Advice for a 8 year-old boy with diffuse midline glioma, BRAFV600E and H3K27M mutation

Dear Stephen, dear all,

Anatole, my 8 year-old son has been diagnosed in May 2018 with a diffuse midline glioma on the right thalamus. We are French and based in Stockholm, Sweden. We followed the proposed protocol with the local medical team who works in partnership with Gustave Roussy institute in France but we want to go further now, and we need your advice. The local medical team is not very aware of alternative medication but is willing to help.

Molecular status of the tumour:

BRAFV600E and H3K27M mutation

NF1 and MLH1 mutation

We have little chance to find new targetable alterations by a deeper sequencing. It is possible now that the V600E BRAF mutation is lost in the resistant cells but anyway we do not think it is wise to treat with a V600E BRAF inhibitor which in our experience could speed up tumor growth.  

History:

18/05/09 Diagnosis: MRI tumour size 3.3x3.7x3.7cm, unusual calcification

18/05/16 Biopsy, leading to light hemiparesis

Proton-therapy 18/07/02-18/08/13, 1.8Gy x 30 = 54Gy. Almost fully recovered from hemiparesis

18/09/07 Headaches

18/09/07 MRI tumour size about 4cm

18/09/12 Ventriculostomy

18/09/19 Beginning og Dasatinib (100+70mg/day), after 18/11/06 alternating with Everolimus (5mg/day) every 2 weeks (Biomede protocol)

18/09/22 Beginning of hemiparesis

18/10/03 Wheelchair for walks more than 20m

18/10/12 MRI tumour size 5 to 6cm unsure if pseudoprogession

18/10/22 Beginning of Bevacizumab then once every 2 weeks

18/11/06 Beginning of Everolimus  

18/12/03 MRI tumour size 4 to 5cm unsure if pseudoprogession

18/12/17 Crook for walks less than 20m

19/01/14 MRI tumour size 5x6x5cm

19/01/22 Stop all current chemo (Dasatinib and Everolimus, last Bevacizumab 19/01/02)

24/01/24 PET scan (methyonine)

New plan established by Gustave Roussy Institute: Mebendazol, investigation for debulking of calcification before re-irradiation, eventually ONC201
Any comment on this plan?

Supplements:

Anatole is 30kg 132cm  

D3 vitamin since 18/12/24: escalading from 40µg/d to 100µg/d now

Fish oil since 18/12/24: 1g

Melatonin since 19/01/10: escalading from 2mg/d to 5mg/d now

Turkey tail since 19/01/25: 500mg/d

We plan to add soon:

Longvida Curcumin: 800mg/d

Milk thistle: which dose would you recommend? 

Green tea extract: which dose would you recommend? 

Broccoli sprouts: which dose would you recommend? 

Metformin: Is it worth considering for a child?

Anything else you would find suitable considering his condition (celebrex, chloroquine, clomipramine, berberine, selenium, probiotics, etc?

Diet:

We follow a light low carb diet now (no refined sugar or flour, very limited sugar, no processed food, only bio food). We are planning to begin a ketogenic diet soon, we are ready to change all our habits. We will contact a dietetician specialist in this diet. Anybody else with an experience of ketogenic diet with children?

Thanks to all of you for your precious help, any contribution could help.

Fabrice

Cannabis oil treatment (THC)

Dear Stephen, dear all!

What do you think about using cannabis oil with a high content of THC component to treat glioblastoma. (Exact component concentration is not known (but declared as high).

Based on recommendations of one doctor, the oil should be applied according to the following scheme (it's also known as Rick Simpson's scheme):

* first day - one drop x 2 times a day;

* then every three days increase intake by one drop in the morning and evening

* reach 24 drops (approximately 1 ml) and take this amount x 2 times a day.

There are a lot of wonderful stories about its anti-cancer effect in the Internet, especially in case of brain tumor. But then I found this research http://cancerres.aacrjournals.org/content/64/6/1943.long#sec-10.

"Treatment of the glioblastoma cell line U373-MG and the lung carcinoma cell line NCI-H292 with nanomolar concentrations of THC led to accelerated cell proliferation that was completely dependent on metalloprotease and epidermal growth factor receptor (EGFR) activity."

"In the light of these results, the use of cannabinoids in cancer therapy has to be reconsidered, because relatively high concentrations of THC induce apoptosis in cancer cells, whereas nanomolar concentrations enhance tumor cell proliferation and may, therefore, accelerate cancer progression in patients."

"Smoking of THC is the most effective route of delivery, as THC is rapidly absorbed after inhalation, and the effects become fully apparent within minutes. Pharmacological activity of smoked THC depends on the depth and length of inhalation. Maximum serum concentrations up to 267 ng/ml (850 nm) are measured after smoking THC, whereas maximum serum concentrations of oral or rectal administered THC or its derivatives as a drug are lower (35–350 nm). Here we observed a proliferative response of glioblastoma and lung cancer cells at concentrations of 100–300 nm THC, whereas THC at micromolar concentrations induced cell death in agreement with previous observations with neuronal cell types and immune cells. These findings indicate that the biological responses to cannabinoids critically depend on drug concentration and cellular context. Taken together, these results have to be taken into account when considering therapeutic applications of cannabinoids. The risk in the medical use of THC or cannabis for the treatment of patients with established tumors is the further acceleration of tumor growth due to the proliferative potential of cannabinoids."

Questions:

1. Has anyone tried to measure THC concentrationt in the blood? Are there any tests for home use that can show the quantitative content of this component in the blood? I know that there are tests for saliva and urine, but how to compare blood concentration and saliva/urine?

2. Perhaps it is easier to measure the THC concentration in one oil drop? And then to estimate what concentration it causes in the blood?

3. Do I understand correctly that THC has a cumulative effect when using daily and in principle it is real to achieve micromolar concentration after some time?

4. Is it possible to avoid the psychotropic effect with micromolar concentration?

5. Is THC effective by itself or only with radiation therapy or chemotherapy?

6. May be it's really better smoking if it allows to achieve more THC concentration? 

I am looking forward to your answers! Thank you!

And please accept my late congratulations with New Year! Let it be full of wonders! Health to all of you and your loved ones!

Irina

Recurrant anaplastic astrocytoma treatment options

Hey all,
Need suggestions for treatment options and supplementation for my brother
His clinical history is-

clinical history	date	remarks
diagnosed in	september 2009	assumed to be begnin tumour
		observation through mri
Tumour surgical resection	18th feb 2016	tumour started to enhance in size
		gross resection of more than 95%
		tumour size 7.2x5.5x5.1( anaplastic oligoastrocytoma)
RT PLUS  CONCURRENT TEMOZOLOMIDE	2ndAPRIL 2016 TO 17th MAY 2016	59.4 gy ,33 fractions plus 120 mg temozolomide
Temozolomide	june 2016 -december 2016	6 cycles
Recurrence                                                  may-18
reradiation +concurrant temozolomide	18th jul 18-16th aug 18	36gy, 20 fractions plus 120 mg temozolomide
temozolomide chemo	1st jan 19-5thjan 19	200mg per day for 5 days
HIS BIOMARKERS ARE- BIOMARKER AND GENOMIC FINDING STATUS MICROSATELLITE STATUS MS-STABLE TUMOUR MUTATIONAL BURDEN  TMB-LOW (4 MUTS/MB) ATRX  LOSS IDH1 R132H NOTCH1 A465T SUBCLONAL,E450K-SUBCLONAL,R353C-SUBCLONAL SMARCA4 T910M TP53 G245S,R273C MGMT UNMETHYLATED(METHYLATION SCORE-0.49) ANTIBODY TYPE RESULT GFAP POSITIVE IDH1 R132 POSITIVE KI-67 POSITIVE PROLIFERATIVE INDEX APPROX 10-15% FISH TEST 1P/19Q CO-DELETION NEGITIVE EGFR NEGITIVE FOR EGFR AMPLIFICATION PTEN LOSS POSITIVE (39.3% OF NUCLEI EXAMINED) His current medications are- Part of Day Medicine Name Medicine count Notes PRE MORNING BROMELAIN 500 MG NOW 3 EMPTY STOMACH TAB PAN 40 MG RT OD 1 STOP ON 30TH JAN 2019 MORNING BREAKFAST CURCUMIN TABLETS 3 NOT WITH AVASTIN OR TAGRISSO/TARCEVA GLYCEROL 30 ML 1 DIAMOX 250 MG 1 METAFORMIN 500MG 1 TWICE DAILY FROM 1ST FEB IBUPROFEN 200 MG 1 CBD OIL 2 FULL DROPPERS 1 LEVIPILL 750 MG RT 1 LASILACTONE 20/50 MG RT 1 TAB DEXA 4 MG RT 1 STOP AFTER 21ST JAN TAB BACLOFEN 5MG RT 1 REFRESH EYE DROP 2 BOTH EYES 2 DROPS LEVOLIN NEBULISATION .63MG 1 STOP ON 25TH JAN 2019 TAB GLYCOPYRROLATE 1 MG 1 STOP ON 20TH JAN TO BE ADDED VALGANCICLOVIR 450 MG 2 CHLOROQUINE 250 MG 1 CELEBRAX 200MG 1 WHEY PROTIEN 2 SCOOPS  WHEN RECD FROM USA GRAPESEED EXTRACT 250 MG 1 STRESS B COMPLEX 2 LUNCH CURCUMIN TABLETS 3 MEBENDAZOLE 100 MG 1 START DOXYCYCLINE ON 18 TH APRIL GLYCEROL 30 ML 1 IBUPROFEN 200 MG 1 LASIX 40 MG 1 REFRESH EYE DROP 2 DROPS STOP AFTER 21ST JAN LEVOLIN NEBULISATION .63MG 1 TIME STOP ON 25TH JAN 2019 TAB GLYCOPYRROLATE 1 MG 1 STOP ON 2O TH JAN TO BE ADDED CELEBRAX 200MG 1 NIGHT CURCUMIN TABLETS 3 ATORVASTATIN 40 MG 1 80 MG FROM 1ST FEB GLYCEROL 30 ML 1 DIAMOX 250 MG 1 IBUPROFEN 200 MG 1 CBD OIL 2 FULL DROPPERS 1 AFTER HALF HOUR GIVE THC 6 DROPS THC OIL 6 DROPS 1 LEVIPILL 750 MG 1 LASILACTONE 20/50 MG 1 TAB BACLOFEN 5MG RT 1 REFRESH EYE DROP 1 BOTH EYES LEVOLIN NEBULISATION .63MG 1 TIME STOP ON 25TH JAN 2019 TAB GLYCOPYRROLATE 1 MG 1 STOP ON 2O TH JAN TO BE ADDED VALGANCICLOVIR 450 MG 2 STOP ON 9TH FEB 2019 CELEBRAX 200 MG 1 BERBERINE 500 MG 1 BEDTIME ARTEMISIA 500 MG 2 WHEN RECD FROM PATRICE TAB FRISIUM 5MG RT 1 PLEASE SUGGEST 1.SUPPLEMENTS TO ADD OR TO BE DISCONTINUED 2.AVASTIN OR LOUMUSTINE OR ANY OTHER TRIAL DRUG BEST SUITED FOR HIM 3.ANY OTHER EFFECTIVE THERAPY TO HELP HIS QUALITY OF LIFE.

Phosphatidylserine

Stephen, are you familiar with the young man from Canada who is a long term survivor of GBM?

Apparently he took Phosphatidylserine but he is not intimating that is the reason for his survival.   Interesting website.



Do you have any thoughts on Phosphatidylserine?



Hope all is well.

Candy

Temozolomide + mifepristone in rat glioma model

• Mifepristone, an FDA and Health Canada approved antiprogestogen, used to induce abortion.

• C6 rat glioma cells implanted into brains of male Wistar rats
• temozolomide applied to the rats at a dose of 5 mg/kg/day intraperitoneally
• mifepristone applied to the rats at a dose of 10 mg/kd/day subcutaneous injection
• rat survival as show below ("sham" refers to rats undergoing sham surgery with no glioma cells implanted)
• combination of temozolomide + mifepristone was effective where either single agent alone was  ineffective

Full study links here: https://www.mdpi.com/2072-6694/11/1/16

advices on cocktails and corticoids

My father in France - 71 years old - has been diagnosed with a GBM grade IV in September 2018. Before that he has always been in good shape and was very sportive.
He has 3 tumors from 10mm to 40mm and seems to be inoperable. He already had 3 sets of TMZ and he is taking already some supplements I recommended based on my researches on Internet. 
Here is his complete current treatment started 1 month after first diagnosis (time to perform biopsy) :

Temodal	3 cycles of 5 days done
Corticoids - Solupred	50 to 60 mg / day
Cannabis suppositories	1g / day (80% THC)
Chinese herbs and mushrooms (including Artemisia Annua)	every day
Vitamin C	5g / day
Nutraexpert Lipo HCA dietary suplements containing:
HCA	1500 mg / day
Alpha Lipoic Acid	1600 mg / day
Capsicum	112 mg/ day
Quercetin	45 mg/ day
Ginger	46 mg/ day
Whey	47 mg/ day
Green tea	30 mg/ day
Nicotinamid	20 mg/ day
Vitamin D3	25 µg/ 1000 UI
Ketogenic diet
Curcuma (Longvida) : added last week	1g / day

Biopsy revealed :

• IDH1 : negative
• FGFR3 : negative
• P53 protein : 15 - 20%
• no information on MGMT

MRI performed early december has show a slight size increase in the 2 biggest tumors, the oncologist says it is not alarming as the treament started one month after first diagnosis.
Currently my father resists well and tries to keep daily walking activity. Next MRI will be next month. 

I just recently discovered the cocktail approach and your blog and I have some questions.

1. It seems many patients are taking Melatonin 20 mg/ day (forbidden in France at this dosage by the way) and that it could be of good help : sustains the immune system, anti-oxidant, anti inflammatory, leads to cancer cells suicide ... Should I add Melatonin to the treatment ? It seems also that Malatonin is non compliant with corticoids as it inhibits corticoids effects : what do you think ?

2. More globally I fear corticoids may have a negative impact on the different supplements. Is there a mean to sustitute it by anything else ? Is Celebrex an option ? If so at which dosage ? (the inflammation is still important, but decreasing).

3. Would you have any recommandation in other supplements or drugs ? PSK mushroom, Valpoic Acid, Metformin? 

Thank you very much for your precious help.

Question about TP53 Mutated Tumors and Use of Chloroquine

In reviewing the section on TP53 from Astrocytoma Options, I noted "autophagy inhibition with chloroquine prevented restoration to normal P53 function" and therefore best to avoid autophagy inhibitors. Would someone kindly clarify whether this suggests chloroquine should be avoided for my husband who was found to have TP53 Variants including insertions/deletions? 
We have been using it for its purported benefit for EGFR amplification.
If so, are there other autophagy inhibitors to avoid?
Would Zinc be worth adding? (Tried it briefly in the past and experienced GI upset).

Many thanks and healing wishes to all--

Limited activity

My personal computer is out of service and I won’t be able to get a new one until next week at the earliest.  Consequently my blogging and researching abilities will be very limited until then. Thanks for your patience and best wishes to all in the new year!
Stephen