Saturday, 16 June 2018

Experience with Avemar?


Has anyone had experience with Avemar (fermented wheat germ extract)?   I am concerned about its possible interactions with Keytruda and Tensirolimus, as well as with Warfarin.  Research and literature are limited (see https://www.mskcc.org/cancer-care/integrative-medicine/herbs/wheat-germ-extract), but it may be anti-angigogenic and promote apoptosis.  We are particularly interested because Avemar is also said to help increase RBC production. My husband's RBC is low and he is feeling very fatigued. 

Just for background - my husband was diagnosed in 2/2016 with giant cell unmethylated and IDH negative GBM in his left temporal lobe.  He never had SOC.  In addition to two resections and hyprofractionated radiation, his treatment initially included an immunotherapy trial for REGN2810.  Now he is on Keytruda and Tensirolimus infusions, 100 mg of daily Temodar, Celebrex, Prozac, Metformin and Optune.  His tumor and cognitive condition are stable and he is fit and strong.  His only problems are anemia and kidney function issues.

Wednesday, 13 June 2018

FUCOIDAN

Hi there everyone,

Has anyone used Fucoidan? It's a seaweed based extraction.

I am trying to build up my immune system before my next round of chemo and have heard this is a good product. However there are vast differences in the retail price and I would love some feedback from anyone who has knowledge of this product.

With thanks,

Geraldine

Sunday, 10 June 2018

To go or not to go beyond the 6 chemo cycle mark?(3 cycles TMZ + 3 cycles TMZ+Lomustine)

Hi folks,

My mother is a glioblastoma patient who was diagnosed in Sep 2017(IDH1 -ve, methylated). She had a complete resection and has completed her radiation. Following the radiation, we did 3 cycles of temozolomide and the following two cycles were Lomustine(CCNU)+Temozolomide, since I stumbled upon a research that the combination of the two results in a significant improvement in life expectancy for methylated cancers.

However, since this research had 6 cycles of lomustine+temozolimde after the radiotherapy, I wish to ask if I should go beyond the total 6 cycle mark for my mom to do a total of 9 cycles of chemotherapy? Has somebody gone through a situation like mine and gone beyond six cycles of chemo with lomustine and temozolomide in their protocol? Does more chemo always mean better survival? I've heard from my fellow caregivers that an increase consumption of CCNU+TMZ has a risk of liver failiure and pneumonitis, how true is that? If it is, is there anything that we can do to reduce the risk and still do this combination for a total of 9 cycles to get the benefit this protocol gives?

Some context: My mom's last MRI 2 months back showed no growth, her health stays decent, she tolerates the chemo well and her platelet/WBC/Hb/RBC stay around 100k+, 2.5k-3k, 12 and 3.7-4 respectively even during the CCNU+Temozolomide combination.

My mom also takes these supplements: Curcumin(4-5 g/day), Boswellia(4000 mg/day), Keppra(1000 mg/day), Quercetin(3000 mg per day), Resveratrol(400 mg/day) Bromelain(700 mg/Day), Celebrex(600 mg/day), Green Tea(400 mg/day), Ashwagandha(500 mg/day), Metformin 1500 mg day, Doxycycline/Mebendezole, Fish Oil(3-4g/day) and is on a ketogenic diet

I would love to hear from you guys!

Thursday, 7 June 2018

Cocktail review after 1 year

Dear community,

I'd like to revise my husband's cocktail after 1 year of doing this protocol. He is at 14.5 months from diagnosis and has just started his 12th cycle of TMZ and just got his 3rd excellent MRI saying that the main part of the thalamic tumor is barely visible at the moment (which was the bigger concern of the two tumor sites) and the frontal one is still non-enhancing. 

Although he is methylated, I attribute the good results to the cocktail approach or at least to the synergy between the chemo and the cocktail because the first MRI after radiochemotherapy showed progression and it couldn't be pseudo progression, at least not on the frontal site because only the thalamic site was involved in the treatment. 

We're reaching the 1 year mark of supplementation with the following: 

Fluoxetin 40 mg
Chloroquine phosphate (Delagil) 250 mg (he already stopped taking it)
DCA  500 mg 2 times a day for a patient who is sadly weighs only 55-58 kg these days
Silymarin 630 mg
Celebrex 400 mg

The rest of the meds were added later on gradually. 

In your opinion, is it good to stick to the cocktail if it's working because we don't know what elements are working or after a year would it be wiser to make some changes in the regimen to disturb the tumor?

Does it make sense to take Celebrex if there's no edema and we are 1 year from radiation therapy?

I'm thinking about replacing DCA with the ALA + HCC protocol. 

Sorry if it was discussed before but is LDN an antagonist to methadon? Can the ALA + HCC protocol be effective without LDN? Combining this protocol with ketogenic diet is not an option for us because he has a sweet tooth and these days his main calorie intake is from fruits and baked goods which makes me frustrated big time but I can't help it, he lost so much weight. 

I'm not sure if we can use 800 mg of ALA 2 times a day instead of RLA 800 mg 2 times a day or should we double the dose of ALA considering that ALA is just 50% RLA.   

What's the longest period of time that a patient can take DCA? My husband is on a fairly low dose although he noticed considerable neuropathy on several occasions when we ran out of methadone for one day. Since it has painkiller effects I suppose that the neuropathy is continuous but methadone may conceal DCA's side effects. So I suppose that after a year we should address this problem and make at least a longer break of DCA.

Since his seizure he is on 300 mg of valproate acid 3 times a day, too. Considering that it became a necessity to take an AED I see reason to maybe replace fluoxetine with LITHIUM and so he would be taking almost the whole CLOVA cocktail. He's been on cimetidine 800 mg since last Sept./Oct. I'd like to exclude olanzapine because I read terrible things about its side effects but this way he is already taking 3 of the 4 medicine of the CLOVA cocktail anyway. 

By the way, at first, he was prescribed the same amount of sodium valproate in the A&E but the NO changed it to valproate acid later on. I know that those two are in the same family but can be any difference between their tumor-fighting properties?

I read here an older comment that stated that a patient's NO advised against taking Silymarin and valproate together because valproate is metabolized by the liver and Silymarin flushes it out. Is it a true statement in your opinion? I'm not sure if we can keep that in the cocktail. 

Cimetidine: I suppose it's advisable to take it together with TMZ. In our case it will be 24 cycles if he can tolerate it on the long term. So should he continue it for an additional year?

If stopping with DCA, Celebrex, chloroquine, he will only take a few prescription drugs (metformin, fluoxetine or lithium, alfacalcidol, D,L methadone and of course the anticonvulsant) and it seems a bit scary that natural supplements will be predominant. 

Do you recommend to add anything to this list at this stage of the disease?

Thank you for your inputs in advance! I think I would be a complete nerve-wreck if this blog did not exist. 

Wednesday, 6 June 2018

metabolic therapies

Hello all,
I'm wondering if anyone has tried the Care Oncology Clinic protocol? They are now in the U.S. and I'm considering it as an additional therapy for my husband. I'm interested in hearing about potential side effects of the drugs, what neuro-oncologists had to say about it, etc. Also, he's currently on a hydroxicytrate/ALA combo and I'm wondering which metabolic treatment would be best/has better data. He's also doing a combination of TMZ/CCNU.

Another question-- his most recent MRI shows radiation necrosis. Is there data that shows any natural treatments that could help?

Thank you all!

Temozolomide + a dropper of curcumin for possible synergy?

Today we made the first dropper of curcumin. 150 mg of curcumin with 250ml of 0.9NaCl. The dropper lasted 2 hours. On this day, the dose of oral curcumin was 5x400 mg (Longvida, SLCP).

There are several reports of possible synergies between curcumin and temozolomide. Does it follow from these studies that a drip of curcumin, oral curcumin and temozolomide should be taken in such a schedule so that their concentrations in the blood are maximized at the same time?

2014 https://www.ncbi.nlm.nih.gov/pubmed/25050915
We demonstrated that CUM enhanced the therapeutic response to TMZ in U87MG glioblastoma by enhancing apoptosis... We demonstrated that CUM enhanced the therapeutic response to TMZ in U87MG glioblastoma by enhancing apoptosis.

2015 https://www.ncbi.nlm.nih.gov/pubmed/26239619
Combined curcumin and TMZ treatment significantly (P<0.05) inhibited U‑87 MG cell proliferation and induced apoptotic death, compared with each alone.

2015 https://www.ncbi.nlm.nih.gov/pubmed/25542083
Autophagy inhibition improves the efficacy of curcumin/temozolomide combination therapy in glioblastomas.

Soon we will have 5 days of temozolomide. I think about whether it will be useful if temozolomide is taken at the beginning of a 2-hour dropper of curcumin?

Tuesday, 5 June 2018

Sulforaphane - an easy and potentially very useful dietary / supplement adjuvant treatment

 Hi everyone,

I thought I'd post a little comment on Sulforaphane today, as I've been spending some time recently studying it, and I'm growing quite convinced that it's a very beneficial compound which continues to be largely underutilized considering the strengthening evidence (for cancer in general) and ease of use.

Sulforaphane is a phytochemical compound which can be sourced especially well from Broccoli (but also from other cruciferous vegetables like cabbage, brussel sprouts, kale etc.) which seems to have a wide range of direct and indirect anti-cancer effects. I'm not going to recap everything here, but the following general video is quite exhaustive for anyone interested in the details:

https://www.youtube.com/watch?v=zz4YVJ4aRfg

One additional effect items not covered in the video is on the immune system, where in-vitro evidence seems to suggest that Sulforaphane may also have very significant immunomodulatory effects (e.g. lowers MDSC population, lowers PD-L1, increases mature dendritic cells...) which could have possible implications for immunotherapy. See study:

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5493295/


Beyond the likely clinical effectiveness, an important merit of Sulforaphane is its general ease of use and strong bio-availability. Clinical evidence suggests that it is easily absorbed, and is thought to cross the BBB (at least in small quantities, based on animal studies). Sulforaphane can be easily used effectively in a variety of ways, as long as the phytochemical interactions are respected.

To produce Sulforaphane, basically an element in the plant called Glucosinolates needs to mix with an enzyme called Myrosinase (this usually happens when chewing, chopping, etc), which is however rather heat sensitive and therefore easily destroyed in a high temperature cooking process. As a consequence, the vegetables are best consumed raw or lightly heated / steamed. Myrosinase is also usually destroyed in the blanching process when mature Broccoli is frozen. So as you can see, it's possible to consume a lot of Broccoli (e.g. frozen, cooked...) without getting much Sulforaphane benefit at all...

Optimizing Sulforaphane production can get quite complicated, but the below gives some idea how to get a fairly good amount:

Broccoli seeds & sprouts
These have up to 100x the Glucosinolates content of mature Broccoli plants, so represent a much more efficient source of Sulforaphane. Seeds actually have the highest concentration (more than 4mg per gram of seeds), and can be crushed and consumed directly. However, most people sprout the seeds 3-5 days, which is very easily and cheaply done at home using a sprouting jar. Ca. 100g sprouts will yield 40mg+ of Sulforaphane. Studies indicate that freezing the sprouts before using them will enhance Sulforaphane content by an average of 1.8x. If you want to go all the way to max the output, heating the the sprouts at 70C for 10 minutes will provide a further significant boost to usable Sulforaphane.

Mature broccoli
As mentioned before, it's important not to cook the Broccoli as the Myrosinase will get destroyed and no Sulforaphane will be produced. Broccoli should be lightly steamed max. 3-4 minutes. Also, frozen broccoli should be avoided as the blanching process eliminates the Myrosinase. If you have frozen Broccoli or plan to cook the Broccoli, then an alternative method to maintain Sulforaphane output is to mix the Broccoli with some Daikon Radish or mustard seed powder after cooking - both of these also carry Myrosinase, which can be used to make up for the enzyme lost in the cooking process.

Supplements
An increasing number coming to market. Important here is that the supplement provides either finished Sulforaphane OR Glucosinalate + Myrosinase. Glucosinalates without the Myrosinase will not be converted into Sulforaphane, as explained above. Studies have shown a strong synergy combining supplements with actual sprouts, leading to 2x+ serum levels of Sulforaphane.
For some reason, I'm finding much stronger Sulforaphane supplements (e.g.40-50mg) in Germany than internationally, not sure why. Examples:

https://www.amazon.de/Sulforaphan-Hochdosierte-Brokkoli-Extrakt-Kapseln-Magnesiumstearat/dp/B07663XZL2/ref=sr_1_5?ie=UTF8&qid=1528199244&sr=8-5&keywords=sulforaphane

https://www.amazon.de/Nutri-Store-Sulforaphan-vegetarisch-120/dp/B0047BU8GE/ref=sr_1_6?ie=UTF8&qid=1528199244&sr=8-6&keywords=sulforaphane

https://hk.iherb.com/pr/Jarrow-Formulas-BroccoMax-Myrosinase-Activated-60-Veggie-Caps/4297

https://hk.iherb.com/pr/Source-Naturals-Broccoli-Sprouts-Extract-60-Tablets/2456


A note on dosage: optimal dosage is not known, but many studies (showing effect) have used ca. 40mg-90mg of Sulforaphane daily. However, I think there is fairly little toxicity risk of going too high, so in my case I'm taking around 100mg+ bid (sprouts + supplements), without any problems so far.


I hope this is helpful maybe to some of you. Good luck everyone!

John







Sunday, 3 June 2018

Boldine

Hi again.  Does anyone know anything about Boldine? Can't seem to find much for it on the internets. Is this available anywhere as an ingredient for a cocktail? Read a report from Invest New Drugs (2009) 27:517–525 DOI 10.1007/s10637-008-9203-7

Boldine: a potential new antiproliferative drug against glioma cell lines
Daniéli Gerhardt & Ana Paula Horn &
Mariana Maier Gaelzer & Rudimar Luiz Frozza &
Andrés Delgado-Cañedo & Alessandra Luiza Pelegrini &
Amélia T. Henriques & Guido Lenz & Christianne Salbego

from 2008 which looks quite interesting.

About Optune Itching

Hello,

When my dad using Optune, he has very annoying Itching.

Right now we cant find any solution for that.. the doctor try to give him some medication that didnt help,.

Anyone has an idea or tip what can help?

Thank you!

Saturday, 2 June 2018

First results of cocktail trial (memantine, metformin, mefloquine, temozolomide)

I'll be working on a review of the latest brain tumor news coming from the ASCO conference currently underway.  Since this is the brain tumor cocktails blog, thought I'd post these results to start off.

Phase I factorial study of temozolomide plus memantine, mefloquine, and metformin as post-radiation adjuvant therapy for newly diagnosed glioblastoma.
https://meetinglibrary.asco.org/record/164026/abstract

The abstract gives maximum tolerated doses for doublet therapy (TMZ + one of the other drugs), triplet, and quadruplet combinations.

2 year survival rate for the entire trial population (all combintions) was 43%, similar to the 2-year survival seen in the EF-14 trial for the Optune + TMZ arm.

Since some of the combinations were probably more effective than others, it will be interesting to see the results when separated by treatment arm.

Friday, 1 June 2018

gene sequencing

Dear All,

I have likely a difficult and too general question. We have a possibility to perform gene sequencing on the  Illumina HiSeq 1500  platform.  Could you please advise and share information which mutations may/should be tested to provide options for the GBM treatment  besides the standard path (radioteraphy+TMZ and TMZ after that).

Many thanks.

Thursday, 31 May 2018

Bioavailability of WokVel Boswellia Serrata vs "ordinary" Boswellia Serrata?

Hi all,

I've read here that WokVel boswellia serrata has greater bioavailability than the "usual" boswellia formulation.  But I've not been able to find anything in the medical literature or on the WokVel website confirming this.  If I could replace the canonical dose of 4200 mg H15 BS/day with a smaller number of WokVel pills (what's listed on the supplements spreadsheet as three 333 mg WokVel capsules/day), that would make my husband really happy.  Anyone have any insight or citations to offer?

I did contact the WokVel company but they're oriented towards the business end, not end consumers, and my inquiry just resulted in an email asking about my business plans.

Tuesday, 29 May 2018

Tagrisso ?

Hello, first post here, from the husband of a dear wife recently diagnosed with a Grade IV glioblastoma.  Red flags at a UCLA Urgent Care led to a ct scan followed by an MRI and admission.  Complete resection was performed 30 hours later. She followed up with radiochem, and is now in her second course of adjuvant Temodar. We were approved for Optune and are now two weeks in with that, holding firm at about 95% compliance and are also madly ingesting basically everything in the "A" list from the list in the library, thanks to a lot of wonderful help from Mike B here.

Anyway, our doctor suggested we might benefit from a drug called Tagrisso, from AstraZeneca Medicines.  Don't see anything about that in the stacks so far, so was wondering if anyone has any thoughts regarding it. It's proven to be an efficacious treatment for lung cancer but could have crossover value since apparantly it crosses the BBB. 

Hopefully human clinical trials won't be too far down the road...

I love out of the box thinking when fighting GBM.

New therapeutic technology that uses Zika virus strains to treat Glioblastoma  -- https://www.zikazoom.com/zika-science/washu-innovates-drs-milan-chheda-michael-diamond/#comment-5324

DCVax Update


https://translational-medicine.biomedcentral.com/articles/10.1186/s12967-018-1507-6

Mike B

Friday, 18 May 2018

HSPPC-96 vaccine Phase 1 trial results in China

Heat shock protein peptide complex-96 vaccination for newly diagnosed glioblastoma:
a phase I, single-arm trial
https://insight.jci.org/articles/view/99145   (open access)

The survival results of this trial are worth remarking upon.

20 newly diagnosed GBM patients received standard treatments plus HSPPC-96 vaccine (also known as Prophage, under development in the USA by Agenus). All had total tumor resections, and the majority had MGMT unmethylated tumors and were IDH1 wild-type.

19 of the 20 were evaluable for efficacy. Median survival for the entire group was 31.4 months.  I've seen only a couple of other small trials (vaccine trials involving complete or near complete tumor resection) with efficacy outcomes comparable to this.

Clear efficacy of the vaccine was shown by tumor specific immune responses (TSIR) being increased on average by 2.3-fold after vaccination, and the fact that those with "high" TSIR (TSIR above the median) had not reached median survival (> 40.5 months), while those with low TSIR (below the median) had median survival of only 14.6 months, showing vaccine efficacy in only a subset of patients.  Median PFS are unremarkable (11 months median for the entire group, 12.3 months for the high TSIR group), but immune-related pseudoprogression could have been a factor in dropping PFS values.

Compared to the phase 2 trial published by Bloch et al. in 2017,  https://www.ncbi.nlm.nih.gov/pubmed/28193626
the Chinese trial had worse PFS outcomes but better survival outcomes, also suggesting that pseudoprogression may have been a factor in the Chinese trial.

Additionally, patients with MGMT-methylatated tumors had far better outcomes in the Bloch et al. trial, but in this Chinese trial, 14 out of 16 tested tumors were MGMT unmethylated.

A trial is currently underway testing pembrolizumab with or without HSPPC-96 vaccine, and I would expect the combination therapy  to improve even further on the efficacy results of the vaccine.
https://clinicaltrials.gov/ct2/show/NCT03018288


Saturday, 12 May 2018

PSK and curcumin source in Europe

Dear All,

probably the subject has been discussed many times, but could you please recommend a source of  PSK and curcumin (also other coctail supplements) available in Europe? I live in Poland.

For PSK, besides Oriveda, I found  https://www.mycomedica.cz/ They explain that the products are sold as "veterinary" due to absurd EU regulations, but they are apparently available across the country, so I suppose that the quality is decent.

As for Curcumin Longvida, I found only

https://www.amazon.de/Longvida-Hochdosiert-Curcuma-Bioverf%C3%BCgbarkeit-Monatspackung/dp/B01NCTQFL8/ref=sr_1_1?ie=UTF8&qid=1526164318&sr=8-1&keywords=curcumin+longvida

https://www.amazon.de/Curcumin-LongvidaTM-500mg-Kapseln-Nutrivene/dp/B003D0A8Q0/ref=sr_1_4?ie=UTF8&qid=1526164362&sr=8-4&keywords=curcumin+longvida&dpID=41nYzvUsCZL&preST=_SY300_QL70_&dpSrc=srch

both of which are rather expensive,  and also

https://pl.iherb.com/pr/Now-Foods-CurcuBrain-Cognitive-Support-400-mg-50-Veg-Capsules/57292

However, my primary concern is quality and safety of these products. Would you please recommend other sellers or product in this group?

Many thanks.

Stefan

Thursday, 10 May 2018

Tumor Mutational Burden and response to immunotherapy

Tumor Mutational Burden as an Independent Predictor of Response to Immunotherapy in Diverse Cancers.
https://www.ncbi.nlm.nih.gov/pubmed/28835386


This study was a collaboration between UC San Diego, and Foundation Medicine.
Response rate, progression-free survival and overall survival following immunotherapies (in general, or specifically for immune checkpoint inhibitors such as anti-PD-1/PD-L1) was increased in patients with higher tumor mutational burden (as determined by genetic sequencing).


My commentary:
Newly diagnosed gliomas including GBM usually have low tumor mutational burden.  At highest risk for high tumor mutational burden (hypermutation) are likely those with MGMT-methylated tumors that recur following standard TMZ chemotherapy.

Pembrolizumab (Keytruda) is approved by the United States FDA, among other indications, "for the treatment of adult and pediatric patients with unresectable or metastatic, microsatellite instability-high (MSI-H) or mismatch repair deficient solid tumors that have progressed following prior treatment and who have no satisfactory alternative treatment options. "

The very high mutational burden sometimes seen in recurrent gliomas following temozolomide chemotherapy is often caused by mutations in one or more of the mismatch repair genes (MHS2, MSH6, MLH1, PMS2).  Having genetic sequencing performed (in North America by Foundation Medicine or Caris, or different companies in other countries) for recurrent post-temozolomide grade IV tumors (especially MGMT methylated tumors) could be a worthwhile way to detect hypermutation/mismatch repair deficiency/microsatellite instability and get access to pembrolizumab outside of a trial.  I can't comment on how easy getting coverage would be (both for the genetic testing as well as the pembrolizumab), as it would in part depend on the policies of the various insurance providers.

Wednesday, 9 May 2018

Androgen receptor as a potential druggable target in GBM

I took note of this abstract from the SNO 2017 abstracts:

CSIG-24. ANDROGEN RECEPTOR IS A POTENTIAL THERAPEUTIC TARGET IN GLIOBLASTOMA  (click on the title for the abstract)

The full study was just published in Oncotarget.  


"The AR gene was amplified in 27% of glioblastoma specimens from men (n=22) and of 38.2% from women (n=21). AR-RNA was overexpressed (>2.5 fold) in 93% (n=30), and AR-protein was induced (>two fold) in 56% of the glioblastomas samples (n=16). Thirty percent of the glioblastomas (n=21) also expressed a constitutively active AR-splice-variant (AR-V7/AR3) lacking the Ligand-Binding-Domain."

"Enzalutamide given orally to nude mice bearing subcutaneous human glioma xenografts resulted in a 72% reduction in tumor volume (p=0.0027)."

Tuesday, 8 May 2018

Intravenous DCA. All the details.

The intravenous (IV) route of DCA has a number of therapeutic advantages, including:
1) higher blood levels because pulsed IV dosing can achieve a higher concentration than is feasible with an oral dosage
2) a longer washout period to reduce the potential for neurotoxicity
3) a bypassing of the digestive system, which is particularly significant for advanced-stage cancer patients.

I want to collect here all the details about the intravenous DCA. Below, I wrote out all the information on the doses and schedule of intravenous DCA in published treatment reports.

1. A Novel Form of Dichloroacetate Therapy for Patients With Advanced Cancer: A Report of 3 Cases
http://alternative-therapies.com/at/web_pdfs/s202khan.pdf
https://www.ncbi.nlm.nih.gov/pubmed/25362214

Case 1: A 79-year-old male sought therapy for metastatic colon cancer
The first dose of 3000 mg (41 mg/kg) of IV DCA was administered on December 22, 2011, together with 50 g of IVC. The second DCA infusion was given 6 days later at a dose of 3500 mg (48 mg/kg) together with 35 g of IVC. A third DCA infusion at a dose of 3700 mg (50 mg/kg) and 50 g of IVC were given 8 days after the second dose.

Case 2: A 43-year-old male sought therapy for metastatic angiosarcoma of the right femur.
IV DCA was started at a dose of 3000 mg (47 mg/kg) weekly and escalated in a 2-week period to 5000 mg (47 mg/kg) twice per week. No side effects were observed. Following a total of 4 months of IV DCA therapy, an MRI demonstrated stability.

2. Long-term stabilization of stage 4 colon cancer using sodium dichloroacetate therapy
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5067498/

A 57 years old female.
The plan consisted of addition of high dose oral vitamin D at 10000 international units per day, a change of oral vitamin C to vitamin C 50 g intravenous (i.v.) weekly, and addition of dichloroacetate sodium (DCA) 3000 mg i.v. (49 mg/kg) weekly (manufacturer: Tokyo Chemical Industry, United States). To reduce the risk of DCA side effects, 3 natural supplements were prescribed: Alpha lipoic acid (racemic) 500 mg i.v. with each DCA dose, oral R-alpha lipoic acid 150 mg 3 times a day, oral acetyl L-carnitine 500 mg 3 times a day, and oral benfotiamine 80 mg twice a day.
DCA was increased to 4000 mg i.v. (66 mg/kg) weekly. The only side effect noted at the higher DCA dose was mild post-infusion sedation.
…DCA i.v. was continued, and the dose was increased to 4500 mg i.v. weekly.

3. Pharmacokinetics and pharmacodynamics of dichloroacetate in patients with cirrhosis
https://ascpt.onlinelibrary.wiley.com/doi/full/10.1053/cp.1999.v66.a101340
http://sci-hub.tw/https://ascpt.onlinelibrary.wiley.com/doi/pdf/10.1053/cp.1999.v66.a101340

Stock dichloroacetate solution (100 mg/mL) was prepared by dissolving sodium dichloroacetate (>99%, TCI America, Portland, Ore) in 0.45% sodium chloride under aseptic conditions, sterilized by 0.22 micron filtration, and tested for sterility and pyrogenicity before use. It was stored at 4°C, where it is stable for >1 year. Purity and stability were verified by negative chemical ionization gas chromatography—mass spectroscopy (NCI-GC/MS, models 5890/5989A, Hewlett-Packard, Pleasanton, Calif) as described previously. Stock dichloroacetate solution was diluted in 0.9% sodium chloride to a final dichloroacetate concentration of 60 mg/mL on the morning of the infusion protocol.
Intravenous dichloroacetate, 35 mg/kg, was infused for 30 minutes. This dichloroacetate dose was chosen for a near-maximal response of plasma lactate concentration without the somnolence commonly associated with larger doses, even in healthy volunteers. After completion of the stable isotope infusion protocol, subjects were allowed to eat and drink for the duration of the study. All subjects were discharged and sent home 24 hours after the single dichloroacetate administration.

4. Preparation and Stability of Intravenous Solutions of Sodium Dichloroacetate (DCA) 

Solutions for injection (100 mg/ml) were prepared by weighing DCA in a laminar flow hood and, using autoclaved utensils, dissolving it in 0.9% (154 mEq sodium chloride per liter) saline solutions. The solution was filtered through a sterile 0.2 u,m nylon Posidyne filter into a sterile pyrogen-free evacuated container. The solution was then transferred asepticaliy to commercially obtained sterile pyrogen-free vials.

______________________

Unfortunately, I can not find any more information on how to prepare an intravenous DCA solution.
I found a ready-made DCA solution, but still can not find where to buy it.
If you have any information about intravenous DCA, share it!







Sunday, 6 May 2018

Comparison of schedule, dose and method of administration of bortezomib in successful and failed studies.

This message is very large, so I decided to publish it in a separate topic.

I analyzed the dose, schedule and mode of administration of bortezomib in successful and failed trials.

As can be seen, only in this successful study (Phase 2 Study of Bortezomib Combined With Temozolomide and Regional Radiation Therapy > https://www.ncbi.nlm.nih.gov/pubmed/29722661) bortezomib was used during radiation therapy. As expected, bortezomib is a radiosensitizer. Further, bortezomib was administered very long - up to 24 cycles (4 times in 28 days) or until progression. Also, perhaps the difference is that in this study from the 10th month bortezomib was administered subcutaneously.

I wrote out some details of each study. The only successful study:

Phase II Study of Bortezomib in Combination with Temozolomide and Regional
Radiation Therapy for Upfront Treatment of Patients with Newly-Diagnosed
Glioblastoma Multiforme: Safety and Efficacy Assessment
https://www.ncbi.nlm.nih.gov/pubmed/29722661

"Bortezomib is given intravenously/subcutaneously at 1.3 mg/ m² on days 1, 4, 8, 11, 29, 32, 36, and 39 during radiation as early as 14 days after surgery. Temozolomide is given daily (75mg/m2) during radiation, followed by 5 days out of 28 with a dosage of 150-200 mg/m2, for up to 24 cycles. Bortezomib at 1.3 mg/m2 is given on days 1, 4, 8, and 11 of each subsequent 28 day cycle. Both bortezomib and temozolomide will continue until progression or up to 24 cycles.

Bortezomib was initially given via intravenous (IV) infusion, but the protocol was later modified to subcutaneous (SC) injection at ~10 months after the first patient had begun treatment (e.g., August 2012), due to the reported similar efficacy with improved safety profile (11, 12).

Our data were encouraging for newly diagnosed GBM when bortezomib was combined with radiation therapy and temozolomide. In preclinical models, bortezomib has been shown to be a radiosensitizer. That could be one of the reasons for lacking of efficacy in the treatment of recurrent GBM with bortezomib and vorinostat (a histone deacetylase inhibitor) when radiotherapy was not used."

It is unclear, however, what effect on the duration of survival was provided by the treatment after the recurrence:
"Among all 24 patients, 3 had no progression at the time of the last follow-up and 1 lost followup. The remaining 20 patients had documented recurrence. The treatments for recurrence were at attending physician’s discretion. For first recurrence, 4 patients were treated with temozolomide re-challenge, 9 with bevacizumab single agent, 4 with bevacizumab plus lomustine (CCNU), 1 with bevacizumab plus onartuzumab, 1 with bevacizumab plus pembrolizumab, and 1 with nivolumab. For further tumor progression, treatment therapies consisted of traditional chemotherapy agents (CCNU, carboplatin or etoposide) with and without bevacizumab. Four patients received stereotactic radiation therapy during further recurrences."

Failed tests or without any outstanding result:

A phase II trial of tamoxifen and bortezomib in patients with recurrent malignant gliomas
https://www.ncbi.nlm.nih.gov/pubmed/26285768
A minimum of 4 weeks after radiation and full recovery after surgery were required.
Each cycle of therapy consisted of 6 weeks of oral tamoxifen 120 mg twice daily and intravenous bortezomib 1.3 mg/m2 on days 3, 6, 10, 13, 24, 27, 31, and 34 of every 6-week cycle.

A phase II trial evaluating the effects and intra-tumoral penetration of bortezomib in patients with recurrent malignant gliomas
https://www.ncbi.nlm.nih.gov/pubmed/27300524
All patients received bortezomib 1.7 mg/m2 intravenously (IV) on day 1, 4 and 8. Patients underwent surgical resection of their tumor on day 8 or 9. Patients started TMZ 75 mg/m2 orally on days 1–7 and 14–21 and bortezomib 1.7 mg/m2 IV on days 7 and 21. Each post surgery cycle was 4 weeks.

Phase I trial of dose-escalating metronomic temozolomide plus bevacizumab and bortezomib for patients with recurrent glioblastoma
https://www.ncbi.nlm.nih.gov/pubmed/27502784
The three agents were administered in 42 day cycles as shown in Fig. 1. Bortezomib was given at 1.3 mg/m2 on day 1 of weeks 1–4. Bevacizumab was given at a dose of 10 mg/kg on day 1 of weeks 1, 3, and 5. Temozolomide was given at doses of 25 mg/m2 (Group 1), 50 mg/m2 (Group 2), or 75 mg/m2 (Group 3) on days 1–28 of each cycle.
___________________________

I was also interested in this article, where it was concluded that "combination of bortezomib and autophagy inhibitors may shed new light on glioblastoma treatment."
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3840293/

The open question remains about the use of bortezomib in a cocktail for MGMT-methylated patients only after radiotherapy.

Saturday, 5 May 2018

Phase 2 Study of Bortezomib Combined With Temozolomide and Regional Radiation Therapy. Fantastic results?


The results of this study have just been published:
https://www.ncbi.nlm.nih.gov/pubmed/29722661

http://sci-hub.tw/https://linkinghub.elsevier.com/retrieve/pii/S0360301618300014
(Thanks to Stephen for the tip!)

"To assess the safety and efficacy of upfront treatment using bortezomib combined with standard radiation therapy (RT) and temozolomide (TMZ), followed by adjuvant bortezomib and TMZ for ≤24 cycles, in patients with newly diagnosed glioblastoma multiforme (GBM).

Bortezomib was initially given via intravenous (IV) infusion, but the protocol was later modified to subcutaneous (SC) injection at ~10 months after the first patient had begun treatment (e.g., August 2012), due to the reported similar efficacy with improved safety profile...

Our cohort included 13 male and 11 female patients with a median age of 57 years old (range 27-75), and a
median KPS score at the time of enrollment of 90 (range 60-100). Thirteen patients had gross total resection and 11 patients had subtotal resection. Molecular biomarkers were tested in 24 patients for IDH1 and 21 for IDH2 mutation status: 3 (13%) were found positive for IDH1 mutation and 0 (0%) were positive for IDH2 mutation (Table 1). MGMT methylation was tested in 23 patients: 10 (43%) were methylated and 13 (57%) were unmethylated.

No unexpected adverse events occurred from the addition of bortezomib. The efficacy analysis showed a median progression-free survival (PFS) of 6.2 months (95% confidence interval [CI] 3.7-8.8), with promising PFS rates at ≥18 months compared with historical norms (25.0% at 18 and 24 months; 16.7% at 30 months). In terms of overall survival (OS), the median OS was 19.1 months (95% CI 6.7-31.4), with improved OS rates at ≥12 months (87.5% at 12, 50.0% at 24, 34.1% at 36-60 months) compared with the historical norms. The median PFS was 24.7 months (95% CI 8.5-41.0) in 10 MGMT methylated and 5.1 months (95% CI 3.9-6.2) in 13 unmethylated patients. The estimated median OS was 61 months (95% CI upper bound not reached) in the methylated and 16.4 months (95% CI 11.8-21.0) in the unmethylated patients.

The estimated value of median OS was 61 months for the 10 MGMT methylated patients; however, the upper bound of 95% confidence interval could not be calculated because 7 of 10 (70%) methylated patients are still alive at the time when data was analyzed.

The addition of bortezomib to current standard radiochemotherapy in newly diagnosed GBM patients was tolerable. The PFS and OS rates appeared promising, with more benefit to MGMT methylated patients. Further clinical investigation is warranted in a larger cohort of patients."
____________________________

Also I found other interesting articles about bortezomib:

Phase I trial of dose-escalating metronomic temozolomide plus bevacizumab and bortezomib for patients with recurrent glioblastoma.
https://www.ncbi.nlm.nih.gov/pubmed/27502784
"Three groups of three patients were scheduled to receive daily doses of temozolomide at 25, 50, and 75 mg/m2. Fixed doses of bortezomib and bevacizumab were given at standard intervals.
Progression-free survival was 3.27 months for all patients and mean overall survival was 20.75 months. The MTD of temozolomide was 75 mg/m2 in combination with bevacizumab and bortezomib for recurrent glioblastoma."

A phase II trial of tamoxifen and bortezomib in patients with recurrent malignant gliomas.
https://www.ncbi.nlm.nih.gov/pubmed/26285768
"The study was closed due to poor accrual and therapeutic futility. Combination tamoxifen and bortezomib has no activity in recurrent malignant gliomas. Poor penetration across blood brain barrier of bortezomib likely limited efficacy."

Bortezomib is an FDA approved proteasome inhibitor indicated for multiple myeloma and mantle cell lymphoma, and has been investigated in various solid tumors as single agent or in combination.

Bortezomib is available, inexpensive and can easily be added to the cocktail. His side effects are not so serious. Your thoughts about adding bortezomib to cocktails and about the fantastic results for MGMT-methylated patients (median OS was 61 months)?
Why did one study with bortezomib fail, and another showed such fantastic results?

Friday, 4 May 2018

Medicenna Amends Protocol of Phase 2b Recurrent Glioblastoma Study of MDNA55 in Response to Strong Safety Data and Early Efficacy Read-outs

http://bit.ly/2FJa4X9

"We are pleased with the safety profile to date and early efficacy signals of MDNA55. We are amending the protocol at the recommendation of our clinical advisors to further improve the chances for demonstrating increased therapeutic benefit for patients living with this life-threatening disease," said Fahar Merchant, PhD, President and Chief Executive Officer of Medicenna.

Principal Investigator, John H. Sampson MD, PhD, of Duke University Medical Center Department of Neurosurgery, commented, "The study has contributed substantially to the improvement of Convection Enhanced Delivery of drugs directly into brain tumors. More importantly, we are seeing definite biological effects of MDNA55 in some patients as we await final study results to see whether these translate into robust longer term benefits."

"We have used the occasion of this recruitment milestone to implement optimal methodologies in the amended protocol," commented Martin Bexon MD, Head of Clinical Development. "With the experience gleaned from the ongoing Phase 2b clinical trial of MDNA55 in rGBM, we are able, for instance, to allow for more personalized dosing based on the tumor load and incorporate advanced imaging modalities to measure treatment responses more reliably, despite significant changes due to necrosis and inflammation."  Additionally, the amendment will allow investigators to administer a second dose of MDNA55 where appropriate.

Thursday, 3 May 2018

Update on phase 2 trial of valproic acid + standard chemoradiation for nd GBM

As reported several years ago, median survival in this trial of high dose valproic acid (Depakote) in combination with chemoradiation was 29.6 months.  This study describes 6 patients who survived over three years (median survival over 6 years for these 6 patients).  Only 1 out of 4 evaluated tumors carried the IDH1 mutation.

https://academic.oup.com/nop/advance-article/doi/10.1093/nop/npy009/4971616  (abstract only)


http://sci-hub.tw/https://academic.oup.com/nop/advance-article/doi/10.1093/nop/npy009/4971616

Note the above link takes you to a PDF download at sci-hub.  If this link fails to work in the future, check wikipedia for the current active locations of sci-hub, and swap out the ".tw" in the URL with something else.  This is technically pirating, but most of us here would agree that fighting a brain tumor calls for such measures.


Wednesday, 2 May 2018

High-dose intravenous vitamin C at home

I want to try to do a drop of high-dosage vitamin C at home.

In some studies, such solutions were used:
- Ascorbic acid MEGA-C-PLUS®, 500 mg / mL (25g / 50mL) from Merit Pharmaceuticals
(in the Riordan Clinic https://riordanclinic.org/research-study/vitamin-c-research-ivc-protocol)
- Ascorbic acid, 500 mg / mL (25g / 50mL) from Mylan Institutional, LLC NDC # 67457-118-50
- Ascorbic acid, 500 mg / mL (25g / 50mL) from McGuff Pharmaceuticals, Inc. Item # 008232
(in this study https://www.cell.com/cancer-cell/fulltext/S1535-6108(17)30062-4)
- Ascorbic acid, 500 mg / mL (25g / 50mL) from Bioniche Pharma (Rosemont IL)
(in this study https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3260161/)

Maybe someone knows some kind of pharmacy or clinic in the US where I can buy (with a prescription) this ascorbic acid 500mg/ml?

I can not find any place where I can buy it in Europe! All I have found in Europe is:
- Pascorbin®, 150 mg / mL (7.5g / 50mL)

https://shop.apotal.de/pascorbin-injektionsloesung-20x50ml-injektionsloesung-09647683;jsessionid=37767953D49085B0A97001EE7A3006CA-memc0.pla2tom1
By the way, the price is quite low compared to Ascorbic acid 500mg / ml!

For example, the cost of 1 dropper 75 grams of Vitamin C (from Pascorbin) - 80 Euros!
The question is how to properly prepare a solution from Pascorbin!

1. In the protocol of the Riordan Clinic (https://riordanclinic.org/research-study/vitamin-c-research-ivc-protocol/) details how to dilute Ascorbic acid, 500 mg / mL.





2. This study also details how to prepare a solution of ascorbic acid 500 mg / ml:



3. Description of infusion in this study:
"For the first 2 IVC doses, the initial infusion rate was 0.5 g/min, starting at 15 g of vitamin C with an appropriate amount of carrier fluid (sterile water and ringer’s lactate, depending on the concentration of ascorbic acid infused). For the next 2 doses, 25 g of vitamin C was given at 0.5 g/min, with an appropriate amount of carrier fluid, with addition of 200 mg of magnesium chloride to prevent vascular spasm. For the subsequent 2 doses, 50 g of vitamin C was given at 0.5 g/min with an appropriate amount of carrier fluid and 200 mg of magnesium chloride. After the first 6 doses, 75 g of vitamin C was given at 0.5 g/min with an appropriate amount of carrier fluid and 200 mg of magnesium chloride. Vitamin C dosage was then increased to 100 g with 400 mg of magnesium chloride for patients with extremely aggressive tumors."

4. Description of infusion in this study:
"Vitamin C infusates were prepared using ascorbic acid 500 mg/mL for injection USP (supplied as single-use 50 mL glass ampules) as a gift from Alveda Pharma Canada, Ltd. The stock solution was diluted in sterile water to achieve an osmolarity of approximately 900 mOsm/L. Any air bubbles formed during preparation were promptly evacuated. The solutions were delivered to the clinical research unit covered by an opaque bag, allowed to come to ambient temperature, and infused by calibrated infusion pump within one hour of preparation. Water and other drinks (preferably sugar-free) were provided and the patients encouraged to consume them freely before, during and after IVC infusions. The dose of vitamin C was 1.5 g/kg body weight when the body mass index (BMI) was 30 kg/m2 or less, and normalized to the body weight corresponding to BMI 24 kg/m2 for patients with a BMI > 30. The vitamin was infused at a constant rate over a period of 90 minutes for doses up to 90 g, and over a period 120 minutes for doses > 90 g."
"When the dose is less than 15 g the stock solution is diluted with lactated Ringer’s to guarantee sufficiently high osmolality to permit intravenous administration. When the dose is equal to or greater than 15 g, the infusate is brought to the required concentration using sterile water to achieve an osmolality between 500 and 900 mOsm/L. The osmolality maybe calculated from the molecular weight of AA assuming it is completely dissociated in aqueous solution. Examples are given as follows.
15 g (30 mL stock qs 300 mL using sterile water): 570 mOsm/L.
30 g (60 mL stock qs 500 mL using water): 684 mOsm/L.
60 g (120 mL stock qs 900 mL using water): 760 mOsml/L.
70 g (140 mL stock qs 1100 mL using water): 725 mOsml/L.
80 g (160 mL stock qs 1100 mL using water): 829 mOsml/L.
90 g (180 mL stock qs 110 mL using water): 933 mOsml/L.
100 g (200 mL stock qs 1200 mL using water): 950 mOsml/L.
110 g (220 mL stock qs 1400 mL using water): 896 mOsml/L.
120 g (240 mL stock qs 1400 mL using water): 977 mOsml/L.
130 g (260 mL stock qs 1600 mL using water): 926 mOsml/L.
140 g (280 mL stock qs 1800 mL using water): 887 mOsml/L.
 Intravenous infusions are administered via a peripheral or central intravenous catheter at a rate of 0.5 g/minute to approximately 1 g/minute, and not usually faster than approximately 1 g/minute. At the dose of 1.5 g/kg an infusion will typically last 105 minutes."

5. https://pdfs.semanticscholar.org/864a/c9c15a0d529702662135020d5b1323dab276.pdf?_ga=2.149448115.464894850.1525286351-1963972769.1523462509
"In this study, we used MEGA-C-ACID PLUS® (500 mg/ml, Merit Pharmaceuticals, Los Angeles, California). This source of AA was used because other clinical preparations in Japan contained preservatives, and there was no data regarding the safety of these substances when administrated at high doses.
AA was given through a central vein catheter on days 7, 9, 11, 14, 16, and 18 during the 2nd course of the CHASER regimen (Fig. 1). A small test dose of 15 g AA in 250 ml Ringer's lactate solution was administered at a rate of 0.5 g/min on day 7, and then 75 g of AA dissolved in 1,000 ml of distilled water was administered at a rate of 1 g/min on each of the other days listed above.
In order to prevent hypocalcemia due to the chelating effect of AA, 0.5 g magnesium sulfate was added to every 500 ml of AA solution."

6. https://link.springer.com/article/10.1007%2Fs00280-013-2179-9
Phase I clinical trial to evaluate the safety, tolerability, and pharmacokinetics of high-dose intravenous ascorbic acid in patients with advanced cancer.
"The solution to be infused contained the appropriate amount of ascorbic acid in sterile water for injection with calcium chloride, magnesium chloride, and potassium chloride.
Incipient changes during the study: the concentrations of calcium and magnesium in the infusion solution were reduced to the same concentrations that appear in blood (5 and 2 mEq/L, respectively). In addition, potassium was lowered to 16.7 mEq/L, which delivers 10 mEq/h, an infusion rate that is considered safe for all patients. Ascorbic acid remained at 100 g/L and was infused at 1 g/min."
_____________________

Everywhere, ascorbic acid 500 mg / ml is used. But how to dilute Pascorbin®, 150 mg / mL, which is available in Europe?
In the instructions for Pascorbin 150 mg / mL (7.5g / 50mL) in Section 6.6, I found: "Before administration, the contents of the vial (concentrate 50 ml for the infusion solution) should be diluted with 100 ml of 0.9% sodium chloride solution or 50 ml of water for injection."
For example, to make an infusion of 75 grams of ascorbic acid, the total volume of the finished solution will be: 10 x (50ml Pascorbin + 50ml water for injection) = 1000ml.

In the American clinic Riordan, as seen from the attached table, 75 grams of ascorbic acid is diluted with 750cc of sterile water (probably this is water for injections). But why is the final volume 750cc? Can anyone help to understand the string from the table, for example about 75 grams?
* cc = cubic centimeter

Prolonged survival following local injection of targeted alpha therapy with 213Bi-substance P analogue.

Fifty patients with different malignant glioma tumors were included into the study at the Medical University of Warsaw. Secondary GBM was diagnosed in seven female and two male patients (age range 21–59 years, mean 38.8 ± 10.8 years) out of these 50 patients.

GBM has been demonstrated to overexpress the NK-1 receptor and substance P can be used as a ligand for targeted therapy. Alpha emitters, e.g. 213Bi, that deposit their high energy within a short range allow the selective irradiation of tumor cells while sparing adjacent neuronal structures.



Treatment with activities ranging from 1.4 to 9.7 (median 5.8) GBq 213Bi- DOTA-SP was well tolerated with only mild transient adverse reactions, mainly headaches due to a transient perfocal edema reaction. The median progression free survival and overall survival time following the initiation of alpha therapy was 5.8 and 16.4 months, respectively. The median overall survival time from the first diagnosis was 52.3 months. Two out of nine patients are still alive 39 and 51 months, respectively, after the initiation of the therapy.



Implementation of catheters into the postsurgical cavity. A cavity of 1.5 cm diameter is drilled into the external tabula of the skull with a central opening. A port capsule connected with a catheter is then stereotactically inserted into the tumor or resection cavity. The wound is then closed. Injections into the capsule were performed some 10 days later.

CONCLUSIONS: Targeted alpha therapy of secondary GBM with 213Bi-DOTA-SP is safe and well tolerated and may evolve as a promising novel therapeutic option for secondary GBM.

https://link.springer.com/article/10.1007%2Fs00259-018-4015-2

https://www.ncbi.nlm.nih.gov/pubmed/29713762

Thursday, 26 April 2018

PDGFRA as a potential target in H3 K27M mutant gliomas

Developmental and oncogenic programs in H3K27M gliomas dissected by single-cell RNA-seq


"We found that H3K27M-glioma primarily contain cells that resemble oligodendrocyte precursor cells (OPC-like), whereas more differentiated malignant cells are a minority. OPC-like cells exhibit greater proliferation and tumor-propagating potential than their more differentiated counterparts and are at least in part sustained by PDGFRA signaling."

PDGFRA is a receptor tyrosine kinase (like EGFR).  No PDGFRA inhibitors have been specifically approved for brain tumors, but inhibitors have been approved for other types of cancers.  Approved PDGFRA inhibiting drugs include imatinib, nilotinib, sorafenib, and dasatinib.

New Approaches to grading of IDH-mutant astrocytomas

Novel, improved grading system(s) for IDH-mutant astrocytic gliomas.

Given the list of all-star pathologists and neuro-oncologists behind this paper (including Andreas von Deimling, David Louis, Wolfgang Wick, Michael Weller, Roger Stupp, Monika Hegi, Martin van den Bent, Michael Platten, and many more), this work will very likely get translated into actual changes of the grading system for IDH-mutant astrocytomas.

"In conclusion, in all three validation sets the tested grading models performed better than the current WHO system."

"Thus a genetic approach to taxonomy would favor a term such as “high-grade A IDHmut” rather than the current term of GBM-IDHmut."      "One possible solution, which we have considered implementing in Heidelberg, would be to restrict classification to the term A[stroctyoma] IDHmut and then adapt grading according to molecular lesions, thereby omitting the term GBM-IDHmut. The term “glioblastoma” would be reserved for those histologically defined glioblastomas lacking IDH mutation or not having had adequate (not otherwise specified, NOS) or diagnostic (not elsewhere classified, NEC) work-ups"

Nice to finally see the above quotes in print, this has been my opinion for years.

This is an excellent study. My only criticism is that hypermutated tumors with very high mutational load were not evaluated as a distinct group.  This is different than the high or low copy number variant load (CNVL) considered in the paper.  Mutational load was only mentioned once, in the discussion:

"An interesting parameter emerging from our analysis was CNVL [copy number variant load]. A proportion higher than 350 Mb either lost or gained in the areas covered by the methylation arrays correlated with poorer OS. Previously, the mutational load has been shown to correlate with tumor grade in IDH-mutant glioma [9]. While our data more reflect genomic instability and those data rely on an accumulation of mutations they also support a quantitative approach to tumor grading."




Tuesday, 24 April 2018

Methadone

Hi all,
thanks for your responses to my previous post.

In germany methadone is a huge topic which is often discussed in media.
Dr. Claudia Friesen, who works in a university hospital was the first who randomly discovered the effects on brain tumors.

On April 21 2018 there was a big convention in Würzburg, called the brain information day she talked about her experiences. She told the audience that she knows 79 persons using methadone between 2013 and 2018. 13 of them died, the others survived till this day:         
35 of them more than 2 years 
25 of them more than 3 years
   4 of them more than 4 years
   2 of them more than 5 years

Unfortunately there is no clinical study to back her results. Dr. Friesen is fighting to get methadone tested in a real study but there is no big support in the established brain tumor research.
Lots of german researchers doubt her results and even refuted them in a little study. Dr. Friesen argued that their study was done wrong. For example they used another formula of the methadone. Dr. Friesen used D,L-methadone in combination with Temodal.
The idea of methadone is to increase the effect of Temodal.

I hope she gets her study, till then you can trust her or not. 

If you want to take methadone, you should start with 3 drops in the morning and evening and increase to 20 - 35 drops two times a day. For example you can take 2 x 3 drops on day one, 2 x  4 on day two and so on and stop when you can not tolerate more. You should then stay on that level. If you want to stop methadone, you have to reduce the dose slowly.
Side effects are mainly constipation but there are lots more possible, especially if you increase or reduce your dose to fast. You can find them in Wikipedia for example. In my experience you need 1 month to get used to it, so be careful and patient.