Hi all,
I had the tumour out on Nov. 10 and just received my completed pathology report today. I’m diagnosed with an AA3, not an Oligo 2 as previously thought. Can you all review the report and help me make my next steps from here? Thanks.
IDH1 R132H positive
ATRX - negative (lost, suggestive of mutation)
P53 - highlights scattered background of glial cells (negative in tumour, suggestive of try care by mutation)
MIB-1 proliferation index is 7.7%
504 kb gain of SOX2
1.9 mb gain of OKI (no gene disruption)
21.2 Mb broad gain of 7q, an
8.7 Mb gain of 12q
Let me know if I should give you anything else. That’s is all that is listed though.
Thank you!
P53 - highlights scattered background of glial cells (negative in tumour, suggestive of truncated mutation)
ReplyDeleteHello Maria,
ReplyDeleteI hope you recovered well! Were they able to get the whole tumor out?
Are you on any supplements & off label medication already? I think the standard protocol for grade 3 is chemo / radiation. There were promising results for CCNU + TMZ for GBM, but I think it was not tried for grade 3 yet. Maybe Toca511 would also be worth checking (first-hand or if standard treatment fails), if I remember correctly there were few AA3 responders.
I occasionally follow blog of a guy who was also diagnosed with AA 3 in 2013 and follows ketogenic diet, still free of reccurrence: http://mybraincancerstory.blogspot.si/
I think Stephen will give the most educated opinion on worthy trials or maybe just going with standard treatment and try to boost chemo with some supplements and medication.
Take care!
I'm not sure what OKI refers to (is this a typo?). It's odd there is no mention of testing for 1p/19q codeletion, given they thought it was an oligodedroglioma.
ReplyDeleteLoss of ATRX does suggest it is an astrocytoma.
There's not much out there in the way of trials for newly diagnosed anaplastic astrocytoma. Do you know if your hospital will send the tumor tissue for MGMT methylation testing? Adding CCNU to TMZ (according to the protocol used in the CeTeG trial in Germany) could be an option as Matjaz mentioned, if MGMT status is methylated (IDH1 mutant tumors usually show positivity for MGMT promoter methylation).
Toca 511 + TocaFC would be an excellent choice for recurrence, but that will hopefully not be for many years (if at all) in your case.
Thanks, Stephen. OKI is not a typo. No idea what it means?
ReplyDeleteHow have the TOCA Trials been going for IDH mutant tumours?
What do you think of the P53 loss?
They did do the 1p/19q testing, that’s where they identified SOX2 and those other things.
I am thinking about a ketagenic diet.
Thank you.
Maria
Their recommendation is radiation and chemo now. The report says mitosis was 3 out of 10 HPF (or something like that). The surgeon said that meant it was considered a grade 3 but not really by much. He says it was respected at 99.9%.
DeleteCurrently I have some speech deficits and writing deficits too. It is getting better, as I wait to get into a speech therapist.
Maria
Respected is a (autocorrect) typo. :)
DeleteSox2 is on chromosome 3. Are you saying they did a complete copy number analysis of all the chromosomes, and the ones you listed are the only abnormalities (gains/losses) they found?
DeleteTypically, TP53 point mutations in astrocytomas lead to a mutant p53 protein that is not degraded as quickly as the wild-type protein, leading to a buildup of mutant p53 in these tumors.
In rarer cases, the TP53 mutation is a frameshift mutation that leads to a truncated (and likely non-functional) p53 protein that is undetectable by immunohistochemistry. This second scenario is what the pathologist was suggesting in your case. The second copy of TP53 is often deleted in astrocytomas.
The Tocagen trials have shown great promise, with a high rate of success for IDH1 mutants (albeit a small sample size).
http://ascopubs.org/doi/abs/10.1200/JCO.2017.35.15_suppl.e13504
Hi Stephen,
DeleteYes, they did a whole analysis and that’s what they found. I guess I’m not sure how many items they should look for but the list has maybe 50. Everything else had no changed detected. It also says the cellurarity is dense, Atypia is severe and mitsoses 3 our of 10, like I said. 7q is also BRAF, though I’m not sure which one?? I emailed my NO yesterday to ask about methylated status.
What does it mean that P53 is non-detected? I think I’ve read that has poorer outcomes.
Did you ever find out if all IDH1 have no recurrence after using Tocagen at first recurrence? I thought all of them did, then some other information came out that said it was more wild types that mutant.
Thank you.
The normal non-mutant p53 protein is a tumor suppressor, while in tumors the full-length mutant forms of p53 have often gained tumor-promoter function.
DeleteOn the other hand, frameshift mutations can lead to a premature stop codon and a truncated protein, which is likely non functional.
In theory it would be better to have a truncated, non-functional copy of p53, than a full length mutant copy of p53 with tumor promoter function. However, I can't recall seeing any studies comparing survival for those with missense mutations in TP53 versus those with frameshift mutations. Either way, one of the classic features of IDH1 mutant astrocytoma is they often have a "double hit" to TP53: one deleted copy and one mutant copy.
In the phase 1 trial of Toca 511 injected into the resection cavity, there were two IDH1-mut astrocytomas with complete response, and three IDH wild-type GBM with complete response. There was one additional patient with complete response who was either IDH wild-type or mutant depending on which abstract you're looking at. There was also an IDH1-mutant patient with complete response in a different trial of intravenous Toca 511 injection followed by another injection into the resection cavity.
So there has been an approximately equal number of IDH1 wild-type and mutant responders. The difference is that the majority of patients in these trials would have been IDH1 wild-type GBM, so the difference is in the *rate* of response: 3/3 IDH1 mutant complete responses versus 3/50 or so for IDH1 wild-type.
Thank you, Stephen. Very helpful.
ReplyDeleteI have the option to relocated and use proton radiation or have the standard at home. My NO says that there’s not much difference really.
ReplyDeleteWhat all do you think?
Thanks.
I would probably choose proton, even if it meant relocating for 6 weeks. For one thing there's less collatoral damage to surrounding healthy brain tissue with proton, as seen in the image at the bottom of this page:
Deletehttp://astrocytomaoptions.com/radiation/
One study also showed proton as being more effective than photon radiation at an equivalent dose, including much higher reactive oxygen species (ROS) generation with proton (see figure 5A)
https://www.nature.com/articles/srep13961.pdf
As I mentioned, IDH1-mutant tumors are especially sensitive to pro-oxidative, ROS-related stresses.
Thanks, Stephen.
DeleteSo, I’m considering the proton therapy, adding Celebrex and I’m exploring implementing a ketogenic diet before starting the radiation. I’m not sure if I’ll stay on this diet after the treatment but from what I’ve read (including on your page) it could have a significant effect on the treatments. I will continue my usual diet (for years) of kind of paleo-esk high fat but not too much protein. I believe I will be doing TMZ at the same time and have inquired about CCNU concurrently (though I’m not too sure about that).
What do you (and others) think. Am I leaving anything out?
What about HBOT? I’m about to look into that. As well as IV Vitamin C.
DeleteI’m also thinking of THC as a way of disrupted glutamate during radiation. Any contraindications of THC and ketogenic diet that you know of?
DeleteNot that I know of
DeleteOne more question - did these patients have subtotal resections? Is that how they are able to tell the CR? That has always confused me some.
ReplyDeleteI know Greg L. is listed on Virtual Trials but from his story it doesn’t seem to be a recurrence? Unless they skipped that part.I thought all CR were at first recurrence.
Yes, usually only patients with some visible residual disease post-surgery are assessable for response.
DeleteI would guess they just skipped over much of Greg's story to condense it into a 3 minute video. As far as I'm aware, all the Tocagen trials so far have been for recurrent disease.
In the published Japanese trials with hyperbaric oxygen, they placed importance on administering the hyperbaric oxygen as close in time as possible to the radiation treatments, ideally within 15 minutes, which can be a logistical challenge.
ReplyDeletehttps://www.ncbi.nlm.nih.gov/pubmed/21420247
"It is recommended to administer RT within 15 minutes following HBO as this is when the partial pressure of oxygen is highest in the intra- and peritumoral regions"
https://www.ncbi.nlm.nih.gov/pubmed/26414129
I read that afterwards, Stephen. I’m not sure I’ll be able to do that.
DeleteSo my plan now is THC, ketogenic diet with emphasis on DHA oils and perhaps intermediate fasting. I don’t know if I will benefit from Celebrex, since there is not list COX2 mutation. There is a SOX2 mutation...I’m not sure on that. Then proton radiation and TMZ. I’ve asked about CCNU, too. This will create multiple pathways, I think, including targeting glutamate, glucose, ROS and, obviously, TMZ is an akalizing agent. What do you think? Should I add anything else? I haven’t read about turmeric during treatment and I have it in my to do list to go over Ben protocol. My blood sugar is really low, sometimes as low as 50 fasting. So I’m hoping I can get into ketosis.
Many iron supplementation during radiation?
DeleteI've never seen a glioma that did have a COX-2 mutation. The normal (non-mutant) COX-2 protein is often overexpressed in gliomas, especially during/after radiation.
DeletePersonally, I'm coming to a position where if I had an MGMT-methylated astrocytoma I would not do TMZ without CCNU. I might even do CCNU in place of TMZ. TMZ has short-term benefit no doubt, but the risk of a hypermutated recurrence is high with TMZ alone. I have watched this happen to friends.
TMZ is an aklyating (not alkalizing) agent. This means that it attaches an alkyl group (in this case, a methyl group) onto specific sites on the DNA, causing DNA mismatches and ultimately, unrepairable DNA damage.
Iron supplementation during radiation increased the efficacy in rodent models, however I've never heard of this being tried in humans, so I can't say how safe this would be.
I would consider disulfiram (Antabuse), during RT and chemotherapy, although one has to be very careful not to consume any alcoholic beverage or anything containing any ethanol (alcohol) for example, herbal tinctures while on disulfiram. Lots of DHA and EPA fish oils (at least 3 grams total per day of DHA + EPA) is recommended.
If you can get into ketosis (you can measure this with strips dipped into urine that change color) for the several weeks period of radiation at least, that is also very recommended.
Thank you, Stephen. I’ll have to think about chemo. My NO says hypermutation is a very small risk. He also says I could possibly skip chemo.
DeleteAs far as dex - steroids during radiation...how likely are people to need them? Is there something else I can do beside a steroid? I’m worried about my blood sugar while on it. Would turmeric help? What are your thoughts of this? I’m off to look it up too.
Maria
Based on what does he say that about hypermutation?
DeleteI think boswellia might help with inflammation.
I’m not sure, Matjaz. I always tend to ignore him when he says that...but I should probably inquire about it.
DeleteBoswellia, yes. I’ll add that to my list to look into.
Stephen, do you have any research on dislufiram? I’m looking now and finding one study that says it has promise with TMZ. What about radiation?
In my opinion you should ask questions...it's your health after all. If I wouldn't be asking questions and doing some of my own research, I'd still be on watch&wait.
DeleteI think Stephen has all the important files in Google Drive, check there.
Thanks, Matjaz. I do try to talk to them and bring my own research. Sometimes I just need to put things on the back burner as to not be overwhelmed by all the information I receive. I will get to that question next time.
ReplyDeleteI’m not sure how to access the Google Drive. Can someone provide instructions? I believe Stephen added me to it.
If you're on Gmail, you can find Drive by clicking on the Google apps icon at the top right (looks like a Rubicks cube with 9 squares), and from there click on the Drive icon (a three-colored triangle, looks like the Recycling symbol).
DeleteOnce you're in your Drive account, you can either click on "Shared with me" on the left and scroll down until you find "Brain Tumor Library", or just type in "Brain Tumor Library" in the search bar at the top.
Oh ok! I know how to do that. Thanks.
DeleteHi Stephen,
ReplyDeleteThank you for all of your help so far. I really, really appreciate it.
I wanted to ask - what about proton radiation and ketogenic diet? I’ve read that ketosis can inhibit ROS and that the mechanism we’d be hoping for with proton therapy. I know ideally the cells would not be about to uses ketones but...what if?
Also, can you shine any light on a truncated P53 mutation and glycolysis and fatty acid metabolism? I have repeatedly seen this alluded to as I read about ketogenic diets. I’ll link a study I’m trying to interpret here.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3135642/
(I apologize if this is on google docs. I cannot access it from my phone right now.)
Thank you.