Sure. Okay. So, our patient is a 77-year-old married lady who is para 4, who has really multiple comorbidities and is massively obese. She initially presented last year in, with postmenopausal bleeding, the first episode. She had her menopause at 54 and bled quite a bit. Unfortunately, she is, she is like 150 kilos and a BMI of 55, has hypertension, diabetes that's not well controlled, has chronic kidney disease, has severe leg edema, elephantiasis, she has sleep apnea, and she is wheelchair bound, very limited mobility. So, on exam, except for the massive obesity and the severe leg edema, the exam was negative. A vaginal ultrasound with difficulty showed a bright endometrium and a 10 centimeter right at neck cell complex mass. We managed to do an endometrial biopsy in the clinic with one of my colleagues and it showed a disorderly proliferative endometrium, but there was no hyperplasia or malignancy. Next. We did an MRI that showed a complex 11 centimeter mass, which on T1 seems to be hyperdense suggestive of hemorrhage. On T2, it was heterogeneous, both with high and low signals, there was no fat content, and the diffusion-weighted images showed area of diffuse restriction with low signal on both the endometrium and the adnexa. The uterus was antiverted and was 12 millimeter. At post-contract, there was heterogeneous enhancement of the lesion in the adnexa. Next. I think this is the MRI, first the endometrium, then the adnexa mass, and the last one is the diffusion-weighted imaging. Next. We also had a CT of the chest, abdomen, and pelvis that was non-revealing. There was nothing except the mass and the uterus, no lymph node, no ascites, nothing in the lungs. Next. Tumor markers showed that they were normal. The FSH was 50, the estradiol was 45. Inhibin B could not be sent because of financial reason, we usually send these out, we don't do them in-house, and they are done outside the country. We did a robotic hysterectomy on her, it was really extremely difficult to manage with a BMI of 55. We did an endometrial biopsy washings and BSO. The washings was positive for atypical cell, and the right adnexa showed an adult-type granulosa cell, and they were positive for carotenin, inhibin, CD56, vimentin, WT1, and CD99 weekly and folic, and they were negative for MOC 31, BIR, EP4, EMA, CAMP 52, 5.2, and C100P. The endometrium showed proliferative with some area of just simple hyperplasia, no cancer. The omentum was negative, so she was staged as 1C because of the positive washings, granulosa cell. Next. We presented her during a tumor board, I mean this is typical, the col-exner bodies, and the typical honeycomb appearance of the granulosa cell in the right adnexa. Next. On follow-up, she was really doing very well. We presented her in the tumor board, and she was not really cleared for adjuvant treatment because of multiple comorbidity, and anyway, she refused. Even if we had accepted some adjuvant treatment, she really did not want to go through adjuvant treatment. She had some post-op bleeding, we had to go back and suture the vaginal vault after the surgery, so it was a bit complicated with her morbidities. Now, I repeated a CT in January, it was negative, and on follow-up, it was really doing well, except that recently her estradiol shot 228 with an FSH of 38. In between, we had an inhibin in October that was less than 10, inhibin B. I could get an inhibin B in October, but the most recent FSH and estradiol in March, which were normal up till that time with low estradiol, as you can see, suddenly shot up to 228. The last CT that I got was in January, I don't have a recent imaging, and I presented her to see what to do with this massively obese lady with severe elephantiasis. I should have, you know, took a picture of her legs, but they were really massive. She cannot walk, she barely can go to the bathroom, okay? And she is extreme age, she's 77, I mean, she's, you know, a bit older than the usual age group. And that's my case. Thank you, thank you, Mike. Please, Susan, can you run the second case? And Razan, you can... Yes, doctor. Okay, so the next case is the case of a 28-year-old patient, newly gravidal. Last menstrual period was on the 10th of December, 2023. The patient has no known family history of gynecological cancers. Next. The patient has a known history of PCOS and was monitored through routine pelvic ultrasound. On her last checkup, a right ovarian cyst was identified. Pelvic MRI was done in October, 2023, and showed the right ovary is enlarged, occupied by a well-circumscribed oval-shaped formation, measuring 4.5 times 4 times 3.5 centimeters. The constellation of findings suggests at first the coma, fibrotic coma, or a highly cellular fibroma of the right ovary with cystic degeneration. Surgical resection was recommended. Next, please. The patient underwent laparoscopic resection in another facility, where the cyst was marcelated, it ruptured, and there was spillage. The histopathological analysis afterwards revealed an adult-type granulosa tumor. A Fuchs L2 mutation was positive. In December, 2023, a chest-abdomen-pelvic CT scan done post-resection showed no abnormality. Next, please. The tumor marker levels in December, 2023, were normal, except for an alpha-fetoprotein that was slightly elevated at the rate of 5.9. Next. The patient then underwent surgery at our facility on the 28th of December, involving a laparoscopic right adnexectomy with an infracollicular mastectomy, a duplasectomy, and laparotectomy. The histopathological study revealed, in the right adnexa, the residual size after the initial surgery was 1.2 centimeters, with millimeter-sized tumor foci on the ovarian surface near adhesion zones and on the tubal serosa. There were also inflammatory and rheumatous changes related to the previous intervention. The findings include the absence of suspicious tumor proliferation in the omentum and retro-ovarian area, and there were millimeter-sized implants corresponding to the diagnosed adult-type clonulosa tumor that were present in the peritoneum, in the douglas. The appendectomy showed no suspicious malignant tumor proliferation. Next, please. Dr. Fadar, are you sure? Yes, some of the histopathological slides. Yes. Can you come on, please? Okay, so on these slides, you can see the ovarian tumor, the proliferation was trabeculated or diffused, and we can see on the ovarian surface that there was a small foci of tumor. So, it was not limited to the ovary, it went on the ovarian surface. Next slide, please. Here, we can see the, no, no, next one, the typical aspect of these cells with the nuclear groove. Next, please. Coffee bean nuclei for the resident. The immunostaining showed positivity for any bean, EMA was negative, synaptophizine and chromogranin also was negative. Next, please. On this slide, you can see sections from the fallopian tube where we can find on the surface two foci of tumor proliferation, and on the right, on the Douglas Cutsack, there was also a foci of this tumor. Next. I think that was all. Yeah, that's it. Yes. Okay. Thank you. So, this patient is undergoing, actually, chemotherapy, BEP chemotherapy. There was a little bit opinions, diverging opinions according to giving chemotherapy, but she decided to have three BEPs chemotherapy. So, she's undertaking chemotherapy now. So, Dr. Saud, the floor is yours. Please, can you comment on these cases about the management, eventual management, and you can start. Would you like me to just go ahead and run through the talk or slides? I think probably incorporate some of the aspects of these cases. Okay. Okay. Perfect. All right. And then I'll be happy to sort of specifically, you know, help discuss these cases as well. At the end, we will do it. So, you start. Thank you. Can you see the slides okay? Yeah. Yes. Awesome. All right. So, I'll go ahead and get started. So, these are my disclosures. So, what I thought I would cover is, you know, briefly, some of the clinical features, and I think that that's already been mentioned. So, I won't dwell on that too much, but then address, you know, the role of surgery, secondary surgery, as well as different therapeutic approaches in terms of chemotherapy, endocrine therapy, and also some of the targeted therapies in terms of, you know, what we know so far. Just to briefly discuss, you know, a timeframe. Prior to 2005, it was kind of a mixture in terms of how the clinical trials were done. You know, all the rare tumors were actually included in phase 2, 3 clinical trials, and as a result, it was hard to understand, you know, what therapies may or may not be effective for given rare tumors. In 2005, the first rare tumor working group was created within the gynecologic oncology group, and then eventually in 2010, this approach was actually endorsed by the GCIG, and then since then, there's been an ongoing working group through the GOG, or what's now called the NRG, that supports or encourages hypothesis-driven research in rare tumors, and looking at, you know, a variety of trials in terms of novel agents, innovative statistical designs, and so on. And then about two years ago, there was a preclinical workshop also held for patients or for rare tumors. So I think that, you know, our knowledge certainly continues to expand around the rare tumors and how incredibly different these entities are, both at molecular and clinical levels as well. So, again, to this audience, I know I don't need to mention at a high level, but regardless, you know, there are three major groups of fovein cancers in the context of epithelial, germ cell, and sex-cord stromal, and each of these has very different lineages. Epithelial, now we're understanding that many of these actually likely don't even start from the ovary. You know, at least 40% of high-grade serous cancers likely start from the fallopian tube, and those that are endometrioid histology, the precursor cell type likely comes from the endometrium in the form of endometriosis, and same thing with clear cell histology as well. Probably one of the few epithelial cancers that truly starts from the ovary is mucinous histological subtype. Then germ cell obviously comes from the germ cell, and sex-cord stromal tumors is what we'll focus on today. Epithelial in terms of incidence is certainly the most dominant and represents about 90% of all ovarian cancers. Even within epithelial cancers, you know, I think we well understand at this point that there is incredible amount of variability. You know, 70% to 74% are high-grade serous as shown in this blue color, and then anywhere from about 1% to 20-some percent in terms of the rare tumors, and the clear cell carcinomas are really quite interesting because it depends a lot on the geographical region in terms of what the prevalence is. In certain parts of Asia, we see, you know, higher incidence of clear cell carcinomas. In the U.S., this is around 5% to 10%. And even within the same histology, it's amazing that, you know, low-grade serous carcinoma, boy, at a molecular level, it's like day and night different from high-grade serous carcinomas. And now I think we even understand that for therapeutic purposes, they really should be treated very, very differently. You know, since today's focus is really predominantly on sex-scored stromal tumors, I thought I'd, you know, briefly address two of the cell types. So the origins of sex-scored stromal tumors, they arise from the sex-scored stromal cells and their precursors and predominantly granulosa cell layer as well as the Sertoli layer. And there are also precursor populations that can give rise to unique stromal tumors. Sertoli, just a couple of slides on Sertoli lytic cell tumors. You know, a lot of these tumors occur in individuals in their teens and 20s. 95% are unilateral, and I think that's important to understand when we consider fertility preservation approaches and so on. Again, a lot of these are solid tumors, kind of yellowish regions. They can have necrotic regions within them. This is a classic microscopic image of the Sertoli tubules that are seen. And then with scattered lytic cells also present within these tumors. These can range from well-intermediate and poorly differentiated cell types, and that can obviously have an impact on whether to consider treatment or not. The red form occurs earlier than other types. In terms of adjuvant therapies, you know, as I mentioned earlier, over 90% are stage Ia tumors, and the stage does seem to correlate with grade. 100% of the well-differentiated tumors tend to be stage Ia, and typically we don't treat those with adjuvant therapy, but only about 50% of poorly differentiated tumors are stage Ia, and the higher grade is associated with more malignant or more aggressive behavior. The recommendation tends to be to treat patients who have stage Ic or greater disease, poorly differentiated tumors of any stage, and then those tumors that have heterologous elements of any stage to consider treating with adjuvant therapy. And they also have some unique features to them. This is really a seminal article that picked up on Dicer-1 mutations being present. In this paper, they predominantly looked at somatic mutations, and the Sertoli-Leidig cell tumors had among the highest rates of Dicer-1 mutations of around 60%. And Dicer-1, it's an important enzyme in processing non-coding RNAs, and now we know that there are germline truncating mutations in families with pluripulmonary blastomas, so you can see familiar tumors and dysplasia syndromes in these individuals, but may have relevance for screening as well as early intervention. Now, I'm going to go ahead and shift to granulosa cell tumors. For adult granulosa cell tumors, again, over 90% are unilateral, and some of the features I think that came out in the cases that were presented is that they can be quite hemorrhagic, and up to 20-some percent of patients can actually present with bloody ascites if the capsule ruptures, then you could certainly see bleeding in that context. What's unique about these tumors is that while the average time to recurrence is about four to six years, you can see recurrences up to 25, 30 years later, so they can indeed occur quite late. Fox cell tumor mutations have now been recognized really as a pathognomonic mutation. I don't think we fully understand what to do about it, but it really is a pathognomonic mutation for adult granulosa cell tumors. Juvenile granulosa cell tumor, again, majority occur in individuals who are their adolescent or teenage years. They can be more aggressive than the adult cell type. While the average age is in the late teens or so, I've certainly seen patients in their 30s or 40s with juvenile granulosa cell tumors, and conversely, young patients who have adult granulosa cell tumors. For this disease, we tend to recommend chemotherapy for any patient with more than stage 1A. The unique feature, I think, to the juvenile granulosa cell tumors is that, while, again, recurrences can occur later, most of the recurrences will tend to occur within the first two years, which is a bit different than those with adult granulosa cell tumors. This is a report from a registry where they looked at about 42-some patients. Most patients had stage 1 disease. The three-year overall survival was 88%, and the three-year EFS was around 69%. At median follow-up of 29 at 25 months, so you see right around a couple of years, 9 of 40 patients had recurrent disease, and 6 of these 9 patients had stage 1 disease at their primary presentation. Unfortunately, 5 of 9 patients with recurrence ended up dying from disease, so it can indeed have a bit more of an aggressive course. Now, a shift years, and this came up, I think, in the cases as well, in the context of surgical considerations for sex-cord stromal tumors. Many of these patients are young, so I think fertility considerations are important, and I'll show a couple of slides around these, but historically, we've done open surgeries with removing at a minimum, the affected ovary. And there are obviously questions that come up with regard to complete versus hysterectomy, removal of both ovaries versus conservative treatment. If childbearing is complete, then obviously we would recommend doing a hysterectomy along with BSO and tumor reductive surgery. And with advanced disease, the goal really should be to achieve a complete gross resection. With minimally invasive surgery, there's limited data. Some have considered this to be a safe route, but I think the issue comes up is, whether or not the tumor can be removed intact or not. In fertility options, they're really similar to those with germ cell tumors. If fertility preservation is important and relevant in this setting, then ideally perform a unilateral salpingofrectomy, not a cystectomy. We know from some studies at least, that those with cystectomy tend to have higher relapse rates. Preserve the remaining contralateral ovary as long as it appears normal. You know, I think we've discussed a couple of times now that the predominant presentation is really with unilateral disease. Staging is still important, and I'll talk a bit more about the kind of staging as well. And the really important aspect is that routine lymphadenectomy is not required for stromal tumors. And I'll show you some of our own data around that. And I'll build on that. So, you know, one of the questions that comes up frequently is what does surgical staging mean along with fertility preservation? And I think that, you know, removing the omentum, doing some additional biopsies is certainly important. But, you know, a few years ago, as I was doing some preclinical work, we recognized that the granulosa cell layer actually doesn't really have lymphatics. It's one of the very few places in the body that doesn't have lymphatics. Another example of that is the uveal melanomas, which do not have lymphatics, and it's not a lymphatically spread disease at all. So because of that, I'd asked Jubilee Brown, who was a faculty member here, she's now in Charlotte, to look at our own experience. So we looked at 111 patients who had complete or partial staging procedures, and 52% have lymph nodes removed. None of these patients had positive lymph nodes. 117 patients out of the 257 eventually developed recurrence. And even in a relapse setting, only about 5% of the patients had nodal metastasis. So we think that while nodal metastasis can occur down the road at a relapse setting, it's likely a secondary event where the lymphatics can be accessed from secondary metastatic sites. From the primary site, we really don't see lymphatic metastases. And a group from Memorial Sloan-Kettering has also presented very similar data. So again, for this part, we think that lymph node mets are really quite rare, and so the lymph node, lymphadenectomy, can be eliminated from routine staging, and we don't do that. We haven't done that in over 10 years at MD Anderson. It can occur in a small percentage of patients, but likely it's a secondary event. Risk of rupture. Now, we know that this can have some impact. So in this study where they looked at about 160 patients with apparent stage one disease, rupture in about 21%, intraoperative rupture in 62%. Overall, the EFS and Fiber OS was still really quite high, but there were higher relapse rates in stage 1C compared to stage 1A disease of 43 versus 24%, and shorter median time to relapse as well. So the tumor rupture may be a significant factor for disease relapse. This is a study of children and teenagers, the TGM95 study that was reported a few years ago, where they mentioned that about 39% had rupture or malignant ascites at presentation. Four patients, 11 received chemo and did not recur, four didn't receive chemo, and unfortunately from this population, all of them ended up developing relapse and died. So from this study, at least they recommended that in the setting of tumor rupture, perhaps adjuvant chemotherapy should be considered. You know, we still think that it's a bit of a gray zone if there's only intraoperative rupture that's completely cleaned out and so on. You know, it's interesting, I've wondered about this. I end up seeing a lot of patients where a tumor was perhaps even intentionally ruptured during minimally invasive surgery. So a few years ago, I'd asked one of our former trainees, Koji Matsuo, who's now at USC, to formally look at this data. And he looked at both CRN and CDB data and showed that since about 2010, in over the five or so subsequent years, with the frequency or the amount of MIS cases obviously continues to go up, but so does the rate of rupture. And in individuals with early stage, apparent early stage disease, MIS and rupture tended to be related to poor overall survival. So I think this is just something we need to keep in mind in the context of, you know, if let's say, if we suspect malignant disease based on visual appearance, and perhaps there are cases we should have a lower threshold for opening and trying to remove the tumor intact rather than having intentional rupture and so on. I'm going to shift gears and talk about different chemotherapy regimens and their evolution and so on. So David Gershenson from here in the mid 1990s really championed the use of bleomycin, etoposide and platinum. Here they looked at about nine patients with advanced sex-cord stromal tumors, pretty high response rates, and only one out of seven though had durable remission. So, you know, relapses and so on can obviously still occur. Subsequently in GOG 115, Howard Holmesley reported in 1999, use of BEP for four cycles where 75 patients received this regimen, 18 were excluded, stage two through four disease. And they used a second look laparotomy, a negative second look laparotomy as the end point of interest. So 37% had negative findings. Again, overall, they considered this as an active regimen. You know, I put this slide here primarily to show that there are a lot of permutations of this regimen. There are, you know, there are different groups that use a three-day regimen for etoposide and bleomycin. There are groups that use platinum on day one only at a higher rate at 75 per meter squared, but there are certainly regimens that use it for days one through five. So there are variabilities in the BEP regimen that are used around the world. Now, the question that we asked a few years ago was, well, you know, if platinum is an important drug, is Taxol and platinum just as good of a drug as a combination as BEP? So again, Jubilee really has led a lot of this work. Again, this is retrospective. So 222 patients with sex-scored stromal tumors, 44 received a taxane, 11 with newly diagnosed disease, 37 with recurrent disease. In those who had no measurable disease, 86% NED at 34 months. Those who had measurable disease, pretty high response rate, 42% response rate with 60% clinical benefit rate, PFS of around 20 months. So it certainly, you know, seemed like a pretty active regimen. Moving, you know, further beyond that, then she also looked at, you know, could, how comparable are these regimens? So looked at 22 patients, 11 with BEP and 11 with taxane-based regimen. There was no difference in PFS or OS at 87 months. In those who had newly diagnosed disease, even in recurrent, those with recurrent disease, there was no difference in response rate, PFS or OS, as long as platinum was included with a taxane. So here at MD Anderson, we've, as of about 12, 13 years or so ago, we've shifted to using taxol and platinum rather than BEP, primarily because BEP is a bit more of a toxic regimen and the outcomes tend to be comparable. This was further looked at in GOG 264 and Jubilee is now writing up the, she has written up the paper, not writing anymore. Again, the doses are written here for taxol-carbo versus the BEP regimen. And this, remember I was telling you there is variability in terms of the doses and the number of days that different groups use it, but it's noted here. And if anybody wants any of these slides, I'd be happy to send these around. So in 264, the primary objective was PFS, secondary was toxicity, OS and response rate. And there are some translational objectives built in and this was a non-inferiority trial with an adaptive design. So Jubilee's presented this data at a meeting, but it hasn't been published quite yet. So in this study, 87% of the patients had granulosa cell tumors, 37% had measurable disease. The estimated hazard ratio was 1.12. The median PFS was 27.7 versus for taxol-carbo versus 19.7 for BEP. It doesn't really, it's not a difference statistically, but again, as I mentioned earlier, the taxol-carbo regimen was tended to be less toxic of a regimen. I didn't include the PFS and the OS curves, but they really overlap completely. Just shifting gears and I'll talk briefly about some of the angiogenic therapies and so on. Remember I mentioned earlier that the granulosa cell layer inherently doesn't really have lymphatics. But I wanted to look at this in a bit more detail, so I helped Jubilee look at some of the samples in our lab, where we looked at 80 tumor samples from 60 some patients from different sites and primary versus relapse and stained these for blood vessels, VEGF levels and a lymphatic marker. VEGF staining was pretty high in many of the granulosa cell tumors. And microvessel density, we looked at it as a binary factor in terms of those with high vessel density versus low density. And what we found is that high vessel density was present in about 40% of the granulosa cell tumors, and it was associated with shorter disease-free interval and a higher risk of relapse, much shorter overall survival, clearly related to VEGF expression and also related to distant metastasis. So based on this, that we felt that it's really a vascular disease, we started to treat some patients with Avastin or Bevcizumab. And initially, again, Jubilee helped us look at our experience here. Eight patients were treated with Bev. One patient had CR, two PRs, two stable disease, and three had progression. So overall response rate was about 38% with a clinical benefit rate of about 63%. So we felt, you know, that's not bad. That's a reasonable response rate. It's better than what we see with epithelial ovarian cancers. And so this was brought into a GOG trial, phase two clinical trial with Bev, given every three weeks at 15 per kilo dose. And in this trial, the partial response rate was about 17%. Stable disease was about 78%. So again, the clinical benefit rate was pretty high, and it met the criteria to declare it as a single active agent. This is the OS and PFS curves. The median PFS was about nine months, so fairly similar to what we saw in our single institution data. Median OS was not reached. Finally, I'll just talk briefly about endocrine therapy. You know, this tumor type, you know, while actual response rates tend to be lower, but I do think there's benefit from endocrine therapies. And over time, a number of these have been used, including aromatase inhibitor, GnRH agonists, even progestins, and on and on. And, you know, you can see that the CR, PR rates are, you know, obviously on the lower side. In one trial, they actually reported about a 30% response rate to aromatase inhibitor. The Paragon trial, the response rate wasn't quite as high, but even in that setting, the clinical benefit rate with the Paragon trial was pretty high. About 76% of the patients had clinical benefit from aromatase inhibitor. By the way, there are now some patients where we've treated with a CDK4-6 inhibitor with aromatase inhibitor, and we're just collecting a case series from patients from some of the institutions, and we're putting that together now. You know, anecdotally, we tend to see stable disease. I don't know that we've seen marked responses with this combination. Here, you know, anecdotally, I have seen some pretty significant prolongation or prolonged use of Luprolide or Lupron. And so I'd asked, so Tyler Hillman is a junior faculty who's focusing on granulosa cell tumor in our group now, and Catherine Foster helped us to look at this data where we looked at the use of Luprolide acetate in different settings as a primary use as well as in relapse setting. And then also compared this to a small cohort of patients who had gotten chemotherapy. So what we find is that in patients with gross disease, the six-month clinical benefit rate was 66%, which is pretty remarkable. And as you look in the swimmer plot, there's some patients who really have fairly prolonged benefit with this regimen. There are a number of patients who still are ongoing on Lupron. And I find this absolutely remarkable because these patients don't have ovaries. The ovaries have been removed and yet they're seeing benefit from this drug. You know, in this drug, just to discuss details around this, for Lupron, different regimens were used. Some use monthly regimen, others have used every three month dosing. I personally tend to favor using monthly dosing predominantly because the mechanism is obviously not through suppressing ovarian function, right? The ovaries are gone. I do think there may be a direct effect of this drug and that's why I tend to use it monthly. Last couple of slides, you know, historically, many of us have operated over and over and over on these patients at relapse settings. When I was a fellow, you know, there were patients we did, you know, five, six, up to seven surgeries on these patients. They get progressively harder. So this was a study where the Jubilee helped to look at, you know, how do these patients do with secondary surgeries? About 75% had optimal surgery, median PFS was about 33 months. And depending on, you know, if it was a single or multifocal site, the PFS benefit varied. And 60 some percent of patients had multiple tumor reductive surgeries. We wanted to look at this a bit more We wanted to look at this a bit more formally. And so again, Jeff and Tyler helped us to look at this in our own data. So where you see PFS-2, what that's referring to is secondary surgery. And then PFS-3 is for a tertiary surgery and PFS-4 is for quaternary surgery. We wanted to see, hey, does it make sense that you keep operating over and over or does the benefit diminish at some point, you know, from these surgeries? Again, in retrospective data, you have to be careful because there are a lot of things that can be confounding factors. But just to show you that to the extent that if you do tumor reductive surgery and you're able to remove disease in that setting, in PFS-2 and PFS-3, there was clear benefit in terms of PFS. For PFS-4, the benefit was less clear and the curves overlapped. But again, I think we have to be really careful because about 40% of the patients for this PFS-4, that the outcome of the surgery in terms of how much residual disease was not clear from the operative notes. So I think we have to be really careful about interpreting the PFS-4 here. The overall survival, certainly there seemed to be benefit from complete gross resection and so on. This is my last slide. So, you know, rare tumors, I think we all can agree now that these are incredibly different from other tumor types. And the more we learn about these, I think the smarter we'll be in terms of picking the treatment regimens and so on. Many of these patients are young, so I do think that fertility sparing surgery is important. But if fertility is not a concern, then obviously complete surgery should be done. For sex-cord stromal tumors, increasingly we've adopted paclitaxel and carboplatin as a first-line therapy, but clearly there are other regimens that are active, including endocrine therapies, BEP-based therapies, and BEP and so on. And then for staging, we've eliminated lymph node sampling as a part of the staging. And with that, I will stop. Thank you for having me, and I'll be happy to discuss the cases or any other aspects. But I think some of the aspects of cases have kind of incorporated into the presentation. Thank you. Thank you, Anil. Thank you for this outstanding presentation. We're delighted. I have two questions. The first, there is this German paper that was published last year about the AGO group showing that there was no benefit for chemotherapy in these adult granulosa cell tumors. That's why we had tergiversation during our discussions. Second, in secondary surgery, after doing secondary surgery and you're given BEP regimen, what would you give as adjuvant treatment after a secondary surgery or tertiary surgery? And a small remark, we had an impression that the juvenile tumor were practically behaving like borderline tumor, not like the aggressive adult. We're seeing that you are showing us data that they are aggressive and each, and when we have a stage more than 1A, they need to have treatment. Please, your comments. Yes, David, great questions. You know, and this is why I mentioned that the role of chemotherapy, especially in stage 1C disease, I don't think is clear cut. You know, it's a gray zone. So to your point, you know, then about after secondary surgery and so on, you know, if a patient has residual disease, we would certainly use chemotherapy in that setting. And typically we tend to give Taxol and Carboplatin for six cycles. But say that, you know, and I just had a patient where I did a tertiary surgery. She just already had chemotherapy twice before. We were able to completely resect disease. She's also been on a rheumatase inhibitor in the past already. Boy, those are harder questions that, you know, is there any role for chemotherapy? I actually, I'm not sure in that setting that it really, that there's much of a role. So I'm gonna actually end up putting her on Lupron at this point for maintenance rather than giving her chemotherapy, David. So I, so very good questions though, I think that you brought up. I think I may have missed one other point or question that you had mentioned. Oh, about juvenile granulosa cell tumors. You know, again, juvenile tumors are, you know, they tend to be very unilateral, vast majority of 95 plus percent of the times. In that setting, it's, you know, we wouldn't treat if it's, you know, if it's convincingly 1A, but anything beyond that, then I do think it's a concerning histology. Then in that setting, yes, absolutely we would treat. I have- And the direct effect on the tumor. It's interesting information. Yeah. Thank you, Anil. I also have some question. We've, you know, when Hypec was at its peak, we did some Hypec on these, you know, granulosa cell because we considered them more or less low grade and they may not respond as well to chemo. And then we were criticized for doing Hypec on them. What's your take on doing Hypec in these patient after an optimal debulking? This is one of the question I have others maybe. You know, it's a, I've seen a couple of case reports around that. So I'm not, you know, based on that, I'm not sure that I, that, you know, we don't really have any large scale data to know how well it may or may not work. I, we, here we don't use Hypec for this histological subtype. And in part, I think that, you know, some of the things I was discussing earlier in terms of the biology of this disease, I do think that this is very much a hematogenously spread disease along with obviously surface spread. In that context, you know, while the Hypec may have benefit, I just think we would need more data to, to really, to consider that in a broader scale. But in the context of rare tumors, where I do think Hypec is a very interesting choice is mucinous ovarian carcinoma. And we actually have a clinical trial now that's active and have some really interesting results from that. There, we would do a very aggressive tumor reductive surgery with, along with Hypec. Thank you. Anil, I have two questions. Excuse me, Mike. I have one more question. Yeah, go ahead. The problem with this carnilosa cell is the very long disease-free interval. And that's the problem, I think, with a lot of the studies is that, you know, some of them, as you said, regard after 10 years, even more than 10 years. And that's my problem with the response rate. I mean, how can you follow up patient, you know, most of the study, you would finish with epithelial in two, three, four, five years, maybe, and most of the patients are going to recur. How can you really tell about the effect with such a very long disease-free interval? It's not easy. It's not. So I think that if you, you know, if you look at the response rate, that's one thing, but even with the response rate, you know, when we look at drugs like aromatase inhibitor, you know, from the Paragon study, we learned that the response is not abrupt. And with endocrine therapies, it typically tends not to be anyway, but it's a slower response, isn't it? And then it continues to for quite some time. So I think that interpreting response, or when we assess it, we certainly have to be careful, but I think in the context of anti-angiogenics and so on, response rate, we can certainly address, but the PFS, you know, can certainly be prolonged in this setting. So you're right. It's not easy in that setting. You really have to look at longer-term follow-up, even for PFS to make conclusions about this disease. There are two questions from a colleague. Yeah. So the first one is, I think, from- David, are these in the chat box? I see them in the chat. Exactly. Any explanation between ER receptors around amount and the response to hormone therapy and any data on family granulosa tumor? And our colleague said, I have a mother diagnosed with granulosa cell tumor and at 45 years old, 20 years ago, and now her daughter at 38 years old has granulosa cell tumor. These are two questions. Yeah, great questions. As far as the first one goes, progesterone receptor is virtually universal in these tumor types. Estrogen receptor, there's more variability. You know, in the Paragon study, they did try to correlate the ERPR with use of the aromatase inhibitor. So I do think that assessing the hormone receptors in the context of aromatase inhibitors is certainly relevant and it makes sense. But in the context of some of the other endocrine therapies, I don't have formal data yet. It is something we're tracking and we will look at, you know, for Lupron and for some of the other endocrine drugs. For the family one, you know, I also have a couple of patients like this and I've talked to our genetic counselors as well about this. So far, nothing has popped up, you know, in terms of a gene that would be seen. If you have these kinds of patients, you know, please let us know. We would love to actually help track these patients. I do think it's worth having them see a genetic counselor and have testing done. But I, so far, at least I'm not aware of anything that's been shown or proven so far, but there are certainly rare families like this where you see other family members. Monia, do you have any question? Or Mike, you have a question, maybe? No, I think it was an excellent. We're almost about time and I really, really enjoyed it. Thank you very much for this exhaustive review. Any question from? No, thank you. Clement, Abir, Bernard, Hussain. No, it was perfect. Maybe one minute. What tumor marker do you use for the follow-up? I mean, some people use FSH, estradiol, some use inhibin B, some CA125. What would you use? And any of it useful? Yeah, great question. So right now, I've been ordering basically four markers, which are CA125, inhibin A, inhibin B, and FSH. Among those, anecdotally, CA125 is the least useful. Inhibin B tends to be fairly useful. FSH is a reverse marker because the levels as the tumors relapse, again, right now, all I can say is that it's anecdotal. We are going to formally look at this, but the FSH levels actually start to decline as the estrogen production from the tumor starts to increase. Estrogen itself, we did look at, and it just wasn't a reliable or consistent marker. So estrogen, I don't check anymore, but these are the four that I checked so far. So what would you do with my patient who suddenly rose her estrogen? You know, I would track her, I would really go based on imaging. What's interesting, though, is that in your patient, I noticed that the FSH level is still fairly high. It didn't really change much. Now, if you see the FSH level start to rise, you know, perhaps I would image her at a more frequent or consistent interval, maybe every three months or so, and keep a track on the markers. But unless there's something that starts to emerge, I don't know that I would treat her, especially given the medical issues that she has that you brought up. Yeah, but that's why we didn't give her chemo. Yeah, exactly, yeah. There was a question about, with our pathologists, after our patient, I operated the patient roughly a month after the rupture of her cyst, and we found implants inside of the peritoneum. Is it classic to find this implant, this invasive implant in the peritoneum after one month only? Or it's simply seen? Yeah, it's not classic, but boy, I'll tell you that, you know, in the cases where I've seen where the tumor was like morselated, not just ruptured, but really morselated, yes, I have seen it in a couple of cases. But in that setting, you know, whether the mechanism is that you're literally actually showering tumor cells, you know, in different areas, and then they implant and grow, it's possible. And I wasn't clear from the presentation whether the tumor was morselated or whether it was simple rupture that was cleaned up. Morselated. Yeah, see, in that setting, David, I actually have seen a couple of patients do precisely that, where within four to six weeks, you start to see implants in peritoneal surfaces. I think we are at the end, David. Thank you. Thank you very much.

Dr. Anil Sood

granulosa cell tumor

chemotherapy

surgical resection

endocrine therapy

angiogenic therapies

ER receptors

inhibin B

HYPEC