Search for tag: "pancreatic"

Dr. Miller: Surgical treatments for uncommon pancreatic cancers. We're going to talk about that next on Scope Radio.

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Dr. Miller: I'm here with Dr. Thomas Chaly. He's a pancreatic transplant surgeon, and we're going to talk about other kinds of pancreatic cancers. I think most people, Thomas, are used to knowing about the standard pancreatic cancer, but what we treat here at the University of Utah are more rare types of cancer called neuroendocrine tumors of the pancreas. Can you talk about that a little bit?

Dr. Chaly: Pancreatic neuroendocrine tumors are a rare tumor, like you stated, representing approximately 5% of all tumors of the pancreas.

Dr. Miller: Not common.

Dr. Chaly: Not very common at all. They can be described as in two ways, nonfunctional versus functional, functional being quite more common than the other. The spectrum of these tumors range from insulinomas, glucagonomas, VIPomas. These may just sound like large terms, but basically my point to get across is these are hormone-producing tumors.

Dr. Miller: So tell me what an insulinoma does.

Dr. Chaly: An insulinoma is a tumor that's secreting insulin from the pancreas.

Dr. Miller: That's where insulin is made anyway, right?

Dr. Chaly: Correct.

Dr. Miller: Okay. So if you have diabetes, your insulin-producing cells of the pancreas aren't producing enough, but in this case, too much.

Dr. Chaly: Right. They're overproduced and then they're secreted based on the tumor so it's uncontrolled. It's an uncontrolled tumor secreting insulin in extreme amounts.

Dr. Miller: And then there are other types of neuroendocrine tumors.

Dr. Chaly: Correct. Like glucagonomas, which are increasing the amount of glucose you have in your body in extreme amounts.

Dr. Miller: Almost the opposite of what the insulinoma does.

Dr. Chaly: Exactly. In addition to that, there's also something that's more common on the spectrum, which would be a gastronoma.

Dr. Miller: Would you think that these neuroendocrine tumors are as dangerous as pancreatic cancer as we commonly know it?

Dr. Chaly: I would say they're dangerous in the fact that they act like ninja tumors, as I like to call them.

Dr. Miller: That's interesting. What is a ninja tumor?

Dr. Chaly: Well, tumors of the pancreas, I would say, can go relatively unnoticed for a longer period of time, kind of like a ninja. Now, maybe that's just kind of a term that's a little too broad, but I would say that these tumors are dangerous in that aspect, that they go unnoticed for long periods of time. Dr. Miller: So they're small. They may not produce much in the way of hormones. People don't notice them, and then later on as they get bigger and produce more hormones, all of a sudden they develop symptoms.

Dr. Chaly: Right. And then at that point, that's when the diagnosis may in some cases be too late. But in other instances, this is just the tip of the iceberg of all their symptoms.

Dr. Miller: One question I have is, are neuroendocrine tumors generally malignant in the sense that they can metastasize or not?

Dr. Chaly: So that's an excellent question, and the answer is 50/50. Most are benign, but some are malignant and in some cases they can metastasize to the liver, which can be very scary to the patient themselves.

Dr. Miller: So to point out to the audience, even though they're benign they still produce hormones like insulin or glucagon and that causes abnormal symptoms in the patient and then has to be treated. So generally, even though they're benign, if they're functional they are taken out or treated.

Dr. Chaly: Right. So there are multiple treatment options, obviously surgical resection being one of the first and foremost. But in addition, there are other palliative measures as well that can temporize the hormone production of all of these tumors.

Dr. Miller: Now, Dr. Chaly, when do you get involved? Are you getting involved when these are malignant and their metastatic?

Dr. Chaly: Well, at this point our division gets involved when these lesions are metastatic to the liver. This indicates what we would call an expanded disease at this point, where they've gone beyond the lymph nodes and beyond the primary tumor sites, and have gone to areas in the liver where maybe not all practitioners are familiar with.

Dr. Miller: Now, that's concerning because when we think about metastatic disease, we think about terminal disease. But you're also saying, maybe not. Maybe we have treatment for that.

Dr. Chaly: Right. There are excellent results here at The U in regards to neuroendocrine tumor resection, in regards to debulking of these tumors, and it has been well-described that these tumors, if debulked and surgically managed, can be beneficial to the patient long-term.

Dr. Miller: Debulking; could you describe that term for them?

Dr. Chaly: It's basically an 80% reduction in the amount of tumor that's in the liver. If you're able to attain an 80% reduction in metastatic volume of the liver, essentially a metastasectomy of the liver, then you are doing a quite significant benefit to the patient's long-term survival.

Dr. Miller: Now, if you leave some of that cancerous tissue in, do you have to go back in later and do another resection?

Dr. Chaly: That's a possibility as well if it continues to grow. Another modality that can be used is interventional radiology and radio frequency ablation, essentially just burning the areas of the liver that would have remnant tumor in certain areas.

Dr. Miller: Now, how do patients with these neuroendocrine tumors, especially ones that are metastatic to liver, find their way to your door?

Dr. Chaly: Well, it's usually a situation where a patient had a primary tumor of the pancreas and it was found to be a neuroendocrine tumor. Then, they were later diagnosed, maybe a year or two later, sometimes less, where they had tumors now in the liver. The original physician maybe thought that a more experienced liver surgeon may have some other modalities that weren't available to him at his initial encounter.

Dr. Miller: Now, I'm curious as to how many of these patients you see a year.

Dr. Chaly: We see quite a number of patients a year. I would say we see close to 100 patients who need liver resections in some capacity. Maybe approximately 20% of those are pancreatic neuroendocrine tumors or neuroendocrine tumors that have metastasized to the liver.

Dr. Miller: Now, I'm thinking that since these are pretty rare pancreatic tumors, patients are coming to see you from all over the place, probably from outside the state, elsewhere. Is that true?

Dr. Chaly: Correct. We're getting patients from all over the surrounding states. They come concerned because of these liver metastases and what we're able to offer them. I would tell that it's not a death sentence by any means. Neuroendocrine tumors that have metastasized to the liver can be treated in a variety of ways. In addition to those that I've mentioned, surgical resection and burning them, liver transplantation is also an option in selective cases.

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Dr. Miller: Pancreatic neuroendocrine tumors and hepatic transplants. We're going to talk about that next on Scope Radio.

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Dr. Miller: Hi, I'm Dr. Tom Miller and I'm here for Scope Radio with Dr. Thomas Chaly from the Department of Surgery. Thomas is a transplant surgeon and he also specializes in metastatic neuroendocrine pancreatic cancers.

These are rare cancers, Tom, as we've talked about in a previous session and my understanding is that in certain cases one might transplant the liver in order to cure a metastatic neuroendocrine tumor of the pancreas.

Dr. Chaly: That's correct. So in instances where resection or interventional radiologic methods are not applicable to certain patients, University of Utah has shown excellent results in transplanting, in whole liver transplantation of these patients, and with a great long-term survival.

Dr. Miller: Would you initially debulk the tumor in the liver, or would you decide to go straight to hepatic transplant?

Dr. Chaly: That's an excellent question. Debulking is one of the primary modalities, and if we could debulk the tumor safely, leaving enough liver remnant, we would do that. But in instances where debulking wouldn't provide a benefit to the patient, transplantation is the next best option.

Dr. Miller: Do you debulk first and then in some cases transplant later, or is that generally not done?

Dr. Chaly: No, that is done. Debulking can offer a temporary solution of patient symptoms, and if this is not successful and there's a recurrence in the immediate post-operative period, approximately six months, we may consider transplantation at that point.

Dr. Miller: Now perhaps for the audience we should distinguish this from regular or more common pancreatic cancer. You would not debulk or transplant a patient with what we know as common pancreatic cancer.

Dr. Chaly: That is correct. Pancreatic cancer, or pancreatic adenocarcinoma, is extremely aggressive and debulking or transplantation, given the immunosuppression that the patient's on, would be of no benefit.

Dr. Miller: So these neuroendocrine tumors, some are functional, that is, that they produce hormones and cause symptoms, and others are silent. I think you like to use the term ninja cancers. I think you might say that the ones that are less functional or not functional, that is, they don't produce hormones, are the ones that actually metastasize more frequently?

Dr. Chaly: Well, that's correct that they metastasize a little more frequently, and that happens primarily because they're so silent and they're not producing hormones, so we're unaware of their activity. And so at this point, after the primary tumor has been controlled, a liver transplant is an option in some of these patients.

Dr. Miller: What percent of patients with neuroendocrine disease in the liver, metastatic disease in the liver, would undergo a transplant versus the debulking that you talked about previously?

Dr. Chaly: I would say the vast majority of patients would actually undergo a surgical debulking, and in select patients where debulking wasn't an option, maybe less than 10% transplantation would be available for them.

Dr. Miller: But if that's the case, it sounds like the University of Utah would be a great place to have that treatment.

Dr. Chaly: Absolutely. We've had an excellent experience in transplanting these patients and have had a great success rate, and these patients have done well over the long-term period.

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Interviewer: A different way of thinking about how cancer starts. Up next on The Scope.

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Interviewer: I'm talking with Dr. Charlie Murtaugh. Professor of Human Genetics at the University of Utah and with Nathan Krah. They've just published a paper in the journal "E-Life."

Dr. Murtaugh, as far as I understand it, your results really kind of put the initiation of cancer in a different light.

Dr. Murtaugh: The standard model for how cancer starts is that you have a cell that accumulates a bunch of different mutations until that cell becomes sufficiently abnormal that it turns into a cancer cell and stops behaving like a normal cell. And we were interested in how that applied in pancreatic cancer. And we and others have found that the genetic mutations that occur in pancreatic cancer in the model that we use are not enough to actually trigger the beginning of the disease. So we knew there's something else had to be going on. And what we think is going on now is that the differentiation state of the cell.

So how the cell knows what it normally is supposed to do. In this, case the cells are cells that make digestive enzymes to break down food. And they are normally focused 100% on that task. They're not really dividing. But then, a change happens and those cells forget what they're supposed to do and then in that context then those mutations that can cause cancer can become hyperactive and the cells start to become transformed and move toward cancer.

Interviewer: Nathan, maybe you can tell me why you're focusing on pancreatic cancer in the first place.

Nathan: Yeah definitely. So pancreatic cancer is one of the deadliest solid tumors that patients can have. It has one of the poor survival rates of just about any cancer with a five-year survival of only about 5%. So really, any clues that we can get that push toward earlier detection or better treatment options would be good.

Interviewer: You're implying principles of development to understand cancer. What does that mean exactly?

Dr. Murtaugh: Right. I have a long-standing interest in the process of differentiation. This maybe does go back 20 years. So it just how cells learn to adopt the mature fates that they're supposed to achieve, starting in the embryo and the differentiation continues in the adults. So, of course, we are continually shedding skin so we have to differentiate new skin all the time, new hair, etcetera. And it was through studies of differentiation in the pancreas and trying to understand how the different cell types, the endocrine and exocrine cells, how they get to differentiate that we began to be interested in how that might apply in cancer.

Because it seemed, based on classical work, that it was possible. That in fact cancer might start from not only genetic mutations that we know are important, but changes that are non-genetic like loss of differentiation.

Interviewer: So kind of the ideas that when a cell is differentiated, it's mature and is thought to be just sort of fixed that way, kind of stable that way. And so if you disrupt that, things go wrong?

Dr. Murtaugh: Yeah, exactly. Exactly.

Interviewer: And how did you move that into the cancer paradigm? I think you've been researching a gene, PTF1, for a while?

Dr. Murtaugh: Right. So PTF1 is a gene that's called a transcription factor. And transcription factors are proteins that regulate other genes. So a lot of what differentiation involves is turning on expression of genes that are important for the carrying out the function of the cells. So, for example, the exocrine cells that we study, they make hundreds of digestive enzymes. Like huge concentrations.

And so what PTF1A does normally, in a mature cell, is it activates those genes. So without PTF1A during development, you can never make the cells that normally digest food. And what we found is that once you are a mature cell you still require PTF1A in order to continue making those enzymes and in order to repress alternative choices.

So cells tend to not like to do nothing. If you take away a factor like PTF1A that forces them into a specific identity, if you take that away they will kind of cast around and look for an alternative identity. And in a healthy cell, that might not be a big deal. And in fact, we find that just taking PTF1A away is not enough to cause cancer.

But in a cell that has an underlying cancer-causing mutation, when the cell starts trying to change its mind about what it's supposed to do, those mutations can kind of express themselves and then the cell very, very quickly becomes abnormal.

Interviewer: You've done these experiments in an environment where there's already something wrong? And so this is like one more step that breaks the camel's back?

Dr. Murtaugh: Yeah, exactly.

Interviewer: Nathan, what do you see when you do that?

Nathan: When we take away PTF1A in the context of cancer-causing genes or oncogenes, we see that these cells are rapidly transformed into pre-cancerous lesions. And what's really interesting is that if we just express these oncogenes or cancer-causing genes alone, that's really not sufficient to do too much. They occasionally form these pre-cancerous lesions, but in the context that PTF1A loss, almost every cell that loses PTF1A will give rise to cancer.

Interviewer: And is there any indication that this happens in human pancreatic cancer?

Dr. Murtaugh: Right. So that's a really good question. So one of the things that we were able to show is that in fact in the lesions of humans, these early stage precancerous lesions, the PTF1A is also being shut down. And in fact, there are some other studies out there that didn't focus on PTF1A, but have all sort of implied the same thing that this must be happening at a very early stage in cancer. And so it does look like it probably does happen to humans and one of the things we're really interested in going forward is sort of doing the reverse, which is if we could turn it back on in human cells, would we be able to stop the cancerous cells from growing.

Interviewer: Right. I mean, will that point to a different kind of therapy?

Dr. Murtaugh: I think so. I mean, most cancer therapies in pancreatic and other cancers are targeted to cell division. And, of course, that's what conventional chemotherapy does and it has limitations because it can kill the normal dividing cells. And there are other therapies that are targeted at the mutated signals that occur in the cancer and in some cases like lung cancer, those have been really effective therapies. But in pancreatic cancer, it's been very challenging to do that. So the oncogene, the cancer-causing mutation that is so central to pancreatic cancer is one that is in a protein that is very hard to make drugs against.

And so this has been a long-standing problem in the field. But we do feel that differentiation is something that there's almost no disadvantage. In theory, at least, there are no side effects from having too much differentiation in the pancreas because it's an organ that is normally very differentiated. So if there were a way to reactivate the normal differentiation of these cells, that by itself shouldn't have any major side effects. And the question is whether it would be effective as a therapy.

Interviewer: Yeah, fascinating. I mean, is there any indication that this happens in other cancers as well?

Nathan: Yeah, that's a really good question. So one thing I think that's exciting to us is if we really look throughout the GI tract, there are a lot of cancers that undergo this process called metaplasia or a change in cell fate, which almost always precedes cancer and is usually associated with chronic inflammation.

And so one good example is in the esophagus, a lot of people have the acid reflex and that can lead to changes in the cell populations in the lower esophagus. And it's thought that those changes are actually necessary for cancer formation. And so we show a very similar story in the pancreas. We think that this actually a broadly applicable principle where you need a loss of differentiation in order to actually initiate cancer.

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Interviewer: This is Pancreas 101. What does it do? What can go wrong, and what can you do about it? That's coming up next on the Scope.

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Interviewer: All right. Time to learn your pancreas basics with Dr. Jeffrey Campsen from the University of Utah, First of all, let's start out with what is the pancreas?

Dr. Jeffrey Campsen: The pancreas is an endocrine exocrine organ, and what that basically means is it sits in the middle of your abdomen, and it secretes hormones and different substances into the bloodstream but also into the intestines. People know it mostly as the organ that secretes insulin which then controls your glucose or your sugar. And if you don't have that, you become a diabetic. But it does a lot of other functions that helps with digestion of food and regulation of the body's means to produce energy through the breakdown of sugar.

Interviewer: So a pretty important organ.

Dr. Jeffrey Campsen: It's a very important organ in the sense that you could live without it, but it's very difficult to live without it, and you can't live without it without supplementation of the products that it produces.

Interviewer: And what problems can arise with the pancreas, and are they just naturally occurring or is it lifestyle oriented?

Dr. Jeffrey Campsen: It's both. First, some people are born with deficiencies in their pancreas. They're most known as Type 1 Diabetics where early on as a child it's found that the pancreas actually doesn't work particularly right. Many people believe that it's an autoimmune disorder where the body is actually attacking the pancreas. It works maybe at birth, but sometime in the next ten years the body actually attacks it and it fails. And then they become a diabetic from that. There's also you can damage your pancreas by treating your body poorly through alcohol, drug use, different substances that you put into your body can actually destroy your pancreas. Then ultimately you become a diabetic, or a pancreas cripple from that standpoint. And then other types of infection can actually ruin the pancreas. It's attached to your liver through a series of ducts, and if you have liver disease or gallbladder disease, that can actually damage your pancreas and cause pancreatitis which then pancreatitis then heals from that, scars, and slowly becomes fibrotic and also stops working.

Interviewer: Let's get back to the lifestyle. So how do you really have to abuse your pancreas before it's going to stop working?

Dr, Jeffrey Campsen: I don't think very much actually. I think to get to the point where it's completely burnt out, that's probably years worth of abuse to the pancreas. But everybody's built differently, and some people are much more susceptible to alcohol or different type substances and can damage their pancreas. Whereas other people are built in a way that they can tolerate it more. So you don't know until it's too late whether or not those substances have hurt you to the point where you can't recover from that.

Interviewer: And what are some of the symptoms then of a pancreas not functioning? What would I experience?

Dr. Jeffrey Campsen: I think acutely, meaning immediately, if there's a problem you would have intense abdominal pain, nausea probably, vomiting. Over the long-term, it sneaks up upon you insidiously with feeling very lethargic, tired, off. And that's basically showing an imbalance of your ability to regulate your sugar. So what you're actually having is very high sugar levels in your blood creating a feeling of basically feeling sick. Then, a lot of these patients go to the doctor. They find out that their sugar which should be maybe at a level of 100 is actually at a level of 600 which actually ultimately can be life threatening. Some people are actually found in a coma before they realize what has happened. And at that point you may not actually come out of that coma.

Interviewer: What type of life do you have if your pancreas fails you?

Dr. Jeffrey Campsen: It's a very difficult life. If your pancreas fails you, you become what they call a "brittle diabetic." Not only can you control your sugars going into high, but then if you add insulin they can actually go very low. And your pancreas keeps your sugars from going too low. If your sugars go too low, the cells in your body can't work, including the cells in your brain that allow you to breathe and your heart to beat. And so it can become fatal.

Interviewer: And what about other lifestyle considerations, like are you going to have to carry a piece of equipment around with you?

Dr. Jeffrey Campsen: Many patients are able to regulate their sugar with something called an insulin pump. And this pump basically then reads your sugar levels and then doses insulin in. Some patients are able to do it with just pills. I think it depends on the type of diabetes that you ultimately have, meaning there's Type 1 where you don't really produce any insulin and then Type 2 where you actually produce insulin but you're resistant to it. To get back to what you were saying as far as lifestyle, the Type 2 diabetics that actually produce insulin but are resistant to it are the patients that you want to counsel to lose weight. Obesity is one of the major health issues in the world today, and the people that are overweight ultimately are hurting their pancreases. Their pancreases can't handle the weight, and then they become a Type 2 diabetic.

Interviewer: And finally, what's your final thought for somebody listening to this when it comes to the pancreas?

Dr. Jeffrey Campsen: I think basically the healthier your body is the better the organs that you house are going to do. And so if you want to live a long time, you have to treat your body well, which is an old concept but it still holds true.

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Interviewer: A lot of people with Type 1 diabetes believe that the insulin shots and a pump is enough, but there might actually be a better option, a pancreas transplant. We're with Dr. Paul Campsen, Surgical Director of Pancreas Transplant Surgery with the University of Utah. That option is pancreatic surgery.

Dr. Paul Campsen: That's correct. Right now we do pancreas transplants for Type 1 diabetics. Type 1 diabetics can't survive without insulin, so they give themselves shots and they can administer this sometimes through am insulin pump which is a very good way to keep them alive. The control that they get from that is not a replacement for the human organ, the pancreas. That's where the pancreas transplant comes into play in the sense that you can help yourself stay alive just like dialysis helps with kidney transplant, or with failure. A pancreas transplant gives you back the human organ that you actually need.

Interviewer: Plus, also a better quality of life.

Dr. Paul Campsen: A much better quality of life. Over the long term the pancreas transplant itself is completely correcting the diabetes, so any of the sequelae of diabetes, whether it be peripheral vascular disease, damage to your eyes, damage to your nerves, damage to your coronary arteries, all of that stuff is stopped with a pancreas transplant.

Interviewer: Not with the insulin shots or the pump?

Dr. Paul Campsen: No, I think that the insulin helps a lot. It slows down the damage. Obviously it literally saves their lives by giving them insulin, but it doesn't stop the diabetes because you're still a diabetic. The pancreas produces a variety of different enzymes and secretes many things that actually help the body including insulin, also glucagon, which keeps the sugars from going too low which can be life threatening, and any of the pancreatic enzymes that help with digestion. None of that' s given with the insulin pump. When you replace the pump with a human pancreas you get all of those benefits.

Interviewer: It sounds like a great solution. Why aren't more people doing it? Is it a dangerous surgery or is it fairly safe?

Dr. Paul Campsen: The diabetics who come to us hate their diabetes so much and they're so scared by it, and their so scared by brittleness of their, meaning they go too high with their sugar or too low, that they would do almost anything not to have to use insulin anymore, but they're scared because surgery is a big deal. The vast majority do very well with this surgery. It's very safe. They stay in the hospital for about a week afterwards, but the moment that they leave surgery they're not a diabetic anymore.

Interviewer: That's pretty amazing, isn't it?

Dr. Paul Campsen: It is pretty amazing. Many of the patients that come to us, their diabetes has also ruined their kidneys, so they're on dialysis at the same time. We'll do a simultaneous pancreas and kidney transplant. The moment that they leave the surgery the next morning they're cured of their diabetes and they're cured of the their renal failure and they're not on dialysis. The other thing that's very interesting in these patients is if you just give them a kidney transplant their Type 1 diabetes will still attack the kidney transplant.

Interviewer: It just kills that organ.

Dr. Paul Campsen: That's exactly right. The pancreas transplant added on top, because it cures the diabetes, actually protects the kidney transplant. Then both organs survive much longer.

Interviewer: Who would be a good candidate for this type of surgery?

Dr. Paul Campsen: I think anybody who has Type 1 diabetes. We're talking about unfortunate people who were diagnosed with diabetes probably before they were 20. We'd like to see these patients well before they get into their 30's. The earlier we see them the better.

Interviewer: OK. What are your final thoughts for somebody that has Type 1 diabetes and is a little on the fence?

Dr. Paul Campsen: I think basically this is a safe surgery. Coming and seeing us doesn't mean we're going to trap you and give you the surgery, but it's something where we can talk about it and see if this is the right surgery for you. If it is, we can cure your diabetes. If you have kidney problems we'll take care of those too.

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