Welcome, everyone, to the interactive updates on selected topics in Gynecologic Oncology webinar. Today, our program will focus on individual cancer. We will just wait a couple of minutes as we are allowing time for people to join. Bye-bye. We will begin in a couple of minutes, as we are allowing time for people to join. Welcome, everyone. Welcome, everyone, to the interactive updates on selected topics in gynecologic oncology webinar. Today, our program will focus on endometrial cancer. I am Dr. Fernando Heredia. I'm an associate professor at Universidad de Concepción and staff in gynecologic oncology in Clínica Andes Salud Concepción in Chile. Next slide, please. This webinar is being provided in Spanish, English, and Portuguese, and a handout with detailed instructions may be found in the chat as well as on this slide in Portuguese and this slide in Spanish. So select the interpretation icon, then select the language you would like to hear. You may also mute original audio to hear interpreted language only. If you have any questions regarding interpretation, please chat IGCS Education. So we have a great session outlined for today's webinar focusing on endometrial cancer. Now it is my honor to introduce today's speakers, Dr. Andrea Mariani from United States, Dr. David Isla from Mexico, Dr. Eduardo Paulino from Brazil, Dr. Angelica Nogueira-Rodriguez from Brazil, Dr. Hannah Simmons from United Kingdom, and Dr. Julián de Wilmi from Argentina. So please know that recording of this webinar will be available on IGCS Education portal within a week. We encourage you to submit your questions via the Q&A feature at the bottom of your screen. Following each session, we will have time for questions and we will do our best to address as many questions as possible. So without any further introductions to kick off today's program, we will share Dr. Mariani's presentation, Historical Evolution of Lymph Node Assessment for Endometrial Cancer Surgery. And who could speak better than Dr. Mariani about this? He has produced most of the milestones regarding this particular issue in the surgical management of endometrial cancer. So thank you. Thank you, everyone. Thank you, everyone, for giving me the availability for giving this talk. In particular, thank you, Renee, for inviting me for this talk. I'm Dr. Mariani from Mayo Clinic Rochester, Minnesota. And I've been studying endometrial cancer for the last two decades. In particular, I've studied the patterns of lymphatic spread and the role of lymphadenectomy in endometrial cancer. At the beginning of this century, we identified a population of patients, about one third of endometrial cancer patients with a negligible risk of positive pelvic nodes based on histology, grade, myometrial invasion, and tumor diameter. And we call this criteria the Mayo criteria for lymphadenectomy. Using frozen section and all of these parameters, we could decide which patient needed the full pelvic and parahortic lymphadenectomy versus those patients that didn't need any lymphadenectomy. But then in 2013, our friend and colleague from Memorial Sloan Kettering, Nadim Aburustum, came to Mayo and he taught us to do the sentinel lymph nodes. And so we started to do sentinel lymph nodes, and we observed a rapid decrease of the performance of pelvic and parahortic lymphadenectomy. But how did we arrive here? And how were we convinced to do sentinel node? In order to answer to those questions, first, we need to answer to this question, is lymphadenectomy therapeutic in endometrial cancer? And if we look at the Cochrane Library in 2017, a Cochrane review told us that there are lymphadenectomy versus non-lymphadenectomy, there is no difference in oncologic outcomes, and the higher risk of lymphedema and the lymphocyst. What about prospective randomized trials? And even there, we see no clinically significant therapeutic effect. In particular, the randomized trial, what we can say about the randomized trial is that pelvic lymphadenectomy does not improve survival in the low and intermediate risk endometrial cancer. But what about the parahortic area? In fact, we know from the Mayo data that the 62% of patients with positive nodes have some dissemination of tumor in the parahortic area. And is there any occult dissemination in patients with a tumor apparently confined to the pelvis? And the answer is yes. There is this Japanese study in which they look at 15 patients with positive pelvic and negative parahortic, but when they do ultra staging, they found that 73% of these patients, they have occult tumor in the parahortic area. Therefore, we can conclude that there is tumor dissemination in the parahortic area in the vast majority of patients with positive lymph nodes. And so if we look at the therapeutic role of parahortic lymphadenectomy, we look at retrospective data and we have mixed messages from the literature. Some papers, they say, yes, it's therapeutic, parahortic lymphadenectomy is therapeutic. And some other papers, they say, no, it's not. This is the most famous paper on parahortic lymphadenectomy and the therapeutic role retrospective comparing only pelvic versus pelvic and parahortic in patients with some type of high risk features. And yes, parahortic lymphadenectomy, according to their paper, improve clinical oncologic outcomes. But it's retrospective data. We have some differences in the administration of chemotherapy between the group. And very important, no patients receive chemo and radiation combined after surgery and only a small group were serious. This is a 2018 meta-analysis focusing on retrospective studies comparing pelvic versus pelvic and parahortic. And in the meta-analysis, they say that parahortic lymphadenectomy improves overall survival. However, the paper that they include in this meta-analysis, you can see when we look at adjuvant therapy, only one of all of these papers had a combined approach. Most of the others, they have adjuvant therapies, chemo only or radiation only. And if we look at that paper with a combined approach, both chemotherapy and radiation, retrospective data, but we see that pelvic patient who had pelvic only lymphadenectomy do better, but they receive more multimodal adjuvant therapy. Therefore, what they conclude that multimodal adjuvant therapy, chemotherapy and radiation is more important than the extent of lymphadenectomy. If no multimodal adjuvant therapy, the therapeutic effect of lymphadenectomy is more significant. And that there may be a therapeutic role of lymphadenectomy, but it's less clinically significant if they receive both radiation and chemotherapy. And what about the data from the Mayo Clinic on the therapeutic role of parahortic lymphadenectomy? We have this paper from 2000, it's an old retrospective data, and we observed that parahortic lymphadenectomy improves survival. But patients receive even here only adjuvant radiation, no chemotherapy combined. In fact, when we look at the more recent data from Mayo Clinic, focusing only on patients with positive parahortic nodes, we see that the most important predictors of survival are grade histology and adjuvant therapy. In particular, if patient had a combined chemotherapy and radiation, they do better. So what we concluded in our patient with positive parahortic nodes, chemotherapy and radiation independently improves the outcome, biology is the most important predictor of prognosis, and the extent of parahortic lymphadenectomy did not predict the outcome. In particular, patients with non-endometrioid endometrial cancer had poor prognosis regardless of adjuvant therapy, and patients die because of distant recurrences. This is a similar paper from Korea, patients with positive nodes, and even here, some patients had adjuvant pelvic radiation alone, some patients had a combination of pelvic radiation and chemotherapy. And even here, retrospective data, but parahortic lymphadenectomy significantly reduces parahortic recurrence in all groups. However, it makes a difference in survival only in the radiotherapy-only group, but not in the patient who received combined therapy. And therefore, the administration of a combined chemotherapy and radiation reduces the significance of the potential therapeutic effect of lymphadenectomy. In this paper, SIRUS patients do poorly independently from the extent of parahortic lymphadenectomy, and this is a similar paper from Mayo Clinic, patients with SIRUS endometrial cancer, they do poorly, and most of the recurrences are hematogenous or peritoneal. This means that the battle is lost at distance, not in the pelvic and parahortic area. So, regarding the therapeutic role of lymphadenectomy, lymphadenectomy, like radiation, is a local treatment. It can reduce local failure, but is less likely to improve survival. And patients with positive nodes are more likely to die for distant recurrence. And a combination of adjuvant therapy, of radiation and chemotherapy, the oncologic outcomes are usually improved, and the clinical significance of a potential therapeutic role of lymphadenectomy is reduced. Now let's look at sentinel nodes in endometrial cancer. Does it work? This is a meta-analysis that tells us that from a diagnostic point of view, it works very well. But do we have prospective data? Yes. This is the FIERS trial, and even here, it works very well from a diagnostic point of view. And yes, it works very well even in a prospective trial focusing on high-risk grade 3 and SIRUS. So what we can conclude from the literature is that sentinel node is a superior diagnostic tool to lymphadenectomy. But what about oncologic outcomes? Are oncologic outcomes compromised? Here we have a paper from Canada in which we compare sentinel nodes with lymphadenectomy, and we see that sentinel nodes have patients with less pelvic side wall recurrence, because we can identify with sentinel node more unusual sites of metastasis. And so sentinel node is superior to lymphadenectomy to identify lymphatic metastasis. We can see less lymphatic recurrences. Then we did the fruitful collaboration with Memorial. We compare an historical series of Mayo with systematic pelvic and parahortic lymphadenectomy versus a more recent series from Memorial with sentinel nodes only. And during the last few years, we published almost one paper per year, five papers, looking at oncologic and diagnostic outcomes. And we conclude that sentinel node versus lymphadenectomy, they have similar diagnostic outcomes. We can actually find the patient with positive nodes, but also similar oncology outcome. And this is mostly a retrospective analysis, but this is what we concluded. Now let's answer to this question. Do you complete pelvic and parahortic lymphadenectomy if sentinel nodes come back positive or if positive at frozen section? And we had a paper about this. Even here, it was a comparison of patients with positive nodes from Mayo Clinic for lymphadenectomy versus sentinel node only from Memorial. There were a few little differences in the amount of patients with chemotherapy versus external BM radiation. And as expected, patients with lymphadenectomy had more lymph nodes removed. But what we observed that either you treat patients with full pelvic and parahortic lymphadenectomy versus sentinel nodes only, there were no significant difference in progression-free survival, cause-specific survival, or lymphatic recurrence. The oncologic outcomes were exactly the same. And predictors of overall survival were mostly related to tumor biology and if we give chemotherapy and radiation after surgery. At multivariate analysis, the most important predictors were grade and histology. Therefore, we concluded that a combination of chemotherapy and radiation in patients with positive nodes seems to improve the outcomes, but biology is the most important predictor of poor oncologic outcomes. Therefore, we conclude that if no bulky nodes, lymphadenectomy is unlikely to provide a significant therapeutic contribution, as this patient, they are already identified with sentinel node and they receive a combination of chemotherapy and radiation. And although the risk of parahortic progression was 3.7 times higher in the sentinel node cohort, the rates of isolated parahortic progression were similar. This finding emphasizes that many parahortic progressions are associated with a concomitant distant dissemination. Therefore, I answer that we do not take patients back for lymphadenectomy if patients come back with positive sentinel nodes. We do not complete a lymphadenectomy as long as they are microscopically positive lymph nodes. What is missing? We are missing large prospective data on oncologic outcomes in patients, large prospective data in patients treated with sentinel nodes only. And therefore, we have been doing this prospective trial in collaboration with Memorial. What about isolated parahortic? Isolated parahortic is a rare event overall, looking at the Mayo series. And when we look at patients with isolated parahortic and we do ultrastaging on negative pelvic nodes, we actually find that 30% of patients with isolated parahortic had in fact occult pelvic dissemination. Therefore, isolated parahortic dissemination is a rare event and even more rare if we do ultrastaging of pelvic lymph nodes. Thank you for your attention. Thank you, Dr. Mariani, that was an excellent presentation. Attendees, remember to submit questions using the Q&A feature. Let's begin with the Q&A portion with a poll for the attendees. So here's the poll. Of the next features, are not part of Mayo criteria? Please select. Okay, we are now closing the poll. So what's the virtual tie there between tumor size under two centimeters and absence of lymphovascular space involvement? Any comments on that, Dr. Mariani? It's really, what is not part of the Mayo criteria is the lymphovascular space involvement. And the reason for that is that we look at that and we recognize it's a very important factor, but it's difficult to know that during the frozen section. And the Mayo criteria are really based on the frozen section. So this is why this was not included in the Mayo criteria. Besides the inter-observer diagnosis of lymphovascular space involvement, sometimes it's not very concordant. Just another comment about tumor diameter, tumor diameter is a very important parameter and it's relatively easy to just measure during the surgery. And so this is why it was an important factor in the Mayo criteria. Thank you. Yes, we have some questions. Is a isolated tumor cells, do you treat with chemo? Thank you for this question. So what we are seeing more and more is that isolated tumor cell is a parameter that it's more likely for the data that we know right now, okay. We are still working at the data and some of the things are still not clear, but what we know so far is that isolated tumor cell, except it becomes important if there are uterine risk factors that, so if you have an aggressive tumor, for example, if you have a serious endometrial cancer or a grade three deeply invasive with lymphovascular invasion and also isolated tumor cells, this becomes more like a patient with positive nodes. And so you approach this like a patient with positive nodes. So you can approach this with chemotherapy or radiation and the chemotherapy. However, what is still not clear is the meaning of isolated tumor cells in patients with no risk factors in the uterus. So patients with a grade one or two endometrioid, less than 50% invasion and no lymphovascular invasion, but with isolated tumor cells, we don't know the meaning of that so far. Personally, I'm still, I know some colleagues in the literature, they say it has no role of that. My answer right now is that we still don't know because this may still be microscopic disease that may grow. And so we still need to have more data about that. But for the moment, both at Mayo and for what I know also at Memorial, we decided to treat these patients with observation so far and we close follow up. So again, the meaning of ITC, it depends if you have risk factors in the uterus. I see. Thank you. We have another question from Dr. Waldo Jimenez, who is originally from Chile. Now he works in Canada. He says, in patients with positive pelvic sentinel nodes, do you recommend extended field radiation to the parathyroid lymph nodes as part of their chemo radiation? That's a good question. Now, yes, that's a fantastic and it's a great question. And it focuses on the same discussion about parathyroid lymphadenectomy. Think about this, because the more I think about this, I've been studying lymphadenectomy for a long time. Both radiation and lymphadenectomy from a therapeutic point of view, if there is a therapeutic role, are local treatment. And so what we have seen, for example, in our comparison with Memorial, is that parathyroid lymphadenectomy can decrease the amount of parathyroid recurrence. So it's a local treatment. There is disease there. Sometimes you take it out, it may decrease parathyroid recurrence. But people die because of distant disease. So overall, the decision of doing a parathyroid extended field radiation, it's a decision if you want to prevent parathyroid recurrence. But it's unlikely for the data that we have so far to give you a better survival. So right now, we don't do this by routine. But again, it's certainly a reasonable approach if you want to decrease the potential role of parathyroid recurrences. Do you know if there's any like prospective open international trial regarding this issue in particular? Regarding the parathyroid lymphadenectomy, I'm not aware of that, but I may be missing that. And if you are aware of any prospective trial focused on the parathyroid lymphadenectomy or parathyroid radiation, anyone, please feel free to speak up so that we don't exclude you from this. If there is a trial, so please speak up. But I'm not aware of a trial focused on parathyroid lymphadenectomy or parathyroid radiation. And also because the problem is this, to do a trial, it's very difficult. Why? Because you need to focus on patients with positive notes and it's a limited role. Second, the majority of patients with positive notes, they are high risk, high grade. The majority, I don't say every single patient and those high risk, high grade, et cetera, they are more likely to die because of distant recurrence. So it's very difficult to have the numbers for that because patients that are more likely to benefit for local treatment are probably patients with grade one tumor. So probably if you do a trial of patient with grade one endometrioid positive notes, perhaps you find some good results, but it's very difficult to have the numbers to do that. Yes. So now a more philosophical question for you here, it says, how were you able to change the paradigm of doing pelvic and parathyroid lymphadenectomy to only do sentinel lymph node mapping? What convinced you? What gave you the switch? Because if you could do that in the big center, we could also do so. What gave you like the switch? Yes. So first of all, we started to look at the data and the data that we had gave a hint that there may be a potential for decreasing recurrences, but it was not as convincing the data of a survival outcome. But then what convinced us is the face of a friend. Our friend Nadima Burustum came to Mayo Clinic. We started to look at our data together. We decided to take the risk. And so we put together the data from Mayo Clinic retrospective historical with the data from Memorial that we're starting to do sentinel nodes and we share the data. We look at this data as friends and we trust. And at a certain point, it was evident that the data were going in a certain direction. So what convinced me is the data, but also the face of a friend. And how important that is, collaboration is the mainstay of everything. Now that it's as easy as to communicate from like, for instance, from Chile to the United States live and to share things like we're all sharing today, it's just wonderful. So thank you, Dr. Mariani. We have lots of questions still, but we have to keep on with the program. Thank you very much. Very nice to meet you. An honor to participate with you. So our next presenter will be Dr. David Isla, good friend. Is there still a role for laparotomy in endometrial cancer? In these days when we feel that the standard for surgical management is almost endoscopic for everybody. Where do we place laparotomy? So please. An honor to greet you, dear friends and colleagues. Thank you so much for the invitation to Dr. Audrey Sonoa, Dr. Rene Pareja, dear friends, colleagues, and friends with the topic that I will be presenting today. If there is a role for laparotomy in endometrial cancer. My name is David Isla Ortiz, I'm an oncologist surgeon. I am the head of the Department of Oncology Gynecology from the Cancer Institute in Mexico. Let's take a look at these graphs which are very interesting and do a stratification with regards to the countries that have low income, mid income, and high income. Where we can see that up to 10 times has been the increase of the incidence at a worldwide level with a growth trend that is faster each time and that we see year after year. And this reflects a change in lifestyle and a higher prevalence of risk factors that are associated to this disease, obesity, and lack of physical activity. And that it's been seen as an important reflection in the new generations. And in this publication, we can also see some graphs that are extremely important where we also observe that laparotomy has increased over time. And if we observe the different years, 2002, 6.5%, and in 2011, more than 30%. And this has also been seen with a logarithmic increase towards current dates. And in the next graphs, we observe how the graph has a decrease between the hospital incidence and it's still a difference of three days between open surgery versus one day to laparoscopic surgery. And it has been decreasing. And I believe that each time more with the use of procedures that are less radical like the sentinel nodes. And this hospital stay most likely will be much more reflected and with a much more significant decrease. And I would like to mention that laparotomy, the surgery like hysterectomy, is the standard of treatment in cancer, endometrial cancer. And there are procedures or we perform procedures that are part of the stratification of endometrial cancer, especially in those that have intermediate and high risk, which is bilateral pelvic endectomy and periartical. And that biopsy that is being done as sentinel nodes is extremely important also because it has been able to avoid doing this type of surgeries, therefore decreasing the risk of complications that are produced by this surgery. Also, the procedures of radical hysterectomy that are performed, especially in not in just in the cervical stroke that we've seen that with just one hysterectomy type A might be enough to eradicate it, but not in those that are bulky tumors and that have incidence in the extension toward the perimeters, there might be a radical hysterectomy, especially to have safe margins and to be able to do a proper assessment of the perimeters. And in those young patients that we've seen, that we've seen in the hospital centers, the preservation of ovaries with certain characteristics of the tumor and the TPA and the characteristics of the patient. So there might be a preservation of the ovaries in those cases. So going back to the question, if there's still a role for laparotomy in endometrial cancer and while considering that the standard is laparotomy. And what is around this laparotomy are the different approaches, approaches of minimum invasion, like robotic surgery, and also vaginal approaches, which have a lower response to trauma, which has a repercussion directly on the patients with better results, both in the operation itself and in the post-operation, and a much quicker incorporation to daily activities. Also, there is a combination of these procedures, minimum invasion with vaginal approaches. But laparotomy, going back to our topic, so which could be the indication? Well, those patients who are not candidates to laparoscopy, whether because of the physical conditions to maintain a position that is very forced during laparoscopy, whether it's a very forced position, or because of the placement of the legs that they don't have this in capacity, or because of the functional status, or because of problems both cardiological and pulmonary, and also because of the disease itself, because of big tumors and big uterus, or because of the use of the manipulator that, in some cases, can have an effect on that as well. Also, at those stages, two, three, and four, that might be where it might be convenient to do a cytoreduction, well, it might be likely that laparotomy can be the best indication. And in those cases where there is a recurrence, a tumor recurrence, laparotomy is extremely important for the management of these patients. But let's take a look at the first point. Those who are not candidates for laparoscopy, and we should consider that the minimum invasion surgery versus the open surgery is an approach. It's an access route. And there have been a lot of studies done, both retrospective and prospective. And in this review of Cochrane, it talks about the estimated blood loss, and laparoscopy was associated to a large reduction and statistically considerable versus the laparotomy in terms of blood loss. So a point in favor of laparoscopy with regards to global survival and free of recurrence. And the first point, there was an increase of the risk of loss through laparoscopy. And we didn't find that there was a statistical difference in regards to the risk of recurrence of the disease. And in this assessment with regards to quality of life, also a point in favor of laparoscopy, the patients with laparoscopy informed much higher scores and that were significant in the assessment, functional assessment of the patients post-operation of the minimum inpatient surgery. With regards to the guidelines of the NCCN or European guidelines, this happens and it is a recommendation that patients can have both of these treatment options with certain benefits with regards to the latest approach. This and the publications of the systematic review from Cochrane. In this prospective study from EP2 that had as an objective, the main objective to compare laparoscopy versus laparotomy for the surgical stratification of uterine cancer with the results of the stratification of endometrial cancer can be done through laparoscopy without an intraoperational increase of lesions with lower post-surgical complications and a hospital stay that is shorter. In the follow-up of the publications with regards to the EP2 group where there was also an assessment and that had as the objective to establish the non-inferiority of laparoscopy with regards to the comparison to laparotomy for the recurrence, the results show that the surgical interference can be done through laparoscopic routes with small differences of recurrence rates. So you can see 1.14, it was really minimum in comparison to the assessment to three years. So in conclusion, with the comparison of CMI versus OPEN, the controlled trials of hysterectomy, minimum invasion surgery, show the following oncological results. They did not show inferiority in hospital stay. That was shorter, a decrease in blood loss, pain, and perisurgical mobility with comparison to OPEN surgery. And minimum invasion surgery is the surgery that is preferred for early stage disease where the uterus, when performing the surgery, can come out intact with good safety. For this, we would have to analyze some subgroups. And here we have obese women. In this analysis from LAP2 with regards to obese women, they have a higher surgical risk and a lower risk of metastatic illness. And the BMI is or was associated to mortality in all of the causes, but not precisely as a specific illness. Also in the same analysis of LAP2, where subgroups were made with respect to the age, under or over 63, and with or without metastatic illness in relation to the BMI. This observed an estimated risk of conversion and was greater or was present in the four groups, and this associated with the BMI. What happens with large uteruses or those uteruses that have a large volume or a large tumor? This, either because of the same size, there is a low probability of being extracted via vaginal, and especially in those postmenopausal patients or premenopausal patients who generally did not have any birth, it can be difficult to extract it. Many will say that it can be extracted by a much smaller incision that could be done with laparotomy and be extracted. But here the question would remain, is it adequate? Can it be done with good security? And also those with very large uteruses make it difficult at the time of mobilization the field of surgery. So, can a safe surgery be performed in this large uterus? Well, surgery can be performed, but it can be considered as a standard management to perform the resection in these large uteruses, and I mean laparotomy. For large lesions with suspicion of infiltration up to the serous layer, and in reference to this article with this publication, it could be avoided the use of manipulators because there is a higher risk of uterine perforation and a risk of tumoral dissemination. Also, the morcellation, and it is already known that the dangers that are with uterine morcellation, and they are already well documented and must be avoided by the contamination that could exist at the intraperitoneal level and cause, either in mesenchymal tissue tumors, sarcomatosis, and in those epithelial, carcinomatosis. The use of the uterine manipulator... Of the uterine that we need to take into consideration, there are some articles that have made some publications with respect to the mechanism that the manipulator has with the fragmentation of the tumor, especially at the level of the endometrius. That can have a certain dissemination through the luteus. But also, as we commented, with the case of luminous uterus, it's not recommended for those that have cirrhosis extension with large tumors because there could be some perforations or it could cause the dissemination of them. Also, the use of the uterine manipulator. In this article of recent publication, it was associated with worse oncological results in patients with endometrial cancer that are confined to the uterus. And if we observe the first graph, we can see that the use of manipulator versus the non-use of manipulator, there is a significant difference, statistically speaking, in terms of the oncological results, the survival free of disease. The same happens with the global survival or the general survival, but it is important to have this in mind, especially with this last publication that we have about the use of uterine manipulator. So the conclusions with respect to this, there are some different data in terms of whether the uterine manipulator increases the risk of recurrence. And the use of these uterine manipulators was associated with a larger percentage of positive peritoneal cytologies. But this, with a clinical factor, is uncertain because the lavages are not incorporated within the FIGO certification. But in some publications, we see that they recommend giving importance to this to reduce the adjuvant behavior of these patients. With respect to the cytoreduction, as we mentioned in one of the points before, the extra uterine disease, the recommendations that we have for the surgery, is to take into consideration the location of the metastases and the probability of having total cytoreduction with these patients. Also, the retrospective series, if we look at the graph that we have up here, there have been reported better results observed in patients that are subject to a primary treatment, especially when they are taken to a complete cytoreduction. It's of no use to make a cytoreduction that is partial, leaving the disease with an R2. That for sure is not going to give us an oncological significant or adequate result. With respect to the primary treatment, with respect to the cytoreduction for advanced stage three and four disease, it is recommended if it's able to do the cytoreduction without residual disease. So that is the recommendation, and that is the important point. If you eradicate the entire disease, it can be, in a safe manner, treating the patients with laparotomy. With respect to the recommendations of ESGO, Estro, and the NCCN guidelines for 2021, their recommendation of initial surgery in the disease, in the stage two, three, and four, where the complete cytoreduction is feasible with acceptable morbidity. Many are going to choose, and might think that they can do this with minimum invasion surgery, but it's important to have in mind that when there is a disease that is advanced, the risk of potential dissemination, interperitoneally speaking, exists. So therefore, it would not be the best recommendation to give. And then the points for you to take home is that the open surgery, and here I'm talking about laparotomy, continues being the standard of treatment for endometrial cancer. And a hysterectomy that is minimally invasive shows oncological results that are not inferior if we compare them with the open surgery. There are some discordant data with regards to the use of uterine manipulators, whether they increase the risk of recurrence, but they have been associated with larger percentages of peritoneal positive cytologies. So the recommendations with respect to the American and European guidelines from last year establish a preference for the initial surgery in the complete cytoreduction, if it is feasible, with acceptable mobility. And when we mentioned Professor Katie Blake and his comment about the world of oncological surgery, biology is the king, the selection in the cases is the queen. And here I refer to the characteristic of tumor biology and the surgical and technical are the princes and princesses, because the open surgery of minimum invasion sometimes also wants to substitute the biology of the tumors and the clinical stages, but afterwards they come back because really it shouldn't be that way. You always have to have into consideration that the main thing and what is fundamental are the queen and the queen continue being the tumor biology and the selection of the cases. So again, I want to thank Dr. Aldous and Dr. Rene Paredes for the invitation to speak here to you. And thank you to all of you for being attentive with this presentation. I really want to thank all of my colleagues and friends and this prize for my friends, Rene and Aldous, which is very good for them. Try to be as big so everybody wants to reach you and be as humble, but everybody wants to be with you. And that's how my dear friends are. So thank you again. Okay, thank you, Dr. Isla. Great concepts in your presentation. We have to think a lot before changing our practices or at least fully switching them to endoscopic. So let's begin with the Q&A portion with our second poll for the attendees regarding endometrial cancer surgery. All options are correct except one. Please participate. Okay, okay, don't be lazy. Participate in the poll, please. Lots of questions for this, for this interesting presentation. Almost there, almost there. Okay, we're closing the poll now. Just a second, okay. Well, it says here, there are no randomized clinical trials comparing minimally invasive surgery versus open surgery in endometrial cancer. We'll start with the questions as Dr. Isla is a Spanish native speaker. We'll make some questions in Spanish and we'll help with that. Okay, let me read some of them. David, que tal amigo? David, hi, how are you friend? In patients with a PMI that is important with more than 35 or 40, without enough to remove a large uterus of 12 centimeters, what do you think of doing everything through laparoscopy and at the end remove this with a transversal incision that is done only for this purpose? Yes, I think that it is an option that can be done with this type of approach, especially those patients that have a BMI that is very high. Doing this through minimum invasion is something that can be more accessible with laparoscopy and that is just much better. So I think that I would be totally in agreement in doing this with minimal invasion, making the extraction with a low incision. And I believe that it gives great results in the repercussion that it has with regards of the difference in terms of the size of the sites of operation. So I think that would be great. Is there like a contention device maybe? Yes, to protect the wall especially, especially at the moment of extracting it, try to manipulate as little as possible the uterus and place a device to cover the wall. Yeah, I cannot mention any brands, the commercial brands, but those that protect and have certain rings could protect and you could make a good extraction of the piece and do it safely. Would you say that maybe that the volume of the uterus is the main indication of whether you perform a laparoscopy? Well, that is one of the things you have to consider and this is something that I brought up during my talk, the use of these manipulators, especially with bulky tumors and those that are at bottom. So using the manipulator has the consequence at the moment of performing the mobilization of it. There is some risk of perforation and this is going to increase obviously the perforating of this and this could disseminate the peritoneal cells. And obviously if I have a big uterus and probably a lesion that is confined to a small lesion that is confined to the uterus that I can do safely, I think that would be the perfect indication. That would represent more than the volume, the size of the uterus would be the volume in general. And I know that with the RMI or with the ultrasound that is going to tell me if that is the right candidate. Others that have contraindications or minimal invasion, whether because the cardiopulmonary characteristics or because the patient has a possibility of being in a certain position with separated legs that is very forced in terms of the position that can take too long, for instance, in that position. I think that those would be the main contraindications to do this with a minimal invasion procedure. Does the behavior of adjuvant treatments change? In other words, this is like amalgamating what happens when there's a rupture. Yes, I think that the discussion is very specific. There's a lot of colleagues over here who are experts in this same topic. So I would say that yes, that we should take another behavior, especially knowing what is a way of perforation that there was. See the histology and the characteristics of the tumor in order to decide whether we are really going to give adjuvant treatment. It's not the same, for instance, to have a uterus that was perforated with a small lesion, with our intravascular permeation. And in those cases, I think that there is no problem at all. And probably you could just leave it under surveillance, but those perforations that have a bulky tumor and it is intravascular, probably we are deciding whether having an adjuvant. Maybe we could say yes, because the perforation of the uterus was there and the probability of dissemination of cells is more probable and elevated. So you have to characterize very well the disease, the size, the permeation, and the volume of the tumor, but also you have to consider in order to change the conduct or behavior. Perfect. We're going to continue now with our schedule, but if it's possible, maybe you can help us answer in the Q&A session, because there's a lot of questions and they are all very interesting. Thank you again, Dr. Isla, for your excellent presentation. So our next presentation will be Dr. Paulino with up-to-date systemic therapy for endometrial cancer. So he will aid us in understanding the newest lines of research in adjuvant treatment for endometrial cancer. And also he will cover new targets for immunotherapy and how this articulates with traditional management. Thank you. Hello, everyone. My name is Eduardo Paulino. I'm a clinical oncologist here in Rio de Janeiro at the Instituto Nacional do Câncer e da Oncologia DOHR. And my topic today is to talk about the updates that we have on systemic treatment for endometrial cancer. These are my conflicts of interest. Combinations, hormonal therapy and its combinations, inhibitors, EGFR, MEK, MET, and anti-HER2. Antiangiogenics with special interest in immunotherapy. I'm going to talk a little bit about the recent inhibitor, XP01 factors, and some general directions. So this is generally diagnosed in initial stages, and they are highly curable patients with surgery or without adjuvant therapy. The problem is when they have recurrent diseases or they have been diagnosed in stage four, where survival is much lower, only up 17% in five years. So why do we need new medications or new options? What we mentioned is that survival is very low, and we know that chemotherapy seems to have ran out in this palliative setting, as I will show later on. So we are bringing now chemotherapy to adjuvant setting, our first palliative line, into the scenario in some cases. And, well, what will we do after this chemotherapy? We are better understanding the molecular options. Talking a little bit about the first line, we saw in GOG209 that compared these different triple schemes with different medications. And in this study, 209 of carboplatin and carbitaxel, it was not inferior to the triple scheme and had a better toxicity profile. So it would be carboplatin and the other medication as the first line of management. So what do we have of chemotherapy after this first line? We saw the results, and we have several phase two studies in immunotherapy, where we see response rates that are very average, from 0% to 15%, up survival free of progression from three to four months, and general survival from 10 to nine months, nine to 10 months. And these data are proven by the phase three studies that we have in this setting. For example, as we can see, two different states, scenarios on our screen, on the left and the right. And in these studies, we see that the response rates for chemotherapy in second line on, and immunotherapy are low response rates, survival free of progression that is low, and a global survival that is also low, that goes between 10 to 12 months. So what do we have that is new then? So beginning with the mTOR inhibitors and its combinations, mTOR inhibitors are also disappointing as a only drug that have low response rates from 0% to 24%, free of progression survival from three to four months, and global survival that is very low. It seems that the combinations are more effective. Here we have some of the combinations that were effective or have proven to be effective in the last few years, like mTOR inhibitors combined with hormonal therapy. We have Niverolimus with letrozole that showed a response rate of 32%, and it would seem that the patients who use concomitant metformin had a response rate of 56%. However, the combination of these three medications in a later study, phase two, did not confirm these findings, and recently we had a study that compared Niverolimus with letrozole versus acetate of distro with tamoxifen, and in this study we saw a response rate of approximately 22%. Unfortunately, this study did not reach use level as a population as a whole, but it showed that perhaps the untreated populations had an interesting response rate of 47% for Niverolimus and letrozole and a free progression survival of 28 months. We have other ways of inhibiting mTOR. For example, this drug that has been recently tested, fistusertib, that inhibits, and when we see that it was associated to anastrozole, we compared it with immunotherapy, and we had a gain in terms of survival, duration of response, and acceptable toxicity, but this drug was not continued to be developed because it was not effective in other solid tumors. Now, talking about hormonal therapy and its combinations, we can see that hormonal management varies very much depending on the presence or not of a low-grade tumor or presence of hormonal receptors that are positive in these tumors. We have a response rate that is slightly better, but in general, the response rates are not very encouraging either. Once more, as we can see with the inhibitors, there seems to be a slightly better result, as I showed you in the mTOR population before, and here I have some combinations that seem to be very promising in the case of hormonal therapy together with a paleo study that we had. We had, for example, letrozole with palpocyclib and letrozole with placebo. We saw that the combination brought an increase of free of progression survival and a higher rate of control of the disease. And more recently, the letrozole plus abimasclib, a phase two study that was presented in the NSGO this year, and Professor Constantino showed us a response rate that had 30% of RR and 9.1 PFS, and this response rate did not seem to be related to the present or not of the hormonal receptor, if this patient was grade one, two, or three, or if they had used hormone therapy previously. There is an interesting data that molecular subgroups showed that these patients with 53 wild type, the response rate was 55% in comparison to a 9% in patients with P53. Talking a little bit about the EGFR inhibitors, HER2 and MET are disappointing results for the EKI inhibitors or trastuzumab, but we saw that the combination of trastuzumab with carboplatinum plus taxel and a specific subgroup, which were the patients that had cirrhosis carcinoma and SR2 plus that was positive, brought a gain in terms of the response rate and survival rate and general survival. And it seems that adding trastuzumab was mainly more effective in patients that had advanced illness in comparison to the recurrent disease. This randomized study, phase two, gave us this scheme as a scheme that was viable in the NCCM guidelines. Through positive results that we have seen of pertuzumab and trastuzumab in serious carcinomas, serious carcinoma, why not try it in endometrial cancer as well? So, unfortunately, in this study, the response rate was not very encouraging in terms of the percentages that it gave us. So, when combining pertuzumab and trastuzumab with chemotherapy, the result could be better. So, as we saw in the study of trastuzumab that I previously showed you. And now going into antiangiogenics, once again, independent of if it's CPI or if it's a monoclonal antibody, in the case of trastuzumab, the response rates for the use of immunotherapy are not very encouraging. The response rate is zero to 16 percent and the survival rate for progression of six months and a general survival that goes from five to 19 months. We have two phase two studies that are randomized in first line. The first study is GOG86P, a study of three stages that compared the historical control of GOG209, laticacel and trastuzumab, carbotaxel plus sirolinum versus carbo with trastuzumab. So, in this study, carbo and vertizumab had a gain in terms of global survival, but this comparison was done with the historic control of GOG209. A second study, MITO-N2, compared carbo with plassy versus carbo and plassy plus vertizumab. So, this showed a gain in free of progression survival, but in the latest publication, we did not see a gain in the overall number and in terms of global survival either. Talking about immunotherapy, this group of drugs were the ones that showed a difference in the management of endometrial cancer. We know through TCGA that we have four submolecular groups of endometrial cancer. So, subgroup A and MSI have a high mutation boarding as well as why not try immunotherapy for this population. We have studies with durvalumab, pembrolizumab, dorsalimab, and abumab in this population with a selected biomarker of deficiencies of mid-match enzymes, and we saw response rates that went from 27 percent and in those patients in the subgroup that had a much lower result. Some of the studies show very interesting data in those patients that were at least treated with zero to one treatment lines, and we see response rates that are even higher, which suggests that perhaps as soon as possible, we should use these drugs in first line, and even adjuvantin can bring us better results. It is not just a matter of the response rate that these drugs present. We see that with immunotherapy, we see a duration of response that is very significant in the case of Keynote 158. In its update, we saw that 68 percent of the patients had a response after three years of treatment. In the GARDEN study with dorsalimab, we saw that 80 percent of patients kept their response for 18 months or longer, and we see this biomarker that was preselected, which is MSS, but the majority of the patients with this type of cancer are stable, so how can we turn cold tumors, stable tumors, into hot tumors? We can add medication that are immunotherapy, other checkpoint inhibitors, chemotherapy, and radiotherapy to try to transform this tumor into more immunogenic, and this is what the Keynote study, 146 and then 70-75, corroborated, which is a communication, the combination of PBRPOS levonatinib showed very encouraging data, which led to the approval in the United States and Canada and Australia, so these data were corroborated by the Phase 3 study, where we compared PBRPOS and lenatumib versus doxo or plaxitexel, and we had an increase in terms of response rate, free of progression survival, and general survival, so data that we have had recently showed that this benefit is regardless of the histology type and the type of previous management that existed, but do we need this combination for the mismatch repair with MSI? So, the study, the Keynote study, Keynote 75-75 included these type of patients. We observed that this population, when managed with the combination of PBRPOS levonatinib, it is true that the comparisons of studies are not very real sometimes, but we can see that the response rates with NTPL1 and PL1 have an isolated response rate and response duration that are very similar and less toxicity in G3-4 toxicity compared at an ADA level to 16 percent and discontinuation of management as well, a lower discontinuation of the management when we used isolated immunotherapy for this population with MSI. We also have other studies that corroborate this combination of antigenic with immunotherapy as the case of nemolibab and cabozatinib in comparison to nevolibab. And a few words about biomarkers. We know that MSI is a good marker for efficiency for the efficacy for immunotherapies, but we do not seem to have a good biomarker, and we know that the TMPi is a good biomarker with response to immunotherapy. In this patient population with MSS tumors, we can have around 67 percent of the patients with TMPi tumors, and they receive the benefits of immunotherapy as if it were MSI. So, perhaps in these patients, disabled patients, we can investigate the tumor TMPi of these endometrial cancers. Another data that is very important is that patients with DMMR have the same response to immunotherapy. So, we have the patients that have a lower response than patients that have mutations, somatic or germinal. So, this was shown in the published studies this year that also had a study presented in MGSO. So, most likely, there is a variation of the response in these two types of patients. Finally, Salinexer is an XP1 inhibitor that is a protein that exports the suppressor proteins like the case of P55. So, if we do this inhibition, it will maintain those proteins within the nucleus. So, this study was presented in ESMO virtual this year, a little bit after SGO, and it shows that patients treated with carboplatinum and platica cell followed by Salinexer had a gain in terms of free of progression survival, and in a subgroup analysis, we established this benefit for patients with P53 wild type that had low interruption rates. I want to give you some future directions, which is that we're bringing this immunotherapy studies each time at an earlier stage in first-line treatments, and most likely at an adjuvant management, such as these studies show, as you can see right here. We need better biomarkers, and we have to think about what we will do next if the patients do not respond to immunotherapy, because we're bringing it in each time sooner. And what will we do after our own immunotherapy? No doubt, we need more investment in what we compare, for example, endometrial cancer with uterine cancer and ovarian cancer. We see that the investment is much lower, that there wasn't an increase when comparing 2013 and 2018. So, what we saw is that there was an increase for uterine and ovarian cancer, and this is related to a lower number of studies in endometrial cancer than in cervical cancer or in ovarian cancer, and directly related to the number of drugs that are approved. We see that there is a lower number for this type of cancer than for ovarian cancer, for example. So, we conclude by saying that we are facing great achievements in systemic therapy for this cancer, and the molecular knowledge has taken this treatment really to the next level in terms of its management. Thank you very much for your attention. Wow, thank you. Thank you, Dr. Paulino. Parabéns, mucho. Una felicidad. Gracias, gracias, Dr. Paulino. Very, very impressive. Lots of studies. Es muy impresionante, muchos estudios y muchas moléculas. Entonces, vamos a empezar con los asistentes. Okay. Regarding hormonal treatment of patients with endometrial cancer, what is true? Start, please, with your answers. We have some questions already provided by the Kim audience. Okay, come on, come on, don't be shy, you have to answer. Almost there, okay, so low-grade disease and hormonal receptor positive tumors exhibit better clinical response, that was kind of easy, wasn't it? So now we'll start with the Q&A's, first, Eduardo, hi, for whom would you consider hormone therapy and which is the best partner for it, mTOR inhibitors or cyclin inhibitors? Good morning everyone, first of all, thanks for the opportunity to be here today, this is a very interesting question, we have data with both hormonal therapy plus mTOR inhibitors and hormonal therapy with cyclin inhibitors, I think that from the standard point of view, I believe that with cyclin inhibitors the results are much better than with mTOR inhibitors, so I believe that we need better biomarkers to decide which one and for whom we could use with mTOR or cyclin inhibitors. I just add one question about the Q&A question, I think that there are two correct answers, the first one we can use in the first line for a specific population, those patients who follow the metastatic disease, hormonal receptor positive, it's also correct and it's included in the asthma guidelines for first line treatment. Good, so there's another question here from Dr. Malouf, do you think we could recommend immunotherapy alone for those patients with no microsatellite instability but high TMD? This is another very interesting question, Fernando, both Fernandos, because we can see that pembrolizumab is approved in the United States for those patients with microsatellite instability or for those patients with TMBH. There are some patients, the sensitivity for the mismatch repair deficient with immunostochemistry is about 95% and sometimes you can lose 5% of the patients, and I read this recent paper regarding the algorithm to test patients and they really consider for those patients who are microsatellite stable disease, you can do the TMBH and if you have a TMBH, as I showed in my presentation, the response rates are very interesting, 75% in the MSK population and 40 and something in the other study. So I believe yes, you can use it in the TMBH and high MSS patients. Any other questions? I assume that we have less questions for you because most of the people connected here are probably surgeons. We have people from all around the world connecting. We have some people from Russia, from India, from Canada, and also especially from Latin America since this was organized by Latin America, but we're really happy we have more than 300 participants and this is really great. This is a global happening. So we're really, really happy for that. Okay, Dr. Paulino, thank you very much again. We will now take a short five-minute break. Please be sure to come back in five minutes for our next presentation, Molecular Classification and Implications for Therapy with Dr. Angelica Nogueira-Rodriguez. See you guys in five minutes. Thank you. Okay, welcome back. Welcome back all to the all of our attendees, our five minute break has officially concluded. Let's get started again with Dr. Nogueira Rodriguez presentation, molecular classification and implications for therapy. I really look forward for this one. This is something really important for us. Remember to submit your questions using the q amp a feature please. Good morning everyone I'd like to congratulate IGCS for putting together this interactive updating on a college cancer in Latin America, as well as express my gratitude for this invitation. It's an honor to be part of it. I feel privileged to take part in this revolutionary moment for endometrial cancer patients, and all should start from adequate clinical and molecular classification. Please pay attention to my conflict of interest. Currently, there is an alarming rise in endometrial cancer incidents and mortality endometrial cancer is already the most common gynecologic cancer in high income countries, due to several factors including population, aging and obesity. The epidemic of obesity is global currently over 20% of Latin American people are obese, and approximately 58% are overweight. And so we from low and middle income countries with limited access to treatment need to prepare for this rising incidents. Endometrial cancer has classically been being divided into two subgroups, according to the Bachman's model, type one 70% of the cases, usually low grades and with a high expression of hormonal receptors and type two generally high grade and negative for home hormonal receptors, and we for worse prognosis. The simplistic division has also guided systemic treatment decision so far. In one hand hormone therapies, and in the other hand chemotherapy. So the bottom line here is that behind the simplistic division, there is a complex disease. For example, type one endometrial cancer is associated with mutations in the 10 k Ross area to one a MPI K three K, and our MSI. And in face of this complex landscape, it was about time we had a new classification. In 2013 that the CGA suggested an integrated genomic classification of endometrial cancer with four subtypes. Oh, you term mutated MSI microsatellite instability hyper mutated with high mutation rating genes involved in the mismatch repair system. 15 to 20% of all endometrial cancers are associated with mismatch repair deficiency. The first conclusion we can reach here is that there are prognosis extremities. And the second conclusion is that there are prognosis extremities from lower to higher risk for home, we'll try to indicate, less or more treatment, respectively. And most agree that when available testing should we start with Paul, using NGS, followed by immunohistochemistry for mismatch repair deficient proteins, followed by 5050 53 by immunohistochemistry. This is the promise group proposal supported by the NCCN guidelines. With Paul, it's considered to be a very strong predictor of good prognosis at the CGA that there were only 17 Paul tumors. And there were no recurrence in this group, but subsequent studies have demonstrated that Paul do recur, but at a very low frequency. We still have a lot to learn about Paul, including differentiation between pathogenic versus non pathogenic mutations, and the role of immunotherapy for these patients. And in case there is a role when it should be used. The goal for Paul patients is de-escalate therapy. Currently, asthma guidelines recommend it, even in the absence of prospective data, and there have been some prospective trials exploring it now. Moving forward to MSI-HI. MSI-HI comprises approximately 30% of advanced disease cases, it presents high new antigen burden, with a strong rationale to explore treatment with immune checkpoint inhibitors, topic where we are going to dig deeper now. Different mechanisms can be the cause for MSI-HI, immunochemistry protein loss, acquired hypermethylation, somatic mutation, or a germline mutation. Additionally, tumor mutational burden and PD-L1 have been explored as biomarkers to NTPD1 and PD-L1 drugs in endometrial cancer. However, selecting patients for immunotherapy based on PD-L1 was able to show only modest response in clinical trials, around 3 to 13%, only 3 to 13% of the patients responded to it. On the other hand, trials which used MSI to select patients presented a significantly better response rate. For example, same drug at the BASCET trial, Keynote 28, using PD-L1 to select patients, 13% of the patients with endometrial cancer presented response to pembrolizumab, compared to 57% of response rate when MSI was used to select patients in the Keynote 158. Same in the GARNET trial. In the cohort of mesometric per deficient patients, response rate was around 42%. And this significant increase in response by the use of MSI was also observed in phase 2 trials of NTPD-L1 duvalumab and avilumab. Here on this table, we are able to see compiled data on immunotherapy on selected endometrial cancer patients based on mesometric per deficiency, ranging from 26 to 57%. In endometrial cancer, there is a significant overlap between high tumor mutational burden and MSI, around 25% of the patients, but not between these two groups and PD-L1 positive. Focusing on sensitivity and specificity, immunohistochemistry has a sensitivity around 92% and a specificity of 99%. Interesting, according to some evidence presented at ASCO last year and SGO this year, there are differences in response rate according to the mechanism behind protein loss in immunohistochemistry. Patients with Lynch syndrome may have the best response among them. According to a molecular retrospective analysis in patients treated in the PORTEX-3 trial, chemotherapy in the adjuvant setting is less active in mesometric per deficient patients. On the other hand, it has a significant impact in relaxed free survival in TP53 mutated patients. Changing gears to seros-like, it comprehends around 10% of all endometrial cancer patients. And according to TCGA, the worst prognosis, 25% of them present HER2 overexpressed. These are the progression-free survival curves from Dr. Fadder's initial study with the combination of tristuzumab and chemo in paclitaxel. There was a clear progression-free survival benefit, which was predominantly found in the upfront stage 3 and 4 tumors compared to the recurrent population. This progression-free survival benefit was predominantly found in the upfront patients and was demonstrated again in the updated analysis. More importantly, there is a clear benefit in overall survival with the addition of tristuzumab to chemo in patients with HER2 positive. Again, this benefit was most profound in the advanced stage tumors compared to patients with recurrent disease. Previous studies of hormonal agents in endometrial cancer have demonstrated modest activity based on response and progression-free survival. These data provide a floor on which to judge future combination therapies, like hormone therapy with NTPiK3K and cyclin inhibitors and hormone therapy. Paleo trials and here letrozole combined to abima-cycloid. And the perspectives are great as trials at the advanced and initial context are including patients based on molecular characteristics. Here, the example of the GOG3064 in front line, including patients based on mismatch repair deficiency, studying pembro combined to chemo or chemo alone. And also in early settings, it's been studied here, the PORTEC4A and the RAINBOW as well. I will conclude here and my heartiest thank you for your presence and thank you for your very kind attention. I will be more than happy to answer the questions. Thank you. Well, thank you again from Brazil, Dr. Nogueira-Rodriguez. That was very, very, very enlightening. It is always so challenging to articulate these things that we surgeons feel like basic scientists, sciences in clinical practice. And the introduction of molecular profiling, although it has been slow, it is now I feel at least here to stay. So probably this will be the mainstay of present and future cancer therapy. We will start the Q&A portion with another poll for the attendees, please. Okay, regarding biomarkers that impact endometrial cancer therapy nowadays, which is the incorrect option? Please answer. Okay, don't be shy. Okay, okay, okay, so most of attendees said that PD-L1 is an excellent biomarker to select patients for immunotherapy. Let's see, hello doctor, how are you doing today? Good morning everyone, great honor to be here. Thank you Fernando, thank you Aldo, Aldo is here with me, we are together in a hybrid meeting today, and thank you René for this opportunity, very good talks. That was a great talk, we certainly see with great interest what is happening in basic science and how that translates into clinical practice, so the implementation of these determinations of this molecular profiling in our countries like low and middle income countries has been really slow, like in Chile for example, I think it should be sort of similar in other countries. Poly determination is very expensive, but immunohistochemistry for p53 and MMH proteins are quite easy. How have you implemented this in your practice, or what would be your recommendations? I think this is a very important point regarding patients from low and middle income countries, but the positive aspect here Fernando is that most of the markers can be checked by immunohistochemistry, so all patients with endometrial cancer should be tested for microsatellite instability, and the positive side aspect here is that immunohistochemistry is the best one to select patients. We don't need TMB for most patients, Dr. Eduardo has shown that 5-6% of the stable patients may be TMB, but we may select most of the patients, so the sensitivity for microsatellite instability using immunohistochemistry is around 95%, so this is very good, and at least in Brazil it's available in most public health hospitals, so I think that this is the positive aspect. Regarding Pol, this is challenging, it's still expensive, it's around $300 in Brazil, but the price will be lower soon, so we need to struggle to have access to it, because it may change, it may well define the prognosis, and we may de-escalate treatment, which is very important for patients. So here we have two very similar questions, one from Audrey Sunoda and from Fernando Malouf, regarding the importance of molecular profiling. When we as surgeons finish our surgery, what should we ask for the pathologists? Because it's not a conventional morphologic biopsy, so what would you add to the normal or common morphological biopsy? The decision to use molecular testing classification depends on the availability of resources and the multidisciplinarity, so if it's available, and I think that we should test patients, all patients for Pol at the beginning, because even in the adjuvant setting, stage one and stage two, it can de-escalate treatment, and now it's included in the asthma guideline, and all patients should be tested for microcytolite instability for the four proteins, and also for p53. So this is the PROMIS guideline, and it's supported by the NCCN and the asthma guideline, and it may help to define treatment even at diagnosis. And very important, only 5% of the patients with endometrial cancer have Lynch syndrome, but if we find a Lynch syndrome patient, the lifetime risk in the family is 70% in a mutated patient to have endometrial cancer. It's also very important to test, focusing on cancer prevention. Of course. What about HER2? Now HER2. HER2 is present in around 30% of serous patients, but it's also present in endometrioid cancer patients, so at least for serous, now that we have data that adding anti-HER therapy may increase progression free and overall survival, it was a phase two trial among the fathers, showing that there is a gain in survival outcomes, it can be tested. But here, especially low and middle income countries, access is an issue, and this positive data was for stage three and four patients. So I defend to test HER2 for all serous cancer patients. Uh-huh. So Jorge Rogel from Venezuela, besides saying hi to everybody and a fascinating conference, he said, is it possible that in maybe in the future to do this molecular study in the biopsy prior to surgery, would that change in any way the conduct of us surgeons? Ah, I hope so. We have so many trials now in medical oncology trying to de-escalate treatment. And for example, if you have the information that the patient is a pole mutated patient, de-escalation in surgery may make sense. Current trials are checking patients based on this profile, classifying in favorable, intermediate, and unfavorable. And patients go to conventional, for example, stage one vaginal brachytherapy compared to de-escalation or using immunotherapy. I think that you should think trials to de-escalate surgery as well. Pedro Hernando is also asking about, what about the use of some other markers like B-catenin and L1-CAM? Yes, these are very good biomarkers. For example, if the patient expressed more than 10% of L1-CAM, the patient is considered a high intermediate risk. And now we don't have prospective data on that. But now the PROTECT-4A is including patients and in the stratifying according to it. And for patients who are L1-CAM, they are classified as unfavorable and they are submitted to external radiotherapy compared to conventional arm, which is vaginal brachytherapy. So the prospective data is coming. We don't have it yet. But when you are deciding, it will balance against de-escalating, for example, L1-CAM. So now we know that those biomarkers, they have prognosis, but the prospective data to ensure that we can de-escalate, we don't have it yet. OK, we have a couple of more questions, but we have to keep on with the schedule. I'll be very thankful, Angelica, if you can answer them internally. But there's lots of, I see some pathologists who are very interested in your lecture here. So please be sure to answer those questions. So thank you again, Dr. Nogueira-Rodriguez. Oh, thank you so much. I will answer all the questions again. Thank you. Our next presentation will be Dr. Simmons, controversies in radiation oncology for endometrial cancer. I'm a clinical oncologist working at the University Hospital Plymouth Trust in the UK and affiliated to Stellenbosch University in South Africa. I have no conflict of interest. And today we're going to talk about endometrial carcinoma and controversies in radiotherapy. So we're focusing only on carcinomas, endometrioid, adenocarcinoma, clear cell, and serous. We're not going to discuss carcino-sarcomas because it's not very well evidenced in the literature. And we're not going to discuss sarcomas, which again is a separate entity of its own. And we're focusing just on the role of adjuvant radiotherapy for these patients. So there are a number of known prognostic factors for endometrial cancer. And these include tumor stage, grade, histological subtype as discussed, depth of myometrial invasion, more or less than 50%, evidence of lymphovascular invasion, whether it's minimal or whether it's substantive, and the age of the patient, usually something more than 60 years old. So how do we take the current evidence and knowledge of these risk factors and apply it to our daily decision making? Keeping in mind that the addition of radiotherapy does not impact overall survival. In early stage disease. So just some definitions for those of you who are not oncologists. When we're talking about external beam radiotherapy or EBRT, we can mean 3D or VMAT. And the radiotherapy is to the pelvis and all the pelvic nodes and periortic nodes as appropriate, depending on the final pathology. And these patients are receiving five weeks of daily fractionation. And then we're talking about vaginal brachytherapy or vault brachytherapy. And this is cylinder brachytherapy, usually given in three to four fractions, if given as standalone treatment. And the chemotherapy is carboplatin pachytaxel. So what is this? We'll start way back when with PORTEC-1, which was a radiotherapy study looking at outcomes of pelvic radiotherapy versus no treatment for early endometrial carcinoma. They included stage 1 patients who had grade 2 or 3 more than or less than 50% invasion or grade 1 and 2 more than 50% invasion. The patients received external beam radiotherapy or randomized to no additional treatment. And the latest 15 year follow up was published in 2011. The main difference in the study was that local recurrence rates were higher and those that didn't receive any radiotherapy particularly patients were noted to have a nearly 75% increased chance of local recurrence in the vagina. But there was no difference in outcome for survival. And this is demonstrated on the graph with no difference in failure-free survival. What they did find on multivariant analysis was patients who were more than 60 years old and were grade 3 were prognostic indicators for a poorer outcome. But the final conclusion of the study is external beam radiotherapy did not have an effect on overall survival in this low intermediate risk group. So this was followed up by PORTEC2 which was published now again more than 12 years ago looking at vaginal brachytherapy versus external beam radiotherapy in this same group of patients or similar group of patients. And they included patients who were less than 50% myometrial invasion in grade 3 more than 50% invasion in grade 1 or 2 and the old 2A which we've now abandoned. And as you can see across all outcomes local recurrence rates overall survival and disease-free survival there was no difference between the two groups. And there is just demonstrating no difference in overall survival. So a very important outcome was reduced GIT toxicity for patients that got vault brachytherapy alone which is obviously beneficial when considering whether pelvic radiotherapy is needed in this group. So the final conclusion following on from PORTEC1 and from PORTEC2 is vault brachytherapy alone is the treatment of choice for these high intermediate risk patients. They then followed up with PORTEC3 which is looking at the other end of the spectrum of high risk patients with multiple risk factors in the stage 1 and 2 groups and all patients with stage 3 disease. And here they were looking at giving adjuvant chemoradiation versus radiation alone. So the groups that were included were 1A serous or clear cell, 1B grade 3 and all lymphovascular invasion, the stage 2 patient and any stage 3 patient. So the regimen was chemoradiation, 5 weeks of radiotherapy with cisplatin 50 milligrams per meter squared in week 1 and week 4 followed on by adjuvant chemotherapy, carbotaxel as discussed for 4 cycles versus just the radiotherapy alone. So the outcomes for the stage 1 and 2 patients was no difference in overall survival or the failure-free survival outcomes but a notable difference in overall survival by more than 10% in the stage 3 patients and more than 10% in failure-free survival for these patients. Again, just demonstrated in the graph, a hazard ratio of 0.63 for patients who received chemotherapy and radiotherapy together versus radiotherapy alone in stage 3. So pelvic radiotherapy is sufficient for stage 1 and stage 2 high-risk patients based on this study and chemotherapy and radiation is probably the better treatment for those who are high risk with stage 3 disease. What is an unknown benefit is for the serous carcinoma patients they did show an improved overall survival for this group but it was a small group of patients of only 100 and possibly too few to differentiate by stage. So what do we know? chemo, is chemo-radiation needed? So are those two cycles of cisplatin needed together with the radiotherapy, or can we just give radiotherapy alone and the adjuvant chemotherapy? And unfortunately these remain all unknown. But wait, there is more to the story. So there were equivalent studies run in the United States. The GOG249 was a phase 3 study looking at early stage high intermediate and high risk endometrial carcinoma patients. And here they gave pelvic radiotherapy versus vault brachytherapy and some chemotherapy. But no difference in overall survival between the chemotherapy and brachytherapy arm versus radiotherapy alone. So pelvic radiotherapy was equivalent to chemotherapy. Here they gave three cycles of carbotaxel, equivalent with overall survival, but there was a reduced local failure rate in the patients that did not get any pelvic radiotherapy. So the conclusion from the study and from the authors of the study is pelvic radiotherapy is the way to go, particularly considering toxicity. And here I would say based on PORTEC3, if you had a serious carcinoma, you could possibly consider the addition of chemotherapy alongside your pelvic radiotherapy. But then came the GOG258, which is the American equivalent of PORTEC3, published the same year. And here they looked at adjuvant chemotherapy plus radiotherapy versus chemotherapy alone in locally advanced endometrial carcinomas. So different than PORTEC3 is there was no radiotherapy alone arm. And here they found no difference in relapse-free survival between chemoradiation and chemo alone. But a higher incidence of vaginal recurrence and nodal recurrence either in the pelvis or the periortic regions for patients that received chemotherapy alone. So for locally advanced stage endometrial carcinoma, if you follow the GOG studies and the conclusions of this group of authors, is chemotherapy is enough. But my caveat here is that chemo plus radiotherapy showed improvements in local failure rates. And as a clinical oncologist, we look at survival and local outcomes together. What would I do? So the only group of patients that I would offer adjuvant chemotherapy with my external beam radiotherapy are stage two, sorry, stage three, A and B patients who are higher grade, anybody with nodal involvement, and stage 1B and 2 series carcinomas. So I think there is no controversy in my mind that all patients with endometrial carcinoma should receive some form of radiotherapy, either Voldebraki therapy or external beam radiotherapy, if they are anything over a low grade 1A endometrial cancer. The future developments for radiotherapy study recruiting at the moment is PORTEC 4A, looking at stage 1 patients with some risk factors, including lymphoblastic invasion or age and high grade. And now we're becoming medical oncologists because we're looking at integrating the molecular profile of the tumor into our decision-making tree regarding radiotherapy. And this study is dividing patients into those who have a pol E mutation, into a favorable group. Those who are MMR deficient, if you are, you will fall into an intermediate group. You can also fall into a favorable group if you are CTNNB1 wild type, if you are non-MMR deficient. And then there's the high-risk group, those that have a substantial evidence of lymphoblastic invasion in the tumor, have a P53 mutation or greater than 10% L1-CAM expression. And as I said, this is the unfavorable group. So these patients will then be randomized, a standard arm, to receive vault brachytherapy. If you fall in the favorable group observation, in the intermediate group, vaginal brachytherapy, and then in the unfavorable group, these will be estimated at less than 5%. The cohort would get external beam radiotherapy. So my final concluding thoughts are you need to consider your resources. For those of you that work in a region with no access to radiotherapy whatsoever, clearly you're going to observe the early stage patients post-op. And for those that are high intermediate risk, you could consider three cycles of carboplatin paclitaxel. And then for the very high risk patients, six cycles of adjuvant carboplatin paclitaxel. And then for those of you that have access to surgery and some access to radiotherapy, but potentially maybe long radiotherapy waiting lists, again, observe the early stage low risk. Give vault brachytherapy as per the PORTEX-2 studies for your stage 1 intermediate and high intermediate risk patients. You could give external beam for your high risk early stage and stage 2 patients as per PORTEX-3 or the GOG-249 if there's not a very long waiting list. And then you could give chemotherapy six cycles and vault brachytherapy if you have it for your high risk stage 3 and stage 4a patients as per the GOG-258 if you have a very long waiting list for radiotherapy and you need to use your resource as well. If you are working in a situation where you have surgery and access to all radiotherapy modalities without waiting lists, then my suggestion to you is to follow the evidence and to pick your team. And here my disclaimer is that I follow the European ESGO guidelines and for the locally advanced high risk patients, I would offer both chemotherapy and radiotherapy together. And in my practice, I would offer the chemotherapy upfront followed by radiotherapy alone. I thank you very much for your attention and I look forward to the questions during question time. Well, thank you very much, Dr. Simmons. As you would say in England now, lovely presentation. So somehow what you've shown us is a real trip through history of radiation therapy in endometrial cancer and also the articulation with molecular profiling of endometrial cancer. So we will begin our question and answer portion with a poll for the attendees, please. Regarding adjuvant therapy or treatment in endometrial cancer patients, what is true? There's only one true. Please select. Okay, don't get lazy. We're almost done. We need a little bit more, a little bit more time. Okay, let's see. All right. It says here, PORTEC2 study concluded that bold bracket therapy should be preferred treatment in patients with intermediate and high-risk features. That's the most answered question on the poll. So, how are you doing today, Dr. Simmons? All good. I wish I was there in person, a little warmer than England. Oh, yes. I'm going to England next week. Okay, so molecules again, see how the molecular profiling is integrating on adjuvant treatment. We spoke before about that with Dr. Noguera. Here's a question for you about PORTEC4a. Do you think that it is already outdated, even before the results, at least for patients with P53 mutation, because the RAINBOW study is already offering adjuvant chemotherapy for all those patients with P53 who are mutated? That's the trouble with these studies, right? It takes a long time to design, it takes a long time to get it going, convince people to do it and to recruit. And the science behind it was already valid. So, I think that there's no question that plenty of people are already using this information in their clinic. A P53 tumor, I would be pretty unlikely not to give them chemotherapy. And though I don't like to criticize my colleagues, I found it interesting that the PORTEC4a did not offer chemotherapy for those high-risk patients, because that is the way that we're going. There's always some slight design differences between American and European studies. And I think that in Europe, we rely less heavily on chemotherapy than perhaps in the States. And they perhaps use less radiotherapy, and perhaps should use a bit more. But I think that it's not unreasonable, the science is real, that you should look at those high-risk features if you have pathology that's able to provide it for you, and then make a decision about what you treat the patient with before the results of the PORTEC4a study. Yes, that's right. So, in your daily clinic, do you use MMR or P53 to define your treatment decision of radiation therapy? For radiotherapy, no. And I think that's because we have both modalities available. I mean, an MMR-deficient tumor, the PORTEC4a study tells you not to go give those patients chemotherapy. But we're not really brave enough yet to leave it out for the Stage 3 patients, because in routine practice, that's what we do. And then a P53 patient, well, usually a P53 patient has got something else cooking, and you would consider them to be high-risk, and then you would treat them with a combination treatment. So, I have to say, in general, coming from a European and South African setting, we do use a lot of radiotherapy. Much more. I understand. We do too. We have some quite good availability of radiation oncology in Chile, but that's not the real thing for most of low- and middle-income countries. So, your last slide was really brilliant, because you have to use what you have in the settings that you have with the tumors that you get in your office. I really would argue heavily for people to consider some form of radiotherapy for intermediate and high-risk patients, because local recurrence is a very unpleasant outcome. And if you don't have good follow-up, like we do in Africa, and maybe yourselves in some centers in South America, it's too late when the patient comes back with their recurrence. Yes, the recurrence in endometrial cancer is horrible. Okay, I think that that would be all. Now we have to move on to our next lecture. Thank you very much again, Dr. Simmons. It was really lovely, again. And now we'll move on to our final lecturer, my good friend, Dr. Di Wilmi, from my neighbor, Argentina, here. We'll be presenting on technical aspects in endometrial cancer surgery. Please welcome Julián. Hello, everybody. My name is Julián Di Wilmi. I work in the oncological hospital in Buenos Aires. I want to tell you how happy I am of being connected and participating in these updates on selected topics in gynecology, oncology, and these interesting talks. And also, for having been invited to talk about this topic, I want to tell you that I do not have any conflict of interest specifically for this talk. And this talk is oriented to talk about those technical aspects of cancer surgery of the endometrial. And I have divided this in two parts. We're going to be talking about some theoretical concepts that can be discussed with regards to the approach. And there are also some small discussion areas that are very specific. For a second part of my talk, we're going to be a little bit more technical and talk about practical concepts in relation to the use of Sentinel and also the surgical techniques. And then we will finish with some final recommendations in relation on how to sort this out based on our practice and the experience that we might have, as well as the therapy to treat this endometrial cancer. The first point that I want to talk about has to do with the approach path that we should have. If we should use the minimum invasive approach for treatment of endometrial cancer. The study that has been the latest one that we have available, it's one of the two prospective ones that we have, is the LACE trial. In this study, there was a comparison done retrospectively of the effect terrestrially doing through the laroscopy through the one done for disease-free survival with the minimum invasive and the open one. And we see oncologically speaking that the results were quite similar. These results of the LACE trial also demonstrated in a previous study that is very well known by all, which is the COC Lab 2. There is something that you can tell me which is reasonable, and it is that the most of the patients in these studies correspond to histologies, a flow degree, and also initial stages. So, in this study that was done afterwards, where we had the patients of COC Lab 2 that had grade 3 or stage 3, it was also demonstrated that the survival rate was the same if we compared the different approaches. So, today the most practical recommendation is that we are all able to do the effort of evolving and having the best training so that our patients that have carcinomas in the endometrium can be treated and diagnosed with a minimally invasive approach, obviously being careful with the oncological general surgeries. So, if we follow this line of thought, I want to propose the area of discussion with the use of mutarine manipulator in the recurrence and mortality of endometrial cancer when we do this with the robotics or laparoscopies. We have to think about the mutarine manipulator, and this is an area that we thought that was very close, and there is an article with evidence in 2017 in which when we compare the patients that have used the manipulator with those that hadn't used it, we can see that the rate of recurrence did not show differences in the groups of patients. More recently, there's a study in Spain that also retrospectively, when they compare the patients that had used the manipulator with those that had not used it, we can see in this graph that there is a highest rate of recurrence and mortality in those patients that had used the manipulator. I don't think that you can conclude anything with either one, but there is a bias here that you don't know why it was used or why it wasn't used, what type of tumor, under which conditions the manipulator was used. But anyway, I think that you have to be very cautious, especially with those patients that have high-risk carcinomas that are bulky, where the manipulator can generate certain problems, and even worse if there is a perforation. So that is why the role is so important. That is why when you place a manipulator or when we are manipulating the uterus during the surgery, you have to be very careful with regards to these oncological surgeries in order to have the best outcome with your patients. The last point that I want to talk for this discussion area is the use of peritoneal cytologies within the surgery of endometrial cancer, because we know that this doesn't constitute a stage as such, but it has a very important role in those patients that have neoplasia in the peritoneal area, and the prognosis in that case is worse. I think that this uncertainty scenario has made this not be used so much. What you can see is that it can help in the global assessment of the patient, especially for those patients that are high-risk. I think that the practical recommendation is to continue with it and not forget it, although it doesn't have a very important role nowadays, it can help you on a long term when we need a certain information about the patient. So let's go now to see the second part of my talk with more practical concepts having to do with the use of the sentinel glands and the technique. The use of these glands in the process of stratification has become today a standard practice. It's less invasive, there are less problems later, and of course it doesn't affect the possibility of metastases. So this can be explained when there is low-volume metastases that appear. So it is important to have clear that the technique has to be united in order to be able to have success in those detections. Over here we're going to see very quickly some of the concepts based on those techniques. The first step within what is the oncological global strategy is to look at the abdomen to discard other advanced diseases and then make a good evaluation of the pelvis, especially to discard adherences or any other type of problems that are going to delay the insection of the coloring and the later search for sentinel glands. And here we can see the green of the endocene that disappears after a while. The second step, and it's the key of success, is the insertion of the dye. In the endometrial cancer it has been seen that the cervix is fundamental. This insertion has to be at hour three and hour nine ideally of the clock, and the coloring or the dye has to be like a delicate technique, especially when you do a surface or superficial injection. Here we see pericatal injection and the needle has to be sufficiently long and the sufficient gauge in order to manage it properly. Apart from being a correct insertion, it's important to have good timing. In other words, you have to make the insertion and as you're doing it you have to see how the dye starts draining on the back part and see in the peritoneal area in order to be able to localize a place where you're going to be able to detect this. This also is related with the mechanisms that the dyes have or the time of use of those in order to get to the gland and then disseminate and stain the field in order to have the right location of the sentinel gland. The other surgical aspect has to do with the technique because when you're looking for the sentinel gland you have to be very delicate in the insertion, especially in the lymph nodes that are in the neck of the uterus towards the sides of the pelvis, because if you at the beginning make a section of all those you're going to be cutting them and the dye is not going to be able to reach the sentinel gland. On the other hand, I think it is also important that when we do this with the sentinel gland you have to identify the vascular nervous and anatomic parts and at least have them identified without cutting the channels and avoiding edemas and also to avoid affecting the large structures of the pelvis. And lastly, and also as part of a correct technique in relation to the entire process of the sentinel glands, you have to see that the specimens that you get through this technique have to be extracted, doing it very carefully, putting them in a bag or in a glove. After the identification of this sentinel gland, you continue with the surgery making a hysterectomy, in which case it corresponds to a level one class A hysterectomy where the section of the vessels is done at the level of the arrival. Differently from what happens with the radical hysterectomies, which are used when you have a cancer in the uterus of neck, and these are done with this PIVER-2 or the PIVER-3, which is its origin. So, the hysterectomies that are radical or carcinoma endometriosis are very limited, very few cases of this. And this is done when this is compromising the neck of the uterus. If you have to do it, then it's going to be longer. And what we're seeing here is that there's not going to be an interference between the radical and the PIVER-1. So, be careful when you do this hysterectomies because the copartomy, as well as the extraction of the piece through the vagina, has to be done in a very careful manner in order to not disseminate or spread the content of these cells through the vagina, because it can go to the cavities. And then we have to see the role of interoperation biopsy. And this occurs because before the use of these sentinel glands, many of our centers were doing this as a detection of risk at that moment. So, the patient that had a high or low risk, we had to see to be able if we could complete and do this lymphatic lepidectomy. And we were not working with these sentinel glands. Over here, we see a use of a novel sentinel lymph node mapping algorithm that reduces the need of these lymphodectomy of the pelvis. And we can only use this in the sense that we have detected one of two sentinel lymph nodes. And this way, we're going to be able to decide what we're going to do with the total lymphodectomy on the side of the sentinel glands. That way, the interoperation or intersurgical biopsy is going to help us to avoid unnecessary work. And to finish, I'm going to make a brief summary of everything. I'm going to give you some recommendations. The surgery of endometrial surgery has to just start with an inspection that is very careful, especially of the pelvis. Do a cytology with your patients and pay more attention to those patients that have a high degree of risk. Remember that you can make a better global assessment of the patient. You continue with the surgery by injecting the dye or try to find the sentinel gland, doing it in a careful manner. And obviously, accompanying this with a deep incision. But the success of this sentinel helps have to do with doing this in a very careful manner. And once you do this, you can place a manipulator. But remember that the uterine manipulator for endometrial cancer can have an effect, especially in bulky tumors of high risk. So you have to be very careful in the manipulation and also during the moment of surgery. And please make your biggest effort to try to progress and advance and know as soon as possible a curve of experience in order to work with the techniques of sentinel lymph nodes. It's necessary to do it with methylene blue or with other types of dyes. But what is important is to be able to do it in a proper manner because this is a technique that has to be less invasive and easier to do and does not need a larger curve of training. So you complete this hysterectomy over here. We see one of class A level one. Be careful, of course, with the extraction of the uterus of the coccytomy, which are the normal processes in an oncological surgery, but try to avoid the dissemination. Use the biopsy that is frozen, the process sections to do this within the operation time. And if you're able to do it or when you're going to do the hysterectomy or you're going to be looking for the sentinel lymph node or when you haven't found one of those nodes. And obviously then do the lymphadenectomy according to the criteria after the mapping that you have done with the criteria that has been mentioned. Thank you so much. I really want to thank you for having listened to my talk and I hope that my talk has been useful. I am more than available to answer the questions that you deem necessary. Thank you so much. Thank you, Julianne. Excellent presentation and beautiful videos and insights in this technique. How important it is to acknowledge all these tips to standardize the procedure. So we will begin with the question and answer portion with this one last poll for the attendees, please. So some technical aspects are important in endometrial cancer surgery. Please choose the incorrect answer. There's only one incorrect over there. Incorrect. Come on. All of you, 271 participants right now. You can answer. Don't be shy. This is the last one. Okay, a couple of seconds left. Please participate. Okay, let's see the answers. Most of people said that once central lymph node is not detected in one side, the recommendation is to rely on the other side for staging. Julián, amigo, ahora en español, ¿qué tal? Muchas felicidades por tu presentación. Julián, my friend, now in Spanish, congratulations for your presentation, and it's important to standardize this technique. And I think that you were one of the pioneers in our region in Latin America. What do you think of this? How have we introduced this technique in our daily lives with cancer patients? Well, good morning, Hernando. Thank you very much, everyone, for the presentations, and thank you for inviting me here to be here. And I hope that I was at the level of those wonderful presentations that we had before. Of course, my friend, of course. Okay, with regards to the specific question, until just recently, even today, we see that you tend to talk about whether this is a standard, how it becomes a standard. And I think that the evaluation, or to say that a technique is standard, depends on the place where you work in the region, the hospital. Like, you might think that this has to be the standard. We just saw Dr. Mariani's presentation. And there's a lot of explanations, and there's evidence, and practice shows us that it's not just a less invasive method, but it also offers better or higher diagnosis rate, like the one that we're looking for, for endometrial cancer. So we have a better statification, the patient to be correctly seen with regard to their prognosis, and it also helps us to have better progress. And this goes hand in hand, not just with the technique that I'm showing, but also to finding specifically the most representative node, but the study of that node also accompanies a process that makes us diagnose more, and will increase the rate of metastasis, lymphometastasis that we're measuring, comparing to what we used to do, and what we do now. But the idea is to encourage a little bit and incentivate the use and development of this technique, that even if it seems something less invasive, it requires its learning curve, and to be able to know how to do it well. Yes, no doubt, Julián, we've talked about it. It's something that we're both passionate about, and we have been pioneers in our corresponding settings. So in that sense, there is a question from Ignacio Chavez, it says, ask who has adopted the Sentinel and the endometrium? Everyone has done their validation with Sentinel and lymphonectomy at the same time, and this has to do with the curve. So the first Sentinel I did in 2006 with blue. Now, of course, I work differently, but there's people who don't have access to all of that. So what would you say to them to start using this technique to be able to validate themselves and their centers? First of all, that it's to be able to do just Sentinel nodes, it's fundamental to do the own validation, the validation of each one. And this, when you normally do lymphonectomy, you compare the Sentinel node with the rest of the elements. But what you can't have are false negatives, that the Sentinel node is negative and the lymphonectomy is positive, that on one side. And then on the other side, obviously, to be in constant contact. And a doctor previously was mentioning this as well. The Sentinel node, unlike the lymphonectomy, should have a study, a pathological study that is deeper. You have to go to the ultrastaging, and if it's negative, to go to immunodiagnosis to be able to detect. So the pathologists have to be aware of the fact of what is the protocol for the Sentinel node, that sometimes it's not very widespread either. Yeah, because if not, it's not useful at all. So once again, the importance of cooperation with this, to be able to say, this node in particular, I want you to study it this way. Because if not, the surgical effort that I'm making and changing my practice towards the Sentinel node to be able to offer the benefits of the technique, then it's useless. If we don't do multistaging, it is useless. So they're also asking here if you would use only the Sentinel node or its technique in cases of patients with high-risk tumors. So if you feel comfortable using that technique in those types of patients. Well, nowadays, we've also seen that for high-risk, we also have a trial for high-risk patients, that when you're used to the technique and you've validated it and the acceptance rate is good, then you can trust the detection of nodes. And there was also a question that I saw that had been asked before. Obviously, you can't have peace of mind when you don't find it. So you have to see what to do in that case. Because a high-risk patient cannot be left without investigating that node state. So I think that that is important as well. But yes, when you have already done your learning curve in the place where you work and you trust the technique, you can manage it in a different way, of course. Yes, no doubt. And the important thing of the standardization of the technique, that our technique is always the same, that's what allows us to offer the results that can be validated and that preserve the oncology benefit of the surgery in endometrial cancer. Many of the questions that we have, both in the Q&A section as well as the chat, make reference to that depth of injection, how many mLs. That's something that is pretty standard. In my case, we've talked it over many times, the one who injects is always the same helper. It's always the same speed while the others are looking. So everything has a perfect timing. So a good question is, how much to re-inject? Well, also, I think that that's part of the global technique and the success between a good injection rate. My recommendation of re-injection is to do it, the patient is injecting and they're looking directly. Once the coloring has not transcurred correctly parallel to the course of the uterus and there is no canal that you can see, and that's the moment to have peace of mind with regards to a re-injection. I think that many times we're going to have that situation. And let me tell you something, Fernando, based on what you were mentioning about the technique. I think that the technique itself has been standardized. I showed you just recently in some videos about recommendations based on standardized techniques for sentinel nodes, things that you should do, things that you shouldn't do. And I think it's a difference between the first work that you used to do that the sentinel node was detected less than half the times. And nowadays, it's standardized with this. And obviously, you put in the learning curve, the detection rate might be very high. Well, we have the last few questions. Let's see if there's any variation in the technique. And using the two different types of colorings, I think that that is something that is difficult to response because we helped us do this much easier with a higher cost. There's second-generation cameras, and they're also integrated. But if you do not have the green dye, you can use the blue dye as long as, as we previously mentioned, you perform your curve and you see the eventual false negatives. Yes, and based on this, what we recently showed about timing, the injection spot, the type of needle, the volume, obviously, the green dye facilitated the capacity of visualization. The fact of continuing a surgery that did not have any blue dyes, I think that in that sense improves the matters. Obviously, in a Latin American webinar, we were also mentioning that sometimes going from one technology to the next or from one technique to the next requires an effort with regards to technology. And it's something that is not easy, always. So we're going to close up our session today because we still have a lot of questions open. But time has run short. We had a very good time. That is all the time we have for today. We have witnessed a great meeting between world specialists in endometrial cancer. I would like to thank the program co-chairs, Audrey Zunoda, Fernando Maluf, and René Pareja, who made this possible. I would also like to thank our speakers today for the time, expertise, and, of course, their insights. And I would also like to thank all of our attending from around the world. I just read that we have an attendee from Kazakhstan that is amazing. And finally, to IGCS for considering me to moderate this webinar. It has been a real honor to moderate this. And the recording of today's session will be available in the IGCS members education portal next week. So please remember to join us again next Saturday for the final session of this webinar series on ovarian cancer. Thank you very much again.

cancer research

cancer treatment

MSI

Microsatellite Instability

TMB

Tumor Mutational Burden

predictive biomarkers

immunotherapy

checkpoint inhibitors

PD-1

PD-L1

CTLA-4

endometrial cancer surgery

sentinel lymph node mapping

lymphadenectomy