Immunology Transcript 11:22:24 CANCER (PDF)

Okay, last class, I went super quickly through this. The only difference is they were just showing differences in rejection depending on the number of mismatches. The lower you can go, the better. It's like limbo. You could win. Briefly from this one, I do not expect you to memorize any of these, th...

Okay, last class, I went super quickly through this. The only difference is they were just showing differences in rejection depending on the number of mismatches. The lower you can go, the better. It's like limbo. You could win. Briefly from this one, I do not expect you to memorize any of these, this is all genetic stuff. We're throwing it in because for funsies, this is like the one time when men are a little bit more complicated than women. So, appreciate the fact that with men, we actually have to do Y matching too. Because they have what's known as minor histocompatibility antigens that can activate all L-reactive. And so there's an additional step involved with that. And it is just showing you, again, the lower the matches, the better. Obviously, the bigger histocompatibility, the major histocompatibility is critical if you have time to go through and do enough sequencing to do minor, even better with men overall. Some other things to do and to mention with those transplantations, like the longest lecture we have, some graft versus host disease helps engraftment and prevents relapse of malignant disease. So this is a really strange phenomenon because it can affect in a good way certain malignant diseases like cancer, so it's referring to cancer, specifically in that like blood cancer. Specifically with NK cells will help out with this. And so graft versus leukemia, there is like this weird effect where we do the transplantation and instead of attacking like the host, because we hear graft versus host is attacking the whole host, in this instance, it's just attacking like hematopoietic cancer. So it can also be a good thing. There's a lot of nuances with this field. And specifically like this, NK cells mediate graft versus leukemia. So graft versus host can be a good instance in this one rare scenario where we're actually targeting the cancer, because that was the goal in the first place. So it's okay that the graft is attacking it, because that's what we want. So it is kind of a nuance with graft versus host disease, when we talk about like the traditional graft versus host disease, it is very, very bad. But that is like one loose exception that obviously if you're targeting something bad with something bad, it ends up being good. Like the enemy of my enemy is my friend. That kind of twisted logic here. Luckily, most patients who need a hematopoietic stem cell transplantation typically have an HLA haploidentical family member who is willing to be the donor. Again, you don't need to memorize this. This is just supporting evidence from your textbook here. Just kind of showing you that there is something similar when you do various genetic mixtures, especially if you have lots of siblings, increases your likelihood that someone's bound to be related, even cousins. Or if you have, like if your mom was an identical twin and her identical twin has a family, there is some instances where cousins can even be pretty similar too. Oh, like the couple, there's a couple of two identical twins who married two identical twins. And so technically, their children are siblings, genetically, but they're not, but they are, it's wild. They're on the news a lot. But instances like that, there are supporting times when for the most part, there's someone in your family typically with bone marrow, specifically in those HLA, the hematopoietic stem cells, where the HLA matches enough that you can find a matching donor here too. And so this one is showing evidence of alloreactive NK cells can provide a graft-versus leukemia effect in patients receiving a haploidentical, so it means similar, genetics, hematopoietic stem cell transplantation. In this case, it's just, again, supporting evidence. I don't expect you to memorize this. It's just less is known, that's how we figured out that graft-versus host disease can be useful in certain instances, especially if the relative that you got, that yes, you're haploidentical enough to get that donation, but then their cells and their NK cells are particularly primed to fight whatever type of leukemia that you have, it ends up being a good thing. So even though we typically don't want that graft- versus host, if that graft-versus host works out where the graft is actually attacking the leukemia in the original patient, it's ideal. And so that's just, again, the supporting evidence of how they were able to figure it out overall here too. The other fun thing we're learning too is that we can actually prime a patient to be better able to receive a transplant if we start with a bone marrow transplant first. Can anyone hypothesize why that might be? I use that something and I feel like it's the right answer with how confidently he said, I have no idea what he said. Oh, Ken is waving his hand. I guess you are correct too, but yes, Ken. Ken, would you like to use the microphone too? I was gonna say, you can transplant bone marrow first so you can train the immune cells to recognize whatever is coming next. It's basically like reestablishing that person's immune system within your own immune system as the recipient. It's that way when the foreign organ is transplanted, it's already some familiarity there. So you kind of have like refresh the immune system a little bit to be more open to receiving a second organ. So again, if we have time, it's not like a critical, urgent transplant now and we have time to be able to do this, we're learning this is one of the safer methods. We also can see it too, especially if they were twins in utero and they shared some similar material too, they can be more tolerant to that twin's tissue as well. So it doesn't always have to be that a bone marrow gets transplanted first. There's also evidence that supported that we're for exposed to hematopoietic stem cells of another variety first. It primes us to be better able to accept that foreign tissue later. So it is a very, very useful thing that we're now learning. And if we have time in science and we're able to do that, one way that we can increase the odds of successful transplantation, but it is a vastly expanding and super lucrative field overall and new advances are being made every day. So I feel like this stuff will be outdated by the time, like more stuff will be added to it by the time you guys learn this in med school. But very, very lucrative career if you guys are thinking about going into immunology or transplantation as a physician. And Alexa, it's Alexa Neff who did the rotation. She works in a transplant center with Riley, specifically working with the graph versus host neonates. So if you have any questions, she said you guys are more than welcome to reach out to her, especially if you want to do a rotation, check it out. See what's going on is something you're interested in. She said you're more than welcome to reach out to her and ask her about it. This is a deer that was found on back campus and sent to me. So enjoy, we do have wildlife here. There are also foxes though. So be careful. All right, last semester here, obviously we're finishing up transplantation and cancer. It's actually supposed to be today. It's like a Wednesday, Friday lecture. Monday, I've already posted the hypersensitivity recording and the lecture and the PowerPoint, like the PowerPoint and the PDF. So it's all up there for you. I already went ahead and posted the quiz for week 14, which is this week. It has some throwback questions there too, just to better prepare you for things you might see on the exam. The hypersensitivity for next week, I'm just gonna lump it in with the lectures after for the quizzes on that one. But those should hopefully be posted soon too, because I'm trying to post everything ahead of time. I'm slightly behind on the learning objectives, but I figured you guys cared more about the quizzes than the learning objectives. So I'm trying to get those knocked out today. So you guys have everything you need to start working ahead, start studying, have that all together. Obviously we don't have office hours on Tuesday. I feel like most of you guys are leaving very quickly after that. I did learn that you have a double block of anatomy on Tuesday though, so whoops, I'm sorry. Last year I was the only person who didn't make class asynchronous, and this year I'm the only one who's making class asynchronous. So apparently there's a mismatch upstairs. But obviously there's no new PowerPoint posted for Friday's class day. It does have a note that we've spilled over so much that I kind of knew that was gonna happen. And so Wednesday, Friday was just gonna be kind of the transition this week. Obviously Thanksgiving break. Then we have autoimmune disorders, and then some fun case study stuff, which is your final 3% of your class, minus the draw to notice that you guys have between now and then. And then final immunology debrief will be going crash course from start to finish everything. It's like foundations in med school, but in an hour. So just to make sure that you guys are all just refreshed and everything, doesn't mean it's gonna be on the exam. It's kind of my send off. I wanna make sure you guys kind of lose to remember, we've gotten into the weeds a lot. I wanna make sure you guys can take a step back. Remember the big picture stuff. Just to prepare you as I send you off to whatever med school you go off to. Our students historically do well regardless at whatever med school they go to. So I know it seems like a lot. You guys will crush foundations and disco if you stay here. You'll crush immunology wherever else you go to. So just to kind of tie it all together. That's that Monday, but there's no testable material here. Technically, some of the stuff we'll see on 12-4 is testable just because it'll be case studies regarding most autoimmune disorders and immunodeficiencies. And so because of that, it ties into that. So therefore it is loosely testable just because we're covering things that we've already talked about, which for sure are on the exam. Besides that, that's kind of the cutoff date for material on the exam is at 12-4. So going through cancer, and I did have cut this down a lot more since in the past, just because Dr. Studding loves cancer, loves cancer. Talks about it a lot. And so, has she talked about it a lot yet? That might be next semester. So, just in preparation, I don't want to steal her thunder. So I'll briefly go through key features with the immune system of it. But obviously I'm pretty sure you guys all know cancer is bad. I would guarantee you either know someone or have had cancer yourselves, it's just that common. In the United States in 2019, it was the second leading cause of death. And again, this is lumping all of the different types of cancers together. It's my favorite joke when everyone's like, oh, they're hiding the cure for cancer from us. There are like 18 different million organs that it can affect millions of different cell types, millions of different pathways it could possibly affect. Our likelihood of finding one cure for all of it is incredibly slim. The most recent one I saw was some guy said, it was a viral thing that was like, oh, we found the cure for cancer, but they wanted us to hide it. They made the guy, they threatened him, so he withdrew his patent. The patent was for salicylic acid, which is an acne medication. And he said it was the cure and the preventative and more of us should be using it. And I'm like, okay, by that logic, anyone who has ever used salicylic face wash should have never gotten skin cancer. There are plenty of people in the world who have used that and have still contracted skin cancer. So I'm sorry, I wish it was that simple, but it's not. So this is showing you the overall incidence. It's so basically new cases that we have with it and the mortality. So of these, what do we die from? Notice other is a lot because there are a lot of different varieties. And so them all clustered together, it makes up a huge chunk. The nice thing is we're all more likely to get breast and prostate cancer, but thankfully the death rate of that is a little bit lower. Whether that's a good thing or a bad thing, who knows, we've gotten better at testing too, especially ones where we know you have a higher risk of mortality, like with BRCA mutations. We can do preventative medicine with double mastectomies, things like that. But again, it makes up a vast majority of healthcare concerns in the United States, costing billions and trillions of dollars per year. So it results at a very simplistic level. It results from mutations that cause uncontrolled cell growth. And there are a couple of different mechanisms by which that can happen, but cancer is an umbrella term, which again, why it would be impossible typically to find one cure for all of it, because it's an umbrella. For a wide variety of diseases caused by abnormal and invasive cell proliferation, it pretty much affect all possible organs in the body. Other definitions, tumor is a growth, you guys should remember this, because it's back to immuno. Tumor, it's growth. Ruber, tumor, chalar, dolar, like inflammation, that's where we get tumor from. A growth arising from uncontrolled cell proliferation, it may be benign and self-limiting, or malignant and invasive. And both malign and benign and malignant tumors can arise from the same types of tissue too. Benign cellular growth is like a wart. It's caused by abnormal proliferation of cells, but is localized and contained by epithelial barriers. Malignant means it's capable of uncontrolled and invasive growth. And so malignant is typically worse. When we talk about different types of tumors too, it also can affect like the sub-tissue that's involved in. And so let's talk about on the side, tumors of the breast. Abenoma is a general name given to benign tumor of glandular tissue, obviously the breast and the mammary glands are glands. You can also have it, lymphoma and things like that in your lymph nodes, those are also glands. And so adenoma is benign tumor, specifically of glandular tissue. It's just providing the breast as an example, it can be found elsewhere. And adenocarcinomas are malignant tumors of the glandular tissue here. And then it shows pictures, so you can kind of imagine what's going on here. It uses breast cancer as one of the main examples throughout, but again, can be applied to a lot of different things here too. This is just showing you the growth and lifespan of a common human tumor. Again, breast cancer is incredibly common, especially in the United States in both males and females. And actually I think isn't no, no October is breast cancer awareness month. Yes, yes. Men and women can get breast cancer, make sure you do your checks, make sure you go to the doctor if you suspect anything. With advanced medical imaging, we are able to like see things when they're really, really tiny and track them overall too. But here it is showing you the growth. It is fairly linear because again, doubling, it will cause grossly linear visualizations here. Tumors are first visible on x-rays roughly about 10 to the eighth. That's getting a little bit more precise now with like the 3D imaging we've got now and like all the crazy cool mammograms they're rolling out now. It can be a little bit more palpable at 10 to the ninth. And again, that also depends on if it's a little bit more superficial. If it's deep in the tissue, it's a little bit hard to find. And then we can typically see death of a patient at even 10 to the 12th. So it doesn't seem like a lot, but depending on where it's at and what type, it can actually be pretty serious overall, but they will grossly expand over time, which is why it is so important to get tested and checked. Like they caught my mom with advanced testing. She had early onset breast cancer and they caught it like right at this very, very early stage and were able to treat it. They were biopsying it and identifying specifically what kind it was and got her on meds pretty much immediately for targeted therapy. It puts me at a high risk. So if you have a family member who is identified below 50, I believe it is, you are more likely at risk to develop one yourself, especially if you've done genetic testing and there's bracket involved too. So it is also important to get checked early, check family history, things like that, because it can progress very quickly, especially with that doubling right here. This is a lot, we'll go through it slowly, but cancer typically arises from a cell that has incubulated multiple mutations, because as you guys have talked about with molecular bio, there are a lot of mechanisms in place to keep growth in check, cells in checked, bad things from happening in checked here. And so when you have a typical series of mutations acquired by a cell while progressing to malignant transformation, that's the changes that occur in a cell to make it cancerous overall. So that's the definition here, is that typical series of mutations acquired that make it cancerous here. At that point, after that malignant transformation, this gives it the ability to become more invasive. The tumor cells will rapidly acquire additional mutations. It's like once it's kind of already messed up, like if you make one tiny mistake on a type, you can just backspace it once. If you've like misspelled your whole document, you guys just like give up, right? Unfortunately, similar things with the body. Once it realizes there's a lot more mutations, the risk of mutations goes up, and so it'll just keep accumulating more mutations overall. Some of these, again, make it more invasive. Others are random and have no effect. Some can actually be for the good, where it actually deletes bad things, which is nice, not always again. It is kind of a Russian roulette situation here, but some things that can affect it for the negative or the positive. An oncogene would be considered negative. This is a mutant or unregulated form of a gene that can cause cells to proliferate abnormally and form a tumor. Most of these are derived from genes controlling growth and proliferation in the cells. But we do have some nice things to counteract that, known as tumor suppressor genes. So like they sound, they suppress tumor growth. And these are genes encoding a cellular protein that normally functions to prevent cells from becoming cancerous. And so sometimes when you see this, you have a combination of an oncogene and other genes that will turn off tumor suppressor genes, which kind of sucks overall. But when you have all these mutations building up, this can lead those tumor cells to become more genetically diverse. Dr. Sedding will talk about that a lot. And so natural selection will favor cells that are more effective at both invasion and proliferation, which is unfortunate for the host of the cancer, because then it can spread pretty quickly too. Usually this accumulation does occur over about 10 to 20 years. Cancer for the most part is usually very slow growing. There are instances where it occurs very, very rapidly. And again, it depends on like, is it rapidly dividing cells like hematopoietic stem cells versus breast tissue? Is it aggressive or not? There are varying factors that tie into this overall. So, but for the most part, the classic example is usually slow over time until there's a point when individuals notice it. Metastasis by definition, sorry, it's cut off on the very, very bottom here, but it's spread of tumor from its origin site to other tissues. Some cells from the primary tumor can invade other tissues and grow and divide to become secondary tumors. So you've heard of instances where it started out as breast cancer and then spreads of the lungs and the brain and everything else. And at that point it's multi-system. There's lots of different cells involved in this. And unfortunately it's a lot more harder to treat once it's metastasized. So it is very critical for early diagnostics and testing to get in front of it and make sure that we can prevent the metastasis because it does make it easier to treat overall. This is just showing you the example of the multiple different buildups that have to occur over time in order to eventually get to that metastasis. But again, it's usually the failure of a lot of different steps again, too. And so again, times in the logic of, again, we're probably not gonna find one cure for all because there are so many different pieces. Like you can still knock out one piece, but you still have parts of it that are affected. So it's quite a complicated field overall. Again, don't memorize this as evidence to support the fact that environmental factors can also facilitate the progression of cancer. Sometimes you need a combination of genes and environmental factors to turn those genes on or even disrupt normally healthy genes. Like if you have one that normally stops proliferation and you get radiated and we turn that thing off, oops, proliferation. And so one of the main ones we'll talk about with especially micro once you progress to that is oncogenic viruses and like they sound, these are viruses that can contribute to causing cancer. Because interestingly, again, only a minority of people infected with an oncogenic virus actually progress to develop a cancer. Sometimes it can be the length of infection with which you've had it can contribute to that. Other times it's just there might be an underlying genetic condition that makes you more susceptible. You get the virus, it's full speed ahead to cancer. Some of the main ones we'll talk about, you guys have all heard of human papillomavirus, HPV. We have vaccines for that now. The data out of that is astounding because they rolled that out when I first turned 13 or so. And my mom was very hesitant to give me a new vaccine. I'm very glad she did just because pretty much the DNA virus, new estimates are like 90% of people will have it because it's spread in saliva and bodily fluids and you know, even if you're not sexually active with someone sharing drinks with friends can also spread it too. And so because of that, there's a, and it's DNA you're with, it's with you for the rest of your life. Lots of people have it. And as a consequence of that, yeah, there is the risk, you can get cancer, but the vaccine has shown like phenomenal, phenomenal data in preventing progression to breast, prostate and ovarian cancer with the HPV vaccine, which is wonderful. Hepatitis B is another one that can lead to cancer too. Usually liver, which makes sense. It's hepatitis, it's affecting the liver here too. Epstein-Barr, EBV, mono, another DNA virus that if you've had mono, it's in your body for the rest of your life. Unfortunately, we do see it associated with Burkett's lymphoma, which is cancer B cells, nasopharyngeal carcinoma, and even B cell lymphoproliferative disease. We also have another herpes virus, which we'll talk about a lot next semester. Human herpes virus 8 or HHV8 is heavily associated with a specific type of cancer known as Kaposi sarcoma, which is also linked to HIV as well. HIV has led to increased rates of cancer, which is fascinating. So again, it does show that there is typically probably a genetic component and environmental, in this case viruses, but you can also have chemicals, radiation, things like that can lead to progression of cancer as well. But again, fantastic data about the HPV vaccine out. You guys are lucky, you're in the generation. I think you guys have like a series of like 11 different strains of it now. Like it got wild, it's nice. I think I got the one that only covered four strains here, but they've identified more and more subtypes of HPV associated with cancer. And so they're getting better and better at vaccinating and covering more strains that could potentially lead to it, which is phenomenal, but we do have greatly decreased risks of those cancers previously associated with HPV as the vaccine here too. Just a fun fact, I like this chart because it also includes the adjuvant and like all the extra details in it, but we've seen phenomenal protection across the board from even general rewards too, not just cancers. So it is phenomenal overall. Common features of cancer cells do distinguish them from normal cells. So I would actually know this chart over here. It should be a learning objective because these are fact features of these cells. All, and again, you guys know, I don't like absolutes. So when I say all cancer causing cells have seven key features in common, that's important. They typically stimulate their own growth. They ignore growth inhibiting signals. They also avoid death by apoptosis. They will develop their own blood supply, which is that angiogenesis, they'll start to create new blood vessels within themselves to get themselves that nutrients to help stimulate their own growth. They do seed from sites of origin to invade other tissues, especially if given long enough time, they will metastasize. There is constant replication to expand that tumor cell population, like I talked about, it's doubling. That's why there's that linear growth overall. And they are unfortunately very, very good at evading and outrunning the immune system and occurring faster than the immune system can keep up with it, and that's typically when we progress from below the threshold of detection to cancer here. And so additionally, cancer cells can be identified by tumor-specific antigens and associated antigens. So specific means specifically found on cancer cells. Associated means highly correlated with it, but can also be found on normal healthy cells too. When we talk about tumor-specific, this is an antigen that is characteristic of tumor cells and is not expressed by healthy cells. So if you get diagnosed with cancer, having tumor-specific antigens makes me feel a little bit more confident just because then we can do a very targeted therapeutic just for those cancer cells, and you won't have any secondary consequences where it's attacking other healthy tissue that might be expressing whatever protein it is. And so these mutations are acquired by somatic cells during that oncogenesis or creation of this cancer, and those will typically give rise to those tumor-specific antigens. With the associated, it's useful in helping identify what cancer it is and sometimes targeted treatment options, but there's an unfortunate consequence because it's also found on some types of normal cells that you can have sometimes side effects where you've unfortunately had to wipe out healthy cells in addition to a cancerous population overall. And so this is just showing you some examples. So again, I don't expect you to memorize it. These are proteins that are tumor- specific antigens here, so people studying all these different types of cancer have gone through and sequenced to identify where these typical point mutations occur in these antigens so they can figure out specifically and make very, very targeted treatments for these tiny changes to these peptides overall. And so it can be something as simple as a point mutation overall, or it can be point effusion where things get crossed, all different types of things, but it is pretty cool that people have. If you're gonna get cancer, at least get one where you have really specific markers too because it makes it very, very easy to create targeted therapeutics and usually treat overall. We talk about leukemias, this is also critical for immuno because again, they affect cells of the immune system. And overall, it is accumulation, again, of dysfunctional cells and loss of that mitotic regulation overall, and so you'll have uncontrolled production of these abnormal cells. Like we talked about, you have a limited volume of blood. Eventually, these cancerous cells will overtake it and you'll eventually see side effects like anemia or immunosuppression just because there's that crowding out effect where you have a limited volume, the cancerous cells are taking over that volume and so you lose those healthy cells. And oftentimes with leukemias, exhaustion is one of... Please don't go home and have med school hypochondriasis because everyone's exhausted in med school. If it continues for a very long period of time and there are other signs and symptoms, maybe. But you can see typically things like exhaustion from anemia because you have the overproduction of other types of white blood cells. You're not producing enough red blood cells. You're not getting oxygen to your tissues. You're exhausted. And so that can be sometimes the first sign with certain types of leukemia overall. So obviously, if you have a decrease in the red blood cells, you do that crowding out effect. You get anemia. If it's wiping out your platelets, you can have easy bruising and bleeding as a consequence of that. And so those can all be signs and symptoms. You may think just like, oh, I'm bruising, who knows? Maybe I'm just a little clutchier than normal. It could also be the sign that something else is wrong. So important to talk to your patients about that here too. This is a chart that I made talking about the four different types of leukemias that we have. They're split up by the lineage, whether they affect your lymphoid cells or your myeloid. And so lymphoid are on the top row. Myeloid are on the bottom. They're also split by type and speed of cancer progression. So acute versus chronic, fast versus slow. And so acute is in this column. Chronic is in this column here. Obviously, if you see the term myelogenous, it means myeloid, lymphocytic, lymphoid. A lot of interchangeable terms. Look at the prefix, it's pretty good. We talk about acute lymphocytic leukemia, or ALL. This is most common in children, but does affect adults. I did have a friend who got diagnosed at 22 with ALL. You have chronic lymphocytic leukemia, again, most common in adults, mostly over the age of 55. Chronic also tends to be mostly in adults too, so that chronic myelogenous is common in adults, or CML. And then acute myelogenous leukemia, AML, occurs in both children and adults. So for the case studies you might see on the exam, I might lean more towards the classic presentation, or if I wanna be a little bit more difficult, because again, it's common in some, but not all or nothing. Age might not always be a useful piece of information. You will also see that on board's exam. They provide age for nearly every board's question, whether it's relevant or not. It's also up to you to kind of sift through to make sure. Like, does it support your diagnosis? Is it critical or not? Nutricles are actually the most common type of myeloid leukemia that you guys will see. So we talk about speed, acute versus chronic. Can you tell us it's also like spiller from when I lectured at LSU? I kept LSU colors, and I just never changed it to Marion. So acute develops from progenitor cells in an earlier stage. These are typically immature and nonfunctional cells. You guys remember BLASTs, they're early young cells that spill into the blood from the bone marrow. They are fast growing and aggressive, but they have a short life expectancy of about a few weeks to months. Immediate treatment is critical though, if you have an acute type of leukemia. Chronic develops from later stages of blood vessels or blood cells. So imagine like those neutrophils with like six nuclei inside. They're a little bit older. They're not working as well. So chronic actually is a little bit better of a diagnosis because they are slower growing and longer survival. That's like, imagine like to help remember that acute is worse just because like, remember they're very gung ho, they're young, they have a lot of energy, they can do a lot of damage. Versus you've got an older adult who might need to take Advil before starting their day. You can work with it a little bit here. And so it does develop from later stages of blood cells. It is the production of more mature cells unlike acute. So if you're looking at myeloid leukemia with neutrophils, if you see a blood smear and it is all neutrophils with six nuclei, do you think it's acute or chronic? Someone say it loudly and confidently. Dan, would you like to phone a friend? Six nuclei in a neutrophil? More nuclei as they get older, it's a chronic. So, neutrophils can range from two to six. The more they have, the older they are. So if you see it with a lot of, and that's okay. We get it wrong now, so we get it right on the exam. I love this strategy. So, the more nuclei we have, the older those neutrophils are, more than likely they are chronic. If we're seeing neutrophils with like one or two nuclei, those are baby cells. That's bad, that's acute. You won't see a blast in the blood with chronic leukemias and it is slower growing with longer survival. So at this point, a lot of times the strategy is just watch and wait, which is wild. I would be a nervous wreck, but science says we watch and wait, we just make sure it doesn't progress because weirdly we can progress from chronic to acute eventually, which is super strange to me. Other types of cancers we'll talk about that affect the immune system specifically. We have Hodgkin's and non-Hodgkin's lymphoma and there are two differences between it. When we're looking at histology, I will not expect you to know this on histology, but you might see a histology picture to supplement the information just because it's a really cool picture. Reed Sternberg cells are malignant B cells. They are very large and they have multiple nuclei. Sometimes you can see macrophages that are large with multiple nuclei. You typically wouldn't see those in the blood. And so typically if we see these guys in the blood, we're going to assume these are Reed Sternberg cells. There are other testings and standings we can do to confirm though, that is B cells with a lot of different nuclei, but they are very, very large. That's a normal lymphocyte, for example, large has got three different nuclei within it. So it's massive. And it typically causes with Hodgkin's. If you identify Reed Sternberg cells, it's traditional Hodgkin's. It mostly affects upper body tumors. You can see exceptions. The highest rates are in young adults between the ages of 15, 24. So the one time the younger age, yeah, is not great, but then it tries to catch back up to you when you're 60. So who knows, but I'm loosely protected right now. Non-Hodgkin's lymphoma, you do not see Reed Sternberg cells in the samples. However, you will usually see tumors in the lymph nodes, LN lymph nodes, all over the body. And again, usually, but there are other exceptions. The exceptions are like Sternberg versus no Reed Sternberg. Non-Hodgkin's, you can see it at all ages, but usually your risk increases with your age. And if you ever see obviously the term lymphoma, you can gather that it is a cancer of the lymph nodes. So, oma, lymph, cancer of the lymph nodes. Another one we'll talk about is multiple myeloma. You guys have already heard of these words because we talk about it with immunological techniques and how we make those antibodies. And you guys remember module three with B cells, we make monoclonal antibodies. We're using those multiple myeloma cells, so they're bad, but we can use them in science for good things too. Multiple myeloma is malignancy or cancer of plasma cells in the bone marrow, specifically in your body. It can obviously spread out to your blood. It is more common in males and more common in people of African Caribbean descent, more than likely due to some genetic component. The median age of diagnosis is 70. I have had a student in my class whose mother was a white woman in her 50s who got diagnosed with multiple myeloma. So it's not an all or nothing instance, but again, and more common in this patient population here. Abnormal antibodies that are produced by these myeloma cells are known as M proteins. And so they look a little bit different than normal here too. And unfortunately, what makes this pretty difficult, myeloma cells secrete mediators that stimulate osteoclasts. So with multiple myeloma, you will see bone loss and skeletal pain because they're triggering effects in bone cells. So sometimes the first symptoms you'll see of this are going to be just joint pain that won't go away. Like there's no trauma to your femur, but like in one spot is incredibly painful. And it's like, you know, bone pain is achy. Like muscles, you guys know when you pull the muscle, right? Or like tendon, you can tell it's kind of soft tissue. It hurts with movement. Bone pain is just that constant ache all the time. It's kind of that deep, just like when you have bone pain, you know it's that dull ache. Sorry to make some of you guys squeamish. But for the most part, most people know and can loosely tell you when they feel like it's in their bone versus, you know, oh, they walk around and it hurts more, more than likely muscle or something like that. Signs and symptoms are some fun ways of remembering. I don't expect you to memorize all of this. These guys here, you should know crab. Crab is a great, great, great, great way of remembering this. Calcium will be elevated in patients with multiple myeloma. You will typically also have renal insufficiency. So they might complain of decreased urine output overall or feeling really thirsty, but they're not peeing a lot or not feeling really thirsty at all. Strangely, you'll also see typically anemia with it too. Again, crowding out effects. You have, you know, plasma cells in the bone marrow affecting, you know, we're creating more osteoblasts, things like that, affecting how many red blood cells we can produce. You'll also see lytic bone lesions. And so again, it ties into that skeletal pain and that bone pain overall. So crab is a great way of remembering what you need with multiple myeloma diagnosis. Thankfully, we do have an immune system to try to control most of our cancers. The immune responses are similar to what we see with viruses, which is kind of cool, because again, think about it. Most viruses are intracellular. Well, they all are, technically. You can find them outside, but intracellular because cancer is mostly intracellular mechanisms leading to it, why we target it like viruses. Immunosurveillance by definition is the capacity of the immune system to recognize cancer cells at an early stage and eliminate them before they cause disease. Right now, every single one of us has cancer cells within our body. Does that mean we have cancer or tumors? It just means that our immune systems are successfully doing immunosurveillance and keeping the cells below the threshold needed to develop tumors and cancer. And so, every time you go to sleep, your immune system gets what it needs to try to fight that off. That's why I recommend sleep, it's very critical. We do notice in individuals who are shift workers, who use their phones late at night without blue light blockers, use a lot of that, we're seeing increased rates of breast, prostate, and other adrenal cancers associated with disrupted sleep. Prioritize that in grad school when sleep will also be disrupted. Control of cancers by the immune system does not require the elimination of all the tumor cells. It just has to be below the threshold needed to progress to tumors or cancers. And again, it's going to be person specific. Successful tumors are ones that evade and or manipulate the immune response to avoid destruction. We do use monoclonal antibodies, as well as to tie it back to immunological techniques. We can use it in both diagnosis and treatment. Because if we want to know what specific subtype of cancer that they have, we can stain and use antibodies for those tumor specific markers to see what are present on biopsy samples. We can also use it once we know there's a very specific tumor antigen on there. We can then make antibodies against that, so those will only bind on two cells expressing those tumor specific antigens, thus signaling our body to say, hey, this is bad, you should kill it, which is fantastic. So these are just specific examples, don't need to be memorized, but we'll help you because you might see something similar on the exam. But again, you can still solve it if you have the logic and the big picture stuff here. This is just showing you a tumor section stained with H and E, showing that typical starry sky pattern you'll see with lymphoma cells. So the lymphoma cells are forming the sky and tumor eating macrophages of the star. So very pretty picture of macrophages overall. Again, some examples just to support the evidence. This is just showing diagnosis of Burkitt's lymphoma using monoclonal antibodies specifically. In this case, we were looking for an anti-mic oncogene associated with Burkitt's lymphoma here. And again, they did an immunofluorescence thing where they actually looked inside and did some nuclear stuff, so most likely fluorescence in situ hybridization, as well as some DABs standing here. Again, it's very boring because it's brown. But we were able to look and target and track that this is Burkitt's lymphoma because we have found tumor specific antigens associated with Burkitt's lymphoma diagnosis overall. So more than likely we would have taken a lymph node biopsy of a patient, stained it, confirmed it, started treatment. Another one, Hodgkin's lymphoma that we have already talked about, it is caused by B cells that have lost B cell characteristics. That's why we either see Reed-Sturmberg's or just other cells that are just abnormal here. Showing an H in E with extra nuclei inside of this lymphocyte. So this would be a normal lymphocyte here. This is an abnormal Reed- Sturmberg cell. We've seen it with a PAX5 antibody. You guys kind of remember that throwback to PAX5 with B cells. Again, these are cells of the B cell lineage that have lost characteristics. And so it's kind of lost its feature of PAX5 within it, but picked up things like anti-CD30, which we didn't really talk about, same as CD15. Thankfully, there are tons of immunologists out there who have actually deeply characterized a lot of different types of cancers. So especially when you make your diagnosis, then you send it off to a biopsy lab, you have clinicians and scientists there who are going through and looking for specific markers to help identify and target. The cool thing about this, because it's expressing CD30 and CD15, and we know that, and say we know, I give you that information on the exam that CD15 is tumor-specific. Can I then treat the patient with anti? If I created a CD15 antibody, do you think I could treat a patient with it if they're expressing it, it's tumor-specific? More than likely, yeah, that'd be a great thing. And so personalized medicine is going a huge way, especially with targeted cancer. Another one, too, again, I don't expect you to know those markers. I would typically give you that stuff in the exam. I'm not trying to trip you up, but I'd give you those things that would just like, I'm giving you the situation, I'm looking for the big picture of what's going on. This one's another one, they were looking at anaplastic large cell lymphoma, again, looked at an HN8, they see increased growth. Anytime you see something, it just doesn't look uniform and unique, and with most cells, you'll see nice, even spaced out distribution. It looks like it's structured. Whether you know the structure or not, it looks structured. Does this look a little chaotic? Like you spilled water on your watercolor and it just kind of went everywhere. This is chaotic. It's a lot of growth here. So even though you guys don't know that yet, like anything that looks a little messy, tends to be chaotic. And so again, this is another one that we just happened to stain, found that it had CD30, we did antibodies to stain for it. We also found NPM-ALK. Who knows what fusion protein that is, but if it's only found on these cells, great. That means we can target it to tumor specific. We can typically make monoclonal antibodies to it and target drugs directly to that too. Again, don't memorize this, but you guys know IgG1, things like that. We can create a lot of different types of drugs by basically creating antibodies. Typically like this we can do too, is inject tumor specific proteins from patient or host or wherever into animals. It's foreign to those animals. Those animals will produce antibodies against it. We can take those out, isolate those, create drugs, name them funny names that all end in mad because they're monoclonal antibodies and inject them into the patient and do very targeted therapeutics. It's fantastic. It is a massively growing field. We are making huge strides in targeted cancer. Childhood neuroblastoma, neuroblastoma typically is very, very, anytime you have any kind of neuro cancer, frequently means death. Again, having targeted drugs that we can go directly to, very targeted glycolipids that we found in this specific type of cancer is phenomenal for treatment. I don't expect you to know this. If I use drug names on the exam and it is not one I've told you to know or memorize from three examples I use in transplantation, and I tell you it's this, I'm not trying to trip you up and be like, oh, you need to know whether it is this or not, no. I'm telling you an example. Like say I said, yeah. If you memorize every single thing and I use the cetuximab, you're like, oh yeah, I know this. But also if I say that cetuximab is an IgG1 and inhibits EGFR signaling and ADDC and is useful for the targeting of head and swamous cell carcinoma, this is the best example of using monoclonal antibodies to target drugs. I'm not trying to trip you up on the more difficult stuff. Does that make sense? You guys have seen questions like this before on the exam. I'm not trying to trip you up. I'm just trying to get the bigger picture that you know, like the consequences, the big picture is that we can use monoclonal antibodies, both diagnose and treat, especially if we know features about these different types of cancers kind of going into it. On the other bottom part here, this is conjugated, it just means it's got other things tied to it. Some of them can be radio labeled, so you can actually do targeted radiation for specific things. My dad had prostate cancer recently and is also in remission, so. I'm kind of screwed on both ends right now. But because I knew what specific tumor antigen he had, they were able to radio label specific drugs, so when they did radiation therapy, it was only targeting the specific cancer cell types, which is awesome because then it also limits the side effects of like doing widespread chemotherapeutics which typically kill any rapidly dividing cells, which is fantastic overall. Antibodies are also used to target toxins to tumor cells. We can have that direct targeting of them by like binding on to triggering normal immune responses or we can be really smart kind of like we did with the radio labeling with the conjugated and we can also type like toxins to it. And so this one's showing, we mentioned CD30 is commonly found with some types of cancers here. Anti-CD30 is conjugated to a toxin or a statin specifically. We were able to genetically modify it so that when that CD30, like antibody to CD30 binds on the CD30 on a cancer cell and that pulls it in, it's then, it's like the Trojan horse. It's delivering the toxin directly into the cell and we can kill it from the inside out, which is phenomenal. Again, it decreases the risk of having to do wide scale chemotherapeutics as a consequence of it. And so great way that we can do it is by directly targeting toxins to antibodies to then bind on to the tumor cells and kill them. We can again also use radioactive isotopes. Like I mentioned with my dad's example, we can use it so that radiation can be targeted specifically to just the cancer cell types. Again, fantastic consequences for the patient overall because again, very targeted therapeutic, typically less side effects, typically a lot faster working than most chemotherapeutics that we have. And so this one in this case, it just induces radiation damages inside the cell. They die naturally. We move on with our lives and it's phenomenal here. We can also deliver tumor cells to NK cells. So again, it's like if we tied a gigantic red flag onto that FC region of an antibody that was specific for a cancer, put it into the body and it's like, hey, party over here and all the NK cells show up, great. So it's basically just providing instructions and telling our NK cells these are bad, do a better job. Like you are not doing your job right now, right here, kill them. So this is a specific example of what's known as antibody dependent cell mediated cytotoxicity or ADCC well-named because basically it is just saying antibodies are leading to the direct killing of cells using NK cells. You can also see this with CD8 T cells because they are cytotoxic and they kill. And so again, you are coding antibodies with specific markers for that cancer cell. So they bind on the cancer cell, but at the same time, these very pretty antibodies with those red flags are signaling those CD8 T cells and NK cells to come over, bind on and extra specially kill those bad cells here. It is phenomenal. So it takes advantage of the features that we already have. And since we skipped a couple also of scientists recently, I want to add professor Korisha Abdul Karim. She was born in Tongat, South Africa and she is known as a symbol of hope for young women pursuing careers in sciences. She is an epidemiologist specializing in HIV in South Africa. She was recently recognized for her groundbreaking work on the Caprisa 004 Project, where they found evidence that a microbicide added to HIV treatment actually decreased a woman's chances of contracting HIV by 54%, which is fantastic. So that is it. We finished early because I talked way too fast. You have four minutes left if there's any specific questions. Does that seem fairly explanatory? I think that's where I underlined these big picture facts because those are the facts. The examples, besides the definitions, which I definitely expect you to know, you might see examples on the exam, but you do not need to memorize these specific examples to be able to get it right. It might be more so like, oh, I targeted an antibody and it attracts NK cells to come in and kill. This is the best example of what? ADCC. Does that kind of make sense? There's a lot of stuff on this exam, but I feel like it's easier because it makes logical sense and it's fairly straightforward and a lot of you guys have already heard of this just from life experiences, scribing, personal experiences, things like that. Cool, cool, cool. And Quiz for this week is already posted. It has one fun question from last week, but it should be all good.