New Approaches to grading of IDH-mutant astrocytomas

Novel, improved grading system(s) for IDH-mutant astrocytic gliomas.

https://www.ncbi.nlm.nih.gov/pubmed/29687258

Given the list of all-star pathologists and neuro-oncologists behind this paper (including Andreas von Deimling, David Louis, Wolfgang Wick, Michael Weller, Roger Stupp, Monika Hegi, Martin van den Bent, Michael Platten, and many more), this work will very likely get translated into actual changes of the grading system for IDH-mutant astrocytomas.

"In conclusion, in all three validation sets the tested grading models performed better than the current WHO system."

"Thus a genetic approach to taxonomy would favor a term such as “high-grade A IDHmut” rather than the current term of GBM-IDHmut."      "One possible solution, which we have considered implementing in Heidelberg, would be to restrict classification to the term A[stroctyoma] IDHmut and then adapt grading according to molecular lesions, thereby omitting the term GBM-IDHmut. The term “glioblastoma” would be reserved for those histologically defined glioblastomas lacking IDH mutation or not having had adequate (not otherwise specified, NOS) or diagnostic (not elsewhere classified, NEC) work-ups"

Nice to finally see the above quotes in print, this has been my opinion for years.

This is an excellent study. My only criticism is that hypermutated tumors with very high mutational load were not evaluated as a distinct group.  This is different than the high or low copy number variant load (CNVL) considered in the paper.  Mutational load was only mentioned once, in the discussion:

"An interesting parameter emerging from our analysis was CNVL [copy number variant load]. A proportion higher than 350 Mb either lost or gained in the areas covered by the methylation arrays correlated with poorer OS. Previously, the mutational load has been shown to correlate with tumor grade in IDH-mutant glioma [9]. While our data more reflect genomic instability and those data rely on an accumulation of mutations they also support a quantitative approach to tumor grading."

Methadone

Hi all,

thanks for your responses to my previous post.

In germany methadone is a huge topic which is often discussed in media.

Dr. Claudia Friesen, who works in a university hospital was the first who randomly discovered the effects on brain tumors.

On April 21 2018 there was a big convention in Würzburg, called the brain information day she talked about her experiences. She told the audience that she knows 79 persons using methadone between 2013 and 2018. 13 of them died, the others survived till this day:         

35 of them more than 2 years 

25 of them more than 3 years

   4 of them more than 4 years

   2 of them more than 5 years

Unfortunately there is no clinical study to back her results. Dr. Friesen is fighting to get methadone tested in a real study but there is no big support in the established brain tumor research.

Lots of german researchers doubt her results and even refuted them in a little study. Dr. Friesen argued that their study was done wrong. For example they used another formula of the methadone. Dr. Friesen used D,L-methadone in combination with Temodal.

The idea of methadone is to increase the effect of Temodal.

I hope she gets her study, till then you can trust her or not. 

If you want to take methadone, you should start with 3 drops in the morning and evening and increase to 20 - 35 drops two times a day. For example you can take 2 x 3 drops on day one, 2 x  4 on day two and so on and stop when you can not tolerate more. You should then stay on that level. If you want to stop methadone, you have to reduce the dose slowly.

Side effects are mainly constipation but there are lots more possible, especially if you increase or reduce your dose to fast. You can find them in Wikipedia for example. In my experience you need 1 month to get used to it, so be careful and patient.

 

Questions regarding supplements/repurposed drugs

Hi,  I want to thank those of you that responded to my previous post.  For some reason, I can write posts but not respond?  Anyway, I am trying to figure out additional repurposed drugs/supplements to have my son take with his "main" treatment.  Briefly, he had IDH1+ AA3 (diag. originally 1/11)  treated with proton alone fall of 2012 with small recurrence found late 12/17 MRI. Eventual surgery showed GBM that is still IDH1+ (as expected) but hypomutated (GTR with very generous margins--tumor in "unimportant" part of frontal lobe).  He is enrolled in a clinical trial (metronomic TMZ/PARP).  I wanted to make certain that he can tolerate his "main" drugs and then sequentially add supplements/repurposed meds (with the approval of the study supervisors).  He is already taking Keppra, melantonin 20 mg and will likely start Celebrex later this week.

--I was going to add Longvida given data...but it states that it "reduces oxidative stress"...isn't the idea to try to stress the IDH1+ residual tumor?
--I was thinking of having him add chloroquine and/or metformin.  However, I have read the inhibiting autophagy (as chloroquine purportedly does) can either promote OR suppress tumor growth?  He doesn't have a BRAF mutation (or many at all--at least not yet).
--I have read about dihydrotanshinone, that can reportedly cause endoplasmic reticulum stress and sensitize to TMZ.  Is this something to consider?

Are there any supplements that seem particularly useful for IDH1+  patients?

Thank you very much,  Marcia

Semyon's mom's profile.

My mother had an operation (in Germany, Frankfurt am Main) - removal of the tumor by 99%, and then - the rapid growth of the tumor to its former size (for 3 weeks)! The doctors were in shock.
(Glioblastoma, MGMT methylated)
10 days after chemoradiotherapy, MRI still showed tumor growth. The doctors decided that TMZ did not work in our case and suggested urgently switching to Avastin and Irinotecan.

Thinking, we decided to use a low dose of Avastin + CCNU.
I also decided to add 5 days of low TMZ after every day of CCNU.

The OncoDeep report showed the likely effect of Sirolimus, Olaparib and Trametinib.
I flew to Delhi (India) and bought at low price LYNPARZA Olaparib (1 bottle of 112 capsules of 50 mg) and MEKINIST Trametinib (1 bottle of 30 2 mg tablets).

Unfortunately, it is very difficult to interpret MRI. 3 doctors who watch my mom's MRI say sometimes the opposite conclusion!

Comments:

1. Suppression of T4 is very slow. We spent 3.5 months to reduce T4 from 12.4 to 3.3pmol / l. Also, T3 has fallen dramatically, although we take synthetic T3. Because of this, drowsiness and lack of appetite.

When suppressing T4, you can not take selenium, since it increases the production of the hormone T4! We started taking selenium and the hormone T4 took off from 3.3 to 5.14! Now with great difficulty again we need to knock it down((

2. For all treatment, my mother lost a lot of weight. From 65 kg (in January) to 52 kg (now). However, I do not see anything that we could refuse.

3. We bought a special meter and ketone strips to check that the mother is ketosis.

4. I ordered Mebendazole chewable tablets from Thailand for 500 mg / tablet. Maybe we will try to take large doses: 2-3 grams per day.

5. We use a higher dose of perillyl alcohol than Dr. Dr. Clóvis Orlando: 30 drops instead of 21. No unpleasant sensations! We plan to increase the dose to 40 drops. Dr. Clóvis Orlando wrote that they use perillic alcohol of 96% from Sigma Aldrich and that the other perillyl alcohol will not have an effect on GBM.

MRI-1: https://drive.google.com/open?id=1tPKrQgjIZzBgefhkknxNlQKbaC04XMI_

MRI-2: https://drive.google.com/open?id=1t3SgxGgJFi19i9qIwc47JucsV6ZCbLFa

MRI-3: https://drive.google.com/open?id=1JbRYk3DCUK87ndeRQK-Q7V7130oObiMV

MRI-4: https://drive.google.com/open?id=1Q6WFd9qtFAd18czkd5ouKYloIVBKuFS1

MRI-5: https://drive.google.com/open?id=1L-O1BgoVMohI7eXxH35qN__rNBDy3hrM

MRI-6: https://drive.google.com/open?id=1xWYd5_UsrAYb-c4wv49DSWTeJEN8Dl_F

MRI-7: https://drive.google.com/open?id=1MCpzZxPnl7eI1iigzJVWrOo2o4s8hKWz

MRI-8: https://drive.google.com/open?id=1De95kb-iZ30X7scIbZkeXxFq4KV5fgdT

11C-methionine PET 17.05.2018:
https://drive.google.com/open?id=18AaVybu5nvBH_cAe5QIfzO-efiwsUfkc

OncoDEEP report: https://drive.google.com/open?id=1A3dophOME6gY1GNdOHWE48wVYJUu_nHc
http://btcocktails.blogspot.ru/2018/02/our-report-oncodeep-what-do-you.html

 

GBM case, debrief

I’ve barely visited this site since my wife passed in August.  My introductory post was:

http://btcocktails.blogspot.com/2016/06/introduction-and-introductory-thoughts.html

There may be lessons or clues to share that could be of use to others. 

Diagnosed with L tempo-parietal 4cm GBM 5/16 after a stroke-like episode.

Gross total resection, with near-total resolution of all symptoms.

Stupp protocol of radiation+temozolamide.  Poor tolerance of TMZ.

Experimental Nivolumab/Opdivo.  Tolerated well at first. 

Follow-up MRI showed severe cerebral edema of much of the L hemisphere.  Clearly an Opdivo effect.

This necessitated halting Opdivo.  Avastin/Bevacizumab produced dramatic, immediate improvement in cerebral edema, far more effective than Decadron, which had to this point had little apparent effect on edema.

Avastin was well-tolerated initially, but after 3+ doses at q 2w intervals, started to suffer abdominal symptoms.

Recurrence diagnosed 4//17.  Almost got into an NIH CAR-T trial, but deteriorated too quickly to qualify.

https://clinicaltrials.gov/ct2/show/NCT01454596

Steady downhill course after that, ending in home hospice care. 

Throughout this time, I gave a supplement cocktail roughly equivalent to Ben Williams’:
http://btcocktails.blogspot.com/2015/07/ben-williams-supplement-list-for.html

Plus ketogenic diet.

One possibly useful addition was Celebrex.  In addition to anti-tumor properties, I note that animal studies show comparable effectiveness of NSAIDs and decadron for cerebral edema.  No oncologist is going to use Celebrex instead of decacron for this purpose, because of lack of human trials.  But we’re all going somewhat off-script here already anyway.

My strong impression (from this N-of-one study) is that during the time she was on the full cocktail and NOT on decadron, there was little or no sign of progression. 

My impression is that Avastin didn’t accelerate her course directly, but that it led to GI symptoms that made her tolerate poorly all the supplements I wanted to give her.  I believe progression accelerated off the cocktail.

My impression also is that Decadron helped little with any of her signs or symptoms, but it caused terrible side effects and (I believe) faster progression.  She developed some psychotic symptoms at a dose of 4mg/d of decadron.

We didn’t do genetic studies (beyond methylation status) on the tumor.  Money was tight and (given the typical genetic heterogeneity of GBM), I’m skeptical that gene-specific approaches are likely to yield more than a few weeks of added survival.

Checkpoint inhibition seemed to have potent effects.  It would seem careful dose titration against cerebral edema effects may be important.  Alas, dose titration wasn’t possible on the study protocol—all or nothing only.  Avastin might prove a useful treatment for resultant cerebral edema in other cases.  But I’d recommend shorter-term use of Avastin, primarily to treat edema.

We were lucky to have long-term care insurance to help with caregiving in home hospice.  We were also lucky to have supportive friends and family.  This is a phenomenally expensive disease to manage--financially and emotionally.  Her passing was ultimately about as humane as it could possibly be.  She is missed.

Best wishes to all,

Steve

Anatomic features vs pathology vs molecular stratification

Found this interesting article - and even though it is quite old (2008) and only involves a small cohort of AA3 patients for it´s statistics, I still found it interesting.

In most, especially recent, articles the main focus is on either pathology (mitosis count, proliferative index etc) or on molecular constitution of the tumors - or at least the combination.

This article is interesting because it also focusses on the anatomy of the tumors - particular enhancement and - even more important - resection degree and growth pattern of the tumor.

And if you look at survival statistics - even though from a small cohort - in the article there seems to be quite some interesting viewports in analysis of the anatomy of the tumors.

https://onlinelibrary.wiley.com/doi/pdf/10.1002/jmri.21593 

This article was of course before the WHO 2016 definitions and it doesn´t concern itself with the further diomensions of e.g. IDH, methylation ATRX etc. That would probably add some explanation to some of the quite dramatic differences in OS in the cohort.

Any thoughts on this aspect of tumor anatomy or other interesting studies to the subject?

Thymoquinone (Nigella sativa) inhalation

Nigella sativa is a widely used medicinal plant throughout the world. Most of the therapeutic properties of this plant are due to the presence of thymoquinone which is major bioactive component of the essential oil.
There is more information about the possible intranasal use of thymoquinone for the treatment of glioblastoma.

Therapeutic Potential of Thymoquinone in Glioblastoma Treatment: Targeting Major Gliomagenesis Signaling Pathways
2018 https://www.hindawi.com/journals/bmri/2018/4010629/
"Due to its multitargeting nature, TQ interferes in a wide range of tumorigenic processes and counteract carcinogenesis, malignant growth, invasion, migration, and angiogenesis.
Its potential to enter brain via nasal pathway due to volatile nature of TQ adds another advantage in overcoming blood-brain barrier."
"Interestingly, even the lower efficacy and poor bioavailability of TQ are the primary bottleneck of TQ, its volatile nature provides opportunity to be exploited for use in novel drug delivery strategy via intranasal pathway to brain due to unique connection provided by the olfactory and/or trigeminal nerve system present between the olfactory epithelium and the central nervous system. Such delivery system provides opportunity to bypass both the BBB and hepatic first-pass metabolism."

2012 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3497894/
"The studies suggest intranasal delivery of TQ to be a promising approach for brain targeting as well as in reducing the systemic exposure."

2016 https://www.ncbi.nlm.nih.gov/pubmed/26976069
"Present work aims to prepare nanoemulsions (Thymoquinone Mucoadhesive Nanoemulsion) in order enhance the bioavailability of drug and hence evaluate the drug targeting in brain via non-invasive nasal route administration."

The question is, how can we now do inhalations with Thymoquinone to benefit from it? In what form can we use Nigella sativa / Thymoquinone for inhalations?
- Thymoquinone, ≥98,5% (GC):
https://www.sigmaaldrich.com/catalog/product/sial/03416
- Essential oil from Nigella sativa:
https://www.amazon.com/Black-Cumin-Essential-Nigella-sativa/dp/B01G8ZTX12
- Or without inhalation, just like a drop for a nose:
https://www.etsy.com/listing/565401697/black-seed-nose-drops-nigella

 


And additionally about the effect of oral Nigella sativa oil on metabolism:
https://www.ncbi.nlm.nih.gov/pubmed/19902033
"A RCT done on 60 patients with metabolic syndrome showed that NS oil (5 mL/day) used in combination with atorvastatin and metformin could decrease fasting blood sugar (FBS), LDL, and TC significantly after six weeks of use."

Medulloblastoma CMyc amplified - searching for pathways

Hi everyone. Thanks for having me here. Long story short: Nikodem 6yo. Diagnosed on 31 dec 2017. Medulloblastoma group 3 with CMyc amplification with spread (sugar coating) all over spinal canal. Full resection in Warsaw on 4.01.2018. (tumour size 2x2x2,5cm). Two cycles of initial chemo: - carboplatin, etoposit & vincristin - cisplatin, etoposit & haloxan Then 15th of february MRI showed NED. We broke polish protocol to speed up radiation - 34 radiations with protons in Essen Germany with 4 doses of concurrent vincristin.            From the beginning of treatment we also deployed:            - b17 amygdalin with pancreatic enzymes, b15 and vit C            - high doses of vit D3 + A            - milk thistle            - melatonine            - flavone            - silicea            - vit E400            - iodine            - vit B1, B12            - zinc            - selen            Boy is feeling ok has loads of energy.            Getting little bit weaker during radio/chemo.            This is happening right now:            We have 5 more radiations to go and then            have option to go back to Poland to carry on with maintance chemo: Cisplatin, irinotecan, temodal & lomustine. Nobody has never done it in the past and this one sounds hardcore. Our doctor is planning to do it for a 1 year period (!) Im thinking about shortening that period and doing some immunotherapy at IOZK after that as a finishing of protocol. Also Im reading now about statins - lovostatin and want to ask our doctor to add it to maintance chemo as inhibitor of CMYC. I know there is a trial for relapse medulloblastoma in Wien where they use fenofibrate - another anticholesterol drug. My thinking is: We have good response for treatment and our biggest problem is to inhibit CMYC as its the main enemy. As the doctors say we have only one shot with this diagnosis - cant let relapse happen. Does anybody has any experience, thoughts, ideas on this. Regards Bart Kinas            Nikodem's dad

The combination of DCA and a high dose of R-lipoic acid.

The MetaBloc protocol, which includes 800 mg of R-lipoic acid BID, looks interesting.
At the same time, the administration of DCA looks promising. It is reported that R-lipoic acid (form of alpha-lipoic acid) reduces the side effects of DCA.
Now my mom takes together DCA (8mg / kg / BID) and R-lipoic acid (800mg / BID).

However, I found an unexpected opinion about this!!! ↓↓↓

https://www.cancertreatmentsresearch.com/dichloroacetate-dca-treatment-strategy/#comment-4502

“The difference between DCA and ALA is that DCA increases the production of ROS already overexpressed in cancer cells, such as chemotherapy to trigger either apoptosis, autophagy or necrosis of cancer cells. ALA on the contrary will tend to reduce the production of ROS to its normal threshold as in a healthy cell, thus triggering apoptosis if the cell detects a corruption of its DNA. In fact the overproduction of ROS, at the first level will lead to DNA corruption (cancerous state), to the next level we have apoptosis, then autophagy and then necrosis. Thus, with chemotherapy, such as DCA, cancer cells are destroyed by increasing their ROS production, but at the same time healthy cells are transformed into cancer cells by increasing their ROS level in the first stage...

DCA and ALA fall into two opposing strategies, DCA acts by citotoxicity like chemotherapy or radiotherapy, ALA acts by bringing the cells back into their normal operating context (normal ROS level for example). ALA is often taken to correct the neurological effects of DCA, but as part of the cancer their actions cancel each other out, so avoid taking them together. When it starts with an anti-cancer treatment citotoxic, after a certain time it will have to be interrupted before it becomes too harmful for the healthy cells and give the relay to the immune system supported by supplements like ALA, HCA, curcumin, vitamin C, etc."

http://treatingglioblastoma.com/treatments/dichloroacetate_DCA.htm
"Incidentally, I have concerns about any chemo patient taking ALA because it is a powerful anti-oxidant and probably increases intracellular glutathione levels in cancer cells, thereby contributing to chemoresistance. In addition, Dr. Michelakis reports that DCA preferentially increases reactive oxygen species (ROS) in cancer, but not healthy cells, which helps induce apoptosis. I have concerns that ALA could also help reduce the effectiveness of DCA."

However, in this article it is written about similar mechanisms of action of DCA and alpha-lipoic acid:
http://crescopublications.org/pdf/CROOA/CROOA-2-019.pdf

"Inhibition of PDK with either α-LA, small interfering RNAs or dichloroacetate (DCA) shifts the metabolism of cancer cells from glycolysis to glucose oxidation. Such metabolic rewiring is effective in reducing cancer cell growth in mice. The efficacy of cytotoxic chemotherapy is enhanced by the combination of α-LA and HCA. Similarly, DCA enhances the efficacy of cytotoxic chemotherapy or radiation therapy."

http://www.portmoodyhealth.com/cancer-centre/integrative-cancer-therapies/intravenous-alpha-lipoic-acid-iv-ala/
"Furthermore, ALA is cofactor of pyruvate dehydrogenase, an enzyme that converts pyruvate to acetyl-CoA, which reduces the formation of lactate. Lactate is produced from glucose in excessive amounts by cancer cells, as a result of altered cell metabolism (a phenomenon known as the Warburg effect). ALA reduces the amount of lactate produced by cancer cells, slowing their growth rate (19,20). In this way, ALA is synergistic with DCA (dichloroacetate) in its ability to alter cancer cell metabolism."

In reports on the treatment of Medicor, DCA is used together with R-lipoic acid.
For example, here:
http://medicorcancer.com/metastatic-ovarian-cancer/
"The patient consented to DCA treatment and was started at 23 mg/kg/day (500mg p.o. b.i.d.), on a cyclic treatment of 1 week on, and 1 week off. She was supplemented with vitamin B1 100mg p.o. t.i.d., and R alpha lipoic acid 300mg p.o. t.i.d."

Stephen also writes in one of his comments:
"Notably, one of the mechanisms of alpha-lipoic acid (inhibition of PDK, pyruvate dehydrogenase kinase) is a mechanism shared with dichloroacetate (DCA)."

Your opinion? Is it possible to combine a high dose of R-lipoic acid and DCA?
Will not they counteract each other?

P.S. An interesting conclusion of this study:
http://www.anaturalhealingcenter.com/documents/Thorne/articles/R-Lipoic12-4.pdf
"In order to significantly extend Cmax and AUC, it is possible to administer three 600-mg RLA doses (as NaRLA) at 15-minute intervals to achieve plasma concentrations similar to those from a slow (20-minute) infusion of LA."
How can we use it? Take 800mg of NaRLA in three doses at intervals of 15 minutes?

Also, because of problems with the stomach, I consider intravenous administration of alpha-lipoic acid. What dose for one infusion should be taken to equal 800 mg of BID NaRLA? And how often to make such infusions? I find different options: daily infusions or 2-3 times a week.

Our experience with TMZ/CCNU

Dear all,

I wanted to share our experience with CCNU/TMZ.

Background: Tumor has MGMT methylated and  IDH1+; surgery + radiation took place in H2 2016. My wife started TMZ according to Stupp early in 2017. Dose was reduced to 150mg/m² with 2^nd cycle because of low blood counts. She tolerated TMZ pretty well afterwards (almost no nausea, good blood measures). My wife continued with TMZ after finishing the initial 6 cycles (total of 8 before switching to CCNU/TMZ). MRIs were stable but not clear. There is an area with contrast enhancement (stable).

We got our oncologist to switch to CCNU/TMZ after the first promising NOA-09 results were released in September 2017. The treatment had a strongly negative impact on blood counts (neutropenia, thrombocytopenia), so that the cycles lasted ~10 weeks (instead of 6) and the initial dose was reduced (no other side effects). My wife got injections to help her over the lows.

Cycle 1 (Oct 17) with 80mg/m² CCNU + 150mg/m² TMZ: Thrombocytes dropped from ~170 -> 50 (low at day ~43, recovered afterwards), leukocytes from 3.5/4 -> 1.3 (low at day 43 and stayed there for ~ 3 weeks with the exception for an injection).

Cycle 2 (Jan 18) with 80mg/m² CCNU + 100mg/m² TMZ: Thrombocytes dropped from ~180 -> 36 (low at day ~45, again quick recovery afterwards), leukocytes from 3.5/4 -> 1.3 (low at day ~45 and remained low again for ~ 3 weeks).

Cycle 3 (Mar 18) with 50mg/m² CCNU + 100mg/m² TMZ. No results yet (third week).

I assume that our oncologist will recommend to pause the treatment for a while (will see her next week) to allow for a recovery.

Medications available

I was recently contacted by a GBM caregiver who no longer needs the following medications, and is looking for a brain tumor patient in need of them:

Email me (Stephen) and I will co-ordinate from there.

Alfuzosine Hcl ER 10 mg tablets

Aprepitant Capsule, USP, 40 mg

Bystolic,(nebivolol) 10 mg tablets

Chloroquine, 150 mg tablets

Dexamethasone, 0.5 mg, 1 mg, 2 mg, 4 mg

Diclofenac Sodium topical, "Voltaran Gel"

Disulfiram, 250 mg

Doxycycline, 100MG Capsules

Enoxaparin sodium injection, 40 mg

Fluoxetine, 20 mg tablets

Finasteride, 5 mg tablets

Flurosemide 20 mg tablets

Hydroxychloroquine, 200 mg tablets

Isotretinoin Capsules, 20 mg (some of these were purchased online)

Lacosomide 50, 100  and 200 mg tablets

Levetiracetam Oral Solution USP, 100 mg/mL

Levetiracetam, 500 mg tablets

Mebendazole, 100 mg tablets

Metropolol ER Succinate 25 mg tablets

Minocycline 

Omeprazole

Pioglitazone, 15 mg

Pravastatin, 20 mg tablets

Prazosin, 1mg capsules

Prednisone, 10 mg tablets

Promethazine, 12.5 mg tablets

Propranolol, 40 mg tablets

Propranolol ER, 80 mg tablets

Quetiapine, 25 mg tablets

Risperidone, 1 mg tablets

Sildenafil, 50 mg tablets

Simvastatin 20 mg tablets

Sulfasalazine, 500mg tablets

Tamoxifen, 20 mg tablets

Telmisartan, 80 mg tablets

Valaciclovir, 500 mg tablets

Valganciclovir, 450 mg tablets

Verapamil, 80mg tablets

Verapamil ER, 180 mg tablets

Hi Stephen and community,

first i want to say thank you Stephen for your great work!

After few month of reading i wanted to ask some questions as well.

My brother has a AA3, IDH+, unmethylated. After a "full" resection and chemoradiation he is getting his 7. round of TMZ chemo(23-5).

We started with a little cocktail while radiation, mainly EGCG. We then started methadone, selenium, Curcumin and ECGC for his first round of chemo. Time after time, with the help of this blog, we added some further supplements and increased the doses. Additionally we did electro hyperthermia treatment while chemoradiation and now in chemo weeks. 

The actual cocktail contains:

·         Sativex 8 drops a day

·         Melatonin 20mg

·         Methadone 25drops twice a day

·         Keppra 2000mg

·         Alfacalcidol 2mg

·         Curcumin longvida 3000mg

·         Q10

·         Maitake

·         Reiki

·         Shiitake

·         Selenium 200mg

·         Omega 3 3000mg EPA/DHA

·         Resveratrol 1000mg

·         Milk Thistle 2000mg

·         Garcinia Cambodgia and Sodium R Lipoate 500/800mg

·         Sulphoraphan 200mg

·         Artemisin

·         Aged Garlic Extract

We are thinking about Metformin.

I would like to ask Stephen the following questions:

·         Should one of the named supplements not be used in the chemo week?

·         Should we use a schedule for taking the supplements when he does not take chemo? He takes the most pills mixed throughout the day. Only methadone (morning and evening), melatonin (before bedtime), keppra (morning and evening) and selenium (before bedtime) at fixed times and curcumin with empty stomach.

·         Should we change our schedule in chemo weeks? Usually he takes methadone, sativex and melatonin half an hour before the TMZ. ECGC, Resveratrol, Curcumin and Omega 3 with the TMZ. The rest 4 hours before the TMZ. In chemo weeks he doesn`t take Garcinia Cambodgia and Sodium R Lipoate.  One hour after the TMZ he does electro hyperthermia on the first,third and last day of chemo.

·         Do you have informations about using Sativex? I asked GW pharmaceuticals about their study but they did not want to give me any information. In which temporal context should it be taken in chemo week and between? How many drops should be taken? 

Thank you for your help!

All the best for you all!

Low grade cocktail

Hi Stephen and everybody else.

I am trying to put together a cocktail for a low grade glioma. I am sorry for my english and hope you can understand.  Here is my history: Craniotomy on 19. 1. 2018 - 10% of the rather big tumor stays in head (right frontal lobe). Diffuses Astrocytom WHO 2. IDH1 R123H positiv (IDH mutant), ATRX lost, MGMT methilated at 14 %, 1p/19q not codelated. Photon radiation therapy 55Gy in progress. At the time of radiation: Vimpat 250 mg/da, fish oil (from algae - EPA, DHA), curcuma, ketogene diet.

After the end of radiation should I start the chemotherapy. 1) Does it matter how long time after radiation should I beginn? 2)Should I do 6 or 12 cycles – on what does it depend?

Here is my plan what to try:

CCNU + TMZ (following the CETEG protocol in a hope that it gives me more time and decreases the risk of hypermutation)

Keppra 500mg 2/day (should I do up to 1000mg  2/day on chemodays?

Methadon (2x 35 dropps) and CBD+ THC (not sure here how much) - I do not know if the combination is possible (would I be too high on those  drugs?)

Dissulfiram 500mg/day on chemodays together with copper glutonate 3x 2mg/day. Should I take it as well on non chemo days and how much?

Melatonin 20mg/day before bed

Vitamin D alfacalcidol (no idea how much. I have very low levels of vit. D recently)

Chloroquine 150 mg/day

viagra 20mg 2/day to open BBB

Selenium, zink and other supplements with minerals and vitamins (because of the diat that is not optimal). 

Fish (algae) oil EPA DHA

Berberine

Curcuma

Should I change the drugs/supplements on chemo/ nonchemo days - sometime more and sometime less

?

Should I try some other supplements and drugs or do I need to leave something out? Any comment is apreciated.

Diet:standart veganish diet few days before chemodays to let the cells proliferate on carbs so they can die in the process. Few days after the chemodays when the drugs are out of the system back to ketodiet with low methionin. This idea migt be a nonsence. What diet should I opt for at the time of chemotherapy or it does not matter that much…?

Thank you for this great blog community and for your advice.

Vojtech (the Czech Rep. / Germany)

Reaction between supplements and CCNU/TMZ combination?

Hi folks/Stephen,

My mother, a GBM patient(Methylated) has completed 3 Temozolomide cycles and starts with her next cycle being Temozolomide + Lomustine. She is on the following supplements:

Boswellia Seratta 4 g/day, Keppra 1000 mg/day, Curcumin 3 g/day, Quercetin(4 g/day), Fish Oil 4 g/day, Resveratrol (400 mg/day), Marrow Plus(6 caps/day), Echinsea(2 g/day), Bromelain, Ginger, Garlic, Ashwagandha, Melatonin, Vitamin D3, Selinium, Molydenum, Artemesia, Malatonin 1500 mg/day, Melatonin 20mg/day, EGCG extract 400 mg/day, Celebrex 600 mg/day

Plan to add: Care Oncology Protocol,  Ruta 6 + Calceria Phos, Cannabis Oil, Low dose Naltrexone

I had three questions, would be great if you could answer:

1. My mom's blood counts are still not really good. Her WBC count is 1700 and her Platelet count is 120k. My oncologist is suggesting we start the chemotherapy protocol as it has already been 28 days since the last temozolomide cycle. He says that we will use fligrastim injections(WBC injections) to manage the further dip in WBC counts, if at all they happen. Wanted to know if any of you have an experience/knowledge of whether it is okay to start the temozolomide+Lomustine combination with the low counts that my mom has, or should I wait further? I ask because my oncologist is using this combination on a GBM patient for the first time, and he thinks it is a little late already to start.

I also ask this because typically the gap between two TMZ + Lomustine cycles is 36 days(6 days of chemo + 36 days for the next cycle, making it a 6 week cycle), while the gap between two Temzolomide cycles is 23 days. Wondering what should be the maximum allowable gap between a temozolomide cycle and a temozolomide+lomustine cycle to make sure the efficacy of the chemotherapy is maintained.

2. I also wanted to know if I should be cautious of any of the supplements? I've read the Ben Williams book in good detail, and all of them talk of how the above supplements increase the efficacy of temozolomide, I don't really know if there is any reaction between lomustine and the above mentioned supplements, and that I need to be careful with or should I consider dosing down on?

3. Are there any adjuvants that you would suggest that can further help increase the efficacy of this combination? I was considering methadone, which I've read works really well with temozolomide, but I'm not sure if it'll work with this combination.

PS: I'd like to mention that I complete 7 months in this extremely tough journey, and this blog is my go to place to find quality answers to my queries. Thank you Stephen for sharing your knowledge and to all the members of this blog for sharing your experiences with us :)

Sensitization of cancer (stem) cells by Doxycycline to Vitamin C, Berberine, Chloroquine and others

Dear all,


I recently came across the below study, which I thought was rather interesting:

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5620172/

The authors used incrementally higher dosages of Doxycycline (12.5 uM, 25 u.M, 50 uM) in vitro on cancer cells in an effort to create metabolically inflexible cells and to test whether these would be then be more sensitive to metabolic inhibitors, including natural agents (Vitamin C and Berberine) and various meds (Atovaquone, Irinotecan, Sorafenib, Niclosamide, Chloroquine, and Stiripentol).

The cancer cells in the study ended up being highly sensitized to some of these agents, for example Vitamin C (4-10 x more sensitive), Berberine and Chloroquine. It's noteworthy that, following Docycycline treatment, cells became sensitive to Vitamin C at a dosage level which is reachable orally (IC-50 = within the range of 100uM - 250 uM). My understanding is that newer Vitamin C formulations using oral Liposomal delivery (e.g.: https://www.livonlabs.com/cgi-bin/start.cgi/liposome-encapsulated/lypo-spheric-vitamin-c.html) can reach concentrations of up to 400 uM in the blood, a level at which cell elimination in vitro was in excess of 90%).

I'm curious if these results could be replicated at least directionally in a human setting, as it would be a rather cost effective and non-toxic approach. Any thoughts?

A few questions I'd have for example are:

1. Is this Doxycycline cell sensitization replicable in a human setting? If so, at what dosage?
2. Is there any chance an oral Vitamin C formulation (e.g. Liposomal) could replicate the effect seen in vitro? Alternatively, I presume IV infusions would do the job?
3. Which of the other agents would be the most feasible otherwise?

Best regards,
John