We are not separated from each other. Veryثful! Thank you. Good morning everyone and thanks for being here for certain grand rounds with treat today Dr. Lindsey Frazier will be our speaker. I'll about make a brief so you know the full time. I'll just say that many of us know her as a local and international real leader and expert of pediatric oncology and just as an example we just came back from the all the fellows in a nation take a surgical oncology review course over the weekend and and during the course of it your name came up several times through papers that were referenced throughout the weekend so I really look forward to hearing which I have to say thank you for being here. Thanks for the invitation and I'm mostly grateful to Brent Wheel who I understand did an outstanding surgical grand rounds about a year ago about the surgical aspects of terms ultimus so I didn't feel compelled at all to cover those topics which I just want to say that as a member of the solid tumor oncology team we feel very grateful for the care that you all provide to our patients and the collaborative way in which we work so I think this is really one of the strengths of our program is are the people that sit in this room and the way we can call you with questions you know night and day so thank you very much. I do serve on clinical advisory board for a company that's developing therapeutics for auto protection so what I'd like to do today is review a little bit of the embryology and how that impacts the incidence of germ cell tumors explain to you why the treatment for pediatric versus adolescents and young adults is different and then tell you about some of the new molecular diagnostics and therapeutics that were developing. So going back to the embryology as you remember the germ cell tumors derived from the primordial germ cell which originate outside of the embryo migrating along the hind guts and then migrate into the genital ridges and this little video here shows you that migratory pathway so the germ cell tumors are left and labeled and are migrating into the gonadal ridges here and that is the reason that the germ cell tumors are thought to arise in the places that they do so they typically occur in the midline starting at the brain and working down through the medius thinum and the heart the head and neck the retroperitum the sacrocoxics and then into the either the ovaries or the testicles so the the embryology determines the position by which we find germ cell tumors. Germ cell tumors arise in two distinct age groups we see them very early on which is most of the tumors that we see here at children are really in the zero to four age group and then you can see in the middle pre cubital years there's really not many cases that are diagnosed at all the incidence and girls starts to go up a little sooner coincident with the fact that the girls go into puberty earlier so the really the age of onset is around eight or nine and girls but the other thing that's also very interesting never explained is why the incidence in girls with exorbitant adult sacrocoxidial tumors is three to one the incidence that it is in boys that's not understood at all nor is it really understood why the incidence in boys skyrockets and is so much higher during adolescents and young adults so you can see that yes it goes up during adolescents and girls but nothing compared to what we see in boys. So really there's some very basic biological questions that we still need to answer but I show you this slide just to remind you that germ cell tumors are really not a pediatric disease but really an adolescent and young adult disease so these are the incidence of testicular variant CNS and extra natal tumors and you can see really the majority of the tumors occur in the 20s and 30s so there really are sort of the prototypical adolescent and young adults solid tumor the most common AYA solid tumor actually. So I just wanted to segue and tell you a little bit about the issues of treating adolescents and young adults because it's relevant to what we've had to deal with in germ cell tumors. So this was a paper how many of you seen this before this is a very overused slide in oncology we call it the blire gram it was published by Archibyly. It really started the whole field starting to think about what's happening in adolescents and young adults with cancer and this is the average increase in survival over this time period this 20 year time period from C or data what you can see is that in every other age group there was a steady one to two percent increase in survival on an annual basis but in adolescents and young adults to find here is 15 to 45 there was less than a 1 percent and in some cases in the 25 to 30 year olds nothing really changed at all over this 20 year period so this really set off a lot of inquiry as to why not. And I think what was apparent as we delved into different diseases was that this was true across a lot of diseases so this is overall survival by age and patients with acute lymphoblastic leukemia 1 to 9 10 to 14 a big drop 15 to 24 in the infants sort of all do badly for genetic reasons and it just keeps going down and the same was true for you so this was a study that looked at youings less than 17 versus over 18 and bifurcated by sites since we know that pelvic site do worse and of course you see that drop by site from 17 other sites to pelvic but you can see here 18 in other sites is way below 18 and above so the same is true for germ cell tumors this is a this is a paper that was published by Nicholas Coste who's a urologist at UTS southwestern and he used his institutional database to look across age so these are the pediatric boys with testicular cancer than the adults with testicular cancer and this is that a lessons in young adults so what's going on here what's what's happening I think there are a lot of potential reasons for this disparity in outcomes the vast majority of adolescents and young adults with cancer are not treated in an academic center so I'll show you that data in just a moment one of the other reasons is that the diseases of adolescents as the young adults are not the common cancers of childhood they're not the blastomas and they're not the common diseases of adults on college UD or to other carcinomas they're really considered rare diseases in the adult world so there's really not the act since they're getting treated mostly in the community where you know the community medical oncologist treat the big four breast colorectal prostate and lung that diseases of adolescents and young adults are really considered rare diseases in that group they typically have very low cruel to clinical trials the cancer biology it is we're probably fooling ourselves by saying that what looks the same under the microscope by histology is the same biology and there's more to say that that's true that the we now know in ALL that the biology changes quite a bit with age and also adolescents and young adults also have different pharmacology and different pharmacokinetics I think has a consequence of puberty so we know now that the drugs are cleared more quickly in some cases and in other cases they are cleared less quickly and the adolescents and young adults have more toxic adverse effects that affect our ability to deliver full dose of drug so this is just to show you the the distribution of disease over age and as I mentioned you know these are the diseases that are the most common in adolescents and young adults biroid melanoma germ cell sarcoma and bone tumors lymphoma and leukemia not the breastoma is not the carcinomas and you can just see how this changes rarely quite quickly with age so for instance here green is breast cancer you can just see how that becomes a much more common disease over time or the blue is colorectal cancer which also you know increases you still thinks of as a rare disease in an adolescent or young adult think it becomes much more important disease this is the gap in clinical trial enrollment so the this light blue is or gray is the percentage of patients by age who are enrolled on a COG clinical trial so 0 to 4 it's 60 percent and this is the percentage of patients who even if they're not on a clinical trial are being treated in an NCI cooperating group center so essentially 100 percent of children under age 4 are being treated in a place that has expertise in treating pediatric cancer by the time you get to age 15 to 19 only 10 percent are on clinical trials and by 20 to 30 that drops to 2 percent only 11 percent are being seen at a cooperative group center and here 80 percent are being seen in the community which rises to 92 percent between age 20 and 30 why is that a big deal well a clinical trial doesn't mean that you'll be cured but it does mean that the care is standardized and so all the decisions that need to be made about whether to reduce the the drug to delay therapy are spelled out in a protocol but it also means that we haven't been collecting biospecimens on any of these patients in any systematic way for ages so we really don't we really haven't had the opportunity to really study the underlying biology of these diseases and figure out why these patients are doing worse so now returning to the treatment of germ cell tumors and what we you know we're working with in this this disease so the history of science moment I mean this platinum which is the primary drug that we use to treat germ cell tumors was actually discovered in 1965 by a chemist at Michigan State University who's actually looking at why what could cause a colonist stop dividing his hypothesis was that you could create a inhibition of cell division by running electric current through bacteria but in oddly enough it was actually not the electric current but it was the cis platinum coming out of the platinum coming out of the electrodes you figured out it was actually causing the bacteria to stop dividing and that was really that was really the beginning of really one of them probably the most useful drugs that we have still in in in treating cancer about one third of pediatric patients receives cis platinum or its analogue carboplatinum so it's still one of our most frequent drugs so that was followed up it took interestingly from 65 to 77 for this to really make it into the clinic and this is Larry Einhorn at Indiana University who first reported that you could cure metastatic cell tumors so the first report of actually being able to cure a solid tumor with chemotherapy metastatic cell tumor with chemotherapy and adults and this was really so unexpected that really quite shortly after that in in 81 testicular cancer was already being held up as the model for a curable neoplasm I think that the problem one of the problems that we've had to face with germ cell tumors is that this early sort of home run in the game I think in really again inhibited the research which I would argue we really haven't advanced much since Larry Einhorn's discovery we still use the same drugs we still use the same regimen and I think it's partially because it's hard to it's hard to motivate research into into a disease that looks like we've already won but you can see here that with the advent of cis platinum that you we can you can see the increase in incidence the increase in survival from the from seared data in children with cancer so here are boys the the genital diseases appeared less than nine and greater than nine and the extra genital disease and this is of course where you see the biggest increases in caring children with extra natal disease so now the overall survival for children with cancer is with germ cell tumors is between 85 and 90 percent but this is this is the problem is that caring a child with cancer does not mean that they're going to have a normal life and I think one of the most sobering things about pediatric cancer today is that we're learning through the late effects study that at least 80 percent of children live with one severe disabling condition for the rest of their lives so we we we're curing them but we're really handing them in return some very serious health effects that they they then have to deal with and we know on average that children with cancer die 10 years younger than than their peers so I think really paying attention to what the late effects are is really sort of the mission for the next generation of pediatric oncologists in terms of germ cell tumors that they're because Larry I'm aren't starting caring men in the late 1970s there are now cohorts of over 40,000 men that can be tracked through population-based cancer registries where we really have a handle at least on what their late effects are and they have a two-fold incidence of early onset cardiovascular disease again two-fold onset of second-religment neoplasms not etoposide related leukemias but solid tumors many men have long-lasting red nodes and progressive ototoxicity and paired renal function hypo-gun addism and suicide which I think is really a psychological effective personally of going through a gonadectomy as an adolescent this is the this is the incidence of solid malignant neoplasms by age by age at treatments of starting at age treated age 20 treated age 35 treated age 50 and the bottom line is the general population and this line are patients with non-seminomas and this is with seminomas and I realize I haven't explained the histology of germ cell tumors to you here the difference is probably that traditionally seminomas were treated with radiation which is why this is a bit higher whereas nonseminomas were treated with chemotherapy but what's important to see here is that the incidence and second-religment neoplasms doesn't plateau that it increases 1% per year and that by age 75 a man treated at age 20 has almost a 50% risk of developing a second-religment neoplasm. Why is that happening? Well we also have learned that cisplatinum is it's a heavy metal it's like lead it's actually measurable for months years maybe decades after treatment so these are cisplatinum levels since the end of treatment that you can actually measure in the blood so I think what's happening that we're exposing children treated with cisplatinum to a long-standing low-level exposure to cisplatinum over many years and that I think may explain at least the rates of second-religment neoplasm. So going back to 2010 when I was asked to take over the germ cell tumor for many there was at COG we really hadn't had a fundamental change in the therapy of germ cell tumors since we put into place our first cisplatinum-based trial in 1980 and though we could lot ourselves for high survival the treatment itself had toxic side effects the part of the problem was that germ cell tumors were being the care of them was being split between pediatric oncology, testicular cancer oncologists and gynecologic oncologists and we never spoke to each other we don't we don't go to the same meetings you know I we you know it's oftentimes we don't even work in the same building you know here Dana Farber were sort of blessed with co-location we had never organized a joint clinical trial we had never done joint biology work together the other thing that were germ cell tumors are really lagging behind other tumors is that we had no molecular markers of prognosis and no targeted therapies to even try because of the lack of an investment in collection of biospestimens and and biology so you know we were really lagging behind I'd say other diseases so to really combat that we form what we call magic the malignant germ cell international consortium this is our brand new logo which we love can everyone see the M's in that so this was work our health communications department at Dave Harbor can't take any credit for it but it really is a consortium now that's about 50 people we've kept it intentionally really small but we've picked experts from around the world in adult testicular cancer gynecologic oncology pediatric oncology but then from the beginning we've made this a very multidisciplinary effort so surgeons Deb Bill-Mired in the Annie University has been really involved with our group biostatistics basic scientist pathologist epidemiologist and bioinformaticist and you know our motivation for reaching out across the the world of oncology into medical oncology is that we realized that we were really never ever in be able to do a clinical trial with the sample size that we could collect in pediatric oncology and we thought that it would just if we could collaborate at least with pediatric oncology outside the United States we might be able to do a clinical trial in a reasonable period of time or the fresh the question would still be fresh and interesting at the end of the trial but really our motivation was to say is the biology different between pediatric and adolescent and young adult germ cell tumors and really could we combine across all age groups and can we find if we work together new prognostic markers and targetable pathways so this is really these were the solutions that we came up with so what we've done is collect all the clinical trial data that we could find from past clinical trials so from the COG of course but this is the UK pediatric germ cell team or group this is the adults to you I and oncology MRC you have run all the testicular cancer trials in the UK and then the Brazilian and French germ cell tumors groups have given us their clinical trial data as well and then linked to those clinical trials data we now have about 1200 biospecimens that we have clinically annotated data on and what we've done is put that into what we call a data commons which is a federated database that links together the clinical trials data and the genomic data and then allows us to really on top of that do retrospective clinical research to answer the questions that no one agrees on that we need to have consensus on to be able to move forward and do design prospective clinical trials so this really this work has really been led by Yang Zi at UT Southwestern and Sam Voltzmbaum who was a pediatric oncology fellow here at children's in Dana Farber and now runs the pediatric cancer data commons at the University of Chicago and it sounds like kind of a no-brainer that you should link all these data together but these datasets live in different places the links between the datasets don't necessarily exist and things are the data are stored in ways that are not compatible with one another for instance in some datasets sex male maybe one and some sex in some datasets male maybe two so all of the data has to be cleaned and harmonized to be able to be combined but now we have a data commons where you can actually sort through and see how many patients you have with certain characteristics and which of those patients have clinical trials data which of those patients have genomic data where the samples live what kind of samples are left that would be available for analysis and we make this this information open to all of the members of our magic group so that's that's really served as the basis for our ability to sort of move forward and design prospective clinical trials but before we did that the key question that we had to ask among ourselves as a group of people who wanted to design a clinical trial is how do you define to risk everyone had a different way of defining it in the different groups that we brought together so we put together all of our clinical trial data from the US and the UK from the past 25 years and came up with a revised risk classification system that we could both agree on and I can't tell you how valuable it was to have all the clinical trial data to look back on because this this process took us a couple of years because there you know we as clinicians tend to rely on our anecdotal experience of having treated patients so you know for instance some clinicians might say well I think that although most children under the age of 11 do well I worry very much about the patients who have a vaginal primary of an extra-genital germinal tumors those patients do terrible and they should be in the poor risk group for sure instead of having to argue about that around the table we could just say well let's look at the data you know is you know is that true over the whole course of the date you know of the data set so this really helped us move forward quite a bit and the new risk stratification that we're using categorizes patients into two groups standard risk and poor risk and what we learned was really it was only the adolescent patients over age 11 with advanced age disease who we would put in the poor risk category and this is a big change from our previous risk stratification in which younger children with extra-genital disease so for instance the stage 4 extra you know sacricotidials had been treated as poor risk patients on prior COG trials and gotten highly intensive chemotherapy which they probably didn't need because the outcome in that group was you know for for the stage 4 sacricotidials was upwards of 85 87 percent you'll notice here that we are using the testicular IgCCC intermediate and poor risk classification so we consciously chose to use the adult classification of poor risk in the testicular cancer patients again so that we could collaborate with our adult collaborators on this in testicular cancer so we tested their classification on adult and adolescent boys and it worked just as well as as a stage definition so that we we have the concordance between our two groups the other thing that we really wanted to look at was whether we could substitute carboplatinum for cisplatinum in the good risk patients why because carboplatinum is much less toxic much less auto-texticity much less renal toxicity it's actually easier to give you can give it we split this as platinum over five days and the carboplatinum can be given as a single dose in one day the problem it has been used since 1989 as the primary way of treating germ cell tumors in the pediatrics in the UK but in adult testicular cancer back in the 90s there were five randomized trials across the US and Europe that showed that carboplatinum was inferior to cisplatinum so there was a lot of resistance to thinking that we could substitute carboplatinum versus fattenum in the world at large people knew the results of these these studies but what we argued was that in pediatric germ cell tumors the UK had been using a much higher dose of carboplatinum so in the adult studies the dose was between 350 and 500 and the the UK had all the pediatric oncologist had always used a dose of 600 milligrams per liter squared and a different dose intensity so in the adult trials that were designed it was prior to the advent of growth factors so carboplatinum is more miles oppressive than cisplatinum so the carboplatinum the arms of the studies were given every 28 days and this is platinum every 21 days and we know that that does intensity matters like one of the probably one of the major advances for ewing sarcoma for instance is that we've learned that giving the therapy every two weeks improves the event free survival by about 10 percent compared to every three weeks so this idea of compressing therapy and giving it you know as as as close together as possible really matters and so in some ways the the carboplatinum trials were doomed to fail in the adults with lower dose and lower dose intensity so because we had all of the UK data in magic we could look to see whether there was a difference between our outcomes where we had always used cisplatinum and their outcomes they had always used carboplatinum of course with the caveat that this wasn't a random isoclinical trial but it was the best we could do to look at that data and we couldn't find this is the this is really small but the main point here is that we looked in a lot of different subcategories here predetermined by our risk work so we first sat down and said what are the risk groups what are the risk factors and then use that to direct sort of what we looked at in terms of a significant difference now come between the two drugs and there isn't a significant p-value here of course there are a lot of again you can see this but the British sample size was a lot smaller than ours it's a lot smaller country so some of these competence intervals are why but I think in probably in two of the more important categories here in age and here you can see that we actually had maybe reasonable sample size to make this conclusion and the p-values are still not significant one of the other arguments always had been that carboplatinum may work fine in pediatrics because most of the pediatric tumors pure yolk sacked tumors which are more chemo sensitive than the adolescent adult tumors which have are more often mixed histology so have corio and in barylonal carcinoma and some of them and those are much harder to treat but again we didn't see a difference by histology either and this work was really sufficient to motivate the next the first joint clinical trial between the U.S. and the UK and we're opening it more broadly than that I just a caveat that I just wanted to say is that through magic because we've had all of this clinical trial data we've really been able to publish in 10 years I think about 30 publications out of that clinical trials database so it's really it's really been an incredible resource for us to learn much more about germ cell tumors but also for us to attract young investigators because we now have a way that people can actually ask questions and you know since the publication is the coin of our realm in academic medicine really build an academic career. Back to carboplatinum versus cisplatinum so that that analysis really was sufficient to convince the science council at COG that it was worth relooking at carboplatinum one more time so we opened this trial nearly two years ago and have accrued about 170 patients to the trial what's new is where we're opening it so the candidate in the U.S. would be the COG sites as well as Australian New Zealand are actually part of COG but we'll be opening it in the UK and in Japan and also at Tatum Memorial in Mumbai for the first time Tatum Memorial sees 2500 new pediatric cancer patients a year we see you know 350 to 400 years so you know an incredible opportunity if this works for us to increase sample size for many of our pediatric oncology trials. I didn't mention to you the low risk stratum in this arm which is really in patients who have stage one completely resected disease we don't recommend any therapy we recommend active surveillance so a certain percentage of those patients will recur and will need to go on to therapy but in ovarian tumors and stage in immature teratoma it's well accepted practice in pediatrics not to treat any stage or grade of immature teratoma because we have we've done a prospective clinical trial showing that the real absolute is very low and if they really occur the best way to treat the second the first recurrence is surgery in GYN oncology every woman who has an immature teratoma that's not grade one stage one gets three cycles of BEP so this arm of the study is really for our GYN colleagues to be able to start to study what happens if you don't treat women with immature teratoma with hemotherapy so you notice that the age here is zero to 50 and this trial in addition to opening internationally is being co-sponsored by all the adult clinical trial groups in the United States we're also looking at the outcome for stage one malignant germ cell tumors malignant meaning they have a component of Yoke's acocharya carcinoma and bryon carcinoma and we're adding a sucker stage for seminoma and disturminoma I'm going to tell you why in a second it's because we have a new diagnostic test that we think is better than alpha-fu to protein and beta-HCG that's going to really help us effectively monitor these patients so that's that's the low risk trial the standard risk trial is the randomization between carboplatinum and cisplatinum and the complication here is that we have to have different regimens for children under 11 versus over 11 is probably more detailed than usurgeons care about but it's actually somewhat relevant because the reason is that when we give children young children Blyamysin they have a very a much higher incidence of developing fatal pulmonary fibrosis than adolescents in young adults so we only give Blyamysin once per once every three weeks in young children where it's given weekly and adolescents in young adults and what we've learned is that that reduction in Blyamysin requires us to treat them with more cycles of chemotherapy so ironically the younger children are getting four cycles of this randomized drug comparison between carboplatinum and cisplatinum whereas the older children are only getting three cycles but they're getting weekly Blyamysin. I'm just going to briefly tell you about the other clinical trials that we have now open for germ cell tumor patients and then go back to telling you a little bit more about the biology that we're working on. So through our collaboration with magic we've gotten to know our artisticular cancer college just as Peter Griminson who is in Sydney and is leading trial for poor risk, intermediate poor risk, germ cell tumor patients through the Australia, New Zealand, Heroologic and prostate society ends up and really through our conversations with an engagement we've convinced them to drop the age eligibility of that trial down to 11 so that we can enroll all of our adolescent young adult patients and as we actually add women to a testicular cancer trial to add the poor risk women to the women, the girls oval are age 11 who have stage four tumors so we've opened this trial in COG it's also open in the UK as well and this trial is looking at compressing BP so giving it every two weeks versus every three weeks sort of analogous to what I spoke about in terms of viewings looking at whether compressed therapy will produce better outcomes they have face to data that looks like it does and that it's deliverable that you can give this flatten them every two weeks that patients recover in time and that the the drug is actually able to be delivered so this trial is ongoing and then the third trial that we're participating in from COG is a trial looking at what to do at relapse and Darren Feldman who's at memorial slow and catering is leading this trial through alliance but through COG we're joining this trial and it's looking at standard chemotherapy with taxile iFOS and platinum versus transplant where the patients get two cycles of taxile iFOS stem cells collected and three sequential transplants with carbohotoposite and again we we initially were able to convince them to drop the age of 14 they're now dropping it to 11 in the next amendment we weren't able to move into but where Darren has data showing that these regimens work as well in women with terms of tumor show probably soon we'll think about adding a stratum for women these are the regimens so four cycles of tip versus two cycles of packed with taxile iFOS from iFOS with stem cell collection and then three sequential cycles of carbohotoposite so back to the biology of germ cell tumors and where i think that field is headed now in terms of new things to to take the field forward so i really haven't spent much time talking to you about the histology i think the histology of germ cell tumors scares many people away it's really not that complicated so you start off with the primordial germ cell and if it normally differentiates fine if it differentiates and then it's blocked going down an embryonic pathway and thematically differentiates a teratoma or immature teratoma if it doesn't thematically differentiate it's known as embryonal carcinoma if instead the primary germ cell tumor does not differentiate it along the route of the embryo but rather stays extra embryonic it's either a yokesc tumor or a chorio carcinoma and then some germ cells never differentiate at all in any fashion remain their pluripotent state and those are these three histologies which are essentially the same but they're they're named different things because they occur in different places which was one of the confusing things i think in the the way the noma creature was developed so seminoma is the same biologically as disterminoma in the ovary and germinoma in the brain but what's relevant here is that although yokesc tumor reliably secrete alpha-queed protein and chorio carcinoma bhtg and ryanocarsinoma and seminoma distermininoma are often marker negative so about 50% are marker negative and so that means that when we're trying to follow patients especially those stage one patients who are trying to follow after having their their tumor resected the only way to follow them is by sequential imaging so to remind you about my caranase which are the basis for the diagnostic test that we're developing these are small non-coding RNAs that regulate gene expression and what is useful about them from from the test making point of view is that my caranase are shed into the from the tumor cell into the circulation so you can actually measure my caranase in the serum and they're very stable so the original discovery by matmurri and palmer and in the UK was that germ cell tumors both childhood and adult germ cell tumors oversecrete for or over-extrust for my caranase my caranase 371 to 373 302 and 367 and here you'll see these are yellow yokesc tumor the blue is germinoma the red is and brinocarsinoma the brown which doesn't really look brown is tertoma and this is normal gonad so you can see that there's a very different pattern expression of these my caranase and normal gonad and teratoma compared to the mormalingant forms of germ cell tumors and we see the same over-expression the patterns a little different but the same set of my caranase over-extresting childhood germ cell tumors and adult germ cell tumors so with that matmurri and nicolman in the UK then looked at the how well you can measure the serum my caranase in the blood and this is the relative fold change of the my caranase up to 4000 fold in the blood and you can see that they are very overexpressed in the blood of patients with germ cell tumors and the color to represent different histology so yokesc tumor brinocarsinoma and seminoma but what was important here is that these tumors that are bracketed were all marker negatives showing that you can measure a marker a my caranase where you couldn't measure a tumor marker and we've shown that they have incredible sensitivity and specificity so with AESU course you know over 90 percent and this is where I think it will be helpful for us as clinicians is this is a case example where this is a boy with testicular cancer who had a small node that wasn't called at diagnosis had an orkiectomy the my caranase fell but then started to rise and at the time of relapse you could see this node emerging here was given chemotherapy in the my caranase then normalized but unfortunately this node got bigger no question is what was going on there I get a lot of e-mail saying you know I treated the patient however and things seem to be going well but the the you know the masses bigger so I'm starting relapse therapy and it's like no weight that could just be growing teratoma you've treated away all of the malignant disease and what's left is teratoma which isn't teamosensitive and you need to take that out and here I think what might help us differentiate that is in this case the my caranase had normalized and when they did the surgery indeed it was just a teratoma so it may help us sort out what's going on at the end of therapy as well and deciding which children do need to go undergo surgical resection versus which children really have viable germ cell tumors still and need to go on to relapse therapy so the last thing I want to talk about is about some really I think exciting advances in our understanding of particularly yolk sacked tumors so particularly the type of germ cell tumor that's very common in children so pediatric and adolescent young adult germ cell tumors occur at a different point in the differentiation of the primary ordeal germ cell we know that from methylation data and as I mentioned most tumors in young children are either teratoma or teratoma mix with yolk sacked or pure yolk sacked tumors and it and these are known as of that label got put in the wrong place but these are known as type one germ cell tumors and as as the migration goes on in the germ cells reach that gonadol ridge they go through sex specific differentiation and it's at that point that you that those are the cells of origin we know from again from from genetic analyses that are the origins for embryonal carcinoma and chorio carcinoma and seminoma so they they occur the the the cell of origin is a primal primal germ cell tumor later stage of development so we're particularly interested in yolk sacked tumors and what what's different about them compared to what's known about adult testicular cancer and this is work that Jim Amitrude has been doing down at UT Southwestern he's looked at somatic SMVs and pediatric germ cell tumors and he found that in in the yolk sacked tumors there a lot and a lot of them all of them had some aberration in the wind pathway in one of the genes in the wind pathway and so he took a deeper look at that we know that again that the methylation for yolk sacked tumors was very different than other forms of germ cell tumors and so he looked specifically at the methylation patterns of these wind pathway genes in yolk sacked tumors versus germinomas so this is the this is the amount of methylation so less methylated and more methylated and what he found was that a lot of these wind activating genes were less methylated in yolk sacked tumors compared to germinomas and much more highly expressed and you see that same thing here in this heat map where the pattern of RNA expression is very different in germinomas the first three columns here versus yolk sacked tumors were yolk sacked tumor gene expression from these wind pathway genes is much more highly expressed in the yolk sacked tumors. Jim went on to really look more closely at the promoter methylation among both wind activators and wind repressors and showed that the wind activators were much more likely to be hypomethylated in the wind repressors methylated and again looked at the copy number variation in genes in the wind activator group of genes as well as wind repressor genes so the wind activators were much more likely to have increased copy number and the wind repressors much much more likely to have loss of function of loss of copy number. And then he went on to look at whether that had any prognostic significance so in patients in whom we knew the outcome in whom we knew who had relapsed and who had not those with multiple activations in the wind pathway were much more likely to recur and here's a Kaplan-Mire plot showing the same thing. Jim then went on to use publicly available data from an analysis of the genomic prognostic indicators of outcome in testicular cancer patients that have been published by Memorial Sloan Kettering and re-analyzed that data and those the specific wind pathway genes that he was interested in in terms of beta-coutine and the frizzled genes and again showed that in patients who overexpressed these wind genes that the outcome was much poorer in those three groups. And then finally in cell culture Jim could show that using some of the wind inhibitors that are now being developed and in the yokes actumer samples you could see you could begin to see that there was an effective suppressing the growth of the yokes act tumors in cell culture compared to really no effects in the embryonic carcinomas of the seminomas which did not have the wind pathway activation. So I think we're we're excited about this in terms of a signal of a pathway that we should start to think about and introducing into especially the poor risk or the highly-resistant terms yokes act tumors that we sometimes see and Jim is sort of taking this work forward now in animal models and in zebra fish models. So and it's also just an exciting time since there's so many wind inhibitors that are being developed and brought to market that could potentially become real drugs for us to investigate going forward. So just to summarize when in you know a decade ago there really had not been any fundamental changes in therapy the care and the trials were split between the three branches of oncology and we really had no molecular markers of prognosis, no targeted therapy. And now we have three open NCI-funded international clinical trials. All those clinical trials are open across the age range at children adolescents and young adults and we think that CMICORNAs are have great potential as a new universal diagnostic marker and perhaps a prognostic marker and that the wind pathway is really an exciting potential new therapy for us to target. We're putting on our first international term-sultimary conference in Cambridge in the UK in September. Anyone who would be interested in coming to abstract submission is open now and this has really been the work of many people from COG, CCLG, the French, Brazilians, our bioinformaticists at UT Southwestern, our GYN colleagues and then we have a lot of international and associate members have joined from other countries as well and all this has really been possible through a consortium grant that we received from the St. Paul Drx Foundation. So thanks very much. Well, I'd like to first thank you for bringing us these updates. I think one thing that's underappreciated is how much our studies are constrained by the number of patients we have is compared with in the adult population where there's a colon carcinoma and breast cancer that you have thousands of patients out there and we just don't have the numbers and increasingly in all of the tumor systems that we deal with in COG we're having to move towards international studies to get enough cohort of kids and young adults, particularly in a germ cell that we can look at together. So it's exciting to see that and I think I should mention everybody that you've assumed the role as chair of the COG committee for germ cell tumors so you're going to be leading a lot of these efforts. I think the other thing that you pointed out at the end is the the need because of the toxicity to try to identify which patients are the highest risk so that they can have the more intensive therapy and the less or the more favorable ones then not get such intensive therapy so we can avoid some of these long-term morbidity and mortality from some of that and it's interesting that in a renal tumor which lag behind, I mean the renal tumor which lag behind neurobastoma some of the molecular markers are now really helping to identify which kids have the worst prognosis and I think it's significant that for the first time the next proposal for the renal cell tumor were actually for the first time pulling back on some of the intensity for some of the patients so they don't get both Adromis and radiation same time with the the cardiac toxicity and such their hand. So I'm sure there must be some questions from the audience. Wow. It's really. I think you've got them all odd. All right, well thank you so much for bringing all of this up. Thank you.
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