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Their colleagues and friends. Uh This is uh uh from Greece. Uh We're having uh today uh an IPV S educational webinar. Uh This is a joint uh webinar uh of the IPV S and OC ANOC is the European network of trainees in obstetrics and gynecology. And the topic of the webinar is new frontiers in uh cervical cancer. So we will try to shed light uh on uh the gray zones of cervical cancer uh regarding uh cervical uh carcinogen cancer, carcinogenesis uh and treatment. Uh And also regarding uh research, current research on uh uh cervical cancer treatment. Uh We have uh with us uh distinguished speakers. Uh But let me first uh welcome uh Sophia. Uh she is the president of OC and on behalf of this uh wonderful uh society, she will uh uh tell us a few things, Sophia. Hello. Hello, good afternoon. Thank you very much. Everybody that he's attending this uh joint webinar. On behalf of the endo executive, I would like to personally thank IPV S for this collaboration that is very fruitful and trying to create new opportunities for the trainees and young specialists, the European group of trainees, we are representing trainees and young specialists in uh in Europe and all over the world as we are participating actively in the World Association of trainees as well. And it was gone uh was from 97 and we had 35 member and uh we are very happy that we are here with IPV to work together in order to who spread knowledge and to raise awareness about Serbia cancer. Thank you very much, All the speakers that they have uh uh kindly accepted our proposal. Thank you very much. Thank you, Sophia. Thank you, Sophia. Uh So let's move to the next slide, please. Uh The International Papilloma Virus Society is the Global Authority on Papilloma viruses. Uh A society with great uh history uh striving to contribute to an improved understanding of uh the biology and pathogenesis of papilloma viruses and their associated the diseases. Uh The the society uh advocates for evidence-based policies, uh facilitates research, uh facilitates new clinical applications and public health uh policies and promotes and supports education about Papilloma viruses. Uh Throughout many uh many, many initiatives uh such as the one we're having uh today uh which is a part of uh the IP VSS uh Education uh committee. Uh Now we have members from all over the world from more than 110 countries. And uh our mission is to contribute to the elimination of uh papilloma virus related diseases. Now, coming to today's uh webinar uh we have uh uh uh 1st, 1st, let me uh let me give you do a little a bit of a housekeeping for our uh for our audience. Uh Everyone attending can submit questions uh to, to the chat box. Uh And uh I will go through the questions and discuss it with uh with our esteem panelists. So, uh this is the place to do it. You can see it uh on the screen, a place to submit questions to the Panelist. Some of those questions will be uh directly answered from the panelists. Maybe uh uh we in, in this uh in this chat books in the book. Uh And so we're, we're going now to our, to, to today's uh program for our webinar. Uh We have uh three distinguished uh speakers. Uh We have uh professor uh Mark Einstein, uh professor in chair uh in chair in the Department of Gynecology and Reproductive Health in Rutgers, uh New Jersey Medical School in the USA. We have uh Professor Marie Plant, a gynecologic oncologist, uh a professor at the Department of uh O Obstetrics and Gynecology in University La Val uh the uh the Quebec. And we have also uh Doctor Patty Gravitt, uh who is a Deputy director at the US NCI uh Center for Global Health in the USA. Uh I'm Kimo Kisa Mau, I'm a gynecologist from Greece. Uh And today I will uh serve as uh your moderator. So moving now to our first uh speaker. Uh we have uh Professor uh Mark Einstein who is sharing his screen now. Uh Professor Min, as I've said, is a professor in of obstetric and gynecology in the rat Medical School. Uh He can serve he also and associate Dean of Clinical Research in this uh uh in this university and uh has served uh from many uh post uh from many esteem positions. And also he has been uh uh uh president of the ACP uh quite recently. Uh his research, I is uh mainly focused on uh cervical cancer. Uh And as far as I know, because I've had the opportunity to listen to his lectures in Washington DC in our uh previous uh congress. Uh He has a very interesting things to, to share with us today. Professor Einstein. Gosh, thank you. Thank you so much for the invitation to speak to all of you today. Thank you for joining us for this innovative conversation that we're having today. And I look forward to talking to you all about some of the questions that you might have with this continuing increasing uh interest um in cervical cancer as well as in all HPV associated diseases. Um So, uh you know, the I was asked to talk about a very broad topic in a very short amount of time. So I'm really gonna just kinda speak high level about some of the more interesting kind of things that are, are there and some of the, some of the things that are really uh coming of age. Um and some of the things that are in, in clinical trials, uh with regards to some of the state of the art precision medicine strategies, many of you have already started to adopt uh some of these strategies for those of you who take care of and manage not only primary cervical cancer, but recurrent cervical cancer. And a lot of this has to do with just the explosion of molecular technologies in uh precision medicine technologies that we have been able to have access to on a regular day to day basis clinically over the past, you know, decade, decade and a half. And this has led to some pretty dramatic discoveries and improvements in patient outcomes. Uh Just very briefly, with regards to my disclosures, I work with a number of different companies. I don't take any money from any companies in some cases. Uh They pay uh my institution for my time and I run a number of trials and I will be discussing nonregulatory, approved uh drugs and uh with wi within this. And I will note that when I, when I talk a little bit about this, so many of you take care of uh whether it be early cervical cancer or even the larger cervical cancers. And let's face it. We you have historically been using rather broad and nontargeted therapies for decades. OK. And not just in cervix cancer. But even in, in other HPV associated cancers such as head and neck cancers or in anal cancers, we are targeting the actual tumor but we are not, we have not been targeting the underlying reason why they developed this tumor and that is HPV or the body's immune response to that virus. When we think about other virally mediated diseases or other virally mediated tumors in a, in a large sense, yes, surgery and multimodal therapies are very much involved in the treatment. But the underlying risk factor behind them is, is typically the virus and we don't cut out viruses. We're not cutting out COVID, we're not cutting out hepatitis yet. We cut these in, out in general or we radiate these or we're using nonspecific cytotoxics. And, you know, generally for early cervical cancers, we have historically been cutting this out and guess what it works pretty well. You know, I mean, we're not just taking out the primary tumors, we're removing all the tissues that are around the tumors. This is something that we spend a lot of time on in training for those of you who would do the surgical training for this, whether it's removing the, the actual hysterectomy doctor plant is with us today. It's an honor to talk with her. You know, she's one of the innovators with trachelectomy as well and, you know, or simple hysterectomies for, for, for microinvasive disease. We're actually spending a lot more time doing less. OK. Uh Our recent ESMO conference, there was a lot of discussion about doing induction chemotherapy to make, to make potentially tumors smaller. So they can actually be even more excised. But yet we're still not targeting the underlying reason behind this disease. And that's HPV. And that's also not even taking advantage of the immune response to that. Um Or we're using chemo, I mean, a and, and one can argue that the field of radiation oncology got its start in, in treating cervical cancer. And these tumors really do melt away. I mean, when we actually look at the disease specific survival of high quality radiation with brachytherapy for early stage, uh locally advanced cervical cancer. It's, it's, it's as good if not higher than any surgical approaches. And, and uh you know, certainly when we actually add a platinum radiosensitizer patients do very well. And now with advances in targeted treatments with intensity modulated radiation therapy over the old, uh or shall I say, the more uh traditional conventional radiation therapy convention, you know, conventional two D conformational radiation therapy with CT guided or even MRI guided treatment planning. Um As long as we're using brachytherapy, we're getting amazing responses with minimal toxicity to surrounding tissues. But again, we are not targeting the precise mechanisms that are behind these types of tumors. And now when we were talking, when they, when they recur, um we have been using platinum doublets for a long time for almost as long as platinum has existed. OK. Uh Until really we've actually identified what those targets are and, and, and some of that came from a number of different studies with some of the molecular tissues. But I think one of the bigger advances came from the Cancer Genome Atlas project. And you know, while this doesn't show cervix in it, initially, there were the top answers that were initially looked at from multiple different platforms, not just gene expression platforms, but some posttranslational platforms as well. Looking at Microrna, looking at other things like methylation, which we know plays a big role in actually modulating uh the post transcriptional work and even turning off tumor suppressor genes. So thereby by turning off those tumor suppressor genes, increasing the potential malignant transformation of those types of cells. But also, um after the initial big ones were done, um the National Cancer Institute moved on to the, shall I say the more rare tumors? OK. And Cervix was one of them um in, in the United States. Um And in the Cervix, um you know, we were part of the Cervix a collection of this in 228 well characterized specimens. So, not only was the primary tumor removed but uh normal from the same patient to really look at the actual tumor related gene differences, tumor related methylation differences that were happening within the same patient. OK. When you actually look hard enough and this is sort of some of the big highlights and I put uh the references down here. So you can actually look at the paper, there's a tremendous amount of data in this paper from Doctor Melano, Doctor Ween. And you know, basically most of them as we expect were HPV positive. Um HPV integration as we would expect is incredibly common. It is a, it is something that we consider uh probably a necessary step in malignant transformation. And when it's not seen, interestingly, a lot of those tumors that were sent, even though they were, they were histologically and tumor boarded as cervical cancers, they were more consistent genetically with endometrial cancers. Um but was also interesting and this is something that's important when we're actually having this explosion of typical. We, we do now ge genome wide analysis on almost every tumor now pretty routinely in the United States and we're getting a lot of new gene targets that are identified. OK? And we continue to have gene targets and gene targets that we now think maybe have some, maybe there's some risk, but maybe 10 years from now, we're gonna find out it has a lot of risk. OK? And there are new targets and with new targets come potentially new drugs. OK. Uh So, so we can also use it as a template for diagnostics. So identifying some novel novel mutations, I mean, we, we used it to identify some methylation patterns. I mean, uh we had uh we had actually used and most all these genome wide uh analyses are public domain. So they're searchable. So you can actually look at these methylation patterns, you could compare it with other tumor types. Um And you could look for some of these patterns. We saw some polycom mediated patterns um in some analysis that we had done uh and published on this, which showed not only hypermethylation but hypomethylation that acted a lot like tumor suppressor genes. There are some patterns in fragile sites which all can be used potentially as diagnostics, not only for identifying uh maybe the aggressiveness of a tumor but identifying new potential targets for treatment. There are also all these are are associated with two with clinical outcomes as well. And then now we're using it pretty routinely for immune based treatments as well. I'll get to the PDL one story a little bit towards the end of the talk, but full next gen sequencing is pretty routine. Now, looking at tumor burden micro um a mutational status, um microsatellite instability is something we routinely do, not only for cervix cancer but other gyn cancers like endometrial cancer. Um Mmr status, we now have Mmr status, non nonhistological type immunotherapies, uh such as doli. OK. So we could use that for any Mmr status tumor and that differentiates whether or not we use it because there's an overall survival improvement using Dostal uh in patients. And I'll talk a little about the Garnett trial. Ok. Um One of the first targeted therapies um was the use of Vegf inhibitor bevacizumab, which is many of us have been using this uh for many other tumor types. Um gog 240 was a three arm trial, one of them that contain did, did not contain platinum in it. Um and patients were randomized with and without bevacizumab and, and any of the arms, any of the patients that received Bevacizumab had on average about a 30% improvement in overall survival. So this led to approvals um in most areas for uh the use of Bevacizumab in front line recurrent or metastatic cervical cancer. Uh uh And this is something that we have been using routinely now since uh uh 2011 in the United States. Uh another targeted therapy that we use and this is actually going after a ti uh tissue targeted factor the TAO time. Um This is using uh this whole wide group of types of agents called antibody drug conjugates. And the nice thing about these antibody drug conjugates and this is in discussions with many of the companies that are developing it because there are many, many adcs that are under investigation. Now it's, it's these are relatively straightforward to develop. OK. So if we got a target, we got an antigen to go after we could develop them. There are some off target toxicities that I think oncologists are now getting used to managing like ophthalmologic toxicities and other things too. But in this particular trial and this is approved in many areas of the world. Um, there, you know, we use eye drops regularly in them, but there's a overall statistically significant reduction in risk of death, um, using Tso and a in patients who historically, um, don't do very well. Ok. Now, granted we wanna get a, uh, an improved, than, you know, just improving risk of death. But, um, I think that with continued development of anti drug antibody drug conjugates, maybe tagging them along with other types of immunotherapies or immune based treatments. You know, we could really try to do some even more precise targeted therapy. Um, let's talk a little bit about, uh, the immune system very briefly. So HPV associated cancers, we know they evade the N A and adoptive immune responses. I mean, HPV is the ultimate trojan horse patients don't get a systemic response to HPV. People don't get sick, they get sick with pretty much every other virus, but they don't get sick when they get an HPV infection. And so they don't get exposed to the systemic immune response and they also tend to control the local immune environment. All right. So they do a very good job in keeping out of the normal surveillance of the immune system. Ok. And, and, and by doing this, um, it makes it very difficult for the immune system to actually go after this. All right. So, as one would imagine. Um maybe if there's a way that we could actually regulate the body's own immune system to go after it, this will help. And many of you are aware of PD one's immune checkpoint inhibitors. This has been, you know, initially tested in, in Melanoma and many other types of cancers and obviously for virally mediated cancers, like like cervical cancer. Um this is actually shown to be um efficacious in a number of different um avenues. Um So very quickly, the PD one pathway does regulate antigen mediated inflammatory responses. OK. And in the presence of this antigen, OK, there's an inflammatory response that's triggered through a activation of these T cells. So, so there is some element of immune tolerance that's elicited following the activation of this PD one. And, and once it's activated, it inhibits that signal and it hinders that T cell activity. So, if you could turn off this pathway with a checkpoint inhibitor, you could make, expose, expose the T cell, the antigen to that T cell. So the T cell will recognize this as potentially something to go after. OK. And, and needless to say this has actually been shown to be pretty effective. And we know that certainly PDL one, it, it's overexpressed in most HPV associated cancers, especially cervix cancer. This can be measured, it can be quantified. It's something we do routinely. Now in uh cervix cancer, um elevated levels uh favor a state of immune resistance. All right, So, when patients have these elevated levels, they seem to do even better when we actually give them an immune checkpoint inhibitor. And there is a direct correlation of overexpression of PD one with poor survival. So, so uh so after a very quickly enrolling phase three, double blind, randomized controlled trial using the triplet of with a VEGF inhibitor. Uh PEM bro, without pem bro, in patients that had PDL one positive scores uh of cervix cancer. There is an overall progression free survival. Now, there's a number of different trials using anti uh checkpoint inhibitors and different types of checkpoint inhibitors. Um a little bit further up, not just in the recurrent and metastatic setting, potentially at the induction setting. So, you know, I think there's gonna be a lot more to come with regards to immune checkpoint inhibitor in the coming years. OK. I talked a little about Dostal iib uh this is, this goes after Mmr. So we really look at Mmr on a regular basis in the garnett trial. Any Mmr tumor patients had an increase in overall survival using dost Carli, which is another anti PD one. So you're gonna see a lot of different flavors of it and we're gonna be able to actually personalize the checkpoint inhibitors based on patients, personalized molecular markers as well. OK. So very important for us to really and we routinely do this stuff in a very synoptic way. Now. So by synoptically doing all of these types of testing on a routine basis. That way everyone gets the same testing on a regular basis. We're gonna be able to expose them because we don't know what we're go. We don't know if that patient's tumor is gonna recur or be in the recurrent setting. It's very important that we have that information. So we're not looking for blocks two years down the line to be able to pull this information from it. Um And we're gonna see what ha what is, what is currently available. Now, there might be other drugs that will be available in the future that might be exposed to other markers too. We're gonna talk a little bit about a very innovative therapy, very personalized cause it's only one person can actually get their own till therapy. OK. Um Some of this was uh was presented at AO relatively recently. Some of this was or the early data was presented in JCO. So the idea is to take actually tumor cells in recurrent metastatic setting culture and expand it look for the T cell populations that actually go after the HPV exposed cells, essentially lymphodeplete the patient through essentially giving like bone marrow, like cytotoxic chemotherapy re infusing it and it it with, with IL two. And um ultimately, um the patients uh potentially uh will now have T cells that will target the HPV infected uh tumors uh that they have potentially throughout their body. Ok. So, til in combination with immune checkpoint inhibitor in patients that really have no other treatments available. There was actually um half of patients had a response rate. So this is pretty impressive. I mean, we don't expect to see this kind of data. This was presented at TSITSI a couple of years ago. There's more data coming out in the coming meetings. Um This is this is this is this continues to be developed this type of therapy where the patient's own tumor, own pills are used to fight their own tumor. So the ultimate in personalized medicine, this is a very, very um expensive uh potentially very, very individualized type of approach to, to treatment. OK. And uh II think what, what we're gonna be seeing is maybe different ways of approaching this. And if I could just have a little bit of a shameless plug, uh We are, we actually Doctor Hendrix was at uh intramural NC. He is now with us at Rutgers. Um He's developing approaches that we could do it without actually having tumor tissue. I mean, we're generally not operating in patients with recurrent metastatic cervix cancer. So we lympho deplete or we take T cells from the blood through various things like um um we, we could actually draw uh either a la lot of blood or we could actually do T cells through some other sorts of lympho depletion. We don't need to take the tumor, we could actually do at cell transfer or a gene transfer. This is a little different than what I was talking to you about with regards to the T cells. And this could all be done as an outpatient and it's not as um shall I say cytotoxic of an induction to basically infuse the engineer T cells in it? I have on this slide. Um If any of you on this side of the pond, um have any patients who are uh potentially want to be part of this trial, we are taking patients. This is an enrolling trial, this is the number to call. But one of the nice things about this um is that uh the patients, you know, are getting their own tills back. The problem is that right now it's HLA restricted and it's HPV 16 restricted. So, you know, we have a very high screen to potential enrollment ratio. So this is why we're looking for patients. Um So as you can see, this is a very highly developed world and I see in the next 10 years, this is gonna be developed even more and I look forward to talking about this with uh many of you. So the future is that we're gonna be seeing a lot more of these targeted constructs for primary or combination uses. So you might get a target with like an immune checkpoint inhibitor. Um or you might see a targeted approach, you know, with G OS data from the actual tumor, you're gonna potentially see a lot more personal T cell therapies that potentially are going to end up being cheaper, more personalized with either engineered T cells or tills. Um um, but you know, obviously there's got some work to do with the HLA a restrictions and the HPV types. But, you know, as this continues to be developed, we're seeing some big home runs with regards to response rate and, and hopefully that will really hold some element of survival. But let's not forget, we still have to focus on our prevention strategies because we, we continue to have to move the needle with this and ounce of prevention is worth a pound of cure. If we could prevent all these, we could do a far better job with all this. And I look forward to hearing what the other speakers have to say and I look forward to answering your questions. Thank you for the opportunity to speak. Thank you. Thank you, Professor Einstein. This was a wonderful talk and this uh was exactly what II had in mind when uh I drafted the, the, the, the, the topics of our webinar and uh particularly the T uh treatment. Uh I see now that uh you are able to extract the T uh T cells from uh from a blood sample. Uh In Washington, you have uh you, you presented the results from your uh research uh extracting T cells from uh a tissue sample uh from uh from the, from, from from the tumor uh itself. Uh So, uh do you have uh do you have uh similar results between the two, the two methods regu uh regarding the, the, the, the, the, the sufficient uh T cell extraction and the expansion. Well, it's a good question. It, you know, it's still a little bit early. I, you know, I think obviously it's a lot better to be able to do it from systemically than to subject the patient to an extra surgery to be able to take a tumor when, you know, they're in a recurrent metastatic setting. And, you know, you and I both know how much, you know, there's plenty of tumor to go after, but it's still a surgery in a patient that, you know, pro probably, um, their life expectancy is in a, a month to live, sort of category as opposed to years to live. And, uh, you know, we don't want to subject them to this, but that being said with, you know, response rates upwards of 50%. That's, I mean, that's a pretty good promise. Um, so if we could make these, any of these types of technologies safer easier, um, and get good, shall I say yields on the T cells? I think that would be good. I, you know, I think, you know, I think that's the million dollar question though. You know exactly what you're saying? Like, can we get good expansion of the T cells or high expansion it's good enough to actually get some sort of response rate. And I think, I think time will tell. Um and, and I eagerly look forward to seeing more data coming down uh at either sit conferences or as o or some of the European conferences because this is, this seems to be the bell of the ball at all these conferences. You know, all these new engineered T cell types of therapies for HPV associated cancers. Thank you. Thank you. And do you visualize this uh treatment uh only for recurrent or metastatic cervical cancer or maybe even uh for uh advanced stage uh first uh cervical cancer uh at first diagnosis. Well, I think, I think we, we all know the s we, we always, we always have to look at the, in the recurrent metastatic phase and we get those responses, we get it working and then we sort of, shall I say, move it up the cycle, you know, move it into the maybe the first recurrence phase, you know, and maybe we'll see even more responses. So I think uh we have to take the typical regulatory paths. This is not um this is, this is pretty, some of the cytoreductive therapies that we use are like bone marrow, like cytoreductive chemotherapies. And even though these patients are generally healthy other than their pretty bad cancer, um uh some of these therapies, you know, can be pretty toxic and they've been heavily pretreated with chemotherapy So this is not something to be taken lightly, the cytoreductive tumors and, and, and IL two use and some of the interleukins that we use. Uh, it's not something that, uh, I think even g on oncologists or medical oncologists routinely do. We, we work with our cellular therapy folks that are used to dealing with this because the BP changes from the L2 is something that, um, unless someone has experience with this, it, it, it can actually be um very troubling to manage it. So I think we have to really perfect the uh shall I say the peritreatment management of this before we really start moving it up to? Uh shall I say more um um highly uh survivable uh levels? OK. And uh we, we have uh thank you. Thank you for your answer. And we have uh questions accumulating. Uh The first one is uh from uh professor to like it is my mentor in gynecological oncology. Uh So he asked uh are there differences between primary and metastatic pattern of the tumor in relation to the T cells? Kind of a similar question to what uh I answered? I asked him before. So, uh do you have a comment on that? So, primary tumor? OK. Yeah, that's an excellent question. And uh you know, for, for, for these uh trials um there is not. And in fact, um I think the key is to make sure that we're getting uh t cells that are in a very sterile environment, which often means that we have to go after a metastatic tumor. Like we, we, we generally are not gonna be getting tumor cells from like uh for instance, from the cervix, which might be exposed to the vaginal environment, which could this has to be done in a very super sterile environment because these T cells have to be grown out um without the potential of actually having some sort of super infections. And we actually literally do the um uh pro some of the early processing in the sterile environment in the or so like we, we are starting the lab processes in, in the or so. Um That's more important than actually where the T cells are. You might be right? That it might, we might actually get, shall I say more high impact T cells in the primary tumor? But I think the bigger concern is operationally that the T cells, we just can't have them being exposed to the bacteria and the potential candida and the microbiome that's in the vagina. OK. Thank you. And we have one last question. Uh Maybe uh this refers to, to this refers to uh vaccines. Uh I presume, so the questions is uh to therapeutic vaccines. I mean the question is, are there any variation in, is a protein sequence among individuals or between ethnically different people uh which might affect the, the, the general approach for E seven related therapies, you haven't come commented on uh therapeutic vaccines. But if you like, you can uh give us a uh a brief answer to that. Thank you. Yeah. You know, I II I'm less um concerned about people's ethnicities than the ethnicity of their HPV. OK. We know that HPV. And you know, this is the International Papillomavirus Society. We know that there are like European types that generally North American types and European types are pretty similar African types are pretty unique. Um You know, some of the Southeast Asia types are pretty unique and you know, when you actually look at E seven, they're, they're regionally dependent, you know, and it's not based on what we look like, it's based on what the HPV gen genome looks like. So I think it's an interesting question that needs to be, I think looked at generally E seven though E seven itself is pretty, pretty conserved. Um Is my understanding, but I II might punt that to some of the other panelists when they speak if that's OK. Yeah, definitely, definitely. So thank you, Professor Einstein for a wonderful Pro protocol and for your insights in the in the future to the future. And now we move to Professor uh plan to our next speaker. Uh Good morning there in Canada in Quebec, Professor Plant. Uh so uh Professor Plant uh is a, is a professor in gynecological uh oncology in uh Quebec uh Canada uh at the de Quebec uh she was a vice president of uh the I GCS International Gynecological Cancer Society. Uh She has uh many other uh many, many other positions also. Uh now the most important thing uh that uh is that she's leading to very, very interesting and important international clinical trials in cervical cancer. The sha trial and the Contessa trial, uh which uh uh uh which might guide us to the future regarding uh treatment of uh earlystage uh cervical cancer. And she will give us uh also uh the uh the evolution of uh of uh the of surgical treatment of uh cervical uh cervical cancer throughout the decades. So, uh Professor plan the floor is yours and thank you for uh for being here with us. Thank you. I'm just gonna uh open my uh my slides. Mhm. Oops, hold on a second. Something has happened. Hold on, stay with me, don't worry. Yeah, of course, things work out well when we do the rehearsal. That's really ok. I'm coming. Just the screen is taking a lot of room. Ok. So do you see my screen now? Yes, that's perfect. That's perfect. Right. There we go. Thank you. Thank you for the uh thank you for the invitation and for the International PAP Virus Society for inviting me. Um It is indeed um a very interesting times that we are in right now um as we are um obviously seeing the, the, the downsides of the persistent HPV infection which is invasive cervical cancer. But luckily there is uh quite a bit of evolution in the management, at least in the surgical management of early stage cervical cancer. I kinda like to show the slides because in that one picture, you can see the remarkable evolution in the management of earlystage cervical cancer. I mean, think about it. I mean, for well over a century, the whole 19 nineties and even up until the mid twenties, 20 twenties, the only option for the management of early stage of cancer was a ver time radical hysterectomy with complete lymph node dissection. It didn't matter if you had a small cancer or a large tumor. Everybody got a radical hysterectomy. And it's only in the 19 eighties when laparoscopy was introduced, we could do the lymph node dissection that things started to change. And I think that what, what was the real driver, the real driver in the change of concept was the fertility preservation uh situation whereby Daniel dje developed what we call now the radical uh trachelectomy, which literally revolutionized the way we now think about the management. And then from then on, we continued to be even more conservative with the sentinel mapping replacing the complete lymph node dissection. And now in very early uh lesions was selected, we even now propose a simple trachelectomy or a large cone. And in patients with slightly bigger lesions, we can downsize the tumor with u adjuvant chemo. So think about the the the evolution between a radical trachelectomy and a cone uh for a small volume lesion. So we'll go through the evidence to show that. And at the same time or in parallel for patients who don't wish to preserve fertility, the radical trachelectomy might be soon replaced by simple hysterectomy in small volume lesions. And we'll see the evidence again for that. I wanna pay a tribute to two friends of mine, dear friends, Professor Daniel DJ. Professor XH, he was a colleague of mine, we worked together for years and I think that the work of these two pioneers has really, as I said, revolutionized how we now treat cervical cancer. Well, let's begin with a simple hysterectomy. What's the evidence? Well, currently, what most investigators do accept as a definition of low risk disease patients with lesions with a stage one, a two or 1 B1 measuring less than two centimeters, but it's just not the two centimeter bar that's important. There are other considerations including the importance of limited stromal invasion. And I'll repeat this several times over the presentations, lesions that are relatively superficial, less than 10 millimeter depth of invasion. If you did a libra cone or less than 50% stromal invasion on the pelvic MRI. And that's very important criteria. Patients obviously have to be no negative. The issue of LV. Si some colleagues consider that they have to be absent to be low risk disease. Others include the presence of LV. Si, it's debatable right now. So the question that has arised in the last decade or so, what is, what are the chances of perimetrial spread in patients with low risk disease with lesions under two centimeters? And does that justify the morbidity of radical surgery? Uh You've seen the difference between a radical his and a simple his, I mean, it's the removal of the perimetrium and the removal of upper vagina and it's also what is responsible for the morbidity of the radical surgery? I mean, does that make sense that a microscopic one, a two disease or a macroscopic one B disease be treated the same way? Of course, it makes no sense. So we need to adapt the radicality to the size of the lesion. So this is a very important study which sort of collected retrospective data on five series totalis over 1000 patients meeting the low risk criteria I just described and it turned out that the probability or the rate of perimetrial involvement was under 1% 1%. And so the question then was, is that necessary to do radical surgeries? And there were many, many articles and editorials to say, well, maybe it's time to sort of think otherwise and how radical we should be. And that's what led us to develop the now famous shape trial, which aimed to compare radical hysterectomy and nodes to simple hysterectomy and nodes in patients with lower disease. And the concept of it is uh the principle of it is that, that that's with, with infectious screening, there's a higher proportion now of women who present at a younger age and with lower disease. And although the radical hysterectomy is very effective, no questions. Very effective treatment. Women are at risk of suffering what we call survivorship issues, which could be long term side effects, which includes compromised bladder bowel and sexual function. And so the concept of the trial was to demonstrate that simple his is not inferior to radical hysterectomy and associated with better quality of life and sexual health. So that was the concept of the trial. Briefly, the trial schema we selected or uh included patients with a typical HPV related uh cervical cancer, squamous adeno and adenocarcinoma. One, a 21 B1 disease. Again, with limited depth of stromal invasion, just described earlier on and lesions under two centimeters. And then patients were randomized to the control arm which is right hysterectomy and nodes or the experimental arm which is simple hysterectomy and nodes. There were 700 patients entered on trial from 12 countries in 100 and 50 centers. So it's a huge international effort. And the primary outcome was the pelvic recurrence rate at three years. Of course, I'm not gonna go over the whole presentation, but just to show you the most important findings is with a median follow up of 4.5 years. As you can see the curves there is no statistical difference between the two groups. And we were able to demonstrate the noninferiority of simple hysterectomy to radical Hysterectomy in patients with lower disease. Those are other effi efficacy endpoints. Um But in the red bar, you can see that the overall survivor in both groups was over 99%. Um As expected, there were more co complications in the radical hysterectomy groups. There were three times for instance, bladder injury, there were more ureteral injuries. And we saw statistically more uh urinary incontinence and urinary retention in the radical hysterectomy group. Again, we are preparing a manuscript on uh sexual health and quality of life. But just to say that uh all the outcome measures were all in favor of the simple hysterectomy patients compared to the radical hysterectomy. So we were then able to conclude that in early stage, low risk of cancer, simple hysterectomy is not inferior to rad, it has fewer urological complications, better quality of life and sexual health and following adequate and rigorous. And I'll come back to that adequate rigorous preoperative assessment. Simple hysterectomy can now be considered, I think the new standard of care for patients with lower disease supporting the concept of surgical desal in those patients. No, that being said, I wanna urge you clinicians either um if you're a general gynecologist or a gyne oncologist to please stay within the study parameters, you will get tempted to stretch the indications and perhaps offer simple hysterectomy with patients to patients with say deeper uh invasive uh lesions, say 12 or 13 millimeter depth of invasion. For instance, I urge you to stay within the study parameters. If we wanna make sure that patients get good outcome. It's not just the two centimeter lesions, it's all the other elements. It's important to be very rigorous, very meticulous. You have to understand the disease. You have to make sure you perform good quality surgery. That means don't skim on the side of the cervix, perform extrafascial hysterectomy and make sure the whole cervix is removed, et cetera. Um You need to have expert pathology, reviewing the slides because most of these patients have had a leep or a cone as their diagnostic method. You need to review this with your pathologist, look at the margin status, depth of invasion. You need to have a good quality MRI with a good interpretation to assess the size of lesion if there is following the Lieberkuhn and depth of it. And so it requires a whole host of understanding, being again meticulous so that we don't wind up with bad outcomes. That that being said, I think that shape now provides level one evidence. I believe it will likely change practice and probably guidelines. We presented the data at AO and we have submitted to New England Journal of Medicine uh for publication, we're undergoing the second rounds of the revision. Um So we're not accepted yet, but we, we're hopeful it will eventually but it's in the works. Um There is also other trial which you might have heard about, which is a conserved trial which was published in 2021. Uh Again, it's a prospective trial for patient. What lowers disease? It's a phase two single lung study. 100 patients. Um And what they showed is the recurrence rate for the group is 3.5%. And again, a rate of positive node besides 5% exactly the same as shape. So lymph node assessment in early disease remains absolutely essential. And what the conserved trial uh was a much more conservative than the shape trial in terms of the requirements. But following publication of conserve NCCN has issued a new guideline whereby as you could see extrafascial hysterectomy is now considered an option for the management of patients with early stage disease. But patients have to meet all the criteria of the conserved trial. So one e 21 B1 patients have to have a cold knife conization have to be LV si negative. They have to have negative cone margins. Otherwise you have to recon the patients, they exclude adenocarcinoma, grade three lesions under two centimeters and again, with minimal depth of invasion, limited to 10 millimeter and no evidence of metastatic disease. So if you feel fulfill all these criteria, NCCN says it's OK to do an extrafascial simple hysterectomy. So with these two trials being published, I think that we can say uh perhaps indeed radical surgery is not necessary in low risk small volume disease if we do a good patient selection. So if it is true that we can go from a radical to a simple hysterectomy, then the same reasoning you ask yourself or can I go from a radical trachelectomy to a simple hyster, a trachelectomy in patients um who wish to preserve fertility again for patients with small volume disease. If we look again at NCCN 2023 patients who wish to preserve fertility if they have a stage one, a 11, a two or 1 B1 radical. His trachectomy is still considered here as a fertility preserving option for lesions under two centimeters. That is a specimen of a radical trachectomy. It's pretty chunky piece of cervix being removed as well as the perimetrium. This is a simple trachelectomy specimen. Again, it's a good size of cervix removed. It's not a wimpy leep. It's a good chunk of cervix being removed. It's another example here where a cuff vaginal um mucosa was also removed. So that's the sort of specimen that is simple trick like represents uh we've published um data from a series of 50 patients a couple of years ago, two years ago and we had only recur one recurrence and death. But importantly, is the obstetrical outcome was really excellent with over 75% of patients delivered beyond 36 weeks. So that is very interesting in terms of obstetrical outcome that is another series from China from Fudan University. Uh colonization with lymph nodes, 40 patients again, only one recurrence. And they consider that it's an acceptable treatment with good reproductive results. I don't know if you've seen it's a little while back now, but it was a huge series uh review of the literature of over 2800 patients. And what that showed is that prematurity is significantly lower after a simple trachelectomy or cone compared to a radical trachelectomy, which doesn't come as a surprise. But nevertheless, it is clear that radical trachelectomy has more impact on fertility. If you have the opportunity to read this article, I leave the reference at the bottom. It's a very extensive literature review of all types of trachelectomy and all sorts and in different uh uh stage of disease. What you see here is for 1 B1 disease, the different types of trachelectomy listed in the blue um um uh balloons. The recurrence rate is similar between the different options, but the pregnancy rate and the live birth rates are clearly better with a simple trachelectomy or with a vaginal approach. So that is to say that it is important. Again, if you perform a simple trick like Jira co to review the leads that were done prior prior to the procedure to assess the margins, sometimes the leads were done in many cases. Pieces, it's difficult to estimate the size but ask yourself if I could put all the pieces back together from how it was at the beginning. Do I think this patient had a lesion under two centimeters or not? And if you're not sure you'd better err on the side of being a little bit more uh radical than too conservative. Here's an example. A patient with a lesion, you could say with the arrows, it's a very exophytic lesion. Patient has a longer end dose of a co canal, as you can see here. And we know that if we do a tr trachelectomy, we'll be able to clear a margin. In this case, it's quite different. If you look on the lateral or transverse cut, you see that the, the lesion is very deeply invasive almost to the edge. This patient should not be treated conservatively because her risk of perimetrial extension or metastatic disease is higher. So you see these are the sorts of things you need to look at. And so not only do you have to be careful when you select patients, but you have to be prepared to follow these patients for a long time. Usually by a gyne oncologist or an expert colposcopist, they are not always easy to follow because they develop stenosis. I think HPV testing and HPV vaccination is fundamental in these patients. I have seen over the years. Now, many patients that I did a trachectomy, they were HPV negative on follow up and I changed partners and over the years and then they come back a are HPV positive again. And so I really would recommend vaccination in patients following trachectomy. And if they remain HPV positive, I kinda worry and once they're finished with their family, this is those are the cases where I recommend a definitive hysterectomy. This is just to show you the proof of what I'm saying. This is an Italian study. We followed patients for 10 years following a cone for early stage disease And six of the seven recurrences were on the cervix. So that's why you need to follow it very, very carefully. As I said, this was not so bad, but we still have patients who develop by retraction and fibrosis. A lot more cle stenosis. They're not easy to follow appropriately. So need to be followed by experienced colonoscopist. So I don't know if I've said that enough, but careful patient selection is critical, rigorous pathology. Good MRI adequate follow up and please never underestimate shale cancer. It will play tricks on you. All right. And so I'm gonna move on now to the la last section of my talk, which is to address the question of patients who have bigger lesion that is between 2 to 4 centimeters. These cases happen and sometimes the women uh wish to preserve fertility even if they have these sorts of tumors. So what is the best way to manage these women in order to preserve, of course, fertility and ovarian function? But what's the best option to uh have good oncologic and obstetrical outcome. In fact, well, there are two options. Either you perform an upfront radical trachelectomy, which is usually done abdominally or you can offer new regimen chemo to reduce the size of the lesions so that you can perform less radical surgery. That's an abdominal trachectomy example. So you see it's very extensive um and it's uh feasible in larger size lesions, but a more extensive uh types of procedure that's a series again from fon uh of over uh 333 patients. And the recurrence rate following abdominal trom is actually quite good. But the problem is up to two thirds of patients have required adjuvant treatment after the trachelectomy. Why? Because there's at least a 15 to even 20% chances of having positive lymph nodes if you have a lesion between 2 to 4 centimeters. So the grade positive node really goes high and even if the nodes are negative and the margins are negative and everything, a significant proportion of patients will meet what we call the set list criteria uh or intermediate risk factors. And at least in the United States and Europe, these patients are recommended to receive radiation therapy. So the problem with performing upfront trachectomy in bigger lesions is that there's a high rate of chances that these patients will require adjuvant radiation, which will impact not only fertility but it will impact ovarian function and quality of life. So Trachelectomy offers good relative, get good radicality and good oncologic outcome. But again, high rates of treatments, surgical morbidities, higher, some more fertility issues and the obstetrical outcome is reduced following Ron trachectomy. So then the other option is to shrink the tumor or try to reduce the vision with chemotherapy. So that subsequently you can perform a less extensive surgical procedure on the cervix. Now, here's an example of some of my patients and when chemotherapy works, it really works. I mean, it sort of melts away in sometimes a a spectacular way. So this is a series uh uh a review literature comparing upfront trachelectomy, abdominal trachelectomy versus new adjuvant chemo followed by fertility, preservation of fertility preserving surgery. And it showed that if you did new adjuvant chemo and more women got pregnant, more women who conceive were successful, a higher chances of live birth and a relatively equivalent number of recurrences. Uh And if you put that on the table, you could see that successful pregnancy was 70% versus 21 which is significant. So the chances of getting pregnant 21% versus seventh recurrence rate was a little bit higher but not statistically significant. That's a yeah us uh series 92% response rate to chemo and a recurrence rate of 6% which is reasonable or acceptable with good obstetrical outcome. That is another series from South America here, the fertility was preserved in 92%. 43% were able to get pregnant. It's wonderful. But I worry, I worry here because the recurrence rate is, it's on the higher side, it's 13%. And so again, fit mo uh in that same um article I mentioned before, also summarize the literature of uh outcomes of patients with 1 B2 disease. That means lesion between 2 to 4 centimeters. And you compare new adjuvant chemo to um uh radical trachelectomy for instance, Bilaro. And you can see with the red boxes that occurrence rate with new adjuvant chemo is kinda high, but the pregnancy rate is twice as better. So there is indeed a tradeoff. The concern I have with those review of the literature which are putting together data from series that have their own. I would say biases. For instance, in some of the series patients did not have a lymph node evaluations prior to this chemotherapy, some patients with positive nodes were included. Some patients didn't get an MRI just physical examination to determine the size of the lesion or to determine the response to chemo. Um there were different chemo agents that were used different number of cycles. So you know, these studies are not really comparable but they're all put together. And then you do a do uh review of the literature and sometimes it sort of skews the data a little bit and that is why that is why we decided to perform or to put together what we call the Contessa trial. Um And what it is is to evaluate the feasibility of preserving uh fertility in patients with 1 b2 cervical cancer. Here's this chema very briefly. Just to say that is for patients with lesions 2 to 4, they have to have an MRI, they have to have a laparoscopy, have a lymph node evaluation. You wait for the pathology. If the nodes are negative patients wish to preserve fertility, she's eligible to receive three cycles of chemo. And after the chemo gets another MRI to assess the response to treatment. And if the response is either complete or optimal, then these patients undergo simple trachectomy con. So it's a very vigorous, standardized well planned study and um uh more, less heterogeneity than the the other retrospective trials I just talked about. And it's a phase two study, uh Multicenter and internationally, it is ongoing. We now have 14 patients on trial. And the good news is that we have no recurrences so far. So I'm hopeful that when we do things properly rigorously, I think the um outcome is uh favorable in most cases. And so if we go back to my initial slides, um again, I think you can appreciate the incredible evolution in the management of this disease, I think for the best. But again, uh in case, I didn't say that enough, uh careful patient selection and and being vigorous is fundamental to get good, good response, but this is where we're heading. And so I'd like to complete by saying that, you know what, it's OK to be less radical. It's ok to wanting to do a my surgery. It is ok to preserve fertility. But let's remember that we shouldn't jeopardize the survival and outcome of our patients because of that. This is a curable disease and you shouldn't miss um the opportunity to cure them um by not um selecting patients properly or do the right thing. So, thank you very much. Um And I'm available for uh questions if you have. Thank you. Thank you. Thank you, Professor Gland for a wonderful talk. And uh I will also keep that what you said in the mi in the middle of your talk uh to not to uh underestimate cervical cancer. Uh So questions have been uh accumulating uh for you. Uh Let me, let me ask you one by uh Susanna me, um an approach of a sentinel lymph node. Uh the sentinel lymph node should be combined with frozen section or not for cervical cancer. This is a question for you. It is an excellent question. Personally, I do laparoscopy sentinel node. I send them for frozen section if they are negative, uncomfortable with af uh you know, conservative fertility preserving surgery if the node is positive. I mean, that's a stage three C one, right? So I am no longer comfortable with the conservative procedure because I think that these patients are different and you know, they're not a stage three and and I think they require more uh complete treatment in these cases. Yeah. Yeah. But uh what if uh in frozen section uh you cannot do ultratag. Uh Is it possible that? Well, well, we understand we all know we all know that frozen section is not perfect that you can miss particularly if they are mm micro uh micro metastasis. It definitely can be missed. In fact, it misses about a third of the lymph node metastasis on first section. But it's as best as you can get it. The other opportunity. The other option you have is what I just described is you do laparoscopy, you do lymph nodes, you wake up the patient, you wait for the final pathology with ultras staging of the lymph nodes and if they are really negative, then you bring them back and you do just um your colonization or your trachelectomy as outpatient procedure. So that's another way of doing things. OK. Uh We have another question regarding uh it's a, it's a bit, it, it's a bit a big, a big question here. We have a uh anonymous though uh asking uh however, it's about the power analysis of uh of the shape, right? Can you come into that? Is it uh OK? To generalize the results of uh the shape trial uh according to the power analysis that it was done uh for it. I mean, they, they comment that they have, they comment that you might have uh uh you might have uh small numbers. This is, this is the comment of the anonymous FD. Well, I mean, of course, when we design the trial, we had the, you know, statisticians to guide us as to how the design the trial. But with, with um um a difference between the two, we accepted the difference in outcome between the two options. A radical his and simple list of 4% and with 700 patients followed for a minimum of three years. The study has 85% power to claim or to identify noninferiority. So I think from a statistical point of view, I think the study is well constructed. Uh 700 patients is uh is a reasonable, a pretty high number of patients for Trump. And um and I think that um the, the data can be, cannot be, as I said, extrapolated to patients who do not fit the study criteria. And I emphasize that again because I see that all the time. Um um And then, so if you go outside the criteria, then I cannot assure you uh that a simple hysterectomy is safe. But within the study criteria, our study is showing very differ, very minimal difference in outcome between the two groups. Thank you. Thank you. And one last question for you. Um The question comes from uh Bernice Goldman and not uh not. Uh and uh says, what is your opinion on substituting Pelvic MRI with expert ultrasound? Uh for the required pre op workup and fertility preservation planning. I think it's a very good question. It, it is indeed AAA good question. And I, I'm appreciative of the fact that in many countries, the access to pelvic MRI is limited more difficult or too costly and particularly like, um in eastern Europe, for instance, I know that radiologist there in particular have developed uh um quite a bit of expertise with, as you say, specialized ultrasound. And uh there have been studies comparing, you know, their findings to the MRI. But again, the, the, the, the, the bottom line is um as long as it is well done uh with someone that is qualified and you get a good report. Um I guess I'm fine uh in other countries, um radiologist either don't have that expertise with expert ultrasound or just go readily to MRI and that's fine too. OK. And uh OK. And one last question for you uh because we have many, many questions accumulating because we have uh quite a, we have a uh our audience uh today has a clinical background. So uh another question for from professor, so like gynecological oncologist uh here in Greece, my mentor, how do you follow up patients after fertility preserving colono ectomy uh regarding smears colposcopy and the HPV test. Do you have a particular plan for them? Yeah. Well, yeah, I usually follow them like any other sort of uh cervical cancer. Uh follow up that is every 3 to 4 months for the first two years and then every 4 to 6 months for another 2 to 3 years and then a yearly thereafter. And then, as I said, I do of course, a PAP test, uh do a good colposcopy evaluation. Um And as I said, um I strongly encourage patients to get vaccinated and along the way, um I do an HPV testing and if they are HPV negative and I feel a little bit reassured that things are ok. But as I said, um sometimes there's a change of partners and there's a risk of getting reinfected, which is why I think vaccination is important. Um What was I gonna say? Um So I think you need good colposcopy examinations patients. And um if, if they are very easy, some patients after trachelectomy, the, the cervix is sort of easy to follow. I mean, you see, well, the outside of Cervix, you can see, well, the junction, the PAP test is not difficult to do. In some of those cases. I uh send them back to their gynecologist because I feel that they can be followed very easily. But there are other patients where it is literally a struggle every time they come to be able to put in the, the cyle brush or to do cytology because it's very difficult to see those cases. I keep in my clinic and I keep following them, some of them for well over 10 years and some of those cases that are so difficult to follow, sometimes I come to a point of suggesting uh a definitive hysterectomy uh in the sense of make it easier uh for follow up thereafter. Um So it's something that I offer the patients or if they say HPV positive that I worry again and I offer a proposed a definitive hysterectomy once family plans are completed. Ok. Thank you so much. Thank you so much for being here and for your talk. Uh You can uh answer the rest of the questions uh here in the Q and A box if you like. Uh And uh now we move to the last uh but not least uh talk uh of our webinar uh which uh will be presented by Doctor uh Patty Gravitt. Well, uh Doctor Patti Rabbit uh is famous within our HPV community uh and an outstanding member of the International Papilloma Virus Society uh has contributed multiple times to our educational activities and she is a Deputy director uh for the NCI Center for Global Health. Uh She has uh she is a molecular epidemiologist and her research uh in a human papilloma virus uh and cervical cancer. It spans the translation of spectrum from the natural history of gentle infection to the translation of evidence based prevention tools uh for uh low and middle-income countries. Uh mainly now today, she will talk to us about new frontiers in the natural history of cervical uh HPV infection, low risk or high risk and the cancer development uh an area uh which um uh which uh is uh uh for, for which we have uh a great knowledge. But the question is, do we, are there any uh gray zones still in cervical carcinogenesis? And this is what we hope that that doctor Gravitt uh will uh explain for us. So, thank you, thank you so much for being here and the floor is yours? Great, Kimon. Thank you so much and thanks for the invitation to come to speak. Um I'm gonna uh change topics quite a bit and I know we're getting a little near the end of the time. So I may um skip over a few slides that I have on here and really try to focus on some points that I think might be relevant to both some of the questions that were coming up in the, the two talks that we just had as it might relate to some natural history data that could be helpful. Um Really in thinking about um what we do and don't know and how to move forward in the field. Um and in our treatment modalities as well as some of the things I've seen in the chat. Um So I am gonna focus on high-risk HPV infection, which are the 13 to 14 types that the IRC has identified as high risk low risk infections. Um You know, such as those that cause genital warts, et cetera. And then there are many, many HPV types that are completely ubiquitous and benign. I will not focus on um I will be focusing on reactivation today cause I think that is the change in our understanding of the natural history that the data have accumulated over the past decade. Um And maybe has not disseminated as well as we would like it to. Um I have no conflicts to dec declare, although I do work for the um United States government and want to be very clear that the ex opinions and interpretations I'm expressing on my own. So what do we know about the natural history of cervical cancer? I don't wanna belabor this slide because I think probably all of you are very familiar with it. We know that HPV um occurs um is acquired uh through sexual intercourse around the age of sexual debut, which may vary by populations. And then if you look over the course of um uh different ages, you see or, or if you follow women who you observe to acquire HPV, that it usually becomes undetectable or as we have um said, kind of um a, a bit cavalierly clears within two years and 90% of women that it's really the persistence of high risk HPV or persistent detectability that leads to the progression of precancerous lesions. And that those while they could re regress um actually hold a high risk of progression to invasive cancer. And if you just look at the agespecific prevalence of HPV precancers and cancers, as you see on this slide, um Y you can see that, you know the course of the natural history from infection to cancer um probably takes quite a while. I think that what we want to be very aware of is that some things that we have developed from these population level natural history studies have no debate and we're not changing our minds on any of this. And that is that individuals with persistent high risk detection remain at the highest risk for progression to precancer and cancer. Women who test negative for cervical high risk HPV are at a low near term risk of precancer and cancer. And therefore using cervical high risk HPV as a screening modality once every five or 10 years is still a very good predictor of the risk within that time period. Women and men with new sexual partners are in fact at a higher risk for new HPV detection no matter how old they are. But I think that what I want to um what I want to talk about um is some of are some of the unknowns in our interpretation of these data. So one of the questions is, do we know what's happening to produce the origi the residual HPV prevalence in older women? Is that really long term persistent? So that 10% that we've seen in natural history studies that don't clear within two years or just those women just really persistent for a very long time. Um And it's not uh different women that we're seeing and capturing in our cross sectional studies. Does that represent some new infections um over the, you know, during that peak period or the plateau period? Uh could it be reinfection with the same type? It's just being passed back and forth between partners or could it be reactivated, latent infection? And so some of the issues that require clarity is when HPV, quote clears or tests negative, what does that actually infer about infection status? Does it mean that you've actually eradicated the virus or does it just represent that you're immunologically controlling the virus? Um What proportion when you're screening in a population of newly detected HPV S so that the person who tested negative, the last screening is positive now is actually newly acquired infection, reinfection, reactivated latent infection, maybe just a deposition from uh a recent sex act or even autoinoculation, for example, from an anal infection um or other epithelial site and is the risk of precancer or cancer the same given the different pathways to new HPV detection? So one of the things that I'm gonna go through these very quickly, given the time, but I think that, you know, as a largely clinical audience, um it's important to understand that despite our best efforts, um when we're looking at HPV in natural history studies, there are significant challenges to the interpretation of our data. And I'm just gonna skip over to the last slide that I have on this, which is that if you, if you follow women and you, one of the things that I think is really important for us to recognize is that we are not looking for HPV infection in a natural history study or in screening what we're really looking at is HPV detection in the sample that's taken, which is generally going to be a cervical swab sample. It's really important to differentiate those things. Um And the reason is because if we follow women over time and this is just a, a hypothetical example of subjects testing pattern for a single HPV type. So this would be, for example HPV 16 and you're uh detecting something, um or presence or absence of HPV 16 at enrollment and then every four months for a period of two years, what you can see are a variety of commonly detected patterns of HPV detectability. One of the things that I want to make sure that we all understand and recognize is that these data are limited in the following ways. The first is something that epidemiologists cause a left truncation bias. What you detect during the first sample in a sexually active woman, um has to be taken with caution because we really don't know their test history or their infection status before enrollment. What we're observing during the study period. Um also has some uh questions in terms of the inference we can make because we don't know the test status um between the study visits. So for example, if someone tests positive on visit fo uh at the four month visit and negative the eight month visit, you know, did that person remain positive all the way through? Were they coming in and out of detectability? We really don't know what happens on a daily basis. Um And haven't. And for most of the natural history studies that I think that have informed um how we think about HPV natural history. And then finally, we really don't know what happens um at the uh you know, after the last study visit. So when we say someone clears within 24 months, um what's the real risk of HPV over the rest of their lifespan? We haven't really studied that um until much more recently. And what that leaves us with because of these different epidemiological biases is that any pattern in a given woman could represent multiple plausible non mu mutually exclusive interpretations. So for example, in subject one, the positivity at eight months could actually be react, could be a new acquisition, but it also could be a recurrence from something that they had before and just was undetectable on the day that they enrolled. Um It certainly looks like persistent detectability. That would be something that would be of concern clinically because if you're detecting um a positive high-risk type over that many months. That's certainly something that we know increases your risk. And then again, for someone like subject two, they're positive at enrollment. We don't know if that was persistently positive up to enrollment. If this was a single time point to infection. What we can say is that they were consistently detected as negative for HPV 16 over the course of the study that may represent viral eradication or clearance. But it may also reasonably represent immune control. And one of the reasons that we think that may be possible is if you look here, for example, at subject number five, who entered the study without HPV 16 was detectable with 16 at two subsequent follow up visits was negative again, then positive and then negative at the last two follow up visits. Um, what that probably represents is that, um, you can see um, recurrent detection patterns that may or may not be associated with uh sexual activity. And so one of the questions that we had is, can we really be certain, what transitions between positive and negatives apply about a woman's current infection status and her lifetime risk of precancer? So I'm gonna go really quickly through these next slides of what we actually know from studies. And one thing is that recurrent detection in sexually adolescents, um, is common, um, w the, um, study results and, and just, um, uh, for the sake of time, I'm, I'm not gonna go over the details of these studies. The references are here. Um but it just suggests that there is um intermittent detectability if you sample frequently enough. Um And that if you go back and test women who apparently cleared an infection up to six years later, seven years later, you see at least 40% of people who apparently cleared infection um were po were still positive. Um After that long re enrollment time, it suggests that HPV infection duration rather than detectability duration is much longer than we may have thought. This is just another study where we actually sampled every 3 to 4 days for 16 weeks. And each um row in this, you know, the blocks represent a woman. Each row represents a type detected over the different time periods. And you can see that if you sample frequently enough, you can see a lot of persistent detectability, but you also see quite a few types which are just coming in and out of detection. Um One of the things that was really important in this study is that we did daily diaries um looking at their vaginal intercourse during the study follow up and I'll just summarize to say there was really no association between whether or not they were having sex on the day that the the sample was collected or in the near term. And that detectability, which does not imply that this is just something that's being passed back and forth by partners um One of the things that uh a recent reanalysis of a seminal natural history study from um Brazil has just shown is that the cumulative incidence of redetection um is higher than the first de detection and it's not different by age. So if you look at the first detection, you can see that the cumulative incidence is highest. Um you know, up to a 8% over about five or six years in women under 25. And it, and it gets progressively lower kind of plateauing again, around 35 or 45 as we might have always expected. But what you can also see in the study is that the cumulative incidence of type specific redetection. So something that was found to be present, you know, quote clear or became undetectable and then was redetect during follow up, that prevalence was quite high up to, you know, anywhere between 15 and 25%. And that didn't change by age. And so based on these data, we've really modified our HPV natural history schema to um be a little bit more specific in this upper arm where we typically were saying that you have HPV, it becomes detectable or clears and if it's persistent, then it progresses, um persistent detection again, doesn't change our interpretation of the natural history. But what the data are suggesting now is that really what happens when you become detectable versus undetectable is that there is probably a sense of um just immunologic control and that women actually can fluctuate between these states possibly through their lifetime. Um We do believe immune surveillance is the important factor um in maintaining a mostly undetectable state. This is just showing that data support from a, a study. Again, I have the reference here. I don't have time to go into a lot of detail on these data. But um a large proportion of new HPV detection in adult women probably represents loss of immune control of persistent infection. Um And this is really particularly shown in the sexually inactive women, um who were HIV, negative or had increasing degrees of HIV associated immune suppression. And you can see that the even in sexually active or inactive participants, the percent with new HPV detected increased proportionately to their immune status. It may ask, you know, we, we questioned whether clearance is even feasible. Um because we really um have to acknowledge that it's nearly impossible to confirm that there's true viral eradication. This is just a paper by an hammer which looked um very extensively um through tissue typing across um, two different services of women who were negative for HPV and an exfoliated swab. And what we can find in these studies is that there is detectability in the tissue which suggests latency within the basal layers. So what proportion of HPV is newly detected versus redetect? Um I think one of the better studies to look at this is the hitch cohort which um looked at 544 type specific incident detections in 849 part participants. And these were pe uh sexual partners who enrolled. So we knew the status of both the male and the female. And we're looking here at the female data um in the center and the male data um on the right, and it was estimated from the study that 43% of all newly detected HPV was not attributable to recent sexual transmission. And again, this was a partner study with um very strong uh data collection about um current sexual behaviors during the study follow up. Um What was important is that the new detections were associated with higher numbers of lifetime sexual partner. And I think that what this implies is that the more lifetime sex partners you have the higher the risk that you've accumulated HPV. And that at any given time point, you could sample and detect that HPV because it's transiently reactivated. Um The study from the L mcgill, um cohort also looked at whether um when they s looked at the risk of neoplasia um determined by high, this is particularly high risk HPV status, um whether it was a first detection or a retection. And I'm just gonna have you focus on the HS I prevalence. You can say that a positive first detection and a redetection had um no difference in risk um for uh HSIL um suggesting that if you're controlling HPV infection any time that you lose control and become persistent, you may actually um have an increased risk. And I think this comes back to Doctor Plant's comments about recurrence of disease after treatment. So it may be due to a newly acquired infection that happened post surgery. We also can consider based on these data that this could just be a reactivation of a controlled infection, potentially even in the vaginal vault, which then got um basically reinoculated um into the cervix. Uh And so the further implications um of this, these data and this new natural history which say we can't really say that. Um and with any kind of uh certainty that ty type specific HPV VI you know, viruses actually clear what we can say is that they're probably controlled and that that controlled state over the course of a woman's lifespan can really go in and out. And so what does that really mean clinically? Um I think we still have a question of what role then there is for prophylactic vaccination in adults. Given the higher proportion of new detection that we think is attributed to reactivation versus acquisition. Should we understand the risk factors for local or systemic immune suppression to design better interventions for HPV, positive adult women? So, could we think about some of the things that doctor uh Einstein was, was suggesting for the treatment of invasive cancers about potentially immune therapies um to treat persistent HPV infection? Is there a lifetime risk of latent infection? Should we consider age to exit women from screening? Given that we know that immune suppression increases with age? Um And I think that some of the data that are coming out certainly suggest that um just kind of a blanket uh exiting at 65 probably will miss significant number of women who develop um invasive cancer after 65 even with the exit HPV negative test. And how do we ensure accurate communication of HPV detection risk when we're screening um to reduce psycho social anxiety. So I think it's important for clinicians who are doing screening to understand these fluctuations so that you can alleviate things like concerns of infidelity when you're going in and out of positivity. So, with that, I'd really like to thank you for giving me the opportunity to present. Um And if we have time, I'm happy to answer any questions otherwise, feel free to email me um at this address. Thank you. Thank you doctor uh grat. We have time. Uh we can have, we can have a, a small discussion and uh you can answer a few questions via from uh our audience. Uh So, uh Veronica Villagra uh asks if uh the test, the HPV testing that was done in your study was a clinically validated test. I presume it needed it, it, it need not be one but uh you can answer. So, yeah. Um most of these studies used um the HPV linear array test with um it's APCR based test with genotyping, which was actually, it's a research use only test that would, but it was um one that was actually used to, you know, help to validate most of the clinically validated assays that we use. Now, it is more sensitive analytically um because it's not been attenuated to pick up the, you know, higher copy that we believe is associated with disease risk. So again, when we're looking na at natural history from an epidemiologic perspective, we're trying to understand the viral infection dynamics. We're not really trying to necessarily estimate um disease risk. And so in that context, um it's absolutely true and I wanna be clear that low copy um viruses that are fluctuating in and out of detection, they're common and they are not clinically important as long as they stay in that low copy fluctuation state. The point that we're trying to make here is that that state is reversible. So at some point, you could stop controlling infection. And that once you do that and you persist detectably for a period of time, you're right back at the same risk of precancer and cancer, even if you're 55 years old and haven't had sex for 10 years. And if you were 21 years old and you are seeing persistent infection from a recently acquired infection, so we do believe that the data taken together suggest that that's just a slight difference in interpretation of the natural history risk across the lifespan. Yes. Uh Thank you for your, for your answer. Uh Now we have another question from uh Marisa FNA again about HPV test uh asking what HPV test do you recommend? There are a lot, a lot of them in Latin America and uh if there are differences among them. So I presume again that she's talking about clinically validated tests used for uh HPV based uh screening. So something different that uh than the one that uh you're talking about, but you can comment on that. Thank you. Yes. Uh Thanks. I mean, it's a great question. Um II think that it's, it's not for me to recommend which HPV test. Um And II was trying earlier to search on for the paper and mark, you may have it um handy, but there have been groups that have done rigorous evaluation of commercially available HPV tests and have published a list of them which look like they have been clinically validated. So that list is available. I think Mark Arbin is probably the first author on that. Um And then, you know, we do have several FDA approved tests which have clearly been clinically validated. And more recently, the who is increasing the number of their who qualified tests which um ensure clinical validation. II will say that it is important because having worked with some colleagues in Peru, we do know that there are a lot of companies who are marketing tests that are not clinically validated. So I think referring back to these papers which, you know, talk about the clinical validation of different commercially available assays is really, really seriously important to make sure that you're using one that, you know, kind of fits within our schema. And among those, they're, they're usually pretty comparable in terms of their sensitivity and specificity mark. Do you have any? Well, yes, yeah, I want, I just, II agree with Patty, just whatever is clinically validated, you know, from your regulatory standpoint and, and a lot of it has to do with what Doctor Gravitt was saying because just because it's detected doesn't mean it's clinically relevant. You have these low copy levels, but those thresholds are established for screening purposes. So when you're picking up those low low copy levels, you're, you're getting a very high sensitivity, lots of false positives. OK? Which means a lot of referral to a potential colposcopy or whatever the next triage is in your region, that is unnecessary. OK. So if you don't have a clinically validated test, you're gonna get a lot more secondary testing that is unnecessary. Thank you. Thank you. Uh Professor Einstein, one last comment uh about HPV testing that uh I have uh and maybe a question for you both to, to close up uh is um the there is, there is a myth uh among clinicians maybe um uh uh may maybe among clinicians uh mainly uh that the M RN test uh shows an active HPV infection whereas other uh validated DNA tests uh do not do that. Uh W well, a and I mean, uh, I mean, I referred to test that, uh are validated for the same thing. Uh and that is HPV based uh screening. So, can you comment on that? II mean, I think you said it, I mean, it's validated, it's a validated test. It works, it's been validated in very large studies. Um uh you know, what, what, what, what it actually represents or stands for. It doesn't really matter. It's an excellent screening test. It's used pretty routinely and a lot of labs, certainly in the United States, it's FDA approved for cotesting in the United States. It's uh it's approved in many eu regions. So, um you know what we, we could talk about, you know, some of the issues with regards to the crossover with 45. Uh just because it's the nature of the technology. Exactly, I think, II think, yeah, I mean, I think that initially there was uh in the development of, of um Mrna tests specifically, I think there was a, uh you know, kind of a hope that it would be more predictive um and more specific because you would be detected, actu detecting active transcription. Um II just think as Mark was saying, if you look at the actual data, they're not that dissimilar in terms of the specificity from the DNA test. So, you know what that means? I think Mark's right. We don't really know. Um But they still work just as well as an HPV DNA test and not one probably not preferred over the other. Exactly. That, that, that is uh my point also. Uh So with that, uh I would like to thank you uh both as well as uh doctor plan for uh for being here with us and for uh uh for giving those wonderful lectures. Uh So, uh we're moving now, uh I will take you this opportunity to invite uh all of our audience to the next uh I PVC, the next conference of the International Papilloma Virus Society, which will take place in 2024 next November in Edinburgh. Uh So I hope that uh II see you both there. Uh And uh thank you so much. Uh I invite uh all our, all of our attendees to uh to participate in the, in the post webinar survey so that they can claim their certificates uh also. And uh I hope that uh everybody will become a member of I BBS because we have a mixed audience today uh of OC. Uh So, and many thanks to Sophia, also the, the president of uh OC for her collaboration. And uh I hope I see you soon. Thank you all. Have a nice day. Bye-bye.