Here to tell us all about the subject is Niden El Rubin. You may know him from his various sessions on Trashing Pearl. The Pearl community loves him for that. He also recently co-founded the company Vultra. And with no further ado, I'd like to help you to help me welcome him on to the stage to talk about Smart Cities. Thank you. Thank you. Thank you. Hello, CCC. It's been great to be here. Let me start with a little apology. I'm feeling a bit sick today, so if I start coughing or spontaneously dying, just bear with me, forgive me. Thank you. And today we are going to talk about something that doesn't work for you. We're going to talk about the smart industry. Now, basically, what we'll do today is talk about how the smart revolution is changing all of our lives without us knowing. As a disclaimer, we in Vultra, my company, are developing security solutions for the smart industry. I'm just putting it out there. So let's talk about Smart Cities. Smart Cities are popping everywhere, in Amsterdam, Singapore, Barcelona, and in many other different cities around the world. But what exactly are Smart Cities? Now, well, in Amsterdam, they decided being a Smart City means they'll have birdhouses that offer free Wi-Fi. And in Kansas City, they decided to take the concept into a more American approach and implemented gunshot sensors, among other things.  Because each city is implemented ideas fit for their own culture, their own atmosphere. In order for us to understand the industry and understand who gains the most out of this technological advancement, we need to look at one specific market, the smart energy market. Smart energy is basically a concept allowing utilities, energy utilities, to better connect with their end consumers, as well as municipal authorities, the cities themselves. I know it sounds complicated, but it's really not. Now, energy utilities gained a lot from this whole smart revolution. Using smart energy, they managed to implement devices that allowed them to define different tariffs for different hours, allowing them to earn more money on peak hours. They could also connect or disconnect consumers' electricity remotely, if, for example, they are overdue on their electricity bill or ran out on their electricity prepaid car. They could also receive consumers' electricity usage instantly without having the need to send someone over physically. All in all, utilities gained the option to better manage their electricity grids, and in some cases, save over 15% of their expenses in that area. So basically, energy utilities have a lot to gain from this whole revolution. Basically, when we're talking about smart energy, we're actually talking about the smart grid, containing all the utilities' devices. And the main appliance that makes it so smart is the smart meter. Smart meters are ordinary electricity meters with two extra features. The first is that it allows the utility to monitor and communicate with the meter remotely using PLC or 4G networks. And the second, which truly makes the smart meters smart, is that it allows the utility to communicate with consumers' home appliances with your home appliances. So you are now probably asking yourselves, wait, wait, wait. These things can control my home devices. The utility can control my home. Well, not only they can, but communicate with your home devices is just the first step. In the future, these things will create a massive mesh network all over the city, allowing them to communicate with the city's smart appliances as well. The entirety of the electricity grid, your home, your city, and everything in between will be in control by your energy utility. And that's a bit scary. But how does the smart meter communicate both with the city and your home devices? One word, zigbee. Nice. By now, most of you already know zigbee is an extremely insecure protocol, exploited many times before. But for now, I'll just say that if you thought zigbee is insecure in regular smart houses, just wait and see how it's implemented in the smart energy industry. Another important point is who develops these smart meters? Currently, there are about 60 different smart meter manufacturers, but the top three covering about 30 to 40% of the market are Eitron, Landis and Gear, and Elster. Remember these names as they will pop up a bit later. For now, what you need to understand is that smart meters are offering a lot of benefits for utilities and cities. They have so much to gain. By installing these meters, the utilities are now forcing smart meter installation in a wide range of cases, even though it is costing them billions upon billions of dollars. But utilities aren't the only ones trying to implement these devices. Governments all over the world are pushing it even further. We can see a very sharp increase in positive regulation all over the world, in the Middle East, in Australia, in Japan, and all of East Asia in general, in the US, but the key region for that industry, the one with the most progressive regulation and goals is actually Europe. The European Union has declared it aims to replace at least 80% of all electricity meters in the region with smart meters by 2020, three years from now, with a total investment of approximately 45 billion euros, 72% of all European consumers will have a smart meter for electricity, 72% from all of all the people in the crowd, for that matter. That extreme push, both by governments and by utilities, has made it so that over 100 million smart meters are already installed today all over the world. And if you thought that the installation of smart meters doesn't concern you, you should think again, because these are the countries that will replace at least 80% of their meters in the near futures. Austria, Denmark, Estonia, Finland, France, Greece, Ireland, Italy, Luxembourg, Malta, the Netherlands, Poland, Romania, Spain, Sweden, and the United Kingdom, almost all of Europe will take part in this massive technological revolution. But what's the problem with that? Progress is always a good thing, right? The problem starts when governments, agencies are forcing the installation of appliances that can interfere and communicate with civilians home appliances. The problem starts when there's a product with a market so huge it is installed in hundreds of millions of homes worldwide. The problem starts when that product is accessing the internal network of both the utility and the consumer. You, the problem starts when this product, forced by governments, installed everywhere with critical access points, is also dangerously insecure. But why are smart meters so critical? Let's have a look at what a hacker can do if he'll hack your meter. First of all, he could see exactly when and how much electricity you're using. He could know when you're in the house if you have any expensive electronic equipment that might be worth stealing and obtain a lot of information about you and your family in general. The second thing he can do is basically a billing fraud. He could set your billing amount to whatever amount he'd like. Whether it's one euro or 10,000 euros, you're going to be in a world of pain just by having to explain to the utility why their meter is faulty, why you didn't use 10,000 euros worth of electricity. If you even catch that in time, of course. But these scenarios aren't that frightening. Sure, an attacker can make your life miserable, but it's not really dangerous if you'll see when you turn on your TV. The scary stuff begins when you think about the power these meters have over your electricity network.  Whether it's your air conditioner, your fridge, or your door lock, an attacker will be able to control each and every device. This will have very severe consequences. The more your house is connected to the grid. Just imagine waking up in the morning just to find out you've been robbed by a burglar who didn't even had to break in because he could control and open your door through the meter. But even if your house doesn't contain any smart appliance, you are very far from being safe. Smart meters are positioned in a critical point in the electricity grid. Because of the high amounts of voltage, the meter is handling, one faulty line of code could cause serious damage. An attacker who controls the meter also control the meter's software, allowing to literally blow the meter up, just cause it to explode and start a fire where it used to be. And these aren't just imaginary scenarios. Puerto Rico has just suffered from a massive amount of billing fraud attacks causing the energy utility to lose $400 million. And in Ontario, smart meters has literally caught fire and exploded without a cause to be found. Allow me to quote one of the firefighters who responds to the event. It's your hydrometer. You have a smart meter.  And just so you realize how extremely dangerous these fires are, this is an image of the damage an exploding meter caused in one case. So let's get technical. How do you hack a meter? First off, there's the physical way. There's always the physical way. In order to tamper with a meter physically, you have to have physical access to it, obviously. Which isn't very viable most of the time and is very easy to detect. Anyway, even if you did have access to the meter, there are tons of physical anti-temporary mechanisms inside the meter hardware, ranging from actual locks to flash anti-reading mechanisms. So the physical approach isn't really going to work. Trust me, I tried. Unfortunately, smart meters also support a wide range of wireless protocols. Protocols like ZigBee and GSM are considered standard in the industry and are used practically everywhere. These wireless protocols have been left in the dark with little to no security and doesn't require an attacker to be physically present near the meter in order to exploit an implementation vulnerability. These protocols also allow an attacker direct access to the smart meter firmware, which allows him to exploit many types of high-level bugs like memory corruptions, for example. So naturally, we've focused more on this wireless protocol in our research. So how does the smart meter communicate? Well, in order to communicate with the energy utility, the meter often uses regular GSM. Sometimes, especially in crowded cities and skyscrapers, the meter communicates with the closest electric box using PLC, which then transmits the data back to the utility using GSM. So far, nothing too proprietary, just ordinary GSM operating on 3G or 4G networks. But what about home appliances? How does the meter communicate with them? Well, this is where the notorious ZigBee protocol comes into effect. In order to communicate with home appliances, the smart energy standard has declared ZigBee smart energy should be used whenever possible. So the utility is using GSM to control the meter and ZigBee smart energy is used to control your home. So why won't we use GSM to control the meter? Well, let's talk about encryption. What prevents attackers from using a GSM broadcaster near the meter in order to control it? Well, nothing. Some utilities are not implementing any kind of encryption but the standard on their smart meters. This has been discussed even at 28 C3 five years ago by Dario Carluccio and Stefan Brinkhaus, I hope I pronounced it correctly, yet many utilities didn't quite get a message and left their communication protocols completely unencrypted. But let's assume our utility is very security oriented and they are using encryption. What kind of encryption are they using? Well, most if not all smart meters around the world only supports the A5 GPRS algorithm in order to communicate using GSM. I already heard left from the crowd and you're completely right because the A5 algorithm has been known for many years to be relatively broken but still kind of secure so attackers can just brute force the encryption key and encrypt all communications. But what about hijacking? What happens if an attacker use some kind of a GSM test station and force the meter to use it by broadcasting stronger than the original base station? Well, in that case, the meter will not only connect to the station, it will also try to authenticate itself using its hard-coded credentials, allowing the attacker to hijack the GPRS traffic and completely take over the meter. But, you know, that's just one meter, right? Why can't attackers do that to all meters one at a time? Well, not only they can, they won't have to because all meters of the same utility is using the same APN credentials. If an attacker would gain access to one meter, it will have access to all. One key to rule them all. The sad thing is that this whole security fiasco could have been avoided. If utilities were using proper encryption in their GSM traffic, an attacker wouldn't be able to hijack it. If utilities were segmenting parts of the network instead of using one giant LAN, an attacker wouldn't be able to access all the meters. And if utilities were actually monitoring their smart meter network, they would stop an attacker way before it could compromise their entire network. All in all, in its current state, the smart meter network is completely exposed to attackers. But that's just how we attack the meters. What if an attacker doesn't want to use GSM? What if he wants to take over your house? Now's the time to talk about Zigbee. Zigbee is a communication protocol used in home area networks, as in the local networks used by your smart appliances. Now, this protocol has been standardized in 2003, a year in which the term information security made a little sense as electing Donald Trump president, for that matter. Now, keeping that in mind, Zigbee also supports a huge amount of different devices, ranging from a simple light bulb to the most complex air conditioner. In order to do that, hundreds of hundreds of specifications has been created and implemented in the application layer of the protocol. This created a situation in which sometimes two different devices serving the same purpose, say two toasters, had the same features implemented in a completely different way. On top of that, because of all the various use cases smart devices serve, the Zigbee protocol have 15 different flavors, including home automation, healthcare, and of course, smart energy, among others. This unique situation in which a mandatory protocol covers an enormous amounts of possible use cases is so difficult to implement, vendors actually chose what they want to implement. And when vendors choose what to support, they more often than not completely skip security. So how do you use Zigbee in order to hack a meter? I'll split this question into three parts. The first is design problems. What misguided design decisions can we try to exploit? The second are implementation bugs. How was the protocol implemented inside the meter firmware? And lastly, management. What mistakes does utilities do regarding their meters? So let's start straight with design problems. When a smart hub, not a meter, acting basically as a router detects a new device that wants to join the home area network, it prompts the user to approve it before starting any form of communication with it. That way, only approved devices will be able to access the private network. Seems very logical. That is important because the entire home area network is basically using the same network encryption key. This means that if an attacker is able to obtain that key, he could access and mask itself as any device. For example, he might mask himself as the hub itself and send different commands to devices around the house. Thus, this network key is a very important thing. That's why Zigbee smart energy networks are using AES 128 bits in order to encrypt its communication, which is my emails are encrypted with 2,000 bits, but sure. Now, in regular smart hubs, the only way an attacker might be able to steal that keys by sniffing the network traffic the exact moment the device is added, which is kind of difficult. This is because whenever a device is approved to the network, the hub sends it the network key. I'm abstracting the whole process a bit, but that's the bottom line. Smart meters, on the other hand, are very different from smart hubs because that's a bit amazing. Whenever a device wants to join the network, the meter does not try to make sure it actually should and just replies with, sure, there's the key. This means that if we'll disguise ourselves as a new smart device, we will be added automatically to the home area network, granting us the secret network key. Using that network key, we could impersonate ourselves as the actual smart meter. We could communicate and control any device around the house from way across the street. For example, we can open up locks, try and cause a short in the electricity system, and basically, you know, whatever we want.  This is not dangerous by itself, but leads us directly to implementation bugs. Now, today, smart meters are based either on ARM Linux or plain proprietary ARM embedded systems. Keep in mind that smart meters are supposed to be cheap. Thus, they are often lacking both CPU power and memory. Because these processors are so modest, so to speak, the embedded code handling ZigBee communication is often shortened and optimized. This sounds nice, but in reality, this leads to code that often lacks security checks, like buffer size checks, for example. But successful exploiting a buffer overflow attack in a meter might prove to be a very tough thing to do. That's why you don't actually have to do that in order to break the meter. A simple segmentation fault will completely crush the meter, causing an electricity shutdown at the premise. On top of that, some crashes will actually cause this, if you remember. So all you have to do in order to burn someone's house is send a very long header string. Putting memory corruptions and exploding meters aside, the other very severe weakness often found in meters and basically a lot of other devices are hard-coded credentials. Most meters have at least one debug port available for technicians. These debug ports are often using the same credentials over and over again. In one case, we saw the credentials for a very popular vendor that's called it Litron. SmartMeter wore root as the username and Litron as the password. Not surprising, though, as they don't think anyone will actually try and communicate with it. They're not making any effort to make it secure. The other very important point about implementation problems is encryption. As we saw earlier, each utility is using only one GPIS key in order to control its entire network of smart meters. But what about the ZigBee network? If it was impossible to inject a new device and hijack the key, like I showed earlier, will it still be possible to bring the encryption? Yes, because, and you won't believe it, the 128-bit ASK I was talking about, it's not really made out of 128 random bits. Instead, the key is derived out of each meter's installation code, as in the code the manufacturer assigns each meter, which can be as high as a 16-bit random string, but as short as six. Meaning the maximum amount of random bits is indeed 128, but because the standard allows it, most keys are only made out of six random bytes, meaning 48 bits. This is exactly what happens when you let vendors decide for themselves which parts of the standard to implement. Security is often neglected, which leads us directly to bad management. Smart meters are already implemented in a very wide scale. These security problems are not going to just go away. On the contrary, we are going to see a sharp increase in smart meters hacking attempts because they are such an easy target. Yet, most utilities are not even monitoring their network of smart meters, let alone the smart meters themselves. Utilities have to understand that with great power comes great responsibility. For their infrastructure, for their municipal, they operate in, for their customers, for you, just as they monitor their other private networks, they have to step up and protect this one too. And in order to do just that, we as a community have to act fast. This is why we at Voltra are releasing, in the upcoming weeks, our own meter fuzzing tool, so you will have the power to inspect smart meters legally by yourself. You need to be in charge again, discover new bugs and vulnerabilities and report them, mail your government officials, arrange debates on a national level, inform the public of the dangerous of neglecting security. We are giving you the tools to regain control, reclaim your home, or someone else will. Thank you very much. I'm scared already. So we have plenty of time for questions. We have, I think, eight microphones here, one there, one there, one there, one there, and two up there. If you can make your way up to the microphone, we will take your questions. Make sure they actually are questions. Preferably. I'll start with one. Yeah, you raised a number of very good points. Thank you. I have been designing electricity meters for five years, and two years ago I started designing a smart grid myself in the Netherlands. As an IT security personnel, or an actual software developer? Yeah, as a security person in the digital grid. Right. I want to make one notice, and that is that exploding meters using software is simply not possible. They simply do not have hardware that can explode that you can control with software. It's as simple as that. So don't be scared about your meter exploding because of a hack. It's not going to happen. If I'm not mistaken, if I'm not mistaken, the Ontario government officials will probably disagree because their meters did explode. Now, in the official report, you know, developed right after these explosions, they couldn't figure out how exactly they exploded. They said the same thing, you know, that the meter isn't capable of exploding because it lacks the hardware. But later, they found out that if one of the chips had electricity short, I think, it could cause the meter to mishandle the entire voltage, you know, passing through it, and just overheat and then explode. Like, the chips just overheat and explode, you know, in that case. They didn't just burn, they exploded because the amounts of voltage was so great. So, you know, it is possible that the Netherlands doesn't have any exploding meters, but, you know, we'll see. I've seen plenty of exploding meters, but never because of anything related to software. It's usually because the installer forgot to tighten the screws and they overheat. Yeah, that's what I'm talking about. I'd like to take a microphone 8 next. That is somebody standing up there, isn't it? Yeah. My question is, is it possible to attack the vendor of the power plants via those smart meters if you attack the smart meters via the Zigbee? The vendors probably won't be a target because they are not using smart meters. The utilities will be a target, you know, because of that. That's why vendors doesn't really care about security because they're not, you know, the ones affected. So, you can hack the utility through the smart meters. It has been proven, both by us and other researchers, but the vendors are probably out of the picture for now. Thanks. Two, please. Yeah, I used to work at an IoT company and it seemed like the problem with a lot of this is that there's not motivation for people installing these devices to make it secure. And even when some of us as developers said this is broken, it was usually ship it because we have to. So, how would you recommend us as engineers addressing the cultural problem of shipping shitty IoT devices? That's a great question. I think, you know, every software engineer has come to a point where he asked himself that very question, but, you know, bottom line is management decisions.  So, the problem should be solved from the top, not from the bottom, in that case. You know, in my opinion. All right, internet. There was a question from the internet just before. Are these searchable via Shodan or other methods? Well, if they're connected to the internet, then the answer is yes. But, you know, most often they're not there. They have their own LAN network and they are not really connected to the internet. If you do happen to find some, please let me know. That will be interesting. Two, please. Hi, thanks for the great talk. We'd like to ask after what you present, I know the talks present in here regarding mass surveillance, everything about it, what do you think if all these bad design decisions are made on purpose so we would be easily tracked?  We do security and for us, it's bad. But for the government, it's actually very good. They want to know what you're using. They want to know when you're using it. They want to predict what you will be using. There's a very obvious reason as to why this whole industry is booming right now. And that is definitely control. I don't know if surveillance is the correct word, but better understanding civilians is definitely on the topic here. Number one, I'm just asking, is there actually a central patch management or stuff for that? Because we saw, you know, some weeks ago that because of shitty implementation of a home router, like a big part of Germany was offline because of an attack.  That's a good question because, first of all, they do have a sort of patching system. They do have firmware upgrades, all right? But the hardware itself is not going to change. The meter's, you know, life cycle is approximately 25 years. So, you know, even with the best firmware upgrade in the world and the best encryption keys in the world, the meter can support, you know, up to a certain level. So we'll see what happens in about 20 years and if the patching system, you know, really worked. I'd like to take a question from the internet again. Why roll out smart meters on home level anyway? Would it technically not be enough to roll them out on street level to adjust the power in the grid? It will be enough, you know, if the cities themselves would be the only ones wanting smart meters. But utilities are wanting smart meters. Utilities want to control each and every consumer's home. So, you know, setting them up on the street can be effective to a certain point for cities. But to utilities, they have to have a meter for every consumer, for every house, for every apartment. Microphone 3. In Germany, we have the situation that the smart meters are becoming mandatory over a couple of years, which is a bad thing in my opinion, but they also go through a very rigid certification process, which is a good thing, although it is not open source and verifiable by the CCC, for example, not so good. However, what is the status in your community and your sphere like, are they becoming mandatory and are there plans to certify them before they can be put online and put into operation? Well, part of the German specifications is online, you can read it, I did so myself. Anyway, the whole, you know, German standardization is often taking security as a recommended thing to have. Both the Germany and the US and, you know, all Europe in its entirety are just recommending utilities to implement security, but once you recommend something to these large organizations, they often won't really implement it. So my hope is that this stock will bring some change. This is why I'm standing here. I want these standards and situation to be changed, but that's gonna happen only if we, as a community, will, you know, act together to make that happen. So microphone 7. Hi. As I'm destined, Europe wants to install it right out everywhere. So they will probably go on by being a good example and rolling out in every public administration and so on. So there might be a bit leverage here if, you know, you go to your administration and, oh, well, the computers don't work anymore because there is no energy. Well, I do not support any legal activities for the protocol. And something needs to be changed and something needs to be done in order for, you know, this large organization to actually change something. How it's gonna be done, that's up to you because, you know, you're Germans, I'm unfortunately not, but I don't know if threatening will be, you know, the key in this debate, but definitely something. Like, I don't want to recommend anything, you know, specific. So microphone 2. Did you look at any data that show the balance between big consumers like factories and shopping malls and offices and households with smart meters and smart devices? The question is, can the controlling of smart devices have a benefit for the managing of the change to renewable energies? Well, of course, smart meters also allow consumers to generate electricity themselves and sell it back to the utility through solar panels or whatnot. So there are a lot of reasons for why smart meters are becoming so popular, for why they are being regulated so heavily. A lot of reasons, trust me. Microphone 4. I have a question about the year 2038 problem because you say, well, smart meters are installed for 25 years. Well, if you can sum up this year plus 25, then you come in the area of 2038, is the problem handled and is it a security issue at all? Are you asking about 2038 right now? Yes. I have no idea what's going to be at 2038. I have no idea. Well, because the time will overflow. So, well, will it then just stop or will it just put a wrong date on the data or what will happen or is it handled at all? I have no idea what's going to be at 2038. I understand the question. I think most of them, date-wise, will probably need a software update patch, but they are acting on a, if I'm not mistaken, a 32-bit kind of processor. So we'll see. Sounds like a great debate for Twitter. Microphone 8. See you in 25 years. Yeah, hi. I'm happy that you put this topic to this conference and I think it's very important to talk about this topic, but I'm kind of unhappy that you did this by fearing and I'm not very happy about how you presented it because you simplified a lot and you simplified a lot and I don't think that this is the way we get a better solution and that's what we should aim for. That's a good point. That's a good point. I did frighten a lot. It was on purpose, of course, because we as security experts, we hear something can get hacked and we want to do something about it. We care about these things because when they understand the situation, but common people who aren't in the security industry doesn't really know the effects of someone hacking their meters. So it is mainly, you know, all the frightening points, so to speak, is targeted to them so they will understand what's going on. But yeah, that is a valid point, you know. The internet has another question. Why use wireless protocols and not use power line? They do use power line. I mentioned they use power lines on skyscrapers and so on. There's a very, you know, hard limit to the extent PLC will work. So they are using it for short distances, but when they're trying to communicate with the command and control server, they have to use some kind of wireless protocol. Microphone 2. Hi. Did you look into any other protocols in home automation, not only ZigBee, because it's, I think, many American big thing there in other countries, continents. There are other protocols. Did you look into that? There are other protocols. The main protocol in the smart energy industry is ZigBee and, you know, it powers about 99 something percent of all smart meters in the world. So we tried to focus on that. We didn't really look at other more proprietary protocols. Microphone 3. I have a question about the possibility of controlling local IoT devices, because I'm not aware of many smart makers' designs, but usually these are connected only passively to the power grid. So what are the chances of controlling local IoT devices separately, not only by turning on or off the whole power grid, if it's even possible? Well, let me answer, you know, on a general note here. If the certain device is using certain wireless protocols, then it won't be only possible to hack it. It will be probably pretty easy. But if it won't use any wireless protocol, you know, it's gonna use only PLC or, you know, I don't know, Ethernet or something, it will be more difficult to hack it, just for, you know, because of the simple reason that utilities can detect it more easily than wireless attacks. Okay, thanks. Microphone 8. Yeah, hi. I'd like to know if you had a look at the German way of deploying smart metering, especially the whole hierarchy of smart meters, smart metering gateways, and then up to the gateway administrator. You're talking about Eitron? Sorry? You're talking about Eitron? No, no, it's called the German way of smart metering, because we have quite a different approach to it. If there's Zigbee or no Zigbee, and more like a more centralized infrastructure. In what way is it more centralized? Just, you know, so I get the whole picture. Well, you have your meters, not only smart meters, but also analog meters. They connect to a smart meter gateway, and both smart meter gateways connect to a gateway administrator to deliver all the data. So we have, say, no Zigbee mesh devices in your home. Well, I don't have a definitive answer for that, because we focused on smart meters that do use Zigbee. And, you know, that's a good question. Maybe come later and we'll discuss it a bit further, because I don't want to, you know, steal time from anyone else, right? So I think there was one question from the internet. There are still a couple questions, but I'll start with one here. Since the smart meters are being legislated into being installed, could we also work on improving legislation regarding security? Of course, of course, that's what we should do. We should improve legislation about security. And, you know, that's the whole point, basically, because if we force vendors and utilities to implement better security, they just won't do it. But if the government will force them, it's a whole different story. So we've none, no more from the floor. Do you want to take another one? Aren't the bug ports you talked about protected by seals? In some meters, they are. In some meters, they aren't. It really depends on the vendor, but technicians that, you know, do come physically to the meter will have access to it. So even if it is sealed, we can still communicate with it and, you know, worry about the feeling later. And I think that's the end of the questions. I would like to thank Natty for his great presentation. Thank you very much. Thank you very much.


Turkey is starting new military operations in Iraq, Erdogan announced. Turkey will continue its fight against terrorism decisively and is poised to resolve problems stemming from the PKK's terrorist presence in northern Iraq this summer. President Recep Tayyip Erdogan has vowed, We are about to complete the security circle to secure our Iraqi border. We will permanently resolve the matter concerning our Iraqi border this summer. Erdogan said, We maintain our will to create a 30-40 km deep security corridor along our Syrian border. We are determined to fill with new steps the gaps in this corridor, part of which we have already established with our previous operations, the president said. The writer of Hurriyet newspaper, Abdul Qadir Selvi, announced some details about the military operations to be carried out by the Turkish army. He said that first, a large-scale ground operation will be carried out in the region where the claw lock operation was conducted and an agreement was reached with the Iraqi central government controlled by the Bahrzani family and the administration of Erbil. Prior to the operation, strengthening of temporary and permanent base areas in the region continues. Terrorist nests within the border of the claw lock will be destroyed by air support operations. The length of the border between Turkey and Iraq is 378 km. It will be implemented with the operation. The lock against terrorism will be closed on our entire 378 km border. The borderline will be reached including the Karah region, famous for its caves. Caves and shelters belonging to the terrorist organization were destroyed in Ghara. But this region will be permanently monitored so that the terrorist organization does not use it again. The caves in the claw lock area will be cleaned and destroyed. Point operations will be carried out in Ghara district, the author noted. Abdul Qadir Selvi emphasized that as in Syria, a safe line with a length of 378 km and a depth of 40 km will be created on the Iraqi border of Turkey, the Turkish armed forces will carry out a lockdown operation. The Iraqi central government and Erbil are expected to provide intelligence support as well as take action against the PKK in Suleymanaya and Sinjar. In addition, while Turkey is preparing for the operation in Iraq, diplomacy in Syria will be given importance. The PKK has its main headquarters and training facilities in northern Iraq from where it tries to infiltrate Turkish territories to attack security forces and civilians. The Turkish government has been actively trying to eliminate the PKK presence in northern Iraq and in northern Syria through operations. Czech President Petro Pavl, the army could be sent to Ukraine. Czech President Petro Pavl did not rule out the possibility of sending foreign troops to Ukraine. He said that European leaders should not limit themselves in terms of assistance to Kiev. Pavl urged Ukraine's partners to extend the forms of aid for Ukraine, including the presence of foreign troops in Ukraine. He noted that it was not about sending combat units but about different forms of aid and non-combat participation. I endorse searching for new ways to help, including continuing the discussion about a possible military presence in Ukraine. We cannot impose limits on ourselves if we do not have to. Pavl said, adding that Europe must play a bigger role in deterring Russia. Pavl added that there was no difference whether Ukrainian soldiers would undergo training with Western instructors abroad or directly in Ukraine. Ukraine remains a sovereign state even though it was attacked, he said, noting that a possible training mission is not a violation of any international rules. We decide on our own which form of aid to choose, he added. The Kremlin has warned that if NATO sends combat troops a direct conflict between the alliance and Russia would be inevitable. Last month Pavl announced at a security conference in Munich that the Czechs had identified 800,000 pieces of artillery ammunition in various countries and were seeking funding for their acquisition to ship to Ukraine. About 15 countries, including Britain, Belgium, Denmark, Canada, Sweden and the Netherlands, have voiced their support for the plan, the Czech government said. NATO Secretary General Jens Stoltenberg, as well as leaders of Germany, the UK, Sweden, Poland and other European NATO member states ruled out sending Western troops to Ukraine. Later Estonian Prime Minister Kaja Kallas noted that European leaders should not exclude this possibility saying this could be a signal to Russia. Canadian Defence Minister Bill Blair said that his country was ready to send a limited number of military personnel to Ukraine but only to train Ukrainian soldiers and not for participation in hostilities. During a two-hour state of the nation address, Russian President Vladimir Putin threatened tragic consequences if NATO troops were sent to Ukraine, claiming the West's support for Kiev risks a conflict using nuclear weapons. Ukraine will attack the Russian army and infrastructure with two million drones. Ukraine is set to produce two million drones this year. Hannah Vodzdaya, Deputy Minister of Strategic Industries of Ukraine said this. At the same time, she acknowledged that the current needs of Ukrainian troops far surpassed the country's financial capabilities even with the assistance of partners, even with our partners, it would be difficult for us. However, we are working in this direction. Vodzdaya stated, we are ramping up drone production, she added. Vodzdaya addressed doubts raised among Ukrainians by President Zelensky's statement about producing a million drones, clarifying that in terms of production, we are far beyond a million. I am confident that this year we will reach the mark of two million. Vodzdaya emphasized, highlighting the capability of Ukrainian drone manufacturers, the Deputy Minister mentioned they can already produce up to 150,000 units monthly. The drone sector in Ukraine involves around 200 domestic companies, with nearly 60 of them already included in state orders. In an interview with the Independent, Oleksandr Kamyshin, the Minister of Strategic Industries, emphasized Ukraine's urgent need for ammunition due to the ongoing war with Russia. He noted that Ukraine requires an amount of ammunition that no single country can deliver, including the United States. Kamyshin also highlighted that the capabilities of Ukraine's defense industry far exceed the funding currently available for its support. Ukraine is positioning itself as a global pioneer in unmanned technologies according to Kamyshin, with UAVs becoming a crucial weapon on modern battlefields. He expressed confidence that this year Ukraine will produce over a million FPV drones and thousands capable of flying more than 1,000 kilometers reaching oil refineries in Russia. In a meeting with Ukrainian and international journalists at the end of 2023, President Zelensky stated, we will produce one million drones next year. We will make a million. We will do everything to make it happen.


In this video I'm going to provide my first impressions on the stock 2021 BMC Team Machine SLR-O13 which is the same geometry and design of the latest 2022 models and I'm going to do this through the lens of someone who owned the previous version of the team machine before the geometry and design was upgraded in 2021 and before according to BMC the BMC team machine became 20% stiffer 9% lighter and 6% more aerodynamic so we're going to split this first impressions into four main parts number one we're going to talk about the weight of this new BMC versus the predecessor and mine had rim brakes number two the geometry and design versus the predecessor number three my riding experience first impressions and number four opportunities for improvement or what I don't like about this BMC so I'm going to keep this first impressions short and sharp because mid-year I'm going to share a full comprehensive review on this bike where I'll also share with you an interview I'm going to be having with a head product engineer at BMC and also some on-road speed tests I'll be doing on this bike but just know before we get into the first impressions I do own this BMC team machine and if you want the full story on that I'll link it up there so number one is the weight of the BMC team machine so this BMC team machine SLRO 1354 centimeter which comes in at 10500 AUD with SRAM force access 12 speed and DT Swiss spline 35 millimeter carbon disc rims which is acclaimed to weigh 7.6 kilograms on BMC's website comes in at 7.635 kilograms that's without pedals but with the BMC mount and integrated bottle cages the only difference on this bike in terms of stock is the saddle I've got a specialized tube there versus what it comes with which is a physique saddle now if we compare that weight to the predecessor at 54 centimeter with rim brakes and that's Ultegra mechanical on that bike with MV 3.4 carbon clinches we have a weight difference of 200 grams number two is the geometry and design geometry wise comparing this 54 centimeter versus its predecessor 54 centimeter we basically have the same bike with some small tweaks notably the seat tube and the head tube which were potential areas where BMC could reduce carbon fiber and therefore frame weight although the stack on the BMC which enables the rider to get more aerodynamic despite the head tube change stays exactly the same no doubt due to some other micro adjustments in geometry BMC have made with this iteration now if we look at the BMC from afar this BMC versus the predecessor they almost look identical which is unlike other brands when you compare say a specialized tarmac sl6 to the sl7 there's been some major changes there or the canondale super six their recent upgrades that was a huge or what appeared to be a huge overhaul whereas BMC have stuck to their guns which I like because they're inadvertently saying they've got a product they stand by without needing major overhauls however getting up close and personal with this BMC I can definitely see some notable modifications including the BMC team machine taking on some of the cam tail tube shapes you see on the time machine which now accommodates custom integrated bottle cages similar to its time machine companion the fork is definitely finer and looks to be one of the focal points in the new design for greater aerodynamics and the back end visually appears to be the same as the predecessor but the riding experience in the rear has definitely changed which I'll explain for you shortly aesthetically I'm a big fan of the Lamborghini orange which has a super polished integration of black into the top tube although I feel like this model is let down by the exclusion of the BMC aerodynamic handlebar system which I'll explain for you in point number four point number three is my riding experience so owning the previous model of the BMC team machine external to price I felt like there was two areas that let that bike down I was a huge fan of it but there were two things in particular that I didn't so much like number one was I felt like there was just too much softness in the back end of the BMC in fact a lot of users including myself complained of a sensation of having a flat tire when riding on harsher roads and number two I felt like the BMC was missing an edge and that edge was speed or aerodynamics while it certainly wasn't a slow bike for me getting on say a tarmac sl6 or a Cannondale super six I would instantly feel more aggressiveness more aerodynamic advantages being on those all-round race bikes over the previous BMC but can I say after riding this BMC team machine for a few weeks now any negativity I had surrounding the BMC has mostly been swallowed up by improvements you still get that soft sensation in the rear from time to time but there's definitely been some modifications there and look whether this I'll call it an enhancement has come about because of 20% more stiffness in the BMC according to BMC I assume so and I don't think you want to lose that sensation completely in terms of softness in the rear because all of a sudden you'll start to feel a lot more of the road in your lower back and BMC will lose its mantle as one of the if not the most comfortable all-round race bikes on the market so I think BMC have got the blend right in the rear of the bike now and in terms of speed and aerodynamics there is a noticeable improvement there what does noticeable mean well BMC say six percent and to me six percent more or less of anything is typically hardly noticeable but can I just say I have definitely noticed not only greater general aerodynamics but more overall aggressiveness whether that be cornering accelerating or descending no longer will I take my BMC team machine to a crit race and feel like I'm perhaps a little bit disadvantaged those competitors who are on an aero bike and in terms of road racing and general riding this bike to me just ticks so many boxes it still remains to be easily the most comfortable all-round race bike I've ever personally ridden and to add these new improvements in I can honestly say I'm super impressed external to one thing which takes us to point number four which is opportunities for improvement so the only thing I don't like about this bike is the front end yes it's the three I understand it's not the one it's not the two but it's still ten and a half thousand dollars AUD or in the US it's 7700 USD or in Europe it's 7500 euro and that's a lot of money so to have to dip out on the ICS the integrated cockpit system which is lighter it's more aerodynamic it looks more aesthetically pleasing and I'm sure a more comfortable touch point for your hands in exchange for what feels like a cheap alloy handlebar with a stem that feels a little bit flexi let's just say I'm a little bit disappointed so what I'm going to do for the full comprehensive review is I'm going to upgrade the front end of the bike to the BMC integrated cockpit system so I can share with you what impact that has to the three if you're keen to see the full comprehensive review and if you're yet to subscribe to the channel please consider doing it below and if you've gotten value out of this video today please don't forget to give it a thumbs up and I'll catch you in the next video


At the point of the bowl game he would have been questionable and to go into Rose Bull to risk the amazing opportunity he has where he could potentially tear his groin again and be out for a much longer period of time. You've got to be smart and it's not letting down his teammates. His teammates absolutely love them. They know what he's all about. The second he showed up during the Rose Bull. Everybody grabbed him, hugged him. They all support him and I support him and I think he's definitely made the right decision. I've been hyping him up to everybody for the past year. I honestly think he's going to blow past me in a few years. It's going to be fun to see.


Hi, so please introduce yourself. Hi, I'm Jonas. I'm a CEO and co-founder of VitriaLab We're a company out of Vienna and we're building laser display components and the aim is to build very high performance VR display as you can see here. So this is a laser backlit LCD Which goes up to 10,000 nits currently and we're gonna push that up to 100,000 nits. That's pretty bright No, indeed And we do this because in modern VR headsets you lose a lot of light, right? You run your 10% duty cycle, you have 10 to 20% of transmission through the lens system So you need a very high panel brightness to start with So we're gonna push this up to 100,000 nits so that you still have a few thousand nits going to the eye You're gonna push it to 100,000 Indeed because of all the reflections and the waveguides and everything No, I mean in a VR headset you just have the panel and the lens, right? And typically you run the panel at 10% duty cycle and you have a lens which has 10 to 20% transmission like a pancake lens So if you want to have a few thousand nits in the in the eye So if you want to have like highlights, then you need a few thousand nits. Meta showed actually a 20,000 nits to the eye prototype So this is where this is going for 10 times higher efficiency 10 times higher brightness 50% larger color gamut Then what? So this is comparing to for example OLED or standard LCD panels So because you have laser you're gonna have a much higher color gamut. You can get up to almost 100% And this is some of your information here, so you could put it right here in the projector This is for the AI indeed. This is the prototype here on the right and that could be a laser DLP This is a laser. Of course could also be a laser DLP So what we what we built it indeed we we built the illumination in the end So this is the base technology you show how this is different from from an LED The LED is on the left or chip is on the right and you can see how how collimated this illumination is compared to the LED, right? And collimation is really the key for all projection systems And a and v are are essentially projection system meaning they have a panel and therefore lens So if you have collimation you can good very high performance Here you can see I was a laser Elko's engine together with a diffractive combiner And the key thing we can show here that I have a good image quality, so you don't have the laser artifacts I can turn on and off the despecling. I'm not sure if you can see now Some kind of grainy pattern now you don't see it anymore So what do you turn off and on? This is a despecling technology we have developed Because if you have laser illumination of an Elko's typically what you have is a lot of speckle And we essentially able to to get rid of that So what's going to be the future of? projectors in VR AR Compared to or is it all projectors even if when it's a micro LED and when it's an OLED it's all projecting I mean for AR you always have projectors Right, I mean if it's now micro LED or if it's an Elko's or if it's an LBS They all projectors, so we're also building projectors what we do is we take a standard LED Elko's projector We rip out the LED and we put in the laser That's the idea On all these cool amazing DLP projectors people buy and there's some really nice ones for 500 euro with the laser For the home, right? Are you doing something similar to that? Yeah, we just fall for AR So we don't do home cinema projectors of this kind of stuff We just do for head mounted this place. Is it a different kind of laser different? Everything's different. Everything is different at home. You need a very very high amount of lumens You need thousands of lumens and you don't care much about the form factor It's a very very well established technology, but we solving very specific problems for for a year and so What more is in here? Is it the same information for some other what's happened there? Yeah, you can see some information About how the technology works in principle how what's the key project is this quantum dark ship The glass that emits a laser rays And on the right here we kind of list how you apply this into a VR product But you can find also a lot of my information on our webpage So you're so much better than these other solutions indeed. That's that's the idea This is coming like because we can use lasers all these other solutions don't use lasers Are there thousands of different kinds of lasers in the world or how does what is laser? No, I mean a laser. I mean what you use is our laser diets, right? And they are they're not many different manufacturers, maybe four or five manufacturers And then these are like in laser pointers and all kinds of stuff And we just use them in a very particular way in this in these products and Some Lasik sir surgeons they use lasers. It's not this it's not gonna what I'm trying to ask is It's never gonna be too bright for the eyes at some point. There's a limit no and It's not gonna be damaging it's actually better or you actually we need much more than this to have realistic AR I mean, it's not damaging to the eye. So this is the one thing so essentially what we do We we also use diffusers and we split the laser beam from the one laser die to many thousand beams So there's no eye safety, but of course it's very different from what the laser eye surgeon is using So it's a very different kind of laser Here So what I'm looking at is that the brightest VR experience in the world is quite possible. Yeah, I mean for sure with an LCD I mean they imagine also has some very similar brightness currently They also like around 10,000 it's but this is quite possibly the brightest via display currently Which is pretty awesome that you have that thank you, but there are Micrality micro display manufacturing they talk about millions of nits. What do they mean by that? Oh, that's before all the Everything you have to differentiate via an AR products because they're very different So there's nobody doing a micro led for VR They could probably do millions of nits if they wanted to but what they typically want to build is AR projectors And they have million of nits they have but this is before you put the combiner Essentially because you want to have like a thousand two thousand nits into the eye from after an air combiner So you have to start with a lot of light. So if you take one million Nits and through all the optics and everything at the end you get a thousand. It's like 0.1% So like the DLP nits is also very high in the beginning. Yeah, and I'll cause yeah Yeah, I can't tell the exact number because it's being specified in lumen in the industry So this is around to lumen currently is gonna go up to 10 lumen and this is then transfers to like a few thousand It's to the eye. All right And you have a quick quick test on this one Mickey and me are So clear in there. All right. So what's your background in the company and who's your team around here? So my background is physics I started the data PhD in quantum physics and then we we use this kind of wave-car technology and span it off from the university to display products We are around five years old. We're based in Vienna in Europe Part of my team is here. We're over all 13 people. Can you introduce them? Yeah, we have we have Hartman over here. So our business developer Yeah, and we have shy over here. So he's running our light engine team Yeah, and then we have you know days. He's running the the way All right Let's ask What's the challenge about a waveguide and do you have to work on that to make the best product? We don't make these waveguide combines. This is something we buy from partners We we build waveguides that go into the projector system. It's very very important distinction The the challenge is to make this many thousand beams happen that they all at the same brightness That you have the correct mix of the different colors that you have a high degree of directionality In the end what it is is a very high performance illumination system Nice, and what is what do we get here? This is just an image in early prototype where we built an air projector So what you see is is the L-Cos panel Here you have a polarizing beam splitter and here you have the lens essentially which then projects the light out And here what you see here is a much much smaller version. So if you go on the left If you go over there on the left, you can see here the metallic part This is essentially the new projector is much smaller But is now going down to what's one cubic centimeter. This is still like three cubic centimeters fiber-powered What kind of conversations do you have here at the display week is it been awesome week for you? It's been a very awesome week and everybody really likes this the statement that we can make like minor reality ten times brighter Because that's what people are looking for And this is exactly that what we can realize. This is the key selling proposition of our technology So how far are we from VR AR world That it's like the matrix or you you're like it's like real life I think that we can bring this technology to the market in around two years It's gonna be the key enabling to make very immersive VR experiences We can really not tell if you like inside outside then the real world and also for AR I mean you always can be in the real world But it's really important that you can go outside and actually still see the image This is one of the key challenges people have faced now to put very strong shades Like with HoloLens or Magic Leap and the ideas that you have essentially normal transparent glasses But you can still see the image because when we're outside on a sunny day, it's a lot of nits. There's a lot of nits So it's okay to get a lot of nits. Yeah, I mean indeed indeed So I mean outside you're gonna find things in sunny day like 10,000 nits So you're gonna need to have an AR goggle which is on a similar scale So you want maybe also 10,000 nits and this kind of stuff So and this is what there's to be the big big struggle, right? And that's why there's also billions of investment going micro led because they so far was the only technology that could deliver the Cybrideness and we an alternative and we say look we we don't have to wait five to ten years for micro led to actually work We can put this on the market on a much faster time scale. So which technologies use the backlight as DLP al-qas we can use both but al-qas is the more accepted standard because it knows it makes more compact devices But we could also equally use the LCD LCD is in the VR system LCD you cannot use transparent We can do transparent, but I mean it's not used in AR because LCD is very low transmission So you want to have this high energy efficiency that DLP and al-qas give you All right any other Like you need to have some guys to come here with the eye tracking Perfect eye tracking and what else is needed the batteries that last forever. How long is your battery gonna last? I mean, I don't care if I have a huge power bank in the pocket, but yeah I have to I mean we're not building the entire glasses, right? So I mean there's a lot of other things not a lot of other companies necessary, but what we can do is we can Quite drastically increase in efficiency. Yeah This is something So what we for example have here we show how I mean with the we can increase efficiency because we can drop off the necessary illumination As your active pixels go down because it's a big topic in AR But you typically only have a few pixels on and you don't want to use a lot of LNG to illuminate your al-qas panel This is something we can do with this technology I get a comment that this is the right solution for daylight AR glasses that could live up to a strong sun outside Indeed. Yeah, that's that's the idea. So we think that around 10,000 It's is really the maximum we will need but that's is what what you should be doing and I need to ask you is your laser tech Going to be used to make TVs. No, no, it's not going to be used to use TVs Maybe in the far future, but we really focus solely focus on this place because there we have a very strong advantage of existing technologies All right, cool. All right. Just finish the video This experience is very interesting. Is it on a loop? What's happening in there? Whatever Apple is launching next week, it's We're jumping but who knows maybe you're ready to partner with everybody in the industry Yes, we're ready to partner with anybody in the industry and bring this technology to the market Can I send you some money?  I'm pretty sure I will not do that But if I did I would use wise it's really amazing. You can send money all over the world 150 countries You can send money to India. You can send money to the US. You can send money to Malaysia Indonesia Korea Everywhere and then you get a local bank account. It's crazy. You get a bank account in the US and Europe It's really amazing and the fees are five to ten times cheaper than your bank So use it as a prepaid debit card buy bunch of stuff on the internet save some money when you buy stuff in different currencies Check my video where I explain a bunch of more stuff Why this is a smart way and use my link so I can make some money


I'm Perry Canoski and welcome to this month's edition of Kidney Cancer News. Research published in the International Journal of Cancer has shown that daily consumption of whole fruits and vegetables, especially bananas, is highly protective to kidney health. The results show that over 13 years women eating more than 2.5 servings of fruits and vegetables per day cut the risk of kidney cancer by 40%. Among the fruits, bananas were especially protective. Women eating bananas four to six times a week have their risk of developing the disease compared to those who did not eat this fruit. So as some of the other speakers have already alluded to, kidney cancer is really not one disease. It's a collection of many different types of cancers. I do believe that as we learn more about the molecular makeup of these tumors, we'll find even more breakdowns of different kidney cancers. And this is a slide that a lot of us show. This is from Marston Linehan who studies a lot of these inherited cancer genes. And as Dr. Chari already pointed out, these cell types look very different under the microscope. But there are roughly, there are several different inherited cancers that have given us a lot of insight into how to go about treating these cancers. And this is a list from the World Health Organization. This is their classification of some of the malignant kidney tumors that exist. And as you can see, clear cell is the most common type. But as you can see, there are many other types of cancer that don't really fit that classification. And that's what we're going to, what I'm going to talk about today. So what is rare? Well, papillary kidney cancer is 15% of all kidney cancers. So I don't really think it's rare if you multiply, if you take 15% of 40,000 cases, it's still thousands of patients that are affected. And chromophobe is 3% and the others make up an even smaller proportion of those. But I think you can consider these rare because they are rare to industry. And it's hard to get people to focus their attention on these kinds of cancers because the squeaky wheel, it isn't, you know, there aren't as many voices shouting about these particular types of cancers. And as Tony already alluded to, sarcomatoid features are these little spindly cells and they can arise from any of these other types of kidney cancer. So the cells can actually change into these spindly types of cells and that can sometimes make the behavior different. And the cancers come from different parts of the kidney. So clear cell and papillary cancer come from the nephrons, which are the area that's really kind of making the urine and breaking down the toxins in the body. But the distal nephron, which is the part that carries it more into the collecting system of the kidney, has other cancers that arise from it. And the chromophobe cancer arrives a little bit more distally as does collecting duct cancer. And somebody earlier in the audience this morning asked one of the speakers this morning about tumors of the lining and they're really collecting duct cancer is very uncommon, but it's kind of a cancer that's in between the upper tract tumors and kidney cancer. So we don't treat it as much like we do the more common types of kidney cancer and we do tend to treat it more like we treat bladder cancer, but it's still considered a kidney cancer. So there's a little bit of a gray area in there as well. This is a, Dr. Chowari has already lined this up for me, but the things that I'm going to be talking about are drugs that are attacking different targets. And VHL, as he alluded to before, is something that's a predominant target in clear cell kidney cancer. But there are other targets that are, these targets are also important in papillary cancer and chromophobe and as you can see it gets very complicated and I'll be mentioning these also when I'm talking about these rare histologies. So several hereditary syndromes have helped to advance the field and these are these syndromic things that don't occur in very large numbers of patients, but when we study these patients we learn an awful lot about how to treat the more sporadic kidney cancer. Bonhippalindo is an inherited clear cell cancer of the kidney. These patients are prone not just to cancers and cysts in the kidney, but these can also occur in the brain and in the spine and the eye and the adrenal glands and many different parts of the body. And about 40% of patients can actually have multiple tumors on their kidneys on both sides. And inactivation of the VHL gene is what's in their germ line, in their, not just in their tumors cancer cells but also in their body and that's driving this. So this is a picture of a patient of mine who has Bonhippalindo disease and this is an MRI and you can see these are his kidneys and you can see just there are just hundreds and thousands of cysts in both of the kidneys and most of us don't have that but by studying these unusual patients and looking at their tissue we can learn a lot about how to treat sporadic kidney cancer. Papillary cancer on the other hand is driven by other genes and papillary kidney cancer falls into two main subtypes right now and I'll say right now because we may end up in a few years dividing this into even more different subtypes but at least under the microscope type 1 kidney cancer has a kind of more regular distribution of the cells. It's the more common type of papillary kidney cancer but it's also a little bit more indolent in that the behavior can show up as hundreds and hundreds of little tumors in both kidneys but they might not spread so fast so at least early on what happens is that surgeons will watch this and when a kidney cancer gets to a particular size they'll take it out but they know that they can't get rid of all of the hundreds of tumors so a lot of it has to do with monitoring. But as the kidney cancer gets more aggressive and spreads one of the things that's been at least in the hereditary population important is this gene which makes a protein called MET and MET is a target that a number of different drugs are in development now for some of these drugs are specific to MET some of them are drugs that treat both VEGF and also MET and so they're important both in clear cell kidney cancer but they're also important in some of these non-clear cell types and some other things that have been discovered to be important in the type 1 papillary are the pathway related to MET which drives a protein called hepatocyte growth factor and hepatocyte growth factor is a common target of a number of different drugs for example Nexivar targets hepatic growth factor and that's why Nexivar is being looked at in liver cancer as well so a lot of these drugs are quite ubiquitous in the types of cancer we use them in but we think that a number of mechanisms including the blood vessel formation such as angiogenesis cell proliferation and also motility of cells may be important targets whereas hereditary papillary type 2 cancer is a very different cancer it's much more aggressive in its growth it can come up very quickly it can spread very quickly the cells look very different under the microscope there's more of a reddish or an eosinophilic component to the cells and in the hereditary form of papillary kidney cancer the type 2 patients can sometimes get tumors involving the uterus and also tumors involving muscles within the skin so they can get bumps on their skin and in this particular cancer the fumarate hydratease gene defect has been found to be an important mutation next slide this is back to if any of you ever took organic chemistry this is the energy cycle that's present in the mitochondria and what we're finding is that different enzymes in this energy production pathway are important in different kinds of cancer so here's fumarate hydratease it's important in this part of the energy metabolism but down here for example sesanil coa or sesanate dehydrogenase is important in a tumor called pereganglioma which is a small tumor that sometimes shows up right next to the kidney and then in the glutamyl pathway which is down here that's been found to be very important in brain tumors so there's a lot of this is a very important pathway for some of these aggressive cancers this is a slide that shows some of the experiences that have been captured for non-clear cell kidney cancer and I think that the biggest thing to point out in this slide is that these are going back to some of the big studies that were done in kidney cancer in general so some of your big expanded access trials and the big first phase 3 trial for Satora cell and so there were hundreds of patients enrolled on these trials and we weren't back at that time there wasn't as the bigger phase 3 trials were directed toward clear cell but as the drugs became more available for you know before they went to commercial availability there were these expanded access trials and in these some of the patients who enrolled registered to have access to the drug had non-clear cell cancers but a lot of these patients had what we call mixed histology so they had both some clear cell parts of their kidney cancer and also some non-clear cells so looking back retrospectively at these we can see that there were some responses to sutent and also to nexivar or seraphonib and there was also activity in temsarylimus at least or torus cell but most of these studies are kind of looking back in time and then this is Dr. Chowari's report where he went back and looked at 41 patients and saw a much smaller response to these patients and these patients I think were more pure papillary cancer and this was a prospective study that was done here at MD Anderson of 23 patients and I didn't put the number here but it was a very low response rate of about 2% or so and what I would say about these studies is don't get discouraged because even in this grouping where these studies were looking at papillary maybe pure papillary we're not looking at whether you know what kind of mutations these patients had and so there may be big differences in patients even in the papillary subtypes where some of these drugs would still work and they might not work in other patients and I think the take home message here is that we really need to look at these in a more integral marker kind of sense in where patients have biopsies and analysis of their tumor specimens and then we look at these tumor specimens after they've you know get perhaps more tissue after they've been treated to see are we hitting targets and this is a list this is an excellent review that just came out and this is a review of some of the different strategies this is for papillary type 1 so this is there have been antibodies now that have been directed against hepatocyte growth factor some against met and then there are other drugs that directly inhibit the gene and don't inhibit kind of the molecules that work against the gene or the protein product and these are some of the therapies some of which have been completed and some of them are ongoing and Dr. Bukowski is going to talk about clinical trials later on this afternoon so I won't spend a lot of time focusing on these but it just shows you that there's a whole range of new molecules that are being looked at in papillary kidney cancer and I think a particularly interesting one is this Excel 880 which is for ratinib and this was a trial that was open to patients who either had a mutation of met or were hereditary or where we didn't know anything about the patients and the company collected information on all of these patients and I was under the impression that they're going to go do a phase 3 trial of this but I'm not sure that that's up and running and where that is in its current form and then for the sporadic papillary again we don't know quite as much about it but the approaches that are being taken are similar to what we're seeing in the hereditary and then for hereditary papillary type 2 there's definitely this inactivation of the fumarate hydratease gene and there's some rationale based on the HIF production that results from this that VEGF pathways are important there was also an EGF trial of erlotinib that was done in papillary renal cell and there was an improvement in survival and based on that there are a number of different trials going on some of them looking at a kind of a dual anti-angiogenic approach with bevacizumab and erlotinib and there have been responses in that as well what I'd say about sporadic papillary is we really don't know a lot about it yet but MIC activation may be playing a role and so MIC is a very active tumor oncogene and perhaps some of the approaches that we use in some other solid tumors such as lung cancer may be important in approaching this cancer as well so the conclusions for papillary are again we need prospective trials with integral markers to really determine which patients with papillary kidney cancer benefit from VEGF tyrosine kinase inhibitors, mTOR inhibitors and other agents but the standard of care for right now are really to include any and all of the commercially available agents for renal cell except perhaps hydro-center lukin-2 and I'd really like to make a plug for participation in clinical trials I think that's really the only way to move the disease forward I'm going to go a little bit more rapidly over these this is Burt-Hogg-Dubey which is another inherited disorder and what I'd like to say about that is that a proportion of chromophobe tumors arise from oncocytomas and there's a mutation in the Burt-Hogg-Dubey gene which leads to this kind of aberrant production of this folliculine protein and this is perhaps important in again in energy metabolism and there's some data to suggest that mTOR inhibitors such as temserolimus or a virulimus may be potentially important therapies for this subtype this is an overlap just to show you how complicated this is this is Burt-Hogg-Dubey, this is something called multiple endocrinoplasia these are people that get many different kinds of cancer and this is tuberous sclerosis which is another gene that affects that part of the pathway called mTOR and leads sometimes to mental retardation, to brain tumors and to a lot of other unusual kinds of malignancy but there are some overlaps in some of the syndromic things that we see here and this is a patient of mine who took a picture of his skin he has the Burt-Hogg-Dubey gene and these are fibrophiliculomas so these are kind of they have a kind of a whitehead appearance this is a very close-up picture he took of his cheek and emailed to me and it's unknown again in sporadic chromophobe if Burt-Hogg-Dubey plays an important role certainly we see kit overexpression and so that lends some interest to whether and to satinib all which have kit as one of their targets may be an important important things to explore but these drugs historically have been looked at in mutated kit not overexpressed kits so again it's very complicated but these are things that are falling out of what we're learning by studying these cancers up front and there has been some reports of improvement 25 percent response rate in non-clear cell in a population of patients who had sous-tent and then there are some other you know an mTOR certainly has a role here but my conclusions for chromophobe again are that chromophobe can behave quite indolently initially and so local therapies may help to control ablative therapies may be important in this but commercially available drugs or a prospective clinical trial that enrolls non-clear cell with integral markers would be a good thing to consider here and then sarcomatoid kidney cancer as we said before can be present in any of these but it's characterized by a kind of a switch to a much more aggressive form of cancer and it's thought to be represent a biologic transformation to a more aggressive behavior so patients who have these in their kidneys at the time the kidney is removed may have a much more aggressive active cancer and this is an area where I think we can say that chemotherapy does have some activity and not just the targeted therapies so this is a busy slide that shows a number of the clinical trials that have been done in sarcomatoid renal cell and this was a trial that was initially done in New York by Janice Dutcher and David Nannis looking at some very aggressive renal tumors of which a large proportion were had sarcomatoid features and they saw these responses in these patients but I think what's the most interesting is that some of these patients had quite durable responses and I realize I made a mistake in the slide this should be here and this should be here so they did a follow-up report and four of the patients that were on this original trial had a remission that was longer than two years and two patients were six and eight years since completion of their treatment we followed up in the Eastern Cooperative Oncology Group and did another clinical trial using the same regimen which is a gem cytobine given at a higher dose, 1,500 milligrams every two weeks and doxorubicin which is also known as Adria mycin and that's given intravenously every two weeks and you have to get the last to keep your blood counts up it's a pretty intense regimen but we looked at patients and 38 of these patients had one complete response, seven partial responses and 10 stable disease and this was a trial that was open all over the country whereas this was a two instance tuition study and so sometimes we do bigger trials all over the country to see if in real life if there's a bunch of different doctors treating with this regimen does it work as well as if you have just a couple of doctors working with the regimen and I think that we also confirmed that we had some patients who did better for a two year period of time or longer and that's how long we followed them but there's been movement in the direction of looking at targeted therapies and so up in Boston, drawer Michelson and his group looked at a small trial where phase one where they treated patients with gem cytobine and a lower dose of suthent so 37.5 milligrams of suthent and in this small, in the initial small group of patients and I think he's treated a larger number but I don't have the updated information about a third of these patients had responses and so that lends some credibility to combining chemotherapy with targeted therapy in this approach and others have taken this farther this was a review that the Cleveland Clinic did of their patients who had sarcomatoid renal cancer features they went back and looked at who got VEGF targeted therapy so who got retrospectively bevacizumab or suthent or seraphonib and they found in 43 patients that there were four partial responses and 20 stable disease and so they did see responses in patients it did seem that the patients who had less sarcomatoid features did better if they had more clear cell it was more useful and others have taken this and combined different chemotherapies gem cytobine with an oral 5FU based drug and then bevacizumab this one was, can't report everything, but this was done up in Chicago and they again saw some well tolerated and some partial responses and oh and I missed Taurus cell down there in the analysis of the ARCS trial they also had sarcomatoid features and had some responses so I'm going to, in the interest of time, skip over this this is the ECOG trial, but what I wanted to point out here is we broke it down into as much as we could and this was kind of a disappointment because we weren't able to get tissue from all of the patients even though it was an eligibility requirement we had a lot of patients where we couldn't actually get the tissue to follow up and be sure of this but in looking at what we know the patients we did see responses in patients who had a lot of their tumor replaced by sarcomatoid features and we did see responses in both clear cell and non-clear cell cancers with this regimen so what I would say is that, I'll skip over this but I think the doxorubicin and gemside bean therapy can lead to durable remissions tyrosine kinase and mTOR inhibitors have some activity and combinations of angiogenic therapies are an area of intense focus and then I wanted to just briefly talk on some kind of cool tumors that have popped out recently and Dr. Chowari is getting a lot of attention at this talk he's done a lot of this work this is his slide from a paper and this is a fish analysis which is staining showing that these chromosomes have moved around, parts of the chromosome have jumped to another chromosome and they've created a protein together and caused these fusion proteins and it's now recognized that a proportion of mainly clear cell cancers can be these translocation tumors and I think it just points out that we're getting to realize that more and more of these cancers are very different when we look up close but the bottom line with this is there may be a particular kind of a tubular papillary pattern that we see with these under the microscope but there have been two reports now looking and it does look as if some of these cancers at least respond quite well to the standard therapies that we use in clear cell kidney cancer and then finally this is a very unusual kidney cancer this is medullary kidney cancer this is present only in young patients generally African American who have sickle cell trait and probably due to inflammation of the medullary portion of the kidney it's a very very aggressive disease uniformly fatal in almost everybody and we typically use approaches such as chemotherapy and bladder cancer there were some reports I guess MD Anderson did an analysis of their patients and found that patients who got anti-angiogenic therapy bevacizumab based therapy seemed to do better in combination with chemo and then recently there was a report of a mutation in the ALC gene and there are now ALC inhibitors that are under development so another area to branch out and then finally collecting duct cancer is as I was mentioning before it's of the lining of the kidney but it's not quite a protract tumor it's kind of a transitional area between kidney cancer and yourothelial and we tend to treat those also with chemotherapy agents so these are trials that are directions that I would point people to for consideration of therapies and I listed here the adjuvant trials because these are adjuvant trials that are open this is open in the United Kingdom this is imminently open in the US and the Usur trial is now closed but these all are enrolling non-clear cell patients and I'd like to make a plea that if anybody participates in this please please let us study your tissue so we can learn more about who would benefit so final conclusions what is it for you the more we look at kidney cancers I think the more differences and the more complicated it gets but the molecular characteristics that we're identifying are opening new avenues indeed and your participation in clinical trials and willingness to allow characterization of your individual cancers is crucial for advancing the field and I'll stop there, thank you very much join us again next month for another edition of kidney cancer news I'm Keri Konoski wishing you good health Hi, I'm Denise Richards in 2007 I lost my mom to kidney cancer like most people who are diagnosed with this disease my family didn't know much about it and unfortunately by the time she was diagnosed there wasn't much that could be done so I'm asking you to help the kidney cancer association stop the pain and suffering caused by this disease check out kidneycancer.org for information on how the association is helping patients and their families through research, education and advocacy and please consider making a donation by clicking on donate now and help us achieve our vision of a world without kidney cancer