Irina's mom genomic sequencing report

Dear Stephen! Dear all!

1) Could you please help me with genomic sequencing report!
Probably you could advice any beneficial drugs for our sitation.
Now we use DCA, metformine, chloroquine, celebrex, prozak, boswellia, pterostilbene, EGCG, BroccoMax, berberine, omega 3, milk thistle, cannabioids with high thc - 74%).












Options 1 and 3 have the most pathological nature.

• Option number 1 is located in the KDR gene, which is an oncogene, and involved in tumor angiogenesis processes.
• Option number 3 is in the gene PMS2, which belongs to the tumor suppressor genomes, and is involved in the repair of unpaired
• bases (edits DNA replication errors). Associated with many tumor diseases. This option, as follows from sources (column PMID) often has a germinal nature (is congenital).
• Option number 4 is located in the gene ROS1, which is a proto-oncogene, and encodes a number of tyrosine kinase receptors. He might be both congenital and acquired. 

These mutations currently have no targeted drugs.

Mutation load (Tmb) - high: 3.79 m/Mb (with a threshold value of 0.8 m/Mb)

Microsatellite instability (MSI) - presence (bottom line):

- 11.9% / 12% repeat

- mutations 2 reparation genes of 4

2) How do you think is it worth to try ONK201 drug for my mom if she don't have h3k27m mutation? I read on the forum on face book that many adults with glioblastoma without mutation use it and have positive results. 

Does it really kill tumor stem cells?

Thank you so much!

Treatment options on recurrence

After diagnosis in August 2015, followed by surgery, radiotherapy and tmz.  Mark had a recurrence in January 2018 followed by 6 months of tmz. He had another recurrence in October 2018 and had intense radiotherapy after rapid growth. We are now faced with a further recurrence and have been offered PCV and surgery is not an option.We are in the UK. During this time we have followed the cocktail approach used THC/CBD. and had live tumour immunotherapy in 2016 and 2018 with monthly NDV and localized hyperthermia  at IOZK. Mark started the Care Oncology Protocol in December 2018

We have incomplete pathology of the tumour but evidence suggest low mutational burden and standard  characteristics of mesenchymal: IDH1 wild type, P10, TERT TP53. High levels of necrosis and inflamation meant that growth wasn't detected until now with a perfusion scan. After radiotherapy Mark showed increasing signs of decline in his speech cognition and walking.

We are unsure about PCV and wondered if anyone had any experience of PCV or other agents during active  progression including metabolic cocktail, chemo, or immunotherapy.

many thanks

Alice and Jane Gray

H3K27M diffuse midline glioma

Hello everyone!

My wife (30 years old) was diagnosed diffuse midline glioma (H3K27M).

The story so far:
27/10/2018 MRI, evidence of brain tumour in brainstem.
11/11/2018 stereotaxic biopsy. According to the results of histological examination: diffuse midline glioma WHO IV H3K27M. H3K27M immunostain is strongly positive.
27/11/2018 MRI, tumour increased as well as brain swelling after biopsy.
03/12/2018 - 06/12/2018: chemotherapy course. Temozolomide (280mg) + Carboplatin injection (300mg).
12/12/2018 VP shunt placement.
29/12/2018 chemotherapy course. Temozolomide (250mg) + Bevacizumab injection (400mg).
09/01/2019 MRI, short decrease of tumour size.
10/01/2019 chemotherapy course. Bevazicumab injection (400mg)
25/01/2019 chemotherapy course. Bevacizumab injection (400mg)
08/02/2019 chemotherapy course. Temozolomide (100mg) + Bevacizumab injection (400mg).
22/02/2019 chemotherapy course. Bevacizumab injection (400mg).
27/02/2019 end of radiotherapy treatment. Truebeam, 31 session, 55,8gr.
07/03/2019 chemotherapy course. Bevacizumab injection (400mg).

Also we made Foundation One Cdx genome analysis. In the accordance with the results:
Microsatellite status - MS stable
Tumor Mutational Burden - TM-Low (5 Must/Mub).
Gene alterations:
CD274 (PD-L1) amplification - equivocal
FGFR1 - N546K
NF1 - Q1993
PDCD1LG2 amplification - equivocal
H3F3A - K28M
JAK2 amplification - equivocal

We have ended radiotherapy about three weeks ago and we must decide what to do next. Our chemotherapist in Moscow suggests to continue taking Bevacizumab every two weeks with no additional treatment.
We are planning to do MRI next week (22.03.2019).

1) Will the immonotherapy be effective in our case? We have contacted IOZK and Verita Life clinics in Germany. There is also an option of immunotherapy in Moscow.

2) Are there any promising ways (clinical trials for example) of treatment of H3K27M?

3) My wife took dexamethasone (8mg daily) for 3,5 months. We quit dexamethasone for three weeks now. Now she has moon face and big belly. When does usually these symptoms go away?

Thank you so much and best wishes to everyone,
Alexander 

Diffuse glioma of the brain stem

Dear Stephen, dear all!

I ask for advice for my friend, she has a child (8 years old). Diffuse glioma of the brain stem (diagnosed 2015).
March - April 2015 received a course of radiotherapy 54 gray. No chemotherapy.
In January 2017, a new tumor on MRI - less than 5 mm (doctors decided just to observe). In December 2017, MRI showed almost 7 cm tumor.
On January 24, 2018, a biopsy was performed - midline glioma, mutation H3K27M.
March-April 2018, repeated radiotherapy course of 54 gray. No chemotherapy.
November 2018 negative dynamics on MRI.

Mutations:
ATRX - contained in the cores
H3.3 - Mutations detected in the H3.3_K27.M gene
IDH1 - no
p53 - accumulation in nuclei (70% of cells)

1) What can be done in this situation (third radiation therapy, chemotherapy, avastin, dendritic cells, viruses)?
2) Please advise promising clinical studies or clinics that deal with such cases?
3) What drugs could be added due to his mutations?

Thank you!

Oligo Treatment

Hello everyone,

In a couple weeks I'll be beginning proton radiation therapy. I have a basic cocktail and diet strategy for the 6 week treatment and I wanted to run it by this blog community while also asking a few questions.

My story so far:

Focal seizure in Oct 2018.

4.5cm mass, frontal/parietal, no contrast enhancement, everything else typical for an oligo.

Surgery late Dec. GTR, no visible tumor remains.

Pathology: Grade III oligo, with 10/10 HPF mitosis, dense cellularity, moderate atypia, no vascular proliferation, no necro.

TMB 6.8
IDH1 mut
TERT mut
CIC mut
1p19q codel
P53 retained
ATRX retained
MGMT methylated

Current plan is proton+TMZ then up to 12 cycles of TMZ.

Did 1 cycle of TMZ in between surgery and radiation start.

Cocktail

Keppra, 1g x 2
Longvida, 1.6g x 2
GTE 1g (450mg egcg) x 2
PSK 1.5g x 2
Maitake, 50mg x 2
CBD  (don't have it yet, still considering dosage)
Omega-3 3g (total EPA+DHA)
Pterstilbene 150mg x2
Resveratrol 250mg x2
D3 5000 IU x2
Berberine, 600mg x3
Silymarin, 450mg x3
Probiotics via yogurt or pills (occasional, can reduce gut diversity?)
Selenium 200mcg
Melatonin, 10-20mg
Magnesium, ~200-300mg

Still trying to get
Celebrex
Chloroquine

Ketogenic diet rough plan
72h fast 3 days prior
Protein under 65g, carbs under 20g and GKI as close to 1 as possible.
1000cal per day, possible 20:4 intermittent fasts 3 days per week, alternating

Lots of walking and probably very light but consistent exercise throughout.

Questions

1) Will any of these supplements (antioxidants specifically) potentially interfere with oxidative stress on the tumor cells?

2)The majority of this cocktail and diet plan is ripped from GBM research and GBM/AA3 posts on here. Are there IDHmt/oligo specific supplements/drugs etc that I may be missing?

3) I've heard GTE can be toxic. I have Nusapure GTE and Swanson's Teavigo caps as well. What are people on here buying for EGCG?

4) Is chloroquine as promising to an oligo as it is to a GBM?

5) Is cal restriction necessary if I were regularly fasting, and vice versa? This is a bit of a grey area that I don't quite have figured out yet.

Also, as of now, I intend to save PC chemo for future recurrences. TMZ is a much less damaging chemo. My main concern with TMZ, however, is hypermutation. I'm not sure how to possibly mitigate that.

Thanks in advance.

High Dose Valganciclovir for GBM

Hello,
Re: Valganciclovir
Has anyone followed the Sweden GBM study's dosing on Valganciclovir while using the Care Oncology Protocol? If so, did you isolate the Valganciclovir to be taken on its own for the first 3 weeks, or did you have no issues with using the 4 Care Oncology drugs while in the 3 week high dose loading period of Valganciclovir?
We just received our Valganciclovir and our Care Oncology shipment and wondering if should wait 3 weeks before introducing others into the protocol.
Thank you!

Advices before radiation therapy

Dear Stephen, dear all!

My mother had an operation (summer of 2018), not completely removed. There was no radiation therapy. Then she took TMZ 5/23 and Avastin, after 7 courses the tumor began to grow.

Next week Mom starts radiation therapy.

In this connection, I have a number of questions.

1) If TMZ ​​5/23 does not work, can we try the metronome scheme for the period of the radiation? Or is it better to change the medicine? The tumor is methylated.

2) What do you think about platinum drugs with TMZ?

3) Has anyone heard of Vidaza? Our doctor says that in Germany they use it in protocols with glioblastoma.

4) How long before radiation therapy should she take thc/cbd oil so that it works as a sensitizer? How much ml? Or we should devide it into 2 doses?

5) Which of the following is better not to include in a cocktail during radiation therapy: (and what is better to add?)

• Coriolus versicolor
• Maitake D-fraction
• Selenium
• Chloroquine 
• Celebrex 
• LDN 
• Aged garlic (What is the dosage of garlic???)
• Omega 3 
• Zinc 
• Prozak
• DCA – 25 mg/kg х 2 times
• Milk Thistle 
• Dandelion 
• Wobenzim
• Berberine 
• Boswellia WokVel 
• Pterostilbene 
• Metformine
• Depakine chrono 
• Probiotics
• THC/CBD

Please help me! Thank you!

Seeking medical marijuana providers

Hi all,

My brother was diagnosed with GBM 8/2017.  He had resection and good response to SOC plus our own added cocktail.  He has been taking THC / CBD but sometimes has issues tolerating and finding the right balance.  Has anyone worked with medical marijuana providers that treat brain cancers.

We are in Boston but willing to travel.

Kind Regards,

Jenna

OK! finally I found a trial in Iran and apparently they are working on Zika and Mesenchymal cells of patient...I will inform you if I find more about. They said two of their patients are alive after 4 years (I don't know how many were there though!?). It seems that the trial is even free.

Well I don't want to be too exited before knowing much about it...

I found that there were some posts on Zika here, but I would like to know more of your opinion about it. Shall we go for it as it is the only one going on here? do you know which type of tumor might reply better to this method?

Do you recommend metronomic Temodal with it? (Since it is going on by a university, I guess they are more open to opinion)

Thanks   

I am quite ashamed for sending this much posts and I promise to make them less. Just want check the cocktails now that we are ending the radio+tmz parts and ask what should be replaced in the following one month off. 

My father is taking these along with 120 TMZ and most of these had been added after the blood test:

6 boswellia wokven

3 longvida

1 melatonin 5 mg (this might become 2)

2 milk thistle (150, standardized to 80 %)

2 metformin 500 (i.e 1000 mg)

3 ranitidine (Just to support  his weak stomach. He took Cimetedin 600 mg for more than a week and then I was afraid...because of Metformin)

1 valporate sodium 500 mg

2 cotrimoxazole (as you guess prescribed by ON)

Still damn 4 mg dexa

He would makes suicide if I add even one more pill now, so I will wait for replacing kepra with valproate and maybe getting rid of cotrimaxazole would give us more room..

His blood test 10 days ago shows these factors to be low:

 W.B.C 3.7

R.B.C 3.54

HGB 12.4

HCT 35.7

1- Do you think adding this MRM Veggie protein is of any help or is it more harmful? So far, that’s what I could find here but if you could suggest any powdery thingy that include those rare blueberry’s stuff, etc. I would be really thankful and I will order it asp.  

https://www.luckyvitamin.com/p-345652-mrm-100-all-natural-veggie-protein-powder-with-superfoods-chocolate-20-1-oz

2- I will try to add vitamin d3 and maybe a bit of Iron thingy after finishing this round. something else you recommend? 

1st Recuurent Help please

Hi All

I hope All are good

My mother Diagnosed with Glioblastoma 2/8/2018 

The previous Mri on 30/12/2018 Showd that there is two new tumors

The first one 3.4 x 2.5 x 3.5 cm the second one nearest the first one but it is small 0.7 cm

We started Daily Temodal on 08 /01/2019 with Drug cocktail

Temodal 60 mg daily

Celbrex 400mg daily

Chloroquine 250 mg daily

Prozac 20 mg daily

keppra 2000 daily

Depakine 1000 daily

We start DCA for second time before 6 days 500 daily

And all Supplements 

The latest Mri on 20/2/2019 Showed

The biggest tumor shrinking to 2.3 x2.5x3.5cm

the smallest one increased from 0.7 to 1cm

What are you suggesting now going with SRS + Avastin Or continuing with Temodar and adding the remaining drugs?

Why one tumor is shrinking and another one increasing?

Is there any benefit if we continuing Temodal??

Is there any chance for second surgery after 7 months of first surgery?she is walking ,eating,doing every thing normally without any problem..

Please help 

Thanks

Modar

Experimental surgery

I need some information for possible surgery of my father … I am quite sure that partial surgery alone cannot help him so much. So I would only insist on surgery if I can find some alternative way of doing that (I mean those which can be done mostly by a crazy, brave surgeon in Iran and does not include some dreamy technology, etc.). I need to be prepare and I would only use it as the last shot.

 For the start, I’ve heard about two patients of DR. John Boockvar who survive for a long time. If I understand correctly, this includes micro cut of BBB, using mannitol to keep them open and then Avastin has been sprayed directly and the result was wonderful. I wonder why it has not become the standard? Or is it now more common there and I am just not aware?

Any other successful experiments that give me the courage to go for finding such surgeon are highly appreciated. And sorry if it is not directly related to cocktail, I promise not to continue this thread for too long.

Ibudilast for a cocktail?

Ibudilast was approved in Japan in May 1989.
In 2017, the drug was approved in the EU.

https://www.ncbi.nlm.nih.gov/pubmed/30814573
https://www.nature.com/articles/s41598-019-39427-4

In vivo, combined ibudilast and TMZ treatment of a patient derived xenograft (PDX) model resulted in significantly longer overall survival. Our findings have significant clinical implications for people with GBM. Since clinical trials involving ibudilast have shown no adverse side effects and the drug readily penetrates the blood brain barrier, treatment of GBM with this combination is clinically achievable.

MIF inhibition in combination with ibudilast and TMZ treatment results in longer survival in vivo. Tumor-bearing mice were treated with indicated drug combinations with the following doses: Ibudilast (5 mg/kg); Ibudilast (20 mg/kg); TMZ (10 mg/kg); Ibudilast (5 mg/kg) + TMZ (10 mg/kg) and Ibudilast (20 mg/kg) + TMZ (10 mg/kg). There were n = 8 mice in all groups. All treatments ceased by day 100.

At 43 days post-implantation, large tumors were present and treatment commenced. When all vehicle-treated mice reached their neurological endpoint (median survival 100.5 days), treatment was stopped. The treatment of tumor-bearing mice with ibudilast only resulted in inferior median survival times compared to the vehicle-treated mice (89 days and 97.5 days respectively) (Fig. 5A). A survival advantage was observed with mice treated with TMZ alone (median survival: 105.5 days compared to 100.5 days; LogRank p = 0.055). Combined treatment resulted in significantly longer survival. Mice treated concurrently with ibudilast (5 mg/kg) and TMZ (10 mg/kg) displayed a median survival of 114 days (p = 0.005) while the combination of ibudilast (20 mg/kg) and TMZ (10 mg/kg) resulted in a median survival of 111.5 days (p = 0.014).

P.S. The authors of the study write about a significant improvement in the survival of mice, but we see that the best survival in the treatment with a combination of drugs is 114 days versus 105.5 days in the treatment with temozolomide alone.

When to begin adjuvant tmz?

Dear all,

Believe or not, we are going into a long holiday here and it does not seem anybody would inform us what to do for the next month or so! My dad tmz + radiotherapy sessions would end within two weeks.

I urgently need your help so I can somehow catch someone before they all disappear in their holidays:

-          1- Is there usually a break before starting the adjuvant tmz? if yes, for how long?

-        2-  From the beginning of the treatment we never had a MRI, when should it be done? Since there was no surgery, could they decide whether tmz is the best choice now, or it is usually after finishing 6 or more cycle of tmz to say?

-          3- He is now on 4mg dexa and 3 wokvel boswellia (I’ve just randomly chosen these dosage and I have no idea if it is enough or not!), how and when should I start decreasing dexa?

BTW, he is loosing his right visual field (left temporal) ...dose it only means progression? his memory is getting better though I guess...

Any thought or experience is highly appreciated, thanks.

Time to say goodbye

Hi everyone,
it's been a while since I have posted anything. The worst has happened and my Dad passed away in September (55 years old). We spent his last three months on hospice care and watching him die was the hardest part. I miss him so much and the only positive thought I can come up with is that he doesn't have to suffer any longer...

My Dad was diagnosed with an inoperable glioblastoma (corpus callosum) in December 2015. He was told he had three months to live but he proofed all his doctors wrong!

An important part of his cocktail was methadone and we're sure that it played an important role in keeping him alive for almost three years. He had switched Temodar to the metronomic scheme, so we have many unopened boxes at home. We would feel very bad if we had to throw them away, so I'd love to send them to anyone who really needs them - just let me know!

Thank you so much for this blog, Stephen. It has been extremely helpful.
And I wish everyone all the best, keep fighting!!!

Take care
Steffi

IDH1 status

Can a tumor originally labeled as IDH1 mutant become IDH1 wild type in the event of a recurrence?

Idebenone as potential anti-cancer agent.

Any thoughts about this?
https://www.ncbi.nlm.nih.gov/pubmed/30602587

Repurposing of idebenone as a potential anti-cancer agent.

Damiani E1, Yuecel R2, Wallace HM3.

Author information

Abstract

Glioblastoma (GB) represents the most common and aggressive form of malignant primary brain tumour associated with high rates of morbidity and mortality. In the present study, we considered the potential use of idebenone (IDE), a Coenzyme Q10 analogue, as a novel chemotherapeutic agent for GB. On two GB cell lines, U373MG and U87MG, IDE decreased the viable cell number and enhanced the cytotoxic effects of two known anti-proliferative agents: temozolomide and oxaliplatin. IDE also affected the clonogenic and migratory capacity of both GB cell lines, at 25 and 50 µM, a concentration equivalent to that transiently reached in plasma after oral intake that is deemed safe for humans. p21 protein expression was decreased in both cell lines, indicating that IDE likely exerts its effects through cell cycle dysregulation, and this was confirmed in U373MG cells only by flow cytometric cell cycle analysis which showed S-phase arrest. Caspase-3 protein expression was also significantly decreased in U373MG cells indicating IDE-induced apoptosis that was confirmed by flow cytometric Annexin V/propidium iodide staining. No major decrease in caspase-3 expression was observed in U87MG cells nor apoptosis as observed by flow cytometry analysis. Overall, the present study demonstrates that IDE has potential as an anti-proliferative agent for GB by interfering with several features of glioma pathogenesis such as proliferation and migration, and hence might be a drug that could be repurposed for aiding cancer treatments. Furthermore, the synergistic combinations of IDE with other agents aimed at different pathways involved in this type of cancer are promising.

© 2019 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society.

What to do in case of recurrence?

I would appreciate your helpful insights for a friend I am assisting regarding what is thought to be the best treatment options in case of recurrence? What are the most promising clinical trials? Would it be better to consider compassionate use of drugs in late-stage trials? I realize everyone's situation is different, so here are a few details:

Full resection in Aug 2018 at age 48. GBM unmethylated, IDIH wild type. Full genetic testing done, which showed he may be sensitized to a PARP inhibitor due to being BRCA1 positive, perhaps niraparib. We read that SLFN11 expression can further indicate sensitization to PARP inhibitors and his SLFN11 expression is “normal” and there are no mutations – so if this gene is important in the response to PARP inhibitors, that should be positive.  However, NO and MO say there is not enough data to show dosages of the PARP inhibitor with TMZ so are holding off on using at this time as he has just completed third round of 5/23 TMZ. They believe BRCA1 sensitizes patients to TMZ even if unmethylated. 

Is consideration for a clinical trial a better option in case of recurrence? There was something suspicious on the last MRI in a new area of the brain, so they have moved up scans to check again. He is consulting with UCSF after each scan along with local doctors. 

His cocktail also includes Valcyte, Celebrex, Metformin, Mebednazole, Keppra, Atorvastatin, Doxycycline, Bosweillic acid, Omega 3, mushrooms, Vit D, Curcumin, Probiotic, Selenium, Magnesium, Green tea extract, Melatonin, Astragalus, Milk Thistle, Lysine, Cimetidine, MCT oil, keto diet, lots of exercise. He is also on Optune.

Thank you so much for your input!

CCNU + TMZ (CeTeG / NOA-09, phase 3 trial), full article

Finally, the full article is published (not only abstract):

Lomustine-temozolomide combination therapy versus standard temozolomide therapy in patients with newly diagnosed glioblastoma with methylated MGMT promoter (CeTeG/NOA-09): a randomised, open-label, phase 3 trial.

https://www.ncbi.nlm.nih.gov/pubmed/30782343

http://sci-hub.se/https://doi.org/10.1016/S0140-6736(18)31791-4

"Between June 17, 2011, and April 8, 2014, 141 patients were randomly assigned to the treatment groups; 129 patients (63 in the temozolomide and 66 in the lomustine-temozolomide group) constituted the modified intention-to-treat population. Median overall survival was improved from 31·4 months (95% CI 27·7-47·1) with temozolomide to 48·1 months (32·6 months-not assessable) with lomustine-temozolomide (hazard ratio [HR] 0·60, 95% CI 0·35-1·03; p=0·0492 for log-rank analysis). A significant overall survival difference between groups was also found in a secondary analysis of the intention-to-treat population (n=141, HR 0·60, 95% CI 0·35-1·03; p=0·0432 for log-rank analysis). Adverse events of grade 3 or higher were observed in 32 (51%) of 63 patients in the temozolomide group and 39 (59%) of 66 patients in the lomustine-temozolomide group. There were no treatment-related deaths."

study on the usage of Metformin

Hi everyone,

I just found this survey that says there were no significant relation between metfomin and OS or PFS of glioblastoma patients, unlike those with grade III.

http://sci-hub.tw/10.1002/ijc.31783

What do you think? Is there still any hope that they might not consider some aspect, dosage, etc that could challenge their data? I mean, is it still logical to include it in the cocktail?