Colon Cancer Treatment Prognosis

>> okay. our last class is next monday. this week i will be preparing the final. it will be multiple guess there is one question from each lecturer. is going to be posted online week, hopefully, right after

class. today, we have met young from the frederick national lab he is in the laboratory of cancer prevention. he is going to talk to us about diet and cancer prevention. traco. >> thank you, everybody from

coming back from thanksgiving. hope you have a happy couple of days off. who over eight? it is good that you are admitting it. who maybe have a few too many to drink at thanksgiving time? who is not raising their hand

because they don't want every one to know that they over eight and had too much to drink? that is one of the problems with dietary translational research is that people won't admit either to the researchers or even to themselves what they

have eaten, if they have eaten too much or if they are off their diet or drinking too much. what i'm going to talk about today is how we do translational research with dietary intervention and we are going to focus on colon cancer

because that is where my work has been focused, but how we do translational research spans across all types of dietary interventions. this is the prevention page. this is where the mice are much happier. they are fed diets rich in

fruits and vegetables. some red wine of course. in garlic and spices and some tea when they wanted. always say this is a healthy place to be. on the menu today for the prevention cage is we are going to talk about doing

translational prevention. i'm going to give you to talk about the anatomy of the: and some of the risk factors and some of the colon trials that we have worked with. what we are doing with our mouse models how we are using microbiota analysis to learn

what is going on in flavored in amongst all of this is stem cells because all of his is probably affecting stem cell and our nutrition. to start with, when you need to know what drives tumorigenesis, tumorigenesis is a multi-staged event starting with initiation

which is dna mutational event that can happen any time in your life. usually a single event can be in multiple event followed by the promotion stage tumor promoters will drive the initiated sell to a benign tumor and this is the weight

limiting step it can occur over many years but eventually you get a benign tumor. some of these benign tumors will progress into carcinoma and invasive tumors. as i said the promotion stuff, if you think about hpv or cervical cancer caused by hpv,

the initiating event occurs early in life, late teens, early 20s which is the infection with the virus. the tumor promotion occurs later in life, 20, 30 years later. this is a broad time frame. the tumor promoters will also

maintain the initiated cell and is stem-like herself renewing phenotype. a lot of our cytokines will keep these cells happy as a stem cell population. what are tumor promoters? they are growth factors, hormones, uv radiation, stress,

cytokines and things we consume and our diet can promote tumorigenesis. they generally feedthrough receptors in the membrane and they activate the kind eight cascade which protein kinase is through transcriptional regulation in the nucleus to

translational regulations of the mrna and finally to miss regulated proteins. more recently we find these events can be circumvented, specifically one part of our diet we can create dna methylation and dna damaging events as well as some of these

protein kinase. for translating cancer prevention, how do we do that? have any of you been in a prevention trial or practice cancer prevention methods? it is a broad topic. we do it every day. and a lot of this is

consequences of studies that have been used to convince us that these are good practices for our health. ibc, smoking cessation is a key for preventing. there is a lot of study that went in to how do we tell our audience are our children are

population that smoking is bad and how we do stop them from smoking? this was very successful in reducing the amount of cancer we get from smoking. weight reduction, diet modification, exercise. it's hard to convince people to

change their lifestyle. there is a lot of research that goes into how do we convince the population to change their lifestyle? when we get into risk factor for groups that have a high risk factor, we can start to use drugs or intervention

therapeutics. tamoxifen is being used for a while for people that are high risk for breast cancer but have not necessarily progressed into the tumor stage. it works very well. dm at all is being used to prevent: colon cancer,

reoccurring polyps that of not progressed the on that. aspirin for breast and colon it works in the colon cancer. for people that are high risk as long as they don't have the cardiac side effects. and of course diet supplements. another mechanism is vaccines.

this works well for preventing cancer. it is probably our most preventive mechanism that we have. with the hpv virus we can prevent the initiation event from happening by preventing that it will never progress and

hpv is also out there preventing liver cancer. finally, antibiotics can be used to treat bacterial infections that can generate tumors, hi gloria and gastric cancer is a big problem that is easily solved by antibiotics. so colon cancer, it is the

third most common cause of cancer-related deaths. this was 2012. it still stays up there fairly high on the top of the list. it is not a pleasant disease. once you get past the early stages. we really need to work on this.

the risk factors, there are some race factors whether it is genetics are diet, we will talk about a little bit. history of inflammatory diseases. the biggest one is obesity. obesity is a strong risk factor for colon and many cancers.

what we see is a rise of obesity in the u. s. this is over the last 10, 15 years so what you could predict as we are going to have a rise in colon cancer over the next population of people agent to their 30s and 40s. colorectal cancer rates the

five-year survival is 90 percent, if we can diagnose colon cancer early while it is that the local stages, we have a 90 percent chance of preventing it from progressing further. the problem is, only about 40 percent of the population is

diagnosed, cancers are diagnosed at this stage. these are you. s. statistics where we have good medical care and insurance beyond the early stages how do we get around this or how can we move forward? this is why prevention is the

key for colon cancer. if we get it early enough we can prevent it from progressing to a stage where we cannot treat it. when she passed beyond this localized stage the five-year survival rate goes down to 15, 20 percent.

there is a critical time point we need to catch that. we need for early detection, currently, the clinics we are using occult blood testing for the stool as an indicator. it's a big window and colonoscopy, is when they go in and see polyps that are

developed they can remove them and you basically prevented from going further. the problem is, we are not touching them all maybe because people aren't getting these diagnostics done are some of the tumors are missed her in the diagnostics.

what we need are biomarkers, positive reinforcement that changes in lifestyle are good for you. and that by lowering or increasing the positive biomarkers you will continue to reinforce our continue on these lifestyle changes.

the case in fact his cholesterol in the low density with it. we know we have to lower our cholesterol below the level and every time you go to the doctor they will tell us that. that reinforces our lifestyle changes.

that is what we are trying to look for in colon cancer. for the anatomy of the colon, these are crips they defined the: this is from the small intestine which is longer and from the large intestine and where the cell starts is in the stem cell population with the

crypt base cell cells these are thought to be the stem cells of the colon. they are maintained as a stem cell by light against and other mechanisms from the microenvironment down in the niche. as the cells migrate out of

this niche the concentration is diluted out and they will differentiate into the transient amplifying cells and they have the capability of dividing, but they have lost the cell renewal capability. once they differentiate into the other populations of the

crips they have lost the ability to divide, so no longer dividing. they will migrate up the crypt until they reach the peak and within about seven to 14 days they will be's loft off into the lumen and loss. this is a seven to 14 date

turnaround, so every this is a constant change over in the crips. what we also have signaling is the microbiota, the bacteria that inhabit the lumen of our gut, food and waste particles that are also within the lumen of the colon or of the gut.

these are creating signals, metabolites from the bacteria metabolites on the food particles that are also signaling into the crips and into the stem cells and can affect how these stem cells are changing and how the microenvironment is changing.

the microbiota is the hot topic now for colon cancer, especially but many different cancers and how it is being regulated. one disease of the colon is colitis. chronic colitis is a big problem that can lead to colon

cancer and what they are finding out is they can do microbiota transplants from healthy donors into people with chronic colitis disease. they can cure these people or at least stop the disease for a significantly long time periods.

the microbiota is a major player in what is going on in back to our tumor promotion. the initiation of that in the colon usually leads to activation of beta-carotene either by mutations of beta-carotene or petitions in the apc gene that will cause

the beta-carotene in the nucleus, with this, you get the benign tumors, the polyps that will develop and with chronic exposure to the tumor promoting agents from the microbiota from the wind signaling in the final kind environment you can achieve multiple events and in

the progress tumors we see activation of pete 10 and these tumors will progress into the carcinoma. the stages of colon cancer, the state zero is basically what we call the polyp that is in the mucosal layer. it is growth.

these are easily removed by the g.i. doctor under a colonoscopy. when we go to stage one, the tumors have migrated in the mucosal layer, again, this is somewhat flexible and they are easily removed. stage ii, the tumors have

migrated through the muscle layer and they are into the sea roses layers. it gets a little more tricky how much can be removed from a colonoscopy or whether they need to be removed surgically. stage iii, they've actually migrated beyond these cirrhosis

and started to invade into the length tissue in the local area , and now some would call this actually an invasive tumor once it is into the lymph node and finally, stage iv is where they have spread to other organs predominantly the liver the long and the abdominal wall.

this is where it is very hard to treat and this is as most stage iv, usually the end. how does our diet affect what we do in colon cancer? if you think this is the normal cell and thetumor promoting agent , our diet provides fuel that we need to sustain life.

and over eating can create an energy imbalance. this energy imbalance can drive the proliferation and inflammation can drive this to the tumor stages. in addition, what is in our diet? what we are eating, red meat,

carcinogens, can directly affect how cells proliferate and drive this stage of it. finally, for the microbiota into the mix and understand what it is doing. it is going to affect the fuel availability either increasing or decreasing it depending on

the microbes themselves. the microbes change the food component of what we. what you have consumed may be altered by the microbes that you have in your got at the time you consume it. finally, the microbes themselves can have an effect

on proliferation and the tumor cells themselves. in amongst this there is a large mixture of how what we need to understand about what is going on in our got that is driving tumorigenesis. finally, what we can affect the microbiota so depending on a

high-fat diet it is going to increase the types of microbes that are unhealthy for us compared to a low-fat diet. to show this, stephen o'keefe did a study comparing native americans with african-americans. how many saw the bill gates

talked this morning? the study is partially funded by his funds to go in and understand the health component of our children, especially in the third world countries. what steve did, he studied the difference between the diets and the metabolite in the

african americans versus the native africans. so the african-americans have a high risk of colon cancer versus the native americans have a significantly lower risk of colon ã§cancer. if you look at their diets, the african americans eat a high

fat, high protein low complex carb diet. typical american diet. caucasians generally eat the same diet but there are other factors going on. the native africans generally eat a low-fat high complex carb diet.

the major difference in the types of diet. generally, you don't find obese native africans compared to the african americans. what o'keefe found was that the bile acids in the metabolites that are generated in the got in the colon, the

african-americans had a higher level of secondary bile acid that tend to be carcinogenic compared to the native africans and they have a much lower level of the anti-neoplastic short chain fatty acid. the conclusions from this study was that eating a high-fat diet

, low complex carb diet is going to generate an unhealthy environment in our microbe that may be carcinogenic. did i miss something? i did miss this. this was sort of the draws it out in the american population where we stand in terms of this

risk factors. this is the risk rate of population of incidents in the mail versus the mortality rates here, what you see with the african-americans incident rate is fairly high among the highest in the u.s. with the caucasians peeking at early

times but it is coming down. this could be insurance, could be healthier diets, could be the environment or social environment, the mortality rate is significantly higher in the african-americans than in the caucasians. there is something different

about that. as i said probably we are eating the same types of diets. so it is probably a genetic affect whereas the african-american versus the native africans they are eating a different diet but they may have a closer genetic

relationship. there is probably a mixture between our genetics and our diets. i would like to point out the hispanic population tends to be at the lower end of the curve with the lower risk rates and we will talk about that in

little bit as we go further. how do we do studies? this was while i was at the laboratory of cancer what we like to do is use population studies as a starting point or to guide us to where we want to go. we want to use that to find

biomarkers and molecular targets. we will take them into our mouse models to validate them to see if there are other markers that we missed and do statistics and when possible we can take them into in vitro self culture models to look at

molecular processing take them back into the mouse to validate these and we can use this to go back and forth to design better clinical trials as well as to use our clinical data to find better studies. this started back in the 90s with a clinical trial, the

polyp prevention trial. this was a multi- randomized controlled trial to look at the effects of low-fat, high fiber, high vegetable diets in people that are high risk for colon the high risk for colon cancer means when they went in and had a colonoscopy there was one or

more polyps the surgeons recommended they come back three to four years later for a repeat to learn whether the polyps are coming back or not. this is considered a high risk population. it's a nice population to do studies in because by removing

the polyp you basically have done all the treatment necessary. now, we can treat them with different diets with different compounds over the next four, five years and we can go back in and do another colonoscopy to see if the tumors have come

back or not. it is a nice population to do prediction studies. in 1996 when they first publish this, the results were inconclusive and basically they said there was no result. the problem was the statisticians included all of

the population in the studies which included the noncompliant. all the people who didn't eat but they were asked to eat or failed to report properly over four years what they were how many of us remembered what we ate four years ago.

here is the underlying problem. what they did was went back and read looked at the data. throughout all the data from the noncompliance or that was inconsistent with how they recorded the data and what they discovered was if they group them into quartiles of how much

dried beans they were consuming, dry beans are high source of protein, a low carbohydrate diet so high energy, low index, if they group them by quartiles how much dried beans they ate in the man they found a significant decrease in the

amount of recurrence of the polyps in these people. if you look at the data with good eating and know what they are eating and how long they are eating and how well they stay on track, we might be able to make sense out of the diet. what i find is interesting,

this is a fairly large amount of beans per day rate, one, two cups of beans a day these people didn't know they were getting better or worse so there was something in this group of people that encouraged them to continue eating this type of diet over those 23 to

four your studies. there are other factors going on. we took this data and took it into our mouse model where we could control some of what's going on. our first study is in obese mouse.

obesity is a risk factor. these mice have a defect in the left jena they get significantly obese when they eat a lot. they have all of the risk factors of colon cancer with elevated bmi resistance to insulin the obesity, hypoplasia

, so it's a good model so if we treat them with chemical carcinogen, ask the methane, they will develop tumors and their colon. we treated them when we started a diet that was enriched in beans and followed them over the course of so many days.

what we found was in the mice that were fed being diets whether the whole beings that were cooked ethanol extracts from the beans were the residual factors that were left after the ethanol extract saw number of tumors that were developed.

basically what this is suggesting is the beans are reducing the obesity promoted tumors in these mice. obese mice were hard to work with. they are very slow. they are very cage confounded there are other problems

associated with breeding them. we went to a second model which is a two stage carcinogenesis. initiation is the axiom methane these cause mutations in the colon, judah beta-carotene and mutation and followed with dextran sodium phosphate this is a detergent that is an

irritant to the got it causes a strong inflammatory response so the tumor promoters are these cytokines and the inflammatory responses are driving the progression or the promotion of these tumors. these mice will develop crips, dysplastic lesions, it is very

similar to what we see in human tumors that develop. a have activated beta-carotene and over expressed classic markers. we were able to do virtual colonoscopies in the mice, basically this is an mri imaging sort of what you could

get done in the clinics as well. this is a normal mouse. this is 29 days after the aom dss treatment you can see the beginning of the benign tumors appearing in this is the same mouse over time so we can see clearly developing tumors in

this model. when we fed the mice the being extracts, we saw a decrease in mortality. so the a.m. dss model wayside decrease in the mortality rate and we saw significant decrease in the total number of tumors that the mice developed.

so again, we are validating what we saw human polyp prevention trial. we want to know what's going on in the gut or in the animals systemically so we've been did a metabolite analysis. it is a systems approach idea where we can follow the

metabolites in the organisms and how they change with diet or with drug intervention or whatever you have in your study. in a sense, the metabolites are major markers of disease you go to the doctors you get a chemistry study, and they

report back your cholesterol and your sugars and your glycerol and low density lipids. these are all metabolites. you get your liver enzymes analyze by metabolites in your urine. we ran metabolite mix, on the

mice during the study both in the serum and in the feces and we were able to detect 430 metabolites in the plasma and 550 metabolites in the feces. these are named metabolites so we know what we can see in these samples and if we look at this column, these are the mice

that have the tumors that are fed the being diet versus the mice that had the tumors on the controlled diet and these are changes in the metabolites that were significantly different in the serum we see 22 going up 47 metabolites going down and more interested me in the fecal

samples we see a lot of metabolites going up, probably from the diet itself, the b extract contains a lot of metabolite that controlled mice not having but these are possible markers for consumption. we know which mice are

consuming the bean by the metabolite but also possible metabolite changes that may influence how those animals are responding to the tumor promotion stages. one of the classes that i highlighted are the bile acids, i told you in the o'keefe study

they had different set of bile acids than african-americans and we see similar effect in the mice on the bean is the eight decrease in all the bile acids and all the bile acids metabolites except for this one here. this suggests we are changing

the microbes to a more healthier metabolism that is more favorable for that acid metabolism. so we are working at some of the differences there. i told you we like to go from the human studies to the mouse and possibly back to the

humans. we did a feeding study. this is different than the large population study in that we have a small group of men that were high risk for colon we brought them into the clinic. we told them what they can and

can't eat. in fact, we give them the food and don't eat anything else. and then we followed the effects of these diets over the course of time and we ran metabolite makes on them. this is the setup of this the patients came in they were

either given a diet that was high in bean or low in meat or a typical healthy american diet which was the protein source was chicken or fish. then, we followed the studies. unfortunately, what we found in this study, they came in with very unhealthy diets.

when we put them on the healthy diet or a healthy diet that was beans, a lot of the biomarkers we were interested in change. you could see the healthy diet having an affect on the biomarkers that we were looking at first serum cytokines and insulin.

the effects of the beans were minimal compared to that. when you design these kind of studies it probably would be better to have a run and stage where everyone is put on a healthy diet, and then do variations in your experimental we did see some effects, and

they were reported by a couple of different papers. one of the complaints of the study was that people were complaining they were fooled when they were eating the bean the design was not to have a weight change. the patients were weighed every

day. the amount of calories they were given was based on their weight gain or loss so that there was no change in weight throughout the time studies. if you were eating the being diet you had to eat the whole diet as well as the other diet

but the complaint was they were getting full. so they put where they had to eat the beans but they were allowed to eat whatever or not afterward. by having this ad blame diet they found a significant decrease in body weight over

the before and after time is about three weeks and a decrease in the bmi on these patients. the bean diet is having a weight reduction affect. they also saw a decrease in markers of obesity. they cholesterol of fasting

glucose went down. this is suggesting the bean diet is having a healthy effect on losing body weight and many of the markers in it. we wanted to know how the bean diets is affecting their metabolites and if we could compare that what we were

seeing in the mouse model. we ran metabolite makes on the bean food we collected serums before they started the diet and collected the same serums from the same patients after the diets were run in may ran studies. not quite as many metabolites

as we saw on the mice. 87 of the biochemicals were significantly a different after eating the bean diet. we saw at least 87 metabolites changing. of interest are two metabolites people call light, these metabolites went in the human's

after three to four weeks after the diet the same went up in the mouse serum over the same timeframe. minimally, these are markers of consumption that we know that based on this data is eating the beans and who isn't eating the beans whether there they

are an indicator are mechanisms we have to work on that. other changes we saw both in humans in the mouse studies, increase in the lifo lipids a decrease in medium chain fatty acids which is suggesting fatty acid metabolism a decrease in the carnitine's set to be

associated with high meat diets and collectively we see an increase in the fatty acid metabolism and the energy that people or animals are getting from the diet so they are burning better is a way of thinking about that. i told you in the beginning

from the polyp prevention trial that if you ate high bean diet you have a significant decrease in the reoccurrence of at gnome us. we don't know who is eating what. we only know who told us what they were eating.

we are now running metabolomics on these patients and compare them to the patients who had a low compliance and we hope to be able to use the biomarkers we got from this study to identify who was compliant and possibly what level of compliance they have.

then, possibly learn what other biomarkers may be usable to predict what patients may be having a healthy benefit from these types of diets moving forward. one last part. when we go into back to the bench to look at how things are

being analyzed and possibly predict mechanisms, from the polyp prevention trial, gary doby was able to make a coral nation to flavin all that are found in beans, to a decrease in cytokine productions or inverse correlation associated with the app no reoccurrence

and linked it to the cytokine again, this is a clinical study done by looking at the statistical data. we wanted to mimic this in our mouse model. we went back to the aomdss model we gave the mice the four different flavin all and only

the had a significant change in our mice. the size significant decrease in tumors, a decrease in the tumor burden and size. by feeding the iso chromatin we reduced the tumor burden in the mice. interestingly in a mechanistic

way we saw the effect on soft. it is a kind that is known to be up regulated in many tumors and drug-resistant tumors and in its active form is phosphorylated at 419 in an inactive form it is 550. this form prevents its ability to bind to the receptors.

what resolve what we saw in the cells we see a high level of active when we were given the iso remington the active version goes down and the inactive phosphorylation event goes up. what we see is the iso remington inactive form putting

into confirmation it is no longer able to be active. in the kinase that does this phosphorylation event and what we see is the iso remington is increasing in the gene expression of the kinase. why is that important for polling cancer?

it is not the key regulator but it is common in colon cancer. if we look at beta-carotene, beta-carotene and is activated in colon cancer and is probably the main player. in addition to being a part of the pathway, beta-carotene is bound to adherence through the

p1 20 alpha catena complex and it anchor cells to other cells through the adherent junction. it can phosphorylated beta-carotene and and it will release that from this complex and what this now allows beta-carotene and to go into the nucleus working miss

regulate gene expression and push more of a stem cell type of phenotype associated with beta-carotene and activity. the other side is when this complex is disrupted, the here and junctions are disrupted and now these cells are easily capable of being migrated or

invade other tissues. what we saw in the cell cultures is looking at beta-carotene in, we see a significant amount in the nucleus of colorectal cancer cells, but when we treat with iso remington we lose the beta-carotene in the nucleus.

what we see if we knock down the sire kinase, this reverses the effects. so what we see is the iso remington through cs k which is awesome for lading beta-carotene and an iso remington is inhibiting by phosphorylation it which

inhibits the phosphorylation of beta-carotene and we lose the nucleus formation. we went back in the animals and looked at the phosphorylated form of beta-carotene and in the tumor tissues and what we see in the control diets a significant amount of fast

related beta catena in the nucleus of the cells were a lot of that is gone or missing in the iso remington diet. now we capitulate what was predicted from the comparison of the diets in the top prevention trial, we were able to take it into the cell

culture, predict the model, verify that in the animals. we have data that suggest that human colon cancer, csk expression is lost it takes a lot more to have a causal effect on that. we will skip the study and jump to the conclusions.

i showed you that diet and populations what we eat can have an effect on colon cancer in colon cancer risk and i showed you the different between african-americans and native africans and i showed you data that showed a diet high in dried beans may prevent

abnormal reoccurrence in our population studies. in our mouse studies we showed the diets can validate what we saw in the clinical trials. we showed you some metabolism make metabolomics data that we can identify markers we can use in the clinic for

compliance to see who is eating what we ask them to eat. showed you two possible markers , what i didn't show you is the rest are all which comes from red wine also against the colon cancer and is probably preventing this by changing the metabolites that are driving

and odc. this one is just to remind me this is jeff gordon's study where they actually are going into africa and measuring the micro by all in the metabolism on different populations of people and so this is a good reading background for you if

you are interested. this is the collaborative work by many different labs over many different years. starting in nancy colbrunn lab a lot of the work has been done by garrick robie from the division of cancer prevention. we have a few minutes left you

have questions or want to dive back into other data if i went to fast. (applause) >> have you looked down stream at the receptors? >>matt: we didn't whether they are downstream or interactive, they receptors can

affect sars. we haven't looked at the effects of the receptors. it might be interested in other tumors that are driven by egf like breast cancer and breast cancer resistant tumors or drug resistant breast cancer cells often have elevated sars that

may be driven through the egf. we are trying to look at that. it's a little more complicated because the mouse models are not simple. but that is a good point. >> look at. >>matt: the question is the diet a genetic event a genetic

consequence? yes, most likely. our genetics is determined how we react and respond to the metabolites to the energy balance. some people are genetically prone to be obese. also, it is the micro biome

that we inherit. i talked to you about the african-american diet. the president, obama, is african-american, but his micro biome is actually hawaiian. he grew up in hawaii. your micro biome is you inherit and develop through your

childhood. the effects of what you are eating has a big effect, yes, the genetics is also how you respond to the metabolites that you eat. we all know people that can gorge and never get fat. and then we know people who are

obese that have significant problems and 10 diet and have no effects. there is also many of our diet elements are going to affect methylation as well as the cytokines and the inflammation that goes along with that.

>> studies of meat consumption . >>matt: the question is, if i understand it, in our clinical trial where we brought the humans into the lab and fed them a being diet how was a prepared? generally, it was cooked by the

lab technicians. they were brought in in the morning and given a breakfast but their main diet was lunch and they were given a box to take home for dinner. it was a variation of beans in their diet. they were generally just cooked

and added into the diet, as you would find in many types of beans, often in latino type they were asked not to eat anything else. but they went home with a box. can you repeat that? the question is: does genetically modifying the food

have an effect on our diet honor micro biome and our health? that is a big open question. you can take it a step broader and ask about how we manipulate our food in itself to bring wheat up as a major component. we've developed wheat to be

disease-resistant and weather resistant. through that development we have increased levels of gluten in our wheat. there is a large population of people that are sensitive to the gluten. there are two types of

sensitivity, the ability to digest the gluten and therefore a problem with digestion is in the gut and there is allergic or sensitivity to high levels of gluten in the serum which can lead to headaches and other problems. and just removing the gluten

can cause that. yes, there is probably a problem with genetically engineered food that you are allergic to components that are put in, but people are allergic to peanuts and people are allergic to shellfish. these are just problems that

have to be dealt with on an individual basis. i don't know the details. in the mice we do it orally and rectally. but the mice will eat their feces anyway. that is not necessarily an unusual situation for them.

i think in the humans it is predominantly through an enema, but i don't know all the details on that. these are patients with severe crohn's disease or colitis that have tried everything and they are on the verge it's a very high tumor rate will.

this is a happy ending for them. one more? the probiotics, and antibiotics will modify microbes that is why we need markers to know when it is good and when you need them and when you don't and when it can be bad.

this is just the beginning timeframe on how, but we need to learn when it is good and when it is too much. good question. >> i let you know earlier in the course, we had people go and visit the tumor boards. they discussed cases of various

today, i'm in the case reports to you. we have doctor he will be talking about case reports. >> think you. thank you everybody for coming. we are going to go through the objective. describe the history of case

report. outline for a good case report. this is a definition of case it is the formal summary of the patient and his or her ailment including the signs and symptoms that cause and outcome. the history of case reports in

the literature and the case report is the first line of evidence where everything begins. some case reports have been described either by the that is where we had the forms recorded. how can we use case reports?

what are the potential of case reports? we can use to recognition of new disease. this is identified by the epidemic of west nile in 1999. case reports can be used to detect drug side effects this could be adverse or beneficial

drug side effects. drug retractions are usually due to case reports. had a 10 year to look at drug retractions. out of the 22, 18 were due to case review reports. viagra, detected as a result of the study that was done was

developed initial t as an antihypertensive agent and it was the side effects study that led to the development. there has been a link between nicotine withdrawal syndrome. and depression. and as a result of that the use of antidepressants as smoking

deficient agent. a look at the family tree led to the discovery of diabetes. what that did was to allow medical science to understand mitochondria. case reports can be used, it can be used in recognition of disease.

it can have impact on policy. in 2010 in the united kingdom the colony came to a conclusion that a man who died from an overdose of dimorphic was he was killed unlawfully and that led to the united kingdom to come up with policies to prevent recurrence of these

type of things happening in medicine. some describe case report for cases of melanoma, described cases two which we now know as hodgkin's disease. buckets live from a 1990 described two patients with a new type of lymphoma.

this has led to more research in the area. this is a 60-year-old lady who went to hospital for right now swelling. she also related sweating on the right flank. initially, she was evaluated and the surgeon did a medial

aspiration of the right unfortunately, because of limited results she had to go to the er. personal history was smoking history and daily alcohol consumption she was also hypertensive but she did not have issues of weight loss,

night sweats. clinical examination she had a mass on the right anterior and on the right flank and a smaller mass on the left side. the scan of the neck the lateral clavicle and superior medial sternal. this is the swelling on the

right side. and again on the ct scanned. she had multiple nodal densities in the long and the chest the ct categorized lung metastasis and a 2.3 centimeter mass. finally, the right neck swelling was inflammation

consistent, that is the then trick your septum in the heart. between the right and left ventricle. the same tumor there. she had a whole body scan that revealed multiple necrotic masses and supraclavicular regions she also had soft

tissue in the right lower extremity. there was also confirmation of the level of the cardiac apex. left adrenal glands was noted. they did a screen for squam us cell carcinoma. they did not do anything for the patient.

that is the hyper metabolic mechanism in the lower limb. that is the neck. this is the squam and sell from the biopsy. this is a 90 year old lady diagnosed with carcinoma presented with diffuse headaches.

she was treated with radiation therapy. for 18 months she was free but subsequently develop pain in the lower back and the biopsy confirmed a relapse. she had radiation therapy. after that she experienced progression after six months.

there was a separate line of chemotherapy. this was controlled for a period of eight months. she initially received she was given therapy with weekly she had progression again after three months. she was treated in a clinical

trial and she developed a mass in the left breast. mammographically identified a mass of one point a mass of 1.9 centimeters. that's it. ct identified the breast mass and rated graphically it was a breast carcinoma.

she had a malignancy consistent with primary breast cancer and the history projected negative. that is the breast mass on the left side. they exhibited the primary tumor as a result with all the evidence she had progressed that was metastatic to the

breast. at the time of the report she was beginning a line of this is the histology. this is the one from the this is a 16 year old presented with a history of mass, she had acne. excessive here.

and menstrual irregularities. she had decreased appetite and constipation. under examination she had diffuse tender abdomen mass extending from the abdomen to the umbilicus. laboratory tests were within normal limits.

ultrasound revealed a mass cystic components mostly arising from the left ovary. ct of the chest revealed local mass just above the umbilical. in the pulpits and abdomen. that is the mass they are. she had a laparoscopy of the left to ovary and the appendix.

the mass was 45 grams and measured 24 by 21, it showed multiple nodules. the tumor was 20 different she a that an ill-defined. and exhibited nuclear that is the tumor. this is histology showing the spindle cells.

this shows some of the olympic cells olympic cells. she was treated with neomycin and after three months there was no evidence of recurrence. a one year old lady who hasn't had any children with a history of pain in the right lower abdomen and back and ultrasound

scan revealed a cauliflower like mass. ill-defined irregular tissue mass in the pelvic cavity. she was in the hospital and had been diagnosed. she had on clinical examination she had laparoscopy revealed two irregularly shaped bodies

positioned near the pelvic ligament. both ovaries are minor in appearance the left kidney was small and non- functioning and she had scoliosis of the spine. the results was below a category five. at surgery and 25 centimeter

and the ovaries were normal. they removed potentially everything. she had bilateral lymph nodes and they did the right per tonio peritoneal histology they had numerous implants. the pelvic mass consisted of areas of well defined issues

with cystic follicles. it was a tumor that had developed on the ovaries. she had chemotherapy, six months after she did not demonstrate any signs of recurring. again, as i described, the tubes and nodules the uterus

had eight by seven by five centimeters had invaded the uterine walls. that is the mass. this is the two uterine. this is the abnormal tumor that developed from the ovary. and histology, this is the normal ovary.

both of these abnormal histologic features now, we go to rare cases. in rare cases it is difficult to do. it almost impossible to do a cases that can be used to treat a patient if they come across a patient.

this is a 65 -year-old male. on clinical examination it is found to have diminished in the left thorax and there was a mass in the upper middle quadrant of the left breast. a mammographic revealed a mass on the upper quadrant of the left breast.

chest x-ray confirmed it involved entire left hemisphere. that is the mammographic that is the mass. it was also confirmed by ct scan. there are multiple lymph nodes with the largest two

centimeters in diameter and there was a mass invading the left region. and the left breast mass was also seen. that is the mass invading the left this is the right lung. that is the left breast mass it was confirmed squam's cell

carcinoma to the breast. this is just necrosis of the tumor. there was a mass 1.5 centimeters of the left bronchus and pathological confirms ct shows multiple node layers throughout the region.

again, that is the mass they are. this is the whole body scan. this area in the pleura, when they did a biopsy it was just the right. examination was consistent with stage iv, patient was treated with chemotherapy.

63-year-old lady had a 14 month history of abnormal vaginal bleeding, hypothyroidism and apps had a diagnosis of endometrial she had exploratory laparoscopy that showed in the pelvic her tony them. biopsy confirmed carcinoma.

she was treated with medicine. she was referred to a hospital in laboratory tests said she had high levels of protein and chest x-ray was negative. she had partial sigmoid deck to me. the cavity was a cauliflower like tumor measuring six by

three by 2.5 centimeters. that is the tumor. confirmed differentiated tumor and demetrio differentiation. the appendix were all negative. the chemical analysis a1 in the a3. p 53 and receptor was negative. the surgery decreased

dramatically and dropped to the normal range. she was treated. 23 months after, and was treated with two cycles of the levels increase. she was left to follow up. case reports of evidence -based some people advocate it is a

waste of time, case reports don't do anything. they don't contribute anything. but we all know that a single report cannot provide evidence of safety evidence in a disorder. 100 published case reports and the expressed concerns about

publication of results. informed consent reporting. and outcomes. from a business perspective, case reports kind of impact they negatively affect the impact factor of the journal. and the journal having a high impact factor can and the

advertising budgets. evidence- raised findings finds the best evidence for clinical decisions by example with therapy or diagnosis is best to apply to the patient. the final evaluation of therapy especially when the clinical value is clear-cut.

the case reports are equally important for the progress of medical science and education. analysis or system reviews of case reports are case history, as a result of their review a clear picture of the toxicity and the severity of the findings was made and they

discovered difficulty in tamoxifen the fallopian tube, that is a more appropriate patient characteristics and they are able to hypothesize for the reason of the diagnosis for treatment and the use of a second laparoscopy. we looked at therapy is used by

cancer patients. 18 of the case reports had toxic effects. the clinical trials in agents like green tea, and the others . what we have concluded was that many of the harm that had from the case reports have not been explored or reported in the

english. we know that case reports what it can do the characteristics and case outcomes. however, in situations where the evidence is not adequate, the best of the first line of evidence must be taken into account.

what impact on case report make on medical research? case reports are followed a public trials. 64 case reports find most 83 percent said no. the outcome, when you look at improvement, most of the report said there was an improvement

for the patient. looking at a similar thing, case reports are followed by published trials. also, when you look at improvement, again, high percentage. how do you have a good case report?

what does it teach us? is it an unexpected association? is it something that would otherwise be missed? case reports are written in a structured manner and definitely relevant in current case reports are evidence to

recommend treatment. over the last years there has been an increase in more general reports so there has been an improvement because the mainstream general most of them don't thank you. >> any questions? >> there is one in cancer.

case case reports reviewed? >> yes. a long time ago there were cases but now they have to be consent by the patient. >> thank you very much.