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.

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. 

DCVax Update

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

Mike B

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

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

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.

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.  

https://www.ncbi.nlm.nih.gov/pubmed/29731997

"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)."

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) 

http://sci-hub.tw/http://journal.pda.org/content/46/1/16.long

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!

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.

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?

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.

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?

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:

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3260161/

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3260161/bin/pone.0029794.s001.pdf

3. Description of infusion in this study:

http://journals.sagepub.com/doi/10.1177/1534735415622010

"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:

http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0120228

https://doi.org/10.1371/journal.pone.0120228.s002

"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."
_____________________

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

PDGFRA as a potential target in H3 K27M mutant gliomas

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

https://www.ncbi.nlm.nih.gov/pubmed/29674595

"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.

https://www.ncbi.nlm.nih.gov/pubmed/29687258

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."

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.

 

Questions regarding supplements/repurposed drugs

Hi,  I want to thank those of you that responded to my previous post.  For some reason, I can write posts but not respond?  Anyway, I am trying to figure out additional repurposed drugs/supplements to have my son take with his "main" treatment.  Briefly, he had IDH1+ AA3 (diag. originally 1/11)  treated with proton alone fall of 2012 with small recurrence found late 12/17 MRI. Eventual surgery showed GBM that is still IDH1+ (as expected) but hypomutated (GTR with very generous margins--tumor in "unimportant" part of frontal lobe).  He is enrolled in a clinical trial (metronomic TMZ/PARP).  I wanted to make certain that he can tolerate his "main" drugs and then sequentially add supplements/repurposed meds (with the approval of the study supervisors).  He is already taking Keppra, melantonin 20 mg and will likely start Celebrex later this week.

--I was going to add Longvida given data...but it states that it "reduces oxidative stress"...isn't the idea to try to stress the IDH1+ residual tumor?
--I was thinking of having him add chloroquine and/or metformin.  However, I have read the inhibiting autophagy (as chloroquine purportedly does) can either promote OR suppress tumor growth?  He doesn't have a BRAF mutation (or many at all--at least not yet).
--I have read about dihydrotanshinone, that can reportedly cause endoplasmic reticulum stress and sensitize to TMZ.  Is this something to consider?

Are there any supplements that seem particularly useful for IDH1+  patients?

Thank you very much,  Marcia

Semyon's mom's profile.

My mother had an operation (in Germany, Frankfurt am Main) - removal of the tumor by 99%, and then - the rapid growth of the tumor to its former size (for 3 weeks)! The doctors were in shock.
(Glioblastoma, MGMT methylated)
10 days after chemoradiotherapy, MRI still showed tumor growth. The doctors decided that TMZ did not work in our case and suggested urgently switching to Avastin and Irinotecan.

Thinking, we decided to use a low dose of Avastin + CCNU.
I also decided to add 5 days of low TMZ after every day of CCNU.

The OncoDeep report showed the likely effect of Sirolimus, Olaparib and Trametinib.
I flew to Delhi (India) and bought at low price LYNPARZA Olaparib (1 bottle of 112 capsules of 50 mg) and MEKINIST Trametinib (1 bottle of 30 2 mg tablets).

Unfortunately, it is very difficult to interpret MRI. 3 doctors who watch my mom's MRI say sometimes the opposite conclusion!

Comments:

1. Suppression of T4 is very slow. We spent 3.5 months to reduce T4 from 12.4 to 3.3pmol / l. Also, T3 has fallen dramatically, although we take synthetic T3. Because of this, drowsiness and lack of appetite.

When suppressing T4, you can not take selenium, since it increases the production of the hormone T4! We started taking selenium and the hormone T4 took off from 3.3 to 5.14! Now with great difficulty again we need to knock it down((

2. For all treatment, my mother lost a lot of weight. From 65 kg (in January) to 52 kg (now). However, I do not see anything that we could refuse.

3. We bought a special meter and ketone strips to check that the mother is ketosis.

4. I ordered Mebendazole chewable tablets from Thailand for 500 mg / tablet. Maybe we will try to take large doses: 2-3 grams per day.

5. We use a higher dose of perillyl alcohol than Dr. Dr. Clóvis Orlando: 30 drops instead of 21. No unpleasant sensations! We plan to increase the dose to 40 drops. Dr. Clóvis Orlando wrote that they use perillic alcohol of 96% from Sigma Aldrich and that the other perillyl alcohol will not have an effect on GBM.

MRI-1: https://drive.google.com/open?id=1tPKrQgjIZzBgefhkknxNlQKbaC04XMI_

MRI-2: https://drive.google.com/open?id=1t3SgxGgJFi19i9qIwc47JucsV6ZCbLFa

MRI-3: https://drive.google.com/open?id=1JbRYk3DCUK87ndeRQK-Q7V7130oObiMV

MRI-4: https://drive.google.com/open?id=1Q6WFd9qtFAd18czkd5ouKYloIVBKuFS1

MRI-5: https://drive.google.com/open?id=1L-O1BgoVMohI7eXxH35qN__rNBDy3hrM

MRI-6: https://drive.google.com/open?id=1xWYd5_UsrAYb-c4wv49DSWTeJEN8Dl_F

MRI-7: https://drive.google.com/open?id=1MCpzZxPnl7eI1iigzJVWrOo2o4s8hKWz

MRI-8: https://drive.google.com/open?id=1De95kb-iZ30X7scIbZkeXxFq4KV5fgdT

11C-methionine PET 17.05.2018:
https://drive.google.com/open?id=18AaVybu5nvBH_cAe5QIfzO-efiwsUfkc

OncoDEEP report: https://drive.google.com/open?id=1A3dophOME6gY1GNdOHWE48wVYJUu_nHc
http://btcocktails.blogspot.ru/2018/02/our-report-oncodeep-what-do-you.html

 

GBM case, debrief

I’ve barely visited this site since my wife passed in August.  My introductory post was:

http://btcocktails.blogspot.com/2016/06/introduction-and-introductory-thoughts.html

There may be lessons or clues to share that could be of use to others. 

Diagnosed with L tempo-parietal 4cm GBM 5/16 after a stroke-like episode.

Gross total resection, with near-total resolution of all symptoms.

Stupp protocol of radiation+temozolamide.  Poor tolerance of TMZ.

Experimental Nivolumab/Opdivo.  Tolerated well at first. 

Follow-up MRI showed severe cerebral edema of much of the L hemisphere.  Clearly an Opdivo effect.

This necessitated halting Opdivo.  Avastin/Bevacizumab produced dramatic, immediate improvement in cerebral edema, far more effective than Decadron, which had to this point had little apparent effect on edema.

Avastin was well-tolerated initially, but after 3+ doses at q 2w intervals, started to suffer abdominal symptoms.

Recurrence diagnosed 4//17.  Almost got into an NIH CAR-T trial, but deteriorated too quickly to qualify.

https://clinicaltrials.gov/ct2/show/NCT01454596

Steady downhill course after that, ending in home hospice care. 

Throughout this time, I gave a supplement cocktail roughly equivalent to Ben Williams’:
http://btcocktails.blogspot.com/2015/07/ben-williams-supplement-list-for.html

Plus ketogenic diet.

One possibly useful addition was Celebrex.  In addition to anti-tumor properties, I note that animal studies show comparable effectiveness of NSAIDs and decadron for cerebral edema.  No oncologist is going to use Celebrex instead of decacron for this purpose, because of lack of human trials.  But we’re all going somewhat off-script here already anyway.

My strong impression (from this N-of-one study) is that during the time she was on the full cocktail and NOT on decadron, there was little or no sign of progression. 

My impression is that Avastin didn’t accelerate her course directly, but that it led to GI symptoms that made her tolerate poorly all the supplements I wanted to give her.  I believe progression accelerated off the cocktail.

My impression also is that Decadron helped little with any of her signs or symptoms, but it caused terrible side effects and (I believe) faster progression.  She developed some psychotic symptoms at a dose of 4mg/d of decadron.

We didn’t do genetic studies (beyond methylation status) on the tumor.  Money was tight and (given the typical genetic heterogeneity of GBM), I’m skeptical that gene-specific approaches are likely to yield more than a few weeks of added survival.

Checkpoint inhibition seemed to have potent effects.  It would seem careful dose titration against cerebral edema effects may be important.  Alas, dose titration wasn’t possible on the study protocol—all or nothing only.  Avastin might prove a useful treatment for resultant cerebral edema in other cases.  But I’d recommend shorter-term use of Avastin, primarily to treat edema.

We were lucky to have long-term care insurance to help with caregiving in home hospice.  We were also lucky to have supportive friends and family.  This is a phenomenally expensive disease to manage--financially and emotionally.  Her passing was ultimately about as humane as it could possibly be.  She is missed.

Best wishes to all,

Steve