Neuroblastoma

Published: 2019-08-24

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Inside this episode

Kai, the Library's AI content creator, listened to this episode and mapped who's speaking, the chapters, key claims, and cases. Every item links to the exact moment in the recording.

AI-enriched

Who's speaking

Ray Hanke — host
Todd Ponsky — host
Dan Von Allman — guest
Erica Newman — guest
Tony Sandler — guest

Chapters

0:00Introduction and Prenatal Diagnosis — Introduction of panel and first case: prenatal consultation for 26-week fetus with left suprarenal mass
2:00Differential Diagnosis and Postnatal Workup — Discussion of differential diagnosis (adrenal hemorrhage, neuroblastoma, sequestration, renal anomaly) and postnatal evaluation strategy with ultrasound and urine catecholamines
6:47MIBG Scanning and Observation Protocol — Role of MIBG scanning, observation versus surgery for localized disease, and surveillance protocols based on GetNucturne study data
11:03Surgical Approach for Localized Disease — Discussion of laparoscopic versus open resection, size criteria for surgery (5 cm threshold), and lack of need for lymph node sampling
14:50Stage MS Disease with Liver Metastases — Management of neonatal neuroblastoma with skin lesions and liver metastases, including respiratory compromise risk and treatment options
18:30Workup of Older Child with Abdominal Mass — Diagnostic approach for 3-year-old with large central abdominal mass, including imaging strategy and role of PET versus MIBG scanning
22:54Tissue Biopsy Techniques — Comparison of open retroperitoneal biopsy, laparoscopic biopsy, and percutaneous core biopsy approaches with discussion of adequacy for biologic studies
30:17Risk Stratification and Staging — Detailed discussion of NMYC amplification, 11q loss of heterozygosity, age criteria, and simplified approach to determining high versus low/intermediate risk
36:54Central Line Placement and Treatment Initiation — Decision-making for broviac versus port placement and timing relative to biopsy for high-risk disease
41:49Timing and Goals of Surgical Resection — Optimal timing after cycle 3-4 of chemotherapy, goal of >90% resection, and debate over impact on survival
47:40Surgical Technique and Avoiding Complications — Principles of starting with normal anatomy, avoiding vascular injury and nephrectomy, and accepting incomplete resection when necessary
55:22Immunotherapy Advances and Closing — Discussion of anti-GD2 monoclonal antibody improving survival and future directions in immunotherapy

Key claims

2:00Adrenal hemorrhage is the most common prenatal suprarenal mass, more common with history of fetal stress — Dan Von Allman
3:27Familial neuroblastoma occurs in about 1% of patients — Tony Sandler
7:24The GetNucturne study showed that many prenatally diagnosed neuroblastomas can be safely observed without surgery — Dan Von Allman
9:09Of 84 prenatally diagnosed cases observed in the GetNucturne study, 16 (about 20%) underwent resection, with 98% event-free survival and 100% overall survival — Tony Sandler
9:58Surveillance for prenatally diagnosed neuroblastoma is intensive in the first year with ultrasound and urine catecholamines at birth, 3 weeks, 6 weeks, 12 weeks, then spacing out — Erica Newman
10:23A case occurred where a prenatally diagnosed adrenal mass resolved but the child presented at age 3 with widely metastatic high-risk neuroblastoma — Dan Von Allman
12:31Five centimeters is used as a size threshold for considering surgical resection of observed neuroblastoma — Tony Sandler
13:20A 50% increase in tumor volume or 50% increase in urine VMA or HVA prompts consideration of surgery — Erica Newman
14:21Lymph node status in neuroblastoma is not as important for changing therapy as it is in Wilms tumor — Dan Von Allman
15:14Stage MS (formerly 4S) neuroblastoma with liver metastases can cause respiratory compromise from mass effect — Erica Newman
15:42Stage MS neuroblastoma can be treated with aggressive observation, chemotherapy, radiation, or emergent decompressive laparotomy if respiratory compromise occurs — Erica Newman
16:32Classic findings of stage MS include high urine catecholamines, blue blebs on skin, liver metastases, and adrenal mass — Tony Sandler
17:32NMYC amplification in stage MS changes classification from MS to M (stage 4) and makes it high-risk — Erica Newman
22:12Ten percent of neuroblastomas are not MIBG-avid and might be detected by PET scan — Dan Von Allman
23:50Open biopsy allows adequate tissue for NMYC amplification, ALK mutation, and ploidy studies — Tony Sandler
26:56Approximately half of children's hospitals use percutaneous biopsy for suspected neuroblastoma — Erica Newman
28:10Percutaneous biopsy is equivalent to open biopsy for diagnosis, high versus low risk determination, and NMYC amplification, but falls short for determining 11q loss of heterozygosity — Erica Newman
29:10Optimizing percutaneous biopsy requires 10-12 cores, higher gauge needle, and pathologist performing frozen section to confirm viable tumor — Erica Newman
30:17Open biopsy patients had higher risk of blood transfusion, higher narcotic use, and more hospital admissions compared to percutaneous biopsy — Erica Newman
31:38NMYC amplification automatically makes neuroblastoma high-risk regardless of other factors — Tony Sandler
33:49Loss of heterozygosity at 11q is the most common segmental chromosomal alteration and can bump NMYC non-amplified patients to high or intermediate risk — Erica Newman
35:25Age cutoff for risk stratification is now 18 months rather than 12 months — Tony Sandler
37:20High-risk neuroblastoma patients require double lumen external central line for bone marrow transplant — Erica Newman
45:31Stem cell harvesting for high-risk neuroblastoma is usually after the second cycle of chemotherapy — Tony Sandler
41:49Optimal timing for surgical resection is after cycle 3-4 of induction chemotherapy — Erica Newman
43:17Tumor volume does not significantly decrease after cycle 2-3 of chemotherapy — Dan Von Allman
43:17After 5-6 cycles of chemotherapy, tumors become more fibrotic and harder to resect — Erica Newman
44:04Goal of surgery is greater than 90% tumor resection based on COG study showing improved event-free survival — Dan Von Allman
45:28European neuroblastoma group study of nearly 1000 cases showed >90% resection improved both event-free and overall survival — Dan Von Allman
45:28About 70% of patients can achieve greater than 90% resection — Dan Von Allman
45:31High-risk neuroblastoma responds well to chemotherapy due to high proliferative rate — Tony Sandler
46:00Recent German/European publication stated that amount of local disease resection does not make a difference in outcome — Tony Sandler
46:40Patients with high-risk neuroblastoma die of systemic metastatic disease, not local disease — Tony Sandler
47:40Good local control is achieved with combination of radiation and aggressive surgery — Dan Von Allman
52:19There is zero correlation between surgeon's operative note description of resection extent and post-operative imaging findings — Dan Von Allman
52:19Surgeons frequently overestimate the amount of tumor resection achieved — Dan Von Allman
53:13Nephrectomy should be avoided in neuroblastoma surgery because it requires reduction of chemotherapy doses — Tony Sandler
53:44Monoclonal antibody against ganglioside GD2 improved two-year survival in high-risk neuroblastoma from 46% to 60% — Tony Sandler
54:40Checkpoint inhibitors have not been successful in neuroblastoma because it is not an immunogenic tumor — Tony Sandler

Cases discussed

0:3226-week fetus with prenatal diagnosis of left suprarenal mass
14:44Neonate with suprarenal mass, skin lesions, and liver metastases (stage MS)
18:30Three-year-old with large central abdominal mass encasing vessels
10:23Child with observed prenatal neuroblastoma who developed metastatic disease at age 3
48:37Eight-month-old with neuroblastoma not responding to chemotherapy

Points of disagreement

44:04Impact of extent of surgical resection on survival in high-risk neuroblastoma
- Dan Von Allman: COG and European studies show >90% resection improves event-free survival and possibly overall survival, goal should be >90% resection
- Tony Sandler: Recent German/European data shows extent of resection does not make a difference, patients die of metastatic disease not local disease, should prioritize safety over aggressive resection

Open questions

What is the optimal surveillance protocol duration for prenatally diagnosed neuroblastomas that resolve?
Should PET scans be routinely obtained for the 10% of neuroblastomas that are MIBG-negative?
Can percutaneous biopsy technique be optimized to reliably obtain 11q LOH status?
Does extent of surgical resection (>90% vs <90%) truly impact overall survival in high-risk neuroblastoma?
How can neuroblastoma be made more immunogenic to improve checkpoint inhibitor efficacy?
What is the long-term (beyond 2 years) survival benefit of anti-GD2 monoclonal antibody therapy?

This episode was analyzed and enriched by Kai, the Library's AI content creator. Every item links to the moment it comes from — click a timestamp to listen in context.

Neuroblastoma Management: From Prenatal Observation to High-Risk Surgery

The episode's teaching points arranged as a structured lesson, building from the basics up to the finer points. Written by Kai from the episode transcript and reviewed before publishing.

For trainees · Teaching arc · AI-written, human-reviewed

Prenatal neuroblastoma can be safely observed

The GetNucturne study fundamentally changed how we approach prenatally diagnosed suprarenal masses. Of 84 prenatally diagnosed cases observed without immediate surgery, only 16 (about 20%) required resection, with 98% event-free survival and 100% overall survival 9:09. Surveillance is intensive in the first year: ultrasound and urine catecholamines at birth, 3 weeks, 6 weeks, 12 weeks, then spacing out 9:58. The protocol works even when MIBG confirms neuroblastoma and catecholamines are elevated — many of these masses will regress without intervention. Families need to understand that while observation is safe based on current data, we lack tissue diagnosis until resection occurs, and occasionally the mass proves to be something else entirely, like pulmonary sequestration [q6]. The cautionary note: one case exists of a prenatally diagnosed mass that resolved, only for the child to present at age three with widely metastatic high-risk disease 10:23. This remains the exception, not the rule.

NMYC amplification is the single most important biologic factor

Risk stratification in neuroblastoma can feel overwhelming — age cutoffs, histology, differentiation, ploidy, 11q status. Simplify it: NMYC amplification automatically makes neuroblastoma high-risk regardless of any other factors 31:38. If NMYC is non-amplified, most tumors are low or intermediate risk. The only other factor that can bump a non-amplified patient to higher risk is loss of heterozygosity at 11q — the most common segmental chromosomal alteration 33:49. This makes adequate tissue sampling critical. The age cutoff has shifted from 12 to 18 months 35:25, but NMYC status carries more weight than age in determining biology.

Percutaneous biopsy can replace open biopsy when optimized

Approximately half of children's hospitals now use percutaneous biopsy for suspected neuroblastoma 26:56. The technique is equivalent to open biopsy for diagnosis, high versus low risk determination, and NMYC amplification, but historically has fallen short for determining 11q loss of heterozygosity 28:10. Optimization requires 10-12 cores with higher gauge needle and — critically — a pathologist performing frozen section to confirm viable tumor rather than necrotic tissue 29:10. When done correctly, percutaneous biopsy results in less blood transfusion, lower narcotic use, and fewer hospital admissions compared to open biopsy 30:17. For stage MS (formerly 4S) disease with classic findings — high urine catecholamines, blue skin blebs, liver metastases, and adrenal mass 16:32 — biopsy may not be required unless NMYC amplification would change the classification from MS to M (stage 4) 17:32.

Surgical timing matters: operate after cycle 3-4, not later

Tumor volume plateaus after cycle 2-3 of chemotherapy 43:17. Optimal timing for resection is after cycle 3-4 of induction 41:49, which avoids conflict with stem cell harvesting (typically after cycle 2) 45:31 and prevents the increased fibrosis that develops after 5-6 cycles, making tumors harder to resect 43:17. High-risk neuroblastoma responds well to chemotherapy due to high proliferative rate 45:31, but waiting beyond four cycles offers no additional volume reduction and complicates the technical aspects of surgery.

Surgical philosophy: aggressive resection without causing disability

The goal is greater than 90% resection based on studies showing improved event-free survival 44:04 and, in the larger European series of nearly 1000 cases, improved overall survival 45:28. About 70% of patients can achieve this threshold 45:28. But the philosophy must balance aggression with safety: "There's no reason to cause disability" [q11]. Nephrectomy should be avoided because it requires reduction of chemotherapy doses 53:13. Vascular injury to achieve complete resection is not justified. "Patients don't die of local disease. They die of systemic disease" [q13]. Good local control comes from the combination of radiation and aggressive surgery 47:40, but what you leave behind is typically fibrous scar tissue along vessels, not viable tumor. The sobering reality: there is zero correlation between surgeon's operative note description of resection extent and post-operative imaging findings 52:19 — surgeons consistently overestimate what they achieved.

The immunotherapy breakthrough

The monoclonal antibody against ganglioside GD2 improved two-year survival in high-risk neuroblastoma from 46% to 60% 53:44 — the first breakthrough with immunotherapy in any childhood cancer. Checkpoint inhibitors have not been successful because neuroblastoma is not an immunogenic tumor 54:40. The future lies in making neuroblastoma immunogenic, but GD2 antibody represents proof that immune-based approaches can move survival curves in pediatric solid tumors.

Takeaways from this story

NMYC amplification alone makes neuroblastoma high-risk regardless of age, stage, or histology — it's the single most important biologic factor
Operate after cycle 3-4 of chemotherapy, not later — tumor volume plateaus by then and fibrosis increases after 5-6 cycles
Surgeons overestimate resection extent: post-op imaging shows zero correlation with operative note descriptions
Percutaneous biopsy equals open biopsy when optimized (10-12 cores, pathologist frozen section) except for 11q LOH determination
Prenatally diagnosed neuroblastoma can be safely observed: 98% event-free survival with only 20% requiring resection in GetNucturne study

Topic overview

A panel discussion on neuroblastoma management featuring pediatric surgeons and oncologists from Cincinnati Children's, CS Mott Children's Hospital, and Children's National Medical Center. The discussion covers prenatal diagnosis and observation protocols, staging workup including the role of MIBG and tissue biopsy techniques, risk stratification centered on NMYC amplification and 11q loss of heterozygosity, timing of surgical resection after induction chemotherapy (typically after cycle 3-4), and the balance between aggressive tumor resection and avoiding vascular injury or nephrectomy. The panel emphasizes that high-risk neuroblastoma patients typically die of metastatic disease rather than local recurrence, and highlights immunotherapy with anti-GD2 monoclonal antibody as a significant recent advance improving two-year survival from 46% to 60%.

Key takeaways

Prenatally diagnosed neuroblastoma can be safely observed; GetNucturne study showed 98% event-free survival with selective resection. (7:24)
NMYC amplification automatically classifies neuroblastoma as high-risk regardless of other factors including stage. (17:32)
Optimal resection timing is after cycle 3-4 of chemotherapy; later cycles cause fibrosis that complicates surgery. (41:49)
High-risk neuroblastoma patients die of metastatic disease, not local recurrence; avoid nephrectomy to preserve chemo dosing. (46:40)
Anti-GD2 monoclonal antibody improved 2-year survival in high-risk neuroblastoma from 46% to 60%. (53:44)

Keywords

neuroblastoma adrenal hemorrhage pulmonary sequestration stage MS neuroblastoma stage 4S neuroblastoma high-risk neuroblastoma intermediate-risk neuroblastoma low-risk neuroblastoma metastatic neuroblastoma NMYC amplified neuroblastoma respiratory compromise abdominal compartment syndrome ultrasound MIBG scan CT scan

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Transcript

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Welcome to the latest episode of Stay Current in Pediatric Surgery, a multimedia production designed to spread the latest knowledge freely. This chapter is created and edited by Todd Ponsky, Alex Kassar, Alex Gibbons, and myself, Ray Hanke. Does your head spin when you think about neuroblastoma, low, intermediate, high risk, and how the management changes for each? Join us as we break down this complex subject with pediatric oncology experts from around the country. Welcome to Stay Current in Pediatric Surgery. This is Todd Ponsky recording live from Cincinnati Children's Hospital, and today we're going to be talking about a topic that I don't know much about, and we get to hear the real experts tell me about what's new in neuroblastoma. Neuroblastoma is a common problem that we all deal with, and it seems like the way to manage this is changing day by day. So we finally got some experts to put some clarity on this. First, I'd like to introduce Dr. Dan Von Allman, who is the Surgeon-in-Chief here at Cincinnati Children's Hospital and is our expert when it comes to neuroblastoma. We also have Dr. Erica Newman, who is at CS Mott Children's Hospital in Michigan, and she has a clinical focus on oncology. And finally, we have Dr. Tony Sandler, who is the Surgeon-in-Chief at Children's National Medical Center, and he also has a focus in oncology and neuroblastoma. Let's dive right in. We're going to, just like we always do, we'll pick some cases that are pretty common and sort of hit on some of the nuances of the disease. Dan, you're in clinic, and you are seeing a prenatal consultation with a woman that has a 26-week fetus that has a prenatal diagnosis of a left-sided suprarenal mass. Otherwise, the ultrasound is normal. What do you do with that? What is your differential diagnosis with a left-sided suprarenal mass? The most common things we think about, first would be an adrenal hemorrhage. That's more common if there's some history of stress to the fetus or something like that, but certainly that's one of the more common things that we think about. And then obviously, if it's solid or cystic mass, you also have to consider the possibility of a neuroblastoma. The other differential diagnoses include things like pulmonary sequestration, which can occur below the diaphragm, as well as potentially a renal anomaly that's been misdiagnosed as a suprarenal mass. So, Erica, what do you tell the family now? So, they come to you, they've got this suprarenal mass, you don't know what it is. How do you counsel them? So, I mostly am quite reassuring at this stage. It's still a bit early. I think you said the patient was a 26-week gestation? Yes. Yeah. So, it's a little early. We still have some time to go before delivery. And I don't really do anything before the delivery. I don't get any more studies. And when the baby is born, then I'll ask the family if it's not born at our hospital. I'll ask the family to please get in touch with me. If it's here, I'll say, let me know when the baby's born. And I'll come up and meet the family and the baby after the baby is born. I think it's important to reassure and help the mom understand that the priority during the pregnancy is the mom. And once the baby is born, then we'll learn more. And the first thing to do is get more information once the baby is born. Tony, would you add anything else to that in your consultation? Yeah, I agree very wholeheartedly with Erica and reassurance. I think often when we're doing these prenatal diagnoses, we get too carried away with the details of the disease. And we get parents all frightened about it. The other thing that I think is important to remember is to ask the family whether there's any familial history of neuroblastoma. I know it's very rare and it only occurs in about 1% of patients. But a familial history of neuroblastoma would help probably guide the diagnosis of a suprarenal mass in this mother. That's a great point. Okay, so you did that, Tony. Now what? Well, obviously, the pregnancy should go along as expected. The mother should have a normal prenatal care. And then once the child is born, we start doing some postnatal studies. And of course, the first one that you would do is examine the child, making sure that this is an otherwise healthy child that's asymptomatic. And if that is the case, then I'd probably start off with an ultrasound of the child's abdomen. The child is born at 38 weeks, you would get the ultrasound. Would you get any CT scan, other MRI or any other axial imaging, Tony? I wouldn't unless the urine catecholamines are high. And unless you're concerned about something unusual. If it's depending on the size of the lesion, if it's probably let's for argument's sake, call it a three centimeter lesion, I would probably just follow it with ultrasounds and urine catecholamines. If the catecholamines are high, then we can start discussing whether perhaps an MIBG would be worthwhile. And that would be my next step if I was going to work this up further. I would agree completely with Tony. I think that the, you know, the ultrasonographers and the radiologists are actually quite good at identifying what looks to them like a adrenal hemorrhage. And you can, while you can't be sure, it certainly helps to get the urine catecholamines to direct the counseling of the parents one way or the other. If the urine catecholamines are high, then you're going to want to counsel the parents about potentially more likely neuroblastoma. But if they're normal and the ultrasonographer is convinced that this is an adrenal hemorrhage, you can really be very reassuring, which doesn't mean you shouldn't follow it, but you can be more definitive with the family about the risk of a tumor. So I'm going to repeat what I hear so far up to this point. Reassurance during the fetal period, all you need to get is the ultrasound. After they're born, you get a follow-up ultrasound postnatally and urine catecholamines. Maybe if those are elevated, you would get an MIBG, but no need for a CAT scan at this point. Any need for a bone marrow biopsy? You know, the only time I would do a bone marrow biopsy is if the MIBG is positive showing bone metastases, then I think it's worthwhile doing a biopsy because at that point, you may want to determine whether this is an NMEC amplified neuroblastoma, which in all reality, in these prenatal diagnoses, extremely, extremely rare. At this point, you have an ultrasound and urine catecholamines that are elevated. Tell me about the MIBG scan. What are you looking for on the MIBG scan, Erica? Yeah. I'm mostly looking to characterize the primary lesion and then also to understand if there are any other areas of disease. What are the more common areas for metastases? So in a neonate or in that perinatal phase, the most common areas would be liver, bone, skin, and lymph nodes. All right. So Dan, you have an MIBG that lights up only at the suprarenal mass. Sure. Do you observe or do you operate? So that is a discussion you have to have with the family because the data from the GetNucturne study would suggest that you can confidently observe these patients, but you have to observe them carefully with ultrasound studies looking for growth, but that many of these patients will actually be spared any surgery if you just watch. Even if you have laboratory studies that confirm neuroblastoma with an MIBG and positive urine catecholamines. On the other hand, families are sometimes unwilling or uncomfortable having a mass in their newborn and they want it out. But I would suggest that probably most, if counseled with the current data, would be willing to simply observe this. Yeah, I agree with that completely. I think that Dr. Nocturne's study has been very reassuring that, particularly in neonates with proper surveillance, that most of the children don't require surgery or chemotherapy. For the first year of life, there's a lot of imaging and monitoring that goes on, but most of these children can be spared surgery. I think one of the other things when you speak to the family, it's really important to reassure them that even if the mass increases in size and you take it out, it is likely to be a very, very low risk tumor. So it's very uncommon to have a bad neuroblastoma. It's possible for sure. In a newborn. In a newborn. If you're watching with serial ultrasound studies and it begins to increase in size and you elect to take it out, it's still likely to be a low risk tumor. Okay. All right. Todd, if I can also take a shot at that. The numbers that I quote the families from that original study is that of the, I think it was 84 patients that they observed, 16 underwent resection for either growth or some other reason. In other words, the families didn't want to wait. And so that's about a 20% resection rate of those ones that underwent observation. And of those patients, I think it was like about 98% had event-free survival and a hundred percent at overall survival. So you're quoting a study that was done with very good outcomes. And I think it's very reassuring for the families to hear that there's data. Great. Agreed. Yeah. So how often do we check ultrasound and urine catacomines and for how long? So it's pretty intensive the first year. They're getting them at birth, then at three weeks, six weeks, 12 weeks. And then as long as things are stable, then they get spaced out from there all the way to one year. And we stop at a year. Then a year, it becomes something more like every six months, after every six months, then a year. I think it's more than up to the oncologist how they would ordinarily do that. But I do think that if they're followed by the oncologist, they tend to be followed long-term, not long-term, but they're followed for probably more than a year. Many of the lesions resolve, so they're gone. And once they're gone, then you get some ultrasounds after that to make sure they're gone. The only caution I would raise is that we had a case of a child who presented with exactly the scenario was observed. The adrenal mass went away. At age three, she presented with widely metastatic, high-risk neuroblastoma. Wow. So that's a cautionary tale, but I still think that the overall outcomes are really, really good, and you should just observe these. Yeah, and that is a very interesting case. You know, that does actually bring caution to our general approach to managing these. The other thing that I'm always a little bit cautious about, I will say, is when I'm counseling the patients and as we're getting through this first year, it's always a little bit unclear to the families because we don't have a biopsy. And really what we're going by is how the lesion looks on the ultrasound and on the CT scan and the catecholamine. But you don't know really what the tissue diagnosis is until we, when and if we take the mass out. And so I'm always cautious in saying, like, all the data we have, it looks like a neuroblastoma. But I will say the last one of these that I had at the 12-month scans, it got bigger. And we took it out and it ended up being a sequestration. And so I was glad that we had kind of prepped the family that this is most likely neuroblastoma, but it could be something else. Because after going a year thinking your baby has a neuroblastoma, and then you end up with pulmonary sequestration that was below the diaphragm. You know, we just, I think it's just important to make sure that we are very reassuring to the family that based on all the information we have, this is what this probably is, but that we have to have some level of uncertainty because we don't biopsy these kids. So the only thing that I would discuss is when does one operate? And I'm not exactly sure what the size is. I've always used the five centimeter size as an indicator for surgery, but I'm not sure. That is sort of my cutoff. If it's obviously getting smaller, I wouldn't operate. If it's getting bigger, I do operate. But I'm not sure what my other colleagues on this esteemed panel, what size they use. I would agree with you, Tony. I think that if the mass, first of all, if it's increasing in size, then that in and of itself is concerning. And there are specific criteria, but once a mass gets to be five centimeters, then I personally would be recommending to the family that we take it out. I agree with that. And then as we're surveying, I use the original criteria of, you know, if it goes, increases in more than 50% volume. And then the other thing we look at are the urine catecholamines and a 50% increase in either the BMA or HVA would prompt us to start thinking more about surgery. That's a great point, Erica. That's, I think it's important that you're not just doing ultrasounds, you're continuing to monitor urine catecholamines. So Dan and I just came up with the same exact question at the same exact time. So Erica, if you do decide to remove it, would you do it laparoscopic or open? Yeah, I think laparoscopic, particularly if it's less than six centimeters, I think it's worth a shot to put a scope in and take a look. I was glad we were able to do that for this baby. I think that sequestration ended up being about three and a half centimeters and it came out very nicely with a laparoscope. The child went home the next day. Do you need to do any lymph node sampling? I don't think lymph nodes give us any more information than we already have in neuroblastoma from the cross-sectional imaging. I agree completely. Unlike Wilms' tumor, the lymph node status of neuroblastoma is not as important in the change of therapy. The biology of the neuroblastoma, which I'm sure we'll discuss later, is more important than lymph node status. Erica, let's say the child has skin lesions and liver mets. Now what? Now things get a little different. This is what we're calling now stage M, the O stage 4S. And I would say I'm still reassuring at this point with the family. The biology of these tumors tends to still be good. These aren't bad neuroblastomas. There is a scenario where things could get bad and that's if the liver is filled and engorged with tumor. What exactly can go wrong when the child has a liver full of tumor? The most common thing that we worry about is the mass. It's the mass effect of the tumor in the liver, which can be really dramatic and causes respiratory compromise. And that's the problem that a newborn would face is increasing ventilatory requirements and inability to ventilate once the tumor gets large in the liver. So how do we treat these children? If they're not in any distress, they're treated with my favorite protocol, which is aggressive observation. That is, you don't necessarily have to do anything other than watch them. But once they begin to get in trouble, then you certainly want to have tissue and make sure that it is in fact MS and not a high-risk tumor. And you can treat them with either chemotherapy or radiation if you get to it early enough. If the child acutely decompensates, then doing a decompressive laparotomy is also described as a potential emergent therapy for kids who have respiratory compromise. So you mentioned if we have tissue. So it is not a requirement to biopsy even the skin lesions in these children. I think that in most cases, and I'd be interested to hear what Erica and Tony say, we want, we would get tissue to confirm the diagnosis and get some biologic information. Yeah, I think if you have the classic findings with high urine, epinephrine or norepinephrine or catecholamine, and you have the blue blebs on the skin with the liver metastases and a adrenal mass, I don't think you really even have to biopsy that kid. However, if you're taking the kid to do something radical like a laparotomy, to place a silo to decompress the abdomen, then I would certainly biopsy the easiest lesion. I'm not sure I would biopsy the liver because once you get bleeding in a newborn liver, it's very hard to control. So I would take another lesion other than the liver unless the liver is the easiest to get to. But yeah, I completely agree with Dan. It's an observation. I haven't in my career had to open an abdomen and place a liver in a bag or anything like that. I agree. I know that our oncologists have often asked us to do a biopsy and they like to get that because if in the rare instance, the mechan is amplified, it changes them in from MS to M. And so for that, we are sometimes faced with, should we be going into the abdomen? If we can avoid, particularly in neonates, going into the abdomen for a biopsy, I think we can decrease the risk of that abdominal compartment syndrome postoperatively. So Erica, Tony, let's talk about another case or another child that we, that we oftentimes see. And this is a three-year-old who presents with a large central abdominal mass. You know, the classic history grandma noticed in the tub, giving the child a bath and they come in with this large abdominal mass, otherwise healthy child. How would you work that kid up? Erica, what's your approach? First, obviously we do a good history and physical exam, finding out if the child has had any other illnesses, any family history, cancer medical history. I saw a child a day that had diarrhea. I thought that was interesting because we, I've always read that you can get, you know, VIP secretion and severe diarrhea from neuroblastoma, but I had not seen that. And I always ask about that. And then with respect to trying to understand more about the mass, I'll typically start with an ultrasound. I get an ultrasound to see if I can get a clue on whether this is a solid or a cystic mass. If it's solid, then most likely we would then move on to cross-sectional imaging. And I usually get a CT scan with PO and IV contrast just because I'm more comfortable reading a CT scan. While we're waiting on the CT scan and the contrast, we'll get some blood work. Routine blood work is, you know, CBC, a comprehensive panel. I'll usually get tack on amylase lipase LDH and just a standard blood work that we would be getting for anyone that would have some abdominal masses. And so we've been sending the urine catecholamine and I'd wait and see what all that showed. Great. Tony, anything you would add to that initial evaluation? No, I agree completely. You know, when you're initially seeing a child with that abdominal mass and you're not sure what it is, I think it's very reasonable to go ahead and get an ultrasound. If it turns out to be Wilms tumor, the ultrasound's already done because you want to see if there's any venous extension of the tumor. And as Erica Kelly stated that you also want to be able to tell whether this is a cystic or solid mass. Yeah, that venous extension thing for the Wilms is a great point. That's a great reason to get the ultrasound. But so you get a CT scan and it shows a big 10 centimeter mass that encases the aorta and the celiac axis, micro calcifications, more solid than cystic. Now what would you do? Tony, what's your group's workup? So Dan, what you're describing is an L2 international neuroplastoma risk group classification of the local tumor. So this is obviously going to necessitate a complete workup. And obviously the oncologists now get involved in our really key to the further workup, which includes probably a bone marrow, the CT scan already been done, you're getting a technician scan or MIBG scan. I also like a CT scan because I can read it better. An MRI is certainly an option. You also want a chest CT because you want to rule out metastases. And then also a head CT can be indicated if there's any clinical symptoms that the patient may have. So now you're talking about the staging of the disease. And then of course, the final aspect to staging the disease is getting a biopsy for pathology and of course, biology in the case of neuroblastoma. So how about PET scans? Do either of you guys get PET scans? Our guys are very fond of PET scans. We're also very fond of PET scans. But the question is for the initial workup, a PET scan is not going to be my workup. An MIBG scan will be. And I'm not sure a PET scan will have any benefit over an MIBG scan in neuroblastoma. Correct me if I'm wrong. No, I think you're right. I agree with you. I think the rationale that's often given is that 10% of neuroblastomas are not MIBG-avid. So potentially they would be PET-avid even though they're not MIBG-avid. And you might also pick up metastases that way. So I agree with you. It's sort of, we get them and we get lots of them, but it may or may not be necessary, especially if it's MIBG-avid, then you have a study that you need to not only make the diagnosis and identify METs, but also to follow it, I think. Dan, I think you outlined that clearly. Certainly if it's 10% and your MIBG is negative, then I would agree. I wouldn't argue against a PET scan. Erica, how about you? Do you guys get them? No, we don't get them. There are very few scenarios we get them where every now and then we have a child where the primary lesion has been resected and there's a funny looking soft tissue area that is MIBG-negative and we're trying to decide if this is a local recurrence or nothing or scar. And so they'll get a PET scan in a scenario like that, but that wouldn't be part of our routine initial diagnosis workup. Tony, you mentioned getting tissue obviously is sort of the key or final step in doing the staging. What do you think about the options for getting tissue? Do you and Erica, do you all do percutaneous biopsies? Do you do laparoscopic biopsies? Do you do open biopsies? Lots of different ways to get tissue. So, Erica, I'm sure you'll probably contradict me, but this is sort of my approach. I'm sort of old fashioned in this way because I've been trained to get that size of tumor that can be biopsied safely and that can give the necessary tissue for further studies in biology of the tumor. And so I've always done a retroperitoneal approach to a large mass and done an open biopsy. I am a little reticent to do a transperitoneal approach and biopsy a big tumor laparoscopically because I'm not sure I can control the bleeding as well as a retroperitoneal approach. You could do a percutaneous biopsy. You would have to do multiple percutaneous biopsies. And I'm not sure the tissue collected is adequate for biology. So, people also say you can take bone marrow and you can get the NMIC amplification on bone marrow, but there's more to do than just NMIC. There's the ALC mutation to look for. There is, of course, adequate biology for pathology. And, of course, you really do want to look at the diploid status of the tumor as well. So, right now, I am still doing open biopsies unless there's some reason that the child is very sick and they can get NMIC amplification of the bone marrow. That's been my strategy right now. Sorry for the long-winded answer. No, that's awesome. That's great. Can you explain to me what you mean when you say you do a retroperitoneal biopsy? Do you go in through the back? I don't go in through the back, but I go in through the most lateral part of my eventual incision, what I'm going to predict to explore the abdomen. And in that way, because the tumor is retroperitoneal and it's usually large and extensive and pushing the retroperitoneum up, I can go through a relatively posterior lateral approach, which is retroperitoneal. And then to control the bleeding is a nice discussion as well. I often will take a nice, healthy, big biopsy and then put pledged in sutures packed with surgery cell to stop the bleeding. These can bleed significantly. The good thing about being retroperitoneal is you've compressed that area. It's got nowhere to expand, even if it does bleed, as opposed to a transperitoneal approach. That's a great technique. I like that technique. I would have to say when I do an open biopsy, I tend to go, I haven't worried so much about whether I was retroperitoneal or not. And I agree with you, they can be dramatic in their bleeding. And my management is usually putting some gel phone and thrombin in there and waiting with pressure and just wait. And it stops. It always stops, but it is a risk. And we have had patients who rebled postoperatively. How about you, Erica? What's your approach? Erica Cooke Well, I will say that at our hospital, we're shifting our practice a bit. Probably about 80% of the patients will get a percutaneous biopsy up front. Now, I say that with the caveat that we've worked really hard to standardize our approach with the pediatric surgeons and with the interventional radiologists and with our pathologists. And we've also, we're looking at this now within the COG surgeons. From what I can tell, probably about half of the children's hospitals are using percutaneous biopsy for massive suspicions for neuroblastoma. What the literature has found and what our experience has been is that percutaneous biopsy is equivalent to open biopsy for a couple of things. One is you can make the diagnosis. It is equivalent with respect to being able to understand high risk versus low risk. And then the MEC and amplification can be determined as well. Where percutaneous biopsy falls short is with determining LOH. LOH is important in the new staging and classification system. We need to know what 11Q is doing. And so that's where percutaneous biopsy has been failing. What our data is going to show is that there are things that we can do to increase the probability that you can get all of the biologic information that you need. So for example, if you have a pathologist there looking at the specimen and assuring that the specimens and the cores that have been obtained are not necrotic. Our pathologist actually does a frozen section on one portion of the core to assure that the tissue that's being obtained is viable tumor. We get up to 10 to 12 cores. So we found that the higher number matters. We've also found that when they use a higher gauge needle, that could help as well. So putting all of that together, higher number of cores, standardizing the size needle you use, and then having the pathologist do sort of a live read will increase the probability that you're going to get all the biologic data we need from percutaneous biopsy. We think it's important because we know open biopsy is safe and they're both safe. The kids that had open biopsy had a higher risk of getting a blood transfusion. They had higher narcotic use postoperatively, and they were admitted to the hospital more commonly. I don't think that we're ready to go live, so to speak, with percutaneous biopsy. But I do think it's worth taking a closer look at how to optimize the technique and standardize the technique so that we can get all the information we need. The most important thing, obviously, is to get all the information we need so that the patients can be stratified pre-treatment. Dr. That's great information, Erica, and it's great that you guys are looking at it in an organized, standardized fashion. You know, we have also transitioned, and I can't give you a percentage, but if a patient's tumor is amenable, we have great interventional radiologists, and they do the same sort of eight to ten core biopsies that you discussed. They can also embolize the track on their way out, which I think helps to limit the bleeding issue. But we've not had a pathologist involved right up front, and I think that's a great addition to make sure that you actually get the right answer. Erica, do they do the approach from a retroperitoneal position? We've done both. Most of the time it is retroperitoneal right through the psoas, often from the back. It just depends on where they can get a good safe window. Right. It just seems like that's usually a good window, and it kind of takes the advantage of what Tony does, and that might be a great approach. So we just got tissue, and now this is a part I always get hung up on, which is the staging. So Tony, can you go through with me the staging of neuroblastoma based on what are the different factors we look at, and how do we determine the risk of the patient? So Todd, as you know, the staging is based on the age of the patient, the histologic category, the differentiation of the tumor, the MEC-N status, there's ploidy involved, and then aberration of 11q. And that really gives you an idea of the pretreatment, the pretreatment risk group, which is either very low, intermediate, or high. But you can simplify it by looking at it in a very different way and not understanding all of the details, because often you'll have to refer to a chart to do that. I sort of think of it like imperforate anus. And you think of it as there's different ways of classifying imperforate anus. But for me, practically, there's high and there's low. Low imperforate anuses are going to do well. High imperforate anuses are not going to do well. And this is a similar entity. And I look at NMEC status, because NMEC is an oncogene that has really been classically described for neuroblastoma. And it really puts neuroblastoma ahead of any of the other tumors in adults and in children. Because it really gives you an idea of the biology of the tumor. And if NMEC is amplified, it is automatically high-risk disease, irrespective of any other categorization. If NMEC is non-amplified, most of them are either low or intermediate risk disease. You do get an occasional non-NMEC amplified, which is a poorly differentiated tumor. It's an older patient with metastatic disease. And it's obviously got diploid that may be high risk. But really, for someone who's not doing neuroblastoma all the time, look at NMEC amplification. It's either up, it's either amplified or it's non-amplified. And if it's amplified, it's high-risk disease, period. Dr. That's great. Dr. That's great. I agree 100%. Dr. I would agree with that. The only thing I would add is that loss of pedrozygosity at 11q is the only other thing that would bump up an otherwise NMEC and non-amplified patients to high risk. And so we see that 11q loss is the most common segmental chromosomal alteration. And so that's why it's so important that the original biopsy to get enough tissue so that in the 60 or 70% of patients where the NMEC is non-amplified, that none of those kids have 11q LOH because that would be a risk factor that could bump them up to high risk or higher, or from low to intermediate at least. I agree. You know, the loss of hemorrhagocity or 11q aberration can be intermediate disease if NMEC is not amplified and it's a differentiating tumor. But getting out of the weeds, and I agree with you completely, Erica, I would say look at NMEC amplification and LOH and you have high risk disease. And I just want to remind people that the difference in outcome is really based on the risk of disease. So intermediate and low risk has a very good outcome. High risk, NMEC amplification has a bad outcome or not very good outcome. So I think that is the criteria for the surgeon in trying to understand the behavior of the disease. What about patient age? Age is important, but it becomes one of those other criteria that have become important to biology of the disease. And it used to be 12 months and now it's 18 months. Less than 18 months, better behavior over 18 months, not bad. But having said that, it still doesn't carry the weight of the biology of the disease that NMEC does. So if you have a patient that has non-amplified NMEC and metastatic disease, are they high or low risk? They can be either. To be low risk and have a metastatic disease that is non-amplified, you have to have a hyper diploid tumor. And that's where ploidy comes into the action. And that could be a low risk. If it's diploid and it's non-amplified and they get an 18-month-old, there would be intermediate risk. If they're greater than 18 months old, they have metastatic disease, they fall into the category of high-risk disease, even if they're non-amplified. If they're less than 18 months old and they're amplified, they also fall into the high-risk category. So that's where age becomes important in the child who has metastatic disease. That's a great summary. So if we have this child now that we've biopsied and has a big central abdominal tumor encasing vessels and the biopsy comes back with NMEC amplified in a three-year-old child, can you just tell people, Erica, what's the plan from there? How would this child be treated at your institution? So I think a couple things. One is a child would need some central access to a port or a broviac. I don't know if this is an important detail, but how do you decide if a patient should get a broviac or port? Certainly in a case for a high-risk patient who's ultimately going to end up with a transplant as long as they respond, we would put in a double lumen external line, a double lumen central line as opposed to a port. We would do the same. Is there an age limit for how old or young a baby should be to get a port? So Erica, we used to put the line in just prior to doing a biopsy or a section. We somewhat changed that a little bit. And of course, everyone has their own nuance. But if we do think it's a neuroblastoma, we first get tissue diagnosis. And then we select the line that we put in because those children who have endemic amplification or high-risk disease, as we're describing in this case, need a double lumen catheter for bone marrow transplant. Now, you could put in a double lumen port, and we do do that at a family's preference. Usually, if you have a high-risk neuroblastoma or a tumor that looks like this, I actually will do it with one prep in the OR. So I put the line in first, so I'm not messing with tumor. I put the line in first, towel that off, and then do the biopsy. Yeah, but which line are you putting in? I would put in a double lumen catheter. Even if it might be non-endemic amplified? Yeah, because it's just intermediate risks are a very small proportion of the cases. So explain the odds. I agree. So you potentially could put in a double lumen line that you don't need. But that is really, really uncommon. I guess I need help understanding. When you see a mass, you have no idea if it's high or low risk, because you haven't biopsied it yet. In the patients we're describing, if a child comes in with multiple bone mets, not bone marrow, but bone mets on the MIBG scan, and they have a big central abdominal mass, and catecholamines are high and such, the MIBG scan is positive. It is, and it's a three-year-old, it is unlikely that that's going to be lower intermediate risk. But if it's a non-metastatic mass? Then you don't know. Then I would get tissue. And do the line after. You only put the line in if you're pretty sure it's high risk. Yeah. It's uncommon for us to, and that's why I was asking Tony, it is uncommon for us to take a child back to the operating room just for a line. We usually put it in at the time. We do, actually we do marrows at the same time. So the child will go to the OR, get a line, a biopsy, and marrows. We'll do the marrows at the same time as well. Now for Wilms tumor, of course, we do our line first and then take the kidney out for the tumor. Yeah. But for neuroblastoma, the interventionists have put in the lines, and so that's how we're doing it right now. Dr. Which makes perfect sense. I mean, I guess. But I do agree with you, Dan. If it's a high risk, if it's most likely a high risk case, which 60% of these are, it's probably very appropriate to play the risk of the game and have a child who's three years old with all the criteria that we've discussed, it's very reasonable to put in a double lumen port or double lumen catheter. So in terms of timing of surgery, you know, we've been through this in the children's oncology group with the timing of the control of the primary site and how many rounds of chemotherapy you give and whether more chemotherapy is helpful or harmful in terms of the surgical resection. So the COG is usually, I think in the protocols, it's usually after cycle five. And we, in our center, we've moved that up to after cycle four. It would be great if you could do even potentially after cycle three, but that begins to conflict with cell harvesting for a stem cell transplant. When do you guys, when for in Michigan and in DC, what's your timing of the primary tumor resection? I totally agree with you, Dan. We've moved it up. We really try and get the kids in between cycle three and four. And we, it's really rare if we go beyond four cycles. So typically what will happen is they'll get their induction chemotherapy and we're checking the scans after cycle. Most of the time, it's after cycle four. And that's really what we found to be the most ideal time to go for local control. I don't think we see much tumor shrinkage after four cycles. I think it was Dr. LaCoglia's study that actually looked to see if there was any biologic or imaging differences in the tumors after four cycles of chemotherapy. I think things pretty, things level out pretty much. And so I don't think that there's any benefit to waiting and giving five and six cycles. And the other thing that we've, that we talk about amongst our group here is that what we found is that sometimes after, you know, five or six cycles, these tumors become more hard and have just a different texture and can perhaps make the operation a little more challenging. And so we really try and encourage our patients and oncologists to let's go ahead and explore for local control after that fourth cycle. Dr. I agree. That paper from Michael Qualia looked at a sort of a heterogeneous group of tumors and showed that after cycle two or three, you don't really get much more change in volume. We actually looked specifically at our neuroblastoma patients with that same evaluation and found exactly the same thing. And I agree that after, when you start getting up to five or six plus cycles of chemotherapy, the tumor gets very fibrotic and I think it makes the surgery actually more difficult. So, um, if you have an isolated suprarenal mass with no evidence of metastases, would you just resect up front? Yes. All right. You're ready for surgery and it is a completely encasing the central vessels. Dan, how do you approach that patient? So, our approach has been an aggressive approach and our goal that we typically shoot for is to take out more than 90% of the tumor mass. And the rationale for that is two studies, one from the Children's Oncology Group, a high-risk study in which we assessed degree of tumor resection and correlated that with survival. And there were only, I can't recall the exact number, 245 patients or something in the study. And there was a statistically significant improvement in event-free survival, but not overall survival. So, you could argue that potentially that doesn't change the overall survival. However, there was a much larger study that is actually, I don't believe still has never been published that was presented at a neuroblastoma meeting several years ago from the European neuroblastoma group in which it was a much larger data set. I think they had close to a thousand cases. And they showed not only with the same criteria, essentially greater than 90% resection demonstrated improvement in event-free survival and overall survival. So, our goal is to attempt a greater than 90% resection. And the data from multiple studies looking at this are that you can achieve that in about 70% of patients. Tony? So, firstly, as far as the cycles to therapy, you know, stem cell harvesting is high-risk neuroblastoma is usually after the second cycle. So, I do agree with you both that around about the fourth or fifth cycle, we will do our resection. We do remember that a high-risk neuroblastoma actually responds really nicely to chemotherapy. And you can get very good response rates. And that's probably because of its highly proliferative rate and its responsiveness to the chemotherapeutic agents. Having said that, a lot of the tumors that we approach are not completely resectable. And what you're leaving behind is fibrous scar tissue along vessels and along the structures within the abdomen. It's not the local disease that usually is the cause of demise in these patients. It's the occurrence of metastases. And in fact, if you look at it, there was a recent publication from the German group that looked at the European data and actually stated unequivocally that the amount of resection of local disease does not make a difference. So, and that came out about six months ago, six months ago, I believe. So, you can find any data in the literature to prove the point that you want to make. And I think neuroblastoma and high-risk disease classically defines that statement. I think in summary that if you can take out as much tumor as possible, you should take it out. But more importantly, you should do it with a safe outcome and a safe technique. So, if you're going to be taking out the retroperitoneal lymphatics with a significant lymphatic leak, or you're going to be removing blood vessels and doing revascularizations, I think it's the wrong thing to do. I think the bottom line is patients don't die of local disease. They die of systemic disease, in neuroblastoma. And you should take out as much tumor as possible without risking bad outcomes. Tony, I actually agree with that 100%. And I would subscribe to exactly that same philosophy. I think the data shows that you get great local control with the combination of radiation and aggressive surgery, but the patients still have metastatic disease. And so, if there is an improvement in survival, it's really hard. It must be so incremental that it's hard to even demonstrate that despite multiple studies showing evidence on both sides of the fence. And I think that it's ultimately whether you can control the distant disease that's going to determine the child's outcome. I can't believe you guys are agreeing. We were hoping for like a battle of the century here. Tony, if they are encasing the vessels, would you go in and resect relative amounts of the tumor for debulking, but not just get too close to skeletonize the vessels? Is that the difference between you and Dan? I'm trying to understand where you two disagree. Well, that's a very good point because, you know, it depends how you describe your surgery. I mean, I think surgeons like to believe they're taking out all the disease. But I don't believe I am, even if I'm taking an aggressive approach to the surgery. And I think one of the teaching points here is I always like to identify normal anatomy, let's say normal blood vessel, and track the normal blood vessel to try to take out the abnormal. But I don't want to risk injuring the blood vessel if I can't take it out. In fact, yesterday, I did an open book procedure for an eight-month-old who had a neuroblastoma that wasn't responding to chemotherapy. But the subclavian artery was diving right through the tumor, and I couldn't identify which direction it was going. And I didn't want to damage the subclavian artery. So I stopped. And I don't know if this is high risk or low risk. They treated it because the metanephrines were high in the urine. They started with chemotherapy, and the child didn't respond to chemotherapy. So instead, they asked me to do a biopsy. As I said, instead of doing a biopsy, I will basically do a trapdoor approach and try and resect the tumor. And I think this child will end up being intermediate stage. And I'm glad I didn't try to get too clever. And I'm glad I backed off and resected about 50% of the tumor, because I suspect that it's going to make no difference to the outcome of the patient. So to answer your question, I think you've got to just be somewhat conservative in avoiding damage to major vascular structures and dealing with the consequences of those complications. So there is no definition of what more than 90% resection is, or what 80% resection is, because you don't know exactly what you're leaving behind. The bottom line is, I think Dan and I both agree that take out as much as possible and leave behind unfettered vasculature or neural tissue. And I think that's the only thing that I try and do. I, again, I would agree with you. I think, first of all, your description of starting with normal vessels, and that's what I always work with the residents on, is start away from the tumor, find the normal vasculature, and then track it up so that you can stay right on the adventitia, because theoretically neuroblastoma doesn't invade the actual vessel, although I have seen that. And I agree, you should take out what is, what you think is safe. And that's impossible to draw a criteria for that. That comes with experience and probably bad experience, but it's just doing the cases enough to know if it's coming off the vessels easily, I keep going. If it's not, then I stop. And the other thing that throws a wrench into this whole argument is I have twice looked at the correlation between what the surgeon's op note says and what the post-operative imaging says with regard to the degree of resection. And the answer is, there is zero correlation, zero. There is absolutely no correlation between the findings on post-op imaging and the findings that are reported in the op note. So then it's a question of, well, who do you believe is, has the right answer? So I would agree with you, Tony. I think surgeons will frequently overestimate the amount of resection that they've been able to achieve. One thing we try to teach the residents is that with neuroblastoma surgery, there's no reason to cause disability. So if you are doing anything that might have the patient be disabled afterwards, so that, that might be another way to look at it. So if it's, you know, we don't, we try not to do a nephrectomy. If the, if you can't peel it off the renal vessels, then you do, do your best and, and, and, and stop there. Or, um, you know, lesions, um, in the chest that's not one today that might involve the brachial plexus. And so that a mask like that, uh, you know, should give us pause to think, you know, how aggressive we want to be, um, with, with surgery. So I think we're keeping safety, avoiding disability, at the same time balancing that we're trying to get a 90% resection is sort of the complexity of, of planning the, the local control operation. I think that's a really important point about the kidney, um, because the approach has been intensification of chemotherapy to try to help these patients. And if you take a kidney out, then they have to reduce their doses. So, uh, trying to preserve renal function is, is, has always been a priority. So, you know, what are the new breakthroughs in neuroblastoma? And obviously it's not a, a, uh, the surgery that we do, um, as Dan and I, uh, spoke, uh, about as well as Erica. I think some of the new changes and what's improving the outcomes is, uh, immunotherapy. And there's a monoclonal antibody against ganglioside GD2 that is now accepted therapy for high risk disease. And it's actually improved survival, uh, uh, survival, um, from about 46% to 60% at two years, which is really significant. The, the outcome longer hasn't been quite, uh, evaluated. The, uh, the ultimate survival hasn't been evaluated, but it really does speak to the role that immunotherapy is playing in a childhood disease. We know that immunotherapy is really a big thing now with all cancers, because we've had some breakthrough with the checkpoint inhibitors, which take the brakes off the immune system. In neuroblastoma, it's very interesting. The checkpoint inhibitors that have been used, uh, have not been successful. And the reason is neuroblastoma is not a, uh, immunogenic tumor. And I think the goal in the end, and the difference that we're going to make in the end is making neuroblastoma an immunogenic tumor. And then we will talk about real breakthroughs with immunotherapy. But the first breakthrough that we've had in any childhood cancer with immunotherapy was the antibody, the monoclonal antibody against ganglioside GD2, which, uh, enabled, uh, cells to attack the tumor. And I think it's been a very nice story, just like Anne-Mick was for neuroblastoma. Immunotherapy has also been for neuroblastoma. Thanks, Tony. It's great to see where things are headed. This is one of the most studied diseases, and we're making a lot of good progress. I want to thank all of you for tackling this difficult disease. It's tough to try to summarize all the complexities in one recording. And we, we did. I think we covered all the major things that I and others around the country, uh, struggle with and always want to know where things are headed. So I appreciate your time. This has been a great recording and thanks for joining us. This is Ray Hanke from Cincinnati Children's Hospital, the contributing editor for this audio chapter. You, our Stay Current family requested more coverage of oncology and we heard you. Stay tuned for the soon to come neuroblastoma Topic in 10 podcast, designed to give you a focused refresher. What else do you want to hear? Let us know on the Stay Current app, Facebook page, or Twitter. And remember, knowledge should be free. Thank you.

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