Considering treatment options for high grade diffuse midline glioma H3k27m for my 8 year old daughter

Hi all,

Thanks so much to Stephen for your in depth reply to my questions about my 8 year old daughter and invitation to this blog. We moved to Norway in July and my daughter was diagnosed in early September with high grade diffuse midline glioma with H3K27m mutation after an extended biopsy, where it was determined that the tumor was not resectable. She underwent 3 further operations to have a double valve shunt put in to relieve hydrocephalus symptoms. She finished 6 weeks of radiation and Temodal about 10 days ago. The doctors want to start her on Temodal/Lomostine 4 weeks after radiation finished. If we follow this path, we could also have a full molecular analysis done and, upon recurrence, may possibly be able to access a trial using afatinib for BI1200.120, if applicable, or another targeted agent. I would also push for using repurposed drugs in the cocktail approach if possible and our conservative doctors could be convinced. 

We are trying to explore other options, and thanks to Stephen, learned about a new phase I peptide vaccine trial opening for paediatric glioma patients with mutation H3.3K27m based in San Fransisco. It is for patients who have completed 6 weeks of radiation and have not yet started chemo again, which is exactly where we are now. https://clinicaltrials.gov/ct2/show/NCT02960230

I am finding it so difficult to determine what would be the most promising, preferably least toxic option for my daughter. Any input on how promising a peptide vaccine targeted to this kind of mutation could be? Compared with temodar/lomostine/cocktail approach?

Many thanks in advance for your input.

Jeni

FoundationOne test now includes "Tumor Mutational Burden" quantification

To my surprise, I just learned that FoundationOne reports now include a quantification of "tumor mutational burden" expressed as number of mutations per megabase of DNA.  This would be the most accurate test for hypermutation.

Foundation One webpage

I believe there is a link between MGMT methylation status, and risk of hypermutated recurrence, which could help explain the increased risk of progression to hypermutated secondary GBM recurrences for IDH1-mutant low grade gliomas (which are usually MGMT methylated) treated with TMZ.

I'd especially recommend FoundationOne for recurrences of MGMT methylated gliomas post-TMZ treatment. This test would tell you if the tumor is hypermutated and therefore if further TMZ could actually make the situation worse.  Unfortunately patients outside the US must self-pay, and the discounted price as of September 2014 was $4600 US.

Other Blogs/Stories

Hey all - I wanted to ask about other stories, since this is about both stories and cocktails.

I've had a blog for years but it's morphed into one about my wife Alison, as you might imagine, after she was diagnosed with GBM.

I just wrote an entry about the night we found out:
http://loganlo.com/2016/11/its-been-a-year-heres-what-happened-that-night.html

And my letter to Joe Biden got some traction:
http://loganlo.com/2016/01/a-letter-to-joe-biden.html

Finally, here's my first real entry about my wife's condition:
http://loganlo.com/2015/12/companionship.html

I follow Jessica's blog, Toom-ah? What Stinkin' Toom-ah, which has been a great source of information and comfort. 

Does anyone else have a (well-written) blog to recommend or a blog of their own?

Looking for a free-thinking Neuro Oncologist in the UK for a second opinion. Any suggestions?

Hi there

Can anyone recommend a good private (or even better NHS) neuro-oncologist or oncologist in the UK who is willing to think outside the box and support the cocktail approach? If I find the right person I might transfer my treatment over to them, so ideally they would be Leeds-based. My current oncologist in Leeds (where I live) is unfortunately not very helpful and doesn't support the cocktail approach at all. I want to try thyroid hormone T4 suppression with methimazole and cytomel (synthetic T3 hormone) alongside radiotherapy (although it is probably too late for that now, as I resume this afternoon) and other treatments. 

As a bit of background I am a 29 year old male, first diagnosed in June 2015 with a grade 2 diffuse astrocytoma. I was encouraged to do a year of Temzolomide chemotherapy to shrink the tumour and then hopefully they could operate. However since August of this year a scan indicated that the tumour had changed and become more aggressive. They recommended radiotherapy but during this the tumour became more aggressive and I was getting terrible headaches and vomiting. They ordered an emergency MRI scan to see what was happening and I was told that I needed emergency surgery to relieve pressure and try and debulk the tumour. A biopsy following surgery showed that my tumour has become a grade 4 Glioblastoma Multiforme. My current plan is to finish off the last ten days of the radiotherapy beginning today, and will then pursue some kind of chemo - either more Temozolomide or PCV. I want a second opinion because more Temozolomide doesn't seem to be an approach supported by the evidence. 

Any suggestions gratefully received!

Many thanks

Liam Raftery

Anticancer mechanisms of cannabinoids

Excellent paper on why cannabis should be part of our GBM routine:  https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4791144/

*Drug repurposing for glioblastoma based on molecular subtypes using a screen of 1348 FDA-approved drugs*

Found this interesting study.  Hope it's helpful!

*I also put an image of GBM subtypes at the bottom for some context.

See full source of study here

Abstract

A recent multi-platform analysis by The Cancer Genome Atlas identified four distinct molecular subtypes for glioblastoma (GBM) and demonstrated that the subtypes correlate with clinical phenotypes and treatment responses. In this study, we developed a computational drug repurposing approach to predict GBM drugs based on the molecular subtypes. Our approach leverages the genomic signature for each GBM subtype, and integrates the human cancer genomics with mouse phenotype data to identify the opportunity of reusing the FDA-approved agents to treat specific GBM subtypes. Specifically, we first constructed the phenotype profile for each GBM subtype using their genomic signatures. For each approved drug, we also constructed a phenotype profile using the drug target genes. Then we developed an algorithm to match and prioritize drugs based on their phenotypic similarities to the GBM subtypes. Our approach is highly generalizable for other disorders if provided with a list of disorder-specific genes. We first evaluated the approach in predicting drugs for the whole GBM. For a combined set of approved, potential and off-label GBM drugs, we achieved a median rank of 9.3%, which is significantly higher (p<e^-7${}^{\mathrm{}}$) than 45.7% for a recent approach that also uses the mouse phenotype data. Then we applied the approach on GBM subtypes. Analysis result shows the variations of enriched pathways, associated phenotypes and prioritized drugs across different subtypes. We ranked the first-line chemotherapy for GBM in different positions for each subtypes, and the rank variation was consistent with the previous finding on different drug responses among subtypes. In summary, this study makes an effort towards translating the molecular stratification into better survival for GBM.

Fig. 4. 

Top-ranked pathways for different GBM subtypes.

Table 5.

Top-ranked drug classes for four GBM subtypes.

Rank	Classical	Proneural	Neural	Mesenchymal
1	Antipsychotics	Antipsychotics	Protein kinase inhibitors	Antipsychotics
2	Protein kinase inhibitors	Antidepressants	Antipsychotics	Protein kinase inhibitors
3	Antidepressants	Protein kinase inhibitors	Other antineoplastic agents	Antidepressants
4	Blood glucose lowering drugs	Blood glucose lowering drugs	Antidepressants	Antiinflammatory and antirheumatic products
5	Cardiac stimulants	Cardiac stimulants	Blood glucose lowering drugs	Antithrombotic agents

GBM Subtypes  - Source here

Sad news

I've posted a few times about my husband's battle with his brain cancer. Unfortunately my husband lost his battle a few days after turning 34 years old on November 3rd. Watch my husband take his last breath was the hardest thing I have ever done but I'm grateful I was able to care for him in the comfort of our own home and give him all my love up until the last second of his life. I want to thank everyone here for their posts, info, and support. Special thanks to Stephen for all the help! I truly believe that all the supplements and some of the off-label meds not only extended my husband's life but gave him a good quality of life until his last couple of weeks. We miss him terribly but know he is in a better place now.  This is a 2 minute video I made ->   https://flipagram.com/f/wWyg9aauqj

Help in evaluating additives to daughter's regime

Hello all-

We have recently been advised by Raymond Chang in NYC to add a number of supplements and off-label drugs to our daughter's regime.  Her current situation/regime:

Our 5 year old:

DOB 9/2/2011

Brooklyn, NY

9/9/2013 admission to:

Weill-Cornell Medical Center

Right neck abscess lanced and drained

March 18th, 2016 admission to:

Weill-Cornell Medical Center

Mass discovered in head after experiencing headaches for a few weeks

Left occipital/parietal brain tumor

Operated 3/19/2016

"Full Gross Resection"

Pathology determines Glioblastoma Multiforme "methylated" 

Transferred to Memorial Sloan Kettering

Photon Radiation treatment for 33 days (Dr. Suzanne Wolden)

Temozolomide chemotherapy for 43 days

MRI on 7/8/2016 'clear' 

'Maintenance' regime of temozolomide prescribed for 12 cycles (5 days chemo/23 days off)

Currently in 5th? cycle 

MRI on 10/5/2016 'clear'

Genetic sequencing/testing

• Cornell _ Precision Medicine

• MSK _ Methylation array

• MSK _ Impact Testing

• Caris Test

Other Diagnosis via 3rd party (non-MSK) bloodwork

• Positive (via Plasma test) for CMV antibodies

• Positive (via DNA test) for Herpes-6 active case

Other Treatments

• Cronaxal (cronaxal.com)

• Cannibas oils (THC/THCa/CBD)

• Chinese Herbs (prescription pending)

• Supplements- Vitamin B, C, D, L-Lysine, Curcumin, sodium selenite, paw paw, cayenne pepper w/garlic, green tea extract, etc.

• Ketogenic diet since appx. June 2016

What Dr. Chang recommends adding:

Drugs:

• Chloroquine; off-label malaria medicine

Supplements

• Ruta 6

• Coriolus PSP capsule - 1 capsule 3x/day

• Scorpion Venom (1/4cc @ 3 times/day)

     - Escozine (difficult to get in USA)

     - Dr. Connealy _ http://cfnmedicine.com

• Add MCT oil; ie coconut oil extract (unless already in ketogenic ketosis)

• Herpes-6

      - Add Colloidal Silver to her diet

What do you guys think about how we see if we should add any of these?  Some are very difficult to get (Scorpion Venom).  Does anyone have any advice / experiences in using these supplements that can comment?

Thanks

Winston

Brooklyn

Advice for making most of last rounds of TMZ? (14/11/2016)

Hi Everyone,

Just wanted to update you on our progress and get some advice or recommendations (here is our intro to group post). Dad will be starting his 4th round of chemo this week, with 2 rounds left after that. We have had a letter stating the MRI results from September, the first one since before the start of chemoradiation in July. It says there is residual tumour at the site of original surgery (he had total resection at the time), plus a new nodule in the region of the parahippocampus (this looks to me to be deeper and therefore less like to be operable if it becomes more of a problem). Dad is still 100% and apart from some tiredness and a bit of weight loss he hasn’t had any other noticeable symptoms. 

Below is what he is taking at the moment. I have tried to add to the cocktail each round. I was a bit reluctant to add more considering this is a fair amount of tablets, but with the MRI result I wanted to make sure we are targeting the tumour from as many angles as possible (in red are things we have added to or have changed).

Prescription 6 months of Adjuvant Chemo therapy following Radiotherapy (to-date 4 out of 6 completed):

Temozolomide (Temodal - Merck Sharp & Dohme 350mg capsule, BMI based dosage) morning for 5 consecutive days every month following Radiotherapy

Ondansetron(Milpharm 8mg tablet) anti sick taken morning for 5 consecutive days every month with Temodal

Ongoing Prescription by special request:

Celebrex (Pfizer 100mg capsule)    1x morning

Chloroquine (Avloclor - Alliance Pharma 250mg tablet) 1/2 tablet twice a week in morning (available off prescription)

Cholecalciferol 800IU (Fultium D3 - MA Hodder Internis, equiv. to 20 micrograms Vitamin D),  1x capsule in morning (available off prescription under other brands)

Ongoing Additional Supplements:

Cannabinoids (CBD Brothers CBD Oil Blue Edition) 3x drop morning and evening

Mycelium Extract psp50 (ORIVeDA 350mg capsule) 3x morning and 3x evening

Fish Oil (Omega 3 - Solgar 950mg capsule) 1x morning and 1x evening

Berberine (Swanson 400mg capsule)     1x morning and 1x evening

Boswellia (Solgar 420mg capsule) 1x morning and 1x evening

Ashwagandha (Solgar 400mg capsule)   1x morning and 1x evening

Milk Thistle Fruits (Silamarie - Bio-Health 450mg capsule) 1x morning and 1x evening

Sulforapahne (Greenwoods 400 mcg capsule) 1x morning and 1x evenin

Optimised Curcumin Extract (LONGVIDA RD 500mg capsule) 1x morning

Mega Green Tea Extract  (LifeExtension 725mg capsule)1x morning

Optimized Resveratrol (LifeExtension 250mg capsule) 1x morning

Zinc (Solgar 50mg tablet) 1x morning

Selenium (Solgar 200mcg tablet) 1x morning

Senna (Senokot - Reckitt Benckiser, 154mg tablet), 1-2 as required, evening, taken only to offset Anti-Sick tablet (Ondansetron) constipation.

Melotonin (Eurovital 10mg tablet) 1x evening

We would welcome any suggestions of anything we should be adding or removing from our list. Things I am considering adding are:  Sildenafil (viagra), Disulfiram (Antabuse), Tagamet (cimetidine), DCA (dichloroacetate). Most of these we would have to try and get the GP to prescribe or find alternative ways of getting hold of.

If anyone has recommendations of what we should be doing or discussing with oncologist post chemo that would be welcome too.

Thanks,

Sam

Update (03/05/2017):  we added cimetidine Jan 2017, Dad has finished 6 months of  Temozolomide and is no longer taking Ondansetron or Senna.

*Sirolimus and Hydroxychloroquine with TMZ increases survival to a 28 month minimum*

I came across this study and the results looked very promising in comparison to standard of care alone for GBM.  However, the sample size is very small and not statistically significant.  With that said, I still think these results are hard to ignore.  Especially since only 3 of 20 patients used this combination and the minimum survival time of the 3 was 28 months. (this individual also had dosage reduced because of grade 2 fatigue so there may be some dosage dependance)

Results: The median survival time of the 20 patients was 13.7 months (range: 2.2 to 37 months). Surprisingly, the 3 patients who received sirolimus and HCQ as an add-on treatment survived for a longer period of time (median 34 months). Transient grade 3 myelotoxicity and grade 2 fatigues were rapidly resolved by treatment interruption or dose reduction.

These patients were much older so would we interesting to see how this therapy would work in younger patients with stronger immune systems.

From Kwan-Hwa Chi, MD in an email to me: " this regimen works better in mesenchymal type of GBM, the worst prognosis one and multiple recurrent case."

See the below link to investigate

Sirolimus and Hydroxychloroquine as an Add-On to Standard Therapy for Glioblastoma Multiforme: Case Report

Survivin Immunotherapy - Buffalo, NY

This is the first I've heard of this experimental immunotherapy so I thought I'd share it with the group:

http://www.wndu.com/content/news/New-vaccine-for-brain-cancer-brings-hope-to-those-fighting-the-disease-400305491.html

If anyone has any further details, please mention it in the comments.

My 38 yo husband was diagnosed with GBM IV. He started with headache and after 12 hours he was paralysed on his left side. The tumor was in his right frontal lobe almost 5cm diameter. They have resected the main mass but it has infiltrated his coropus callosum on area of 1cm, which they say is unoperable. His tumor is IDH-1 wild type and methylated. Next week he is starting his chemo and radioteraphy. I am trying to educate myself between hospitals, work, child but it is too much for one person to handle. Doctors are refusing to use coctail aproach so here I am on my own on this path. I am so grateful to find this site and truly admire all of you for work and support.
This is what we have got so far but I will truly appreciate every tip or insight.
What is crucial at this point?
I am putting him on ketogenic diet.
He is taking
Metformin 500mg twice a day
Dekapote 500mg twice a day
Celebrex 200mg twice a day
Curcumin Longevida 2 capsules a day
Boswelia serrata 600 mg twice
Pterostilbene twice
alfa lipolic Acid once
Green tea extract twice
Broccoli sprout extract once
Reishi 1 caps Coriolus 3g Maitake 3g once
Melatonin 10mg once
Cannabis oil cbd
We have got chloroquine and disulfiram are they necessary now?
As for channel pomp inhibitors I was reading about them but still don't know if you are going for all them during chemo -like telmisartan, nexium, verapamil?
I am waiting for Cymetidine Tagamet - you are using it also during his radiochemotherapy? It is interacting with almost all drugs but I suppose I have nothing else antymigrating in his coctail.
I am a little confused with Keppra and risk of demethylation - if he is methylated is it necessary? If so when it is best to incorporate this?
What else should /could I do? Thank you and wish you all the best !

NanoTherm Therapy - MagForce - hyperthermia

Hello all,

Has anyone heard about the NanoTherm Therapy in Germany (but also other countries)? The idea behind it is to inject magnetic fluid into the tumor, the fluid then is heated through a fast alternating magnetic field and the temperature fights the cancer cells. I haven't found any other research about it, only their own. Also they run a trial since 2014.

I wonder what your opinions are on this? Can it do any harm?

Thank you,

Anna

Update Post Avastin, 18 months post diagnosis

My husband, diagnosed May 2015, with inoperable tumor in his right frontal lobe, had the usual radiation/temodar protocol, post radiation chemo only four months. Important to note; 60% of his brain was radiated because of the placement of the tumor(s). After much urging from his UCLA neuro-onc, he had four infusions of Avastin, starting end of August 2016. The results were not what we had hoped, he got weaker after each infusion, to the point that he was back in his wheelchair after being ambulatory post shunt in early July. He is just now clawing his way back from the effects of Avastin, which also include fatigue, and fogginess. It is too soon to tell if Avastin will have any beneficial effects for him. His post Avastin MRI showed a sizable reduction of his tumor and much less inflammation. It also showed possible necrosis.  Two weeks ago he had a major seizure, his neuro-onc can't explain it. I also asked my husband's neuro-onc if he was experiencing aphasia and her response said no, that the EEG showed a slowness of the brain. I'm not sure what that means.  I asked if conflating thoughts, ideas, imagining experiences that didn't occur, word confusion be defined as slowness? And doesn't an EEG just map one moment of time? Would the results of an EEG be different without medication, morning vs afternoon, etc? I need help understanding and also to set my expectations on remapping and what I thought was a pliable brain.  I thought these symptoms would have been a left temporal lobe issues, not right. Does anyone have a similar experience to share?
BTW, his tumor is MGMT methylated and IDH1 non-mutated.

IOZK clinic / NDV

Good morning Stephen and all,

Does anyone has experience with the IOZK clinic in Cologne? I can't find much data on the vaccination they use along with the NDV except in few pediatric cases. Has anyone had success with it in adult Glioblastoma?

Thanks
Noha

Other tumor tissue banks?

Storemytumor is very expensive. Anybody knows about other live tissue banks and pricing?

GcMAF

Stephen,

Do you remember about a year ago there was a story about a bunch of doctors in southeast US, mostly Florida, that wound up dead?  Here's an article published last year on it:  (http://thefreethoughtproject.com/florida-doctor-murdered-bringing-total-8-dead-5-missing-month/). 

I stopped following the story but today I ran across this rather amazing news that I wonder about (http://worldtruth.tv/big-pharma-is-injecting-us-with-cancer-enzymes-doctors-who-made-the-discovery-found-murdered/).  This Dr. Ted Broer insists that these doctors all worked on autism and discovered that the autistic kids had been given an enzyme called nagalase in their immunizations.  He states that this nagalase creates a cytokine "storm", paralyzing some kids' immune systems, which ends in a myriad of maladies, one of which, besides autism, is cancer.  An article about also appeared in a FB GBM blog I follow.

Not wanting to get into conspiracy theories, and let me just say I'm in favor of getting kids immunized, I'll just ask a GBM-related question:  is it true that the antidote, as it were, called GcMAF, is a killer of cancers?  Have you heard of this?

PD-1/PD-L1 antibodies and hyperprogressive disease in a subset of patients

Sadly, a new study shows that out of a total population of 131 patients with various sorts of tumors treated with anti-PD-1 or anti-PD-L1 monotherapy, 12 of these (9%) had hyperprogressive disease (HPD) following treatment, defined as an increase in tumor growth rate at least 2 times higher than the reference growth rate (before anti-PD-1 treatment).  The subset of patients with hyperprogressive disease were older on average than the rest of the cohort (66 versus 55 years on average).  "At progression, patients with HPD had a lower rate of new lesions than patients with disease progression without HPD".

The mechanism for this increased tumor growth rate in this small subset is currently unknown.

"By RECIST, a total of 49 (37%) 66 (50%) 15 (12%) and 1 (1%) patients exhibited progressive disease, stable disease, partial response or complete response, respectively".  Therefore, stable disease was the most common response overall.

The study was published today (November 8) as an OnlineFirst article by Clinical Cancer Research.

Click here for abstract

I've uploaded the full study to the Library, Immunology and Immunotherapy folder, Immune Checkpoint Inhibitor subfolder

Celebrex and Anti-coagulants

On 10/17, my husband was diagnosed with a recurrence of GBM and was removed from his PD-1 trial.  We are now anxiously awaiting another resection and, in the meantime, are investigating potential off-label treatments like Celebrex. Unfortunately, Celebrex apparently increases the chance of bleeding when taken with anti-coagulants, which my husband must take.

I am writing to ask if you or your loved one are taking both Celebrex and Warfarin (or a similar anti-coagulant) and what your experience has been with them. I think this can be addressed by low dosing and careful monitoring, but I would prefer to proceed based on concrete experience than on speculation.

Thank you for your sharing your information.

Margaret

Risperidone

A newly published case study describes the case of a 57-year old GBM patient, with poor prognosis due to a KPS of only 50 and postoperative neurologic symptoms.  The patient was being treated for schizophrenia at the time of GBM diagnosis with risperidone at a dose of 6-6.5 mg per day.  He ended up going 5.5 years without recurrence, and then lived for an additional year after first recurrence.  This paper posits a possible correlation of his unexpected progression-free survival with his use of risperidone.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5066542/

In 2010, Richard Kast published a paper hypothesizing that risperidone, pimozide, and paliperidone could be useful for GBM treatment as 5-HT7 serotonin receptor antagonists.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2990148/

Additionally, risperidone is a potent inhibitor of D2 and D3 dopamine receptors. D2 has been described as a valid target for GBM therapy:

https://www.ncbi.nlm.nih.gov/pubmed/24658464

Finally, a more recent paper by Richard Kast and Marc Halatsch proposing D3 dopamine receptor as a target for GBM therapy.

https://www.ncbi.nlm.nih.gov/pubmed/24242756