Thank you. Thank you, Josep and Jessica, for inviting me. So, last but not least, hang in there, there's coffee coming. So, the task today is going to discuss, my task is discussing diagnosis and management of ACC in patients with obesity. So, I'll try to go over that data. These are my disclosures. So, I'll first talk about diagnosis, first pertaining to surveillance and diagnosis, and then talk about management. So, as has been said, I'm not going to rehash all of this, but obesity, obviously, is an important risk factor for NASH, NAFLD, specifically, but also in other diseases, alcohol, viral hepatitis, and other liver diseases that lead to cirrhosis and thereby causing ACC. In terms of surveillance, as has been mentioned by Dr. Buglianesi, ultrasound and AFP is the mainstay of treatment in patients with cirrhosis, and this is one of the largest meta-analyses and evaluated that aspect. And this has been endorsed, as has been mentioned, by different societies throughout the world. But most of the concentration is really on the benefits of surveillance, which is early detection, early stage detection, but there are some harms associated with surveillance, and this is something that Amit Singhal, in our group, has been interested in trying to measure the harms. So, in this study, actually, he evaluated 600 patients with cirrhosis over a three-year period. Early detection was achieved in about 70% of patients, so that's the benefit. However, he observed physical harms of surveillance in about 28 patients and moderate to severe harms in 10 patients. These harms were mostly requiring biopsy, not that they got harmed from the biopsy, but they required an invasive procedure to diagnose a tumor or evaluate the finding of the abnormal surveillance test, or they require multiple cross-sectional imaging over time to determine if that patient had cancer or not, or invasive angiogram. So they require more than just the diagnostic test in order to diagnose a tumor, and that's where it kind of codified as harms. So looking at this data in another way, especially with ultrasound, and I'll touch on AFP, but on ultrasound, these patients that had either a false positive, and that's just the test itself, but they had significant harms, and it happened with ultrasound as well as with AFP. And a lot of these harms, especially with the indeterminate causes, were also in obese patients that led to the indeterminate finding that led to further exploration. So obesity impacts the harms associated with surveillance for HCC. And then he, in our group, we continue doing this, looking at this further. So we get an ultrasound in our patients, especially in the United States, that is a technician that does the physical ultrasound, but in other areas like Europe, actually the physician performs the ultrasound. But in the United States, the technician performing the ultrasound, the quality can vary significantly. We looked at a series of patients with HCC that underwent surveillance, and we looked at the quality of the surveillance. So 65% were definitely adequate. However, about 25% were less than adequate, causing problems. And when we look at those patients that had an inadequate ultrasound, basically there are three major variables. The childhood view function, so the worse the liver function, basically the more inadequate the study. The higher the BMI, or the weight category, then the worse, or the higher the percentage of inadequate ultrasound, and it increased eightfold in obese patients. And also determining the etiology of the liver disease. So those with alcohol fatty liver cirrhosis, or NASH fatty liver cirrhosis, you had an increase in the number of inadequate ultrasound examinations. So I think obesity and NASFLD are important risk factors in having an inadequate ultrasound examination. And that is a big, big problem, because that's the major tool that we use for surveillance. Our biomarker development is not up to the validation and up to speed in order for us to use a biomarker clinically at this moment in time, but it is definitely urgently needed in patients with either obese as well as with those with NASFLD. And using MRI, it might not be the answer as well, and this is not to poke fun, but this is a case of a lighter, a patient with a pelvic tumor that had an MRI to follow up, but there was this big shadow, and there was basically a lighter that was hidden in the penis. So patients with obesity will have problems obtaining the diagnostic imaging, as well as having other problems associated with that. Importantly, the capacity. Do we have the capacity to do diagnostic imaging in patients with obesity throughout the world, especially in the United States as well? So this is a group that evaluated the supply of large MRI and CT scanners in the United States. These were all the hospitals that were sampled, and then academic hospitals. So here is the CT capacity. Pretty significant for the lower bound, especially those less than 350 pounds. However, the higher the number went up, the less availability of the diagnostic ultrasound. The same, or excuse me, the lower the capacity for CT scanners, and the same was found with MRI. So going to MRI or CT scan may not be the answer given the weight limits for the machine for this modality. So I think as we're seeing the hepatitis C cohort kind of pass away, and we're dealing with morbidly obese as well as obese patients, it's going to be an issue, the capacity, how good the quality of the testing that we're going to use for surveillance, and that will be a significant issue, I think, in the next decade or so. What are we going to do with these type of patients? And I think we're seeing the start of that wave as we speak. This is a data of MRI versus ultrasound. This is done in Korea with thin patients, and this is in the square shows the comparison of early detection for ultrasound at 26% versus 59% for MRI. However, the false positive rate continues to be significant. This study doesn't go further in delineating the obesity or the degree of weight, but more likely than not, this is going to be a problem in obese patients, the diagnostic ability of ultrasound or MRI in this kind of patients, and there's this technique of shortening the interval of MRI with abbreviated strategies, but again, this does not solve the capacity of performing MRI in obese and morbidly obese patients. So stay tuned. I think biomarkers have an opportunity to help us in this patient population rather than the imaging, especially for surveillance and maybe diagnosis, but stay tuned. So we're going to change gears now, talk about management of ACC in obese patients, and this is from the ASLD guidelines. Resection improves survival over ablative techniques, mostly RFA, in early stage ACC, and these were the number of RCTs that were evaluated in the systematic review performed for the guidelines themselves. It extended overall survival, event-free survival, two-year survival. It had more complications and a moderate increase in length of stay. So this was the recommendation to do resection in this kind of patients. Obviously, these were selected patients that had no portal hypertension and no other comorbidities. So what happens to resection in obese patients, and this is data from the National Surgical Quality Improvement Program in the United States, and they look at morbidity and mortality in several thousands of patients, and what they found is that in morbidity, if you're underweight, it's a problem. You can have significant morbidity up to 26% of patients. However, your normal weight, then the morbidity decreases. Actually, I expect that a much lower morbidity, but it does happen. However, the obese with metabolic syndrome had the highest significant increase in morbidity in this patient population. Pertaining to mortality underweight, it's a problem. You can have a significant mortality compared to normal weight. However, if you're obese with an aspect of the metabolic syndrome, then it increases the mortality significantly. So in these patients with resection that are obese that have metabolic syndrome, perhaps thorough patient selection, not only with regards to portal hypertension and medical comorbidities, but with pertaining to obesity as well. And these are other series of studies that evaluated resection in obese patients, an Italian series, a French, Brazilian. These last two are American. So basically there is an increase in morbidities and complications related to obesity perioperatively. However, only one study showed overall mortality, and one study showed increased hospital mortality, but not overall mortality. So obesity does impact the quality of the resection, as probably could be predicted. Transplantation. So we know that obesity and transplant causes significant problems in the pre-liver transplant complications of comorbidities, cardiovascular, nutritional, as well in the peri-liver transplant period and the post-liver transplant period with weight gain and other modalities. So this is where the group at the Mayo has really been leading this field of obesity and liver transplant. They started in 2006, and they started a protocol that obese patients over a BMI of 35 underwent an intensive program to try to reduce weight with dietitian and some interventions like exercise interventions. If the patient started this protocol and did not achieve a weight reduction less than 35, then they would do a liver transplant, and immediately, simultaneously, they would do a sleeve gastrectomy. And this is a picture with a nice-looking liver, just transplanted, and then the scar from the sleeve gastrectomy that was performed. So in this paper published in Hepatology last year, they did a long-term follow-up of what happens to these patients that undergo either liver transplant alone, undergoing that weight loss, weight reduction intensive therapy. And this is in blue. And what happens to the liver transplant plus the sleeve gastrectomy? They had to have three years of follow-up, and as you see, there's a slight weight reduction in the first four months of transplant, but the liver transplant alone then kind of starts gaining weight. And we see that routinely in the liver transplant population. However, in those that underwent the simultaneous transplant and the sleeve gastrectomy, their weight persisted to be off. And then in third year, there's a slight uptick, and we'll see what the latest numbers. But importantly, in the sleeve gastrectomy, there was lower proportion of the metabolic syndrome, at least a trend, although it was not significant. Liver transplant alone had a higher prevalence of hypertension, and required more medications. Hyperlipidemia was not different, but required more medications. Hemoglobin A1c was not different, but insulin requirement and HOMA as a measure of insulin resistance was better in the combined group. Quality of life was not different, and survival not different. So it might be an option in some patients, and we've done it in one patient, and so far he's less than a year, and he's lost a significant amount of weight. But I think maybe this is an avenue for more endoscopic therapies instead of doing a morbid operation immediately following transplant. And I'm not going to go through all of these, but there are different endoscopic options that can be performed with balloons and so forth that may be options down the road. Percutaneous ablation, I only found this study from Japan. The BMI cutoff was 25, and they evaluated the results of lower BMI, lower than 25 and above than 25, and there was no difference in overall survival or recurrence rates, as well as local tumor progression. And this is the only study that I found in the literature. So it doesn't seem to impact ablation. If you can see it ablated, go for it. However, in taste, this was one study that they evaluated taste response in those that were obese, and this is an example of a patient that had a taste, and then six months later there was really no response to the taste, and in fact the tumor increased. So higher BMI resulted in lower response rates, higher progressive disease, as well as new lesions in the contralateral liver that was treated. So it sounds like at least in this paper with taste it did impact the overall results. I looked at TARI and other modality and it doesn't seem to be an impact of obesity in those kind of interventions. So in systemic therapy, this is a very active area. Sorafenib, we have now Lenvatinib, and then just recently there's a press release on atezolizumab and vevazizumab combination, although we don't know the results yet. So this remains to be seen. Lenvatinib, because it's the only systemic therapy in which weight matters and the dosing matters above 75 kilograms or below. The other second-line agents that are available, there's no weight-based dosing, and the majority of patients on all of these trials really have been patients with a lower BMI, especially given that they're mostly European, Asian, rather than from Texas or the United States. We have a lower BMI. In terms of immunotherapy, I didn't find anything, but this is from the melanoma literature, and this is the main analysis. And if you look on the left, looking at the immunotherapy and tumor-free survival, if you are on target therapy and immunotherapy, actually you did better in obese patients compared to systemic cytotoxic chemotherapy, especially in males. But that advantage disappeared in females. If you look at overall survival on the right, that advantage to immunotherapy persisted in, you see it in both groups, as well as in males. You don't see the advantage in obese in systemic immunotherapy or in females, which is very interesting. And the author didn't have any postulation about why. But this year in Nature Medicine, there was a mechanistic paper that showed the paradoxical effects of obesity on T cell function during tumor progression and the results of PD blockade. So these are melanoma cells that were given to mice in red that were obese compared to lean mice, and their tumors were larger, more aggressive, had more inflammatory component in those in obese mice. And when they did transcriptomic analysis of the CT cells, they found a significant difference between the obese mice, the tumors on the obese mice compared to the tumors on the lean mice, and they had more T cell dysfunction. And the author postulates that this is related to exhaustion of the immune system, as well as significant inflammation associated with tumors in the obese mice. And one of the mechanisms that's not shown here is that it's mediated by leptin. But interestingly, when they used the PD-1 in these mice, the obese mice did better. So those that had poor tumor characteristics, aggressive tumors, actually responded better to anti-PD-1 compared to the lean mice. So it's very interesting. I didn't find anything on HCC, but it's something, I guess we have to increase the BMI of our patients that require systemic therapy, but it's something, it will be interesting to see if we're seeing that effect in HCC and the gender differences in HCC as well. So to conclude, obesity does impact surveillance as well as diagnosis. Modalities of treatment for HCC resection and transplant. Perhaps bariatric procedures can be done at the time of transplant, either or with endoscopic therapies. And we need to see what happens, the impact of obesity with systemic therapies, especially with immune-mediated therapies. Thank you for your attention. Thanks. Thank you, Jorge, for this nice presentation. It's time for questions. I have a very short question regarding surveillance. When you will start surveillance with other modalities rather than ultrasound? Which BMI you will recommend to explore the patient with, for instance, fast MRI? Really a very difficult question, because we don't know. There's no data. But I think overall, you look at the patient overall, if the patient may be a candidate for a surgical intervention for a curative therapy, then perhaps that patient, instead of going to ultrasound, I would try the index ultrasound, and if it's of poor quality or inadequate, perhaps you go to the cross-sectional imaging. But there's really no data. That's my opinion. Okay. Thank you. Please. Very good presentation. I've been impressed by your pointing out the possible harms of surveillance. But I think that this is particularly true if we target our surveillance to a population that's not at high risk of developing the event. So you have false positive results in the amount. So is it not time to tailor our surveillance and to perform a model of risk? We have a lot of factors right now available. We have just heard from Elisabetta Buggianese before. We have polymorphism. We have FIB4. We have Fibroscan. We have elastography. Why not perform an algorithm to address surveillance to the higher risk patients? That's the key question. And right now, in hepatitis C, with Hashim, he has a model that can seem to stratify the risk that we can then tailor the surveillance to the higher risk. Outside of the viral hepatitis, it's very difficult. So far, even with these available SNPs and other biomarkers, it has been really difficult. Dr. Hoshida has a molecular signature that may be able to stratify the risk across serotics. So we can tailor it differently. But that's really holy grail. To my knowledge, it's not readily available at the moment. But I think it's coming. And we need to stratify better the risk for then performing interventions like surveillance to improve survival. Thank you. We really feel that it was fascinating to understand experimental models in melanoma, that obese animals respond better to checkpoint inhibitors. I think this needs to be explored in HCC, in this course, with Atesoveva, Nivolumab, and Pembroke. Let's see what happens. Thank you very much to all of you and all the speakers. Thank you.

liver cancer

obese patients

surveillance methods

AFP tests

surgical resection

immune-mediated therapies