Hello my dear friends and partners!
I had many doubts and I still have them despite of reading much.
And I decided to ask for your help at least.
My father had surgery 4 month ago. Chemoradiation finished 1 month ago. Left side of brain was damaged. He has Glioblastoma.
He has problems with speech and memory now.
That is why it is too hard to establish the cause of some uncomfortable and bad feelings after taking medicines and CAMs… He can not describe it correctly and can not remember when it was started for example…
---------He has no mgmt/idh1/braf/msi
---------He has 30% PD-l1 expression.
---------MRI shows continued growth (mono TMZ was not effective).
This month we started:
avastin+TMZ (5+23, 400 mg)
It is risky because TMZ did not worked well before. But I found it can do other work: reduce PD-l1 expression. And decided to use PSP(PSK) Oriveda together (6 pills =5 days with TMZ, 2 pills other days).
!) MAIN QUESTION: is this mechanism can work or not?
https://www.ncbi.nlm.nih.gov/pubmed/30709339
!) SECOND QUESTION IS: he is getting shakes. What can it be? (inside based like fever). But temperature is ok. Blood pressure is pretty normal. Pulse is ok.
Problem is – he can not remember when it was started (may be after avastin). It was more than 1 time. He is hiding his condition may be…
And he sleeps much.
These supplements was added (after radiation/before or together with new chemo):
avastin (1 in 2 weeks) +TMZ (5/23)
++++++ melatonin 20mg only 5 days (or need to use all time?)
---------1) alpha lipoic acid (2x300=600)
---------2) curcubrain (1x400=400)
---------3) PSP(PSK) Oriveda (2x350 = 700 or 6 at TMZ days)
---------4) Carvedilol for pulse (1/2)
---------5) started to change carbamazepine (200mg) to keppra (250mg) – TOGETHER 1 week. Then more keppra less carb.
PS – keppra for unmethylated MGMT (still risk if TMZ not working)
Help me to connect his fever/shake with suppliments.
I can guess 1) it is avastin 2) keppra together carbamazepine 3) may be PSK/PSP… But may be you know bwtter?
Also he is taking (from the beginning)
---------metformin (1500)
---------Boswellia (2000)
---------D3 (4000)
---------Omega3 (1500)
---------allopurinol
---------Losartan
---------Nifedipine
---------Aspirine low dose
He has diabetes 2 type/hypertonia/
-----------What can I add or remove? (may be malatonin all days not only 5)? may be lower dose TMZ/ methronomic or replace TMZ with Irinotecan? (to not risk with combinations).
------------Is my combinations effective (TMZ+melatonin+PSP+keppra) with our mutations? (add/remove?)
------------What can be the reason of weakness and shake/fever?
------------Do you have link for Japan protocols (psk/psp)?
Thank you!
Regarding the first question about PD-L1. The tumor basically uses PD-L1 as a "shield" against attack by immune cells. When there is a lot of immune activity, the tumor needs more of a shield so PD-L1 expression increases. When there is less immune activity, the tumor doesn't need this shield as much so PD-L1 expression goes down. So an indirect decrease in PD-L1 is not always a good thing - it may just mean that there is decreased immune activity. It is probably actually better to have high PD-L1 expression (implying the tumor is trying to shield itself from active immune attack), and then inhibit this "shield" with a drug that inhibits PD-1 or PD-L1 (pembrolizumab, nivolumab, durvalumab, avelumab etc.). This study concludes by saying these drugs are probably not as effective in recurrent GBM due to the decreased PD-L1 in recurrent samples.
ReplyDeleteHi, Stephen!
DeleteDoes it mean that PSP/PSK will not work (even after TMZ using) because of PD-l1 expression?
My theory was 1) to reduce PD-l1 expression with TMZ 2) to increase the amount of T-cells with PSP (and let them go through the shield)
PSP/PSK could help regardless.
DeleteMy understanding is that the recurrent tumors post-TMZ are simply less immunoreactive, and so the tumor doesn't rely as much on PD-L1 because there is less immune activity. PSP/PSK and other medicinal mushrooms could be one way to attempt to reintroduce an effective immune response, although the most effective way to do this is probably through personalized vaccine approaches.
30% PD-L1 expression is significant, so his tumor may be a type that could respond to immune checkpoint inhibitors against PD-1 and PD-L1 (nivolumab and pembrolizumab are the most well known of these). Have you discussed this class of drug with his doctor?
DeleteIt shows that TMZ-based treatment can be combined with active specific immunotherapy. TMZ increases the antigenic burden, and makes the cells more prone for an immune attack. It shows that TMZ-based treatment is not to be combined with anti-PD1 strategies like now proposed in the NivoGlio trial.
ReplyDelete20 mg melatonin might be too much for him. You could try going to 10 mg and see if anything changes in a positive way? Are you giving this only in the evening before he goes to sleep? I can't properly answer the question about the shakes. What does his doctor say?
ReplyDeleteOur doctors are not specializing at supplements. It is our choice
DeleteThe shaking isn't necessarily related to supplements, it could also be related to the disease itself. The doctors job is to give an opinion on this sort of thing.
DeleteWe asked the doctor. It seems like blood pressure problems. And we will try to cancel his medicines for hypertonia (losartan and Nifedipine). May be it is because of alpha lipoic acid (it is normalizing blood pressure). And losartan making it lower.
DeleteIs he on losartan because of hypertension, or is this part of his anti-tumour cocktail? If it is the second, telmisartan might be a more effective drug.
ReplyDeleteI know which mutations he doesn't have (IDH1, BRAF), but I don't know what mutations he DOES have. Was his tumor tested for EGFR amplification, or EGFRvIII. There are drugs approved for other cancers that target EGFR, and some other EGFR-targeted therapies in clinical trial for GBM. Chloroquine may also be esp. effective in tumors with EGFR amplification or EGFRvIII mutation.
I have already sent his tumor for EGFR test. Waiting for results. May be you can advise what other mutations also has targets? (I've tested only what I wrote above).
DeleteNivolumab and others are not included in insurance program of our country.
May be vaccines will be more available for us. Do you mean dendritic cells or other?
Just in terms of mutations (not including deletions, gene amplifications), the only gene that is commonly mutated in GBM that has approved targeted drugs is EGFR. In terms of gene amplifications and protein overexpression, EGFR is also the prime candidate, but PDGFRA may also be amplified or overexpressed, more commonly if EGFR is not. It's kind of an alternate tumor-driving growth factor. But there aren't any really good PDGFR inhibitors for GBM. Ones like imatinib etc. probably don't cross the blood-brain barrier very well (this is also a problem for EGFR inhibitors). Components of the PI3K family are often mutated in GBM, and PTEN (a negative regulator of PI3K) may be mutated, but again there aren't that many good drug options approved for this pathway, though there are many in clinical trial.
DeleteThe biggest drawback to vaccines is their expense. You generally get what you pay for, and the best vaccines are going to be very expensive. Dendritic cell vaccines are one type, but there are also vaccines based on peptides for tumor-associated antigens, or tumor-specific antigens found in the tumor. Also some private immonotherapy clinics offer drugs such as nivolumab, but again the main problem as far as access is the expense.
Hi, Stephen!
DeleteThey've found EGFR amplification (but not tested for EGFRvIII). And also found herpes cells in tumor...
One thing you could consider with this new information is chloroquine. EGFR-driven tumors seem to have special dependence on autophagy for survival and one of the mechanisms of chloroquine is blocking late stages of autophagy.
Deletehttps://www.ncbi.nlm.nih.gov/pubmed/29377763
https://www.ncbi.nlm.nih.gov/pubmed/23891088
The patented version of PSK was always given at a dose of 3 grams in the Japanese trials.
ReplyDeleteYou can find studies of PSK in my Brain Tumor Library on Google Drive.
https://drive.google.com/drive/u/0/folders/0B5NygvEcCgmyaFQtM29aWUdtLTQ
Send me an email if I haven't shared this with you yet.
Yes, I have an access. Thank you!
Delete