Thursday, 22 February 2018

My father has GBM - What should he take?

Hi,
My father has GBM, 71 years old from Israel.

Right now he is going to finish radiation, and taking with it TMZ. (protocol)

He is also taking this supplements

1. PSP (Psk)
2. KEPRA
3. Melatonin 
4. Boswellia 
5. Longvida (Curcumin) 
He can’t use celebrex  ince medical problems.
Any other suggestions what to do? Add something? Remove?
Any idea will be great! any tip will be very appreciated  !


Thank you very much!

Nimrod

Friday, 16 February 2018

Stable MRI!

I had a stable MRI on Monday. The doctors were nervous because I’ve had no follow up treatments since surgery on Nov. 10. A relief, for sure. It is a grade 3 AA.

Maria

Wednesday, 14 February 2018

DNX-2401 oncolytic adenovirus phase 1 trial results

Phase I Study of DNX-2401 (Delta-24-RGD) Oncolytic Adenovirus: Replication and Immunotherapeutic Effects in Recurrent Malignant Glioma (click here for abstract)

I've uploaded the full PDF to the Brain Tumor Library -> 1. Therapies - human studies -> DNX-2401

In group A, 5 out of 25 patients (20%) lived for at least 3 years post-injection of DNX-2401, and three of these (12%) had dramatic responses (at least 95% reduction in cross-sectional area of enhancing tumor) and at least three years of progression-free survival.

This therapy is currently being tested in combination with pembrolizumab (anti-PD-1).


Need recommendations for consulting for CCNU+Temozolomide for my mom

Hi folks,

My mother is a GBM patient who was diagnosed in September. Her GBM is IDH1/IDH2 -ve, is methylated and she almost had a complete resection. She has completed her 6 weeks of radio/chemotherapy and has complete 2 cycles of 5/23 temozolomide. The following study about using a combination of CCNU(Lomustine) + Temozolomide for methylated GBMs has had me interested for quite a while now:

http://btcocktails.blogspot.in/2017/11/sno-summary-episode-1-ceteg-trial-ccnu.html

I wish to switch to the CCNU + Temozolomide cycles for my mom since this protocol, I see it brings about a significant improvement in life expectancy for methylated GBM patients.

However, when I brought this up to my oncologist, I received quite some discouragement on doing this protocol because he said it wasn't global standard of care, which is why I began with the usual temozolomide cycles. I recently got to know that this is almost standard treatment given by oncologists in Germany with methylated GBMs.

I reached out to several oncologists in Germany to consult on this protocol via skype/call, but they refused to do so since it is a toxic therapy and they don't want to do it from distance.

I'm stuck. I probably know this protocol will definitely help improve my mom's life expectancy but I don't have an oncologist to do this protocol under.

My questions

- Can somebody with a good oncologist/hospital in/outside Germany which can consult me on skype/call for this chemotherapy protocol? It shall be of great help for me.

- If you don't know of one, would you recommend switching to the Lomustine+Temozolomide cycles by myself? I don't really want to self medicate since I don't know the answers to the following questions:

a. Whether it is okay to switch from temozolomide to temozolomide+lomustine cycles
b. What are the possible side effects that can happen with this chemotherapy regime and how to tackle them(Low blood counts, nausea, weakness, headache etc)
c. How many more cycles of Lomustine+Temozolomide cycles should I really do, and how should I dose them.
d. Reactions with the supplements that my mom already is on.

I really look forward to your response.

Dabrafenib and trametinib in BRAFV600E mutated glioma.


I started looking for information about Trametinib and found encouraging information about the treatment of BRAFV600E mutant tumors with a combination of Dabrafenib and trametinib.

2017 http://www.jnccn.org/content/16/1/4
"BRAF V600E mutations have been successfully treated with targeted therapy in melanoma, non–small cell lung cancer, and thyroid cancer. Interestingly, these mutations have also been identified in a subset of pediatric and adult brain tumors, with several cases reportedly responding to targeted therapy. However, these reports have been limited to single-agent BRAF inhibitor therapy and recurrent disease. Herein, we report dramatic clinical and radiographic responses to combination dabrafenib (BRAF inhibitor) and trametinib (MEK inhibitor) in 2 adults with high-grade gliomas (HGGs), with 1 patient treated in the first-line setting. These observations, together with prior case reports, advocate for routine screening of BRAF point mutations in adult HGGs, and suggest that treatment with dual-targeted therapy, even in newly diagnosed cases, is safe and effective."

2017 https://www.ncbi.nlm.nih.gov/pubmed/28984141
"BRAFV600E mutations have been identified in a number of glioma subtypes, most frequently in pleomorphic xanthoastrocytoma, ganglioglioma, pilocytic astrocytoma, and epithelioid glioblastoma. Although the development of BRAF inhibitors has dramatically improved the clinical outcome for patients with BRAFV600E mutant tumors, resistance develops in a majority of patients due to reactivation of the MAPK pathway. Addition of MEK inhibition to BRAF inhibition improves survival. Here we report successful treatment of two patients with BRAFV600E mutant pleomorphic xanthoastrocytoma using the BRAF inhibitor dabrafenib in combination with the MEK inhibitor trametinib."

2017 https://www.ncbi.nlm.nih.gov/pubmed/28062673
"A phase I/II clinical trial suggests that dabrafenib shrinks or stabilizes low-grade gliomas in children with the BRAF V600E mutation. Objective, durable responses occurred in 38% of patients, and the side effects were less severe than with chemotherapy. The researchers have started a second trial for patients with glioma and other BRAF-mutant tumor types, this time evaluating dabrafenib combined with trametinib."

To determine which dose of Trametinib can be tolerated and effective, for my mother who does not have the BRAF mutation, I began to look for reports on the treatment of patients. I found two such reports. Unfortunately the articles are paid:
https://www.ncbi.nlm.nih.gov/pubmed/28984141
https://www.ncbi.nlm.nih.gov/pubmed/26936308

Have you seen information about the used doses of trametinib in these reports and clinical trial?

I also found a pediatric clinical trial:
https://clinicaltrials.gov/ct2/show/NCT02684058
But here too, unfortunately, no dose is indicated.

In this studies, not related to the brain, such doses are suggested:
https://clinicaltrials.gov/ct2/show/NCT02034110
Dabrafenib is a 150 mg twice daily capsule administered orally on a continuous basis.
Trametinib is a 2 mg once daily tablet administered orally on a continuous basis.

https://clinicaltrials.gov/ct2/show/NCT02124772
Trametinib Dose-Escalation: Trametinib is administered orally once daily (OD) under fasting conditions. The starting dose of trametinib (0.0125 milligram per kilogram per dose [mg/kg/dose]) is 50% of the recommended fixed dose in adults (2 mg OD). The second dose level (0.025 mg/kg) is equivalent to the recommended dose in adults (2 mg PO daily). The third dose level (0.040 mg/kg) is equivalent to the maximum tolerated dose [MTD] in adults (3 mg PO daily).

Tuesday, 13 February 2018

IDH1 R132H Mutation Enhances Cell Migration by Activating AKT-mTOR Signaling Pathway, but Sensitizes Cells to 5-FU Treatment as NADPH and GSH Are Reduced

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5215606/#!po=0.595238
Has this been shared here yet?

The AKT/mTor pathway is related to glucose metabolism. 5- Fu is the chemo ancient used in the Tocagen trials which have had complete responses in all IDH1 patients. It’s probably safe to assume that these patients had IDH1 mutations.

It is also interested to me because I’ve been in contact with a number of IDH1 mut patients who are having good success with a keto diet. It was been a little counter intuitive since it’s said that IDHmut tumours use glutamine as their metabolic preference. I have read that rather than using glutamine to profilerate perhaps they use it to invade surrounding cells but this seems to have lost out in favourite of using it for their metabolism.

Maria

Saturday, 10 February 2018

Newly diagnosed family member hoping for some clarifications

Hi,
My name is Ashley. My mom was diagnosed with GBM unmethylated December 2017. She is 54 and healthy with a huge loving family that wants her around longer. She went in for emergent surgery due to headaches/pressure and this is how the tumor was found. They have removed the majority of the tumor. She is half way through radiation/chemo right now. She is essentially doing great as she has only hair loss and fatigue at the moment with some cognitive delays at time. I have researched extensively Ben Williams info, the Musella foundation, articles, journals etc. to help find the best treatments. Right now she is on these supplements:
fish oil 3g
melatonin 20mg
PSK trying for 3g
Genistein 125mg
Curcumin 4g
green tea (one-two cups a day)
Boswellia 1000mg but will be going up to 4200mg
Resveratrol 100mg/kg roughly 6000mg
Silibinin 420mg

Medications:
celebrex 200mg  BID (recently just started)
Metformin 2000mg (will start soon-introducing drugs one at a time)
Disulfiram (500mg on chemo days with 250 on non chemo days-4mg copper also with this)-starting soon
Aralen (chloroquinine) 150mg BID --starting soon
Doxycycline 100mg BID-unsure about starting this? (this was recommended by Ben but I just haven't seen many recent trials using this)

My biggest question is how long do we have our family members take this? Is it every day or on just chemo days? There isn't great detail on how long people should be taking these.

Thanks,
Ashley

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.

Friday, 9 February 2018

leucine restriction for IDH1mut?

Hi all,

This article here says that leucine is an activator of GLUD2.

http://www.pnas.org/content/111/39/14217

This is the article they sited:

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3944346/

Leucine is an essential amino acid, which means we must eat it in order to get it. The first article seems to say that leucine is stored in IDH1 mutant gliomas…but I read another article that this depends on the concentrations of ADP and L-Leucine — which implies they can be diluted. Is there an ADP inhibitor? (An initial google search seems to say there is but I'm not sure how they will impact the brain or health in general. I'm going to search that when I have more time.)


Thanks.
Maria

Thursday, 8 February 2018

Do statins, ACE inhibitors or sartans improve outcome in primary glioblastoma?

This is a new paper (click here for abstract) brought to us by some of the same authors who earlier produced:

Does Valproic Acid or Levetiracetam Improve Survival in Glioblastoma? A Pooled Analysis of Prospective Clinical Trials in Newly Diagnosed Glioblastoma

The group concluded:

"This secondary analysis of two large glioblastoma trials thus was unable to detect evidence for an association of the use of statins, ACEI or sartans with outcome in patients with newly diagnosed glioblastoma."

As with the previous study, there are some important caveats.  Some of the most intriguing data supporting the potential for angiotensin system blockers was in combination with bevacizumab:

Effect of angiotensin system inhibitors on survival in newly diagnosed glioma patients and recurrent glioblastoma patients receiving chemotherapy and/or bevacizumab

It would have been interesting to look at outcomes in those using/not using ACE inhibitors or sartans in combination with bevacizumab, for example in the Avaglio and RTOG-0825 trials.

Angiotensin-II has been shown to increase tumor-promoting macrophages in preclinical models:

https://www.ncbi.nlm.nih.gov/pubmed/23333075

and these tumor-infiltrating myeloid cells may play a significant role in resistance to anti-VEGF therapies such as bevacizumab.

https://www.ncbi.nlm.nih.gov/pubmed/26404753


Monday, 5 February 2018

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


 

 




Saturday, 3 February 2018

Inhibitors of autophagy

Given the increasing role of inhibitors of autophagy, I would like to discuss the choice of an inhibitor of autophagy, as well as the possibility of enhancing their effect.
___________________________________

This study focuses on the comparison of some of these inhibitors:
2015 http://thejns.org/doi/10.3171/2014.12.FOCUS14748
"...the authors of this study set out to investigate whether chloroquine (CQ) analogs, in particular clinically established antimalaria drugs, would also be able to exert antitumor properties, with a specific focus on glioma cells.
...the authors treated different glioma cell lines with quinine (QN), quinacrine (QNX), mefloquine (MFQ), and hydroxychloroquine (HCQ) and investigated endoplasmic reticulum (ER) stress–induced cell death, autophagy, and cell death.
All agents blocked cellular autophagy and exerted cytotoxic effects on drug-sensitive and drug-resistant glioma cells with varying degrees of potency (QNX > MFQ > HCQ > CQ > QN)."

Thus, it follows from the study that cloroquine (CQ) shows a weak effect, even lower, that hydroxychloroquine (HCQ) (?!) Maybe this explains the choice of hydroxychloroquine instead of chloroquine in some tests?

And another quotes from the study:

"Cytotoxicity of QBAs for Glioma Cells:
To determine whether other quinoline-based antimalarial (QBA) compounds could mimic the cytotoxic effects of CQ in glioma cells, we used MFQ and QNX. Results showed that these drugs effectively killed U251 cells at much lower concentrations than CQ."

Blocking Autophagy and Inducing Apoptosis in Glioma Cells:
Based on information that CQ induces apoptosis by blocking autophagy, we analyzed whether the other QBA compounds can function in a similar manner.
Quinacrine, the most potent QBA, not only blocked autophagy, but at 20 μM it completely disrupted U251 cellular functioning, which was evidenced by a high level of PARP cleavage, as well as the absence of CHOP/GADD-153 and LC3B expression.

In Vivo Antitumor Activity:
The TUNEL assay for apoptosis demonstrated a significant increase in the number of TUNEL-positive cells in QNX- and QN-> MFQ-> CQ-treated tumors, as compared with untreated controls."

There are also many reports of another inhibitor of autophagy - 3-methyladenine (3-MA).

___________________________________

Since many people here take chloroquine, I would like to discuss the possibility of enhancing its effect. While I see there are the following options:

chloroquine + cimetidine
"Cimetidine pre-treatment caused a 53% decrease in the clearance rate of chloroquine, and a 49% increase in the elimination half-life. Cimetidine inhibited the conversion of chloroquine to monodesethylchloroquine in terms of reductions in the AUC, Cmax, and urinary excretion of monodesethylchloroquine. The serum Cmax of chloroquine was increased by approximately 30% in the cimetidine pre-treated group."
The downside is that since there are many medicines in the cocktail, numerous unpredictable interactions with cimetidine are possible.

increase in the dose of Chloroquine
Instead of using cimetidine, can it be easier to increase the dose of Chloroquine? The standard is 250 mg / day.

chloroquine + hypoxia-inducing agents
2017 https://www.ncbi.nlm.nih.gov/pubmed/28797031
"This work shows that inhibition of autophagy is a promising strategy against GBM and identifies ATG9 as a novel target in hypoxia-induced autophagy. Combination with hypoxia-inducing agents may provide benefit by allowing to decrease the effective dose of autophagy inhibitors."
What hypoxia-inducing agents are they talking about?
___________________________________

I also found several preliminary studies on the synergy of chloroquine and other drugs. It is interesting to study more ..

Dihydroartemisinin + Сhloroquine
2017 https://www.ncbi.nlm.nih.gov/pubmed/29033794
Dihydroartemisinin Exerts Anti-Tumor Activity by Inducing Mitochondrion and Endoplasmic Reticulum Apoptosis and Autophagic Cell Death in Human Glioblastoma Cells.
"Co-treatment with chloroquine (CQ) significantly induced the above effects. Furthermore, ER stress and mitochondrial dysfunction were involved in the dihydroartemisinin-induced autophagy."

Asparaginase + Сhloroquine
2017 https://www.ncbi.nlm.nih.gov/pubmed/29207624
"combination treatment with autophagy inhibitor CQ significantly enhanced anti-glioblastoma efficacy of asparaginase in U87MG cell xenograft model."

Sorafenib + Сhloroquine 
2016 https://www.ncbi.nlm.nih.gov/pubmed/26971793
"we combined sorafenib treatment in GBM cells (U373 and LN229) and tumors with the autophagy inhibitor chloroquine. We found that blockage of autophagy further inhibited cell proliferation and migration and induced cell apoptosis in vitro and in vivo. These findings suggest the possibility of combination treatment with sorafenib and autophagy inhibitors for GBM."

Tuesday, 30 January 2018

Blood-brain barrier and immune checkpoint inhibitors

Blood-brain barrier and immune checkpoint inhibitors

My partner has a recurrent and unoperable glioblastoma.
He is considering a therapy with immune checkpoint inhibitors (e.g. pembrolizumab or atezolizumab) as his tumor has extremely high mutation burden. Some doctors are in favour but some are not convinced and say that it won't work because of blood brain barrier (BBB).
Is there any research showing immune checkpoint inhibitors don't cross BBB?

Chloroquine for GBM with EGFRvIII mutation

EGFRvIII expression triggers a metabolic dependency and therapeutic vulnerability sensitive to autophagy inhibition
http://www.tandfonline.com/doi/pdf/10.1080/15548627.2017.1409926?needAccess=true

Some of the data contained in this study was used as justification for the CHLOROBRAIN trial
https://clinicaltrials.gov/ct2/show/NCT02378532



Final results of disulfiram pilot trial for newly diagnosed GBM

Final results of a phase I dose-escalation, dose-expansion study of adding disulfiram with or without copper to adjuvant temozolomide for newly diagnosed glioblastoma
http://sci-hub.la/https://link.springer.com/article/10.1007/s11060-018-2775-y

Sadly, median PFS and OS were not improved above historical controls receiving standard treatments alone.

However, only 6 of 18 patients also took copper supplements in this trial in addition to disulfiram, leading to another phase 1/2 trial of disulfiram + copper for newly diagnosed GBM which is still recruiting.
https://clinicaltrials.gov/ct2/show/NCT02715609

Intravenous zoledronic acid for cocktail?

There are many articles on the possible benefits zoledronic acid in the treatment of glioblastoma.
https://www.ncbi.nlm.nih.gov/pubmed/?term=Zoledronic+glioblastoma

For example, MTZ Regimen (2016) suggests using:
oral minocycline 100 mg three times daily, oral telmisartan 80 mg twice daily, and intravenous zoledronic acid 4 mg once every 28 days
https://www.dovepress.com/toward-a-noncytotoxic-glioblastoma-therapy-blocking-mcp-1-with-the-mtz-peer-reviewed-fulltext-article-OTT
https://www.ncbi.nlm.nih.gov/pubmed/27175087

Since many patients with glioblastoma include in their cocktails minocycline and telmisartan (or captopril), may be necessary to think about adding an injection of zoledronic acid as non-toxic supplement, 4mg once every 28 days?

Saturday, 27 January 2018

Intraarterial bevacizumab

I found information about the intra-arterial administration of bevacizumab. It looks very interesting.
Does anyone know any details?

Long-term benefit of intra-arterial bevacizumab for recurrent glioblastoma.
2017 https://www.ncbi.nlm.nih.gov/pubmed/28472567
"Standard treatment for recurrent GBM is not yet established. We present a case demonstrating the benefit of intra-arterial (IA) bevacizumab with blood brain barrier disruption (BBBD) for the treatment of recurrent GBM. A 31 year-old man diagnosed with GBM, following primary resection, received temozolomide. After a second resection, he received one dose of IA bevacizumab with BBBD using mannitol, preventing regrowth for 2.5 years. Following tumor regrowth, the patient received another dose of IA bevacizumab with BBBD, which has prevented regrowth for another year."

2012 https://www.ncbi.nlm.nih.gov/pubmed/22946342
Intra-arterial bevacizumab with blood brain barrier disruption in a glioblastoma xenograft model.

Mannitol was used to prepare the solution:
https://www.drugs.com/monograph/mannitol.html

The practice of such treatment in Ukraine:
2013 https://cyberleninka.ru/article/n/ispolzovanie-metoda-vnutriarterialnogo-vvedeniya-himiopreparatov-v-sostave-kompleksnogo-lecheniya-patsientov-s-gliomami-golovnogo
For the intra-arterial administration of drugs, the endovascular technique was used.
"It was found that the method of intra-arterial delivery of chemotherapy is effective and efficient in treatment of patients with malignant gliomas of the brain, can reduce the toxic effects of chemotherapy on the patient, to improve the quality of life for patients."


Carmofur (ASAH1 inhibitor) is more potent than TMZ in killing glioblastoma cells?

I found an interesting study published in November 2017:

https://www.ncbi.nlm.nih.gov/pubmed/29348854
http://www.oncotarget.com/index.php?journal=oncotarget&page=article&op=view&path[]=22637&path[]=71521

"The standard glioblastoma chemotherapy agent, temozolomide, had minimal GSC-targeted effects at comparable or even higher concentrations (IC50 > 750 μM against GSCs). ASAH1 is identified as a de novo glioblastoma drug target, and ASAH1 inhibitors, such as carmofur, are shown to be highly effective and to specifically target glioblastoma GSCs. Carmofur is an ASAH1 inhibitor that crosses the blood-brain barrier, a major bottleneck in glioblastoma treatment. It has been approved in Japan since 1981 for colorectal cancer therapy. Therefore, it is poised for repurposing and translation to glioblastoma clinical trials."

"ASAH1 inhibitors are highly more potent than temozolomide in killing GSCs and U87MG cells. Due to its high level of expression in GSCs, ASAH1 inhibition is proposed as a new anti-glioblastoma therapy that specifically targets GSCs."

2017 https://www.ncbi.nlm.nih.gov/pubmed/28765947
"inhibition of ASAH1 and Sph-1P, either with humanized monoclonal antibodies, small molecule drugs (i.e. carmofur), or a combination of both, led to suppression of GBM cell growth. These results suggest that ASAH1 and Sph-1P may be excellent targets for the treatment of new GBMs and recurrent GBMs, especially since the latter overexpresses ASAH1."


https://www.drugs.com/international/carmofur.html
Unfortunately, I did not find any trials with carmofur (or mifurol) at https://clinicaltrials.gov

https://en.wikipedia.org/wiki/Carmofur
"Carmofur has also been used as adjuvant chemotherapy for curatively resected colorectal cancer patients in China, Japan, and Finland for many years. Trials and meta-analyses have confirmed that the drug is effective on patients with this cancer type, extending their survival.
A clinical trial for small hepatocellular carcinoma was stopped prematurely because 56% of the treated patients had unacceptable side effects. Moreover, the treatment had no survival advantage for stage 1 and 2 cancer patients. This may be a reason why carmofur was never pursued for FDA-approval in the US."

Maybe there are more modern and safe ASAH1 inhibitors crossing the blood-brain barrier?

Thursday, 25 January 2018

Need suggestions to incorporate supplements in my mom's cocktail(GBM Patient)

Hi folks,

My mother(Age 47) was diagnosed with glioblastoma(IDH1/2 -ve, Methylated) in September 2017, and it has left me devastated ever since. She has completed her 6 weeks of radiation/chemo and her first cycle of 5/23 temozolomide. Her next cycle of temozolomide starts 5 days from now. I stumbled upon this blog just a week back, and have found this to be immensely helpful and resourceful.

I need help from you guys on what else should I incorporate in my mom's cocktail. Following are the supplements that are present in her cocktail per day already:

Metformin: 500 mg
Boswellia Serratta: 4000 mg
Resveratrol: 400 mg
Fish Oil: 3600 mg DHA+EPA + 400 mg of other omega 3 fatty acids
Curcumin with piperine: 5000 mg
Longvida: 400 mg
Quercetin: 5000 mg
Melatonin: 20 mg
Selinium: 200 mcg
Vitamin ADK supplement with 5000 IU Vitamin D3
Ashwagandha: 500 mg
Garlic: 6 cloves
Ginger: 6 cloves
Dendritic cell therapy: On the cards
Cannabis oil: Dropped because it was suppressing her WBCs

She is also on ketogenic diet and has done about 2 weeks of hyperbaric oxygen. We are looking at two more weeks of hyperbaric oxygen.

I'm looking for more supplements that are good adjuvants to temozolomide/standalone good adjuvants that I should definitely include in my mom's cocktail. It'd be great if you guys could help out in more supplements that I should include, I'm finding it very hard to self medicate my mom. Basis Ben Williams' book and reading several blogs, the following supplements have repeatedly been catching my attention:

1. DCA
2. Chloroquine
3. Care oncology clinic protocol(Metformin + Doxycline + Mobendezole + Atorvastatin)
4. Ruta 6 + Calceria Phos(Not sure if it is a good idea to use while on chemo)
5. Methadone
6. Veramapil
7. Low Dose Naltrexone
8. Disulfiram
9. Perilyl Alcohol
10. Methadone
11. Celebrex

She is already taking a total of 50 meds per day and I think she can take only 10-15 more. Would be great if you can help me from above list/any other supplement that should definitely be a part of her cocktail.

Thank you in advance!

Wednesday, 24 January 2018

The importance of re-testing IDH status in IDH "wild-type" low grade gliomas

PATH-36. REPEATING TESTING IN IDH WILD TYPE LGG CASES. THE IMPORTANCE OF NEXT GENERATION SEQUENCING
Link to abstract

"the observation of a particularly favorable outcome in a group of 42 patients with IDH wild type LGG (OS=93.7 months) led us to assess IDH mutation with a more sensitive technique. Next Generation Sequencing (NGS) was used to evaluate IDH status in these tumor samples, and the results of NGS assay were compared with previous findings"

"Twenty-one (50%) of the 42 initial IDH wild type LGGs were found to present IDH mutation when tested with NGS. Four patients had R132H mutation and 17 cases showed other IDH mutations (4 patients with IDH2 mutation, 5 patients with IDH1 R132C mutation, 5 patients with IDH1 R132G mutation and 3 patients with IDH1 R132S mutation)."

"Repeating testing in IDH wild type LGG cases is crucial, as well as the technique used to assess this mutation. NGS is able to find IDH mutations in 50% of patients previously misdiagnosed"

Increased expression of androgen receptor (AR) in GBM. Enzalutamide (androgen receptor inhibitor)

SNO 2016 abstract: CSIG-13 ANDROGEN RECEPTOR IS INVOLVED IN GLIOBLASTOMA AND PRESENTS A POTENTIAL THERAPEUTIC TARGET

SNO 2017 abstractCSIG-24. ANDROGEN RECEPTOR IS A POTENTIAL THERAPEUTIC TARGET IN GLIOBLASTOMA

"Enzalutamide given orally (20 mg/kg three time per week) to nude mice bearing human gliomas (U78MG) resulted in reduction of 72% in tumor volume (p=0.0027) as compared to mice treated with vehicle. We hope that the results of this study together with continued laboratory efforts will lead to a new approach for the treatment of human glioblastoma."

Enzalutamide is an androgen receptor inhibitor approved by the FDA in 2012 for treatment of prostate cancer.

PARP inhibitors for PTEN-mutant cancer cells

Most GBM tumors (IDH1 wild-type) have a loss of one copy of chromosome 10.  Additionally, about 30% will also have a deactivating mutation in the remaining copy of PTEN, leaving no functional PTEN in these tumors.

In these tumors, PARP inhibitors may be an effective therapeutic option, based on a study showing therapeutic effects of olaparib in PTEN-negative HCT116 colon cancer xenografts, while HCT116 xenografts with restored PTEN didn't respond to olaparib.

These results are not necessarily generally applicable, as the HCT116 line is also known to have mismatch repair defect (loss of MLH1), so there may have been some interaction between loss of both mismatch repair and PTEN that sensitized cells to olaparib.

Study title:
Synthetic lethal targeting of PTEN mutant cells with PARP inhibitors
Full study available here

Chloroquine has therapeutic effect in IDH-mutant U87 mouse model



This was an orthotopic mouse model: U87 GBM cells with either wild-type IDH or genetically engineered to contain the IDH1 R132H mutation were injected into brains of nude (immunodeficient) mice. Chloroquine was injected intraperitoneally.

According to this study, 2-hydroxyglutarate produced by the mutant IDH1 enzyme leads to endoplasmic reticulum (ER) stress, autophagy of the endoplasmic reticulum, and reduced biosynthesis of membrane phospholipids (as the ER is the site of phospholipid synthesis). Inhibiting autophagy with chloroquine triggered apoptosis (programmed cell death).

Chloroquine-treated IDH1-mutant U87 tumors had increased caspase activity (a marker of apoptosis), while the IDH1 wild-type U87 tumors had no increase in caspase activity with chloroquine treatment.

Study title:
2-hydroxyglutarate-mediated autophagy of the endoplasmic reticulum leads to an unusual downregulation of phospholipid biosynthesis in mutant IDH1 gliomas
Pubmed link

I've uploaded the full study to the Library (Folder 2 Therapies - preclinical -> Chloroquine)

Best place for dendritic cell therapy for my mom(GBM Patient)


Hi folks,

My mother is a grade 4 brain cancer patient, who was diagnosed on 17 September 2017. She has completed her 6 weeks of radio/chemotherapy and her 1st 5/23 cycle of temozolomide. I'm looking for immunotherapy(dendritic cell therapy), and where to get it done from is something that I'm terribly confused about. I shortlisted the following: 

1. IOZK(They say they will do hyperthermia) while my mom is on chemo, and will do the DC after my mom is done with the Chemo. They say they won't be able to use the tumor block because it is stored in paraffin. They tell me they have their own set of GBM antigens that they shall use.

2. Dr Nesselhut: They say they will give 4-6 vaccines of dendritic cells and can be given while on chemotherapy(1 week before or after). But they say that they can use the tumor block for making the antigens, despite the fact that the block is in paraffin. They say they can 'de-parafinise' it. I'm not sure if they really are true with their claims, but they were the only place that said they can use the block to make the antigens

3. Verita Life, Bangkok: They say that they can give the dendritic cell therapy while on chemotherapy with their own set of antigens, but can't use the tumor block. They shall couple the treatment with a lot of herbal IVs like quercetin, curcumin, resveratrol, Vitamin C etc.

4. Dr Robert Godner: They've asked me to wait for another MRI since the recent one came out clean, but with choline elevation(which is either a sign of radiation injury or residual tumor/recurrence).

I wish to know what shall be the best place to get the immunotherapy done from? Would love objective inputs from you guys. I would also want to know how many times you were made to travel to these places, if you've experienced the dendritic cell therapy from them.

PS: My personal preferential order is the order in which I've placed the above places, but IOZK and Dr Nesselhut, I foresee will easily call us to Germany about 8-10 times, which I'm not very sure my mom will be able to go. So, travel for a GBM patient a few months from now is a concern. 

Sunday, 21 January 2018

Improvement of the ketogenic diet


In many studies, it has been shown that a ketogenic diet can be a useful supplement in the treatment of glioblastoma. I would like to discuss the improvement of this diet on the basis of recent research.

1. Ketogenic diet + α-lipoic acid and hydroxycitrate
2017 https://www.ncbi.nlm.nih.gov/pubmed/28122260
"To decrease anabolism, glucose uptake should be reduced (ketogenic diet). To increase catabolism, the oxidative phosphorylation should be restored. Treatment with a combination of α-lipoic acid and hydroxycitrate has been shown to be effective in multiple animal models."

2016 http://crescopublications.org/pdf/CROOA/CROOA-2-019.pdf
"Combination of Metabolic Treatment of Aggressive Primary Brain Tumour
and Multiple Metastases of the Brain"
"We report the cases of 12 patients with advanced brain tumor. They were all treated with
conventional treatment and a combination of sodium R lipoate (800 mgbid), hydroxycitrate at 500 mg tid and low-dose naltrexone at 5 mg at bedtime. Eight patients had primary brain tumour (n=8 including five glioblastomas) four patients had multiple brain metastases."

2. Ketogenic diet + Fenofibrate ?
2016 https://www.ncbi.nlm.nih.gov/pubmed/26869992
"Our results reveal a new, intriguing aspect of cancer cell biology and highlight the benefits of fenofibrate as a supplement to both canonical and dietary (ketogenic) therapeutic approaches against glioblastoma."
2015 https://www.ncbi.nlm.nih.gov/pubmed/26172294
"Given that fenofibrate is a widely used non-toxic drug, we suggest its use in patients with glioblastoma multiforme (GBM)."
2017 https://www.ncbi.nlm.nih.gov/pubmed/28459367
"...the lipid-lowering agent fenofibrate...have potential to lower synthesis or effects of G(M)-CSF and thus deprive a glioblastoma of some of the growth promoting contributions of bone marrow and G(M)-CSF.
It's strange, but in this blog I did not find any information about Fenofibrate. So is it necessary to add it to the ketogenic diet?

3. Ketogenic diet + Inhibition of glutamine metabolism ?
2017 https://www.ncbi.nlm.nih.gov/pubmed/28720668
"Inhibition of glutamine metabolism slows the in vitro and in vivo growth of GLNHigh GBM cultures despite metabolic adaptation to nutrient availability, in particular by increasing pyruvate shuttling into mitochondria."
"...the pleiotropic metabolic inhibitor EGCG, targeting glutamine metabolism, specifically reduces tumor proliferation, in vitro and in vivo, of mesenchymal GLNHigh cells."
How can the findings of this study be used? Only EGCG can not inhibit glutamine metabolism. Maybe there are more options?

4. Ketogenic diet + Specialized medium-chain triglycerides (MCT) ?
2016 http://clincancerres.aacrjournals.org/content/22/10/2482
"MCTs were specifically chosen based on carbon chain lengths (C8:C10::97%:3%), which allow them to rapidly diffuse from the gastrointestinal tract into the hepatic portal system and travel directly to the liver where they are converted into ketone bodies."

5. What other ideas can you offer to enhance the effect of a ketogenic diet?

Friday, 19 January 2018

Total resection followed by multimodal immunotherapy: 15+ months remission without RT/TMZ

HGG-05  Can Multimodal Immunotherapy Replace Radiochemotherapy in Completely Resected Adult GBM?

4th Biennial Conference on Pediatric Neuro-Oncology Basic and Translational Research, June 15-16, 2017, New York City
Link to complete abstracts
Link to abstract HGG-05

While this is only a single case, the long duration of remission in the absence of radiation and chemotherapy is intriguing.  This patient was also IDH wild-type, and was in EORTC recursive partitioning analysis (RPA) class IV, as are the majority of GBM patients in phase 3 trials.

The patient was treated at IOZK in Germany with "multimodal immunotherapy consisting of 2 cycles of 6 days Newcastle Disease Virus (NDV) infusions and local modulated electrohyperthermia (mEHT) sessions plus an autologous DC vaccine loaded with serum-derived NDV/mEHT-induced antigenic microparticles + NDV, and additionally four more treatments with NDV infusions + mEHT"

More detailed information on IOZK's methods can be found in this publication.
http://www.iozk.de/aktuelles/iozk_austin_oncology_case_reports_2017.pdf

In addition, a technique has been developed at IOZK to use blood serum-derived antigenic microparticles, where no fresh or frozen tumor tissue to produce a tumor lysate is available. This latter method was used in the case report above.









Thursday, 18 January 2018

Fluspirilene (schizophrenia drug)

Identification of antipsychotic drug fluspirilene as a potential anti-glioma stem cell drug
link to full study in Oncotarget

The TGS04 GBM glioma stem cell line used in the mouse study was established from a human glioblastoma at the University of Tokyo.  These cells were implanted in the brains of nude mice. Fluspirilene was administered intramuscularly, as it is in humans.


Above: Fluspirilene treated mice had reduced tumor volume, increased survival and more sharply defined tumor borders (less diffuse).


Above: fluspirilene treated tumors showed greatly decreased expression of STAT3 with phosphorylation at serine 727.  In other words, there was less activated STAT3 in these tumors.
"STAT3 can be transcriptionally activated by phosphorylation of its tyrosine 705 or serine 727 residue"

STAT3 is an important target in GBM and other cancers, helping to co-ordinate such cellular behaviours as invasion, angiogenesis, anti-apoptosis and immunosuppression.

Wednesday, 17 January 2018

A difficult choice of treatment for a large progressive GBM after chemoradiotherapy

From some studies it follows that:
- Avastin in the first line increases the quality of life and survival for partially resected GBM;
- combination of CCNU + Avastin is more advantageous than just Avastin for MGMT-methylated GBM;
- I can not also not use TMZ immediately after chemoradiotherapy, especially after CeTeg results for MGMT-methylated GBM;
- low Avastin dose (<3.6 mg / kg / week) with Telmisartan, is more beneficial than the Avastin standard dose and will not be so toxic for use with CCNU + TMZ.

As a result, after sleepless nights, I decided to try this combination:

The cycle of 42 days:

0 day - Verapamil 240mg, Disulfiram 500mg, Copper 4mg, DHA 1200mg
1 day - Avastin 6.5 mg / kg
1 day - Lomustine 75 mg /m2 (+ Verapamil 240mg, Disulfiram 500mg, Copper 4mg, DHA 1200mg)

2-6 days - Temozolomide 90 mg/m2 (+ Verapamil 240mg, Disulfiram 500mg, Copper 4mg, DHA 1200mg, Curcumin 2000mg)

7-41 days - Telmisartan 40-80mg, Disulfiram 300mg, Copper 2mg, DHA 900mg)

15 day - Avastin 6.5mg / kg
29 day - Avastin 6.5mg / kg
42 day - Verapamil 240mg, Disulfiram 500mg, Copper 4mg, DHA 1200mg

+ every day Melatonin/Agomelatin, Berberin, Shark Oil, Oxaloacetate, Honokiol...
If possible, DCA will be added 6mg / kg / twice every day.
If possible, the doses of CCNU and TMZ in the next cycle will be increased.

Histone deacetylase inhibitors (HDACi)

I find a lot of information that histone deacetylase inhibitors (Trichostatin A (TSA), Vorinostat, 7-ureido-N-hydroxyheptanamide derivative (CKD5)) have potent anti-cancer effects in glioblastoma.

2017 https://www.ncbi.nlm.nih.gov/pubmed/27852054
"Our results demonstrate that the novel HDACI CKD5 is a promising therapeutic candidate for glioblastoma."

2017 https://www.ncbi.nlm.nih.gov/pubmed/27766591
"We conclude that the combined administration of TSA and CCNU eradicates GBM cells with a higher efficacy than either drug alone, thereby opening a novel avenue for the treatment of GBM."

2015 https://www.ncbi.nlm.nih.gov/pubmed/25634603
"...these results indicate that trichostatin A (TSA) suppresses ESCC cell growth by inhibiting the activation of the PI3K/Akt and ERK1/2 pathways. TSA also promotes cell apoptosis through epigenetic regulation of the expression of apoptosis‑related protein."

2014 https://www.ncbi.nlm.nih.gov/pubmed/24464841
"Here, we investigate the effects of the HDACi trichostatin A (TSA) in U87 GBM cultures and tumorsphere-derived cells. These findings indicate that HDACis can inhibit proliferation, survival, and tumorsphere formation, and promote differentiation of U87 GBM cells, providing further evidence for the development of HDACis as potential therapeutics against GBM."

The results of clinical trials, however, did not give a good result:

Phase I/II Trial of Vorinostat Combined with Temozolomide and Radiation Therapy for Newly Diagnosed Glioblastoma: Final Results of Alliance N0874/ABTC 02.
2017 https://www.ncbi.nlm.nih.gov/pubmed/29016887

Phase II Study of Bevacizumab and Vorinostat for Patients with Recurrent World Health Organization Grade 4 Malignant Glioma.
2017 https://www.ncbi.nlm.nih.gov/pubmed/29133513

"Valproic acid has also recently been demonstrated to be a potent histone deacetylase inhibitor."
Many patients with glioblastoma take valproic acid (Depakote) against epileptic attacks. However, this has no effect on overall survival. Perhaps it is necessary to increase the dose or combination with something? I found that disulfiram increases the content of valproic acid in the blood.

And by the way, I can not find any medicine containing Trichostatin A.

Tuesday, 16 January 2018

One reason mouse studies don't translate to humans

I just came across a study that looked very interesting, showing increased survival in an orthotopic glioma mouse model when metformin is combined with temozolomide.

High-Dose Metformin Plus Temozolomide Shows Increased Anti-tumor Effects in Glioblastoma In Vitro and In Vivo Compared with Monotherapy



Especially interesting was the finding that the higher dose of metformin + temozolomide eliminated the expression of fatty acid synthase in the tumor specimens.



Fatty acid synthase (FASN) may be an especially good target in IDH1-mutant gliomas, as FASN is one of the most differentially overexpressed transcripts in G-CIMP (for the most part IDH mutant) gliomas versus non G-CIMP (for the most part IDH wild-type).



As is usually the case, the devil is in the details.

The study states several times that the metformin doses used in this study are clinically relevant, and this is true, except for the fact that the mice were injected with metformin intraperitoneally, rather than fed the metformin orally the way humans would take it.

From a different study, we know that intraperitoneal injections of metformin can lead to peak plasma levels 150-fold higher than what can be achieved with oral dosing.

"Notably, HPLC-ESI-QTOF-MS pharmacokinetic analysis showed that the plasma levels of metformin immediately after the last i.p. injection were ~150-fold higher than those obtained with the oral dosing schedule. Thus, mice that were treated with the i.p. dosing schedule achieved 679 ± 16 µmol/L (~87 µg/mL) metformin, a circulating dose of metformin that is within the lower limit observed in an individual with metformin poisoning..."

Pharmacokinetic differences between the methods of drug administration used in mouse studies (often intraperitoneal) and the methods used in humans, may account for some of the failures of mouse studies to translate into clinical results.

It would be interesting to investigate the anti-diabetes drug phenformin, a much more potent biguanide which was removed from the market in the 1970s due to increased risk of lactic acidosis, for cancer treatment.

Sunday, 14 January 2018

Lomustine or Axinitib? Phase 2 results.


Randomized phase II trial comparing axitinib with the combination of axitinib and lomustine in patients with recurrent glioblastoma.
https://www.ncbi.nlm.nih.gov/pubmed/28988341
https://static-content.springer.com/esm/art%3A10.1007%2Fs11060-017-2629-z/MediaObjects/11060_2017_2629_MOESM1_ESM.docx

Axitinib improves response rate and progression-free survival in patients with rGBM compared to historical controls. There is no indication that upfront combination of axitinib with CCNU improves results.

From this study does not follow that instead of Lomustin it is better to take Axitinib?
I need to decide what to add to Bevacizumab for my mom.

Saturday, 13 January 2018

Thursday, 11 January 2018

Avastin + Irinotecan?

It seems that my mother's tumor (MGMT methylated) did not decrease after radiation therapy + TMZ.
Doctors offer a combination Avastin + Irinotecan.
They say that if TMZ did not help by the time of radiotherapy, then TMZ will not even help with Lomustin!

But I have not seen a single message on this blog about Avastin + Irinotecan combination!
If we use it, what drugs do you recommend adding to increase efficiency?

Wednesday, 10 January 2018

Anaplastic Astrocytoma questions

Hello,

First of all, thank you all for the time and work put into this site. I wish I had thought to look for it when my sister first got sick. This is the scariest stuff and it helps to see other families fighting and winning.

My sister was diagnosed with Astrocytoma 2 / 3 back in April 2016 which was determined to be Anaplastic Astrocytoma 3.

I don't understand what she meant but she said her tumor had "favorable" mutations.

She had 95% removal of the tumor at Sloan-Kettering, then moved on to radiation and chemo. She finished chemo in September(?) of last year.

All of her MRIs look good and her last one on 12/18/2017 was still clear.

My questions are:

1) Right now she is not really doing anything for maintenance. Would it be worth looking into a Ketogenic diet or meditation or anything? I would like to have her try the ketogenic diet, but I have read mixed things about it. Also, I want to push her to do this, but it's not my choice and it's hard to remember that.
2) I've read that Asctrocytoma conveys a huge risk to siblings and a lesser risk to parents. Would it be worth having my brother and parents get an MRI?

Thank you.
-Ray

Tactics of treatment for early continued growth.


10/27/2017 My mom had a surgical operation. Glyoblastoma was removed by 95%. (MGMT methylated)
After 3 weeks (11/16/2017) MRI showed that the tumor AGAIN grew to a size of 3.5 x 5 x 5 cm (accumulation of contrast medium)
Doctors were just shocked by such rapid growth!!!

From 21.11.2017 to 29.12.2017 my mother had radiation therapy + TMZ (+2 last weeks DCA, metformin, celebrex, chloroquine).
Now mom has a break. She accepts nothing. We want to restore blood counts. In addition, she had a terrible rash on her leg and on her arm.

Today's MRI showed continued growth. The size of the tumor is 4x5x6cm. (accumulation of contrast medium). Doctors say that this is not a pseudo-progression, since there is pressure on the brain and its displacement. We are at a loss.

Two weeks later, we wanted to start CCNU + TMZ (as in the CeTeG study) + DCA + rapamycin + hydroxy / chloroquine.
But now I'm not sure. Maybe we should start a daily low-dose TMZ + CUSPv4?
Or daily low-dose TMZ  + DCA + rapamycin + hydroxy / chloroquine?

I'm afraid that my mother has little time. Her hand begins to work worse, she walks badly and does not speak well (

The tumor grows very quickly and I pray that we have a chance to try something.

Tuesday, 9 January 2018

Response to Optune imaged by amino acid PET

Amino Acid PET Imaging of the Early Metabolic Response During Tumor-Treating Fields (TTFields) Therapy in Recurrent Glioblastoma

I've uploaded this to the Brain Tumor Library (Optune/Novocure/NovoTTF folder)


Metformin in vivo, C6 glioma - Wistar rat model

This is the first study I've seen testing metformin in an orthotopic glioma model with oral (rather than intraperitoneal) administration.  The survival gain was modest, but threre was a gain nonetheless.



http://exp-oncology.com.ua/wp/wp-content/uploads/2017/12/2419.pdf?upload=   (see figure 4)


Monday, 8 January 2018

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?


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



Saturday, 6 January 2018

Consequences of radiation therapy?

Please share your experience.

A week ago, my mother finished radiation therapy + temolozolomide.
The condition was good.

Now she has great weakness, all the time very sleepy, it's hard to walk, sometimes unnatural speech.
I can not understand, such weakness is the consequences of radiation therapy?

Also the last 2 weeks my mom takes every day Metformin (2х1000mg), DCA (2х1300mg), delagil (1х250mg), celebrex (2х200mg).

P.S. My mother also had a very low leukocyte count to 1.66 (norm 4.5-11). What do you recommend food additives for their increase?

Thursday, 4 January 2018

First post- looking for advice on cocktail treatment

Hello,

This is my first time posting to this site, although I have come across it many times in my research. My name is Jenna and I am here on behalf of my father who was diagnosed at age 66 and will turn 68 this February. Although his tumor is currently stable, his symptoms appear to be worsening. He has increased confusion and sleeps on and off all day. I am here looking for some suggestions as to what we do next.

A brief history: my father was diagnosed with grade 4 GBM in August 2015 and had a successful resection on his right frontal lobe and started temozolomide and radiation treatment. We tested the tumor material with FoundationOne and found six genomic alternations: EGFR, PIK3CA, CDKN2A/B, FAT1, and TERT. We also learned that it was unmethylated. His first recurrence was in September 2016, again in the right frontal lobe. We decided to try the Tocagen immunotherapy study, but unfortunately in late March, we saw growth again in the right frontal lobe as well as new growth in the corpus callosum, making it inoperable. Since then, my dad started getting infusions of nivolumab with re-radiation and we’ve been getting scans that show a slight improvement which has given us a few small but welcome moments of relief. At the same time, the re-radiation or nivo have caused inflammation and we believed the added pressure from that was giving him balance and bladder control issues. He recently had a seizure and now we are trying to work out whether his balance issues were actually the results of something called Todd's Paralysis. It's possible he's been having several small seizures that have been going unnoticed which then cause weakness in the limbs for days to months. If this is the case, we might be able to decrease or remove the steroids. We also reduced his nivolumab infusions from every two weeks to once a month to see if it lessens his inflammation.

I read Ben Williams' book as well as some posts here about cocktail treatments. I would love to create a regimen for my Dad but am confused about where to start. I work in anti-counterfeiting as well which makes me extra wary about procuring drugs from the internet. I would love to hear from some of you about which combinations of treatments are working, where the agents can be safely obtained, what the dosage is, and whether or not there are any side effects. 

Many thanks and wishing everyone a happy new year ahead!


Jenna

Tuesday, 2 January 2018

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

Monday, 1 January 2018

Drug for a cocktail before bedtime?


Melatonin, agomelatin, imipramine, amitriptyline or something different?

As I can see, many patients take 20mg of melatonin before bedtime.

However, as written in CUSPND
"Agomelatine’s circulating half-life in humans is ~2hours versus 30 to 40 minutes for melatonin. This is a significant advantage of agomelatine. Further complicating the use of melatonin would be the variable and generally poor absorption after oral administration. Agomelatine penetrates the blood-brain barrier."

This study (https://www.ncbi.nlm.nih.gov/pubmed/28500556) compared agomelatine and other drugs and concluded that the most effective for glioblastoma - imipramine or amitriptyline.

However, here (https://www.ncbi.nlm.nih.gov/pubmed/27480195) on the contrary it is reported "that imipramine and tranylcypromine reduced the cytotoxic efficacy of temozolomide under some oxygen conditions while fluoxetine did not demonstrate such effects".

So which of these drugs should be added to the cocktail before bedtime?




CLOVA cocktail - Your opinion?


It was published in February 2017:
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5410264/
"The patients treated with CLOVA cocktail in combination with TMZ showed increased survival compared to the control group treated with TMZ alone."

CLOVA cocktail:
TMZ + 800 mg cimetidine, 400 mg lithium, 10 mg olanzapine, 800 mg valproate.

Perhaps one of these drugs (to inhibit the activity of GSK3β) can be replaced with more effective?

Saturday, 30 December 2017

Treatment options post-RT/TMZ phase for IDH1 mutated, MGMT unmethylated GBM

Hi all,

I was diagnosed in late September with a GBM (frontal, left, with large cyst, IDH1 mutated, MGMT unmethylated), which was subsequently successfully operated (gross total resection) at the end of September. I guess as many/most here, I eventually stumbled across Ben William's book, the Glioblastoma Treatment options guide and ultimately this invaluable blog and community, which I have been studying and following closely since. I recently concluded the first phase of my treatment, following standard Stupp Protocol (6 weeks concomitant RT/TMZ) and am currently planning next steps (plus waiting for first post-RT MRI next week...).

While I did not get 'smart' in time to save my tumor material from being paraffined post-OP (unbelievably, this is still standard practice here in Germany in most hospitals), I did actively supplement my first phase of treatment with what I think is a reasonably aggressive 'cocktail' approach, including the following components:

--------------------------------------------------------------------------------------

Meds:
- Chloroquine, 1x 250mg
- Celebrex, 2x 200mg
- Disulfiram, 1x 250mg - 500mg (+4mg copper)
- Sativex (THC/CBD spray), ca. 3-4 sprays (approx. 15-20mg)

In general, I tolerated these medications without any major problems or side effects, with a few exceptions. Notably, towards the end of the treatment I developed some peripheral neuropathy in my left foot, which has now almost recovered, however (took around 3-4 weeks to recover). Nevertheless, it cause me to cease the Chloroquine and Disulfiram shortly before the end of my RT treatment phase. In addition, I found it a little hard to tolerate Sativex as I wasn't too keen on the psychoactive effect, which gave me some anxiety / mild panic attacks from time to time at night. As a result, I took it only for around 3 weeks or so.

Supplements:
- Berberine: 1000mg
- Boswellia Serrata: up to 4400mg (gradually increased dosage over course of RT to protect from Edema)
- CBD oil (8%), 5 drops (started after ceasing to take Sativex)
- PSP, 2100mg
- Curcumin (Longvida), 2000mg, increased to 3000mg towards end of treatment
- Green Tea Extract, 3625mg
- Lycopene, 20mg
- Matiake D-Fraction Pro, 65mg (3x 23 drops)
- Melatonin, 20mg
- Omega 3 DHA/EPA, 3528mg
- Probiotics, ca. 40bn units
- Pterstilbene, 250mg
- Resveratrol, 500mg
- Selenium, 200ug
- Silymarin, 1500mg
- Soy extract, 3750mg
- Vitamin D, 9000IU

In general, all of the above were well tolerated without side effects. I'd also like to mention I was able to avoid any kind of Edema / Cortisone use during my RT therapy, which I believe may have been at least in part facilitated by Boswellia in combination with Celebrex.


Other:
- Ketogenic diet, max 40 g Carbs per day; generally constant medium to high Ketone bodies when measuring. Started 1 week before RT, and continued to last day
- Caloric restriction, lost ca. 8 kilos in 6.5 weeks of RT, which I think equates approx. 600kcal or so in daily caloric restriction
- Daily morning smoothie, with variety of hopefully beneficial things like berries, broccoli sprouts, spirulina, tumeric powder, Matcha green tea, cocoa powder,  etc.
- Daily walks of ca. 1 hour to combat radiotherapy fatigue and keep fit

Ketogenic diet was somewhat difficult to maintain psychologically, but possible due to my partner's kind help in continuously seeking out new and often tasty dishes to keep things interesting. Caloric restriction much easier, since Temodal anyway caused me lack of appetite. I believe daily walks were very helpful to avoid RT fatigue, which affected me only in very minor way and much less than I expected.

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NEXT STEPS & QUESTIONS

I am currently considering next steps, and having talked to various NOs and other Brain Tumor specialists, I am still not entirely convinced what the right way forward is. As expected, most doctors do not want to deviate from the Stupp Protocol (i.e. follow up the RT/TMZ phase with 6 months of 5/23 TMZ cycles). However, I am not convinced such a treatment would necessarily add much benefit in my case, since my tumor is MGMT unmethylated.

One of the leading specialists in Germany told me that the unmethylated MGMT status is irrelevant in the case of IDH1 mutated tumors like mine, since a study (NOA-4) showed that there was no significant difference in responsiveness  between MGMT methylated or unmethylated IDH1 tumors.

https://www.ncbi.nlm.nih.gov/pubmed/19901110

However, upon further research I stumbled across the following interesting study from China, which seems to suggest that IDH1 mutated tumors might in fact be particularly resistant to TMZ (3-10x more resistant in cell culture test). The study also notes that in China they observed relatively little additional benefit of TMZ cycles for the IDH1 mutated group of patients compared to RT alone, and the authors argue that survival benefits for IDH1 mutated tumors may simply be the result of a less invasive / more benign type of tumor relative to wildtype. It makes me wonder if the fact that MGMT doesn't seemingly play as big a role for IDH1 mutated tumors is simply the result of the fact that neither responds well to TMZ...:

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4747376/

I'm therefore a bit hesitant to simply go ahead with TMZ therapy hoping for the best, and would like to consider other options.
One approach I am considering is Immunotherapy at the IOZK clinic in Cologne, which is not far from my house. However, because I don't have frozen tumor material, they would have to make a personalized vaccine using a liquid biopsy approach. This, in turn, could make the treatment even more unproven than vaccines anyway are even when made from tumor lysate. An additional option which could possible materialize down the road (but not yet, as no trials are running here presently to my knowledge) is to try to get hold of an IDH1 vaccine on a compassionate use basis.


My immediate next step is to see the MRI results next week, but I'd be very grateful for any advice on how to proceed from here. Especially, I'd like to try and resolve the following questions:

1. Would it be unwise to not do any additional TMZ cycles? Are there any obvious chemotherapy alternatives perhaps?

2. Would the immunotherapy using liquid biopsy at IOZK clinic be a good alternative for ongoing chemotherapy cycles? Would it be advisable to start this right away (i.e. without any additional TMZ cycles), or should I do some TMZ cycles first just to hedge my bets?

3. Any other recommendations in terms of maintenance strategies. E.g. what medication(s) could make a good maintenance therapy, without concurrent chemotherapy?


Thanks in advance for any comments, and wish you all a very happy and most importantly healthy 2018!

Best,
John