2016 Classification of Diffuse Gliomas

This is a handy diagram showing the current (2016) classification of diffuse gliomas. I snipped it from Chapter 6. Molecular Classification of Gliomas (Kenta Masui et al) from the Handbook of Clinical Neurology, volume 134 (2016) edited by Mitchel Berger and Michael Weller.

Our cocktail and report "OncoDeep". What do you recommend to pay attention to?

Since the tumor after surgery (removed 99%) increased again in the same size (3.5 x 5 x 5 cm) in 3 weeks and the tumor did not decrease after radiotherapy + TMZ, we probably have a very unusual cocktail for the first line:
- cycle 42 days: Avastin (3mg/kg/week) + CCNU (1 day 75mg/m2) + TMZ (5 days 90mg/m2),
- disulfiram 500mg (+Copper 5mg + DHA) and verapamil 200mg only on the days of TMZ + CCNU administration, and 2 days before and after.  I'm not sure, maybe it's advisable to take Disulfiram every day? Otherwise, disulfiram may not start to influence so quickly?
- every day: cloroquine phosphate 250mg, telmisartan 80mg, alfacalcidol 2mcg, oxaloacetate 100mg,  melatonin 20mg, curcumin longvida 2000mg,  Berberine 1000mg, DHA/EPA 1000mg, PSK / PSP 1800mg, Methimazole + T3, R-lipoic acid + hydroxycitrate + ketogenic diet, omeprazole 20mg + DCA 20mg/kg (10mg/kg/BID) + caffeine (2 cups of coffee and 5 cups of black tea) + vitamin B1 200mg

My mother has been responding well to taking DCA + caffeine for a week in the form of black tea and coffee. However, my mom's pulse increased to 90-95 after sleep or rest. To reduce it, we now take 10 mg of propranolol per day. An increase in the pulse may also be caused by the intake of the hormone T3.

Also I consider the addition of a low dose of naltrexone before bed.
We also ordered perillyl alcohol at www.sigmaaldrich.com and expect it soon.

Today we received a report from OncoDNA. The last 3 months I read and search for any information about glioblastoma, but unfortunately I find it difficult to understand this report. Doctors in Russia do not order such reports at all! Our doctor in Germany said that unfortunately, such reports will not help us in any way.

Maybe you can tell me what to look for in this report? Any comments?

For example, I can not understand, is there overexpression (amplification) of EGFR?
"Damaging TP53" = mutation of TP53? Not understanding this, I can not draw conclusions from this review (http://astrocytomaoptions.com/exploring-strategies-for-tp53-mutated-gliomas/) and other studies.
"Damaging PTEN" = loss or mutation PTEN? An interesting article in this case: http://btcocktails.blogspot.ru/2018/01/parp-inhibitors-for-pten-mutant-cancer.html
Which of the drugs on the list of potential clinical benefits to pay attention to ?

Here is a link to the report itself and some pictures of him:
https://drive.google.com/open?id=1A3dophOME6gY1GNdOHWE48wVYJUu_nHc

 

 

Predicting immunotherapy response

1. The company OncoDNA provides test OncoDeep: 70 genes + predicting immunotherapy response.
https://www.oncodna.com/en/immunotherapy/
Price: 2990Eur.
Are there any studies predict immune therapy in other laboratories? Is this study useful?

2. By the way, in Moscow (Russia) a study of 50 genes costs $480. Can this research give some useful information? Or these 50 genes is very limited and such information is not sufficient?

http://www.genomed.ru/onkokarta/

3. Here (https://www.cegat.de/en/diagnostics/tumor-diagnostics/ovarian-cancer/) it is reported that "The detection of a somatic or germline mutation in the BRCA1 or BRCA2 genes is a requirement for treatment with Olaparib (LynparzaTM)"

There are also 4 testing options.
"Option 1: BRCA1 and BRCA2 analysis in tumor tissue only
In option 1, only mutations in the tumor are analyzed, no differentiation between germline and somatic mutations can be made. We do not recommend this option, but will perform it when it is explicitly requested by a patient."

Is it necessary to do such a study to determine the possibility of treatment with Olaparib or is it enough to study Oncodeep (by OncoDNA)? But in Oncodeep only mutations in the tumor are analyzed.

Option 1: BRCA1 and BRCA2 analysis in tumor tissue only

Option 4: Somatic Tumor Panel

P53 loss questions

Hi all,

I'm in the middle of determining what my next steps will be following my AA3 (previously thought to be an Oligo 2) diagnoses.

The tumour is listed as having P53 loss (or truncated mutation), which I know is more unusual in this type of tumour. While doing research on a ketogenic diet I repeatedly came across brief descriptions of p53 playing a role in metobolism...so I decided to look into it more. Below are a few links to different papers I've read. It's seems like you can exploit this loss in a number of different ways.

Firstly, there is evidence that it has some role in fatty acid oxidation and glutathione oxidation (I do not have a mutation to the MYC gene - which also plays a role in glutathione oxidation). According to these papers, these tumours (with p53 loss) are highly vulnerable to glucose restriction, they allow the PPP to become unchecked - which is a pathway that metabolises glucose. (I have read that p53 loss may prevent gene mutations (I think I was understanding that right), which maybe why I do not have an MYC mutation (the mutations I do have are listed in my post called Pathology Report from a few weeks ago).

It also regulates ROS homeostatsis, either through pro or anti-oxidant means (would loss of p53 mean that ROS was unchecked and how would this impact IDH1 mutant gliomas where ROS is already significantly altered, right?) In general, I'm questioning how IDH1 mutation works with loss of p53? IDH mutation metabolises glutamate at high rates, correct? So if p53 is lost (therefore the tumour would not generate GLS2 (at least through P53) and I do not have an MYC mutation (which allows the tumour to uptake large amounts of GLS1 - both GLS1 and 2 metabolise glutathione, then what others ways what the cells use glutathione?

I'm also questioning whether a ketogenic diet would be useful if I am able to use Proton therapy. I believe all radiation therapy uses ROS as one mechanism, proton therapy using more. A ketogenic diet has been said to limit ROS (sort of like antioxidants) but if it will limited it in standard therapy will more be better in Proton therapy? And then, the P53 in relationship to ROS question also comes in here.

I have read that keto may not be good for an IDH mutant tumour because of NAD+. Can someone elaborate more on that?

Just some more info - I had a gross total resection (surgeon said 99.9%). I'm considering Proton Therapy (do people have a hard time getting that covered by insurance), CBD/THC is try to block glutathione uptake during radiation, ketogenic diet to block glucose with attention to glutamate and methionine intake and DHC fatty acids, if needed boswellia and celebrex to prevent need for steroids, Stephen has recommended disulfiram, which I will look into and I'm going to look into metformin (seems to have a special interest with P53 loss), curcumin ( I was taking it before surgery) and I'm considering not taking any chemo at this time.

I apologize that I'm not as organized as I could be in asking these questions. I am experiencing aphasia following surgery.

Here are the links:

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3135642/
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2763495/
http://www.pnas.org/content/107/16/7117.full
http://www.sciencedirect.com/science/article/pii/S0005272809000115
https://www.ncbi.nlm.nih.gov/m/pubmed/21336310/

Thank you all.

Maria

Pathology Report

Hi all,

I had the tumour out on Nov. 10 and just received my completed pathology report today. I’m diagnosed with an AA3, not an Oligo 2 as previously thought. Can you all review the report and help me make my next steps from here? Thanks.

IDH1 R132H positive
ATRX - negative (lost, suggestive of mutation)
P53 - highlights scattered background of glial cells (negative in tumour, suggestive of try care by mutation)
MIB-1 proliferation index is 7.7%
504 kb gain of SOX2
1.9 mb gain of OKI (no gene disruption)
21.2 Mb broad gain of 7q, an
8.7 Mb gain of 12q

Let me know if I should give you anything else. That’s is all that is listed though.

Thank you!

Oligoastrocytoma grade 3, progression, next steps?

Hello all and thank you for this great community!

My sister (30yrs) was diagnosed with anaplastic oligoastrocytoma GIII a year ago. This was a reoccurence, since 5 years ago it was oligoastrocytoma grade 2. Back then she received surgery + 8 cycles of TMZ.
This latest one was partially removed in surgery (it's in temporal lobe). She received RT + TMZ (60Gy, 30days) and after that she has completed 10 TMZ cycles. Latest MRI showed that there might be tumour progression, but it's not definite according to doctors. Next scan will be in two months. Until then she will continue on TMZ for two cycles more.

We're a bit concerned since part of the tumour is still there even after RT and chemo and it might be progressing.
PAD report says: IDH1 negative, mitosis 33/10 HPF, MIB activity 25%,
Previous tumour showed 1p19q deletions.
We have asked for a more specific analysis of the tumour and will receive results in couple of weeks (MGMT, EGFR, etc.).

Until then, our NO recommends to continue with TMZ and see what MRI shows in July.

We have plans to try Keytruda or other aPD1, what's your view? Or is there some other sytostate (CCNU, PCV) we should try before aPD1 ?

Her clinical condition is very good so we try to balance between good quality of life and try to treat this when there's better changes for that.

Supplements she currently takes:
-D3
-Selenium
-Longvida Curcum
-Probiots (L. Casei et al.)
-Leveriacetam

br and thanks,
Juha

Post SOC Advice

Thank you very much Stephen for allowing me to post my question here.  I've been reading this wonderful blog for awhile and I'm hoping to receive some guidance.  My husband 59 was dx with GBM (left temp) in March of last year.  He had surgery to remove 80-85%, received 30 Proton therapy treatments with TMZ, then 6 rounds of TMZ (5/23 schedule).  His follow up MRIs have shown swelling (the NO is calling it treatment effect).  He has just finished SOC so I'm looking for suggestions to look for potential trials and things we can do ourselves to keep from recurrence. His pathology is below and it is difficult for me to understand what we should be pursing.  We are mostly happy with his care but want to be as proactive as possible.  He is also on Keppra 1000mg 2x per day, Tagamet 200mg 2x per day, steroid 4 mg AM, 2 mg PM.  We eat mostly organic, no sugars, and try to limit dairy.  I also would like to incorporate more of the cocktail approach but I'm not sure what to try based on his pathology.  Any suggestions would be greatly appreciated.
There is no
immunoreactivity for mutant IDH1(p.R132H). p53 stains the nuclei of a
relatively small subset of tumor cells, which also retain nuclear ATRX
expression. Reticulin special
stain shows low reticulin content.
Methylation specific PCR analysis of the MGMT (O6 methylguanine DNA
methyltransferase) DNA repair gene promoter is in progress and will be reported
as an addendum  (he is not methylated)

NEGATIVE- FISH result for EGFR gene amplification
NEGATIVE - FISH result for loss of 10q/monosomy 10

EGFR FISH
In
this particular case, there was polysomy of chromosome 7 in 61.5% of the 200
interphase nuclei examined. The average copy number of CEP7 was 3.01 (ranging
from 1 to a high of 8 copies). The average copy number of EGFR was 3.16
(ranging from 1 to a high
of 8 copies). The resulting ratio of EGFR to CEP7 for this case was 1.03. There
was no evidence of EGFR gene amplification, as defined below, in the 200
analyzed cells.
In glioblastomas, the cut-off point that defines amplification is controversial,
although the most commonly accepted criterion for EGFR amplification is an
EGFR:CEP7 ratio of = 2.0 (Appl Immunohistochemial Mol Morphol 14:91-96, 2006; Am
J Surg Pathol

PTEN FISH

There was no evidence of PTEN deletion or monosomy of chromosome 10.

Unmethylated treatment advice

Hi,
My beautiful husband had removal of GBM left parietal tumour last October.
Histopatholgy results:

The sections show multiple fragments of hyper cellular brain parenchyma, diffusely infiltrated by tumour composed of hyper chromatic and atypical glial cells, set in a fibrillary background.   The glial cells have a broad morphological spectrum which includes scattered epitheloid forms with abundant pink cytoplasm and smaller glial cells with a high nuclear to cytoplasmic ratio. Frequent mitotic figures are present including atypical forms. Multiple foei of palisading tumour necrosis and microvascular proliferation are seen.

ATRX: retained 

IDH1 (r13211) immunonegative

EGFR; strongly and diffusely positive

P53: positive in approximately 30% of the tumour cells

Ki67 prolification index: approximately 20%

Unmethylated 

Glioblastoma IDH-wild type grade 4 

After surgery we have commenced veliparib  + radiology.

We are now on a break and due to commence veliparib + temozolomide in about a week (6 month treatment:one week on tablets ; three weeks off)

Current supplements

Curcumin 

Silymarin 

PSK

Selenium 

Vitamin D

Multivitamin 

+ Ketogenic diet 

Because we live regionally (in Australia), we are now assigned a local oncologist (not neuro-oncologist).  This VERTU trial is the only offered treatment.  The oncologist is reluctant to discuss other options/supplements.

The registered nurse overseeing the trial said that if I approached the doctor and asked to add a medication they would consider it, so we have an appointment next week that I have an opportunity to put a case forward for other treatment, hence I am asking for advice.

Question: should we be pushing for Keppra?  

Question: should we be looking for other treatment... I am not hearing much of anyone on veliparib.

Question: Please advise if it would be beneficial to add artemisinin to the supplements, and if so how will that work with the veliparib  + temozolomide 

Question: Do you have any other recommendations for supplements?

Thank you in advance for any assistance.

And I also thank you all for writing on btcocktails  and sharing stories and knowledge... It makes me feel not so alone.

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.

39 y/o female - Biopsy results

Hi -

My friend was told she has GBM.  Here are the results of her biopsy:

NEUROPATHOLOGICAL DIAGNOSIS: 
Left occipital mass: stereotactic biopsy:
Integrated diagnosis: GLIOBLASTOMA, IDH WILD TYPE, WHO 
GRADE IV
Histological classification: GLIOBLASTOMA
WHO grade: WHO GRADE IV
Molecular information: 
* IDH: MUTATION NOT IDENTIFIED BY IDH1/2 SEQUENCING 
(EXON 4)
* ATRX: RETAINED NUCLEAR IMMUNOREACTIVITY
* p53: LOW IMMUNOREACTIVITY, 
<10% OF NEOPLASTIC CELLS
* 1p/19q: RETAINED BY FLUORESCENCE IN SITU 
HYBRIDIZATION
* MGMT: GENE METHYLATION NOT DETECTED

I'm out of practice on everything except MGMT.  Can someone please help me understand what else this tells us, and what drugs this may prioritize for her?  She's not as willing to take lots and lots of pills as my Dad was.  I would like to pick maybe the top 5 if we can.

Thank you!
Annie

Tumor Genetic Test

All,
We did tumor genetic test at UCSF. Here's the mutations they found...

Please let me know your insights and suggestions for what medicines or therapies are more vs. less effective given these genetic mutations. Mom's radiation is over now and we are planning the next steps. What FDA-approved as well as experimental drug should I push for? thx