His estranged relationship to competence, honesty or basic human decency hasn't been any barrier to achieving success. Being sacked from the times for making up a quote didn't stop Boris Johnson from landing a column at the telegraph worth £275,000. The leak of a phone conversation in which Boris Johnson passes on the address of a journalist so his old mate Darius Guppy could haven't beaten up didn't stop him from being deemed fit for public office. Having a history of publishing racist on homophobic screeds in the spectator didn't stop him becoming mayor of diverse and progressive London. And indeed writing an article backing Remain just two days before coming out for leave didn't stop him from being hailed as a true Brexiteer by ERG headbangers. And his woeful record as foreign secretary including making comments which endangered a British citizen who is still incarcerated in an Iranian prison hasn't stopped him from attaining the highest elected office in the land without actually having to face a general election. Boris Johnson's career has had the quality of a particularly gnarly strain of cystitis. There is no blunder so catastrophic nor a resignation so decisive as to permanently prevent his return to the forefront of national politics in an ever nastier form. So you can see why he makes such an attractive candidate for the Conservative Party the man looks unstoppable or untreatable. But from where I'm sitting Boris Johnson doesn't actually look all that invincible. In reality he faces many of the same problems which managed to end Theresa May's premiership plus a few more. So as some of you may remember back in 2017 Theresa May lost the Conservative Party's majority in Parliament which meant that the Conservative Party had 310 seats backed up by 10 DEP MPs in a confidence and supply arrangement. So that meant that Theresa May had to rely on 320 MPs versus 317 MPs which is the sum total of Labour, the SNP, the Lib Dems, the Tinge Appendent Group for Change or whatever it is they're called now, Plaid Cymru and the SNP. Did I already say the SNP? The SNP. Okay so pay attention. The two numbers that you need to remember are 320 and 317. The two spanners in the works for the Conservative Party are the fact that there is a by-election being held in Brecon and Radnyshire because the Tory MP was convicted of expenses fraud and the fact that Charlie Elfwick, a Conservative MP who's just been charged with three counts of sexual assault has had to have the whip suspended. So if the Lib Dems win in this by-election next week which the polls predict they are likely to do, you've got the opposition number of MPs going up to 318. And if Charlie Elfwick is forced to step down from Parliament and there's a by-election in Dover which Labour then win, it was a Labour held seat before, that means that the total tally of opposition MPs goes up to 319. So Boris Johnson in his first few months as Prime Minister could have a working majority of just one. And this problem of a wafer-thin majority in Parliament inevitably has consequences for Brexit. It makes the pathway for a negotiated deal that bit more difficult for Boris Johnson and also makes the pathway towards a no-deal exit that bit more difficult as well. The reason why a no-deal will still be difficult even though it's the legislative default is that Boris Johnson will find it very tricky indeed to suspend Parliamentary democracy, also known as pro-roging, because Parliament have already said that that course of action would be unlawful.  And finally, a little bit closer to home, Boris Johnson's got problems in Uxbridge and South Rhyslip. His majority there is about 5,000, which isn't enough room to be comfortable between him and the nearest competitor. If there is an early general election potentially before we leave the European Union, he'll have the Brexit party snapping at his heels and splitting his vote, meaning that there could be a pathway through for the Labour candidate, Ali Milani. This would make Boris Johnson the first Prime Minister in history to lose his seat. The media says he's Donald Trump, but the maths says he's John Major. He's in a uniquely vulnerable position as Prime Minister and it's going to take a lot more than canny branding and an acquiescent press to get him out of this particular jam.


This is stock number HA235A. We are here at Summit Automotive in Fond du Lac, Wisconsin. Your new and used Jeep headquarters. Today we are checking out this super clean like new 2018 Jeep Grand Cherokee Limited with the Sterling Edition. From this HD video you will be able to tell that this Jeep is like new all the way around. Very very clean inside and out. It has the satin finished front tow hooks, bumper valance, border and it also has the seven slotted grille with that satin finish. You get the satin finish around the projector lamp fog lamps. You get the LED running lights and projector lamp headlamps. Bright white is the color on this vehicle. We shoot all of our videos in 1080p so if you have HD capabilities on your computer tablet or smartphone device, turn them on right now because it is like you're right here looking at the vehicle with me. You get these satin finished painted alloy rims. These are 20 inch rims and they have Bridgestone Acopia 26550R20 tires on them with just about all the tread left. Very good looking rims for this Sterling Edition. Those rims are special for the Sterling Edition. As we come around the front here, once again, no dents or dings on that hood. The grille and front bumper is in excellent condition. No dents, dings, cracks or scuffs on it. Passenger rim is absolutely perfect as well. No scuffs or scrapes on that and as you go down this side of the vehicle, you can see just how clean the body is, how reflective and mirror like that paint is. We take these HD videos so if you are far away or even if you're close by and just cannot make the trip down, you can still see the vehicle, hear the vehicle and have confidence in the vehicle that you're looking to purchase before you even get here. Roof is in excellent condition and I didn't see one single dent or ding down this side of the vehicle. Especially high ticket priced item like this, you don't want to make sure that it's everybody's clean as you hope it is. Back tires have just as much tread as the front tires and there are absolutely no scuffs or scrapes on that back rim. As we come around to the back of the vehicle, you can see it has a dual rear exhaust, the towing package which includes the receiver, 4 pin and 7 pin wiring and that is a factory tow package which means that you get the rear load leveling suspension on this vehicle. LED tail lamps, the rear gate is in excellent condition and you get this really cool 25th anniversary Grand Cherokee badge back here and that is part of the Sterling edition. Power lift gate, back storage area is very very clean. There are no rips or tears in the carpeting back here. This one comes with the 9 amplified speakers with the subwoofer and it has the spare tire with the jack tools back here as well. Those seats do fold down for extra storage and to put this gate down you press that button. It will be bet you three times and then make its descent. Back up sensors, also part of the blind spot and cross path detection system. For full disclosure this back rim is in excellent condition as well and I did not see any dents or dings down this side of the vehicle. So in addition to the satin finish and the rims and the rear badge you get the special black leather interior. So it's got this neat bolstering right here and here, part of that Sterling edition. Normal limited do not have that bolstering. You get the power driver seat, both these seats are heated. Factory floor mats throughout, memory driver seat, power windows, power locks and power mirrors. You get the nice dark charcoal wood grain trim. Auto headlamps, you also get the power tilt and telescoping steering wheel. And as we hop inside the vehicle here you can see that this Jeep has 1,898 miles. You get the 7 inch TFT display with the digital speedometer, outside temperature display. Time, you can do compass, you can do miles to empty, you can do miles per gallon. Whatever you'd like to do on that display you can pretty much do it in all the corners. It has the heated leather wrap steering wheel, no rips or tears on this. This vehicle has never been smoked in, locally owned, always serviced here. Purchase brand new from here, you have Bluetooth and cruise controls. And these are your information center controls for that center console. You also have the factory 8.4 touchscreen radio. This is the 4C radio which gives you the factory navigation, but it also gives you Android Auto and Apple CarPlay capabilities. AM FM and Sirius XM radio capabilities as well. And this is also where your backup camera is. You can do your heated seats right here as well. And you can check out the backup camera without actually putting it in reverse. You have the Quadra Track 2 system here which gives you four-wheel drive low, snow, sand, auto, mud, and rock, as well as the neutral feature and downhill assist control. Key fob has the enter and go system, keyless entry, keyless remote start, and the power lift gate buttons right there as well. You get this neat kind of, not really sure what it, what you'd call it, but it's a textured finish on the dash here. I believe that's special to the sterling package as well. Pass and receipt, no rips or tears on that. And finally we have the Power Vista Roof slash Sun Roof. So that shade opens up all the way to create a nice airy space inside.  And you have SOS and assist buttons in the mirror. We'll take a quick look at the back seats and then we will check out under the hood. Back seats are just as clean as the front seats, no rips or tears back here. These back seats are heated as well.  Factory floor mats throughout back here. There are your heated seat buttons to USB jacks and 115 volt, 150 watt plug-in back here. So these seats go down like so and they go down very nice and flat, which is nice if you've got a haul of extra stuff. We'll take a quick look at the back seat or under the hood, I'm sorry. Under the hood we have the 3.6 liter Pentastar V6 motor with start-stop technology. Engine-based, very clean runs, very smooth. This vehicle has been fully safety and inspected by our service shop. All the fluids have been checked and topped off and this vehicle is 100% ready to go. To see more pictures of this Jeep or one of our other 400 new and used cars, trucks, SUVs, minivans, Wranglers, halftons, three-quarter tons, one tons, you name it, we got it.  Videos of every single used vehicle that we have all at summitauto.com. Thank you so much for checking out the video. If you want to make this one yours, give us a call right now,<PHONE_NUMBER>. Ask for one of our sales associates to make this Jeep Grand Cherokee Sterling Edition yours today. Once again, that number is<PHONE_NUMBER>. Thanks again for checking out the video. And if you'd like to check out more videos, you can go to youtube.com. Remember to like, subscribe, and share on this video and all the videos that you see there. In fact, in a second you will see a link to subscribe to our YouTube channel on your left. A link to more used inventory videos like this one on your right. And if you haven't been to our website, on the bottom link to this vehicle on our website, click those check us out and we really look forward to helping with this super clean Mike New 2018 Jeep Grand Cherokee Limited Sterling Edition. Thanks again.


I hope you are having a good summit so far, good evening to you all and a very warm welcome to all the attendees joining this event virtually. I am Park Guzmami and today I will be trying to highlight some of the open source CNI plugins and their approaches towards IP address management and container networking. Now before I start my talk, I wanted to highlight that networking is one of that aspect in the container or maybe even cloud computing that is open, often overlooked maybe because of various, maybe it can be a bit complex topic to some of the folks or they might be scared, I mean towards the networking apart for various reasons. So this is one attempt to make it a bit simplified and I am going to give a very high level overview about the topics and concepts that we are going to touch. So the approach that I am going to follow today is, so we are going to talk about adapting open source CNI plugins for IPAM, we are going to start with understanding in brief what CNI is, we will touch the topic about plugins, what exactly plugins are, we will try to understand what IPAM is and then we will focus on the need to adapt the open source CNI plugins. Alright so the textbook definition given by cloud native computing foundation about CNI is that it is a specification that defines how to configure networking for Linux containers. Now it does that by providing a set of APIs for networking solutions to integrate with different container run times. Now if you take a look at the pick over here, there is container run time of your choice and then the CNI sits on top of it and within CNI it ships lots of components called as plugins. Now what exactly these plugins are, so before we take a look at plugin let us try to understand a bit more about what exactly CNI does and how it does whatever it does. So for example if I need to establish a network within a container, I need to have its own network namespace. So I create a network namespace, now once I have that I need to create a bridge between the host network namespace and the container network namespace, once I have the bridge I create a couple of virtual Ethernet pairs via virtual because we are dealing with containers and not like virtual machines or physical hardware. So any Ethernet any networking component that we will be dealing with is going to be virtual. So we create virtual Ethernet pairs and then we attach one end of it to the networking namespace and attach one end of it to the bridge and once we have that we finally assign the IP address to uniquely identify that pod and we bring up the interfaces and this is how the interface comes up and the pod goes live. So this is a sample kind of a algorithm sample code sample program to achieve certain steps to achieve a certain desired result. Now this exact same requirement is there for almost any other container orchestration RKT, Docker, Mezos, Kubernetes. So why not we kind of create a standardized version of it and then try to ship it with any other orchestration. So the very thing of creating a standardized version of it, creating kind of a library of it is called as a plugin. So before we move on to plugin, let's try to understand that if we want to create our own CNI, what it must do or what are the absolutely most necessary roles that this CNI should perform. So I don't want to bombard you with a whole lot of theory. So I'll just highlight a couple of points from this must have roles. So it must be able to create a network namespace as we just discussed, then it must be able to identify the network of the container and it should be able to deal with the bridge. If we are adding container or deleting container, then it should deal with one of the output format. It must support command line arguments so that we are able to fire the commands and interact with it through our CLI. It must be able to manage the IP addresses, which is the exact topic of this talk. And it must return the results in one of the desired output format, JSON, text, tabular, whatever it is. So if any CNI is able to do some of these roles or majorly all of these roles, I think that would be a pretty good thing. Next, so what we have seen so far is the textbook definition provided by CNCF of what CNI is. Basically, a plugin is a collection of program or a code. So here you see a few examples of plugins such as loopback, bridge, PTP, Mac will land, IP will land, and then there are many third party plugins as well. So examples of third party plugins that has been adopted or that has been accepted by Kubernetes is Calico is there, Vibnet is there, Flannel is there, Cilium is there. So just to give you a brief introduction about all these third party plugins, so Calico is a popular CNI tool that deals around network security based on cloud native architecture. And it is mostly used in the enterprise version, enterprise level environments, Flannel is something that is simple and lightweight and very easy to install, but it is mostly preferred for small scale clusters and not something that is larger in size. Then we have Vibnet, it is into providing network automation and observability features and then we have Cilium that is basically based on the identity based access solutions. So these are all open source CNI plugins and since they are not maintained or developed by CNCF itself, they are third party. Now let's try to understand what exactly IPAM is. Now here I'm not touching IPAM from the Kubernetes or from the continuous point of view, I'm just talking about the simple plain IP address management. So basically it means that if you are doing something which falls under assigning, monitoring, tracking or managing IPs, you are kind of dealing with IP address management. So it's not that you have a device, either virtual or a physical device, you assign an IP address and you just go about it. No, it's not that because at your level, at an individual level, you're dealing with just one device, but at an enterprise level, you are dealing with huge clusters which might have thousands of nodes and it's a combination of nodes, virtual node, physical node, etc. So you need to have a proper procedure set, a methodical system which will define how your assigning of IP address will work, how the tracking of IP address is working, whether the device is, if it is not in function, whether the IP address is being revoked or not, it should not be reused. So all this mechanism needs to be there properly being set and defined. So that is basically what IP address management is and it is basically an integrated suite of tools. And it also like encompasses the concepts of DHCP and DNS. Next, now with respect to Kubernetes, what exactly IPM is? So Kubernetes also relies on IPAM. Since Kubernetes mostly works at the cluster level, it needs to manage or deal with thousands and millions of containers, pods, and it requires those many IP addresses as well. So there is no option for Kubernetes to skip IP address management. So it needs, it requires IP address management and it definitely relies on it. Now Kubernetes has its own inbuilt tool to manage IP address, that is Qproxy, but definitely that comes with certain limitations. Now before that, in Kubernetes, each pod will require its own IP address to talk to each other, I mean to talk to other pods, to talk to services, and to talk to external network. So if IPs are required for so and so reasons, then IP need, the addresses need to be managed. Qproxy is something that is actually handling the IP address management, but the limitation is it can't scale. So it works, it works fine, it works efficiently to a certain extent. But once you cross the, cross its threshold, I'm not sure about what the threshold is, but if you cross it and move to a very large complex cluster, or maybe a very complex topology of network, then Qproxy seems to not, seems to not work efficiently. So that is the main limitation of the current by default IPAM plug in that, that Kubernetes has. Next, so then there are some challenges presented by IP exhaustion. So basically what IP exhaustion is, back in 1980s, when we came up with this concept of IPv4, it was divided, I mean it is divided into four blocks of 8 bits each, 32 bit. So back then, everybody thought that this many millions of IP addresses or billions of IP addresses would be enough. But then within 10 to 15 years by late 1990s, it was very clear that those many IP addresses would not be sufficient because it is not about an IP being used by a single user, it is about an IP being used by a single device. And it was very clear soon enough that a single person can, would need or would require multiple devices. So in our day to day life, we are, at an individual level, we carry phone, we connect our laptops to VPN, we have a number of devices. So each and every device at any point would have at least two to three IP addresses. If you just check about the ethernet that you have, you would see the number of IP addresses being consumed at the individual level. Now just extrapolated to a scenario where you are running enterprise level clusters and you would understand that the need of IP addresses is actually a very complex issue and it's something that needs to be managed very efficiently. So there are, so this causes IP exhaustion and there are some problems or some challenges that is presented by IP exhaustion, the first is network congestion. Now since the IPs are getting exhausted, the pods in the Kubernetes cluster would compete to have the same IP address or compete to have the IP address from the same pool and that might result in network congestion. That might result in potential downtime or maybe service interruptions. Now that can be a result in factor in network congestion. Then there is security risk if IPs that we are adding or the IP addresses are exhausted. It can be tempting for the network administrator to reuse the IP address. By reuse, what I mean is if there was an IP address that was assigned to a pod, the pod gets killed or whatever, the IP gets released to the pool. Now before the IP was properly released, the admin ends up using it or assigning it to a new pod. So that might lead to having the live access to the previous pods sensitive information. So that poses like a sensitive, like a security risk. Next is difficulty in scaling. Since my pool itself has, for example, 100 IPs and my cluster demands 500 pods or 1,000 pods, that definitely would not allow me to do so. So if IPs are getting exhausted, my cluster would not scale the way I would want it to be. And then increased complexity, in case of IP exhaustion, if my pool itself is having less or limited number of IPs, it is the network and admins would be tempted to go for much complex solutions, such as netting or maybe go for overline networks, such kind of complex solutions. So there are much more challenges by IP exhaustion. So let's see what can be done about it. Okay, so this brings us to the main topic that because Kubernetes uses, by default, Qproxy and Qproxy comes with its own limitation. Hence, there is a need for the Kubernetes itself to adopt open source based CNI plugins. Now, there are various third party CNI plugins in the market, in the market space that approaches FAM differently. So let's understand what exactly the limitations of built-in plugins as of there is. So there are a couple of plugins, Hostlocal and DHCP. So Hostlocal plugin assigns IP address from a predefined pool. This approach is good for smaller cluster, but once we go at a bigger level, it will surely cause problem. Then DHCP, IPame assigns IPs to pod using DHCP IPame plugin. It can be good enough for a large cluster, but it needs an overhead, like a DHCP server. So again, we don't want such overhead. Now, one of the IPame or one of the third party CNI plugin that I have been working on and used is Calico IPame. It is a completely open source plugin and it has certain key features that because of which it is being widely used as one of the most sort of network plugin. It uses distributed IPame architecture, meaning for every node, there would be a separate and specific IP pool, not at the cluster level, but at the node level. So this ensures that the IPs can be assigned or allocated to the pods residing on that node very efficiently and quickly. And it doesn't need a centralized server, like the DHCP IPame. Since the IPs are allocated at the node level and not the cluster level, it doesn't require a centralized server. And if the local pool itself gets exhausted, it can request for more IPs from a central pool managed by Calico IPame control itself. Next, Calico IPame supports network using BGP, Border Gateway Protocol. This allows network admins to segment their network into different subnets. Now, this segmentation can come from the request by the application itself or from the maybe there are some security concerns that needs the segmentation. So this allows the network admin to enforce some traffic related policies. Then it also support, it has support for network security, network security such as policy informant and encryption of traffic between pods. So these features ensure that the cluster is compliant with industry standard, along with handling the management of IP addresses. Yeah, so that was all about the topic. And if you want to check out more about this Calico open source or Calico approaches IPame, if you wish to contribute more to this project, just check out this GitHub repo. And there is also a program being run by Calico called as Calico Big Cats, where you get to meet the maintainers, the developers on a monthly basis. And you can just try to understand more about the project and be involved at a very deeper level. So this is the recap. We saw about what CNI is, what IPame is, what plugins exactly are, then what are the current challenges faced or presented by IP exhaustion, how Kubernetes is dealing with IP management and what are its limitation, and what features or what solutions third party open source plugins such as Calico present. So yeah, so that was all about it. And I am Parth Goswami, I work as a customer enablement engineer at Cloudera and also am a Calico community ambassador. And that is my community platform where I regularly write blogs and share my open source stuff. So yeah, thank you, that's it.


Well, good afternoon everyone. I'm Eric Green, Director of the National Human Genome Research Institute, and I want to welcome all of you to the one and only annual lectureship we host at NHGRI each year, and that's the Jeffrey Trent Lecturing Cancer Research. I'm going to just briefly tell you about the history of this lectureship, and then I'm going to turn this over to Dan Kaster who introduced today's speaker. The intramural program of NHGRI was founded in 1993, when Francis Collins arrived on the scene to be the director of the institute. But upon arriving here, what Francis did was to create an intramural research program at the institute which previously did not exist. And he recruited Jeff Trent, a colleague of his from University of Michigan, to come here and to be the first scientific director, in other words the director of the intramural program at NHGRI. In turn, Jeff recruited a number of people, including myself, to the intramural program, and the rest is sort of history. Jeff was responsible literally from building the program from essentially a non-existent program, recruiting a number of individuals and ably leading the program for the better part of nine years, and really taking it from just complete sort of conception of an idea of having an intramural program dedicated to genomics to actually having been a thriving intramural program that I think has greatly influenced this entire campus through the expertise it's been able to provide in genomics and its application to study human disease and eventually clinical medicine. So when Jeff departed in 2002, I was appointed the scientific director at that time, and one of the first things I did was to start a lecture series that would honor Jeff and to, as much as anything else, just thank him for everything he had done. And so we created the Jeffrey Trent Lectureship, and we focused it on cancer research, and since that time there has been just a remarkable set of lecturers who have come and given that lecture, and it's been just wonderful to see a number of people just sort of come through and give talks really at the inner failure phase of cancer and genomics, something that Jeff was and continues to be passionate about and a real expert in, and it's sort of his legacy in terms of providing leadership to our intramural program very much is reflected by the type of people we're consistently able to attract to give this annual event. So with that as a historic background, I'm going to introduce you to the third scientific director of NHGRI, and that's Dan Kastner, who will introduce today's speaker. Thank you for coming. Well, thanks very much, Eric, and it's my enormous honor and pleasure this afternoon to introduce to you Dr. Catherine Janeway. Dr. Janeway is currently a senior attending physician at Boston Children's Hospital in the Dana-Farber Cancer Institute. Dr. Janeway did her undergraduate work at Barnard in New York, but then went on to Boston where she has been ever since, and she did her medical school training at Harvard Medical School and also got a master's in medical science there at Harvard Medical School as well. She did a pediatrics residency at Boston Children's Hospital in the Dana-Farber and went on to become the chief resident in pediatrics and then did her fellowship in hematology oncology at Boston Children's and Dana-Farber and she has begun to join the staff there at Boston Children's and Dana-Farber and she has become an absolute leader in the application of genomics to pediatric hematology oncology and during the course of the 10 years that she has been on the staff at Boston Children's and Dana-Farber she has become the program director for solid tumors at those institutions. She has become a real leader in Ewing's sarcoma and osteosarcoma. She is the chair, co-chair of a number of different national consortia and collaborative studies looking at ways of improving the treatment of those diseases and she has really been someone who has taken the lead in terms of applying genomics to these very important problems in pediatrics. So, without further ado, I will give you Dr. Jane Way, the title of whose talk will be Bringing Genomics to the Pediatric Oncology Clinic, Diagnosis, Treatment Selection and Rational Clinical Trial Design. Catherine, take it away. Well, thanks very much for the introduction and for the invitation. I'm delighted to be here to speak with you today.  And then I'll try to sort of concisely wrap up what we've learned from the clinical sequencing studies that have been conducted to date in pediatric oncology and how they inform precision trials. And then I'd like to give you a sense of where we are in pediatric oncology in terms of precision cancer trials. And I'll touch on a couple of different approaches to that. One is to discuss basket trials and relapse disease using the example of the pediatric match. And then I'll touch on two alternative precision trial designs. And then finally, I'll end the talk with a brief discussion of what's going on in the data aggregation or big data analytics space in pediatric oncology. So, I think I don't need to just really convince this audience of the importance or significance of precision cancer medicine. But I pulled a couple of recent examples just to kind of bring it to the front of your mind. And the first on the left here is a very recent publication in the Journal of Medicine demonstrating that in women who have germline BRCA mutations who have newly diagnosed metastatic breast cancer who are randomized to receive either Elaprib, which is a targeted therapy in this disease, or standard therapy, there's a significant improvement in progression-free survival. And Elaprib is a drug that has been studied in the sort of relapse and refractory setting for quite a long period of time in the BRCA deficient cancers. And it's really, I gave this example primarily because it's nice to see this work moving into the upfront treatment setting. And then the second is a very well-known example of really unbelievably dramatic and frequent responses to PD1 blockade in mismatch repair deficient cancers leading to the first FDA approval of a drug for a genomic biomarker. And it's really gratifying to see the sort of beginnings of examples of these types of precision cancer medicine successes in pediatric oncology. This is a slide taken from the ASCO 2017 annual meeting from a presentation of a Phase 1 trial of Lerotrectinib which is a TREC inhibitor in TREC fusion positive malignancies. Turns out that TREC fusion positive malignancies span the age range. And what was incredibly significant for those of us in the pediatric oncology community was to see that the Phase 1 trials in adults and pediatric patients were conducted simultaneously and presented together in a very nice plenary presentation. And this is just a case example of a dramatic response and if you look at the timeline this is the patient at baseline and after four doses of the drug. So it's an incredibly effective targeted therapy and it's really nice to see that our pediatric patients did not need to wait to access this clinical trial. So you know that just hopefully brings to the forefront of your mind why we're here talking about bringing genomics to the clinic and now I'll throw a little bit of cold water on that. So this infographic is beautifully simple and very logical. Patient A has mutation A, gets drug A and has this dramatic response. But I think what we've learned from bringing genomics to the clinic is that the devil really is in the details. It's not that simple. And just to begin there's an incredibly important issue in this field that adds to the complexity is somatic variant interpretation. And so when you draw this nice infographic there are a couple of assumptions that are made, right? One is that mutation A is a well known or well characterized mutation that you know what it's doing to the protein that you know what that protein is doing in that particular cancer type that's sort of undergirded by a huge amount of basic science research that this line between mutation A and drug A is a strong and forceful line meaning there's a ton of evidence that supports a link between this mutation and activity of drug A. But in fact, we really don't we work in a space where when we're bringing genomics to the clinic we often get mutations where we're uncertain about the type of mutation the line drawing the line between this mutation and a drug that's sometimes difficult. And finally, you have to consider the drug itself. Is it really a targeted therapy, right? There are many drugs that are thought to be or that are called targeted therapies that may in fact have off-target activity. And so we really in this field of precision medicine have only just now begun to approach the sort of difficulty of characterizing the somatic variants and what they mean for the patients both in the space. So this I'm showing you now a publication in genome medicine that came from the ClinGen somatic variant working group which basically tries to break this down. And so this is the sort of characterization labels that have been used in the germline space for variants and really they've been posed using these characterizations in the somatic space. And if you have a pathogenic mutation meaning it's likely to alter protein function that you think about the implications in the diagnostic, prognostic and predictive meaning prognostic sorry predictive space. But what's really important in this schema in several other schemas that recommend make recommendations about how to do somatic variant interpretation is the evidence piece, okay? So what do you mean by evidence? So there's evidence about the variant and then there's also evidence about that line connecting the variant to the drug in that example mutation A to mutation B. And that evidence can be preclinical evidence, it can be a case report or it can be a randomized clinical trial. And the reality is that in the pediatric oncology space and also in other rare cancers we're very often operating in a realm without sufficient evidence. I didn't really talk much about germline variant interpretation, I just want to say there are more better established criteria and terminology for variant classification, but germline variant interpretation still requires time and appropriately trained personnel. And so the whole both somatic and germline variant interpretation can be difficult. And then to add to the complexity of sort of bringing genomics to the clinic in pediatric oncology are some aspects of the pediatric cancer genome. So I think all of you know and are familiar with this diagram from Bert Vogelstein's review and science and there are other pictures of this that show that the pediatric the cancers that tend to occur in the pediatric age range have a very low number of amino acid changing single nucleotide variants or indels. And so where adult cancers have sort of 1 to 10 mutations per megabase of DNA pediatric cancers even those with a high mutation rate have about 0.4 to 0.5 mutations per megabase of DNA. And some pediatric tumors have very few mutations and the best example of that is rabdoid tumors. However I would like to point out that it may be that other genomic mechanisms that are not detected by whole exome sequencing which is what most of these types of figures are based on may in fact be present and may in fact be targetable. So some have interpreted this lack of mutations to mean that there are more limited opportunities for practicing precision medicine in pediatric oncology. Others have said well if you find a mutation it's more likely to be a driver because there's less noise. So in fact pediatric oncology is the ideal circumstance in which to base therapy on the genomic mutations that you find. In fact we have taken a slightly different interpretation and that is really demonstrated by this figure which is from one of Mike Lawrence's recent pan cancer papers and that perspective is that we know very little about the genomes of most of the cancers that occur in the pediatric patient population. And basically what this figure shows is that the ability to detect recurrent mutations at the level of somewhere between 1 and 10 percent when you're doing a sort of discovery sequencing study depends on the number of tumor normal pairs sequence and the baseline somatic mutation frequency. And while pediatric oncology has a number of quiet tumors so the baseline or the background somatic mutation frequency is low our diseases are incredibly rare. And in fact the only disease in pediatric oncology that doesn't meet the NIH definition of a rare disease is leukemia and the only other disease that's been had a relatively large number of tumor normal pairs sequenced over a thousand is neuroblastoma. In fact, most of our cancers are like the one shown in this study and circled here in red where the number of tumor normal pairs sequenced to date is too few to say with any confidence that we've ruled out the possibility of a recurrent somatic mutation present at the frequency of 5 to 10 percent. In addition we have sequenced very few tumors from relapsed or refractory disease. And so really this is the simplistic way of saying that what we know about the pediatric cancer genome is really the tip of the iceberg and I promise that at the end of the talk I will come back to sort of how additional sequencing efforts discovery sequencing efforts like the target project and the pediatric cancer genome project led by St. Jude are hopefully going to help us move beyond this. But because we understand so little about the pediatric cancer genome the key question that we really wrestled with and continue to wrestle with is is it possible to extend the successes of precision medicine to pediatric patients with cancers where the key gene variants are not yet known. And at the time that we started wrestling with this question we were I was fortunate to be at the Dana-Farber and Boston Children's where an institute-wide project called the data file had been launched. This is an enterprise level research project between three hospitals Dana-Farber Cancer Institute Boston Children's and Brigham and Women's and it started in 2012 and essentially all children with cancer or suspected cancer seen at Boston Children's or Dana-Farber offered the opportunity to participate. And participation allows use of clinically acquired left over specimens for research sequencing for research which includes sequencing. We have pilot study in solid tumors where we have actually allocated some samples for creation of patient-drive models including cell lines and PDXs you can ask me questions about that at the end I won't touch on that more in this talk. It allows us to collect blood, cheek swabs and urine for research to use specimens and derivatives and place them in a tumor bank which is a virtual tumor bank so you can actually select the actual physical tumor bank and then the genomic data can be linked to clinical data for research purposes. Patients who have within this project or this study patients who have greater than 10 FFP unstained slides with 20% viable tumor have a sample submitted for tumor-only sequencing performed in a clinical lab and results with potential clinical impact with potential to impact clinical care or return to the primary oncologist and the patient. I will come back later to sort of where we are with this study but when this study started we sort of looked around and thought to ourselves if we do this at the Dana-Farber only we will never learn anything or at least it will be a long time until we learn anything from this project and I'm very impatient and so we actually launched a multi-institution study that's based loosely on the profile study. The sequencing test that is performed within profile and multi-institution study I'll tell you about is called Oncopanel. The sequencing success rate is very high it's 96% we use FFP as our sort of starting material the results are concordant with gold standard assays and it's both sensitive and precise. And it's performed in the center for advanced molecular diagnostics at the Brigham and Lemons hospital. There have been three versions of the Oncopanel test I'm showing you the 450 genes included in the most recent version these the top genes are sequenced for coding region changes and there are 60 genes where we capture across the introns so that we can identify translocation events. The report generated from the center for advanced molecular diagnostics includes a diagram of the copy number alterations the variants are tiered based on sort of loosely defined criteria of clinical action ability and because this is tumor only sequencing I just want to point out that if particularly if a patient is of a non-caucasian ethnic background there will be a large number of tier 4 variants which are primarily rare germline polymorphisms and then there can be interpretation provided for the variants and the extent of interpretation is variable depending on who's signing out the report. As I mentioned we decided that we would actually like in pediatric oncology to conduct this project as a multi-institution study and this is actually the first multi-institution precision cancer medicine study in pediatric oncology and we called it the individualized cancer therapy or ICAT-1 study and our goal was to determine whether it was feasible to identify key gene variants and make what we called individualized cancer therapy or ICAT recommendations using the clinical sequencing test that were available to us at the time. Patients were eligible if they had high risk extra cranial solid tumors and we allowed patients to enroll up to age 30. The tumor samples used for sequencing were as I mentioned sort of clinically acquired meaning they were sitting in the pathology department which most often means that they are paraffin embedded samples. We accepted samples from diagnosis relapse and preferred to have paired samples if possible. Tumor was subjected to mutation detection was performed using the oncopanel test and I forgot to mention it's a target capture followed by you know next generation sequencing using alumina. We did perform a race CGH when there was sufficient tumor material for additional assessment of copy number changes and then occasionally would do sort of follow up test if that was recommended by the expert panel. We had an expert panel or a molecular oncology tumor board that reviewed the results for clinical significance. We made an ICAT recommendation if there was a variant present that we thought was likely to alter protein function. Other people have called that pathogenic. We prefer to use the term altering protein function that we thought was that there was sufficient evidence to support that it might actually be involved with cancer related behavior. We needed to have we sort of tiered the ICAT recommendation depending on what evidence linked that variant to response to targeted therapy and we only made an ICAT recommendation if targeted therapy was actually available meaning that there was a dose in formulation that was appropriate for that patient. Our tiering system was we used tiers one and two. If there was clinical evidence supporting the link between the variant and response to targeted therapy, tiers three and four if it was preclinical evidence and tier five if we just thought it was a good idea because you always need that basket for consensus opinion. We issued what we called an ICAT report and sent that back to the patient via their oncologist. So in terms of results the first results that was really notable and was not known at the time was that there was a high degree of physician and patient engagement in a study like this. So that graph appears are the blue is our projected accrual and the red is our actual accrual. The second was that we actually could do this as a multi-institution effort in that 40% of the enrolled patients came from our three collaborating institutions and the first sort of take home knowledge was that 30% of the patients participating got what we called an ICAT recommendation and this has been published for some time now and you can look up what those recommendations were based on but loosely it was actual single nucleotide variants or indels, copy number alterations and then various rearrangement events. An additional 10% of patients had results that had implications for patient care and I'll go into that more in the next two slides and then we had someone from our population sciences department working with us who conducted surveys of the participants in this study and over 90% of the participants recognized that they were doing participating in this study to further our knowledge of cancer care which is how we explain the study to them and more than 90% said they would participate again. Okay so going into that additional 10% who had results with implications for patient care the first we found that 10% of the patients on tumor only sequencing had a somatic result that suggested the presence of a germline cancer predisposition syndrome but we did not do germline sequencing so it's actually better to turn to Will Parsons study which was one of the CSER funded projects called basic three where he actually enrolled a very similar patient population in that they had solid tumors so no hematologic malignancies but he enrolled patients at initial diagnosis and they did clinical sequencing using whole exome sequencing of tumor and germline and in his study he identified 10% of patients had true inherited cancer mutations those are the sort of known pathogenic mutations and this has been shown in subsequent studies as well and so an important lesson from these initial set of studies is that germline cancer predisposition is much more common in pediatric oncology than we previously appreciated so there were a few other patients who had interesting results that had implications for Karen and this slide really highlights that group of patients we did a pilot study where we selected nine cases for RNA sequencing and we based that selection on patients having undifferentiated sarcomas or translocation associated sarcomas where the translocation was not identified with standard testing in two of the patients the expected translocation was identified so that helped us to clarify diagnosis and in three patients translocations were identified that had either potential therapeutic or diagnostic implications for example a patient who was thought to have had Ewing sarcoma actually had a variant EWSR1 translocation that is associated with other diagnoses we had a patient who was diagnosed with melanoma who in fact had an EWSR1 ATF1 mutation which is much more consistent with the diagnosis of cutaneous clear cell sarcoma and then a patient who was called intermediate grade spindle cell sarcoma who because they had an ETV6 fish a break apart fish that was negative and this is the test that is typically done for infantile fibrosarcoma in fact they had an Ntrek3 fusion it was just a fusion with a different fusion partner EML4 and so in reality having an Ntrek3 fusion with an intermediate grade spindle cell sarcoma is infantile fibrosarcoma it's just that the standard test was unable to detect this novel fusion and so the lesson here is really two fold one is some of the genomic sequencing results you know we sort of got into this because we were interested in precision therapies but in fact we're starting to learn that genomics can help us with precision diagnosis but in addition we while some of these fusions could be detected by our current panel test some additional fusions that we found are unable to be detected that way and so the use of RNA sequencing in this way really highlighted the fact that it's really not yet known which tumor profiling assays optimally balance the competing factors of minimal tissue requirement comprehensive genomic assessment and rapid data analysis and results reporting so and then finally you know everyone's interested to know in our study how did the patients do right who got matched therapy right you have 30% of your patients who had an eye cat recommendation well it turns out that we had a relatively short follow up time of only six months and only three of the 31 patients who got eye cat recommendations actually got targeted therapy matched to the eye cat recommendation we did a little physician survey which of course had a low response rate asking why or why not did you give matched targeted therapy in some cases the expert panel had reviewed the case and you know theoretically a clinical trial was available but in reality for the patient that clinical trial wasn't available we didn't have access to sort of all the criteria for eligibility for that particular patient in other cases the clinical status was not what it needed to be in order for the patient to get therapy in some cases the patient was in second remission with standard relapse therapy and in some cases the disease was too advanced or the patient was deceased similar results were found in another clinical sequencing study that came out just before ours this was another NHGRI Caesar funded study conducted at the University of Michigan in which patients with all diagnoses were had clinical sequencing done using whole exome sequencing tumor normal pairs in this case as well a very small proportion of patients got matched targeted therapy and I think really we've learned in this field that this magic sweet spot that's required to receive matched targeted therapy where the gene variant is identified the patient has an appropriate clinical status and the drug is available is relatively rare and it's hard to make this happen and so we have we think that future studies in this space need to assess reasons for failure to receive matched targeted therapy and really importantly in pediatric oncology particularly we need more trials of targeted therapy where there are biomarker criteria for trial entry oh by the way none of the three patients responded we can talk about that more later if you want to ask me questions about that so I've told you about sort of the first three clinical sequencing studies that were published in pediatric oncology they all have very consistent results the sort of 30 percent rate of potentially targetable or potentially actionable variants germline cancer risk and this sense that there's probably more in the genome than what you can find by just looking for SMVs and indels there are additional clinical sequencing studies that have been published since then I just give you a list of those here but again the findings are very similar but we still have an answer question the first is our I should just emphasize here that the majority of these studies have primarily patients with either intracranial or extracranial solid tumors and the leukemias the feasibility of doing clinical sequencing returning results and looking for sort of match targeted therapy has been much not as well studied in the hematologic malignancies that's there I think there are a number of reasons for that some of it has to do with the pace of disease and relapse hematologic malignancies some of it has to do with the possibility of bone marrow transplant for those patients but I actually just want to point out that Minyon Lo and Kim Stegmeyer at UCSF and Dana Farber have collaborated with a number of other institutions to do sort of a very similar feasibility study that's focused on high risk leukemias and relapse leukemias and there's the clinical trial identifier for that the second unanswered question is what is the actual impact of receiving much targeted therapy on outcome so none of the sort of feasibility studies really answer that question they don't even we didn't even propose to try to look at that question in our ICAT-1 study the third I already mentioned what sequencing approach is really the optimal approach and finally I think we really don't yet understand the full spectrum of actionable variants that we see in our diseases so but what all of those clinical sequencing studies do is to provide us with enough evidence to say yeah we can do precision trials and pediatric oncology we think that's a good idea so I'll spend the next 20 minutes or so telling you about the precision trials that are ongoing in pediatric oncology and I'm gonna highlight three examples and I'll start with basket trials and recurrent disease and I'll start with the NCI Children's Oncology Group pediatric match and the first thing I like to say when I get to this slide it's very important to point out I am not one of the co-chairs of this study so if you don't like anything about it it's not my fault I am highly involved I'm the vice chair of the screening protocol and I am very involved in selecting study agents so basket studies are basically trial okay the term has been used loosely so I'll explain this basket trial but basically the idea is patients enter and in this case it's a relapse refractory trial and it's children are eligible if they have relapse refractory solid tumors or lymphomas and that includes histiocytosis which is important because those have activating mutations in the RAF MAP kinase pathway there needs to be some sort of tumor material that can be subjected to sequencing and in this case tumor material that's required needs to be from a relapse or refractory disease state it cannot be the newly diagnosed I'll talk a little bit more about that on the next slide the tumor is subjected to genetic sequencing and the way that this trial is designed is everything up until here where this little box drops down which is actually a targeted therapy trial arm is part of what's called the screening protocol so patient enrolls actually on the screening protocol we collect the tissue we do the sequencing we figure out whether or not there's an actual mutation detected and then we make a match to a clinical trial arm if one of the predetermined or pre-selected mutations is present so then there's a cassette of trial arms and for each trial arm of a targeted therapy the variance that would be allow a patient to get onto the trial are predetermined so this matching is done in a sort of automated fashion although there is human review before the patient is actually assigned to that arm of the trial then the patient is essentially on a phase 2 trial and the primary endpoint of each of those phase 2 trials is an objective response rate importantly some of the trial arms actually allow for enrollment of biomarker negative patients and that was done if there was a sense that there were biomarkers but that we didn't understand the full spectrum of the biomarkers that might predict response to a targeted therapy and I'll show you the example of that when we get to the slide that shows what drugs are actually part of this trial and then one final aspect of the design is that for each of these phase 2 trials of a study agent if there is some signal of activity in a particular histology so if I think it's 3 patients with a particular histology or on that arm and there is a signal of activity you can actually expand the trial for that particular histology so that you get a full phase 2 trial where the patients have a set of variance that predicts response plus a specific histology some more sort of detail about these specifics in terms of specimen requirements this trial actually allows for biopsy to be performed for study purposes if the biopsy is low risk and there's a whole description in the protocol of what that means and there's a good deal of evidence to suggest that complication rates from these low risk biopsies are very low in our patients and are not outside of the realm of the risks that our patients face in everyday care in terms of secondary objectives I just want to highlight a few one of them is that we do have a cell-free DNA objective and what we're really looking at here is the ability to use cell-free DNA to detect the genetic alterations that are present at the time a patient enrolls and then to use cell-free DNA to look for mechanisms of resistance there are three time points when cell-free DNA is collected we are interested in the patients will have germline mutation testing performed and it will be returned and that's because of the importance of germline mutation in these cancers and then finally I just want to mention that the match assay which many of you may be familiar with is using an ion torrent or hot technology and as I already mentioned the reporting which is sort of this automated reporting the results that get returned will either tell you that you match your patient matches to a trial arm and then here are some other variants that were found with minimal clinical interpretation of those additional variants so I am co-chair of what's called the target and agent prioritization committee with J. Cho our charge was to prioritize the most relevant molecular targets and corresponding agents to recommend to the trial leadership for consideration of inclusion as sort of trial arms the members of this committee represent this children's oncology group disease committees the NCI CTAP and NCI match which is we call adult match so match trial being done in adult patients and the FDA basically we went about this in a very sort of like you would a grant review we did a detailed assessment of all the target agent pairs that could be considered and we assigned those target agent pairs to reviewers who looked at all the literature we asked them to consider the following factors how common is the target in the eligible patient population what level of evidence is there linking that target to the agent activity or that mutation to the agent activity the minimum we required that there had to be at least some kind of clinical level of evidence so our minimum clinical level of evidence is a case report and a patient who has a variant in the target gene that's expected to alter protein function who has a response but with that because you can get that randomly right so occasionally patients respond to phase one trials you also have to have really good clinical data that demonstrates the mechanism or the sort of underlying biology that links the variant in that gene to response to that class of agents as I mentioned we sort of had this grand style review we discussed, we voted and then we had co-chair review we assessed the suitability of the match assay to identify the variants in the target gene or set of genes and also we looked at the impact of the trial design on priorities so importantly this mostly came up with the CDK46 inhibitors which were thought to be more cytostatic than cytotoxic and when you have an objective response rate as your primary endpoint you sort of have to think about whether or not you're going to expect objective response rate and then we made recommendations to the match leadership who then there's a sort of follow up process where you engage industry to actually select the agent from that class of agents so these are the initial arms of the NCI COG pediatric match protocol and we're showing you the agent class and the actual agent that's included in the trial and the example that I mentioned that allows biomarker negative patients are the PI3 kinase mTOR inhibitors because there are sort of signals that there might be predictive biomarkers but on the other hand there are certainly patients who respond to this class of agents without necessarily having a predictive biomarker so that basket trial like the NCI COG match trial is sort of what people typically think about when they are thinking about precision trial designs however in medical oncology there's been exploration of a lot of other precision medicine trial designs and I'm going to highlight two that are ongoing in pediatric oncology the first is sort of a real world evidence type of design and the second is a pragmatic trial and the two of them are sort of related to each other the first one is our follow up to the ICAT one study and the second is the American Society of Clinical Oncology what's called TAPER trial after finishing our feasibility study the ICAT one study really was meant to be a feasibility study as I mentioned we felt that there were a number of questions remaining to be answered and a number of investigators at other institutions fortunately agreed with us and we formed a 12 member consortium called the genomic assessment informs novel therapy or gain consortium and our first clinical sequencing cohort study is actively enrolling patients and it's called the gain consortium ICAT two study the title is too long to read so I'll just tell you about it patients are focused on the same patient population as we focused on in ICAT one patients have extra cranial solid tumors that are either high risk for relapse due to their initial presenting features recurrent or we've actually brought in our eligibility just a little bit for this trial to specifically target patients who have an unclear diagnosis after standard histopathology review and molecular testing and the reason we actually called out these patients in our eligibility criteria is we realize they actually fit into this high risk group we actually don't know their prognosis so it's hard for the investigator who's seeing that patient to say they're eligible based on we by the way we define this newly diagnosed high risk is expected overall survival of sorry two year event free survival of 50% or less so that we would include high risk neuroblastoma these patients who have an unclear diagnosis there's no way for the investigator or the clinician to actually decide what their prognosis is but we all have a sense that their prognosis probably isn't great right if we don't know what they have we don't know how to treat them and treatment is the number one prognostic factor so we specifically allow those patients to enroll in terms of tumor profiling we continue to perform primarily on co-panel as our targeted next generation sequence pan sequencing panel test it says here tumor plus normal we are still doing tumor only sequencing because the center for advanced molecular diagnostics timeline for initiating normal on co-panel testing has been longer than we anticipated but we actually have all of our normal samples banked and plan to send them for testing as soon as they're able to do that which they promise me will be quite soon and then we actually have a very complex diagram where we then select patients for either whole exome sequencing and or RNA sequencing depending on what the diagnosis is and just I would summarize that to say we tend to send rare tumor types for whole exome sequencing because we think there's still discovery potential to that approach and we tend to send patients where we think there might be fusions for RNA sequencing and certainly all of the patients with an unclear diagnosis have their tumor sent for RNA sequencing the targeted panel and the whole exome sequencing are done in a clinical lab the RNA sequencing right now is done as research both of the whole exome and RNA seek are done in collaboration with the Broad Institute and we're hoping RNA sequencing will transition to a clinical lab to the clinical side of the Broad Institute before too long one thing that's sort of changed over time in this protocol is that more and more of our consortium partners have their own clinical testing labs now that are doing targeted panel testing or they've developed a relationship with a commercial lab and so we have after much discussion decided that we never want to repeat a targeted next gen sequencing panel test with a similar with a test that covers essentially the same set of genes which many of these tests do and so we actually have modified the protocol so that rather than accepting a sample for testing we can accept a report and data so that we don't actually waste tissue on repeating something that's already been done a very important part of our project is the variant curation that I touched on in the beginning of the talk what is this variant what is it doing to the protein what do we think its role is in cancer and then what we call the clinical interpretation which is determining what sort of clinical significance that variant has for that patient and we make an ICAP recommendation very similar to what we did before continuing with our sort of tiering of the evidence and then what's different in this study is we do quite a bit of follow up data collection of the patient's vital status treatment and treatment responses we do have a self-re-DNA aspect of this project as well we're assessing barriers to receiving treated therapy we are planning to hopefully integrate this project into the collaboration we have with the Broad where we're trying to create patient derived cell lines I was mentioning to a couple of people that to be honest my least favorite part of this project is the piece the informatics infrastructure that's needed to support a project like this so when you're collecting samples from different institutions you're doing testing and you have to return test results you have to make sure you don't lose things and you have to make sure you know how long you've had something so that people are waiting so we learned with our first project that you really need good informatics support for that and that there aren't really products out there that you can just that are off the shelf products that can do this and so we've worked with the University of Chicago which is one of our collaborating centers somewhere here it is and they have a pediatric oncologist who runs an IT group to develop what we call our gain cast and sample tracking or gain cast system which allows us to track everything and return results and even more importantly we've worked with them to develop a knowledge base which is also what we use to create our clinical interpretation reports which we call gain reports and the idea here is really to decrease the burden of that somatic variant interpretation by being sure that we're holding our knowledge and making it easily accessible so we can re-access knowledge about variants and about their clinical meeting in our diseases there are a number of knowledge bases out there my cancer genome is an example it's probably the first one that existed but we don't find them to be that helpful for our cancer types they tend to focus on phase 2 and 3 clinical trial evidence and sort of FDA indicated therapies and we tend to operate mostly in the pre-clinical realm so we tend to find that we need our own knowledge base so our study activated in November of 2015 we were active for about a year with only the Dana-Farber as a site then we had a second site that activated and finally once we got all the lawyers actually working on our project we were able to activate all but the final remaining site and we're now accruing at the rate that we expected to accrue patients we have 200 patients enrolled this gets me back to the point I made in the very beginning pediatric cancers are a collection of rare diseases so these are enrolled patients broken down by diagnosis and you will see that osteosarcoma is the most common diagnosis but our second most common diagnosis is rare this is a collection of single cases of various cancer types and you'll see that not far down is non-rabdo soft tissue sarcoma which isn't actually a single diagnosis it's a collection of rare diagnoses we've completed 137 oncopanels 24 and 23 and RNA sequencing and then we validated two of our RNA sequencing results and we have about 59 cell-free DNA samples collected this is the obligatory slide of the single case which I won't dwell on but just to say we've seen some dramatic responses this is a novel BRAF fusion patient who received a MEK inhibitor which was seen in a neuroendocrine carcinoma again a rare tumor so how are we going to analyze this study what is our primary objective well we are we have a descriptive primary objective we are going to describe progression free survival and overall survival is really where we're going to focus comparing patients who received not matched and matched therapy this is very similar to what was done by the MD Anderson phase 1 program it's not definitive proof that precision medicine works it's really a way to sort of start to explore whether or not this approach makes sense and we think that doing this practicing we also can learn we have a very long list of secondary objectives where we can learn derive key lessons that can really inform future either basket trials or types of precision trial designs so to answer this question some of our patients need to receive matched therapy and you'll remember that on the first study only 3 out of 30 patients received matched targeted therapy so we're really interested in approaches to sort of improving access and that's where this American society of clinical oncology taper or targeted agent and profiling utilization registry study comes in this trial was started to address the problems of patients with advanced cancer having no standard treatment options having had a genomic profiling test performed having a potentially actionable alteration detected and having an FDA approved drug that was available but finding it difficult to get that drug and also losing the opportunity to learn if they did actually get access to that drug so I'll go through these taper slides quite quickly basically this study starts with somebody already having had molecular profiling done deciding to participate in the study if there's a predetermined match to one of the taper arms the patient just goes on that arm if not there is a molecular tumor board mechanism where the profiling result can be reviewed and then the pharmaceutical company actually provides the study drug at no cost to the patient and then the patient is followed for toxicity there are two sets of eligibility criteria one for the general protocol and then drug specific eligibility criteria but important to note that patients who are 12 and older are eligible and that was a sort of policy decision on ASCO's part and patients are eligible if they had solid tumors or B-cell non-Hodgkin lymphoma and the primary objective here is to describe anti-tumor activity and toxicity of commercially available targeted anti-cancer drugs in patients whose tumors have a genomic variant known to be a drug target or thought to predict sensitivity to a drug and the primary endpoint is objective response rate or stable disease at 16 weeks and the sort of statistical analysis plan is to enroll 10 patients per group and the groups are determined by tumor type variant and drug interestingly they're experiencing a very similar very long tail of rare diagnoses that we are and so there's probably going to be some modifications to this plan to do type variant drug they're probably going to have to lump some of the tumor types together the drugs will look very familiar to you there are only so many truly targeted therapies in the world and so many of these precision trials are using overlapping drugs and then so that really concludes the precision trials that I was going to go into in detail but I wanted to point out that there are many ways to conduct research in precision oncology and so there are other basket trials in relapse disease there are disease specific basket trials there are precision trials in newly diagnosed therapy in newly diagnosed parent patients which are primarily in pediatric oncology being conducted in leukemia and there are early phase targeted therapy trials in biomarker positive patients like that Lerotrectinib trial I showed you the image from in the very beginning of the talk and then we spoke about these in detail so in the last two minutes I just want to put a plug in for data aggregation and big data this is not my field so please don't ask me hard questions about this I just want to point out that there are several efforts to aggregate pediatric sequencing data each of them has their own kind of their own approach and their own kind of sweet spot so there's the genomic data commons which is an NIH funded effort which is really focused on the target data set which is the sort of TCGA of pediatric cancers and they are accessing primarily data from our cooperative group trials and are really working on standardization of clinical data elements St. Jude pulls any pediatric data that gets put anywhere into something that they call PCAN which stands for pediatric cancer their ability to achieve clinical annotation is a little bit less because they have incredible computational biology sort of acumen in the pediatric oncology space Gini which is the one that I most involve with is a project that's funded by ACR that's really trying to get clinical sequencing labs that are in hospitals to deposit data and aggregate data it tends to be focused on targeted gene panels the sort of sweet spot here is that there's incredible potential for clinical annotation because the data lives in a hospital space where we have the entire medical record to pull from now how you exactly pull meaningful clinical data from the medical record and annotate it with the genomics is another topic and then finally foundation medicine has actually made its pediatric sequencing data publicly available and I'll just show you a case study using some aggregated data so in the NCI COG match trial I mentioned that we looked for frequent like we wanted variants or targets that were had frequent alterations well we've sort of mined all of those and we have arms for all of those so we're starting to look at what are some of the rare variants that we might see now that we have more sequencing data available to us in these aggregated spaces when you look at that you actually see that there are EGFR mutations in pediatric cancers and MDM 2 amplification by the way this is from 981 cases where the diagnosis would make them eligible for the NCI match trial and the MDM 2 amplification is present at about 2% I'm going back to our profile or institutional study we now have 1200 patients enrolled and about 650 patients have ankle panel results available and we're able to mine those as well and when you look there again you see about one and a half percent of patients with MDM 2 amplification and so you can begin to think about whether or not you want to create another arm of the pediatric match trial that has the ability for these rarer mutation patients to enroll so in conclusion I would say that with the current technologies and understanding of genomics and complement of targeted therapies available many children with cancer still do not benefit from a precision medicine approach but when all aspects of the precision oncology paradigm align clinical impact can be significant for individual patients we have now completed studies demonstrating feasibility and pediatric precision cancer the pediatric precision cancer medicine field is transitioning to evaluating clinical outcome through precision trials and I believe that the number of children with cancer benefitting from a precision oncology approach will increase we'll need continued sequencing particularly of our rarer diagnoses that means anything other than leukemia and neuroblastoma and we'll need to use multiple approaches and sequencing so we can be sure to detect the variants that are not SMVs and indels we will need multiple precision trials with various and innovative designs and we definitely need data sharing and most importantly analysis of that data and so we need more computational biologists who care about pediatric oncology okay because this is the Trent lecture I'm doing an advertisement for Dr. Trent if you enjoyed this talk which I hope you did you can learn more about pediatric precision cancer medicine at a conference Dr. Kahn and Dr. Trent are leading which is going to be in March in Scottsdale, Arizona and it takes a village to do this kind of work and this is my very long acknowledgement slide with my very nice research team pictured down here on the bottom thank you very much for your attention well thank you very much Catherine for that terrific talk that was really fantastic I have just a small token of our appreciation of your giving the Trent lecture this afternoon for you to take with you. Thank you very much and maybe I'll start out the questioning since you wanted to avoid questions on big data and aggregation I'll start there with the interrogation but maybe an easier question it would seem like you know using the analogy of the tip of the iceberg there probably are lots and lots of cases out there where sequencing has been done in the United States but where those data have not yet been incorporated into this analysis. What do you think the magnitude of that is and what are the opportunities even internationally to increase the number since it clearly is the case that this is a matter of numbers to help things along. Yeah that's a great question I it's interesting I mean there aren't that many places that are doing the kind of sequencing that is high enough quality that we really want to see it so or that we want to use it for analysis so I think that the majority of those places are depositing their data somewhere the question is can you get it all in one place and can you stimulate sort of computational biologists to really work with that data and discover now I think that's true in the U.S. internationally is another question Europe has a very cooperative approach to this and they will have plans for data aggregation where I think that we have not made great efforts or at least I am not aware of great efforts is sort of extending beyond Europe and there I think there's probably potential for aggregation. Of course there's huge capacity sequencing capacity in China. Yeah exactly. Where one would think that a lot of opportunities. I think one of the challenges or one of the hurdles has been concerns about consent and that I think is actually an informatics problem that can be solved at least that's what I'm told. Why don't we open things up for others who may have questions as well are there any other questions from the group. Well if not we have a reception outside and you can direct your questions to Dr. Jane Way at the reception. So anyway thank you again very much for being here.


Hey, good morning everyone. It is the first trading session of October here now is Jim Kramer on the floor of the New York Stock Exchange. Jim, obviously it's tough to follow the markets given what the tragedy in Las Vegas. Yeah, I mean, look, I think that what happens in these kinds of things is that it's subdued, but at the same time that it's subdued, there are people trading debts all over the country who say, look, it's subdued, but I've got to position myself. The position that I see, by the way, is that all the stay-at-home stocks in Amazon and Domino's are doing well, and that's because people feel that there will be some change of behavior after this. Historically, that has not been the case, but I understand the desire to try to take advantage of what people see and believe that something like Mandalay Bay will make it so that you don't go out as much. Well, and we're also seeing some of the gun stocks rise. Well, there, I mean, what's happened historically is that people feel that when there's a tragedy that there'll be something that comes out of Washington that makes it so that it's more difficult to get by a gun. I would say that after Sandy Hook and Democratic president, nothing happens. So that is not a reason to buy those stocks. I would sell those stocks. All right, Jim, it's obviously a tragedy. We'll continue to watch it. Let's move on, though. It is the first trading session of October, and great timing because you have a fantastic real-money column. Thank you. About 12 sectors that everyone should really be watching.  Now, oil, by the way, is not one of them. There was a head of steam going in for oil, and we talked about this with my action alert team for the club this morning, where oil had 52, and once again, the oil companies came in and sold a ton of futures, but the transports are amazingly strong, housing, auto.  And I think that people have underestimated Houston and Florida, underestimated the rebuild, underestimated the amount of resources that go into it, and underestimated how the population in Houston is different from the population in New Orleans, where there's much more insured and the damages are very oriented towards auto and oriented towards fixing houses. So you're seeing all the stocks that do well in that situation really flying, and that's not going to stop, that's going to continue. Well, and you also mentioned the bank stocks in your column, and you point out this interesting timing that earnings are next week for banks, which is after that critical jobs number on Friday. Yeah, I mean, you know, the jobs number is going to be able to be subject to a lot of interpretation, given what happened in Houston and what happened in Florida with the storms. I think that the interpretation will be that the economy is strong, and if the economy is strong, then I think it will make it even more likely that we get the December rate increase, if we get the December rate increase, then the banks, if they get hit, you want to buy. Wells Fargo will be testifying tomorrow Tim Sloan from the Congress, and I happen to recognize a stock that does well here. We own a city for the club, and that's been terrific, but I think Wells could go up, JPMorgan could go up, Bank of America's been going up, and there were a bunch of downgrades today. There were a downgrade of regional banks. I think that that's a downgrade that I would not do. I think the regional banks, which were red-hot going into this quarter, will stay red-hot. Staying with the financial sector, AIG stripped of its systemically important label, any reaction there? Yeah, I mean, AIG is an inexpensive stock, and it's going to save $100 million. It is interesting to note that AIG is the only insurer that really hasn't done well here, and that the strongest insurer-related stocks are Marshmack, Aion, Gallagher, these are brokers. The insurance brokers are very strong. That stands to reason, given the fact that of the storms. And I think that progressive rates are going to go higher there. So I think that the insurers remain one of the great groups of this year. Alright, meanwhile, NVIDIA's price target was raised at SunTrust. No surprise to club members. Now NVIDIA reaches 180, and there's just a wall of selling every time the stock gets to 180. It's funny, there's a wall of selling at TJX, at 74. There's a lot of stocks that really get stopped at particular levels. And I think that NVIDIA is going to have to have far more buying power to get through 180. Do we get there? I think maybe you have to wait for the quarter. Okay, Jim, some good news for you as an LG subscriber. Disney reaching a deal with the Campbell Company. Right, I thought that was, I mean, I used Moffett-Nathanson. They were very bullish on Disney. I haven't think this is a very important call for Disney. I think that Disney, at a certain point, is going to do all the different methods that you're going to use to get Disney programming going to kick in. Maybe it'll be less of a focus on the subscriber numbers. So I think that this was a clarion call to buy Disney, but longer term I've never wavered. I think that Disney's an inexpensive stock, longer term. Yes. All right, and Jim, Pepsi was downgraded at Jeffries. That's a club name. Yeah, look, I mean, we trim PepsiCo. It doesn't matter. We're not going to get rid of PepsiCo. We understand the group is challenged. But this is the strongest of the consumer packaged goods companies. And I feel like that after it gets hit, no matter what, you know, if they report people are critical of it, it will bounce faster than all the others. And while we're talking about Pepsi, remind us of your view of Coca-Cola. Coca-Cola is just either here or there. I mean, I think that if yields, if Treasury yields go up, then Coca-Cola is less useful. I do think Coca-Cola will be wise to buy Monster, even though Monster's moved a lot. It's like, I wish Allagham would buy Align technology, Align being the company that would take care of the tea so that the whole face obviously aligns very expensive. Monster's very expensive. But what we've seen is that the companies that have made big acquisitions this year have done quite well. Even United Technologies, whose stock is now at 116, it got hammered down to 109 when they bought Rockwell Collins, one of the bigger gains of the third quarter. You know, so the companies that make acquisitions are doing well. I just think that the Monster's a natural acquisition. In addition, Coca-Cola says it wants to be even bigger in beverages. I don't know how else to be bigger except for buying Constellation. Constellation is not for sale. They report this week. Also reporting earnings on Tuesday is Lenaro. And we, of course, talked a little bit about housing. Yeah, the housing business. Now, there's a Florida-based home builder. I don't know what they can say, but I think that we saw really good numbers from KB Homes last week and that accelerated everything. What was really kind of interesting was that KB Homes has been having good numbers over and over and over again, ever since we recommended it at 14. And yet, suddenly it matters. It's almost as if the analysts who had been denigrating the stock for so long are now on board. And it just shows you, once again, be patient when you have a really good stock. And Jim, before we end, tonight on Mad Money, you have the Haynes Celestial CEO. Yeah, and, you know, let a lot of people feel Haynes for sale. I think we're going to find out it's not for sale. And Haynes is going to be trying to rebuild its earnings profile. Let's listen to whatever one Simon has to say. Perfect timing for that interview. Jim Kramer, thank you so much as always. We'll leave it there. Alright, for more information on the stocks Jim mentioned, please head back to TheStreet.com.


At Audiology Associates of Prestonsburg, you can live your life the way you want and find the freedom of better hearing. With 40 years of being in the hearing care industry, you'll experience patient care that is specific to you with exceptional follow-up care that ensures your hearing and balance needs are being met. Audiology Associates at 1428 Northlake Drive in Prestonsburg. Olivia Tussie, a freshman at Prestonsburg High School, is raising funds to send Prestonsburg police officers to Washington D.C. during National Police Week. During this week, the three officers killed in the Allen shootings. Names will be read at a candle light vigil and placed on the National Police Officer Memorial. I wanted to see our Prestonsburg Police Department go to Washington so they could say goodbye to their, well one final goodbye for their brothers. We have, you can donate, you can, we are having like a calendar where you can fill it in. I'm selling suckers at school. We also have, we're going to have a sale and lunch soon and we're also, you can like, we're filling eggs and you can egg people's yards like, and I mean, we'll have more fundraisers in the future. Tussie hopes the community will help support her fundraising efforts and help honor the officers lost in a shooting that shook Eastern Kentucky. I was very sad because I loved them and I mean the community definitely felt lost. They like part of my Stenic family and I, and I wanted to see them get to go to Washington. They protect us, so we had to help them. To donate, go to Olivia Tussie on Facebook. Reporting for Mountain Top News, I'm Brianna Robinson.