DR. BRENNAN: I think the question is, Jon, whether your group would be comfortable with what is there. If you are, then that would obviate a lot of discussion.

DR. WEISS: As a pathologist, I am real comfortable with it. The problem, I think, is best practice versus what is really going to happen in the community despite what you might say. For example, Raph Pollock does FNAs two thirds of the time, can get the answer while he is sitting there --

DR. POLLOCK: Sharon, just to make sure that we understand what I am saying when I say FNAs are performed about two thirds of the time: those are confirmed with cores in the majority of those patients. We can make the diagnosis with FNA and we can extract DNA from the FNA and PCR it and do other things with it.
Certainly, the ultimate standard is still FNA confirmed with some core material. It really comes down to, I think probably, how much core does one really need ultimately for diagnosis as well as research purposes.

DR. BRENNAN: I don't think this is about diagnosis. I think you can make the diagnosis any way you want. I think the issue here is, if you are not coming from diagnosis to the ultimate biopsy -- i.e., resection -- then we are obligated to suggest that greater tissue be available prior to treatment. The first part is easy. You can make the diagnosis any way you want. You are going after the ultimate biopsy. It is the other patients in whom the pathologist has an extraordinary problem once we radiate them, give them chemotherapy, whatever, that we will lose that biological information if we have two or three cores.

DR. POLLOCK: It is not only the pathologist. It is the people in the laboratory as well.

DR. BRENNAN: The same issue. Sharon, if you and the group itself is comfortable, as this is a best practice guideline -- this doesn't mandate anything. It doesn't say that you can't do something. It says, if we are going to make a difference, this would be helpful.

DR. CHRISTOPHER FLETCHER: Let me let Sharon and Jon off the hook, because I am the blunt, rude one. It is what made it difficult for them and why you may be surprised that there wasn't a recommendation from us for the same thing.

Two of the leading centers in the country still recommend FNA and needle biopsy -- M. D. Anderson and Mayo. Whereas the centers which are really most interested in correlative studies -- Memorial, Toronto, Brigham -- we are all doing open biopsies in high-volume sarcoma centers, because we want the tissue. It is driven by the centers that really recognize the value of the tissue where, if you like most of the translational research is going on. There are very polarized camps. That is why there wasn't a recommendation by our group.

DR. BRENNAN: This is a way around it. This says you can make the diagnosis any way you want. No one will be unhappy. What it does say, if you are not coming to the ultimate biopsy immediately, then the best practice to make a difference in the future for the patient would be adequate tissue.

DR. CHRISTOPHER FLETCHER: So, you have to persuade your surgeons. We would all love open biopsies.

DR. BRENNAN: This was, to some degree, a surgically-based group. That is why I think it is worthwhile.

DR. BAKER: I would like to ask the question, is there evidence that doing multiple core biopsies is not sufficient?

DR. BELL: There is anecdotal evidence in our group Larry. The recent paper in Lancet from the Stanford group, I think, established a standard for what you need to do a microarray analysis of soft tissue sarcoma to be sure that you have adequate material, and that is that you have to get a frozen section from the sample that you are going to extract RNA from. That is their standard.

Now, our standard in doing that is that we probably lose on open biopsy specimens. Where we have done an adjacent frozen section at time of harvest, we are still throwing away probably 20 percent of the samples as being inappropriate for RNA extraction. Now, if you are going to do that level of quality control on the tissue that you are banking at the time of harvest, if you get a frozen section from each core, you are not going to have much material left.

I think you have to do a frozen section from each core, because we all know that cores oftentimes don't have viable tumor in them.

DR. CHRISTOPHER FLETCHER: If you speak to the guys who are actually doing the work -- Jon Fletcher, Paul Meltzer and so on -- needle biopsies are hopeless for this. Half the time they don't even know whether they have got tumor, and certainly not enough to get enough DNA for example for cDNA microarray.

DR. BELL: I think by the time we do 15 or 20 cores to get 100 micrograms of RNA extracted from the material, we are doing more damage to the patient than with an open biopsy that is well-controlled by the surgeon who is going to be doing the resection.

DR. BRENNAN: The phrase is, "may be necessary". Is there anyone can't live with "may be necessary"? If your institution can get the DNA that you want out of 10 cores and the patient is willing to accept that, there is no problem. This says "may be necessary".

DR. CHRISTOPHER FLETCHER: It' as wimpish as whn we said that our guidelines are voluntary.

DR. BRENNAN: I understand that, and we are doing it for the same reasons that you did what you did, Christopher.

DR. CHRIS FLETCHER: And we failed.

DR. WEISS: Just to sort of wrap it up from our group -- I think you wouldn't have any objection, particularly from the pathologists, about the necessity for having an open biopsy if you are going to give neoadjuvant therapy. I mean, we would all love to see more tissue. I can personally tell you that I will go back to Emory and say this, and I will not get an open biopsy. I almost promise you that I will not get this.

I will get multiple core biopsies in lieu of it; but I don't think I am going to get, even with a best practice recommendation, an open biopsy.

DR. BRENNAN: I think in practicality you will get an open biopsy, if the core biopsy is not enough for you to give the kind of diagnosis that says you should get pre-operative chemotherapy. If you can commit to that, then yes, they may proceed. Too much talk by the chairman.

DR. HEALEY: This is the basis for how the Children's Oncology Group works currently: if you don't submit tissue, you don't get entered into the protocol. Unless you are participating in the biologic studies, you are not going to participate in the therapeutic studies. Ultimately, you, as pathologists, hold the key to entering into any therapeutic studies. If you don't give a concrete diagnosis, then there is no go.

DR. BENJAMIN: I am delighted to see that the pathologists and the surgeons have such confidence in the ability of neoadjuvant chemotherapy to destroy the tumor, that they think they won't have anything to make a diagnosis with by the time the tumor comes to them.

DR. BELL: We are more concerned about radiation Bob.

DR. BENJAMIN: Okay, radiation, fine. I mean, I would really like to know the data on which it is based. How often is it that you see a resected tumor -- and let me take it to the extreme -- because you are now recommending that we do an open biopsy on a retroperitoneal sarcoma to get --

DR. BRENNAN: No, we are not, actually.

DR. BENJAMIN: But they are going to get neoadjuvant therapy, as Dr. Pisters is going to describe. So, we are recommending an open procedure --

DR. BRENNAN: Let's not make this too complicated. It said, "may be necessary". Let's address your specific question.

The specific question is, for us to be able to answer on a biological basis why that patient did or did not respond to the chemoradiation, you need adequate biopsies at both ends. That is the question.

DR. BENJAMIN: I agree with you, that if we get to a point where we want to answer the question of why a patient has a complete response to some sort of pre-operative therapy, that we need enough pre-treatment tissue to be able to answer that. I think the clinicians are more interested in why the patient didn't respond, and you should have that information on the post-treatment specimen, which I believe you will get.

DR. CHRISTOPHER FLETCHER: Listen, Bob, you need to understand, when you get these post-treated specimens, even in those ones where you don't have much effect with either your chemo or radiation, you still characteristically get hideous aneuploidy, crazy chromosomes, bizarre pleomorphism, aberrant expression of antigens, purely as a consequence of what you have done, even if it hasn't helped the patient. It screwed the biology of that piece of meat and it is no longer interpretable for the purpose of basic science. Once it is treated, it is no use.

DR. BELL: The other thing that is very important about this recommendation is actually the converse argument. That is, Institutional Review Boards will occasionally say, as has happened to us in the case in osteosarcoma, the standard of practice is needle biopsy, you cannot do an open biopsy.

I think this kind of best practice recommendation -- that it may be necessary -- is something that would be very useful for going to IRBs to approve tumor-banking protocols. I think it is real important.

DR. BRENNAN: Dr. Borden reminds me that the focus of this meeting was to move the research and the science forward. I think this will move the research and the science forward.

DR. HOGENDOORN: One issue I would like to address again, and Jaap has already said, is an issue we have in Europe -- and I am not proud of it -- and that is the issue of privacy rules and adequate rules for uses of material, even after informed consent.
That is a big problem in Europe now, getting this material in proper clinical settings.
With regard to your first line, I completely agree, but I think, nationwide, there should be recommendations about the uses of material.

DR. BRENNAN: We have equal concerns about that, but we thought that, to address that before you had the tissue -- if you didn't have the tissue, it becomes irrelevant. If you do have the tissue, then it is an important issue to address. I think we are all sensitive to that, and most institutions now require, in this country, defined informed consent. Even that will provide the problems you have. If you don't address it first, then those issues become moot.

DR. NIELSEN: I think if we are moving ahead, I know there could be a lot of logistical problems, and that is the routine and how you do it, and the number of patients may be difficult to handle with our own biases. Still, I think it is very important, if we want to move ahead in this area, I think we definitely have to agree that, in as many patients as possible, get enough tissue, and tissue from patients not being treated, in a bank.

Otherwise, I think we will really regret in the future that we don't have this. I can demonstrate. In Denmark, we have a tradition for open biopsies, and just across the border we have Sweden, where they have fine needle biopsies. I am pretty sure the discussions we have in Scandinavia will very soon move also to Sweden, that we will have more and more patients not having fine needle, because we realize that we definitely need untouched, not treated, biopsies of these patients.

Then, of course, you can start saying that open biopsies or core biopsies -- but I think at least we should try to get enough untreated tissue in the bank. Otherwise, I think we will really regret that in the future. I can only support what is up there, because that is really moving ahead, not moving backward, taking into account all the problems we have right now.

DR. BRENNAN: Would you accept, those that are uncomfortable, if we inserted a phrase that says, "for the science of the study of sarcoma to advance, the following would become…", or some phrase that puts the -- we are supposed to be talking about the science. We are having a party. You can all come. You don't have to bring cake.

DR. BELL: I am just a little worried about adding "science" here. Then that opens it up for Institutional Review Boards to say they are doing something as part of a scientific protocol.

DR. BAKER: I agree with that. I think we still have an open mind about this. I recognize that it is still difficult; but I think your phrase may be necessary. It behooves those of us who think you can do this on multiple core needles to prove that and, if we can't, then we have to do open biopsy.

DR. BRENNAN: It sounds like we have as close to consensus as we will get. Any other comments on this particular issue? Bob, thank you very much.

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