Smilow Shares: NETS Awareness Day 2025

Transcript

• 00:00Alright. Well, great. Thank you
• 00:01so much everybody for joining.
• 00:03We're really all excited to
• 00:04be here. So happy official
• 00:06NET Awareness Day. It is
• 00:08actually on November tenth, which
• 00:09is why we picked this
• 00:10evening.
• 00:11Our goals tonight are to
• 00:12highlight awareness and diagnosis and
• 00:14treatment for patients with neuroendocrine
• 00:16tumors.
• 00:18So I have an,
• 00:19wonderful panel of colleagues.
• 00:21So I, my name is
• 00:23Pam Coons. I'm a professor
• 00:25of medicine and medical oncology.
• 00:26I direct the center for
• 00:28GI cancers at Yale Cancer
• 00:30Center and Smilow Cancer Hospital,
• 00:32and I co lead the
• 00:33neuroendocrine tumor program.
• 00:35Doctor David Klimstra is a
• 00:36professor professor of pathology,
• 00:39and he will be speaking
• 00:40about understanding,
• 00:42your pathology.
• 00:44Doctor George Al Fakhri is
• 00:45a professor of radiology and
• 00:47biomedical engineering. He directs the
• 00:49pet center, and we'll talk
• 00:50about pet scans tonight.
• 00:51And doctor John Kuntzmann is
• 00:54an assistant professor of surgery
• 00:55and surgical oncology, and we'll
• 00:57talk about surgical approaches to
• 00:58NETs. And then we will
• 00:59finish up with a thirty
• 01:01minute q and a.
• 01:04Alright.
• 01:05So as of twenty twenty
• 01:07one, the state of Connecticut
• 01:10recognizes November tenth
• 01:12as NET Cancer Awareness Day.
• 01:15So thank you to governor
• 01:17Lamont and to a number
• 01:19of,
• 01:20NET
• 01:21advocacy organizations
• 01:22for really advocating for this,
• 01:24and so most states acknowledge
• 01:26this day.
• 01:28So I will talk a
• 01:29little bit about neuroendocrine
• 01:30neoplasms
• 01:31one zero one, and neoplasms
• 01:33encompasses
• 01:35neuroendocrine tumors and the higher
• 01:37grade neuroendocrine carcinomas, and I
• 01:39will talk briefly about some
• 01:40medical management tips.
• 01:44So I love just acknowledging
• 01:46some history here, and some
• 01:48of you may be familiar
• 01:49with the term carcinoid.
• 01:51It was coined by a
• 01:52German pathologist in the early
• 01:54nineteen hundreds
• 01:56to describe,
• 01:58neuroendocrine tumors, and it meant
• 01:59cancer like.
• 02:01Neuroendocrine neoplasms can actually start
• 02:03throughout the body. That's called
• 02:05the primary site where it
• 02:06starts.
• 02:07And
• 02:08neuroendocrine neoplasms are derived
• 02:11from neuroendocrine cells,
• 02:13in the gut and in
• 02:14other places. Most grow slower
• 02:16than their adenocarcinoma
• 02:18counterparts. Adenocarcinomas
• 02:20are often a more common
• 02:21cancer type. Think of run
• 02:23of the mill colon cancer,
• 02:24for example.
• 02:25And another really key characteristic
• 02:27that I suspect doctor Alfaquer
• 02:29will get into is that
• 02:30somatostatin
• 02:30receptors,
• 02:31or like a target,
• 02:33are usually present on the
• 02:34cell surface of neuroendocrine neoplasms.
• 02:38So
• 02:40NNs are really not that
• 02:42rare. They used to be
• 02:43considered rare.
• 02:44They are low in incidence,
• 02:46meaning the number diagnosed per
• 02:48year, but you can see
• 02:48we're nearing about ten per
• 02:51hundred thousand persons
• 02:53in the US. That's the
• 02:54yellow line,
• 02:55compared to overall cancers, which
• 02:58is the blue line, which
• 02:59has really stabilized,
• 03:00over the last many years.
• 03:02But neuroendocrine neoplasms are increasing.
• 03:03We're getting better at diagnosing
• 03:05them.
• 03:06But there is probably a
• 03:08a truth to this line
• 03:09indicating that perhaps their environmental
• 03:12environmental reasons or other causes
• 03:13of this increased incidence.
• 03:16NENS are
• 03:18more prevalent than previously appreciated.
• 03:20Prevalence is the number of
• 03:22patients alive at any given
• 03:24time,
• 03:24and the prevalence of neuroendocrine
• 03:26neoplasms
• 03:27is about equal or slightly
• 03:29higher than that of stomach
• 03:31and pancreas cancer combined.
• 03:34There are several key characteristics.
• 03:36I'm not gonna go into
• 03:37details on all of these,
• 03:38but I talk to when
• 03:39I meet with patients, I
• 03:41talk about these
• 03:42categories or ways that we
• 03:44describe
• 03:45neuroendocrine tumors,
• 03:46whether or not they secrete
• 03:47a hormone that's called functional
• 03:49status,
• 03:49where the cancer starts,
• 03:51that's the primary site, what's
• 03:53the stage, that means where
• 03:55in your body is the
• 03:56cancer,
• 03:57the volume of disease, is
• 03:58it low volume or high
• 04:00volume,
• 04:01whether or not you have
• 04:02a somatostatin receptor on the
• 04:03surface of the cell,
• 04:05the grade of the tumor,
• 04:07degree of differentiation.
• 04:09We're starting to look more
• 04:10and more at genetics,
• 04:12so genetics passed from parent
• 04:14to child and also genetics
• 04:15of the tumor itself.
• 04:17We know that sex and
• 04:19racial differences can occur. And
• 04:21then our environment in which
• 04:22we live can also impact
• 04:24both our diagnosis, but also
• 04:26the type of care we
• 04:27give. Those are called social
• 04:28determinants of health.
• 04:31So the primary side I
• 04:33mentioned already is where the
• 04:34cancer starts. The small intestine
• 04:36is by far the most
• 04:37common,
• 04:38followed by the lung and
• 04:39then the pancreas and then
• 04:41other.
• 04:42And if a cancer spreads,
• 04:43it retains the properties of
• 04:45that primary site.
• 04:47So, for example, if a
• 04:48neuroendocrine tumor spreads to the
• 04:50liver, it doesn't become liver
• 04:52cancer. It is still, for
• 04:53example, a pancreatic neuroendocrine tumor
• 04:56that spread to the liver.
• 04:58We used to be lumpers,
• 04:59but we are really now
• 05:00splitters, meaning
• 05:01that NENS of different primary
• 05:04sites really have different incidence
• 05:06rates, different biology,
• 05:08they respond differently to treatment,
• 05:10and they're often now studied
• 05:11in different trials.
• 05:15So this is a very
• 05:16detailed example of something that
• 05:18we call the AJCC
• 05:20or American Joint Committee on
• 05:21Cancer staging.
• 05:23And staging helps us determine,
• 05:26in three different categories,
• 05:27tumor,
• 05:28lymph node, and metastasis,
• 05:31how the cancer is involved
• 05:32in each of these,
• 05:34categories.
• 05:35And I'm not gonna go
• 05:36into the details, but I
• 05:37wanted to just
• 05:38teach you that that's how
• 05:40we as physicians really think
• 05:41about this. So t refers
• 05:42to the primary tumor. It
• 05:43involves depth of invasion,
• 05:45the size of the tumor,
• 05:47n refers to regional lymph
• 05:49nodes, whether they're present or
• 05:51absent and sometimes
• 05:53is defined by the number
• 05:54of lymph nodes.
• 05:55And then m refers to
• 05:57distant
• 05:58metastasis,
• 05:59again, whether it's present or
• 06:01absent, and there are some
• 06:02nuances.
• 06:03And then we combine
• 06:05that those t, n, and
• 06:06m to come up with
• 06:07an overall stage, which you
• 06:10can see kind of in
• 06:11this top right Cornell table
• 06:13two,
• 06:14allows us to come up
• 06:15with that combined stage.
• 06:18I'm gonna really let doctor
• 06:20Klimster go into the details
• 06:21of understanding your pathology,
• 06:23but suffice it to say
• 06:25that this has really evolved
• 06:26over the last thirty or
• 06:28forty years. We think about
• 06:31differentiation,
• 06:32which is really what the
• 06:33cells look like under the
• 06:34microscope,
• 06:35grade, which is how rapid
• 06:36they are they are dividing.
• 06:37And there are a number
• 06:38of features that help pathologists
• 06:41determine this, and then that
• 06:42in turn
• 06:44helps oncologists,
• 06:45both medical oncologists like myself
• 06:47and surgical oncologists,
• 06:49tailor the treatment based on
• 06:51a number of these characteristics.
• 06:53A key takeaway, and I
• 06:54would imagine that doctor Klimster
• 06:56will touch on this,
• 06:58an expert pathology review is
• 07:00just as important as getting
• 07:02an expert medical oncologist
• 07:03or expert,
• 07:05surgical oncologist or even radiologist.
• 07:08So really having people who
• 07:09are familiar with these cancers
• 07:11is critical.
• 07:13Understanding your pet. So we
• 07:15talked a little bit about
• 07:16stage and determining
• 07:18extent of disease. So DOTA
• 07:21PET scans are really one
• 07:22of our best tools to
• 07:24help determine extent and volume
• 07:26of disease.
• 07:27Again, I know doctor El
• 07:29Fakher will go over this,
• 07:30but just to give you
• 07:30a little bit of a
• 07:31teaser, you can see really
• 07:33big differences,
• 07:35in these three different DODA
• 07:37PET scans. This first one
• 07:38is localized.
• 07:40The middle one is metastatic
• 07:42with
• 07:43high volume large liver lesions.
• 07:46It's liver predominant.
• 07:47And then on the far
• 07:48right, the patient has metastatic
• 07:50disease, but it is lower
• 07:52volume,
• 07:53but lots of little scattered
• 07:55bone metastases.
• 07:56So pets
• 07:58give us incredible resolution and
• 08:00really, again, help us tailor
• 08:01treatments.
• 08:03Doctor Kunstman will touch on
• 08:05surgery.
• 08:06Really, one of our first
• 08:07steps in tailoring a treatment
• 08:10for a patient is asking
• 08:11this question, is surgery feasible?
• 08:14The answer is yes for
• 08:15several situations. If it's localized,
• 08:18we can often offer curative
• 08:20intense surgery to remove the
• 08:21primary tumor. If it's metastatic
• 08:24and patients have symptoms from
• 08:25their primary tumor like a
• 08:27blockage,
• 08:28we sometimes will still remove
• 08:29that primary tumor.
• 08:31And if metastatic
• 08:32with low grade or low
• 08:33tumor burden, we sometimes even
• 08:35can offer
• 08:37surgical removal of some of
• 08:38those metastatic sites, which we
• 08:40call a cytoreductive
• 08:41surgery.
• 08:43If the answer to is
• 08:45surgery feasible and no, that
• 08:47often will happen for patients
• 08:49who have high tumor burden
• 08:50or if it's high grade
• 08:52or just if a patient
• 08:53is not a good surgical
• 08:55candidate, and then we will
• 08:56think about doing systemic treatments.
• 08:59So systemic treatments fall into
• 09:02kind of the the, realm
• 09:04of a medical oncologist,
• 09:06and they fall into five
• 09:08main treatment categories.
• 09:10Somatocyan analogs,
• 09:11many of you have heard
• 09:12of these monthly hormone injections.
• 09:14They're not
• 09:16they don't have anything to
• 09:17do with male or female
• 09:18hormones, but involve
• 09:20hormones that are related to
• 09:22net tumor growth.
• 09:24So octreotide and lanreotide
• 09:27are two examples.
• 09:29There are targeted therapies such
• 09:31as everolimus
• 09:32and sunitinib,
• 09:33and we actually have a
• 09:34a new one called cabozantinib
• 09:37that was just FDA approved.
• 09:39These target very specific tumor
• 09:41growth pathways for neuroendocrine neoplasms.
• 09:43There's true chemotherapy,
• 09:46and there's a range of
• 09:47different chemotherapy options.
• 09:49There is immunotherapy
• 09:51generally only reserved for patients
• 09:53with higher grade poorly differentiated
• 09:56neuroendocrine
• 09:57carcinomas.
• 09:58And I'm happy to answer
• 09:59some questions on that in
• 10:00the q and a. And
• 10:02then one of our,
• 10:03newest, maybe not even that
• 10:05new, FDA approved in twenty
• 10:06eighteen, but newer category,
• 10:09of treatments is something called
• 10:11radioligand therapy. And this is
• 10:13really takes advantage of knowing
• 10:15that we have that somatostatin
• 10:16receptor on the cell surface
• 10:18from the pet, and we
• 10:19target a therapy
• 10:21to that,
• 10:23that receptor or that target,
• 10:25that is a radioisotope,
• 10:27in this case, lutetium one
• 10:28seventy seven, but we have
• 10:30several clinical trials looking at,
• 10:32a new radioisotopes.
• 10:35So systemic treatments, just as
• 10:37I was saying earlier, we
• 10:38are
• 10:39splitters now and think about
• 10:41pancreatic nets differently than small
• 10:43bowel nets. So our systemic
• 10:45treatments differ
• 10:46by primary site. So it's
• 10:48important for us to try
• 10:50our best to figure out
• 10:51where your tumor originates.
• 10:54There are still some situations
• 10:56that arise where we can't
• 10:58figure that out, and there
• 10:59are some treatments that actually
• 11:00can apply to several different
• 11:02primary sites.
• 11:03But often for starters, for
• 11:05a lower grade neuroendocrine neoplasm,
• 11:07we will use
• 11:08observation if it's
• 11:10slow growing and patients are
• 11:12asymptomatic
• 11:13or consider octreotide or lamreotide.
• 11:15For pancreatic NETs, we have
• 11:17several options, including some of
• 11:19those ones I mentioned.
• 11:20For small bowel NET, there
• 11:22are actually fewer options. And
• 11:23for pancreatic NETs, chemotherapy does
• 11:25not work as well for
• 11:26small bowel neuroendocrine tumors.
• 11:28And I wanna just highlight
• 11:30that the NCCN or the
• 11:32National Comprehensive Cancer Network puts
• 11:34out guidelines for physicians, but
• 11:36there's also a patient
• 11:38portal that is very helpful
• 11:40and and describes these algorithms
• 11:42that we rely on as
• 11:43doctors,
• 11:44and puts them into lay
• 11:46terms.
• 11:47They are specific for each
• 11:48primary site.
• 11:51Really critical to thinking about
• 11:53systemic treatments and really moving
• 11:55the needle forward
• 11:56is thinking about clinical trials.
• 11:58We have several clinical trials
• 12:00for neuroendocrine tumors and neuroendocrine
• 12:02carcinomas.
• 12:03At Yale at present, I
• 12:04wanna just mention a few.
• 12:06So this first one in
• 12:07the table is for patients
• 12:08who've had a pancreatic net
• 12:10removed.
• 12:11And we're asking the question,
• 12:13does four months of capecitabine
• 12:15temozolomide
• 12:16chemotherapy
• 12:17help reduce that risk of
• 12:18recurrence?
• 12:20This second row,
• 12:22is a new trial looking
• 12:24at lutetium dotatate. That's the
• 12:26radioligand
• 12:27therapy kind of earlier in
• 12:29the disease course. So this
• 12:30is a first line treatment
• 12:32for patients with grade one
• 12:33and grade two
• 12:35GI neuroendocrine tumors.
• 12:37We also have a new
• 12:38trial that's just opened looking
• 12:40at symptom control. I mentioned
• 12:41that,
• 12:43some patients with NETs, about
• 12:44thirty to forty percent, may
• 12:45secrete hormones,
• 12:47and there is a new
• 12:48oral form of octreotide
• 12:50called paltucitine,
• 12:52and we are looking at
• 12:53that for carcinoid syndrome.
• 12:56And then for neuroendocrine carcinoma,
• 12:58we have two trials.
• 13:00One is looking at the
• 13:01combination
• 13:02of chemotherapy
• 13:04and immunotherapy.
• 13:05That's atezolizumab.
• 13:07And then a new kind
• 13:09of earlier phase trial that's
• 13:11looking at a very exciting
• 13:12new target called
• 13:14DLL three.
• 13:15And this is, paluntamid,
• 13:17which is a new drug
• 13:19that's being
• 13:20studied both alone and with
• 13:22chemotherapy.
• 13:24So I really
• 13:26like talking about the advances
• 13:28that we've made. As you
• 13:29can see, all these advances
• 13:30are clustered on the right
• 13:31side since twenty eleven,
• 13:33and I think that these
• 13:34advances really
• 13:36make me hopeful for the
• 13:37future of, this field. I
• 13:39think they impart hope to
• 13:40patients.
• 13:41I think we're doing lots
• 13:43of exciting work in clinical
• 13:44trials, and hopefully, we'll have
• 13:45some new treatments available in
• 13:47the next couple of years.
• 13:50I think also
• 13:51as patients and caregivers, it's
• 13:53important to arm yourself with
• 13:54information. This is just an
• 13:56example from,
• 13:57LACNets
• 13:58and, which is a patient
• 14:00advocacy group, and they have
• 14:01something called NETVitals,
• 14:03which is a wonderful tool
• 14:05to help you learn what
• 14:06questions to ask your doctors.
• 14:09So a few parting thoughts.
• 14:11So primary site matters for
• 14:13treatment selection.
• 14:15Stage indicates where the cancer
• 14:16is located, and grade refers
• 14:19to biology or degree of
• 14:20aggressiveness.
• 14:22Again, we've made several incredible
• 14:24advances in the last ten
• 14:25years in terms of treatment
• 14:27and in terms of imaging,
• 14:29and clinical trials are really
• 14:30critical to make some progress
• 14:31in, in the field.
• 14:34And so I will stop
• 14:36share here.
• 14:37I am going to pass
• 14:39the baton to doctor Klimstra,
• 14:41who will
• 14:43will go next. And, actually,
• 14:45what I forgot, I what
• 14:46I do need to do
• 14:47is I will be playing,
• 14:48a video.
• 14:49Doctor Klimstra is on, but
• 14:51we have prerecorded
• 14:52his video.
• 14:54So bear with me for
• 14:55just a moment.
• 15:02Okay.
• 15:04Here at Yale. And I'm
• 15:05very happy to share
• 15:07I'll start that from the
• 15:08beginning.
• 15:10Good evening. I'm David Klimster.
• 15:11I'm a a pathologist,
• 15:13here at Yale. And I'm
• 15:15very happy to share,
• 15:17some information about understanding the
• 15:19pathology of neuroendocrine tumors.
• 15:22But first, a few words
• 15:24about pathologists.
• 15:26Pathologists are physicians that don't
• 15:28directly interact with patients,
• 15:31most of the time unlike,
• 15:34gastroenterologists
• 15:35or
• 15:36an oncologist or a surgeon.
• 15:38They're essentially behind the scenes,
• 15:41and
• 15:44I sort of think of
• 15:45them as being behind the
• 15:46curtain. If you remember The
• 15:48Wizard of Oz and the
• 15:50little dog opens the curtain,
• 15:52and, there's a a statement,
• 15:54pay no attention to the
• 15:55man behind the curtain.
• 15:58Well, pathologists are often behind
• 16:00the curtain, but I think
• 16:01we should pay attention to
• 16:02the man behind the curtain
• 16:03or perhaps the woman behind
• 16:05the curtain because pathologists have
• 16:07a lot, to contribute to
• 16:09the knowledge about, your disease.
• 16:13So what is pathology?
• 16:15If you Google it, this
• 16:17is the definition that pops
• 16:18up. Everything is AI these
• 16:21days, and it says pathology
• 16:22is the medical science that
• 16:23studies the causes, mechanisms, and
• 16:25effects of disease.
• 16:27It involves examining tissues, fluids,
• 16:29and organs to identify and
• 16:31understand the underlying underlying causes
• 16:34causes of illness.
• 16:36Typically, we do this using
• 16:38a microscope,
• 16:39looking at,
• 16:41glass slides of of tissue,
• 16:42but increasingly, we're using genetic
• 16:45sequencing and other more advanced
• 16:47technologies.
• 16:48In practical terms, what does
• 16:50pathology provide for the patient?
• 16:53Well, pathology establishes the diagnosis
• 16:56of a neuroendocrine tumor.
• 16:58It can help identify where
• 17:00the tumor originated if it's
• 17:02not, immediately,
• 17:04parent.
• 17:05We can assess the adequacy
• 17:07of a surgical procedure to
• 17:09remove a neuroendocrine tumor. We
• 17:11can also look at factors
• 17:12that predict how aggressive a
• 17:14particular tumor is likely to
• 17:16be.
• 17:17We study factors that predict
• 17:19responses to treatment. These are
• 17:21known as biomarkers,
• 17:23and we can even analyze
• 17:24the risk,
• 17:25for hereditary disease.
• 17:29So if we think about
• 17:30neuroendocrine tumors,
• 17:31just some general principles,
• 17:33and neuroendocrine cells are cells
• 17:35that produce various types of
• 17:37hormones,
• 17:38and they're distributed throughout most
• 17:40organs in the body. Essentially,
• 17:42everywhere, there are neuroendocrine cells,
• 17:45and therefore, neuroendocrine tumors can
• 17:47arise
• 17:48in these
• 17:49various organs throughout the body.
• 17:52And we call them neuroendocrine
• 17:54tumors or NETs.
• 17:55This is a relatively recent
• 17:58standardization
• 17:59of of the nomenclature.
• 18:02In the past, they were
• 18:03often called carcinoid tumors.
• 18:06And in the lung, even
• 18:08now, that term is is
• 18:09commonly used. So it's important
• 18:11to know that NET and
• 18:13carcinoid tumor are synonymous.
• 18:17Now in the spectrum of
• 18:19of cancers, and NETs are
• 18:21regarded to be cancer,
• 18:23malignant,
• 18:25neuroendocrine tumors are considered well
• 18:27differentiated.
• 18:28Now what exactly does that
• 18:30mean?
• 18:31Well, differentiation
• 18:32has to do with how
• 18:33closely a tumor resembles its
• 18:35normal counterpart.
• 18:37So for instance, if we
• 18:38look at a piece of
• 18:39pancreas and there's
• 18:40an organ called the islet
• 18:42of Langerhans
• 18:43composed of normal pancreatic neuroendocrine
• 18:46cells.
• 18:47And if we look at
• 18:48a pancreatic neuroendocrine tumor, you
• 18:50can see that the tumor
• 18:51cells look very similar
• 18:53to their normal counterparts.
• 18:55This is what's known as
• 18:56well differentiated.
• 18:59In,
• 19:01clinical terms, this equates to
• 19:03a relatively slow growing tumor,
• 19:06which is which is good
• 19:07news. It means that neuroendocrine
• 19:08tumors are not as aggressive
• 19:10as other types of malignancy.
• 19:13That being said,
• 19:15some neuroendocrine tumors are more
• 19:16aggressive than others and predicting,
• 19:19which ones are likely to
• 19:20be more aggressive is an
• 19:21important,
• 19:22role for pathology.
• 19:25It's also important to remember
• 19:26that the proper treatment depends
• 19:28on quite a number of
• 19:29different factors.
• 19:30Depends on where the neuroendocrine
• 19:31tumor originated,
• 19:33how aggressive it is. In
• 19:35other words, is it a
• 19:36relatively,
• 19:39slow
• 19:39benign behaving
• 19:41neuroendocrine tumor, or is it
• 19:42a more
• 19:44aggressive,
• 19:46malignant behaving
• 19:47neuroendocrine tumor?
• 19:49Also, how advanced it is?
• 19:50Is it still
• 19:52localized within the organ where
• 19:54it originated, or has it
• 19:55spread?
• 19:56And furthermore, what genetic abnormalities
• 19:59it has can be important
• 20:01to help direct treatment.
• 20:04Now neuroendocrine tumors have been
• 20:06increasing
• 20:07over the past decades, and,
• 20:09you can see this as
• 20:10a comparison
• 20:11that shows the top line
• 20:13for all malignant neoplasms is
• 20:15relatively flat,
• 20:16whereas the red line for
• 20:18neuroendocrine tumors
• 20:19has been increasing,
• 20:21year to year, which means
• 20:23that they're becoming much more
• 20:24prevalent
• 20:26and important for us to
• 20:27recognize.
• 20:29So how do we establish
• 20:31a diagnosis of an organoid
• 20:32tumor?
• 20:34First of all, there has
• 20:35to be some suspicion either
• 20:37from some symptoms the patient
• 20:38may be experiencing
• 20:39or from some,
• 20:41finding on an imaging study.
• 20:44And then typically,
• 20:45we try to,
• 20:47obtain a piece of tissue
• 20:48to make the diagnosis through
• 20:50endoscopy
• 20:51or through interventional
• 20:52radiology using a needle,
• 20:55or even through surgery.
• 20:57And all of these,
• 20:58procedures give rise to,
• 21:01a biopsy or a tissue
• 21:03sample, which is then sent
• 21:04to the pathology laboratory.
• 21:06We make this,
• 21:08tissue into glass slides that
• 21:10are stained so we can
• 21:11look at them with a
• 21:12microscope.
• 21:13And this is what we
• 21:14see.
• 21:16These these are neuroendocrine tumors
• 21:18viewed through microscope. So this
• 21:20is the histology of neuroendocrine
• 21:22tumors.
• 21:23The image on the left
• 21:24is from the small intestine.
• 21:26The one on the right
• 21:27is from the pancreas.
• 21:28And if you look at
• 21:29this, you can see a
• 21:30number of different cellular structures
• 21:32that we pay attention to.
• 21:34You can see the cells
• 21:36have cytoplasm, which is stained
• 21:38pink. They have nuclei, which
• 21:40are stained purple.
• 21:43They also have, in this
• 21:44case,
• 21:45these dark pink
• 21:47hormone granules, which are recognizable.
• 21:49And all of these features
• 21:51are very characteristic
• 21:52pathologically
• 21:54when we look at them
• 21:55in the microscope.
• 21:57Some of the nuclei have,
• 21:59this very coarse pattern,
• 22:02in them, which is known
• 22:03as salt and pepper chromatin.
• 22:05You can imagine if you
• 22:06were to combine salt and
• 22:07pepper together, you would have
• 22:08a similar appearance.
• 22:10And this is so typical
• 22:12of neuroendocrine tumors.
• 22:14And the other feature is
• 22:15the fact that they the
• 22:16cells tend to be arranged
• 22:18in nests.
• 22:19So all of these findings
• 22:20when we look through a
• 22:21microscope are able to suggest
• 22:24that we're dealing with a
• 22:24neuroendocrine tumor, but how do
• 22:26we confirm the diagnosis?
• 22:29Well, there's the characteristic microscopic
• 22:31appearance, which by itself can
• 22:33be very, very suggestive.
• 22:35But there's also techniques to
• 22:37demonstrate,
• 22:38even more specifically
• 22:40that the cells we're seeing
• 22:43are represented in our endocrine
• 22:44tumor.
• 22:45It turns out that there
• 22:46are very specific proteins,
• 22:49that are characteristic
• 22:51of of all or most
• 22:53neuroendocrine cells,
• 22:54and we can actually detect
• 22:56these proteins.
• 22:57How do we do this?
• 22:59A procedure known as immunohistochemistry.
• 23:03It's not actually that complicated.
• 23:06It it involves using antibodies,
• 23:08which
• 23:09recognize very specifically these proteins.
• 23:13And the antibodies
• 23:14are tagged with a colored
• 23:16product.
• 23:18In most cases, a brown,
• 23:20color that we can see
• 23:22through the microscope.
• 23:23So if we have a
• 23:25piece of a biopsy,
• 23:27we can apply these antibodies
• 23:29to it. And if the
• 23:30proteins
• 23:32that are characteristic of neuroendocrine
• 23:33cells and neuroendocrine tumors are
• 23:35present,
• 23:36they will stain brown
• 23:38like this.
• 23:39And these are two of
• 23:40those proteins, chromogran a and
• 23:42synaptophysin.
• 23:44And by applying this technique,
• 23:46we're able to verify that
• 23:47the tumor we see that
• 23:49has a microscopic appearance of
• 23:51a neuroendocrine tumor,
• 23:52in fact, has the proteins
• 23:54we expect
• 23:55to find in a neuroendocrine
• 23:56tumor.
• 23:58This is a
• 23:59very standard technique applied in
• 24:01pathology for many different,
• 24:03tumor types and many different
• 24:04applications.
• 24:07Another example is that we
• 24:08can,
• 24:10try to identify the site
• 24:11of origin
• 24:12of a neuroendocrine tumor if
• 24:14it has spread
• 24:15to a distant organ like
• 24:17the liver, and it's not
• 24:18clear where it's coming from.
• 24:20And these, this is the
• 24:21list I showed you before
• 24:22of all of the different,
• 24:24neuroendocrine tumors
• 24:26that can occur. And it
• 24:27turns out that we have
• 24:29antibodies
• 24:30that stain,
• 24:32each of these different tumor
• 24:33types very specifically.
• 24:35So for instance, we have,
• 24:37specific formal markers
• 24:39that can be used to,
• 24:41identify tumors from some locations,
• 24:44and we actually have other
• 24:45markers
• 24:46for, different, proteins that are
• 24:49specific to other sites. And
• 24:51so by using these stains,
• 24:52we're able to characterize,
• 24:55the origin of many neuroendocrine
• 24:57tumors.
• 25:00What about assessing neuroendocrine tumors
• 25:02after surgery?
• 25:03If you're having surgery for
• 25:05neuroendocrine tumor, the hope is
• 25:06that you have removed it.
• 25:08And one of the roles
• 25:09of pathology is to look
• 25:11at that,
• 25:12specimen and determine whether or
• 25:14not the tumor has been
• 25:15completely removed.
• 25:17This is Moll's looking at
• 25:19the margins or the edges
• 25:20of the tissue.
• 25:22And if the tumor has
• 25:23been completely removed, there should
• 25:24be normal tissue at the
• 25:26edges.
• 25:27On the other hand, if
• 25:28the tumor has been incompletely
• 25:30removed, it may extend
• 25:32to the tissue edge. And
• 25:34by seeing that, we can
• 25:35recognize that the resection
• 25:37of the tumor has not
• 25:38been complete.
• 25:40Another thing that we do
• 25:42with,
• 25:43surgical specimen is look at
• 25:46evidence of spread.
• 25:48Has the neuroendocrine tumor spread
• 25:50from its primary site to,
• 25:52distant sites or lymph nodes?
• 25:55And typically, lymph nodes are
• 25:56removed
• 25:57at the time of surgery
• 25:58and sometimes also biopsies of
• 26:00distant sites will be
• 26:02provided for us to assess
• 26:05the extent of disease.
• 26:08So how do we predict
• 26:09the aggressiveness of neuroendocrine tumors?
• 26:12Well, the first is what
• 26:13I just said. We look
• 26:14at the stage. In other
• 26:15words, the extent of tumor.
• 26:17How big is it? How
• 26:18deeply invasive is it as
• 26:20it spread to lymph nodes
• 26:21or distant sites? And each
• 26:23of these different parameters
• 26:25correlates with increasing aggressiveness as
• 26:27it moves from the local
• 26:29organ into other,
• 26:31distant sites.
• 26:33But another very important parameter
• 26:35is to establish the grade.
• 26:37And what the grade refers
• 26:39to is the inherent aggressiveness
• 26:41of the tumor.
• 26:42Is this a bland
• 26:44mild tumor, or is this
• 26:45a real bully?
• 26:47And we have a way
• 26:48of measuring that.
• 26:50And it's actually based on
• 26:52the growth rate of the
• 26:53tumor, which makes sense. The
• 26:54faster it's growing, the more
• 26:56aggressive it is.
• 26:58So how do we measure
• 26:59the growth rate?
• 27:01Well, for a tumor to
• 27:02grow, the cells must divide.
• 27:04They go through the process
• 27:05of mitosis where one cell
• 27:08replicates
• 27:09its DNA and then splits
• 27:10into two cells.
• 27:12And this process of mitosis
• 27:14is visible microscopically.
• 27:16So So if you look
• 27:17at cells, you can see
• 27:19the,
• 27:20condensation of the chromatin,
• 27:22in the or the chromosomes,
• 27:24I should say, in the
• 27:25middle of the cell. And
• 27:26this these mitotic figures as
• 27:29they're known can be found
• 27:30within,
• 27:32neuroendocrine tumor samples.
• 27:34And so by looking at
• 27:35the histology of the neuroendocrine
• 27:37tumor with a microscope,
• 27:38we can find these mitotic
• 27:40figures and we can quantify
• 27:41them. And they're typically expressed
• 27:43as the number of mitoses
• 27:46in a certain,
• 27:47area of the tumor. Two
• 27:49square millimeters is typical.
• 27:52Another technique we can use
• 27:54to assess the growth rate
• 27:56or the cell divisions
• 27:58is again by immunohistochemistry.
• 28:01And there's a protein called
• 28:03k I sixty seven or
• 28:04k sixty seven,
• 28:06which is expressed in cells
• 28:08that are,
• 28:09that are growing and and
• 28:11and and,
• 28:12reproducing their DNA.
• 28:15And it results in brown
• 28:16staining of the nuclei.
• 28:18And the more brown staining
• 28:19you have,
• 28:21the more rapidly growing the
• 28:22tumor is.
• 28:23We express this as the
• 28:25p sixty seven index
• 28:27or the percentage of tumor
• 28:29cells that show brown staining.
• 28:32And it turns out that
• 28:34the World Health Organization has
• 28:35established a grading system for
• 28:37neuroendocrine tumors
• 28:39that is based on both
• 28:41the mitotic rate that I
• 28:42mentioned
• 28:43and the p sixty seven
• 28:44index.
• 28:45And you can see that
• 28:46as the, rates of proliferation,
• 28:50growth of the cells go
• 28:51up, the grade goes up
• 28:52correspondingly.
• 28:56Here's a a comparison of
• 28:57the key sixty seven staining
• 29:00for a low grade or
• 29:01g one
• 29:02net,
• 29:03an intermediate grade or g
• 29:04two net,
• 29:05and a high grade or
• 29:06grade three g three net.
• 29:08And you can see the
• 29:09dramatic change in the number
• 29:11of the nuclei that are
• 29:13staining brown. And this is
• 29:14a very commonly used technique
• 29:16to establish the grade of
• 29:18neuroendocrine tumors.
• 29:21It turns out that the
• 29:22grade correlates very well with
• 29:24clinical outcome. So if we
• 29:25look at,
• 29:27for instance, this study of
• 29:28patients who have metastatic neuroendocrine
• 29:31tumors, those that have spread
• 29:32to distant organs,
• 29:34the ones that are low
• 29:35grade still have a very
• 29:36good survival. The top line
• 29:38shows that,
• 29:40nearly ninety percent of those
• 29:41patients are still alive after
• 29:43five years.
• 29:44But as you get into
• 29:45intermediate grade, the green line,
• 29:47or high grade, the orange,
• 29:50line, you can see that
• 29:51that survival declines
• 29:54from fifty percent to very
• 29:55low,
• 29:56over the course of of
• 29:58five years. And so grading,
• 30:00it turns out, is a
• 30:01very essential,
• 30:03pathologic
• 30:04parameter that we have to
• 30:06assess.
• 30:09I mentioned before that we're
• 30:10also doing genetic sequencing of
• 30:12neuroendocrine tumors, and this is,
• 30:15again, a a fundamental
• 30:16aspect of the pathology.
• 30:18How is this useful?
• 30:21Well, it can help verify
• 30:23the diagnosis. There are certain
• 30:24mutations that are highly characteristic
• 30:27of neuroendocrine tumors. And so
• 30:28if we find those mutations
• 30:30by sequencing the tumor's
• 30:32DNA,
• 30:33it can help support the
• 30:34diagnosis of neuroendocrine tumor.
• 30:37It can also predict the
• 30:38outcome.
• 30:40Some of these mutations are
• 30:41associated with the prognosis, and
• 30:43so finding a certain mutation
• 30:45may
• 30:46tell you that this tumor
• 30:47is likely to be more
• 30:48aggressive than
• 30:50another neuroendocrine tumor.
• 30:53Probably the most exciting
• 30:55feature of,
• 30:57sequencing the the tumor DNA
• 30:58is to identify mutations
• 31:01that we have drugs for.
• 31:03So some of the,
• 31:05treatments you may be offered
• 31:06for neuroendocrine tumors,
• 31:09acts by targeting specific
• 31:12mutations.
• 31:12And we can find those
• 31:14mutations that will predict that
• 31:16that drug will work in
• 31:17that given tumor. And this
• 31:18is what's known as precision
• 31:20medicine, a very exciting,
• 31:22current way of managing patients.
• 31:26And finally, if we look
• 31:27at not the tumor DNA,
• 31:29but the normal germline DNA,
• 31:32we can identify
• 31:34if there's a risk of
• 31:35hereditary disease.
• 31:37And this is very important
• 31:38because if the answer is
• 31:40arising because of a hereditary
• 31:42mutation, it means other members
• 31:43of the family are also
• 31:45at risk.
• 31:46And just for example,
• 31:49in pancreatic neuroendocrine tumors, there's
• 31:51a whole list of hereditary
• 31:53associations.
• 31:54These are,
• 31:55inherited diseases
• 31:56that give rise to neuroendocrine
• 31:58tumors.
• 31:59And by sequencing the the,
• 32:02germline DNA, the normal DNA,
• 32:04we're able to recognize these
• 32:06to help,
• 32:07identify patients with a family
• 32:09risk.
• 32:10Up to sixteen percent of
• 32:12patients with pancreatic neuroendocrine tumors
• 32:14have a hereditary cancer predisposition
• 32:17mutation, and so this is
• 32:18very important.
• 32:22So just to summarize,
• 32:24pathologists
• 32:25provide some of the most
• 32:26vital information to establish the
• 32:28diagnosis,
• 32:29predict the clinical
• 32:30behavior, and predict response to
• 32:33specific treatments.
• 32:35But it's important to remember
• 32:36that pathology is an interpretive
• 32:38discipline.
• 32:40Some aspects
• 32:41are subjective,
• 32:43and this is the interpretation
• 32:44of an individual pathologist.
• 32:47So this little cartoon, which
• 32:48I've shamelessly stolen off the
• 32:50Internet says, good. You've got
• 32:53the pathology report.
• 32:55What did the lab say?
• 32:57And the response is
• 32:59as though it was a
• 33:00dog wolf
• 33:01because the lab isn't saying
• 33:03anything. It's the pathologist who
• 33:05wrote the report
• 33:06that is conveying the information.
• 33:08And so you have to
• 33:09understand that just as any
• 33:11other physician gives an opinion,
• 33:13the pathologist is giving an
• 33:14opinion on the pathology.
• 33:16Now many aspects of it
• 33:18are
• 33:19quite black and white, and
• 33:20you should be able to
• 33:21obtain,
• 33:23the definitive diagnosis, the results
• 33:26of any immunohistochemistry,
• 33:28the site of origin of
• 33:29the cancer, the stage,
• 33:31the grade of the cancer,
• 33:33and the results of any
• 33:35genomics or biomarker studies. All
• 33:36of these
• 33:37should be conveyed within a
• 33:39pathology report, and you should
• 33:40look for this information
• 33:41if you see a pathology
• 33:43report on
• 33:44a neuroendocrine tumor or really
• 33:46any kind of of of
• 33:48cancer.
• 33:49And if there are any
• 33:50doubts about the pathology, the
• 33:52physician,
• 33:53treating you is is a
• 33:55little uncertain or you have
• 33:56concerns,
• 33:57it's always possible to get
• 33:58a second opinion. Pathology cases
• 34:00can be sent
• 34:01to experts in their endocrine
• 34:03tumor pathology,
• 34:05to ensure that everything is
• 34:06is done correctly.
• 34:08So with that, I hope
• 34:09you've learned a little bit
• 34:11about,
• 34:12what pathologists do in the
• 34:13care of patients with neuroendocrine
• 34:15tumors,
• 34:16and, I'll be happy to
• 34:17participate in the discussion in
• 34:19a little while.
• 34:20Thanks so much for listening.
• 34:28Wonderful. So doctor Klimster will
• 34:29be available for for the
• 34:31q and a.
• 34:32I'll just remind everybody that
• 34:34the q and a will
• 34:35be done through the q
• 34:36and a webinar tool. You're
• 34:37welcome to start putting things
• 34:39in if you had questions
• 34:40either from my presentation or
• 34:42doctor Klimstra's, and we can
• 34:43start answering some of those,
• 34:45but also can take those
• 34:46questions live. So doctor El
• 34:48Fakhri, I will pass to
• 34:49you.
• 34:55Thank you,
• 34:56doctor Kunz.
• 34:58Hello, everyone.
• 35:00It's a pleasure to join
• 35:01you here. I joined Yale
• 35:03only two years ago,
• 35:04and I lead there the
• 35:06Yale Biomedical Aging Institute and
• 35:07the Yale Pet Center.
• 35:09And, what we're gonna talk
• 35:11about is understanding your pet.
• 35:14And your pet in this
• 35:15case, I'm sure you all
• 35:16know by now that's positron
• 35:18emission tomography. That's not,
• 35:20your pet at home.
• 35:22So how does,
• 35:25positron emission tomography work?
• 35:27If you've had a pet
• 35:28or if you googled one,
• 35:30you'll see that, usually, we
• 35:31will inject you with a
• 35:33radio tracer,
• 35:35and that radio tracer goes
• 35:36everywhere in your body.
• 35:38And then it's gonna be
• 35:40a radioactive material that is
• 35:41gonna be emitting,
• 35:43some, positrons. These positrons will
• 35:46annihilate,
• 35:47and,
• 35:48we will have photons detected.
• 35:50So you have something like
• 35:51this where you have some
• 35:53relations inside the body, two
• 35:55photons detected,
• 35:56and that tells us where
• 35:57that happened.
• 35:59Then we will have literally
• 36:01millions of these that we
• 36:03will be
• 36:04mapping back to where,
• 36:06they were originated from.
• 36:09And that will give us
• 36:10a map of,
• 36:11what,
• 36:12the PET scan looks like.
• 36:14And these are the kind
• 36:16of typical PET scans you
• 36:17would see,
• 36:18with,
• 36:19if you're coming for the
• 36:21suspicion of a neuroendocrine tumor.
• 36:23We're gonna talk a little
• 36:24bit later about what DOTATATE
• 36:26PET is. But, just to
• 36:27give you a sense, we'll
• 36:29see things that are very
• 36:31abnormal. Here, this is disease
• 36:33or tumors.
• 36:34There are also a lot
• 36:35of normal things we'll see,
• 36:36like the kidneys or the
• 36:37bladder or physiological,
• 36:40GI,
• 36:41or GU, you know, intestinal,
• 36:44uptake gastrointestinal uptake.
• 36:46We'll see also the pituitary
• 36:47gland. It tends to light
• 36:49up on data tape. So
• 36:51what our job is, is
• 36:52to when we're doing the
• 36:54imaging is to parse out
• 36:55what is normal uptake and
• 36:57what is abnormal because the
• 36:58abnormal is what we are,
• 37:00looking for, what we're interested
• 37:02in.
• 37:03Not that the normal is
• 37:04not important, but what we're
• 37:05looking for is the abnormal.
• 37:07So,
• 37:09how does that work?
• 37:11Doctor Kunz mentioned this earlier.
• 37:13What we are looking at
• 37:14here
• 37:15is,
• 37:17something that is very specific
• 37:19in neuroendocrine
• 37:21tumors,
• 37:22which is that they express,
• 37:25especially, you know, as we
• 37:27go for high grade tumors,
• 37:29they will express,
• 37:31levels of a receptor called
• 37:33the somatostatin
• 37:34receptor.
• 37:35For those who like, were
• 37:36buffs of biochemistry,
• 37:38that's what the somatostatin
• 37:40receptor looks like.
• 37:42And this is very tempting
• 37:44for us in pet because
• 37:45if we know what a
• 37:46structure is,
• 37:47we could make up
• 37:49something like a GPS that
• 37:51will hone on that somatostatin
• 37:53receptor,
• 37:54and that will be emitting
• 37:56back to the scanner
• 37:57where it is. And that's
• 37:59exactly what we do in
• 38:00a PET scan,
• 38:01of
• 38:02a neuroendocrine
• 38:03tumor. We have injected a
• 38:05compound that is binding to
• 38:06the somatostatin receptor.
• 38:08That compound is, and the
• 38:10binding, I'm not gonna bore
• 38:11you in the details, but
• 38:13usually, we do some chelation
• 38:14some form of chelation where,
• 38:16we have an emitter that's
• 38:18usually,
• 38:20either a spec emitter like
• 38:22NDM or a gallium for
• 38:24PET or
• 38:25later, we're gonna see a
• 38:26little later what we're gonna
• 38:27do with this when we
• 38:28do treatment with Leticia because
• 38:29we're gonna treat with the
• 38:30same thing. But for now,
• 38:31let's concentrate on the,
• 38:34imaging side.
• 38:35That
• 38:36that molecule now is bound
• 38:38to that tumor, and it's
• 38:40telling us, here's where I
• 38:41am.
• 38:43And,
• 38:44that is very helpful because
• 38:45that will tell us something
• 38:46that is very specific
• 38:48about neuroacrine
• 38:50tumors
• 38:50that is not something that
• 38:52will be shared with other
• 38:54uptake or tumors. So for
• 38:56example,
• 38:57you may have had in
• 38:58the past another form of
• 38:59PET scans called FDG, fluoridoxyglucose.
• 39:02That's by far the most
• 39:04widespread that we will do.
• 39:05Ninety five percent of all
• 39:07scans we do are FGG
• 39:08scans. Well, that doesn't work
• 39:10very well in neuroendocrine tumors.
• 39:12I'm showing you here an
• 39:13example
• 39:15where,
• 39:16on the FDG PET,
• 39:18there is no there's nothing
• 39:19abnormal here. Whereas you can
• 39:21see, you don't need to
• 39:22be really a radiologist to
• 39:24know that this is abnormal.
• 39:25There's clearly an abnormal uptake
• 39:27here,
• 39:27that is related to the
• 39:28somnostatin
• 39:29receptor. So that,
• 39:32that side of the imaging,
• 39:34looking at the
• 39:37so to stand receptor is
• 39:38incredibly important
• 39:39because
• 39:41it's gonna tell us what
• 39:42is the tumor avid? If
• 39:44it the tumor is avid,
• 39:45that's a good thing. Because
• 39:46when we're gonna hit it
• 39:47later with a beta emitter
• 39:49for therapy, well, we'll be
• 39:50able to do some damage,
• 39:51which is what we wanna
• 39:52do.
• 39:54There have been several trials,
• 39:57many led by, doctor Kunz
• 39:59who's here. The netter one
• 40:00trial was the one that
• 40:01led to the approval
• 40:03of lutetium dotatate. We're gonna
• 40:04talk a lot more about
• 40:06this in the next slide.
• 40:08The netter two trial
• 40:09expanded the use from a
• 40:11second line
• 40:12of therapy that was in
• 40:13netter one to a first
• 40:15line of treatment for the
• 40:16high grade disease.
• 40:17And the netter three trial,
• 40:19which is kind of about
• 40:20to start, and doctor Kunz
• 40:21is one of the, two
• 40:23chairs of that,
• 40:25trial. She's leading that trial.
• 40:27Is for low and now
• 40:28we're moving to low grade
• 40:29disease.
• 40:31And,
• 40:33so you see we're going
• 40:34further and further upstream
• 40:36from the
• 40:37second line,
• 40:40high grade, first top line,
• 40:42high grade, and now lower
• 40:44grade.
• 40:45So what are we doing
• 40:46there?
• 40:47Until now, we talked about
• 40:49the
• 40:50pet side of things where
• 40:51we image the patient.
• 40:53But the same way here,
• 40:55we chelated,
• 40:59a gallium or an indium
• 41:00to image.
• 41:01Instead of that, we could
• 41:02chelate a lutetium.
• 41:05And now we get ourselves
• 41:06a beta emitter that can
• 41:08do some serious damage,
• 41:10whatever it's gonna be. And
• 41:12if this molecule were to
• 41:13go only through the somatostatin
• 41:15receptors
• 41:17and nowhere else, you know
• 41:18that's not true because I've
• 41:19showed you that some goes
• 41:20to the bladder and we're
• 41:21gonna come back to that
• 41:22and some goes to the
• 41:23kidney. So we have to
• 41:24be careful with the organs,
• 41:25normal organs, which we call
• 41:26at risk. But if we
• 41:28have a lot of that
• 41:29going to the disease, like
• 41:30here,
• 41:31and if we're gonna inflict
• 41:32some serious damage with lutetium
• 41:34one seventy seven,
• 41:35we got ourselves a treatment.
• 41:37And not only we got
• 41:38ourselves a treatment, but we
• 41:39got ourselves a treatment where
• 41:41we can see what we
• 41:42treat
• 41:43and we treat what we
• 41:45see, which is something that
• 41:46is incredibly important. That's a
• 41:48that's a first that has
• 41:49been only so a few
• 41:50years that we have. The
• 41:52only treatment we had in
• 41:53that space was iodine, and
• 41:55that was since the forties
• 41:56for,
• 41:57thyroid cancer. We haven't had
• 41:59anything since iodine.
• 42:01So,
• 42:02and cell hurts.
• 42:03So now we are we
• 42:05have two of these, one
• 42:06for prostate and one for
• 42:08neuroendocrine tumor. And unlike chemotherapies
• 42:11where you
• 42:12basically treat blind, you're bombing
• 42:14everything.
• 42:15Here, we see where we're
• 42:16going. We see where our
• 42:18agents are killing tumors,
• 42:19and we can image them
• 42:20afterwards to see if there's
• 42:22still a lot of the
• 42:23tumor or not so much
• 42:25that is left.
• 42:26So theranostics
• 42:27is this combination where we're
• 42:29gonna do,
• 42:30at the same time diagnosis
• 42:32with PET, respect,
• 42:34and then therapy with a
• 42:35beta emitter or later we'll
• 42:37see with an alpha.
• 42:39And, you know, while the
• 42:41antibody drug conjugate deliver chemotoxins,
• 42:44here we're gonna be delivering
• 42:46ionization energy to tumor cells
• 42:48to break the DNA and
• 42:49just kill them off.
• 42:50And then we reduce with
• 42:52that the off target radiation
• 42:53effect
• 42:54because,
• 42:55we're killing where the tumor
• 42:57or where the molecule went,
• 42:59and we're not killing anywhere
• 43:00else. So the toxicity is
• 43:02gonna be a lot less
• 43:03than
• 43:04if we're not selective.
• 43:06Since the first radiopharmaceutical
• 43:08drug has been approved,
• 43:10there's now FDA approval, as
• 43:12doctor Kunz mentioned, for these.
• 43:14And the radiopharmaceutical
• 43:15are gaining recognition as a
• 43:17viable target. So, you know,
• 43:19this is something that we
• 43:20are very excited about.
• 43:23Alright.
• 43:23Now all this is good
• 43:25and great.
• 43:26We could stop here.
• 43:28Unfortunately
• 43:30well, or fortunately,
• 43:31each patient is unique.
• 43:34Each cycle in the treatment
• 43:35is unique, and each lesion
• 43:37is unique.
• 43:39What I mean by that
• 43:40is every patient will have
• 43:41a unique tumor burden and
• 43:43distribution,
• 43:45and that is gonna be
• 43:46also changing
• 43:48at every cycle.
• 43:49Think of it this way.
• 43:51If this didn't change from
• 43:52cycle to cycle,
• 43:54it means the therapy isn't
• 43:55working. It's not doing anything.
• 43:57So it is a good
• 43:57thing that it's changing, but
• 43:59it's something that we should
• 44:00be taking into account. The
• 44:02paper that I'm showing here
• 44:03on the slide shows you
• 44:04the what we call the
• 44:05sink effects, which exacerbates,
• 44:08this during the treatment.
• 44:09What this means the sink
• 44:11effect means is that
• 44:12the more the tumor is
• 44:14gonna take up
• 44:16the,
• 44:17the treatment,
• 44:18and the less of that
• 44:20molecule will be available
• 44:22to circulate for the normal
• 44:24tissues, which is a good
• 44:26thing for us.
• 44:27And
• 44:28it shows you here that
• 44:29in the scatterplot
• 44:31that
• 44:32the the tissue uptake or
• 44:33SUV,
• 44:34right, decreases
• 44:36as a function
• 44:37of,
• 44:38the total,
• 44:39lesion burden or total lesion
• 44:41uptake. So the more the
• 44:43lesions take up the the
• 44:45the tracer, which is either
• 44:46the treatment or the imaging,
• 44:48and the less of the
• 44:49uptake is in the liver
• 44:51or in the parotid gland.
• 44:53And remember, I showed you
• 44:54some of those kidney and
• 44:55spleen, which are the organs
• 44:56at risk that we wanna
• 44:57preserve.
• 44:59So this reinforces
• 45:00the idea that
• 45:02instead of giving everybody the
• 45:04same dose, which is what
• 45:05we do now,
• 45:06we could give maybe higher
• 45:08doses to start because they
• 45:09could be tolerated in the
• 45:11beginning when the tumor burden
• 45:13is largest, and then there's
• 45:14the most, sync effect. And
• 45:16then as we go,
• 45:18down the the treatment path,
• 45:20well, we reduce that dose.
• 45:21So this is one way
• 45:23we can individualize
• 45:25our treatment to lesions.
• 45:28We can
• 45:29personalize in the treatment also.
• 45:31Leasing personalization matters. So not
• 45:33only patient personalization
• 45:34matter, but the lesion personalization
• 45:36matter. You see here that
• 45:38the PET uptake, what we
• 45:39call the study
• 45:40uptake value SUV, the PET
• 45:42uptake
• 45:43is significantly correlated
• 45:45with the SPECT uptake that
• 45:46we can see during the
• 45:47treatment.
• 45:48But there's a lot of
• 45:49variance,
• 45:50alright,
• 45:51which is what we just
• 45:52said. You know, every tumor
• 45:54is unique. Every patient is
• 45:55unique. Every cycle is unique.
• 45:57But you can see intuitively,
• 45:59you could understand here
• 46:01that the tumor control appear
• 46:02to be a function of
• 46:03the absorb dose. Why? Because
• 46:05the more you absorb dose
• 46:07and the more you're likely
• 46:08to kill the tumor.
• 46:09So we do wanna have
• 46:11an absorb dose that is
• 46:12maximized because that would give
• 46:13us the best tumor control.
• 46:15You can see also here
• 46:16that for the higher observed
• 46:18dose, there was higher,
• 46:20better outcome than for lower
• 46:21observed dose.
• 46:22So how do we
• 46:24quantify this? How do we
• 46:26maximize this? Well, this makes
• 46:28the point that we should
• 46:29aim to tailor the treatment
• 46:31to maximize those for all
• 46:33tumors, not just the average
• 46:35tumor, not not one of
• 46:36the average tumors, but for
• 46:37each tumor alone.
• 46:38And the only way you
• 46:39can do this is by
• 46:40imaging. Because remember, when we
• 46:41do imaging, we see all
• 46:42those tumors one by one,
• 46:44and we see what is
• 46:46the uptake in each of
• 46:47them. So the higher the
• 46:48tumors,
• 46:49the more likely we can
• 46:50give a higher dose to
• 46:52start.
• 46:54And and, you know, it's
• 46:55worth noting also again that
• 46:57these numbers are on the
• 46:58low side, meaning that, you
• 47:00know, there is room to
• 47:01increase within reason our treatments.
• 47:04So how can we do
• 47:05this?
• 47:06This is something that we
• 47:07are actively working on with
• 47:08doctor Coons to try to
• 47:10personalize,
• 47:11the treatment planning for the
• 47:12pharmaceutical
• 47:13neuroendocrine therapies,
• 47:15and neon radiology and radiation
• 47:17oncology and the cancer center
• 47:18are collaboratively working on this.
• 47:20The idea is the following.
• 47:22If I do my,
• 47:24pretreatment
• 47:25of gallium dota tape, I
• 47:27have a good idea of
• 47:28what the my tumors where
• 47:30my tumors are. I can
• 47:31define the targets.
• 47:33I can define the sensitive
• 47:35organs,
• 47:36and I can
• 47:37try to then extrapolate from
• 47:39this imaging
• 47:40what would the dose be
• 47:41for each of those. And
• 47:43I could put
• 47:44bars and thresholds on. I'm
• 47:47not gonna allow more than
• 47:48a certain dose to the
• 47:49bladder.
• 47:50I'm not gonna allow more
• 47:51than a certain dose to
• 47:52the marrow, to the liver,
• 47:53to the pituitary gland. And
• 47:55with that, what is the
• 47:56maximum dose that I can
• 47:57do then for my for
• 47:59my tumor?
• 48:00And then I can try
• 48:01to hit the tumor with
• 48:02a lot more,
• 48:03than a standard dose of
• 48:04two hundred millicurie per cycle
• 48:06for six cycles.
• 48:07So in a way, we
• 48:08are
• 48:09tuning the dose to maximize
• 48:12tumor killing
• 48:13while minimizing
• 48:14the side effects to the
• 48:16organs at risk.
• 48:18Great.
• 48:19I could do this at
• 48:20every cycle, but you can
• 48:22imagine that and you are
• 48:24probably
• 48:25the best you can imagine
• 48:26this, that this is gonna
• 48:27take a lot of effort
• 48:29on our part but also
• 48:30on your part. Because now
• 48:32we're talking about you're getting
• 48:34not only a pet scan,
• 48:36but also getting
• 48:37a SPECT scan
• 48:39at four hours,
• 48:40twenty four hours,
• 48:42forty eight hours,
• 48:43seventy two hours to see,
• 48:45well, how is the activity
• 48:46changing in your body? What
• 48:47is the dose that you're
• 48:48getting for the tumor?
• 48:50What is the dose that
• 48:51you're getting for,
• 48:53the lesions?
• 48:54For the, sorry, for the
• 48:55healthy tissues, the organs that
• 48:57risk.
• 48:58But this is a a
• 48:59good start because the pre
• 49:01therapy
• 49:01is giving us a highly
• 49:03predictive,
• 49:05indicator of the patient response,
• 49:07and this is now a
• 49:08standard that we use for,
• 49:10patient selection to decide who
• 49:12qualifies and who doesn't. And
• 49:14I'm showing you here a
• 49:15patient.
• 49:16This is where hope there's
• 49:18a lot of hope where,
• 49:21you see, this is the
• 49:22patient scan after one cycle,
• 49:24after four cycles, and you
• 49:26can see that the activity
• 49:27is decreasing.
• 49:28And this is one where
• 49:30we started with one milligram,
• 49:32where we escalated and then
• 49:34went down again. So there's
• 49:36there's hope. There's also a
• 49:38lot of work we're doing,
• 49:40in my lab to try
• 49:42to
• 49:43avoid some of what
• 49:45you would have to go
• 49:46through to have every single,
• 49:48dose,
• 49:49measured every so have, you
• 49:51know, multiple scan. And the
• 49:52idea here is using artificial
• 49:55intelligence and new networks to,
• 49:58from our
• 49:59pretreatment,
• 50:00and
• 50:02what are two,
• 50:03treatments predict the next treatment.
• 50:05So instead of having one
• 50:07size fits all, we use
• 50:09a wealth of data from
• 50:10the redose pet
• 50:12and plenty of scans of
• 50:13plenty of patients that we've
• 50:15scanned before you to say,
• 50:17well, you know, your scan
• 50:19fits your pet scan fits
• 50:20best as
• 50:21this person, like a digital
• 50:23twin of yourself.
• 50:25And this is how
• 50:26these guys all these girls
• 50:28did,
• 50:29when we treated them with
• 50:30this dose. And that gives
• 50:31us a good indication
• 50:33as a predictive dose distribution
• 50:35of what we should be
• 50:36doing.
• 50:37And then, of course, we
• 50:38do cross training validation of
• 50:39these. So here's an example,
• 50:41and I'll I'll finish with
• 50:42this. This is an example
• 50:43of one where
• 50:45we did the first dose.
• 50:48And from the first dose,
• 50:49we
• 50:50predicted what the second dose
• 50:51is, and then we compare
• 50:53it to what we measured
• 50:54in the second dose. So
• 50:55we did the first dose,
• 50:57and we measured it. We
• 50:59did the cycle two. Again,
• 51:01second cycle of treatment, we
• 51:02measured the dose. But then
• 51:04we used only the first
• 51:05dose in our artificial networks
• 51:07to predict what the second
• 51:09dose would be. And the
• 51:10error you see is mostly
• 51:12in the bladder, which is
• 51:13the least of our worries.
• 51:15So our prediction for the
• 51:16tumors was very good. So
• 51:17we really hope that this
• 51:19prediction from one cycle of
• 51:21the next cycle would be
• 51:22would be a huge step
• 51:24to personalize the treatment without
• 51:26increasing too much the burden
• 51:28on the patient,
• 51:30and and
• 51:31and and making it more
• 51:32of a personalized treatment for
• 51:34every patient.
• 51:35This is all I have.
• 51:36So thank you for tuning
• 51:38in, and I'll turn it
• 51:38back to you, Pam.
• 51:41Great. Thanks, doctor Alfaqueray. So
• 51:43we will finish up,
• 51:44with doctor Kunstmann talking about
• 51:46surgery.
• 51:47So, hopefully, our audience can
• 51:49start thinking about questions and
• 51:51start putting them in the
• 51:52q and a. So, John,
• 51:53we'll turn to you.
• 51:57Everybody hear me?
• 51:59Yes. Great.
• 52:01Okay.
• 52:05Let's see here.
• 52:10Alright.
• 52:12Everybody can see my slides,
• 52:13I hope.
• 52:18Alright. So hi. I'm John
• 52:19Kunstler. I'm a surgical oncologist,
• 52:22at Yale.
• 52:23Happy to be chatting tonight
• 52:24about neuroendocrine tumors, one of
• 52:25my favorite surgical topics.
• 52:28So for my portion of
• 52:30the discussion,
• 52:31really three,
• 52:32objectives that we wanna get
• 52:34across is what are the
• 52:35indications for surgery? I'm gonna
• 52:37try to not be too
• 52:39duplicative with, doctor Coons.
• 52:41But I did wanna spend
• 52:42a moment talking about other
• 52:44times when neuroendocrine tumors
• 52:46can actually forego surgery even
• 52:47though they might be operative,
• 52:49you know, candidates.
• 52:50What are the options for
• 52:51surgery?
• 52:52And we're gonna really focus
• 52:54on two paradigms, One being
• 52:55pancreatic neuroendocrine tumors and the
• 52:57other being enteric or intestinal
• 52:58neuroendocrine tumors, the two
• 53:00most commonly encountered in our
• 53:02practice,
• 53:03and then also learn what
• 53:04role surgery can play in
• 53:05the setting of metastatic disease.
• 53:08So just to remind you,
• 53:10for pancreatic neuroendocrine tumors, I
• 53:12know this is touched on
• 53:12before,
• 53:13you know, the broad classifications,
• 53:16that are relevant for surgery
• 53:18are those
• 53:19pancreatic neuroendocrine tumors that secrete
• 53:21hormones or functional tumors.
• 53:24Yeah. Some of those are
• 53:25more aggressive, others are are
• 53:27more indolent.
• 53:28But most cases that we
• 53:29diagnose today are nonfunctional. In
• 53:31other words, they're not secreting
• 53:33any hormones
• 53:34that we can detect.
• 53:37And most cases in such
• 53:39diagnoses are incidental, although some
• 53:41patients can have
• 53:42discomfort, weight loss, pancreatitis
• 53:44associated
• 53:46with their,
• 53:47with their lesion.
• 53:50Treatment of pancreatic neuroendocrine tumors
• 53:53is very stage specific. So
• 53:55the first question as alluded
• 53:57to by doctor Coons when
• 53:59we make a new diagnosis
• 54:00is whether or not this
• 54:02tumor is localized to the
• 54:04pancreas,
• 54:06or has it spread to
• 54:07other organs.
• 54:08As we'll talk about a
• 54:09little later, even in stage
• 54:11four disease surgery,
• 54:12potentially with curative intent is
• 54:14still appropriate in some cases.
• 54:16But we'll come back to
• 54:17that. But for localized PNET,
• 54:19in other words,
• 54:21a case where the tumor
• 54:22is localized only to the
• 54:23pancreas,
• 54:24surgery is the primary treatment
• 54:25modality.
• 54:26We almost always will resect
• 54:29functional PNETs.
• 54:30Again, those are those hormone
• 54:32secreting peanuts,
• 54:34and certainly any any nonfunctional
• 54:36peanuts that are symptomatic.
• 54:39Some cases can involve some
• 54:41other critical structures, so we
• 54:42call locally advanced tumors.
• 54:45These have previously been called
• 54:47unresectable. Sometimes they truly are
• 54:49unresectable, but we've been able
• 54:51to devise ways to to
• 54:52offer surgery to many of
• 54:53these patients.
• 54:55And also, you know, another
• 54:56special case is those that
• 54:57are associated with genetic syndromes,
• 55:00as alluded to, by doctor
• 55:02Klimstra, but we're not gonna
• 55:04necessarily touch on those tonight.
• 55:06For people,
• 55:07that have their peanut diagnosed
• 55:10incidentally,
• 55:11which again is the majority
• 55:12of patients these days,
• 55:14we try to make a
• 55:15determination about whether it's, you
• 55:17know, the more or or
• 55:18less aggressive
• 55:21behavior based on some of
• 55:22those factors here, some some
• 55:24other ones as well. You
• 55:25can really see why that
• 55:26pathologic assessment is so important
• 55:28in these,
• 55:30in making these treatment decisions.
• 55:32I think, you know, boiling
• 55:33it down though, the thing
• 55:34I always try
• 55:35to describe to patients is
• 55:36that all peanuts,
• 55:38are cancers, and they have
• 55:39the potential to grow and
• 55:41spread. It just so happens
• 55:42that the likelihood of spread
• 55:44is extraordinarily
• 55:45low in a certain subset
• 55:47of pancreatic neuroendocrine tumors, which
• 55:49has given rise to this,
• 55:51paradigm for observation that we've
• 55:53seen. And this has really
• 55:54come, about I'm gonna go
• 55:56through this kinda quickly, but
• 55:57this has really come about
• 55:58in the last ten to
• 55:59fifteen years with a number
• 56:00of case series, and there's
• 56:01some newer studies as well
• 56:03that shows that patients, you
• 56:05know, that undergo observation,
• 56:07if they're carefully selected, they
• 56:09actually have,
• 56:11you know, oftentimes
• 56:12no change in their overall
• 56:14outcome as to patients that
• 56:15go straight to surgery.
• 56:17So this has really become
• 56:18kind of the new,
• 56:20mindset for patients with small
• 56:22asymptomatic
• 56:23non functional
• 56:24incidentally discovered,
• 56:25pancreatic NETs.
• 56:27So the question about are
• 56:28some safe to observe? Well,
• 56:29the answer to that is
• 56:30is yes. But who are
• 56:31they?
• 56:33You know, as I said,
• 56:35they have to be asymptomatic
• 56:36and and nonfunctioning.
• 56:37In other words, not secreting
• 56:39a hormone in excess. No
• 56:40evidence of spread to the
• 56:42lymph nodes or elsewhere.
• 56:44A well differentiated
• 56:46pathology, in other words, one
• 56:48that we believe will behave,
• 56:50a little bit more indolent.
• 56:52Ly. Generally speaking, a small
• 56:54tumor because it's much likely
• 56:56it's less likely to spread
• 56:57without us understanding it.
• 56:58And, also, I think probably
• 57:00the most important thing is
• 57:01the patient has to,
• 57:03be amenable to surveillance.
• 57:06What does that mean? Both
• 57:07follow-up and and scans to
• 57:09make sure that this this
• 57:10tumor doesn't grow and spread.
• 57:13So if all those criteria
• 57:14are met,
• 57:16we we can and and
• 57:17do observe some of these.
• 57:18But when we take patients
• 57:19to surgery, what are our
• 57:21goals?
• 57:21For me as a surgeon,
• 57:23obviously, I wanna maximize,
• 57:25the control of the tumor.
• 57:26And by that, I mean,
• 57:27remove it, and have doctor
• 57:28Klimstra come back and tell
• 57:30me that, those margins are
• 57:31completely clear and it's been
• 57:33entirely removed, and we wanna
• 57:34remove the lymph nodes
• 57:36along that area as well
• 57:38because we don't know usually
• 57:40before surgery whether or not
• 57:42any of those lymph nodes,
• 57:44carry disease, and we certainly
• 57:45want them out of the
• 57:46body. You know, the overall
• 57:48goals are to prolong survival
• 57:49and and also improve quality
• 57:51of life, especially in the
• 57:52cases where the tumor is
• 57:53symptomatic or metastatic.
• 57:55But we also wanna minimize
• 57:56the risks of surgery.
• 57:58And by risk, I mean
• 57:59complication.
• 58:00You can see some of
• 58:01the complications there that we
• 58:02watch out for. Each are
• 58:04are sort of individualized
• 58:06and unique,
• 58:07in terms of how we
• 58:08mitigate them.
• 58:10But in terms of what
• 58:11operation
• 58:11we choose, it really depends
• 58:13on where the tumor is
• 58:14and how much, you know,
• 58:16lymph node harvest
• 58:18and and really what kind
• 58:18of,
• 58:20you know, comorbid conditions or
• 58:22or other medical conditions a
• 58:23patient may have. Certainly, some
• 58:25patients,
• 58:26you know, may not be
• 58:27a candidate for a very
• 58:29extensive operation. We may look
• 58:30for nonsurgical alternatives to treatment.
• 58:33You know, the simplest operation
• 58:35we do is something called
• 58:36enucleation.
• 58:37That's really just taking the
• 58:38tumor out of the pancreas
• 58:40itself. You can see it's,
• 58:42not quite as easy as
• 58:43the cartoon suggests,
• 58:46but it really is just
• 58:47removing the tumor itself while
• 58:48leaving all of the pancreas
• 58:50behind. It does have a
• 58:51very low complication rate, but
• 58:53the problem with that is
• 58:54it's really only,
• 58:55correct for the most,
• 58:57indolent and small tumors.
• 59:00Insulinomas
• 59:01are are the kind of
• 59:02classic example. You can see
• 59:03a pathology specimen there, what
• 59:05it looks like when it
• 59:06comes out. It also has
• 59:07to be away from the
• 59:08pancreatic
• 59:10duct so we don't get
• 59:11a pancreatic leak after surgery.
• 59:16Most patients are not candidates
• 59:17for enucleation.
• 59:19Again, the main thing is
• 59:20the tumor location,
• 59:22but mostly, and what I'm
• 59:23gonna talk about today is
• 59:24two main procedures, what's called
• 59:25a Whipple procedure, a pancreatic
• 59:27or duodenectomy for tumors in
• 59:28the head,
• 59:29and then a distal pancreatectomy
• 59:31for tumors in the neck
• 59:32or or body.
• 59:34You know, is it safe?
• 59:35You know, especially when people
• 59:37talk about
• 59:38Whipple procedures, they may have
• 59:39heard that or Googled that
• 59:41or, you know, heard about
• 59:42it from a friend or
• 59:43a TV show.
• 59:44The bottom line is, it
• 59:46is a big operation. And
• 59:47even a distal pancreatectomy is
• 59:49a big operation.
• 59:50But at the same time,
• 59:52at centers and with surgeons
• 59:54that have experience and high
• 59:55volume,
• 59:56of patients, it can be
• 59:58done safely and it can
• 59:59be done with a reasonable
• 01:00:00risk of complication.
• 01:00:03You know, for instance, here
• 01:00:04at Yale, these numbers are
• 01:00:05a year too old,
• 01:00:07but we do about a
• 01:00:08hundred, pancreatic resections a year.
• 01:00:12Know, that number has gone
• 01:00:13up in the last two
• 01:00:13or three years,
• 01:00:15and we've also developed a
• 01:00:16number of of things here
• 01:00:18at Yale to minimize risk
• 01:00:19of complication.
• 01:00:21You know, the mortality for
• 01:00:22a Whipple procedure, for instance,
• 01:00:25you know, used to be
• 01:00:26considered to be three percent
• 01:00:27or less was was a
• 01:00:28good number here. It's under
• 01:00:29two percent. The length of
• 01:00:31stay has gone down.
• 01:00:33And, you know, at at
• 01:00:34Yale, again, the risk of
• 01:00:36complication,
• 01:00:37you know, is better than
• 01:00:38the ninetieth percentile nationally. So
• 01:00:40a distal pancreatectomy,
• 01:00:42which is oftentimes
• 01:00:43the tumor or the treatment
• 01:00:45of choice for a neuroendocrine
• 01:00:46tumor,
• 01:00:48is for tumors that are
• 01:00:49located in the body or
• 01:00:50tail of pancreas. It can
• 01:00:51be done open. It can
• 01:00:52be done laparoscopic. It can
• 01:00:53be done robot assisted. We
• 01:00:55do all of them here
• 01:00:56at Yale. We certainly favor
• 01:00:57a minimally invasive approach in
• 01:00:59in most patients,
• 01:01:01you know, that are that
• 01:01:02are candidates for it.
• 01:01:05Removal of the spleen is
• 01:01:06done on a case by
• 01:01:07case basis. You can see
• 01:01:09there in the cartoon, you
• 01:01:10know, the reason the spleen
• 01:01:11is oftentimes removed is that
• 01:01:13the vessels, both the artery
• 01:01:15and the vein that go
• 01:01:16to the spleen, are oftentimes
• 01:01:18very, very intimately involved with
• 01:01:20the tumor.
• 01:01:22You know, for adults, removal
• 01:01:23of the spleen has has
• 01:01:24really no consequence,
• 01:01:27in terms of your overall
• 01:01:28health.
• 01:01:30However, sometimes it can be
• 01:01:31spared,
• 01:01:33in in properly selected patients,
• 01:01:36but not really
• 01:01:38a concern that,
• 01:01:39we worry about too much
• 01:01:40if that spleen needs to
• 01:01:41be removed.
• 01:01:43I'm gonna put just a
• 01:01:44couple of surgical photos. So
• 01:01:46if you're a little bit
• 01:01:47you don't like the the
• 01:01:48sight of of organs, you
• 01:01:49may wanna close your eyes
• 01:01:50for just a moment.
• 01:01:52But just to show you
• 01:01:53a picture, you know, this
• 01:01:54is what it looks like
• 01:01:54when you perform a laparoscopic
• 01:01:56procedure.
• 01:01:57This is a spleen preserving
• 01:01:58procedure. You can see this
• 01:02:00staple line here is on
• 01:02:01the remaining pancreas, which is
• 01:02:03over here. The part of
• 01:02:04the pancreas that's been removed
• 01:02:05is right over here. Here's
• 01:02:07that splenic artery that's going
• 01:02:09along and the splenic vein
• 01:02:11that's going on, and here's
• 01:02:12the spleen. You know, if
• 01:02:13the spleen needs to be
• 01:02:13removed, then these vessels are
• 01:02:15are removed. But you can
• 01:02:16see all of the lymph
• 01:02:17nodes and tissue has been
• 01:02:19removed along there.
• 01:02:20This this case was done
• 01:02:21in a minimally invasive way.
• 01:02:25Anyways,
• 01:02:26so for peanuts, pancreatic neuroendocrine
• 01:02:29tumors, again, the goal of
• 01:02:30the surgery is to control
• 01:02:31the disease,
• 01:02:32increase the quality of life
• 01:02:34if we can, and do
• 01:02:35it with minimal complication rig.
• 01:02:37Three operations are are usually
• 01:02:39done most frequently, a Whipple
• 01:02:40procedure, a distal pancreatectomy,
• 01:02:42or or enucleation
• 01:02:43in rare cases. And, again,
• 01:02:45the operation is dictated by
• 01:02:46the location of the tumor,
• 01:02:47and the outcomes really are
• 01:02:49are excellent at high volume
• 01:02:50centers.
• 01:02:51I'm gonna shift gears, for
• 01:02:53the last few minutes to
• 01:02:54talk about intestinal neuroendocrine tumors.
• 01:02:57These can occur anywhere,
• 01:02:59from your esophagus to your
• 01:03:01rectum,
• 01:03:02but most commonly, they occur
• 01:03:03in the small intestine or
• 01:03:05appendix,
• 01:03:07what we call midgut neuroendocrine
• 01:03:09tumor.
• 01:03:10So it is the most
• 01:03:11common tumor of the small
• 01:03:12bowel.
• 01:03:14Some patients do present with
• 01:03:16obstruction
• 01:03:17or abdominal discomfort or symptoms
• 01:03:19from them.
• 01:03:20Sometimes it can cause a
• 01:03:22full blown obstruction or what
• 01:03:23was called an interoception,
• 01:03:24which I think there's a
• 01:03:25photo here. Yep. That's an
• 01:03:26interoception there,
• 01:03:28some bowel. You can see
• 01:03:30that that that could cause
• 01:03:31a problem there. It's sort
• 01:03:32of like a windsock,
• 01:03:34going inside out.
• 01:03:36But most patients are diagnosed
• 01:03:37incidentally.
• 01:03:40Patients that do have these
• 01:03:42tumors, the primary tumor actually
• 01:03:43tends to be rather small
• 01:03:44and starts in the intestines
• 01:03:46here, but when they spread
• 01:03:47to the lymph nodes, these
• 01:03:48yellow
• 01:03:49nodules here along the blood
• 01:03:51vessels,
• 01:03:52those lesions the lymph nodes
• 01:03:54can get quite large, and
• 01:03:55those lymph nodes actually are
• 01:03:57oftentimes the source
• 01:03:58of the pain or discomfort
• 01:03:59or obstruction or what's noticed
• 01:04:01on a scan that leads
• 01:04:02a patient to get the
• 01:04:03diagnosis.
• 01:04:05You know, the staging of
• 01:04:06these patients,
• 01:04:08as before can include testing
• 01:04:10both labs, studies, biopsies.
• 01:04:13If possible, we wanna try
• 01:04:14and understand the grade so
• 01:04:16we understand the best treatments.
• 01:04:18But the goal of all
• 01:04:19these, you know, tests is
• 01:04:20to determine the resectability and,
• 01:04:22again, whether or not there's
• 01:04:23been any spread.
• 01:04:25You know, so you can
• 01:04:26see here, you know, this
• 01:04:28teeny tiny thing here is
• 01:04:29a is a one of
• 01:04:30these lymph nodes,
• 01:04:32you know, along the vessel
• 01:04:34there. You can see on
• 01:04:35the cartoon the matched set
• 01:04:37from the CAT scan there
• 01:04:38on the left side.
• 01:04:40But sometimes they can be
• 01:04:41quite large as you can
• 01:04:42see here. Here's that same
• 01:04:43lymph node,
• 01:04:44much, much larger in this
• 01:04:45particular patient. And like I
• 01:04:47said, that that's usually what
• 01:04:48catches the eye of the
• 01:04:49radiologist when you get a
• 01:04:50scan.
• 01:04:51And you can see sometimes
• 01:04:53they can be quite involved,
• 01:04:55including some major blood vessels
• 01:04:57and and, sometimes be quite
• 01:04:58a challenge for removal.
• 01:05:01Again, just like with the
• 01:05:03pancreatic
• 01:05:04operations, our goal is to
• 01:05:05remove the primary tumor. Oftentimes,
• 01:05:08in these cases, there is
• 01:05:09quite a bit of lymph
• 01:05:10node spread or or even
• 01:05:12multiple
• 01:05:13primary tumors in a third
• 01:05:14of cases.
• 01:05:16And again, if the patient
• 01:05:17is metastatic or symptomatic, we,
• 01:05:19of course, want to improve
• 01:05:20quality of life in the
• 01:05:21operating room.
• 01:05:22And as before, we wanna
• 01:05:23minimize complications, different set of
• 01:05:25complications,
• 01:05:27with these particular patients as
• 01:05:29opposed to the pancreatic
• 01:05:31surgery, but, still something we
• 01:05:32watch out for. Here's a
• 01:05:34just a couple of more
• 01:05:35surgical photos again so you
• 01:05:37can see what I'm talking
• 01:05:38about.
• 01:05:39You know, here's somebody with
• 01:05:41multiple lesions in the bowel.
• 01:05:43You can see one, two,
• 01:05:44three, four, five there. And
• 01:05:45then on the picture on
• 01:05:46on the right, you can
• 01:05:47see these lumps and bumps
• 01:05:48here, not necessarily in the
• 01:05:50intestine, which is on the
• 01:05:51outside, but these are those
• 01:05:52lymph nodes that the instruments
• 01:05:54are are are pointing to
• 01:05:55there.
• 01:05:56And that's that's all disease,
• 01:05:57so we need to clear
• 01:05:58that out if we're we're
• 01:05:59in the operating room.
• 01:06:02Just real briefly at the
• 01:06:03end,
• 01:06:04just wanna touch on on
• 01:06:05stage four of metastatic disease,
• 01:06:07which oftentimes is in the
• 01:06:09liver, but can be in
• 01:06:10many other sites.
• 01:06:13In these
• 01:06:14operations,
• 01:06:16we do believe there's a
• 01:06:17survival benefit if we can
• 01:06:19clear the majority or all
• 01:06:21of the disease.
• 01:06:23Sometimes we can do that.
• 01:06:24Other times, you know, we
• 01:06:25can't, and we have to
• 01:06:26rely on systemic treatments.
• 01:06:27Most often in these cases,
• 01:06:29we actually use both. In
• 01:06:31other words, a patient might
• 01:06:32get a systemic treatment as
• 01:06:34a bridge to surgery or
• 01:06:35hopefully to reduce the size
• 01:06:36of the tumors in order
• 01:06:37to facilitate surgery.
• 01:06:40So there's a a particular
• 01:06:42p tumor in the liver,
• 01:06:43and then we remove that
• 01:06:44portion of the liver there.
• 01:06:47And so that patient was
• 01:06:48was rendered free of disease
• 01:06:49again.
• 01:06:51So just in summary,
• 01:06:53as always, each patient should
• 01:06:54be managed individually based on
• 01:06:56how their, you know, how
• 01:06:57their symptoms and presentation go
• 01:06:59and, you know, as their
• 01:07:00disease and the grade and
• 01:07:01whether or not surgery is
• 01:07:02the right choice for them.
• 01:07:04We always wanna talk about
• 01:07:05these patients with our colleagues
• 01:07:06from medical oncology, radiation oncology
• 01:07:09to come up with a
• 01:07:09multidisciplinary
• 01:07:10plan.
• 01:07:13But when we do these
• 01:07:13operations, we need to you
• 01:07:15know, there's usually more than
• 01:07:16one side of disease, and
• 01:07:17we wanna try and and
• 01:07:19clear out
• 01:07:20as much as we can,
• 01:07:22preferably all the disease if
• 01:07:23we're going to the operating
• 01:07:24room and committing to surgery.
• 01:07:28And then like I said,
• 01:07:29even in the setting of
• 01:07:30advanced or metastatic disease,
• 01:07:33some patients can, again, still
• 01:07:34be treated with curative intent.
• 01:07:36In the future, we hope
• 01:07:37some of,
• 01:07:38those newer drugs that doctor
• 01:07:40Coons was mentioning
• 01:07:41can help facilitate operative candidacy
• 01:07:43for more patients,
• 01:07:46you know, including,
• 01:07:47treatment that could downstage or
• 01:07:49or reduce the size of
• 01:07:50their tumor to facilitate,
• 01:07:52an operation as well as
• 01:07:54image guided surgery and some
• 01:07:55of those molecular targets that
• 01:07:56doctor Klimster mentioned.
• 01:07:58So I think that's my
• 01:07:59last slide. Here's my partners,
• 01:08:01and our research staff.
• 01:08:03Thanks everybody for their your
• 01:08:05attention,
• 01:08:06and, of course, be happy
• 01:08:07to answer any questions.
• 01:08:13Thank you, doctor Kunstman.
• 01:08:14Well, that was great. I'm
• 01:08:15gonna ask my
• 01:08:17co presenters to turn on
• 01:08:18video if they can.
• 01:08:20And,
• 01:08:21we had one question come
• 01:08:23into the chat, and then
• 01:08:24I will I also have
• 01:08:25some other questions. But please,
• 01:08:26to our audience, feel free
• 01:08:28to put in your burning
• 01:08:30questions.
• 01:08:32So the first question is
• 01:08:33a really practical one. I
• 01:08:35know some of the answer,
• 01:08:36but I might ask doctor
• 01:08:37Elfockery to answer it.
• 01:08:39So how can we get
• 01:08:40pets faster?
• 01:08:42And, maybe, George, you can
• 01:08:44speak to kind of newer
• 01:08:45pet modalities that are coming,
• 01:08:47but really the practicality
• 01:08:49of
• 01:08:50getting pets. And I think
• 01:08:51this really speaks to we
• 01:08:53are using them more.
• 01:08:55Buried on one of your
• 01:08:56slides was the fact that
• 01:08:57we are actually using this
• 01:08:59approach of getting pets and
• 01:09:01targeted radioligand therapy also for
• 01:09:03prostate cancer.
• 01:09:05We are gonna see just
• 01:09:06an explosion of this this
• 01:09:08PETS and treatment combined,
• 01:09:11and other solid tumors. So
• 01:09:13how are we meeting those
• 01:09:14needs?
• 01:09:15Right. So,
• 01:09:17we are,
• 01:09:19and somebody has asked also
• 01:09:20how does that compare to
• 01:09:21a CT scan. I can
• 01:09:23try
• 01:09:24to answer that as well.
• 01:09:25So we are trying not
• 01:09:27to be victims of our
• 01:09:28own success. This is,
• 01:09:31an incredible opportunity to be
• 01:09:33a lot more
• 01:09:35personalized to each patient.
• 01:09:38The difficulty is twofold. One
• 01:09:40is in terms of scanners,
• 01:09:42and we are putting in
• 01:09:44more scanners. There are,
• 01:09:46there are new PETCTs that
• 01:09:48are coming to Yale New
• 01:09:48Haven Hospital and some are
• 01:09:50up and running now.
• 01:09:52We are also working on
• 01:09:53more efficient scanners.
• 01:09:56One of the things
• 01:09:58that technology is available now
• 01:10:00is for full body scanner
• 01:10:02where instead of having a
• 01:10:03thirty centimeter axial field, you
• 01:10:05have a meter and a
• 01:10:06half.
• 01:10:07So that would be a
• 01:10:08scan in two minutes instead
• 01:10:09of twenty five minutes, and
• 01:10:10then you can imagine you
• 01:10:11can do a lot more.
• 01:10:13We don't have one of
• 01:10:13those at Yale New Haven
• 01:10:15yet, but one will be
• 01:10:16coming to the Imaging Institute
• 01:10:18in two years from now,
• 01:10:19and we will
• 01:10:20be making every effort to
• 01:10:22have days available for clinical
• 01:10:25use. So that's the equipment
• 01:10:26side. The other side of
• 01:10:28this is the radiopharmaceutical
• 01:10:30because,
• 01:10:31as you know, most of
• 01:10:32the time we talked about
• 01:10:33gallium sixty eight dotatate, so
• 01:10:35that's a half life of
• 01:10:36sixty eight minutes.
• 01:10:37So
• 01:10:38that means you you can't
• 01:10:40make that in,
• 01:10:42say, California and then ship
• 01:10:44it over. By the time
• 01:10:45it's here, there's nothing left.
• 01:10:47So there,
• 01:10:48so far, we have been
• 01:10:49tributaries of, you know, who
• 01:10:51is delivering those. We are
• 01:10:53also on that front working
• 01:10:55on making,
• 01:10:56there's a major effort happening
• 01:10:58at the ATL to,
• 01:11:01have a GMP facility that
• 01:11:02would be also in three
• 01:11:04years from now, two and
• 01:11:04a half years from now,
• 01:11:05where we'll be able to
• 01:11:06make those compounds ourselves and
• 01:11:08then send them to the
• 01:11:09hospital so that we won't
• 01:11:10be tributaries where there's a
• 01:11:12snowstorm which happens in the
• 01:11:13winter or there's a a
• 01:11:16a strike or or there's
• 01:11:17no a failure of synthesis.
• 01:11:18And I would be able
• 01:11:19to do more of those.
• 01:11:20And working on both of
• 01:11:21those.
• 01:11:22The question that was asked
• 01:11:24is how does a PET
• 01:11:25compare to a CT scan?
• 01:11:28In three words, much much
• 01:11:29better. Much more. That's three
• 01:11:31words.
• 01:11:32So in a PET CT,
• 01:11:33you always get a CT
• 01:11:34for free because there's a
• 01:11:36a PET CT, it has
• 01:11:37a CT,
• 01:11:38a scanner, and a PET
• 01:11:39scanner.
• 01:11:40But,
• 01:11:42to give you an analogy,
• 01:11:44and I think
• 01:11:45Doctor.
• 01:11:46Kunstmann had very nice CTs
• 01:11:48that were all obvious. You
• 01:11:50know these were like the
• 01:11:51ones if you have this
• 01:11:52there's nothing else you need.
• 01:11:53More often than not that's
• 01:11:55not what we have. What
• 01:11:56we have is something where
• 01:11:57this could be a tumor,
• 01:11:59it could be something else.
• 01:12:00What you're looking at with
• 01:12:01CT is just a change
• 01:12:03in density, and that will
• 01:12:04happen sometimes in the tumor,
• 01:12:05but it can happen for
• 01:12:06all sort of other reasons.
• 01:12:08That is so if you
• 01:12:09if you touch if you
• 01:12:10look at those images, the
• 01:12:11beautiful images that we saw
• 01:12:13from doctor Kunstmann, you can
• 01:12:14see, like, it has a
• 01:12:15different
• 01:12:16appearance and consistency.
• 01:12:18But then there could be
• 01:12:19all sort of other things
• 01:12:20that have the same changes
• 01:12:21in density. Whereas with PET,
• 01:12:23we're looking at the somatostatin
• 01:12:24receptor that will be only
• 01:12:26expressed when it is a
• 01:12:27tumor. So it's a lot
• 01:12:29more sensitive,
• 01:12:30meaning you can see a
• 01:12:31lot less of it, a
• 01:12:32lot more specific it's only
• 01:12:33for tumors. You can see
• 01:12:35it on CT when you
• 01:12:36have a lot of the
• 01:12:37tumor present.
• 01:12:39That's
• 01:12:40probably
• 01:12:41about a million times you
• 01:12:43need a million times more
• 01:12:44cells to see it on
• 01:12:45CT that you'd need on
• 01:12:46PET. So it's a lot
• 01:12:48more sensitive. But it's also
• 01:12:49a lot more expensive,
• 01:12:50a lot slower, and there
• 01:12:52are a lot fewer of
• 01:12:53them.
• 01:12:53I I I would just
• 01:12:54add to I would just
• 01:12:55add because I was gonna
• 01:12:56ask you to comment on
• 01:12:57that, John. Yeah.
• 01:13:00I would just add to
• 01:13:01that that depending on the
• 01:13:03question that's being
• 01:13:05asked,
• 01:13:06the scans can be much,
• 01:13:08much better to answer one
• 01:13:10particular question versus another.
• 01:13:12So,
• 01:13:13you know, patients that are
• 01:13:15being evaluated for surgery
• 01:13:18may need
• 01:13:19a particular type of CT
• 01:13:21scan or PET scan or,
• 01:13:23you know, depending on the
• 01:13:24question being asked. So for
• 01:13:25instance,
• 01:13:27you know, as I was
• 01:13:28alluding to in those small
• 01:13:30bowel neuroendocrine
• 01:13:31tumor
• 01:13:33slides,
• 01:13:34many times these very infiltrative
• 01:13:37masses and and nodes
• 01:13:39will be along the major
• 01:13:40vessels,
• 01:13:41and it's very hard for
• 01:13:43us to tell on a
• 01:13:44PET scan, which is lower
• 01:13:45resolution CT as opposed to
• 01:13:47a dedicated
• 01:13:48CT
• 01:13:49angiogram
• 01:13:50or sometimes venogram
• 01:13:53that, you know, we'll get
• 01:13:56to facilitate surgical planning.
• 01:13:58So it may be a
• 01:13:59different question that's being asked.
• 01:14:01It's not just that we're
• 01:14:02being, you know, sticklers.
• 01:14:05It's it's really to answer
• 01:14:07a very specific question. So,
• 01:14:08you know, for instance,
• 01:14:11the operation I just did
• 01:14:12today on a patient with
• 01:14:14a neuroendocrine tumor in the
• 01:14:15mesentery,
• 01:14:16it was critical that we
• 01:14:18understood how many
• 01:14:19branches of the intestinal blood
• 01:14:22supply were were free
• 01:14:24such that we could do
• 01:14:25the operation and preserve the
• 01:14:27intestines and the digestive function.
• 01:14:29So, you know, that's the
• 01:14:30kind of specific question we
• 01:14:32may get a particular scan
• 01:14:33to to understand.
• 01:14:35And and those are things
• 01:14:36that that cannot answer because
• 01:14:38you only see in the
• 01:14:38somatostatin receptor. You don't see
• 01:14:40think of it as, like,
• 01:14:42you know, the Where is
• 01:14:42Waldo kind of cartoons. You'll
• 01:14:44see Waldo lighting up, and
• 01:14:45you won't know anything around
• 01:14:46him. Whereas with a CT
• 01:14:48scan, you'll see all the
• 01:14:49anatomical details that are, around
• 01:14:51you, but you may not
• 01:14:52see well dilating.
• 01:14:53So both of those are
• 01:14:54incredibly useful. Yeah. All good.
• 01:14:57Doctor Klimstra,
• 01:14:58nice to have you live.
• 01:15:00I'm gonna ask you a
• 01:15:01question. I know you focused
• 01:15:03primarily on the well differentiated
• 01:15:06neuroendocrine tumors.
• 01:15:08I wondered if you could
• 01:15:09comment just briefly for our
• 01:15:10audience. What's a neuroendocrine
• 01:15:11carcinoma?
• 01:15:13We treat those very differently
• 01:15:14in medical oncology.
• 01:15:16Sure.
• 01:15:17So, yes, what I talked
• 01:15:18about was exclusively the well
• 01:15:20differentiated category. And as I
• 01:15:22said, they can be low
• 01:15:23grade, intermediate grade, or rarely
• 01:15:25high grade.
• 01:15:27The neuroendocrine carcinomas
• 01:15:28are really not that closely
• 01:15:30related even though the name
• 01:15:31sounds very similar.
• 01:15:33These are proper carcinomas that
• 01:15:35are that more closely related
• 01:15:38to adenocarcinomas,
• 01:15:39squamous cell carcinoma, other types
• 01:15:41of cancer that can arise
• 01:15:42in the pancreas or the
• 01:15:43lung or the or the
• 01:15:44colon.
• 01:15:46They're very highly aggressive.
• 01:15:48They share
• 01:15:49the the immunohistochemical
• 01:15:51staining that I demonstrated,
• 01:15:53for for neuroendocrine markers, but
• 01:15:56they differ in almost every
• 01:15:57other way. They're very, very
• 01:15:59highly proliferative, rapidly growing.
• 01:16:02They have a totally different
• 01:16:04spectrum of mutations
• 01:16:06and they respond
• 01:16:07predominantly to different drugs, which
• 01:16:09of course you'd be much
• 01:16:10better to comment on than
• 01:16:11I, but,
• 01:16:13so the distinction
• 01:16:14between the well differentiated and
• 01:16:16the poorly differentiated is extraordinarily
• 01:16:18important.
• 01:16:19It can sometimes be challenging,
• 01:16:20but, we're we're we're pretty
• 01:16:22good at it.
• 01:16:23Yep. Thank thank you. That's
• 01:16:25great. I'm gonna mention one
• 01:16:26thing that a, an audience
• 01:16:28member texted in or or
• 01:16:30messaged in. Is is this
• 01:16:32webinar available afterwards? The answer
• 01:16:34is yes. So stay tuned.
• 01:16:36Our team will actually send
• 01:16:37out a message with that
• 01:16:38link, and it will be
• 01:16:39available on our YouTube channel.
• 01:16:42So if you didn't take
• 01:16:42notes or if you want
• 01:16:43to send it on to
• 01:16:44family members or friends, this
• 01:16:46will be available afterwards.
• 01:16:48I'm gonna tackle one of
• 01:16:49the questions in the chat.
• 01:16:51So one of those was
• 01:16:53why wouldn't you immediately
• 01:16:54start treatment for a patient
• 01:16:56with
• 01:16:56a small intestine or any
• 01:16:58NET that is stable and
• 01:16:59nonfunctional but has spread to
• 01:17:01other places? That's an awesome
• 01:17:03question and one that we
• 01:17:04actually talk quite a bit
• 01:17:06with patients about.
• 01:17:08So for patients who have
• 01:17:09a
• 01:17:10asymptomatic,
• 01:17:11maybe they were an incidentally
• 01:17:13diagnosed. They came in for
• 01:17:14a completely different reason and
• 01:17:16were found to have a
• 01:17:17low grade,
• 01:17:19neuroendocrine tumor that is spread
• 01:17:21perhaps to the liver as
• 01:17:22a as a very common
• 01:17:23scenario.
• 01:17:24Why wouldn't we start treatment
• 01:17:25immediately?
• 01:17:27There is an option to
• 01:17:28either
• 01:17:29observe those patients and monitor
• 01:17:31very closely with scans or
• 01:17:32just start perhaps on something
• 01:17:34like octreotide or lanreotide.
• 01:17:37The reason is be many
• 01:17:38of those patients, you may
• 01:17:39have had that for years
• 01:17:41already, and we don't know
• 01:17:42the pace of growth.
• 01:17:43And if the tumor itself
• 01:17:45is gonna remain stable,
• 01:17:47generally, my recommendation is to
• 01:17:49monitor until we see clear
• 01:17:50evidence of growth. We are
• 01:17:52sparing you side effects of
• 01:17:54that those monthly injections
• 01:17:56until the time that you
• 01:17:57really need it where we
• 01:17:58start seeing some evidence of
• 01:17:59growth.
• 01:18:00Now that is a
• 01:18:02difficult conversation, especially with a
• 01:18:04patient that's newly diagnosed, and
• 01:18:05we use shared decision making.
• 01:18:07And if if it is
• 01:18:08really important to you,
• 01:18:11to start something, we absolutely
• 01:18:13will have that conversation, and
• 01:18:14I,
• 01:18:15really try to do that
• 01:18:17as a kind of a
• 01:18:18joint decision with the patient.
• 01:18:21So, doctor Kuntzmann, there was
• 01:18:23a question that came in
• 01:18:24around
• 01:18:25stage four disease,
• 01:18:27and the goals
• 01:18:29of of surgery.
• 01:18:32Can we cure patients with
• 01:18:33stage four disease?
• 01:18:35And is specifically, the question
• 01:18:37is in a situation where
• 01:18:39the primary tumor is pancreatic
• 01:18:40and will differentiate and has
• 01:18:41metastasized to the liver, if
• 01:18:43you're able to remove those
• 01:18:45liver spots in the pancreas
• 01:18:46spot, how often do you
• 01:18:47see recurrence?
• 01:18:49Yeah. It's a great question
• 01:18:50too. And much like everything
• 01:18:53in neuroendocrine disease,
• 01:18:55it depends.
• 01:18:57So, you know, the scenario
• 01:18:58where
• 01:18:59we have,
• 01:19:01you know, doctor Klimster was
• 01:19:02talking about a really well
• 01:19:03differentiated
• 01:19:04low grade tumor. Actually, many
• 01:19:06of these
• 01:19:07with a single or or
• 01:19:08maybe even two or three
• 01:19:09lesions
• 01:19:11can be resected, and patients
• 01:19:12can go for many, many,
• 01:19:13many years being free of
• 01:19:15disease, perhaps their entire life.
• 01:19:18Again, as doctor Coons was
• 01:19:20just alluding to,
• 01:19:22one of the challenging things
• 01:19:23is at the time of
• 01:19:24diagnosis, you don't know whether
• 01:19:25this particular
• 01:19:27tumor or tumors have been
• 01:19:28there for six months or
• 01:19:31six years or sixteen years
• 01:19:33sometimes.
• 01:19:34So when we are operating
• 01:19:36in the setting of metastatic
• 01:19:38disease,
• 01:19:39I often use the analogy,
• 01:19:42of sort of resetting the
• 01:19:43clock on patients.
• 01:19:45You know, yes, we still
• 01:19:47need to watch and and
• 01:19:48basically watch them for life
• 01:19:50for any other signs of
• 01:19:51recurrence.
• 01:19:53But sometimes we can reset
• 01:19:55the clock to such a
• 01:19:56point and the pace of
• 01:19:57the disease is slow enough
• 01:19:58that they go through the
• 01:19:59rest of the natural life
• 01:20:01and, you know, without any
• 01:20:03recurrence of disease. That can
• 01:20:05be a little more challenging
• 01:20:06in higher grade disease, grade
• 01:20:07two, grade three disease. You
• 01:20:09know, recurrence is more often
• 01:20:11and is essentially the rule
• 01:20:12rather than the exception.
• 01:20:15At the same time, you
• 01:20:16know, same kind of scenario
• 01:20:18if we can knock the
• 01:20:19disease back considerably.
• 01:20:21There's also some evidence that
• 01:20:23some of the treatments doctor
• 01:20:24Coons can give work better
• 01:20:26in the setting of lower
• 01:20:27volume disease than higher volume
• 01:20:29disease.
• 01:20:31You know, this is part
• 01:20:31of the reason, you know,
• 01:20:32having a a multi specialty
• 01:20:35and multidisciplinary,
• 01:20:38management team is so important
• 01:20:39is not only are these
• 01:20:41treatments tough to align,
• 01:20:43but
• 01:20:43they're sometimes really important to
• 01:20:46sequence correctly as well.
• 01:20:48You know, in other words,
• 01:20:49what comes first, second, or
• 01:20:50third really matters. So,
• 01:20:53I hope that answered the
• 01:20:54question.
• 01:20:55Yeah. That's great, John. Thank
• 01:20:57you.
• 01:20:58So one of my favorite
• 01:21:00ways to end these webinars
• 01:21:02is really forward looking.
• 01:21:04I'm gonna go around.
• 01:21:06John, I'll start with you
• 01:21:07since you've heard me ask
• 01:21:08this before.
• 01:21:09I really like asking
• 01:21:11what are you most hopeful
• 01:21:12for? What are you most
• 01:21:13excited about in your field,
• 01:21:16for NETs? So, John, I'll
• 01:21:17I'll start with you.
• 01:21:19Well, I I'll answer it
• 01:21:20the same way I did
• 01:21:21a few months ago.
• 01:21:23The, thing that's most exciting
• 01:21:25to me, you know, what
• 01:21:26what really, really,
• 01:21:28gets me out of the
• 01:21:29bed, out of bed in
• 01:21:30the morning,
• 01:21:31is taking
• 01:21:33tumors, you know, neuroendocrine tumors,
• 01:21:35either the pancreas or the
• 01:21:37intestines that
• 01:21:38some other institution or surgeon
• 01:21:40or oftentimes surgeons
• 01:21:42have said is unresectable,
• 01:21:45and turning it into something
• 01:21:46that's resectable.
• 01:21:48You know, all of those
• 01:21:49one of the best things
• 01:21:50about neuroendocrine disease is that
• 01:21:52it is moving so quickly.
• 01:21:56You know, and some of
• 01:21:57the treatments that are coming
• 01:21:58out in the last few
• 01:21:59years and imminently
• 01:22:01can sometimes cytoreduce, shrink, or
• 01:22:04alter tumors in such a
• 01:22:05way that,
• 01:22:07we can consider curative operations
• 01:22:09on patients that we never
• 01:22:11could have thought about that
• 01:22:12before.
• 01:22:13So that's that's what's really,
• 01:22:14really satisfying to me,
• 01:22:16and exciting in terms of,
• 01:22:18what's next.
• 01:22:20Great. Thanks, John.
• 01:22:22David, I'll I'll go to
• 01:22:24you next.
• 01:22:25You and and me I
• 01:22:26will, just acknowledge David has
• 01:22:28been in the neuroendocrine field
• 01:22:29and has really, like, literally
• 01:22:30written the book on neuroendocrine
• 01:22:32tumor pathology
• 01:22:33books.
• 01:22:35And so you have seen
• 01:22:36the field evolve over many
• 01:22:38years.
• 01:22:40What are you most excited
• 01:22:41about?
• 01:22:42It's a great question,
• 01:22:44Pam. And,
• 01:22:45I think,
• 01:22:47John Kunstwena alluded to this
• 01:22:49a minute ago in one
• 01:22:49of the comments he made
• 01:22:50about
• 01:22:51staging treatments.
• 01:22:53You know, we've we've learned
• 01:22:54so much about the pathology,
• 01:22:56the genetics
• 01:22:58of these various neuroendocrine tumors,
• 01:23:00and especially for some sites
• 01:23:03like pancreas, we now have
• 01:23:04many different treatment options,
• 01:23:06but I think it's still
• 01:23:08challenging to decide which one
• 01:23:09to try first
• 01:23:11in a given patient.
• 01:23:13You can correct me if
• 01:23:14I'm wrong about that, but
• 01:23:15I think we can use
• 01:23:17a lot more information
• 01:23:18about which treatments are most
• 01:23:20likely to be effective.
• 01:23:21And we're beginning to unravel
• 01:23:23this based on the fact
• 01:23:24that some
• 01:23:26treatments target specific
• 01:23:28mutational pathways,
• 01:23:29but a lot more study
• 01:23:30is necessary. And so my
• 01:23:32what I get excited about
• 01:23:33is the possibility that we
• 01:23:35can discover
• 01:23:36ways to predict response to
• 01:23:37therapy that we don't have
• 01:23:38today so we know which
• 01:23:40of these
• 01:23:41various approved therapies
• 01:23:42would be the best for
• 01:23:43each individual patient.
• 01:23:47Thanks, David. George.
• 01:23:50I would say,
• 01:23:51you know, my answer is
• 01:23:52gonna be on the thermostat
• 01:23:54side, but I I think
• 01:23:55moving Can you define can
• 01:23:56you define that word for
• 01:23:57everybody?
• 01:23:58Yes. Oh, well, if you
• 01:23:59haven't if you missed the
• 01:24:00lecture,
• 01:24:01or the presentation. So being
• 01:24:03able to use the same
• 01:24:05molecule
• 01:24:06to image and to treat
• 01:24:07So that you can have
• 01:24:08a PET scan, you see
• 01:24:10where your somatostatin receptors are,
• 01:24:12and then you change
• 01:24:14one
• 01:24:15radioisotope
• 01:24:16from a positron emitter to
• 01:24:17a beta emitter or better
• 01:24:19yet alpha emitter. And now
• 01:24:21you are treating.
• 01:24:22Moving to alpha emitters is
• 01:24:24a huge promise. It's still
• 01:24:26not there yet but because
• 01:24:27the kill, the cell kill
• 01:24:29will be much higher. There
• 01:24:30will be a lot more
• 01:24:30DNA damage. I think the
• 01:24:32other part that is very
• 01:24:33exciting in addition to moving
• 01:24:35earlier and
• 01:24:36using theranostics
• 01:24:38is combining theranostics with other
• 01:24:40treatments because so far it
• 01:24:41has been
• 01:24:42done on its own. So
• 01:24:44combining this with other treatments
• 01:24:46that are already that some
• 01:24:47many discussed today I think
• 01:24:49is another exciting area where,
• 01:24:51hopefully we'll see better results.
• 01:24:53That's great.
• 01:24:55I'll I'll I'll go also.
• 01:24:57So,
• 01:24:58I have to say as
• 01:24:59someone who's a clinical trialist
• 01:25:00and has been in the
• 01:25:01neuroendocrine space for a long
• 01:25:02time, I'm really excited about
• 01:25:04the attention
• 01:25:05that NETZ has finally been
• 01:25:07getting over the last five
• 01:25:08to ten years,
• 01:25:09in clinical trials. We need
• 01:25:11data to really
• 01:25:13provide us with information
• 01:25:14on the best treatments to
• 01:25:16use, what order we can
• 01:25:17do them in, how to
• 01:25:19better select patients and identify
• 01:25:21patients. And when I meet
• 01:25:22with patients in clinic and
• 01:25:24I'm asked, well, what's the
• 01:25:25next best treatment?
• 01:25:27You know, we don't we
• 01:25:28haven't historically had clinical trials
• 01:25:30like our colleagues in colon
• 01:25:32cancer or breast cancer to
• 01:25:34say we have hundreds of
• 01:25:35patients that have been treated
• 01:25:36in this trial, and this
• 01:25:37is what we this is
• 01:25:39our best evidence or best
• 01:25:40data. And I think we're
• 01:25:41getting there.
• 01:25:42So I find that really
• 01:25:44exciting and very hopeful.
• 01:25:45I think that many patients
• 01:25:47who are alive now with
• 01:25:49NETs will directly benefit from
• 01:25:51clinical trials that are ongoing
• 01:25:54and,
• 01:25:55you know, with really help
• 01:25:57from from this entire multidisciplinary
• 01:25:59team. And so I think
• 01:26:01a key takeaway is,
• 01:26:02be sure you have some
• 01:26:04NET experts, whether they're NET
• 01:26:06pathologists,
• 01:26:07NET radiologists,
• 01:26:08or NET surgeons, or medical
• 01:26:10oncologists on your team.
• 01:26:12There are ways to get
• 01:26:12that regardless of where you
• 01:26:14live, and we are we
• 01:26:16work well with community oncologists
• 01:26:18and community
• 01:26:19team members, to really try
• 01:26:20to help get you best
• 01:26:21of both worlds.
• 01:26:23So
• 01:26:24we are gonna end there.
• 01:26:25This again, this webinar will
• 01:26:27be available afterwards. Huge thank
• 01:26:29you to my colleagues for
• 01:26:30spending their evening,
• 01:26:32and happy net awareness day.
• 01:26:34So thank you everybody. Have
• 01:26:35a great night.