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Summary

This on-demand teaching session gives a deep understanding of neuroblastoma, a common type of childhood tumor. Relevant to medical professionals, the presentation covers everything from potential causes and protective factors, to the varying symptoms and methods of diagnosis. Fundamental topics such as neuro-oncogenes, the role of tumor suppressor genes, and associated syndromes are also discussed. The presentation evaluates the staging of neuroblastoma, from localized tumors to metastatic disease, and uses a Children's oncology risk grouping to break down low, intermediate, and high-risk diseases. The session also includes a detailed look at the management of the disease, examining chemotherapy, radiation, surgical options, and new modalities like immunotherapies. By the end of the session, attendees will be well-versed in the origins, diagnosis, treatment, and overall outcome of neuroblastoma.

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Description

"Neuroblastoma" by Dr Mzwandile Jula

Learning objectives

  1. Understand the pathophysiology and etiology of neuroblastoma, including genetic associations and risk factors.
  2. Identify the clinical presentation and symptoms of neuroblastoma, including local and systemic features as well as visual manifestations.
  3. Interpret diagnostic techniques for neuroblastoma including histological, radiographic, and laboratory findings.
  4. Apply the staging and risk grouping systems for neuroblastoma, distinguishing between low, intermediate, and high-risk disease.
  5. Analyze the various management techniques for neuroblastoma based on staging and risk classification, including surgical options, chemotherapy, and radiation, with the ability to determine the sequence and type of treatments suitable for different patient conditions.
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The following transcript was generated automatically from the content and has not been checked or corrected manually.

So also um medication exposure to amphetamine, inflammatory, uh diuretic and vaginal um infection treatment. The vaginal creams, uh breastfeeding and folic acid have been found to be protective in this condition. So, the because this is may be sporadic but uh there's a small percentage of um a small percentage of this disease, which is uh familial 1 to 2%. So, um looking at the causes, so you can look at um some of the on oncogenes that are associated with the disease. So, these oncogen, there's um one when they are turned on which is amplification and my c application which are associated with um with, with your high risk um poor prognosis um disease. And you also get the mutation of your tumor suppressor gene when you get the deletion of those disease, which is associated with the fox. Um two B and chromosome one and 11 those that are seen in your um in your familial uh group. So, um associated um syndrome with this disease. So, as you can see it, some, most of these conditions, they are associated also with the nervous um uh which are peripheral uh nervous system. So, disease like disease, the ais of your intestine, the central hypo regulation syndrome and your heart disease, your hos uh syndrome as well, which is mostly as a, as a complication of basically the compression of the tumor that's growing in the neck that will give you this um Horner Syndrome clinical features. So, clinical features are related to the rapid uh local growth of the disease. We look at the clinical features that are related to the metastasis of the disease and those that are related to hormones, p features that are related to local growth. Um So you may be able to appreciate a solid abdominal um mass. The patient may present with the abdominal distension. It could be abdominal um pain. Also, the distension could be also from the metastasis to the liver already. Um or it can be related to the metastasis which it can be to bone. And this uh disease like to go to the, to the bone, uh the liver and as well as the lymph nodes. So in the bone mets, you get um patient presenting with raccoon eyes which um basically the mets, they cause um some in the rest of the sku um um basically um e chemosis uh around the eyes. And then you also get skin lesions which are described as purplish and painless um skin lesion as well related to hormones is the release of the catecholamines, which would result in the loss of weight, hypertension, sweating and flushing as well. So this um is um bluish uh nodules on the skin. So the birds, they look like this, they are painless. They, they feel like they're just under the skin. And here you've got a baby also who's got um Luminal distension. And on the other side, you can see also the, the skin mats that, that are throughout the body and the diagnosis, diagnosis of uh neuroblastoma. It can be made based on histology. It can be made based on um urine where you look for your catecholamine, you can measure GMA and M MA as well. Then we can do your laboratory uh chemistry where you look for LDH, you look for ferritin as well and your neurons specific analysis, even uh things like uh basic full blood count can give you an indication when the patient has had a bone marrow mass. They can come in with an anemia as well that you will be able to pick up from um from your full blood count. Imaging is uh part of the investigations. So you can be able to appreciate a mass on your plain chest X ray or CT scan. Um MRI even an ultrasound, one of the basics um scans that you can do. And there's also an emerg scan which basically looks at um at the mets that um you are unable to pick them up on the CT scan. You can also do a bone marrow uh biopsy. This is the the presentation of the M IB scan which shows areas of high uh uptake the dark, the darkened areas. Those are the areas which show the presence of um metas disease. This is an, an MRI of the back, let's see on your left, um which shows um the tumor, it's a large solid um the tumor that's invading the neck and on the side, you can see um the thoracic um tumor there. OK. And then um so now looking at the staging of, of this disease, so it is stage from stage one to stage four s where basically you have a stage one, stage one here, which is your local tumor, which can be completely excised with um negative lymph nodes of the same size. That is um your stage one and then you have your stage um your stage two A which is also basically, it's a localized um tumor with incomplete um resection, but uh with a negative lymph nodes of, of, of, of, of the same side. And then uh two B is a tuber which is completely excised, but with um positive um with positive uh ipsilateral um lymph nodes and then moving to stage um stage three. So stage three, it's, it's a tumor that is in the midline. You can either have uh you can have three possibilities. In this case, it's an irresectable tumor uh which is crossing the midline. And the other option, you have a local tumor which is completely um excisable but uh with positive lymph nodes of the opposite side or you can have a tumor localized tumor which has a bilateral um positive um lymph nodes. And then you're stage four, it's basically your metastatic um disease. So you have your distant mets on the liver, on the, it could be on the liver, on the bone or on the skin. Then you have a schedule group which is a group which is um four s this one is limited to the infant and they, they present with a localized to which already present with Mets either to the skin, um to the skin, the bone, to the skin and the bone um as well. But um this one to stage four had a good uh has a good prognosis because it can actually re can still um regress if it's not showing any um symptoms that would need a treatment at that time. So, yeah. Ok. So there, there is um it is a new international um Neuroblastoma risk uh staging system which is, it looks at um the local um the well, which looks at locally or and the meta uh process of the disease. So it basically looks at what does it involve um your vital um structures that it also look at um whether it, it has uh your image uh defining risk factors and that's your L1, your L2 is your local regional tumors with the presenting of one or more of the image uh defining risk factors that um is then is for distent uh metastasis disease. This exclude MS which is the one that is we referred to as for S as well, which is limited to the infant with the spread to the skin, liver and the bone marrow. So risk grouping, uh this is a Children on college risk grouping. So you get your uh low risk, intermediate risk and your and your uh at high risk um you know, high risk disease. So, on your low risk disease, this is uh your stage one and stage two A with a favorable um histology. Uh intermediate uh risk is stage two B and stage three with um nic AM application and high risk is um case of um my um amplification and uh stage four diseases. This is a more detailed uh page of um of looking at that disease. And it's basically we, it's what uh we have gone through. But this looks at now, you have your histology, you look at your mindset, you look at the piety of the disease and it gives you your risk um uh stratification here based on all your biological histological and your and your genetic uh features. So, um management of uh the disease, it is based on uh staging, low risk um that can be surgically resected uh without uh additional um adjuvant um chemotherapy intermediate risk. Uh these ones, they can be resected these tumors that can be resected with chemo and then they will need um adjuvant chemo with or without um radiotherapy high risk. Um two months. Do they need chemotherapy? Um to downstage uh the uh uh the, the, the chemo, it could be chemotherapy and radiation even before the operation to downstage the, the disease and then they can be tried for operation or if it's the, if it's non, then they will only receive chemotherapy and, and, and, and, and, and radiation. So, um the mainstay of treatment is um chemotherapy. It is an also an option of uh bone marrow, um trans transplant of radiation. And you have your radiotherapy, your surgical resection and your new um modalities. Now, your immunotherapies. So, um so your surgical um management, you have laparoscopic uh options, uh your open uh surgical uh options. This depends on the site of the tumor and the uh and the size of the tumor as well as the experience of, of, of the surgeon. You also uh surgical timing. It depends on the stage of the disease and also it it it depends on, on the available um scales at the time as well because this can be a very difficult uh tumors to, to operate on, especially around the vessels as they tend to grow around and very close the vessels. So, in conclusion, uh neuroblastomas, they are the the tumors of the neural cell origin. They are very common, adequate biopsy uh is required for diagnosis. There are multi modalities uh for diagnosis, um poor outcome for those that are present at a late stage. Uh neuroblastoma have a favorable um outcome if they are discovered at the infancy and treatment is also based on um stages. And uh so uh all references. OK. Thank you. Let me see if I can go back. Ok. Mhm. Ok. We we have to find a way way. Yeah, to cancel your screen sharing. So uh OK. Try that. Uh OK. I think I can do it from my side. Ok. Ok. OK. Um That was a good basic talk. Um I'll invite you show that to first comment and, and give her advice, opinion and then one after the other, then I'll ask to ask questions or give comments you sure that. Ok. Pro um can you hear me? Yes. Yes. OK. OK. Thanks, Miss. And um yeah, it was quite basic. I've missed the beginning, unfortunately, I was having problems connecting but um you said it was very common. How many have you seen? Not many? Yeah. So where did you see that? It was very common? Um So actually I think the statement I will revise it, I wouldn't say very common. Um So it's a very, it's a common uh childhood tumor. OK. And this develop where all the data is coming from. So um it is actually they said that it's, it ha it's quite, it's more common than what we see because um some of the tumors, they actually regress before they even present or before we even see the symptoms. They did say that in the percentages are quite high on the infants that they did postmortems on who had other uh causes of that and even higher on the infants that have cardiac um that had cardiac anomalies as well. Um So, but with that information, this is when they decided that cause I think uh countries like Japan, they had done something like um surveillance screening and then they discovered that screening basically doesn't change um the mortality and the morbid the morbidity of the disease itself. So they also did away with the, the screening cause they picked up a lot of tumors but most of them regressed it. Yes, for, for the, for that reason. So they regress with time because they mature with time. So yes, they did do screening in Japan in neonates and they found that there was a high uh incidence but they regressed with time and that brings into the forefront. The the my other point was that this is a spectrum of disease, right? So you're getting, you're talking about the neuroblastoma, the one that we, that's the immature one, the one that we are more concerned about, right. Yes. So that's uncommon, right? OK. OK. So I just wanted to clear that up to clear that. Yeah. OK. Yeah. What's the most common solid tumor that you see, sorry, I can't hear you. Now, I said, what's the most common solid tumor that you see? Uh those are nephroblastomas that I see. Yeah. So what you want to do is you want to differentiate between them, right? When you see a patient? So how, how do you differentiate between them? Ok. So you see a child with an abdominal mass and it could be a neuroblastoma. It could be a nephroblastoma. What, what differentiates them for you? Ok. Um Well, the nephro the nephroblastomas don't uh usually processes uh the midline and also the type of the mass that they present with if it's an abdominal mass, um Some uh nephroblastomas, you can uh actually they move with um respiration, inspiration and aspiration. But um neuroblastomas, they don't uh give you that um that, that, that sign also with uh some of the clinical um presentation as uh uh I II, I've mentioned that the neuroblastomas they might even present with already with a metastatic disease. They progress, the progression is quite um faster than that of the nephroblastomas. Ok. So how do they feel like when you feel the child's abdomen? How does it feel? So, I I'm sure I've told you this before, but if I haven't, um the, the, the nephroblastomas are smooth and they, they feel like a watermelon and the neuroblastomas are irregular. So they feel like a sack of potatoes, right? That's one of the first things that you can notice about them but if it's coming from the adrenal, then it's gonna look just like a nephro. Right? Yes. Yeah. So, and yeah, but you're right about the metastases and things then on the X ray, you said you would do an X ray, what can you see on the X ray? So um on, on, on the X ray, if, if, if you have AAA, if you AAA thoracic mass on the chest X ray, you can see maybe a widening of the mid. Sure. Yes. And you can also see you might be able to see also what might look like an epical um sort of like a lung, epical mass in when you have um the the tumor that is from the neck that's going into your thoracic inlet. OK. So you have an, if you have an abdominal mass and you, you do an X ray, what can you see? You can see calcifications in these uh tumors? Yeah, that's what I was looking for, right? So that's, that's gonna differentiate it from as well because you can, you can see calcification. OK. So you, you didn't mention that. So I was just checking with you, you know, it's important, it is important to mention plain abdominal X ray because some of them will probably come with a plain abdominal X ray. Yes. So yeah, but you, you did mention x-ray but you didn't say why because yeah, but you know, you know it, that's fine. Then another presentation I would like you to um cover was uh uh paraplegia. Have you heard of Children? Um presenting with paraplegia with ne uh neuroblastoma? Yes, I did, I did um uh find that they can present with the neurological symptoms which are as they can also present with your bladder um um continent issues as well uh associated with that if they have uh pelvic extension of the disease. Yeah. So they can invade the spinal cord, the spinal column, right? And they can even invade the vertebral um the vertebral bodies and cause compression. So they do, they can present with spinal abnormalities. So it's very important because during surgery, you're gonna have to address that. And do you know how you, you address that because it's causing compression? So how do you decompress? Have you come across this? No, no. So, but um it, well with some of the neurological emerge oncological emergencies um that uh will give you paraplegia or neurological uh sign. I think some of the patients, they will need an urgent um uh radiation. Ok. That, that it is an option. But if surgery isn't, uh if surgery can be done safely, it's quicker and it is an emergency, you know, to decompress the spinal cord and you do a laparotomy for that or laminectomy. So you open the lamina to just decompress and then you remove the, the tumor, so you excise the tumor. So that's a, it's an important presentation to know about because, um, they can confuse you when they come in with sudden paraplegia and you have to do something about it. So it is important. Uh, then what, what is an M IG scan? Ok. It's a nuclear medicine, uh, scan. Yes. So, you know what I've done for, I've, it's, I saw, um, the, the name, I think the name of the, of the, of the uh oo oo, of the agent that they use. It's Benzo, it's uh sorry. OK. Me Ido it's meta iodo Benzylguanidine right now. It's, it's important to know because um it, it resembles the, the molecule of noradrenaline. All right. So that's why it's only, it's, it's, it lights up for, for neuroblastoma. OK? Because it's taken up by those tissues that are making noradrenaline, but it's not excreted. So it's, it's retained and that's why it lights up. Mm OK. OK. So, but it's important to know that because you don't use it for any other tumors. And it is. So you should have wondered why, why, why do we use MG in neuroblastoma? I know. You know, it just, it's just good to know. Yes. All right. OK. And then, and um what else did I wanna tell you? OK. So, as a surgeon, the, the most important staging that you talked about is the image defining risk factors, right? Because that is telling you about encasement of the vessels and vital structures, like you said, so that, that risk grouping is the most important to you as a surgeon for you to make a decision whether you can operate or not. And the neuroblastoma, did you come across what the survival is in a stage four? Sure. That, yes, I did not hear much about the prognosis and the survival. Huh? Sorry, I didn't get that. The last part. Yes. II did not also hear about the prognosis and the survival. The last part. The, the, the, yeah, the, ok. Well, yes. Ok. Then the prognosis. So, um, no, it's, it's ok. That, that's something to, to remember and to cover uh so on the, on the risk, um, on the can I just, no, the, the risk will, will, it's, it's important for that. It's so important for prognostication as well. Why? Because the stage four has an 11% survival, right? So, when they are stage four, we don't normally uh operate on them, but I wouldn't, I wouldn't say never because there are some, you know, tumors that will respond and the, the metastases regress and it is very rare but it can happen and we have operated on one that was a stage four. So I won't say we never operate on them, but it has a very, very low survival generally. Ok. Um Yeah, sure. That, can I ask other consultants to comment now? Yeah, sure. You can, you can comment uh or, or make any advice. Oh, sorry. I just, I missed the last part cause I was, um, having a cough. But, um, as I, yeah, it's, it's quite basic, uh the, the presentation which basically covers the initial part of what he, what he needs to know when it comes to the disease itself. Um, so yo has gone through some of the, the stuff that I wanted to just clarify with him as well when it came to basically the clinical assessment of these kids, because these are the ones that really come in quite sick. Although the because of the late presentation and also because of the aggressiveness of the tumor, and you also mentioned about just the typical X ray that they'll have calcification. When it comes to uh uh diagnosis. You can besides um you need to have a histology, which is where the rosette, uh the where histology comes in where you have your blue round um cells. And that you can also do on just a uh uh a bone marrow biopsy. And also, but you need to have uh positive uh uh catecholamines in the urine cause with those two, then you can diagnose that this is a neuroblastoma without doing anything further. Although you'll still go through the other things of getting your images so that you can state the child and then it has been changed now because at the stage four S we used to say it's the prognosis is good for a child who's less than a year. So it's been upgraded to less than 18 months. So that's the new thing that you just need to add on to the slides. So it's less than 18 months now, not less than 12 months, but then any everything else, I think it's fine. I'm I'm not sure what you talked about in the last 10 minutes because I was on a call. No, but, but ii fully agree with you and Yashoda. Uh this is, this is very basic presentation to start with. But uh there are not many details which uh you and all the other registers need to read, to understand and subsequently be to answer. Uh So uh are you able to comment or just one more thing? Yeah. Sure. Sure. And then um we, we're not uh II think he left out surgical management on purpose because we, we, he didn't cover it. So I don't think we should, I should speak about it. Sure. Sure. OK. Yeah. Um uh Sella. So are you able to talk? That's why I said to him. Can you hear me? P Yes, yes, we can hear you. Yeah, we can hear you. Yeah. Yeah, same. Uh I'll, I'll invest in fiber uh soon. Um My, my, my one comment or it's uh uh it's Matoma is quite challenging. Um I think concept of, but the only thing I wanted to ask Nile, yes, about surveillance that you can question whether we do it or don't do it. And the other question is linked to that, why specifically is it a favorable thing to have nos when you are one year or 18 months? So we your voice quality is not good. Yeah, it sounds like an alien. There is a lot of echo. He has five years. Does he know? Uh No. So I think he's talking about four s Yeah, he's talking about four A but I think you've covered it because he mentioned this. You mentioned about surveillance. I missed part of ses comment. Yeah. No, he was asking you if have you come across surveillance uh which you spoke about with Yashoda when you mentioned the Japan studies and then he also mentioned why is it better to have the tumor quite early when we're speaking about the four S so that you can answer? Why is it better to have neuroblastoma quite early, less than 12 months to less than 18 months as compared to the other older Children? More than three years? Yes. So, so um in younger Children, um it tend uh to regress and it tend to be uh less aggressive. It's more aggressive in Children mostly over the age of um of of, of five. Um ok. Um um Let me, can you hear me? Yes, yes, you we can hear you. So yes, we can hear you. Oh yes. So sorry about the connection here. My thing is, yeah, you know, we are, it's the, it it sts on that uh those uh cells in the. So uh your voice quality is poor. So maybe you can type, type your comment gland when you're looking there, you can. Hello? Sorry, we can't hear you. Um Doctor Kolo and Delgado are with us. So I'm just going to ask uh Doctor Kalou first. Uh I know he could only join a bit late but uh fo uh if you are able to comment, fun. Yes. Yes, I know you could only join bit later. But is there anything you would like, please comment or, or um or say uh about whatever you could attend? Like it's very little that I've attended. I'll just listen to the comments. Thank you. No, no problem. Thank you. And I think Prop Delgado also could join quite late. I'm just going to say hello to him. Um Arturo. Hello. Thank you for joining n now. Um uh y you can make comments or, or ask questions. Sure. Um So prof um the presentation was good. Um I have just want to answer what Sella was trying to. Um Sorry. Can you all hear me? Yes. Yes. Yes, we can hear you going. OK. So the question he was a, he was asked. So my understanding is that in a child who's less than 18 months, the reason why um the response to surgery and chemotherapy is better because the cells are more immature and more closer to fetal origin. So the response to chemotherapy is better. That's what I understand by it. And as they, they progress in their age, the tumor obviously changes its histology and it becomes more aggressive, more difficult to treat chemotherapy wise. Is that what the understanding is? I'll ask uh to come in first and then I'll ask to come in. Yes. All right. So, so yes, the, the, the reason for the, the, the four or the younger kids to respond better is basically that their response to chemotherapy, it is, is better. Um, as compared to the older Children because of the closeness of, as you said, of the, of the cells um to the, to the fetal cells. And also they haven't, um, they're still immature and haven't really differentiated to the more aggressive type of, uh I will change into the more aggressive type uh of the cells. So that's why because they, they respond better to, more to chemo than to surgery because the four A usually they, they, they present, um with, if I can say the more sort of later sort of not late presentation, but the way they present is sort of like they look more aggressive cause they have already got metastatic to the liver. They've got big, big livers, they look quite low. But when you initiate them on uh chemotherapy or neo adjuvant therapy, then they respond and become better as compared to the older chil child who won't respond as well as the other ones. So, um just I have another question. Sorry. Yeah, the comment on your first question. Sure. Sure. Uh Yes. So II missed uh a whole lot of that because it was breaking up for me. I don't know if it was breaking up for everyone else. Uh But I think I got what may I was trying to ask? And I think they could do an answer. But the, the, the other thing to remember is that yes, they do present early on in infancy. And then what happens is that they mature with time. So the ones that don't mature with time present, you know, with late the aggressive disease, so you won't see the ones that have matured. Mm. You understand? So that's why they look like aggressive uh tumors when you see them in older Children and they have a poor prognosis because they usually stage four, they usually aggressive tumors, which we're going to get to stage four anyway. So you see, those are the ones you are seeing in the older Children. The ones that are maturing you, you don't see them. You might actually see, I think we did see take out a ganglion neuroma recently, which is the mature type of this tumor, which is mature type. Yes. Right. So, so the ones biologically and usually they're the ones with the chromosomal abnormalities and um, and make ification, those are the ones that are aggressive. That's why it's important to group and stage them. Yeah, according to histology, according to those um those factors because that will tell you how aggressive this tumor is gonna be. Mm OK. And how your next for biology is very important. Yeah, I maybe I um missed one thing. Um So uh my understanding for diagnosis, you need three things. You need histology, you need um your urine catechol mines and you need um a bone marrow as well. Is that correct? So your histology will tell you about the type of tumor. Um, the, it will also give you a bit of the biology. So the, the N mic application, it will give you all the factors. He mentioned the DN APD, the T RK, the um stromal red stromal poor if it's nodular, not nodular. What type of neuroblastoma is it? And the M I the, the mic um mm I the mic. Um ok. Yeah, you, you can answer and then yes. And then it's your urine cate mine that you also have to collect and you also have to look at your bone marrow as well. Is that correct? Yes. So that's diagnosis and that's staging. So you diagnosed it um with those, uh uh he went through all of those quite well. I think the investigations that you do. So, yeah, tho those are all the things you'd have to do and you'd have to stage it. But because like I said, the staging matters a lot to you, uh, and how you're going to risk, um, you know, weigh the risk of, of surgery and chemotherapy and radiotherapy, et cetera. So this pre op stating is very uh important as well. So the imaging and how far it's already spread is important for you to now make a plan for your management pre op. Does that answer your question there? Yes, thank you. Ok. Um Anybody else want to make a comment, ask a question? Just raise your hand. I might have to unmute your mouth. Mi Mike. Oh Yes. Yeah. Um Just what they were talking about. So uh na for diagnosis for diagnosis, you just need to two things. You need a bone marrow biopsy and you need a positive catecholamine, but you still need the other stuff for staging and planning of uh your treatment. So just for diagnosis, you just need two things, the bone marrow aspirate and the catecholamine in the urine. OK. Yeah. OK. OK. I understand that. Yeah. Yeah. Mm uh Kirsty, there's a question from Kirsty. Uh Jaundice. Can a a answer that question? So OK. So like uh could you read the question? So first she's asking in the ba baby where it resolves, does there remain a nodule or scarring or is it completely gone leg? So can you hear us? I think John delay is probably uh is losing connection. Kirsty to answer your question. It depends at what stage you look at that. So some tumors which may completely differentiate, they may become a smaller nodule, some of them do disappear. So to answer your question is it depends on, at what stage of the tumor you do the imaging or you have gone in and seen the tumor. Does it answer your question? Kirsty, yes. So that's why screening isn't so useful. No, because you don't know at what stage you're catching the mass. No. So it was done in Canada, It was done in Japan. They were thrilled because they diagnosed 100s of neuroblastomas. Um but many of them later on regressed in, in almost in infancy. So it was not found to be useful. Ok. I'm just going to summarize uh I hope John delay can uh can um hear um uh ok. So can you hear us? Leg? Sorry. Um Exactly leg. Yes, ca can you hear us? Yes, I can hear you now. I'm just, I'm just going to summarize now. So delay. Uh it was good presentation as a very basic presentation, but I don't know whether you read African Textbook of Pediatric Surgery. If you didn't read African text Textbook of Pediatric Surgery, you need to read that and a general comment is this is a spectrum of disorders. This tumor arises at different sites. It can arise in the neck, in the chest, in the abdomen, retroperitoneum in the, in the uh adrenal, the pelvis, it can give various symptoms because of pure size with compression. It can uh give symptoms because of hormones and there are some symptoms which are not due to either pressure or hormones, but they are just because of some things. It, it secretes also, it has got very different or varied biological factors and make uh oncogene. Um then T RK ploidy, diploidy. Uh So there are various factors we need to consider to understand this tumor, to understand the spread stage. It plan the treatment plan surgery and also prognosticate. So I think next time in a year or so, um delay, we will expect uh a more sort of advanced presentation from you. Ok. Um I think if everybody, ok, I'm going to then close the meeting. I think it went well and I have recorded most of the meeting. Thank you very much. Uh Everybody including Delgado, Doctor Crystal and I don't know who is Yamla. She's probably from, from Umtata. So, yeah, we will uh thanks for, yeah, we will have a meeting next time. Ok. Thank you. Sure. Thank you. Bye bye. Thank you.