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Published: May 29, 2020, 8:19 p.m.

Dr Hayes interviews Dr. Lawrence Einhorn and patient, John Cleland, on the cure for testicular cancer.

Dr. Daniel F. Hayes is the Stuart B. Padnos Professor of Breast Cancer Research at the University of Michigan Rogel Cancer Center. Dr. Hayes’ research interests are in the field of experimental therapeutics and cancer biomarkers, especially in breast cancer. He has served as chair of the SWOG Breast Cancer Translational Medicine Committee, and he was an inaugural member and chaired the American Society of Clinical Oncology (ASCO) Tumor Marker Guidelines Committee. Dr. Hayes served on the ASCO Board of Directors, and served a 3 year term as President of ASCO from 2016-2018.

 

The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.

Welcome to JCO's "Cancer Stories, The Art of Oncology," brought to you by the ASCO Podcast Network, a collection of nine programs, covering a range of educational and scientific content and offering enriching insight into the role of cancer care. You can find all of the shows, including this one, at podcast.asco.org.

Welcome to the "Cancer Stories." I'm Dr. Daniel Hayes. I'm a medical oncologist and a translational researcher at the University of Michigan Rogel Cancer Center. And I've also been privileged to be the past president of ASCO. I'll be your host for a series of podcast interviews with the founders of our field, have been, and will continue to be over the next several months.

In this series of podcasts, I'm hoping to bring the appreciation of the courage and the vision and the really scientific background among the leaders who founded our field of clinical cancer care over the last 70 years. I hope that by understanding the background of how we got to what we now consider normal in oncology. We can all work together towards a better future for our patients and their families during and after cancer treatment.

Today, my guests our Dr. Larry Einhorn, who first demonstrated the cure of testicular cancer with cisplatin. And we have a special guest, Mr. John Cleland, who as far as I know was the first man to be cured of this cancer with cisplatin in the world. Dr. Einhorn is currently the Distinguished Professor of Medicine on the faculty of the section of hematology oncology at Indiana University School of Medicine. Mr. Cleland is now retired after a distinguished career as a high school teacher in track and field coach in Indiana.

This interview is really particularly poignant for me. I knew John Cleland socially before I had ever heard of Larry Einhorn because our respective wives worked together while I was in med school as I began my clinical training. I then had the enormous privilege of being assigned to the oncology ward at the University Hospital for one of my rotations in internal medicine during my third year of medical school in 1977. And Dr. Einhorn was the attending. And frankly, for me, the rest is history. I had no chance. I had to become an oncologist.

Dr. Einhorn received his undergraduate degree at Indiana University, went to medical school at the University of Iowa. He then returned to Indiana for his residency and fellowship. But he spent an oncology fellowship year at MD Anderson, Houston. After that you then returned back to IU in 1973 and has remained there ever since.

He has won nearly every award and honor available in clinical research. And I'm not going to try to name them all, but most importantly, like me, as many people in this podcast series, he has served as president of ASCO, in his case, in the year 2000 and 2001. Dr. Einhorn and John, welcome to our program.

Thank you. Thank you.

Thank you.

Dr. Einhorn, I'll start with you. Obviously, your greatest contribution is the cure for testicular cancer, which is pretty good. Can you kind of walk us through the history? How did you get involved with cisplatin? How did you derive the three drug regimen? What were the early obstacles? Especially with your returning back to Indiana. Can you kind of just walk us through that history?

Certainly. So as you mentioned, I did a one-year fellowship in oncology at M.D. Anderson before returning to the faculty in 1973 and Indiana University. And in that time period, which was 46 years ago, the thought was that you might be able to cure adult leukemia like was cured with childhood leukemia from the wonderful studies from St. Jude's and that the studies that were ongoing in lymphomas and other hematological malignancies were very promising. But it was felt that you really don't want to do too much toxicity in a solid tumor, where you're getting a one log kill before you get progressive disease. And there was a clear pervasive atmosphere of pessimism of what can be done with solid tumors in general.

So when I joined the faculty in 1973, I was the only oncologist. We had two hematologists that were there in our small faculty, which went from 2 to 3. And I wanted to be involved with both liquid tumors as well as solid tumors. But I wanted to be involved with solid tumors that were chemo sensitive. And even back in the early 1970s, testicular cancer was responsive to older drugs like actin or myosin-D and later with a two-drug combination of vinblastine plus bleomycin. And there were a small number of not just remissions but cures, and that was one of the few solid tumors that actually had a modest cure rate back at that time.

And then the platinum story came around. And this is a podcast of itself with the wonderful work of a biophysicist at Michigan State, Dr. Barnett Rosenberg, who first discovered that platinum could be the first heavy metal ever to be looked at as antineoplastic agent. And when platinum entered first in human clinical trials in 1972 and 1973, it was [? selfed ?] at an NCI-sponsored phase I working group that I attended that this drug was producing minimal benefit and tremendous toxicity, especially horrendous nausea and vomiting. And the drug was pretty close to being discarded as a interesting novel mechanism of action, but not a drug that really had much of a future.

But what changed the history of platinum and changed the history of testis cancer was the fact that among the phase I patients were treated with platinum, which included melanoma, lung cancer, colon cancer, breast cancer, the usual type of patients that enter phase I studies back in those older days were 11 patients that had testicular cancer who had failed actin or myosin D, failed vinblastine, plus bleomycin, and so they received single agent platinum. And when we, even today--

Actually, where were those studies done?

That was done at Roswell Park actually, phase I study. And Roswell Park-- and this was an era, by the way, that there were only four NCI cancer centers in the United States, Roswell Park, M.D. Anderson, Memorial Sloan Kettering, and, of course, the NCI. So Roswell Park did a broad-based phase I study. Jim Holland was there at that time. He has unfortunately subsequently passed away. He was one of the real pioneers and also a past ASCO president.

So among the patients in that phase I study were 11 patients with testes cancer. And there were three complete remissions and two partial remissions. And even in 2019, if we saw that with the phase 1 novel agent, there would be a tremendous amount of enthusiasm generated.

We also looked at some of the preclinical work with platinum. And it is a drug that can cause testicular atrophy. In my youthful ignorance, I didn't realize that there are many drugs that cause testicular atrophy.

So with that as a background, in 1974-- and I was on the faculty for one year at that time-- we wrote a protocol to simply add platinum, a novel experimental drug, and added it to the established two-drug regimen that I learned about when I was at M.D. Anderson, namely vinblastine and bleomycin. And the principles of combination chemotherapy aren't complicated. We want each drug to have single agent activity, different mechanism of cytotoxicity, different toxicity, and platinum as a non-mild suppressive drug, which can be given in full dosage, with vinblastine as a mild suppressive drug, and evidence of synergy. And one of the unique characteristics of platinum is it is synergistic across a panoply of cytolytic agents.

So we started to study in the late summer of 1974 as a phase II study. And so we treated 47 patients when we first presented this data at the American Urological Association, later at ASCO. And I would be the first to admit that I was as startled as anyone that we were able to literally have a one logarithmic increase in the cure rate, because most progress in oncology is going from a 5% to a 10% to a 15% long-term survival rate. But all of a sudden with this three-drug combination, 60% of these patients were not only complete remission, but durable complete remission and cures.

There was a lot of toxicity with platinum. And over the years, we learned, as science tends to learn, when a drug is active to mitigate the side effects as far as nephrotoxicity and nausea and vomiting. And we made modifications to the treatment regimens as the years went by, as you know, with changing the dosages have vinblastine, lowering the duration of maintenance therapy, and eliminating maintenance therapy, reducing the number of courses of platinum, substituting etoposide for vinblastine to where it's now the standard, bleomycin, etoposide, platinum, or BET.

And I will make a final comment, in my long career, that this was a very exciting time in 1974. There were several chemotherapy drugs that were experimental drugs, such as doxorubicin and even a nitrosourea the first drugs to have penetration into the blood brain barrier. But the era of chemotherapy is gone and appropriately so. And science and medicine has moved forward. And now, we look at molecular targeted agents and immune checkpoint inhibitors and immunooncology. And that's what is exciting, so much more exciting about the field in 2019 than it was in 1974.

But nevertheless, platinum has had legs. In 2019, it is still first line therapy in 12 different types of malignancies. Of course, testis cancer being the poster child for curable cancer. And I often mention that just as platinum has cured thousands, tens of thousands, hundreds of thousands of young men with cancer, testicular cancer saved platinum, because if it weren't for those early studies showing activity of platinum, I think I can say without fear of contradiction that the drug wouldn't be around right now because of this tremendous toxicity in the early phase I studies.

Yeah, Larry, let me ask about that, because in the early 1970s when-- I wasn't around, but you didn't have antiemetics. You didn't have drug fractures. You didn't really understand the renal toxicity. Just briefly, how did you get around those? How do you get people-- I'm going to ask John the same question in a minute. What were you thinking, John?

John is the recipient of our ignorance in that era. So taking it one item at a time. Platinum is a heavy metal. And we were somewhat slow in realizing that other heavy metals, like mercury, can cause acute tubular necrosis. And so when patients were getting platinum, as is true in those days, they would often just get IV pushed platinum.

And so we learned that in order to prevent acute tubular necrosis, we needed to make sure that patients were well hydrated with IV saline solution before they start chemotherapy. We then give the intravenous platinum and then follow that with intravenous saline hydration, so that the drug doesn't accumulate in the proximal tubules, and we force a diuresis. And we never needed mannitol. And some people back then, in fact, perhaps even now, are doing the silly thing of mannitol diuresis, which is totally unnecessary. And so back in the early days before we had antiemetics, everyone had to be treated as an inpatient because we had to give 24-hour continuous hydration because of the [INAUDIBLE] from severe nausea, vomiting, and dehydration that would happen. Of course, today, it's all done as an outpatient with three or four hours of hydration.

As far as nausea and vomiting is concerned, one of our first studies we published in The New Journal of Medicine was a cannabinoid derivative from Eli Lilly, called nabilone. And so nabilone, didn't produce a marijuana-type of high. It didn't cause euphoria. It caused some dysphoria and had a variety of side effects. But it lowered the incidence of nausea and vomiting.

But what revolutionized chemotherapy induced nausea and vomiting, and ASCO recognizes this as one of the five leading advances in the past 50 years, was the discovery of the first 5-HT3 receptor antagonists. And this was a rational, selective pharmaceutical development. And this truly changed the face of how we give chemotherapy with drugs like platinum. Instead of having an average of 10 to 12 emetic episodes on day 1 of platinum, today with appropriate anti-emetics, the median number of emetic episodes is zero. People still get nausea. People still get occasional vomiting. But everything is done as an outpatient now.

And it's done as an outpatient because of the discovery by others of what is the mechanism with platinum, which is not a gastrointestinal mechanism, but affects the emetic center in the medulla oblongata and the chemo receptor trigger zone and finding that patients get drugs like platinum, they get high level of 5-HT3. And developing a selective 5-HT3 receptor antagonist change the field completely. And, of course, now we also [? weigh ?] a methasone and neurokinin-1 antagonist, aprepitant or fosaprepitant. And we also have olanzapine as far as the nausea issue. And olanzapine is probably the best drug for nausea. So patients today have no concept of what patients like John went through when we had no knowledge about any of this whatsoever. And we were looking at things kind of naively by 2019 standards.

I don't think I'm making this up. I recall as a medical student walking down the inpatient at University Hospital and thinking this smells just like my fraternity house.

Without the fun involved.

Yeah. And I got a kick now out of the so-called medical marijuana. But didn't you talk the administration into looking the other way for a while so that these guys could do that?

Sort of. What had happened with nabilone, it had to be under lock and key, as if it were gold at Fort Knox. When we had an audit by the FDA and we had-- I don't know how many, I think 60 or 70 patients on nabilone, you know, we had to make sure we had every consent form and every safety guarded and everything. You know, here, we're using these incredibly toxic chemotherapy drugs and there was no regulation at all. And here we're using a pill to lessen nausea and vomiting, and it was just the hoops you had jump through were tremendous.

When did you start realizing you had something big. Was it, you know, after two, three patients, or later--

Well, again, when you're young and dumb, it's easy, because you treat someone like John and you get the first chest X-ray three weeks later and things are gone and with pulmonary metastases. And you naively think, not only this cool, but, gee, that's great, it's not going to come back again. But we know even 40 years later that most epithelial malignancies that we get nice remissions with, the disease does come back again. So we had initial enthusiasm that platinum vinblastine myosin was a very active, but very toxic regimen. And we had the hope that this might be durable remission.

And, Dan, I actually first presented data with testes scores, not at ASCO, but with the Annual American Urological Association meeting, and that was 99% urologists there. And so we had 20 patients that we had treated. And then that following year, I submitted an abstract to ASCO. And back then, it wasn't done online. We would send a paper abstract with a self-addressed postcard that they would send back to us whether it was accepted or not.

And so when I sent in the abstract, I get the postcard back saying it was accepted as a plenary session paper. And I had no idea what plenary session even meant. It's true. And we get this postcard back in January for this June meeting. And all of a sudden my naivete went away, and I thought what, if I make a fool of myself? And I had this initial abstract with these complete remissions, and by the time June rolls around every one of them would have relapsed, which I was starting to learn happens in other tumors like small cell lung cancer, that are chemo sensitive disease. But fortunately, the time of presentation everyone was still disease free. And, of course, everyone for the most part remain disease free.

So we had the first glimpse of activity with the first few patients. But it really wasn't until patients were out at a year that we really had the realization that these were not temporary remissions, but these were durable. And as it turned out, permanent remissions and cures.

I wasn't there, but I understand that after you recorded that it looked like you had change the ratio of [? puranoctur ?] from 10%, 90% to 90%, 10%, that people in the audience, you had a standing ovation at the end of your presentation.

Yeah, it was very heartwarming. It's literally the walk on the moon type of things is the things that you do once in your career, you know, that you never forget about. I had the opportunity to do that and not one of those four NCI cancer centers, but little Indiana University with our faculty of three. And we had one oncology nurse at that time, Becky Furness. We had no data managers. We had no compliance office or anything else. And we were giving [INAUDIBLE] back in the 1970s.

I'd like now to turn briefly to your relationship with John Cleland. John, can you give us a brief history of your cancer treatment before you and Dr. Einhorn decided to go with the cisplatin.

I was a student Purdue University, the fall of 1973, when I discovered I had a lump on the my left testicle. And I went to a local urologist. And he examined me on a Tuesday afternoon, in the middle of November, and told me he wanted me at the hospital the following morning. And the following day after that, they performed surgery. And I was diagnosed with testicular cancer. That was November 15, 1973.

On the 29th of November then, I had a retroperitoneal node dissection. That was at the UI Cancer Center by Dr. John Donohue. And then on December 3, 1973, on a Monday morning, Larry Einhorn walked into my hospital room. And that was my first introduction to Dr. Einhorn. He talked to me a little bit and said we were going to put me on a 5-day course of a drug called mithramycin. We took mithramycin for five days. And then a couple of days after that, I was released from the hospital. So that was in the 1st of December of 1973.

The middle of February of '74, I returned to IU Med Center just for a routine checkup. And I was diagnosed there again with testicular cancer had returned. And Dr. Einhorn began putting me on a three-drug regimen-- adriamycin, bleomycin, and [INAUDIBLE]. And I was on that until about July of '74. Then I was on actin myosin-D for a couple of months. And then we ultimately started in on the cisplatin in early October of '74.

You have to tell us the story that you actually had to tell Dr. Einhorn about cisplatin because of a radio show you listened to.

Well, by the middle of the summer, I had been pretty beat up, after all the chemotherapy and the nausea and everything. And I didn't really have a job-- or I couldn't do a job or anything. So most of the time, I just lay on the couch in our apartment and listened to the radio or watch TV. And one day-- I really like Paul Harvey-- and he came on the radio every day at noon there in Lafayette, Indiana.

And one day he begins talking about researchers at Michigan State University. have maybe come up with the cure for cancer. So I begin listening much closer. And they talked about this chemotherapy called cisplatin. So I just made a mental note to myself, well, the next time I go see Dr. Einhorn, I'm going to ask him about this.

Well, a couple of weeks later, I'm down at IU. And he's palpating me and listening to my chest and all this type of thing, you know. And I began asking him about that. And he said, John, just don't get too excited about that. We've heard of these cancer cures before. Probably nothing important has happened here. Don't worry about it, you know. And then two or three months later, I'm taking it. So that was my introduction, Dan, to cisplatin.

Well, I can't to you--

Some of those Purdue graduates are pretty smart every now and then.

We get lucky, like a blind squirrel.

I just say, I can't tell you how many-- probably 100, 200 patients will told me things like this. And I've said exactly what Dr. Einhorn said to them, yeah, yeah, yeah. I wonder how many cures I've missed. OK, and the second story I want you tell us, John, is about your readmission to the hospital after your first cycle of chemotherapy.

Yeah, I started this platinum October 7, 1974. I had five doses in the hospital. And then I was released. That was on October 7. October 20 rolls around, which was a Sunday, and I was violently ill. I had a fever of over 104, almost 104 and 1/2. And I was just completely almost derelict. My wife and a couple of friends, we contact Becky first, us my oncology nurse. And I guess she called Dr. Einhorn. And he said, well, come on down and check in through the emergency room at IU. And so that's what we did.

We got there late at night, 9:30, 10:00 at night, something like that. And they always-- if I went to the emergency room, they always took a chest X-ray, which they did. And then in the hospital overnight and middle of the next morning, I see Dr. Einhorn and Becky getting off the elevator. My room was kind of in a corner. I could see part of the lobby out there and the elevator and the nurses station. And I could see them kind of go past the nurses station.

And I could just tell that something was up. Somebody had good, let's put it that way, just by their body language, and the way they looked at each other and talked and walked. And they kept coming closer and closer and closer to my room.

And finally, they walked in. And Dr. Einhorn says, John, your chest X-rays are clear. That's really good news. And, you know, I kind of interpreted that as, hey, I'm cure, you know. And ultimately, I guess I was, because from that chest X-ray the night before, my chest film was-- the weak before, my chest film was just riddled like Swiss cheese. And then the film was totally clear.

You probably don't know this, but I've seen your chest x-rays, which is probably illegal now.

Probably did a lot of illegal things back then.

And, you know, that's when the scales fell from my eyes and I said, I'm going to be an oncologist. This is unbelievable. But, you know, I think to emphasize, it wasn't clear you were going to survive that weekend. To survive, you would be cured. But that goes back to how toxic this drug was at the start.

Right. Right. It was not a lot of fun. I know that.

Yeah. Well, I want to get back, Larry, to you for a moment, because there were two people in your life who were really essential to this story. One, of course, was Dr. Donohue, with whom you have published the, I think, seminal and classic paper in the annals of internal medicine. You want to say a few words about John.

And the other is I'd love you to talk a little bit about Steve Williams. Steve was a fellow when I was a med student that I used to tease-- I mean, he's the only guy I ever knew who went from being a fellow to cancer center director I think in one year. I'm making that but-- he kept saying, you know, I might as well put me on faculty because he doesn't have any other fellows.

Sure. So when I joined the faculty in 1973, in July of 1973, as I mentioned, I was the first oncologists. There were two hematologists there. And John Donohue is a true gentleman, one of the world leaders in urological oncology and the urological transplant with kidney transplant and many other fields. His ability to surgically cure patients with extensive retroperitoneal disease was known worldwide.

And because of who John was and the fact that there were very few oncologists in the state of Indiana treating solid tumors, when he would see patients who would relapse after a retroperitoneal lymph node dissection, he would give chemotherapy himself, usually with actin myosin-D, which, by the way, causes almost as much nausea and vomiting as platinum did. And when I first got there, I knew John by reputation, but not by his interpersonal relationships with others. And with some fear and trepidation, I walked into his office because I told him I wanted to start looking at clinical trials in testes cancer. And I thought we might have a turf battle because he was treating patients with chemotherapy himself.

And he just welcomed me with open arms. And he was so enthusiastic about finally having a partner and someone to collaborate with. And we had a wonderful, 30-plus years of collaboration with many important discoveries that John made equally, as I did. And, unfortunately, after John retired, he subsequently died when he was in Florida.

And it's a similar sad story with Steve Williams. So Steve Williams was in my third fellowship class, which means we had one fellow a year. He was great, very humble, from Bedford, Indiana. And father was a newspaper reporter from the small town newspaper. And Steve was the eternal optimist. And to show you what an eternal optimist he was, when the Indianapolis Colts would those 14 games in a row, he always knew they going to win the next game, you know. And that's Steve. And John Cleland talking about Paul Harvey, Steve would have believed that platinum was going to be the cure too, you know. He was just a very positive person.

And Steve was very gifted. He has a great relationship with patients. And there's not a person, a doctor, nurse, or patient, who has ever said anything unkind about Steve. He's one of the kindest people that we ever had the privilege of knowing. And Steve was very much involved with our testicular cancer research studies and many other pivotal studies as well.

We decided to be a NCI cancer center, which is an enormous amount of work. And by then, we had about 10 faculty members in hematology, oncology. And no one wanted to do it. And so we went up to poor Steve and said, boy, Steve, this would be a great career move for you-- without telling him how much work is involved. We are cancer center today because Steve Williams made us a cancer center and everything that goes along with that.

And before leaving, and fortunately, we're talking about John being cured with fourth line therapy with platinum combination chemotherapy, whereas if John had had that disease diagnosed a year earlier, quite honestly, John, you wouldn't be alive right now. And it's sort of the opposite for Steve Williams. He eventually developed metastatic melanoma before any of the marvels with immunotherapy or even the BRAF inhibitors were around. And he eventually died from these diseases that he fought so hard to palliate and prolong survival and cure with metastatic melanoma.

And now there's a 30% cure rate--

30%, 5-year survival and continuous 5-year survival with single agent PD-L1 inhibitors. And I want to make a final comment about John. And if this were 2019, rather than 1974, and you're looking at a patient who has been through mitramycin, which is used by me as adjuvant therapy briefly for adenocarcinoma, which is what John had, and then going through actin myosin-D and all the toxicity with that drug and then gone through a adriamycin combination chemotherapy, and looking at fourth line therapy.

So when we started platinum combination chemotherapy, and John his fourth line therapy, yes, his chest X-ray looked like Swiss cheese, as he mentioned, but he was pretty much asymptomatic. And the courage and fortitude that it takes to go through treatment like this, because we knew what the side effects were with platinum. It had been around for about eight months, and we knew about all the horrendous side effects of the drug. We had no idea whether this would produce as fourth line therapy any prolongation of survival or any meaningful quality of life. And to go through this therapy without any idea whether it's going to help you, but to do it with truly altruistic motives and knowing that maybe this will help other patients in the future is really noble and admirable. And this is why John over the decades has been such a role model for clinical trials and for the cancer patient population.

And I want to follow up. John, briefly, tell us about your history since then-- your family, your athletics, your career. I think it's inspirational, frankly.

Well, I worked for the animal science industry for five years following my cure. And I decided finally I needed to give something back a little more to society than what I was actually doing. So I knew I wasn't smart enough to be a medical doctor. Male nursing wasn't exactly in vogue at that time, which might have been honestly a pretty good job for me. So I thought, well, I could be a teacher. I can teach life sciences. So background is pretty much life sciences in agriculture.

So I did. I turned to teaching and teaching biology for 31 years and did a lot of coaching of track and cross country. And my wife and I have three kids. I married my college sweetheart even before I had testicular cancer. And, you know, I owe her just about everything in life. She hung in there with me when times were really dark. And I say we got three kids. And I've had great job and great career and friends.

I want to emphasize you've had three children since your treatment. I also want to emphasize I know you've run one or two marathons since your treatment.

Actually, Dan, I ran four marathons.

So you ran four marathons since your treatment.

Four full marathons, yes, sir. And I believe that your baseline creatinine is something like twice normal. And, Larry, you probably know this better than I do. But, again you've been inspirational to all of us.

Well, thank you. Thank you, Dan. I'll tell you this. Every day I live is a blessing. I should have probably died 44, 45 years ago. I could drop dead at the end of this telephone conversation and have no regrets in life whatsoever.

Well, John, you keep thinking that maybe one day you'll live long enough to see Purdue win the NCAA, but I wouldn't count on it.

I was going to make a point, it must pain him truly to thank two guys from Indiana and also be appreciative of Michigan State, you know, for a guy from Purdue that must really be painful.

Well, yeah, you know, testicular cure is basically Big 10 centered with Michigan State coming up with this cisplatin and Dr. Einhorn being on the IU you faculty. But it took a Purdue Boilermaker to be tough enough to handle all that to begin with, you know.

That's true. OK, we're running out of time. I need to bring this to an end. I want to thank both of you again, both of you're inspirational, John for all the things we've talked about and Dr. Einhorn for so many of us who've gone into the field that we've trained and even the ones we've never touched directly, you touched hundreds of thousands of oncologists around the world indirectly. So thanks for all your contributions and what you've done. And thank you both for being on this podcast. I hope it opens up more inspiration for other young investigators and other young oncologists who don't really realize how we got where we are.

So with that, we'll end this. And thanks a lot. And hope you have a nice weekend.

OK, thanks, everyone. Have a good rest of the week. Bye, bye.

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