Ovarian Tissue Transplantation: Pediatric Oncofertility 2017

OK, great. So I think on this part I will be talking about ovarian tissue transplantation. It's an area of innovation we're just talking a lot about but still remains to be experimental in nature. Uh, the slides I'll cover a bit about the experience that's out there, some of the procedures that are available, some of the literature, a couple of papers I'll review and some data that's out there, as well as some other considerations. The successful pregnancies for this intervention were initially reported in the time frame about 2004 or 2005, and the significant experience in this realm is really coming from a number of areas in the world, including Belgium, Denmark, Israel, Germany, a number of areas, and this stems, I think, from some of the recommendations that both come here in the US as well as international organizations to encourage the consideration of not only ovarian tissue cryopreservation. But then the step that leads then forward to transplantation. I would say that network development is important in the field of oncofertility regardless, but has been instrumental in moving ahead many of these innovations. For instance, it's moved ahead ovarian tissue cryopreservation as a whole with the Onco Fertility Consortium in the US and then in Europe, you'll hear me mention there are also some other networks that have developed that work together even for centralized cryopreservation of tissue and that sort of thing. Those nationalized programs allowed pooling expertise so that in those centers there is the expert management of the tissue with using the newest protocols and evidence that's available to support it and then implementing the optimal management of the tissue as well at the time of not only banking the tissue but thawing and using the tissue in the future. There are a couple of different procedures that have been described in literature to be successful, and successful is really looking at a number of different indices. You'll see as we look at these studies, there are some definitions that talk about ovarian tissue transplant and its role in providing hormone, a hormonal milieu that's more like what you would find with the ovary functioning normally versus success in becoming pregnant. So there are different roles of the ovary as we know as providers. The ovary can be transplanted on or into a remaining ovary, or you'll see the transplantation can also occur in a pocket of the peritoneum, in the pelvic peritoneum. Most of the time has been described in the area of the ovarian fossa, although, as our surgeons here at the table will tell you that sometimes these descriptions are not as exact about exactly where the tissue is placed in the reports. If we talk about on or into a remaining ovary, there are descriptions of removing atrophic cortex or the outer surface of the ovary, then attaching the thawed strips in a number of different ways, typically involving some modality of excuse me, suturing the cortex to the remaining ovary. Other investigators have described tunneling the tissue into the ovary, which allows bi-directional development of revascularization of the tissue, and so there are some that advocate more for that methodology. More recently, there's been more focus on the peritoneal pocket, probably for a variety of reasons. Some experts think there may be better blood supply that can be established from revascularization. Some say better functionality. Again, surgically, I would say that is a bit easier about developing a peritoneal pocket and placing the tissue there, but it does still allow natural conception with good communication between the actual fallopian tube and the transplanted ovarian tissue. These are some pictures that have been supplied by the group in Brussels um they have these uh images that they have shown from their technique and I'll be showing those um these are from Marie Madeleine Dolmans, and she is in the Catholic University of Louvain in Brussels. I'm showing on this particular image so that you can see that this is on the remaining ovary and that the investigator then would then open the atrophic area on the cortex to allow suturing of the ovarian tissue. I'm showing you here because in this particular picture, and we'll talk a little bit about it, that many of the investigators will use a product such as a cellulose barrier or fiber and glue to close the area when making a peritoneal pocket, which you'll see momentarily. If you're placing ovarian cortex either on the surface of the ovary, you would likely then be doing some suturing of that ovarian cortex onto the ovary. So some of the investigators have thought that this particular intervention requires a little bit more surgical expertise. Some have described using a robotic methodology versus straight laparoscopy to be able to do this particular procedure. And this is showing you an image of suturing that to the surface of the remaining ovary. Down below again you'll see a little glimpse you can see in the peritoneal area of a piece of cellulose barrier that you can see that's been doused with fiber and glue. Which is covering an area in the pelvic peritoneum. So this is to show you the development of a pocket in the pelvic peritoneum, and this is where you see that opening that was created. And in this particular image you'll see those pieces that you see of the ovarian cortex that are being placed in that pocket. And this is just giving a view multiple pieces are placed in each pocket, and that is determined a bit subjectively about how much tissue is placed in those pockets. But then the area is covered then with a cellulose barrier with fiber and glue, and that is the closure of the area at least from this particular group and the images that you see here. So there are a variety of different mechanisms, but some might be more straightforward surgically and thus some might entertain those approaches based on what their resources, skill set and experience may be. I mentioned about those networks because FertileP Protect was founded in 2006 and does have more than 100 centers participating in this particular European network. The storage of tissue occurs in central cryobranks that exist in the countries that you see listed, and this provides a nationwide cryopreservation service, and the goal is to have good quality control over the cryopreservation techniques and the storage of the tissue more long term. Within this group that's the first paper that we'll talk a little bit about that you can see the reference at the bottom of the slide, and this group published some of their experience with ovarian tissue transplantation for them through June of 2015 they had 95 transplantations in 74 women. And you can see on the next bullet, the ages of the patient aren't pediatric, although you can imagine that patients when they're requesting transplantation are at a time that they're likely thinking about their future reproductive capacity and thus would likely be over an age that we might see in this particular institution. We can engage as we go along through the course of the day how that might translate into the services that are provided and where they're provided somewhat piggybacking on what we talked about about resources and access. The reason I include this information, as you'll see on future slides, is there is some relationship to the age that the tissue of the patient that when the tissue is cryopreserved, as well as the age of the patient when the tissue is then transplanted, as far as the potential success of that tissue. So that's the reason that we include that information and might be something important to look at as you look at other publications of data. Dated for this particular population is included for those patients in whom a one year follow up would allow a pregnancy to occur. So that's why I included this 2015 and 2014 date. So just emphasizing that giving enough time for the patient to be able to have a pregnancy occur. In most of the publications that are available, it can take somewhere in the order of 3 to 4 to 6 several months after transplant to see activity of that transplanted ovarian tissue. So that's where many of the publications will use about 1 year of time to look at. They also stratify their population into several groups and you'll see on the next slide I will focus a bit in this group on subgroup 5, not because 5 is my favorite number, but because this is the group where they define them as having what they described as POI or um premature ovarian insufficiency as amenorrhea for 6 months. Many of these publications are contaminated somewhat by the patient populations that they report. So although this may be a bit challenging to see on your computer presently, hopefully you're not looking at your phone, but in this population you see 95 transplantations in 74 patients. But when you look at that, there are several that have had repeat transplantations and there are others that continue to have a functioning ovary in place and so it is hard for us sometimes to separate. Um, how did the pregnancy occur and was it really from the transplanted tissue or not? So my focus for this particular study was looking at subgroup 5 because at least by their definition they didn't have any functional ovarian tissue at the time that the transplant occurred. We may have a dispute about if 6 months of amenorrhea is the true definition of POI, but that's why we're having this fun global cast so that we can all encourage our thinking. I talked about the age groups, but what I wanted to highlight is there are a number of diagnoses, and we say that about 62% had active tissue one year after transplant, which is measured by menses and menstruation in this population, but the pregnancies were 11 out of 40 or 27.5%. And then deliveries were 22.5% so I say that because that is comparable to the reports by other centers and we will highlight that as well as we continue through the slides. I'll quickly go over these because we have a lot of great engagement, but this did also use the slow freeze methodology which is typically been that, uh, method that has been reported in these successful reports. I think that's something that people are exploring about vitrification. We talked about transplantation techniques and in this particular study again for subgroup 5, there is still some contamination, although the majority of the patients had the peritoneal pocket of ovarian fossa and so that is an area where it looks like there may be some opportunity to get some data. Their primary aim was the ovarian activity one year after transplant, but the secondary information or aim that they were looking at are pregnancy and birth rates. So the transplant is still being active one year afterwards in the entire group was about 67%, but then again, looking at that specific group that we defined as POI was still a great number at 62.5%. We look at those secondary outcomes, we look at 21 pregnancies and 17 births in total for the 95 transplantations, but again, I keep going back to the subgroup 5 where I showed you those numbers. The interesting aspect I think about the subgroup 5 is all of the pregnancies were spontaneous, which again I think for me as a provider is more interesting than some of the other ones that may have still done IVF. Again, a little bit hard for you to read, so this just talks a little bit about that relationship to age. And that patients who were a bit younger seemed to fare better and this is that the outcome for the women for the peritoneal pocket. So remember we said there were 30 of those patients who had the peritoneal pocket, and then we look at their active tissue one year after transplant, and that was 68%. 28% became pregnant and 23% delivery rate. I'm sorry, so the considerations that we want to talk about are age at cryopreservation and transplantation. In this particular publication, there was no maximum age, and there were patients all the way up to the age of 44. I know that in other facilities they have recommended an upper limit for the age of transplantation. Some have said that at 35 and 40, others have pushed that back to 42 to 44. I mentioned a bit about the surgical techniques and that has evolved over time. The publication I was just talking about had some admixture of laparotomy within it, using surgical microscopy to be able to put the piece of cortex back onto the ovary, or really laparoscopy is much more mainstream nowadays, and maybe we're thinking that that's more of onto the ovary or into the peritoneal pocket. Again, is suturing better than fiber and glue, less trauma to the ovary? Are we going to have damage of the follicles that's in the ovarian cortex? So I think there's still a lot of questions, and actually the group that published that paper we were just talking about has a prospective randomized controlled trial which started in December of 2016. You can look up the trial actually online. And they're randomizing for the transplantation site for the ovarian tissue, so it'll be interesting that outcome. Why do you put the cellulose, is that sergic? Why do you put that on there? Um, it's actually interseed, but, um, what, what's the purpose? It's to close the pocket in lieu of surturing the pocket closed. You just bring the peritoneum together and put the interseed in the fibrine glue. Why is that? OK? We, we just, I know it's not mesh, but we're so afraid of putting mesh anywhere near because it decreases fertility. So I'd be surprised at putting any foreign interseed has been something that we use for an adhesive barrier, and again, I'm just saying because that's the tissue they used, a cellulose barrier, um, on ovaries and on the fallopian tubes and in that region for many years to decrease adhesions and has not been a concern. Decrease adhesions. So that's really something that's been historically used in the GYN community for many years, particularly in the area of um. Concern about potential future fertility and so um it's an it's a there's so many techniques about how people might try to transplant the ovary and I think this uh randomized trial might be helpful to provide us a little bit of more standardized data about that. I think that the storage and transfer effects are also something that we cannot eliminate. Um, there are different cryoprotectants that different sites use, for instance, some are using DMSO, some are using glucose. There are lots of different cryoprotectants that are utilized. Does that play a role? And then I think it is important for the network development and follow up. I think Doctor Woodruff mentioned that early on that it's very important for us to share information together in progress so that we can really get adequate numbers of patients to report. I think that Doctor Hefkin mentioned that one of the largest publications that we've seen regarding a cohort of patients came from the group in Brussels and so you see the paper that Doctor Hefkin mentioned earlier. I won't touch on every aspect, but I will say that this is some useful data for us to look at and using as we decide and talk to patients and families about what might be options for them moving forward. In this group they typically had an upper age limit of 35 years for transplant and sometimes in these papers it's not 100% clear are you referring to your discussion regarding the cryopreservation or are you referring to a discussion about the actual transplantation so sometimes teasing that out of the paper is a little bit harder. As we mentioned from Doctor McGowan, they go hand in hand, but many times I think in our discussions we're talking more about an insurance policy, and we're not always clear what will be the utilization of that tissue in the future. And so that's where some of that innovation may come into play in the future. Again, slow freezing technique is used in all of these cases as well. They keep an ongoing database, but in this particular study, as Doctor Hefkin mentioned, they developed a questionnaire to assess some of the opinions and satisfaction of patients who had undergone different parts of the procedure the cryopreservation, transplantation. And they again sent this out again thinking they wanted to have at least a year of time for people, and they put the time frame. They did not want patients who were still being treated, but those who had completed their treatment and allow them enough time to be able to conceive. Doctor Hefkin talked a little bit about the populations that I won't emphasize about their 15% of the people who underwent the cryopreservation technique were pre-pubertal, and the follow-up time, at least at the time of this publication, was about 7.5 years plus or minus 3.5 years when they sent out the questionnaire. I included this slide specifically because as we progress over the afternoon you will see a similar slide from our team about the number of procedures we have performed over the years and it does show that there was a significant increase that you can see in the 2005 to 2011 time frame and things seem to have stabilized out. You can also see that over the same period of time, w site vitrification had some increases as well over that time. Providing again some different options for patients. In their particular study, the questionnaire was different than many of the others, so it was important to mention it. There were 451 patients who were sent the questionnaire, 54 were deceased, and 40 patients did not have an address that they could send that questionnaire to. And so they had 143 responses, or about 32%. Interestingly, patients who were younger. At the time their cryopreservation were performed were more likely to respond than patients who were older at the time of their cryopreservation. So if we look at the characteristics of the people who responded and didn't respond, the um information I shared with you about the ages of the patients of responders versus nonresponders, the age at the time of the questionnaire, the follow up time was fairly similar, and again we said that those patients who were younger at the time of their OTC were more likely to respond. I think that when we get to these consideration slides at the end about who we offer procedures to and their risk status, those patients who often are at very high risk also are patients who would also perhaps be at high risk due to the treatment that they are getting. And they condition themselves it's sort of what I describe as a year on a future slide is high risk high reward, and we just really have to explore and have a complete discussion about risks, benefits, and what their expectations should be. Again, Doctor Hefkin mentioned 9.9% overall of the patients OTC had died from their disease since the procedure, but if we look at the younger patients, those numbers are a little bit higher, and you'll see in the slides and in the paper they just sort of hone out those diagnoses, and those may be a little bit higher risk as we think of things as sarcomas and those patients who may be getting BMT. And we look at return rate, we mentioned that it's a small percentage of patients that have returned and to have transplant from their overall OTC numbers, so 24 of 545 patients returned for transplantation. Of those patients, 21 were transplanted because there were 3 patients who the team declined to do the transplant due to the diagnosis of leukemia previously. You'll see coming up in a couple of slides there are some ways to assess the tissue, but there isn't a way that is 100% for us to ensure that the patient is not re-exposed to their previous malignancy. And 7 of the 21 patients conceived after transplantation. So what I wanted to show with you on that on this slide is that those ranges go from about 25% to about 35% in best case scenario of any of the reported papers that are available. I did want to highlight that BMT is a pretty high risk population, and you'll see that on future slides as well. Doctor Hefkin mentioned about complications from the procedure and it was interesting because we sat next to each other here on the panel and we both had a little different assessment about what the paper is telling us because I think sometimes when you read these papers again sifting out the complication coming from the ovarian tissue cryopreservation. Complications that come from the actual transplant themselves, so it's really important to look at those papers, um, very closely. I think what the emphasis would be is that at least from the ovarian tissue cryopreservation component, the risk is fairly low. Again, it's interesting our terminology is different and bowel irritation to me again is not essentially clear what bowel irritation is and like is that like an ileus is that a bowel obstruction? It's definitely an irritated bowel. Um, the intraabdominal hemorrhage due to ovarian biopsy is what Doctor Hefkin mentioned. It certainly would be classified as a major complication. And again in the paper, 96% of patients did not report any complications. And so again, is this strictly from the patients reported questionnaire or is this also pulling from their ongoing database? Again, those are things that it's important to look at as we review the data. The satisfaction rates were described by the patients, and 96% of the patients were satisfied with the procedure. Of those patients, when you look at them, um, 3 of the 140 were not satisfied. One patient noted they weren't able to understand the procedure fully. One patient found the procedure unnecessary, and I added below that she had a spontaneous conception. And the patient who one of the patients who was not able to transplant due to leukemia risk, clearly was dissatisfied. So what their conclusion is that the transplantation technique was effective in 7 of 21 patients who delivered a baby after autografting, so a 33% delivery rate after their ovarian autotransplantation. 24 out of the 545 returned and really again consistent with other groups. They talk about the range of premature ovarian insufficiency. Really the highest outside of removing the ovaries themselves is really associated with bone marrow transplant. And again, it's it's certainly important to review these risks in patients who may be candidates for BMT. So their conclusions were that there are low complications rates, high satisfaction rate, and they put forth 4 arguments for proceeding with ovarian tissue cryopreservation. I think that Doctor Hefkin touched on these as well, but that there are patients that may require additional gonadotoxic therapy after their first round of treatment that may be associated with such things as recurrent or resistance to the treatment that we are offering. And thus may have sustained some gonadotoxicity before they get to the next point in those, could we, is there a way that we can predict those patients early on? That we need longer follow up for the timing and the onset of premature ovarian insufficiency. I think that the comments we were making on the panel and eye looks we were giving each other is that is 6 months of amenorrhea really POI and could there be some sporadic function of those ovaries and when is the time that we really say is the time to proceed. The current that current patients show a high satisfaction rate and seem to be low procedural related complications. I would say there are several considerations. The safety of transplant is one that we've already mentioned several times on the panel that the risk of re-exposure to whatever malignancy is important, and I had listed the different cited techniques of reviewing and looking at the tissue for any signs of malignancy that can be looking at histology on the frozen specimen either at the time of thaw or the time of freezing. We do not do that at the time of freezing the tissue in our institution. People can use immunochemistry techniques to look for signs of the malignancy in the particular tissue prior to transplant. There are molecular biology techniques, and there are some that are reported in the research arena of using immuno incompetent mice to be able to use those techniques to assess if transplanting the tissue into the mice causes those mice to be able to manifest the malignancy as well. Again, some of those are still on a research protocol, and I'm not sure it would be real time when discussing transplant for the patient. Some of these reports have said consider removing the transplanted tissue immediately after a successful pregnancy to minimize that risk or to discuss with the patient a defined time limit for attempting to use the tissue. And then as you heard earlier on the opening session today, other options include maturation of follicles in vitro without transplanting the tissue or the artificial ovary to deliver those follicles, minimizing that risk. Last point I'll make before we take a break for the afternoon is factors influencing the longevity of the graft because that's an important aspect about when do you time that transplantation, the age of the patient at the time of cryopreservation, i.e., the way I think of it is, are you giving them back a 12-year-old ovary? Are you giving them back a 38-year-old ovary, and there the follicular density may be different, and that may give a different longevity of the graft. The baseline ovarian reserve, which I'm sure we'll get into this afternoon about some of those measurements of ovarian reserve, including looking at the tissue for follicular density versus using things like AMH. We mentioned a bit about the graft site. Does one site, uh, allow a greater longevity of the graft? The degree of ischemia at the time of transplantation can influence the survival and the density of the follicles, and then those freezing and thawing techniques, as well as the patient's medical history. Included this slide that is from the Belgian group and it just shows uh in this publication from 2015 that they found over the first several months that their indicators, one of them, the FSH, fell significantly and was trying to demonstrate sort of the longevity. Or lifeline of the actual graft that was placed so you can see that of these 5 patients that are described, there are patients who have that graft that can function for some of them over several years. The challenge, of course, to all of us is how long will each graft last for each patient. So at that point was what I had prepared to mention about ovarian transplant, I certainly think we can talk a little bit about it, but it might be best to consider a break for now, hold questions for when we do our next session.