45So indeed I was thinking now that
40:47despite the morphological you know
40:51similarity this underlying pathogenesis
40:53you know so quite different and this
40:57paper publishing the clinical Cancer
40:59Research and you know so this is a
41:01you know all the small cell customer
41:04regardless human origin they always
41:07share similar molecular funding that
41:10is RB one loss TPC loss and but
41:13individually they may have different
41:18you know there's underlying bladder
41:20you will see stood promote mutations so
41:24that's the one and but OK so so let's
41:29switch gear talk about some more exciting
41:34things and what's the what's happening
41:37outside of college and so this is
41:43this table this came from our paper
41:45it's going to be published in the
41:48BMG soon and also so what's the.
41:51I think this is truly exciting that
41:54convergence of molecular physician
41:58medicine college and the and the
42:00genomics you know that's a tumor
42:02classification you know it's a very
42:04robust tumor classification system
42:06has been proposed they are most
42:08importantly it's not just simple you
42:10know luminal basal luminal that link
42:12to the patient prognosis and also where
42:16the patient patient treatment we have
42:18to go back ten years ago you know this
42:21paper was published in JCO and then
42:24my friend doctor Nohan he's now Johns
42:27Hopkin and he's one of the brilliant
42:29oncologists in this clinical trial.
42:31He cannot.
42:31You know this is a patient with
42:34advanced stage bladder cancer.
42:36You know overall survival is less than
42:39two years really it's kind of bad cancer.
42:41So back until you know 2011 this,
42:45this is still but you know Elizabeth
42:48review paper pubs in the 2017
42:51whether we can see I want to draw
42:54attention to the bladder what those
42:56.0 means that means back in the 2017
43:01this is no FDA approved standard
43:03care for bladder and also very few
43:06would be in the clinical trials.
43:09But that has changed two years
43:11later in the 2019 finally finally we
43:15have this first FDA approved target
43:18therapy for for bladder cancer that's
43:22targeting FG last three mutations.
43:25And in the same year you know FDA
43:28also approved carding companion
43:30diagnosis for bladder cancer as a
43:34single as a Johnson Jensen drug.
43:37And so this is a,
43:40this paper I was you know kind of
43:43first announcing SQ meeting that in
43:462019 is the paper was published in
43:50the medicine you see that's truly
43:53phenomenal significant objective tumor
43:55response more than half patient you
43:58will see you know almost immediately too
44:01much shrunk and truly it's remarkable.
44:04Well, you know the question is that,
44:05well what that means tumor progression
44:08and all those things, what that means?
44:10How about patient survival,
44:12you know,
44:13do they have integral patients
44:14About the last question we always
44:15have from the target set up all
44:17the data previously published,
44:21you know, yeah, it's sure
44:22they can improve the patient,
44:23but how about survival?
44:25This data this paper just published last
44:28month in the New England General just
44:30three weeks ago in New England German,
44:32let's say, you know you can see here
44:35that true data FGF three treatment
44:37inhibitor make a difference.
44:39This is the line you know,
44:40you know the patient was treated
44:42with it FGS 3 inhibitor that also
44:45valves four months almost double the
44:48patient without target therapy someone
44:50with E mouse that's substantial.
44:53This is really a major breakthrough
44:55for the black cat square yet.
44:57So this is kind of a lack kind of results,
45:00you know it's almost like a
45:02mandatory all the black cat patients
45:03you want to try it out,
45:05you need to do the test you know to
45:07see you don't want to miss opportunity
45:09for patient to extend patients
45:11life that's really exponential.
45:13So we liquid biopsy is also another
45:19important value interesting you know
45:21that you know basically more more more
45:23important as in the bladder not just
45:25in this you can do the liquid biopsy
45:28in the serum but also in the urine.
45:30You can test the FGSE in
45:32the urine specimen as well.
45:34And these people are pushing the
45:37journal clinic on college and
45:38they found that you know that the
45:41presence of cell free DNA in the
45:43blood and in patient related you
45:44know C Class number you know can
45:46predict patient survival.
45:49So that's kind of a,
45:51it's not
45:53surprising you know when you have
45:55more tumor shut into the blood,
45:57those patients probably have high tumor,
45:59low high tumor burden.
46:02And there's another paper
46:04landmarks paper published in
46:07Nature and the Fairfield papers.
46:10This all will lending to this
46:12kind of clinical people will land
46:14in nature and to see the key,
46:16the key message the foundings that
46:18you know this is for a different PD1
46:23media media immunotherapy.
46:25The patient if you use for
46:28your serum, you know if you're
46:36liquid biopsy
46:39negative for free plasma DNA and
46:43the chemo atriphant chemo therapy
46:46doesn't make much difference
46:48that will not make a difference.
46:50In contrast, in contrast the patient the,
46:56the atriphant immunotherapy only
46:59matters when the patient have positive
47:02similar mark of positive CFDMA.
47:05So, so that's really kind of changing
47:07I think about you know nowadays
47:09we always say we know there's a
47:11treatment a fair very expensive you
47:13don't know which patient may benefit.
47:15PDL one is fantastic spa market,
47:19it's good you know Johnson that has
47:21been pioneering analyzing all this
47:23spa mark and this is so but you know
47:27it's especially in the blood that
47:28we all were already removed that
47:30indication you used to be like using
47:33you know 10% cut off in FDA indication
47:35that label has been removed for two
47:37years maybe I think two years ago.
47:39So we're not we're not using PDL one
47:41understanding to God you know that's
47:42so really this is kind of interesting
47:44study that showing you that another
47:46patient you know that's a you really
47:48need to kind of more more importantly
47:50you can see here the impact will also
47:54baffle 25 months versus 15 months
47:57that's fast especially so really I
47:58think the the calling for you know
48:00the the the CLM DNA test the next
48:06frontier I think small exciting things
48:08really the the Spatial Transcriminate
48:11transcriminate study and what what's
48:14the underlying mechanism for you know
48:17to overcome you know immunotherapy
48:19tumor resist immunocellular resistance
48:22and it's emerging field and I'm very
48:28honoured privilege to be able to
48:30participate in in this study there was
48:33a publishing that cancer communication
48:35last two months ago and then we found
48:37that you know that you know that's
48:40crucially linked for structure and it's
48:42a bar marker you know that's associated
48:45linked to the the PDL 1 inhibitor
48:50immunotherapy affect resistance.
48:51And the key message here is that you
48:54know for the patient if you have those
48:58neutrophil in MYLOD derived suppressor
49:01cells you know those patients can
49:03do have a much better prognosis.
49:06So this line here if you have a
49:09positive MDSC and they doing much
49:13better than patient a lot with cells.
49:16So so the question is that how to tuning,
49:19how to train,
49:20how to select patient also how to convert
49:23those you know the code tumor to hot tumor.
49:26So that's really kind of interesting
49:29and I would like to you know ending my
49:32talk with this paper view paper just
49:35published in Nature Medicine about
49:39Sudan who's a fantastic amazing you
49:42know oncologist who's leading many,
49:44many clinical trials and this is we
49:48are in the next phase of physician
49:51medicine on college and as we
49:54are seeing the verge of all the
49:58different technology platform AI,
50:00trans clinic liquid biopsy genomic you
50:02know let's see the bar marker is already
50:06entrenched in our current practice.
50:09It's it's, it's fair.
50:11It's profusing.
50:12It's everywhere not so nowadays
50:13We're now in the next phase you
50:16know that how to integrate in our
50:18informatics integrate all this
50:19information and so so this will
50:21be integrate approach regardless.
50:24You know that's you know you don't
50:26want enough when you come back
50:28to you among you I think it's a,
50:30you know morphology still remain
50:32that you know the cornerstone and and
50:35actually you know you have seen you
50:37start from you know 10 you have to
50:40absolutely morphology and and here
50:43also I just want this paper we also
50:48just published this month about two
50:51weeks ago and and this is a book I
50:54will recommend that just you know
50:57covering every single open system
50:59and so all right so stop my talk here
51:04leave for some time for questioning.
51:19No that was great.
51:22So what do you see as far as some of
51:25the first case utility uses of AI. Yeah.
51:32Also in terms of AGU in the West we heard
51:36so much everything you know on the bladder,
51:39weeding, all those things.
51:40I was, I was trying to put some good
51:43slides for this talk in the AI.
51:45The only significant paper I have
51:48found that was a is a publishing
51:50The Lancet on college using AI
51:53to predict you know metastasis.
51:55So so in that regard and also try to
51:57look in some good paper I'm thinking oh
52:00breeding must be you know I'm sure you
52:02are probably doing that stuff as well.
52:04I'm not doing that complex study
52:06not breeding or BLAD how to use
52:07to train a art better breeding.
52:09So there's one paper publishing American
52:13Journal Pathology 4-5 years ago that was
52:17using AR acquisition to predict the breeding.
52:20You know that but in terms of like you
52:22know BLAD is such thing that we are,
52:24you know, Gu is,
52:26you know well behind breast,
52:28lung and in terms of bladder,
52:30we'll even feel a bit high.
52:33So AI comes come to the AI in the
52:36bladder and this is some few scattered
52:39study talking about you know you know
52:42talking about you know predicting or
52:44training more from your knowledge you
52:46know surgeon or on college point if
52:48you know how to you know machine or
52:50like you know that's a you know wasn't
52:53you know the same topic on college
52:55side how to manage the treatment
52:57side but not pathology application.
53:00And there's one paper and I'll talk
53:02about predicting not you know detect
53:04you know follow follow predict with
53:06no meta phases based on equity.
53:08So very I think this is just a single
53:11so we can see here kind of expanding
53:14on that I have not presented,
53:16we have actually actually we have
53:17very very interesting data
53:20for publication and we we do find
53:22you know you know it's kind of small
53:24niche but not you know we're using
53:26the AI we're able to tell in for the
53:28papadoma first you will see the papaduma
53:30but I think we're going to make AI
53:33definitely let's let's you know kind
53:35of AI is going to be very important
53:37you know in practice but how to how
53:39to funding you know that niche. So
53:46my understanding
53:52we
53:55have like basically yeah yeah.
53:57So my question is
54:00mutations, do you think they both
54:02countries like at the same rate or
54:05yeah I don't think the truth is going
54:08to be distinguisher, it's going to be.
54:10So you know I guess it's
54:11probably one of the mutation,
54:13the highest instance mutation we talked
54:14in the old days we talked we also
54:16talked about P phase three mutation,
54:18you know universal mutation
54:20in the all organ system.
54:23Now I think you know you know TURD
54:25is 80% of plastic tumor will have
54:27a will have the turtle mutation.
54:29So it's kind of background also in
54:31terms of how that playing to role
54:33you know TURD will not be be draft
54:35or distinguishing different way
54:36going to be public going to be just.
54:40But again, I think it's kind of TURD FGF 3,
54:43they're more link interesting,
54:45they're more related to kind of more
54:48benign and more less aggressive tumor.
54:51My question pressed on the fact that you
54:53mentioned that you have that nested fires,
54:55right.
54:55Yeah, the FGFR 3, yeah, yeah,
55:01yeah.
55:02So if if we would have a tumor
55:05that derived from the popularity,
55:07yeah would that mean that it lost the
55:10FGFR 3 as if we think well if it just
55:14is not you know nowadays we have to
55:17break the concept of mutations bad,
55:19you know it's worth isn't a lot
55:21of mutation not just in the
55:22bladder but also you know you can
55:24see mutation in the non lesions.
55:27So funding mutation really doesn't
55:29mean you know you can have P for
55:31three mutation a bit in the banana
55:33lesions as well including bladder.
55:35So it's not you know signature you
55:38know I think more moving forward
55:40we can look look into the profile
55:43for example in the bladder the
55:45certain cubic type like basal type
55:47a neuronal type those are use of
55:50molecular classification probably
55:51going to be more useful in terms
55:54of of non frame not just how to you
55:56know how it's it's not single genes
55:58you know that going to defining you
56:01know the pathway obviously but again
56:03there's a few key players you know
56:06just less going to be important
56:08and and I think you know there's a
56:10probably if you put all together I
56:12think like you know just research
56:14it's common FGF stream mutation
56:15it's a it's a it can happen both
56:18in aggressive non aggressive but
56:20in terms of preference wise it's
56:23more commonly seen in less you know
56:25superficial less aggressive tumor.
56:28In terms of general preference
56:57the
57:17yeah we this is very very kind of
57:21important question you know So what
57:25molecular classification going to
57:27come into play in our practice and our
57:31soup have assembled the team address
57:35the same almost the same question
57:38twice in the 19/20/19 and also 2022.
57:40The paper you know that we're going
57:43to be publishing in January you
57:45know that's in the in the currently
57:47our singular conclusion is that in
57:50unless it has code great potential
57:53but it will be take some time become
57:56clinically useful or adapted into
58:01our current you know practice.
58:04But nonetheless let's really very
58:06exciting I'm thinking about if you're
58:08looking at some data you know it's a
58:11molecular subtype like neuronal like
58:15subtype those are associated with
58:18that data immunotherapy treatment.
58:20So definitely and also we we just
58:24started I think we're you know I think
58:27that's that's really we just see the
58:29body which is still we see we start
58:31to see the ball the evidence has been
58:33built up you know that you know so,
58:36so I think you know so but at the
58:38moment at this as today or maybe even
58:41next year and I think we can probably
58:44reliable predict this it's unlikely going
58:46to come into our daily practice yet.
58:48So
58:55thank you.