So it's my one of the pleasures of being at a place like Stanford is part of our mission is to is to do research is to deliver good clinical care but part of it is also to train our next generation of trainees so it's really my pleasure to have young people like Shemit Shah who's a medical oncology fellow he did his medicine training up at UCSF and then joined Stanford as an oncology trainee he has had significant interest in working with our group I think has made a good choice and is interested in urologic oncology so it's really my pleasure to have him talk to us about how do we pick the best therapy for systemic therapy for kidney cancer and I'd like to thank him for coming on a Saturday where he brings his little child so that they can be part of our group as well so thanks Shemit thank you very so thank you very much to Dr. Srinivas for this wonderful opportunity like you said my name is Samit Shah my third year oncology fellow here at Stanford I've been very fortunate to be trained under the tutelage of Dr. Srinivas so if if this talk goes terribly or if you learn nothing you know who to direct your comments towards and I also apologize in advance like Dr. Srinivas said my two-year-old sons here as well as my mother and I know that I'm 35 years old and still bring my mom to my talks but everyone has a number one fan and she's mine so so before I actually talk about the evolving landscape of treatments for kidney cancer I should step back a bit and say that we are in a very special time in oncology and over the last 50 years we've seen a considerable amount of headway that has come in the form of cancer therapeutics and I think that no one else actually describes this better than Dr. Siddhartha Mukherjee in his book The Emperor of All Malades and if you haven't had a chance to check out this book I highly recommend it to all of you history buffs out there I think to to gain an appreciation of where we are in cancer treatments right now it's important to look back to where we've started Dr. Mukherjee has essentially written very eloquently on cancer biography and in this book he actually talks about the four pillars of cancer therapy the first pillar being surgery so if you ask a surgeon what to do with something that's abnormal in the body they're gonna tell you to cut it out right seems very logical and then at the turn of the 20th century we actually saw the rise of what we call radiation treatments radiation treatment using high-energy beams to essentially create DNA damage and kill these rapidly dividing cells which we know as cancer and then what happened after World War two was actually very interesting we saw the rise of what we call chemo therapeutics which is revolutionized the field of oncology in a lot of ways one of the first chemo therapeutics was actually nitrogen mustard gas believe it or not which was actually used as a weapon in World War two what happened is that we actually saw soldiers when they were coming back from the war who were exposed to nitrogen mustard have toxic effects in their bone marrow and while that was unfortunate a lot of researchers were thinking hmm that's interesting perhaps we can reset the bone marrow and give these patients with leukemia nitrogen mustard and see if that works and lo and behold it did and that gave rise to the whole field of chemotherapy and has really revolutionized the way we we treat cancer these days and then the last decade has actually been very exciting because we've seen this development of what we call targeted therapy targeted therapy has given rise in the last decade or so because of our improved understanding of the molecular pathways of cancer specifically in kidney cancer we know that VEGF for instance which is Vasculin and Othelial growth factor plays in a very important role in having tumors recruits and develop blood vessels okay so to allow the tumors to grow by developing his own blood supply so if we were in theory able to develop an inhibitor or a drug to target that one VEGF receptor we could in fact shrink these tumors by cutting off this blood supply for these tumors in a different pathway we know that met or sorry mTOR also plays a very important role this is mammalian target of rap demycin is a essentially a protein that is a signal that tells the cell that needs to replicate okay and if we can actually target that mTOR pathway we know that we can actually shut down this entire process of kidney cancer and so you've probably have seen drugs like Tensorolimus or everolimus also known as a finitor being used in this application okay so this is actually very reflective of this explosion of medications and therapeutics that has occurred in the last decade in 2005 we saw the emergence of seraphid which is one of our first what we call a tyrosine kinase inhibitors or one of these targeted agents that we're using and then Sutent which is a medication that many of you may have been on in the past or on currently as a first line agent for metastatic kidney cancer okay when kidney cancer has actually left the kidney and gone to other parts of the body we typically use Sutent or another drug you which you may be familiar with is Pozopinib or Votrient which was FDA approved in 2010 okay so there have been a number of targeted agents over the last decade and even in the last six months we've actually seen two new medications that were just approved one was Cabozantinib just a few months back and then as little as two months ago we saw the FDA approval of Levantinib with everolimus so it's actually a very exciting time and compared to many other cancers we actually feel that we're very fortunate to have so many weapons in our armamentarium to attack kidney cancer so this is actually we do feel that in some ways this is a luxury now going back to our analogy of the four pillars so we talked about surgery, radiation, chemotherapy and the most recently targeted therapy in the last decade but now we're actually in a very new brand new era of oncology as extremely exciting actually a lot of the gray hairs from Stanford are actually staving off retirement just to come back into the game and even my son is excited about this and and because of this brand new field of what we call immunotherapy right and I'm sure you've all heard about this in the past but we're all incredibly excited about where this platform can take kidney cancer over the next decade or so in fact the immunologist at the the leader of immunology at Johns Hopkins was quoted as saying I have such confidence in the potential of immunotherapy that I think the years from 2010 to 2015 will be looked at historically as the time that immunotherapy became the fifth pillar of cancer treatment okay so there's a there's a lot of hope there's a lot of expectations on what we can do with this type of therapy so what exactly is immunotherapy so that I think there's a lot of a lot of different answers to this question you know is it vaccine therapy is it cell adoptive therapy there are a lot of ways to answer this my simple salute my simple answer when patients ask me is I say that it's a way for the body to harness the power of the immune system to fight cancer okay so we're using that we're using the power of the immune system to fight cancer in a way that we haven't been able to do before okay and a lot of people think actually that a lot of people think that this is a brand new concept that this is something that was just developed in the last couple years there are all these fancy drugs out there there's all these fancy ads that you see on TV but in fact the origins of immunotherapy started much earlier actually back in 1891 okay and it started with this man Dr. William Coley who was a oncologist who dealt with this cancer soft tissue sarcoma and Dr. Coley noticed that the vast majority of his patients were dying unfortunately but when he actually went through the charts of his patients he noticed something actually pretty intriguing there was a couple of patients who actually exceeded expectations and lived much longer than they should have okay back then in the 1890s the average expectancy for someone who was with advanced sarcoma would probably have two to three months at the most and these patients were actually living on beyond a year and some of them were actually cured of their disease so he was looking through the charts and actually came across something that was actually very interesting about these patients he noticed that each of these patients who lived a lot longer than what was supposed to each had well each contracted infection with this bug called streptococcus pyogenes and then what happened later was even more interesting is that all these patients actually developed a facial rash called erycypolis and so Dr. Coley was thinking hmm though this is interesting all the patients that did well developed this facial rash and their tumors actually started to go away so he had one of two hypotheses one is that this bacteria streptococcus pyogenes is actually killing the cancer cells which we now probably know is probably not the case or a second hypothesis is that because of this facial rash we've actually essentially woken up a dormant immune system okay and now this immune system is revved up ready to go and fight something and it happens to actually fight this cancer so what's the next most logical step that Dr. Coley did well you go out there and start injecting patients with streptococcus pyogenes of course so which is actually a very interesting he actually started doing this in 1899 and they called this Coley's toxins where he would actually take a vial of streptococcus pyogenes and inject it into patients veins so the good thing is that he actually saw remarkably regressions of these tumors these tumors started to actually shrink and people no longer died of their sarcoma the bad part is that they started dying of streptococcus pyogenes infection so but regardless it was at that time in the 1890s kind of the dawning of the era of immunotherapy so that's really where we attribute a lot of the origins of immunotherapy and we contribute we now attribute Dr. Coley as kind of the father of the field now our understanding of immunotherapy with modern-day science is a lot more mature than that of course we do understand that there are relationships between the immune system and cancer so this is a group of patients who were who have undergone a kidney transplant okay so after a kidney transplant you're on medications to suppress your immune system so you're effectively immunosuppressed the reason we do that is because we don't want your immune system to reject your new kidney that you just received however if we follow out these kidney these kidney transplant patients for 20 years we see that they also carry a significant risk of cancers and you also see this in HIV patients and other immunocompromised patients okay so in this graph here you can see that the risk of developing skin cancer lymphoma or sarcoma is 20 fold higher if you are a kidney transplant patient who was on immunosuppression which is actually quite interesting the risk of developing kidney cancer is also 15 fold higher for patients who are immunosuppressed so we do know that there is this balance between the immune system and developing cancer and the hope is now that we can then harness that fact and use the immune system to cure cancer in the same regards so actually one of the first therapies that was used back in the 1960s of immunotherapy was happened to be actually in kidney cancer and that's IL-2 I don't know if there may have been a handful of you that actually had this therapy in the past and this is actually at the time was an extremely exciting exciting drug so IL-2 is a type of cytokine or an immune modulator and what it does is actually non-specifically kind of accelerates or revs up the immune system it's not cancer specific like some of the things that we have today potentially but it is just kind of a general booster of the immune system maybe liking it to something that you get a Jamba juice when they put into your milkshake but on steroids though so but this is with a very exciting drug back in the 1970s and when we actually gave this to patients with kidney cancer with advanced kidney cancer we saw something miraculous so this is a Kaplan-Meier plot and you may have seen a few of these throughout the day but essentially the takeaway is that the higher the up you are on the curve the better you are okay on the y-axis there is the proportion of patients who are surviving over time and on the x-axis this is survival in years and this goes all the way out to 20 years and you can see that there is one group of patients 20 patients out of 250 that they looked at that's surviving for 20 years after IL-2 therapy and this is with advanced disease and so these patients all had of what's called a complete response meaning that their tumors completely vanished after giving them IL-2 therapy and so 20 patients out of 250 is around 10% so you're getting a 10% cure rate with with with with for metastatic disease which is still even to this day pretty much unheard of right none of the therapies that we have is actually could give you a 10% therapy even to this day and back in the 70s and 80s there was multiple case reports going out as IL-2 being the cure for kidney cancer and you can see here on your left that there is a large tumor in the patient's liver okay the darkened area in the in the liver there and then you can see after a few weeks of IL-2 therapy that that liver lesion completely disappears so back then again it was thought as maybe this is the big breakthrough that we've been looking for the problem with IL-2 though is that it's extremely toxic to the body so we actually give it extremely rarely even today unfortunately there are ways we're trying to figure out ways to make it a little bit more amenable to safer for patients but unfortunately it's very very very toxic so the patients who actually get it tend to be very young very healthy very fit and with very good kidney function and even then we tend to give it in the intensive care unit just because the risk of mortality is so high from the treatment itself so we're hoping that we can figure out ways to make this a little bit safer drug but right now we typically don't use this the very often especially in our patient population which tends to be a little bit older so fast forward now so that was back in the 1970s the the landscape of a cancer immunotherapy is very very different than it was even 30 years ago there's a lot of buzz about it and you probably have seen a lot of this in the news it's on the cover of news week it's on the cover of Time Magazine even our former presidents have had immunotherapy which is quite remarkable you may know that Jimmy Carter was recently diagnosed with metastalic melanoma so he actually had melanoma skin cancer that had gone not only to form his skin but also to his lungs into his brain now reportedly we don't treat Dr. Mr. Carter but he reportedly has gone into complete remission after immunotherapy he's been on several cycles of therapy and now even his brain metastases have even completely cleared which is which is pretty much a very very rare to hear in any patient but this is really remarkable though so there's a lot of hype about where we can go with this type of therapy this date November 23rd 2015 turns out to be a very important date in kidney cancer for patients with advanced disease because this was the date that this drug nevolumab op-devo was FDA approved okay and you may have also seen all the ads of op-devo Bishul Mahler likes to put these on over billboards all over San Francisco so you may have seen these this chance to live longer so to speak but you know the big question is like what does nevolumab actually do and how does it actually work okay so I don't know if a lot of you have I've had the opportunity to learn a little bit about how nevolumab works but I thought I would give you a slight introduction today so as opposed to talking directly about nevolumab initially what I'll do is give you a little primer on immunology 101 which you may remember from your grade school days so I'll give you an example so what exactly happens when you get the flu right so you you get the flu you take some chicken noodle soup you take a little bit of honey water and lemon water whatever your mom told you to take when you're 10 years old and everything gets better within two weeks right you're back on your feet you go back to work you didn't take any IV medications you didn't take any chemotherapeutics and all of a sudden your body figured out what to do right so what was actually happening so it turns out that you had these T cells that are floating around your body right these T cells are your natural defense mechanism against anything any foreign substance right and they're just waiting to kill something and so what happens is that it needs to be told what to kill so what does that then so then you have this called these antigen presenting cells in green here so these antigen presenting cells are going around the body looking for foreign substances so this antigen presenting cell will find a piece of flu molecule or a little bit of the flu and we'll gobble that up and present it to this antigen or to this T cell and once it actually engages with this T cell you have what's called an activated T cell and now you have a programmed killing machine it is going around the body looking for the flu and we'll kill it wherever it finds it that's pretty remarkable right and now the big question is why doesn't this work in cancer right shouldn't your body recognize that you have kidney cancer have as old particle go up to these T cells activate them and then fight the cancer that's exactly what it should do right but why isn't it doing that well there is a big discovery that was made just in the last decade which has actually been quite intriguing and we found that cancer has actually developed this white flag and it's waving this white flag and basically telling this the immune system I'm one of you guys don't eat me okay so these cancers are unfortunately you're very very smart so this this white flag happens to be called PDL one so PDL one is the white flag on these tumor cells that's basically it's a way to evade the immune system right so when the immune cells come in it engages with the immune system with the with the tumor cell and what does the tumor cell tell the immune system it says don't eat me okay so it's essentially saying don't eat me don't attack me I'm one of you guys so then how does Nevolamab come in and work against this process so Nevolamab then comes in and targets this interaction between the tumor cell and the immune cell okay between PDL one and what's called PD one and it blocks that interaction effectively lowering this white flag so the white flag is now lowered and you've taken this invisible cloak off of cancer and you're now changing that don't eat me signal and reversing it into a eat me signal and then what do you what happens next is then you have these immune cells come in and gobble up that tumor cell right so that's actually how Nevolamab works which is actually really interesting but now you're thinking well that's great doc but does this actually work right does it actually work in patients so that's the big question and you know we're fortunate at Stanford to be you know very evidence-based a research institution so we were part of this trial as well and dr. Schrinne-Voss was as well I should say as part of this part of this trial looking at a phase three randomized trial of Nevolamab versus Everolimus okay this is called the checkmate 25 trial it was a big lame mark trial for kidney cancer and they were taking patients who were with advanced kidney cancer and there were about 800 of them for 400 of them they put into a group that was getting the immunotherapy Nevolamab and they're getting a dose every two weeks and then the other the other group was getting Everolimus which is one of those targeted therapies that was discussing earlier and they were getting that daily every day okay and then they look to see how these patients do over time so they look over the next several months and years to see how they how they do so you should know that whenever you're thinking about clinical trial you should always ask yourself am I the type of patient that would have been on this clinical trial right because in the end this clinical trial only applies to the patients that represent so who are these patients so these are patients who are meeting age of 62 years old okay so our which is about average for kidney cancer so it is representative of our patient population that we see here at Stanford the performance status for these patients was 90% on a scale of 1 to 100 okay which means that these were relatively fit robust patients that were doing well pretty healthy so if you're feeling really really sick and not be able to get a bat out of bed probably not the best drug for you potentially and all these patients did have prior therapy so they had been on Suthent they had been on Pazopenib they had tried Exitinib so they have been on prior therapy and again please remember that these are patients who have had advanced cancers either metastatic largely metastatic tumors though okay and so what happened with the overall survival here well this is another Kappa Meyer curve looking at patients on the top line is nevolumab and the yellow line is everolimus and you can see that there is separation between the curves again the y-axis here is the proportion of patients who are surviving and the x-axis is time and months and you can see that there is a difference between how each group does and we do have a rule of thumb in oncology and is called the rule of thumb what you do is actually you take your thumb and see if you can put it in between the two lines all right and if you can't fit your thumb in between lines the drugs probably not worth its lick but in this situation I think you can actually say that you know that you can put your thumb your thumb in between those lines so there is an overall difference but was that it's a big screen it does it does kind of depend on what what's kind of screen you have but you can put your you can put your thumb there and say hey there is a difference and I think more importantly though is that we're starting to see this tails potentially diverge even more okay now we're starting to see that if you respond to immunotherapy you actually have a very prolonged response and so if we look at the objective response rate so what are the chances you'll even have some kind of response to this therapy you see that in 25% of patients with nevolumab they were getting a response meaning that they were either getting stable disease or potentially regression of the tumors or in very few instances one percent of patients they were actually getting a complete response meaning they were disease free after getting nevolumab okay so that's good okay because if you look on the other column ever all of us they're only 5% of responders there right so the thing is we're only getting right now though 25% of patients to respond to this therapy so the big question is how do we get that 25 into 85 into 95 into 100 right that's eventually the goal but right now we feel that this is potentially a good platform so what are the side effects of these medications right like we talked about IL-2 before being too toxic do we see the same kind of toxicity profile in nevolumab well not quite actually it's actually in the in general pretty well tolerated so we see that in 80% of patients that there was some type of side effect that they were having 20% of patients actually had no side effects and the most common side effect was fatigue in about a third of patients rash was seen in 10% of patients pneumonitis or inflammation of the lungs was seen in 4% of patients an anemia which is lowering of your blood counts was seen in a handful of patients as well but this is actually very much in parallel with what we know about immunotherapy in general right because if you imagine basically what we've done is taking the brakes off the immune system right we're letting we're letting their immune system run rampant so you can imagine that it's not only attacking cancer but now it's potentially targeting other parts of your body right so it's not completely unreasonable that you might have effects of what we call autoimmunity so pH patients can get hypothyroidism they can get hepatitis or inflammation of the liver you can have adrenal insufficiency or a decreased amount of hormone and steroid that you're putting out so you may have to be on steroid replacement you can have rashes pneumonitis which I said before which is inflammation of the lungs and you can also have colitis which is inflammation of your colon which is manifested typically by diarrhea so these are all side effects that are seen but in general I would say reasonably well tolerated though so the next question is how long do you actually treat for which I think is actually one of the most interesting questions that has been asked in the last year so it's very different than the way that we actually treat for chemotherapy okay in chemotherapy we actually treat for a certain amount of time and after eight weeks we get a CT scan right and the CT scan was if we see progression or enlargening of these tumors we stop therapy and we think about giving you something else but in immunotherapy we actually think about going if you actually progress after eight weeks meaning if these tumors look larger we actually may still keep on going okay and this was actually looked at when we looked at that old trial that we just talked about just a few minutes ago there were a number of patients who were treated beyond progression again they were treated even though their CT scan showed enlargening on the CT scan okay and the reason why we do this is because of a phenomenon called pseudoprogression so what is pseudoprogression so pseudoprogression well I'll start with actually regular disease progression which is the traditional model so it's what I was saying before you get you have a baseline tumor eight weeks later the tumor grows and then eight weeks after that if you check again it grows again and now you have yeah you're absolutely sure this tumor is growing and you take them off therapy put them on something else on the first on the first row you see pseudoprogression so that's your original tumor and then eight weeks later you actually if you get a CT scan or a PET scan you see growth on these on the CT scan but the issue in this situation is that doesn't necessarily represent tumor it could also represent immune infiltration so those immune cells that we discussed earlier are now infiltrating the tumor and make it appear bigger but it's actually not bigger so if you keep on treating eight weeks later you actually may see a regression of your tumor okay so it's a possibility we're still not in the days of the exact science of what do we know whether to keep on treating beyond progression or not we we try to if we can sometimes the tumors get overwhelmingly big after after eight weeks and we feel that maybe this is not safe to keep on going so there's a lot of judgment right now but it is a little bit of a slippery slope but there is this concept that you could do this and this is actually proven by data as well so this is a waterfall plot which I think is a little bit tough to interpret if you've never seen one of these before but essentially there there's the zero access there and all of these blue lines represent patients and if the bar goes up that means that their tumors have actually gotten bigger after they've already progressed okay these are all patients who've had progression at one point in the past and now the next time point you're seeing what happened to their to their tumor size and you can see all those patients on the left there their tumors actually did grow so they would to be taken off therapy but all these patients on the right side you can see actually had a response so their tumors actually shrank despite them growing earlier and you can see about 15% of these patients they've had about over a 30% reduction of their tumors despite progressing earlier which is actually quite intriguing though again this is very very different than we've ever treated with regular chemo therapeutics so where do we go from here so I think that one of the they just pick Saturday so at least I hope we all feel that our institution is safe and they're doing periodic tests that's right but it's really not a true alarm so we can continue yeah okay what's that yeah this talk is on fire that's all right um so um so the the combination trial thank you the the next directions I think are in combination therapies so we're going to be using multiple of these immune checkpoint inhibitors which was as I was looting to earlier so it turns out there's not just pdl1 we talked about pdl1 being or earlier a pd1 uh being a way to escape the immune system right it turns out there's multiple white flags that cancer has not just one so it's very very tricky there are also many what we call uh activating receptors that these immune system has so these are ways if you can actually stimulate the immune system on another way to actually encourage the immune system to fight cancer so there's there's uh inhibitory pathways and also stimulating pathways and now we're trying to figure out can we mix and match the drugs that we have to see if we can do even more than what we've done before right so we're trying to mix and match like these pd1 inhibitors like nivolumab with potentially a cd27 receptor on the other side which actually stimulates the immune system so we're actually doing this here at Stanford Dr. Srinivas and I myself are involved in this clinical trial where we're looking at a anti-cd27 antibody to stimulate the immune system and then in combination with nivolumab which which we just discussed as a way to take away this inhibitory effect of the immune system right and so we're now we're using this in combination to see if we can use two immune drugs to further enhance the immune system which is very exciting uh potentially up the pipeline as well as vaccine therapy right so you may have heard of vaccine therapy uh vaccines in cancer are a little bit different from the vaccines that you get when you go to wall greens or your primary care physician for the flu uh you these don't necessarily prevent cancer in this the way it's being used right now this would be for patients who have actually already have cancer so what we do in this situation is a personalized vaccine approach and this is actually for a company that we may be working with in the future we don't know uh and you would actually take a biopsy of the patient's tumor so you take it the patient's tumor biopsy it and sequence it okay so you get the genomic library of what actually is composed of that tumor and then you actually look to see if there are certain neo antigens or uh particles or proteins that are specific to that cancer that the immune system can recognize so you've sequenced it you find out what makes that cancer so unique about your cancer and then you make a vaccine out of that and put it back into the body so now your immune system can figure out hey that's a bad guy I need to go figure out where all the other bad guys are too and it starts to destroy the cancer so that's called a personalized vaccine approach and that will be in the pipeline as well okay so uh that was a little primer about immunotherapy I mean there's a lot you could talk about about cancer therapeutics and I think that for our purposes I kind of wanted to focus on immunotherapy just because it's such a you know in the news these days and a very you know hot topic um so just to kind of recap about what we talked about is that you know we've made enormous progress over the last several decades but in the last decade with between targeted therapy and uh immunotherapy and I think the future is incredibly bright for for kidney cancer uh we know now that the immune system and cancer have this very close and dynamic relationship uh and that cancer may arise because of weak weaknesses in the immune system but potentially can be cured if you can strengthen the immune system we know that immunotherapy such as the checkpoint inhibitors that I talked about earlier this is nivolumab uh do work very very successfully in a subset of patients so we know that 25 percent of patients will respond and those those patients may have a very prolonged response which is quite remarkable the question is how do we increase that 25 percent um and now you know the question is how do we use these immunotherapies in different settings so right now we're using in metastatic patients right when the cancer is spread outside the kidney but can we use it in the adjuvant setting meaning after you've had your surgery can we give you immunotherapy or potentially can we use it as maintenance so if you do have metastatic cancer and we give you and you have a very good response to sous-tent or or votrient instead of taking that toxic drug all the time could you be on immunotherapy and maybe have a prolonged response with that you know these are all ideas floating around that need to be tested and then the next steps as I talked about will be combination trials mixing matching these different immunomodulatory agents potentially these vaccine studies and then I think a very big you know concept is coming out right now is we need a very reliable biomarker to determine who's actually responding to immunotherapy right so it'd be nice to know if I take you know Mrs. Smith's blood and see a biomarker in there that says that she would actually be susceptible to this type of treatment then I'll be more inclined to be giving it right and so we need to start developing you know a better way of of a triaging patients to know who should get immunotherapy and who who shouldn't because we think it may not work okay so that's what I have for today I wanted to also thank all our patients we really are indebted to all of you I think you know the field has grown so much because of of your courage and your brave bravery and every day I come in to work incredibly inspired so I do thank you all for giving me a lot of meaning to what I do every day any questions yes hi was there any correlation between two more grade and the response one and two you talked about patient selection and biomarkers how do you push drug companies to actually invest money in developing companion diagnostics and biomarkers instead of jumping to first develop the drug that's a good question so you know so in these immunotherapy trials they didn't necessarily actually take a look at grade per se I mean it was looked at but it wasn't the one thing that actually had a big effect they did see that patients with a poor performance status or I guess who had a worse prognosis which does include grade end up doing better with immunotherapy so that's known but the big question was does the expression of pdl1 this protein the is the amount of that expression actually determine how you respond right so they actually looked at patients who had more than five percent expression of pdl1 on their tumors and less than one percent expression of pdl1 on their tumors and they actually realized that there was no difference it wasn't predictive okay it was somewhat prognostic but it wasn't predictive of how you would do a treatment so we're still not quite there yet and to answer your second questions actually there is for the for the pharmaceutical companies I mean that is a big field in itself they are all trying to figure out how to make a predictive biomarker what they want to do is make a predictive biomarker so that you can use their drug to do this there's actually a big market for it the problem is that no one's actually panned out to have a very good biomarker so one you know a bristle meyer's pdl1 expression assay may be very different from merc's and it's this there's still a lot of to be done in developing an accurate one so nothing's really accurate and that actually may be reflective of the fact that pdl1 is also a very dynamic process so when you actually biopsy that tumor at that time your pd1 expression may be very different than the time when you're actually getting treatment and so it's not as static as we once thought as well so i think it's a lot more challenging than we initially understood and so i think we still have some homework to do any other questions on the clinical trials a lot of times they exclude rare types of cancers and also the immunotherapies and all the drugs that they don't seem his cancer doesn't seem to respond to any right what what what do you do at that point yeah you just kind of try them and hope because there's there's like zero data right right i do think it's very very difficult when you have a rare tumor to get into some of these larger trials because what they're trying to do also is show just like we're showing that they're like each age group in each each group of patients was 62 what they're trying to do is balance these groups out so that way you have a homogeneity between the groups and if you have some patients some groups with you know rare type of cancers they may respond differently and they're just trying to make the groups as equal as possible i completely agree with you i feel that these patients should all be included personally but i think that in general i think that you know immunotherapy for right now is fda approved for kidney cancer you know so i think that it's a possibility that we can actually use it in the certain setting after a first line setting for kidney cancer regardless of the regardless of the indication the one thing about that is though is that we know that it may not always work either though okay that from that way what we've seen in other types of tumors that are similar to kidney cancer that immunotherapy may not be efficacious that's right boss do you want to i just want to say that the national cancer institute you know has come to recognize that for rare tumors how do we get them a novel drug and this has been a challenge because in order for a drug to be approved we need like thousand patients to be part of it so as part of this whole cancer initiative the national cancer institute has a trial called the match trial so they'll take people with rare malignancies and they'll have their blood drawn or their tumor typed and if there is an abnormal mutation that your particular tumor might have you might not have access to a drug but via this match trial they'll be able to match your mutation to a drug provided your cancer has that mutation so even if we can find a specific trial just for your cancer type at least there is a resource right now that should your cancer have an abnormal mutation they'll be able to link you with this appropriate target so we suddenly have that trial open here at stanford there are many academic institutions that are part of this match initiative so that might be one way around it yes so sumit i have a question about immunotherapy in general it seems like a lot of the immunotherapies are started in melanoma and then they come out to other areas and there seems like definitely different efficacy in melanoma versus kidney cancer are there any efforts to kind of personalize or at least specific get specific immunotherapies for specific types of cancer or is that still going to be the way it's going to it's a very interesting question it's an astute observation so a lot of these immunotherapy trials are done in melanoma first because we know that in general melanoma is actually a very immunogenic tumor so it's actually responsive to immunotherapy so why is that so it turns out if you look at the actual amount of mutational burden in melanoma it's actually very different than a lot of other cancers it's very very very high so we know that because of all this prolonged sun exposure that causes melanoma or for smokers that are that cause lung cancer there's a lot of mutations that are occurring right and so these mutations are essentially developing these neo antigens or basically it's more ways for the immune system to latch on and see the cancer right so these these types of cancers that have what we call a more of a mutational burden actually are better or more immunogenic and they tend to respond better so in terms of why why melanoma first I think it's because it's so you know immunogenic too is that drug companies obviously want to go towards something that actually works they can kind of move things along so that's the main reason though was that oh so then going back to well so kidney cancer itself has also been found to be very immunogenic though it also has a very high mutational load and it does respond very well to immunotherapy so I think that you know a lot of these trials were now be coming out and we'll start having some at Stanford as well but I would say in general everyone wants to do stuff in kidney cancer right now that it is a very hot subject and you know we're very fortunate in that regard we have companies coming in all the time trying to figure out you know can they work with our patients because it is a great opportunity so I think you know in terms of though if you talk to a drug company I think what everyone is looking at right now is melanoma potentially smoking lung cancer uh renal cell carcinoma and bladder cancer are for the biggest one so we're very fortunate to be dealing with two of those so yeah I think this will be a big a big thing in kidney cancer to that to that point you know I mean unlike other care previously we used to have specific chemotherapy for lung cancer specific chemotherapy for bladder cancer we don't treat them the same but one of the beauties here is that our body every one of us have an immune system so right now nivolumab or other checkpoint inhibitors appear to work in lung cancer they work in melanoma they work in head and neck cancer right now they are being worked at in breast cancer so I think in the next decade what we want to see is how can we manipulate a kidney cancer patient's immune system so that it works 100% of the time and such technologies have already come in where they're able to remove your lymphocytes and genetically um engineer it so that and put it back into the body so that it goes and fights the cancer cells those are called chimeric antigen receptors right now it's called CAR technology and they have gone forward with hematologic malignancies like leukemias are now given this and patients are in complete remission but that technology is being looked at in solid tumors including kidney cancer yes how much research and who is doing research on what cripples the immune system in the first place to become weak yeah it's a great question you know the base scientists are certainly looking at this there are theories everything from potentially this is even viruses causing this to you know we don't know exactly but you know I think that there there does need to be a lot of work into why these immunodeficiencies happen I would say right now it's not quite well known but why all these mutations happen but there is a lot of work being put into it and we're just not quite there yet yeah so neutrophil to lymphocyte ratio I mean it is being looked at an in kidney cancer also those are more prognostic they don't help us predict whether a treatment is going to work or not right now all of those just tell us that somebody's is going to do better or worse so thank you I'd like to thank Schmidt it's been an awesome talk


We're here at Panera Bridge, trying to get this bridge. I see me having a jade, you got all the Jordans. I got like over 200 pairs. Same big money at my nards. Order number three and four. We are here getting to this though. I need to exercise. Fridays, three items, 6.6 miles for $11. We are holla. Hopefully soon we will pop into our colligan. It's DDK, and I'm back to everybody's room. If you aren't subscribed, make sure you smash that subscribe button. Give me a thumbs up and do not skip those ads. Today is March 4th and we are about to get to this bag. We already got two orders. Order number one, we about to get it done. Well, we're not going to get this done. We're going to get the other one done. First, we're going to come back and get this one. All the way sparked up. Two orders, 9.6 miles for $18.56. We about to get in the mix. Order number two, what it do? Panera brand five items, .9 miles for $5.75. Let's drive. It is currently 8.32 what it do.  Then I'm trying to make it here back here by like 8.40. So we can pick up that all the way sparked up order, baby. So I hope you guys enjoyed the video. Make sure you smash that subscribe button. Make sure you give me a thumbs up and do not skip those ads. One more thing. I hope you guys have a great day. Happy Fridays to everybody and let's get this Monday. Let's go. We are here at Panera brand trying to get this brand. Hopefully it got us done, baby. So we get this Monday. Excuse me. I think this goes with this, huh? Does it? Yes, it does. Let's go. We are here with same big money at my north. Hello. I'm going to have a delivery for Gabrielle. Gabrielle? Okay. Thank you very much. Alice, you have a good one. Let's go. We have a lot of people in the morning, don't y'all? Yeah. And that's why everything is slower. So when do other people usually come in around what time? Around 10 o'clock. 11. Okay. So a lot of times there's only one person back here. One or two people. Yeah, one or two people. Yeah. Yeah. I'm the one with the most lucky one. Yeah. I understand. I see you be having a jade. You got all the jord. I got one. For real? It's bad. No, it ain't bad.   I know, right? Yeah. All right. You have a good one. I'll see you later. Let's go. We are here to drop off order number one. Let's get it done, baby. Hello. Hi. I'm going to have a delivery for Michael Foreman. Okay. You can sit over there on the couch. All right. Thank you. You guys have a good one. Let's go. Two. What'd it do? Right here. So, Michael, what's the deal? I don't know. Order number three and four. We are here getting to this door. Order number three was Einstein Bros. One item, 5.9 miles for 925. Let's drive. Order number four is the car order. 34 items, 5.4 miles for $51.96. Let's get rich. I'm waiting for all the way sparked up is 952 right now Hopefully all the way sparked up pop up again, so we can get these dividends. Let's go order number five staying live Let's drive Chick-fil-a 1.4 miles for 575. Let's drive We are here at Chick-fil-a Bay Bay. Hopefully guys together Yes, sir. I'm right on time Three thank you guys have a good one We are here to drop off this Chick-fil-a Bay Bay It says send the text I'm sending the text hanging over a door, but let's go order number six. We're trying to get it in the mix To orders 4.1 miles for 2382 what it do. I'm pulling up right now Let's get to it, baby And just like that, we are here to drop off order number one. Let's get it done, baby. I Got they got big pops and stuff drop this right here for now But the pops over here Pop Pop ain't let me ask you guys a question. Do you guys call it pop or soda? Everybody in different states call it different guns here. I don't know. We just say pop That's trip, baby get this money Excuse me, man, if you want to I can just put them all right here if you want me to in your door So you don't have to come out and get them Okay Don't we all All right, you have a great day Order number two what it do they got a lot of Easter candy in this y'all a lot of do's or else They got to get some water don't they Take this first batch Order number seven. Thank God for his blessings Denny's two items 1.5 miles for 675. Let's drive Just like that. We are here at Denny's trying to get these pennies, baby. Oh my god. I got it together How you doing sir? Have a pick up for Diane M Diana M It's all right here. Thanks. All right. Thank you very much. So you have a good one Just like that. We're here to jump with this Denny's work, baby I just heard before 10 a.m. What's it before 10 things? Hello Thank you very much. I follow directions. You have you very detailed with the direction. Thank you. You're welcome You have a great one Let's go order number eight my business partner out there getting to this cake, baby Order number eight was instance car order two orders 44 items 15.1 miles for 41 11 thank God for his blessing. Please don't drop me. I might get to Mac 11 Just so you guys know for order number four is car order instead of 51 something she got 59 39 She on the grind to the end of time. Guess what now we have order number nine We're doing just fine apps all around. I guess this is Friday's from what the description says Friday's three items 6.6 miles for $11. We are holla. Hopefully soon we pop in our collar. Guess what else? It is closing day, so we have a deal in the works right now We represent the center so we didn't have to go to closing because my um because our client did not Have to go because she signed the papers early So we're waiting for that to convince keep getting complete and we're gonna go pick up that check today, baby We simply champagne today, baby Hopefully we get off before hopefully we get off real soon because my business point out there going crazy She already got like a hundred some dollars already. What's she done with these two orders? And it's 1126. We're trying to get in the mix right now, so we've been going crazy Hopefully continues because you keep going and keep growing cuz you're already doing begin to this dough and I hope you guys I hope it don't snow it. I hope it's not snowing wherever you at But make sure you smash that subscribe, but make sure you give me a thumbs up do not skip those ads And let's continue to get to this bag baby. Let's go We are here to drop off this Friday it's on a Friday Order number 10. We are here getting it in Wendy's two items 3.2 miles for 625. Let's drive I have a pick up for Stephanie V Thank you pick up for Stephanie V Yep, thank you very much All right, you guys have a good one. We are here to jump off this Wendy's baby Excuse me, oh I didn't even see you're dealing it for Stephanie. Of course, I'll take it to her Thank you. You have a great one This the plan stand it is now watch 1157 thank God for his blessings What I'm gonna do is I'm gonna go get this white castles drop that off and hopefully I'm right in time to catch this All the way sparked that word. That's the plan stand. I don't know if it's gonna happen I don't know if it is gonna happen But I do know that you just smash the subscribe button and I do know you should give me a thumbs up And I do know you shouldn't be skipping those ads and I hope you guys are out there getting to this bag Let's go. We are here a white cast. Hopefully got us together. I did receive a message and if they did Hopefully so Hi, you don't have a pick up for Courtney R. Courtney R. Yes, ma'am Guess what? We just got another add-on Panera bread five items point eight miles for five twenty. We're gonna get that too. Let's go Thank you. Thank you. You have a good one We are here for never trying to get this bird. Okay guys together Um Just so you guys know that That white castles set us back man. They took too long. Let's go drop off order number one. Let's get it down Thank you very much sir One on three. Hello, how you doing? I'm fine yourself Thank you. You guys have a great one We are here to talk about this for never bread. Let's get this I love I have a delivery for P. Feldman. Yep. There you go. Thank you. Have a great one Ordered number 12. We're trying to prevail Panera bread eight items two miles for six seventy five. Let's drop We are here at Panera bread. Guess what? We're about to get this bread, baby. Hopefully got us done Um, they have like eight items on this y'all too. So For our spot Thank you Panera bread Ryan, here you go sir. Thank you. You have a great one Ordered number 13. We hot like scorching Chick-fil-a three items two miles for six twenty five. Let's drop Yes, sir. They got us together, baby. Let's Stand we are here to jump off this Chick-fil-a Bay Bay And just like that it is the end of the video. I hope you guys enjoyed the content Guess what in five hours we made Two hundred and twelve dollars two twelve, baby I ain't talking about one twelve. I ain't talking about no peaches, but we got that cream though, didn't we? Two twelve five hours. I hope you guys enjoyed the content Make sure you guys lock in tomorrow because it's going back down because we ain't playing around If you get into that money go ahead and hit the like button If you get to that money go ahead and put that money back in the comment section, baby. Hey, we honestly It was critical. I ain't gonna lie It was sweet, but it was critical. It was it was this tire angle. I'm kind of exhausted guys It is what it is, but it ain't what it ain't. We got that two twelve and on top of that I'm on my way right now to go pick up this real estate check if you just closed on this house right here So we just sold that house and we got that 200 plus a day and today we go drink some champagne, baby So I hope you guys enjoyed the video make sure you lock in tomorrow because it's going back down like young jock I see you guys on the next one. We going we going we throwing you already knowing the zdk and i'm on my way


Radio 59 WROW, first on the dial. And now, another tale well calculated to keep you in. Are you a commuter? When you hurry onto that late train in the evening, how do you choose your seat? You try to get as far as possible from the big black cigar? Or as near as possible to somebody reading your favorite periodical? Next time, look out. You may be sitting next to the man who murders people. Now, before tonight's story of suspense, let's listen to some words of wisdom from a good friend of yours and mine, the host of CBS Radio's Daily House Party. Hello, this is Art Linkletter with a few words about that crippling disease known as arthritis. What is arthritis? It's the most widespread chronic disease in the United States. Actually, more than 11 million people suffer with arthritis. Men, women, even children. 11 million. No wonder it's called our country's greatest crippler. What causes this cruel disease? Nobody knows. It's still a medical mystery. The Arthritis and Rheumatism Foundation is searching for the answers, and they need your help. Research is costly, so is treatment. This humane work can be carried out only with your support. So send a generous contribution today to your local chapter of the Arthritis and Rheumatism Foundation.  You made it here. Step up. Oh, I thought I'd never make it. Watch and miss your bundles. Look out. Oh, oh, my package. Stay right on there. I'll get them. Here's your half box newspaper. Hello, one of you girls stumble wearing those spike heels. My purse. Where's my purse? Right here. Don't worry. Give it to me. Hey, watch it. You'll dump the stuff again. And our two boxes. I guess that's everything. So I didn't have enough to worry about. Everything has to go wrong at once. Take it easy, miss. You caught the train. That's something. Oh, I wish I didn't have to take it. Well, too late now. Board, over. I wish I didn't have to take it. What's the matter, miss? Oh, I'm sorry. I didn't realize. I'm sorry, miss. I'm sorry. I'm sorry. Oh, I'm sorry. I didn't realize. I was speaking out loud. Something you're reading in that paper, Bobby? Yes. I wish I hadn't bought the paper. Not by any chance the Roseville murders you're reading about. But how did you know? Everyone has those murders on his mind these days. I guess I'm awfully cowardly about it. Not at all. There are long men who find themselves afraid of the dark since those bodies began to turn up around Roseville. It's not something to take lightly. You don't sound very scared. Me? No. As a matter of fact, I've always been rather interested in murder. Interested? Yes. Murderers are very clever people, you know. Geniuses, some of them. You can learn a lot studying these cases. I wish someone would learn who the killer is. What's the matter with the police anyway? Why don't they catch him? Why don't they? Because he's cleverer than they are, that's why. But they had... This man is the coolest, smartest killer that's ever been known in these parts, my girl. Yeah, let's look at what the paper says. Oh, no, no, please. I can't bear to see that picture again. Poor man he murdered last week. Now, I studied that picture for some time myself. It sounded very interesting. You know, figuring out just what kind of a man he was, what kind of trick he might fall for, just how he'd react when he knew he was going to be murdered. Oh, please don't. Well, you're trembling. Well, I believe you're really frightened. Don't, don't, don't you see? I live in Roseville. Oh, live in Roseville, eh? How do you think it feels to get off at that lonely station at night? Not knowing in what shadow this, this creature may be standing watching me? So you live in Roseville. See, I'm not far from there myself. Ever pass Arthur Jenkins' antique shop on Bowley Road? That's my place. I remember seeing it. My aunt's very interested in antiques. You must bring her in sometime. I'll show her my personal collection. That's very kind of you. Glad to do it. Old weapons are my specialty. I got some pretty rare stuff. But, uh, getting back to this murder business. Oh, must we, Mr. Jenkins? Tickets, tickets, have them ready, please. Oh, where did I put that darn thing? Tickets, please. Here you are, conductor. Thank you. Everything okay now, miss? Oh, yes, thanks. I was just awfully nervous about missing the train. My aunt worries so if I'm not on the early way. I know how it is.  Here's my ticket. Thank you. Tickets. Tickets, ready? Huh. Let's see now. Where were we? Oh, yes. The paper. Oh. Get out. First victim two months ago. Young mechanic from the Parkway filling station. Found in the reservoir, stabbed in the heart. Apparently thrown out of a car. No clues, whatever. And he was such a nice young fellow. We often talked while he was servicing my car. Then when I, when I saw this in the papers. Second murder. Wealthy broker left New York on the 445 one evening and never arrived home. And then, just like the poor mechanic. Body turned up three days later at the foot of the Mill Road embankments. Again, a knife wound in the heart, but no knife, no weapon, no clue, just a body. That's the one that horrified me so. Suppose I should have a flat tire in my car tonight when I get to the station. I'd have to phone the garage and then sit and wait in the dark shed all alone. I can see how you feel. Or even if I try to drive to the garage. I'd have to go slowly. And it's right through the woods and...  Yes, definitely something to be nervous about. I hate to leave the house to go to work in the morning. And poor Aunt Maude. She worries all day till I get home. Doesn't a pretty girl like you have a boyfriend to look out for? Well, I haven't been living in Roseville very long. You know, I've been thinking. I get off the station after Roseville, but if you like, I could get out and see you to your car and then take the bus on up. Oh, I couldn't let you do that. It's not much out of my way at all. As a matter of fact, I often drive down that way in the evenings. It's a beautiful drive up the middle road past the reservoir. But you're looking at me so strangely. I think I will go with you and see you to your car. No, no, I don't want you to. Well, we can talk about it later. But get back to the murderer again. You know, I wouldn't mind being called crazy if I could baffle the police as cleverly as this fella does. You take last week now. That was the third case.  What? What's the matter? Stop talking about the Roseville murder. Oh, no. I don't want to hear anymore, I tell you. I don't want to talk about bodies being found and beans with long knives hiding in the woods.  Now, this man who strikes so cruelly, don't you wonder what started him murdering? Do you suppose power was what he wanted? Power over. Pardon me, may I sit down? What? Is this seat taken? No, no, I turned it forward so I could put my bundles there, but I can move them. Here, I'll just pile them on top of each other. There. Plenty of room. Well, I think I'll go back and have a smoke. Goodbye, Mr. Jenkins. I'll talk to you again later. In just a moment, we will return for the second act of... Suspense. Do you start out for a drive in a car with the faithful anxiety of a soldier going into battle? Cars have been created for our pleasure and convenience. However, carelessness has made them responsible for more human death than any planned carnage in the history of man. It's hard to know why people who have no desire to destroy themselves should be guilty of this kind of irresponsibility. Despite the many automatic features in today's automobiles, nothing has yet been invented to take the place of human intelligence in control. Whenever you take your car out, whether for an errand in the neighborhood or a long trip on the highway, remember it takes only one split second of inattention on your part to make all the safety features of your car meaningless, to turn the whole comfortable, luxurious machine into a weapon as personally destructive as any H-bomb. Drive with constant caution, common sense, and courtesy. Keep your car from destroying you. Miss, are you crying? No. No, it's nothing. Gosh, is there anything I can do? I mean, I'm sorry. I'm the one who should apologize. It's silly of me, but I've been so nervous. Then that man... That man? You mean that heavy-sit guy who just left? Yes. That... Well, has he been annoying you? Oh, no, no, no. It's not that really. It's just that... Well, I live in Roseville. Oh. I guess you've heard of the murders that have been going on in that area. Well, say, some guy's been knifeing people at night and leaving the bodies around. Yes, and the killer is still at large, and, of course, everyone in the neighborhood is terribly frightened. Police can't seem to get any clue at all on the case. No. And the papers are so full of it that it's hard to put the ghastly thing out of your mind. What about this guy who was sitting here? Well, that's what I'm getting at. I was terribly nervous to start with, but this man sat down beside me just as we were leaving New York. And the first thing you know, he started to talk to me about those murders. He's got a charming approach. I didn't want to talk at all, especially about that, but he couldn't stay off the subject. Found? And he kept saying what a genius the murderer is and talking about the men that were killed and how they felt when they... but they knew they were going to be murdered. Oh, no. Please, don't cry again. What's the matter with that guy talking to a girl like that? And then he said he'd get out at Roseville with me and take me to my car, and I was scared and didn't want him to, and he insisted. Insisted, did he? Wait till that guy comes back. I'll tell him a thing or two. What are you up to? What's going on here? You, I'll tell you what's going on. Oh, no, no, please. Look, you've annoyed this lady until she's almost hysterical, that's what. Why, what are you talking about? I know you think you are forcing your conversation. The girl was frightened and nervous and wants to be left alone. Who says I forced myself on the girl? You must be crazy. There's something wrong with one of us, but it's not me. Now, get out of this car. Do you hear me? What do you mean ordering me around the train? I mean business, brother. Like this is outrageous.  So get going before I really get mad. I never heard of such a thing. These young hoodlums try to tell a respectable man. Yeah. I don't think he'll be any more bothered. I was sure he was going to hit you. You having a little trouble up here? No, it's all right, conductor. Fella was a bit annoying to the lady, but nothing serious. We straighten it out. I don't know if it's the murders or what, but this Roseville Runch, you're as hard on the nerves lately.  Guy annoys, girl ladies, smacks another lady's kit, man breaks a window because it won't open. I don't know. Well, that's that. All quiet? Uh-huh. Gosh, I'm sorry to let you in for that scene, but I thought it was best to show my men business. I guess you're right. But, oh, I'm glad it's over. What a train ride. All included on your commutation. No extra charge for the fireworks. I'm just exhausted. You'd think I'd been doing the work. Well, you've been under a strain. How about sitting back and relaxing? Let me fix that back for you. Oh, thank you. There, there now. Just take it easy from here in. It's pretty nerve-wracking for you. I don't know what I would have done if you hadn't come along, Mr. Mr. Mackenzie, Bill Mackenzie. Mr. Mackenzie. You know, I, uh, I believe I've seen you on this train before. I'm certainly glad you saw me this time. I'm glad too. For more than one reason. Well, now that it's over, I guess I was a bit silly about the whole thing. That man didn't really have such a bad face at all. He's no monster, just tactless, that's all. That's right. But me with my frayed nerves waving in the breeze, I suspect a rabbit of being the Roseville murderer if I met one on the Mill Road in the dark.  Well, I do thank you for stopping him. By the way, my name is Kay Murray, Mr. Mackenzie. I live just outside of Roseville, the other side of the reservoir. Well, I'd annoy you, Miss Murray. I live in Umbury myself, but look, if you're still frightened, I... Oh, thank you. But I don't feel a bit frightened now. My car is quite near the tracks, and it's only a 10-minute drive home. I'm sure you'll be all right. Because I could see you home, and then I could grab a bus back to Umbury if you'd like me to. Oh, it won't be necessary really, Mr. Mackenzie. Call me Bill, won't you? Since we're kind of neighbors, we ought to get better acquainted. All right. Bill. Kay. Yes? I told you I've seen you on the train before. Yes? Well, to tell the truth, I've, uh... I've noticed you particularly. That's flattering. And, uh, since luck has brought me your acquaintance, may I take the advantage of it and suggest I'd like to see you again sometime? Well, I... How about dinner or a show some night? Or whatever you'd like to do. I'd like to, but... It's kind of sudden, Kay, but... please say yes. Well, you might come up to the house some evening and meet my aunt. You mean when I have a stamp of approval we can go on from there? That's about it. All right, suits me fine. Let's see, um... this is Wednesday. How about tomorrow night? Um, afraid I can't make it tomorrow. Oh, Friday then. Friday will be all right. About eight o'clock. No, Barry. No, Barry. I've got to get off here.  Oh, no thanks, Bill. I'm not scared anymore. How about your address, Kay? Oh, I'm on Ferncliffe Road number 42.  I'll find it all right. See you Friday, Kay. Bye. In a moment, we will return for the third act of suspense. Hi. Maybe you'll recall this tuneful reminder of times past. This is Dennis James with something else worth remembering. It's this. You're so right to stay regular with Kellogg's All-Brand. See, it's the normal natural way to youthful regularity. The whole brand content of Kellogg's All-Brand supplies your system with all the bulk-forming food that you need every day. There's only one All-Brand. It's Kellogg's All-Brand. So relieve irregularity from lack of bulk, as millions do, with a bowl full of Kellogg's All-Brand each morning. A-L-B-R-A-N. It's Kellogg's All-Brand. Oh, darn these doors. They never do open. Yeah, Miss, let me do it. Oh, scared me, conductor. Yes, will you please? I have so much to carry. She'll just let me get in there. Oh! Oh, my God! Oh, my heaven's sake. Oh, Sam, sorry. That was clumsy of me. Yeah, let me pick them up again, huh? Oh, dear. Oh, look out. Don't step on that bag. I got them rolling all over. Yeah, wait till I catch that hat box. Here's the two packages. Hat box and the pocketbook and your newspaper. Thank you, conductor. Here. I'm through with the paper. I'll let you enjoy the Roseville murders. Oh, thanks, Miss. Wait a minute. There you are. You got everything? Yes, thank you. May I sit down? Oh, I certainly do. What? Why, what do you want? I want to apologize to you, Mr. Jenkins. I've been feeling dreadful about that young man being so hasty with you. Young Sir Gallagher, huh? If I annoy you, why don't you keep away from me? That's just it. You don't annoy me. Well, if I don't, you certainly let that... Honestly, Mr. Jenkins, it's hard to explain just how it happened, but... Well, I was so tired and nervous and all, and... the young man got the impression that you'd been upsetting me. The bit impetuous of him, wasn't it? I guess it was. Actually, I... I know you didn't mean to upset me, and... I was terribly embarrassed when he spoke to you that way. Well, pretty embarrassing all around, I'd say. I didn't know what to do. He meant well, you see, and... it all happened so fast. Anyway, I thought I'd walk back and find you to tell you how sorry I am over the whole mix-up. Well, I don't know. I'm not accustomed to being taken for a measure. But you weren't at all. I wouldn't have been speaking to you in the first place if you hadn't looked like a respectable person. Well, I certainly wasn't being treated like that, but... And I would have enjoyed talking if I hadn't been so unstrung. But you know what nerves can do to a person. Well, I knew you were jumpy about something the first time I looked at you. My name is Kay Murray, Mr. Jenkins. Can't we shake hands and know hard feelings? Well... All right, young lady. I guess it was all just a misunderstanding. I didn't intend to be rude, and... Well, it's nice of you to understand. Housville! Housville! Hey, here's your station now. Yes. You're right on time. Oh, let's see. I forgot everything. You have quite an armful. You know, Miss Murray, I'll repeat that offer I made before, if you like. I mean about seeing you to your car if you want me to. Oh, no, it really isn't necessary. Pretty dark night, young lady. Gee, I don't know. Now that it comes right down to it, I... I guess I would feel better if you'd walk over with me. Then I can drop you off at the bus station. If you're sure it won't make you too late. Oh, no, I never run on a schedule. I'm often busy half the night. Well, we'd better hurry. Is the car far? No, no, just the other side of the grove. Watch your step. Jump. Yeah, yeah. Which way? Oh, right over here. There's a path. All right. You see that you don't stumble. You certainly don't waste much electricity in these stations. Now, this is the bad part. In through the trees here. Well, I'm glad you came. Yeah. Yeah. It's dark all right. And quiet with the train run. Hmm. Say, did you hear something? What do you mean? There it is again. Let's stop a minute. Hear it? There's someone following us. I don't hear a thing. It must have been the trees. I could have sworn. Well, maybe not. Let's go. Oh, gee. You really had me worried for a moment. Strange what tricks mental suggestion can play. Very strange. Why, there probably isn't a living soul within half a mile of here. Not at this time of night. Now, if I'd been alone and thought I'd... There he is. Look, between the trees. Stand still, both of you. He's got a gun case. Stand still. No. No, it can't be. I don't know if you're here. It's not too dark for me to shoot straight. No. How is it? It's the conductor on the Roseville train, Kay.  No, you won't. Don't run, Kay. He'll shoot. You've killed her. I doubt it. I aim too low. Let's see. That's what I thought. Bullet didn't even touch her. It was those heels she tripped and hit her head. You almost got away from me. Well, what are you waiting for? Where's the knife? You'll see it soon enough. Come over and give me a hand with this girl. I won't help you. I won't move. Hey, do I have to get disagreeable...  Just a minute. Who do you think I am? I know who you are. The one day everyone will know, do you hear? You can't get away with it. Oh, mister. I happen to be riding that train a special investigator. What? This gal dropped her purse boarding in Grand Central and was so edgy about it, I began to wonder what was inside. I managed to spill her bundles later and look in the purse while retrieving them. Then I remembered the madman's third victim was last seen walking with a pretty girl. Well, why do you think I followed the two of you? I... I don't know. I... Well, what... What was in the purse? You ever see one of these? A... A pruning knife. You never know what's turned a normal mind into a crazy whirlpool of hate. Me? I would have been... the fourth victim. My... My purse. Where is it? You're trading it for a pair of bracelet, sister. You never thought the man I was after would be wearing spike heels. Suspense. You've been listening to the man who murders people. Written for Suspense by Mariana Norris. In a moment the names of our players and the word about next week's story of suspense. Ever stop to think about this? Radio is the swiftest, most flexible news medium. In addition, as veteran CBS Newsman Lowell Thomas observes... I wonder if you are taking full advantage of something that radio can do best of all. That is, keep you informed on national and world events. The Daily Human Show. That's what I'm here for. And I hope that you will join me each evening for a fast swing around the world. Lowell Thomas. Each Monday through Friday night at this radio address. Now, here's news about CBS News. Soon, Broadcasting's foremost news service brings you twice the coverage. Double the detail. Double the depth. Starting Monday, November 28th, each weekday, CBS News goes double for you for a full ten minutes every hour on the hour. The first word in speed. The last word in accuracy. CBS News goes double for you soon on CBS Radio. Bird and Tonight story where Vivian Smolum as Kay. George Petrie as Jenkins. Alan Manson as Bill. And Maurice Tarplin as the conductor. Listen again next week when we return with Night on Red Mountain by William N. Robeson. Another tale well calculated to keep you in suspense.


Hello and welcome. Now let's look at key quotations to remember and memorise when it comes to the character of slim and of mice and men. Now the first quotation that's really important in illustrating the power that slim holds as the quintessential Darwinian male, very strong, very powerful, very respected, is the quote calm godlike eyes describe of course his eyes. Now the word level analysis you want to do here is a simile godlike like god. And what this shows is that slim is almost revered by all of the men. There's this reverence and this aura that accompanies him when he's on the ranch. Even if he's one of the employees, he really sits at the top of that their social hierarchy And he's almost viewed as this messianic figure. He really rallies all the men. They listen to him. They follow what he says, okay? And he's almost like this godlike figure. The second quotation for slim's character is when he's described to the description of him being a jerk-line skinner, ellipsis, driving ellipsis, 20 mules. Now the word level analysis you want to do here for this quotation is firstly the verb driving. So it's showing his sheer power in commanding all of these mules. And the second word level analysis you want to do here is the adjective 20 to describe the number of mules that he's really harnessing. Now what this key quotation shows in the case of slim's character is just how powerful and how commanding his presence is. He also is the quintessential, as I've mentioned, Darwinian male. He's very powerful. In a race for the survival of the fittest, not only is he intellectually adept, he's clever, by the standards of the other workers on the ranch, but equally he's very, very powerful. And of course this illustrates just this brute force and strength that he has. And of course this is in sharp contrast to the character of Curly, who's constantly trying to show his sheer power, but this is completely overshadowed by slim. Okay, now for third quotations remember when it comes to slim's character is how he's described as the prince of the ranch. Again, this is in contrast to Curly. So whilst Curly actually, he's the son of the boss. So technically he's the rightful prince, actually slim is the one that's revered right at the top of the social hierarchy of the men, even above Curly, okay? And of course the word level analysis you want to do here is that this is a metaphor describing just how all the men are almost in awe of slim. He's such an awe-inspiring figure and of course also Curly's wife is very attracted to him, hence why Curly is very threatened by slim. The fourth and final quotation to remember for his character is when it states his word was taken on any subject and of course this kind of ties into when slim is the one that essentially passes the death sentence on candy's dog. So candy's dog is very old, it smells, however candy is very attached to it and the dog had been very very loyal in terms of its work on the ranch. But ultimately it was betrayed and killed by the other men and it was slim who basically accepted that it can be killed. So they all looked to slim. Candy also looked to slim to try and see if you can get slim's approval for the dog to remain, but of course the dog was killed.  Remember a noun is a place, person, a thing. An abstract noun is an idea, a thing that we cannot touch, feel, taste or see, but it exists nonetheless. So of course in this case, it's word, but also the other word level analysis you want to do is the adjective any subject and again this illustrates just how slim is seen as such an intellectual by all of these men, they look at him, he's judge and jury, he really anything that he says on the ranch goes. Okay. So that's it when it comes to the character of slim. Of course what you want to do always is consider how slim is a sharp contrast with curly. Slim's power and position is very much guaranteed on the hierarchy of the ranch, of the bunkhouse. Whilst curly, his power is superficial. It's only insofar as his dad is the person that owns the ranch, but the men really don't respect him. Okay. And of course you also want to think about slim in terms of how he is able to be seen almost as a visionary and he also understands the unique relationship that George and Lenny have. And ultimately he's the one that also empathizes when he realizes that it's George that killed Lenny. Okay. So that's it and thank you so much for listening.


Dyna yn ysgol yma y cwm iawn i'ch gwestiwyr i Gwmp Nesaf i Andrews. Ond mae'n ymddai'n gweithio i'r cynllun o'r ffawr. Mae'r ffawr i'r gwmp Nesaf i Andrews o'i ddiweddol. Mae'n gweithio'r magi ac mae'n gallu i'n gwneud y ddau cyflogwyr. Dwi'n dechrau'r gweithio a mi ddechrau o'r gwmp Nesaf. Efo'r gweithio'r gweithio'r gwmp Nesaf. Mae'n ddiddor o gweithio'r gweithio. Dyna gael bod yn fwy o ddyn nhw'n gweld y parau mewn ddyn nhw, Ac mae'n fydd yng nghymru yn eich dderbyn a'r ddyn nhw'n bwynt o'r ddyn nhw, Fyddwn ni'n sydd eu gwirio'r sungan yn y cyd-437. Fe ydych chi'n sgwr o'r camera yn y rhan, fe'u gwirio'n diwylliant yma. Mae'r cyfrwyng o'r sylfa o'r ddyn nhw, ac mae'n gwirio'n ddyn nhw, i'r sylfa fyddwn y rhan o'u ddyn nhw, i gydag y llun o'r gwein. Mae'n fwy o ddigon o'r ddweud. Felly mae'n ddweud o'r ddweud. Rhaid, mae'n ddweud. Fy llwyddiad ystod o'r camera i'r wneud ychydig o'r wneud. Felly mae'n ddweud o'r camera o'r wneud oherwydd mae'n ddweud o'r wneud o'r wneud o'r wneud o'r wneud. Mae'n rhaid i wedi bod o sydd o ffr robotwr 40 o辣 nowe cael bod y grannu. Mae y cendryס a bydd nes bydd ddylai. Ond mae'n wneud yn rhaid i'r bobl â hynom, ac mae mae'n y dymr Cymru. Bydd hyn o'n rhaid i we lim yn nodol.. Dwi'n iddi'n meddyliod Стodol, dweud. Mae'r gaelig pare routine! Ond mae'r bobl sydd wedi bod yn pawb yn gyntaf. Yna'r llaw yr unrhywbeth yn ymddangos. Fe yw hefyd o'r rhaid yw'r ddweud. Yn ychwaneg sydd yn ein rhaid o'r llaw ffordd, mae'r ddiweddau sydd wedi gweld yn gyweithio'r llaw. Mae'r llaw rhaid o'r llaw'r ddweud. A dyna'r cyffredin, mae'n gweld yn ymgyrch. Mae'n cyfrifio gwirionedd. Mae'n cael ei ddweud. Mae'r cyffredin dyma'r gifith yma. Yn ymddangos fel yna. Wel, yna'n ddweud yma? Nid yw, mae'n gweithio bod yn boge 4. Yn y gallu lleol yn 9 o'r gweithio. Mae'r gweithio'r gweithio'r gweithio. Mae'r llyfr yn oed yn gweithio sydd yn llyfr â'r rhagol, a'r gweithio'n gweithio ac yn gweithio, mae'n gweithio'r gweithio'r gweithio. Mae'n rai gynnwys bryd, oherwydd, oeddi'n gwneud. A gweithio ar gyfer, mae'n gweithio'r gweithio'r gweithio Wych! Felly beth rydyn ni'n hynny'n gwahoddiad i'r gwrdd! Rydyn ni'n hwyl gan dafod yn fwy, ni'n fwy! Rydym yn i'ch yn edrych fel y bêl, eich ffynithau oedd yn fwy nefyd, dyma eich gwynt bob. Diolch yn fwy o'i fod o gyrtau myfwun. Rydyn ni'n holl i'r gyrtau yn gweithę i ddyn nhw. Rydyn ni'n hollwn chi i gael, ac wnaeth yr hwn hynny'n hynny'n gofyn yn ffônfa. Rydyn ni'n rŵn myfwng yn gweithi'r ffynfa, ydy, fe yn stopu eich gwrdd erion mwygole, ychwanegor wedi y cwrnod a'i gweithredu chyrwyddon ar eich platt o'r lyth. Yn beth o'r golygoid ysgolwch. Ryeb i fitfodol drwg, nad oedd rhaid o'r celffennydd yn gwych, ac rai'n gweithio i chi'n ei ddoedden. Roedd yn'r eich gweithredu iawn ei ddysgu yn credu. Roedd yn ddysgu, mewn eich gweithredu er mai mewn arall, o'n ddi'r pwngh afael. Roedd shuttol wedi'u eich gweithredu chefaf. Dyna'r griffau fath o'r ddau. Felly, mae'n cyffredinol, mae'n cyffredinol, bod mae'n cyffredinol yn sgwllt, ac mae'n cyffredinol sy'n cyffredinol. Ond oes, mae'n gwybod i'r cyffredinol, mae'n cyffredinol yn bwysig i'r ddau. Mae'n cael ei ddweud. Ac yna'r ei ddweud, a fyddwn i'n gwneud hynny. Dyna'r ymddorol o ddweud. A, ydw i'n gweithio arlaed. Ydw i'n gweithio arlaed. Wel... I can't believe from the middle of the fairway, from the tee shot that I hit, I can't believe I've got some of the 10-12 football par. Wow! 13 is a bit of a backdrop, bit of a view. I don't really want to bring the camera around this way a little bit because you can see the hotel at the back of the 18th green there at St Andrews. St Andrews just took away the town of St Andrews just to the right and then obviously to see the waves there in the distance. That's a pretty decent backdrop. This is called Braw View. Beware of the downward sloping fairway to the right of the green. This green is best approached from the left side. OK, we will do our best. OK, so I can see the tip of the flag. I'm going to aim towards that sort of, if the left side I'm going to bunker, fairway bunker, slightly down the left and that's the line. That's too far down the left hand that stayed there. Oh, that's absolutely fine. That's not bad at all. It's on a bit of a brow and that bunker seems to be, I will have avoided it anyway. What a view though. Look at that. You can see for miles. Right, I probably, like I said, just a bit further left than I would want to have been, but we've got a line into the flag. I'm playing it a bit blind. I've got 120 in. I've got an amazing view from up here, but I can't see the green. So we're reliant on this yardage. I don't think I've got enough of that, have I? Have I? Has it got up? You can see better than me. Oh! Go ball! Oh! I'm asking the camera woman to walk forward. Can you see it yet? Right. Well, again, I think slightly on the lucky side because I thought I might have got that just a little bit heavy, but that has worked out perfect. We now need that putter to kick in and do its work for a birdie. What a golf hole. Well, we're going to take this one serious. We're going to see if we can finally nab that birdie. I can't believe, and I don't think we'll quite get it on the camera just how big these slopes of run-offs are. The information that was in the course planner was well worth noting because you don't want to miss this on the right-hand side whatsoever and feeding off that left, which my ball did, like I said, perhaps a little bit fortunate, but that's where it needs to be. Right. Now over to the putter. Mammoth bunkering and great protection of the hole. Oh, I didn't move at all. Didn't move at all. Played it on the left-hand side and it just stayed there. Unfortunately, missed the birdie, but we've got the par. Great views. Great layout and, yeah, all together. Great golf hole, that is. What I like about the design of the juicer is the fact that every hole is very much secluded. I don't think we've seen anybody else onto another fairway. What that also does as someone like me who's first time playing it is very much a surprise each time you get to the next tee box as to what's going to be laid out in front of you. And again, another stunning par three, which is what brought this thought to my attention, to be honest with you. But we've got breeze right into us. I had to play in 180. And, yeah, not too easy. And obviously those bunkers make an appearance. Ah, this has gone enough to get there. Yeah, it has. Do you know what? I was a decent shot into the breeze over to the putter for another 40-foot birdie. Right. We'll switch back on again and see if we can get that infamous birdie put. This is a long one. Green complex is a huge and plenty of movement on them. And that's no difference here either, to be honest with you. Par movement off the right hand side. And that's high enough, is it? Roll out, roll out. No, not firm enough hand. And all of a sudden from birdie put, it's that slippery. I don't know, four or five footer, which nobody likes. And with break. We made it. Why get your driveway on 17? And there's the question, can you it straight down between those two trees? Flag is right in the middle of them. Frame, absolutely stunning. Well, that's just drifting off to the right, is it? Go ball. No, that was short anyway. Oh, what a stunning looking golf ball. And now that's framed, that second shot. Delightful. Right, down the steps, I've got wedge and putter. I've just missed the green down in this little hollow and that stone wall is gorge. But I'm hoping just for a chip and a put on 18 to finish off this round. Run on ball, run on, run on. Ah, well that's good in terms of the chip. Can I finish it off and make what will be a great up and down. The views I've got right now right over the town of St Andrews. Gorgeous again. The clubhouse on the top is not too far away either and the views they've got from there are incredible.  Can we hold it? Yes. A good finish. The putter finally did its piece on the last hole. And a great golf course here, the Dukes in St Andrews, something totally different from what we've experienced so far and well worth a visit.