Mechanisms and therapeutic implications of hypermutation in gliomas.
https://www.ncbi.nlm.nih.gov/pubmed/32322066
https://sci-hub.tw/10.1038/s41586-020-2209-9 (sci-hub link to the full PDF document)
Unfortunately this study provides negative evidence to the idea that hypermutated gliomas would be more responsive to treatment with PD-1 blockers such as nivolumab and pembrolizumab.
from the study
"MMR-deficient gliomas were characterized by a lack of prominent T cell infiltrates, extensive intratumoral heterogeneity, poor patient survival and a low rate of response to PD-1 blockade. "
"Because our prior analyses indicated that patients with hypermutated gliomas might have reduced survival, we used a second set of historical controls to compare the outcome of hypermutated gliomas treated with PD-1 blockade versus other systemic agents. Unexpectedly, we observed a longer median OS for patients treated with other systemic agents when compared to those treated with PD-1 blockade"
However, the mismatch repair deficient, hypermutated tumor cells were sensitive to the chemotherapy agent CCNU (lomustine).
"We next treated native and engineered isogenic MMR-knockout glioma models with temozolomide or the nitrosourea lomustine (CCNU), a chloroethylating alkylating agent that generates DNA interstrand crosslinks and double-strand breaks (Fig. 2c, Extended Data Fig. 8g–i). All MMR-deficient models were resistant to temozolomide and sensitive to CCNU, consistent with the lack of hypermutation in samples from nitrosourea-treated patients"
This confirms advice I've given to patients with temozolomide-driven hypermutated recurrent gliomas: CCNU (lomustine) chemotherapy is probably the best choice in terms of conventional chemotherapy options. However it argues against advice that PD-1/PD-L1 blockade (drugs such as pembrolizumab or nivolumab) would be the best option.
Tuesday 28 April 2020
Wednesday 8 April 2020
Niacin reactivates myeloid cells, slows tumor growth in GBM mouse models
This was just published a few days ago in Science Translational Medicine.
Control of brain tumor growth by reactivating myeloid cells with niacin
Sarkar et al.
https://stm.sciencemag.org/content/12/537/eaay9924.editor-summary
"Although innate immune cells are typically present inside tumors, they often have an inactive phenotype such that they are ineffective at killing the cancer cells or even promote tumor growth. Sarkar et al. discovered that it may be possible to reprogram these cells to a more active type using niacin (vitamin B3). The authors showed that niacin-exposed monocytes can inhibit the growth of brain tumor–initiating cells. Moreover, niacin treatment of intracranial mouse models of glioblastoma increased monocyte and macrophage infiltration into the tumors, stimulated antitumor immune responses, and extended the animals’ survival, especially when combined with the chemotherapeutic drug temozolomide."
I have uploaded the full study to the Brain Tumor Library, follow this pathway:
Folder 0. Important Reference documents -> subfolder 1. New Uploads -> "2020 Sarkar Niacin reactivates myeloid cells"
Control of brain tumor growth by reactivating myeloid cells with niacin
Sarkar et al.
https://stm.sciencemag.org/content/12/537/eaay9924.editor-summary
"Although innate immune cells are typically present inside tumors, they often have an inactive phenotype such that they are ineffective at killing the cancer cells or even promote tumor growth. Sarkar et al. discovered that it may be possible to reprogram these cells to a more active type using niacin (vitamin B3). The authors showed that niacin-exposed monocytes can inhibit the growth of brain tumor–initiating cells. Moreover, niacin treatment of intracranial mouse models of glioblastoma increased monocyte and macrophage infiltration into the tumors, stimulated antitumor immune responses, and extended the animals’ survival, especially when combined with the chemotherapeutic drug temozolomide."
I have uploaded the full study to the Brain Tumor Library, follow this pathway:
Folder 0. Important Reference documents -> subfolder 1. New Uploads -> "2020 Sarkar Niacin reactivates myeloid cells"
Unused temozolomide
from Candy:
I have 4 months worth or TMZ that has not been opened. Downside is it expired 2/2020. Not real sure that matters since recent. If anyone is in need, I will be happy to mail in US at no cost for items or mail.
Stay safe.
Candy
from Stephen:
if there are any takers I can connect the parties by email
I have 4 months worth or TMZ that has not been opened. Downside is it expired 2/2020. Not real sure that matters since recent. If anyone is in need, I will be happy to mail in US at no cost for items or mail.
Stay safe.
Candy
from Stephen:
if there are any takers I can connect the parties by email
Sunday 5 April 2020
Posted on behalf of a caregiver:
My sister (aged 42) has glioblastoma grade IV, IDH mutated.
Previously diagnosed with an infiltrating astrocytoma (WHO grade II) in 2015 in the left inferior front temporal region, now transformed to glioblastoma.
She had 2 surgeries in 2016 to take out as much of the tumour as possible, and followed up with radio and chemo. She has been taking the following medication:
Her MRI has been coming back ok (I.e. tumour size remains d same, not increasing nor reducing), most recent MRI being in Feb.
However since late last year, she has been losing her balance and falling.
Previously diagnosed with an infiltrating astrocytoma (WHO grade II) in 2015 in the left inferior front temporal region, now transformed to glioblastoma.
She had 2 surgeries in 2016 to take out as much of the tumour as possible, and followed up with radio and chemo. She has been taking the following medication:
Anti-seizure
Levetiracetam – 1000mg/morning and night
Apo-clobazam – 10mg/ night
Vimpat (Lacosamide) – 10mg/morning and night
Anti-cancer
Disulfiram – 500mg/morning
Copper (Bisglycinate) – 10mg/morning
Disulfiram – 500mg/morning
Copper (Bisglycinate) – 10mg/morning
Niacin (No Flush) – 500mg/morning
Anti-"pup" medications
Metamucil fibre therapy
RestotaLax
Supplements
Boswellia – 307mg (115 mg Boswellic acids)
Turmeric / Curcumin (Anti-inflamatory) – 500mg twice daily
Mushroom Complex 2-3 pills twice daily
Melatonin – 10 mg
Green Tea Extract – 300mg
OMEGA 3 FATTY ACID (FISH OIL) 3000mg daily
COENZYME Q-10 -100mg once daily
Repurposed Meds for brain tumor
Metformin – 500mg X 2 tables
Mebendazole – 100mg X 2 tables
Atorvastatin – 40mg X 2 tables
Doxycycline - 100mg (alternantes monthly)
Her MRI has been coming back ok (I.e. tumour size remains d same, not increasing nor reducing), most recent MRI being in Feb.
However since late last year, she has been losing her balance and falling.
My question for this group is if anyone here has experienced something similar? I’m seeking some insight on why MRI is clean but balance is worsening.
@Stephen, I’d appreciate if you have any comments on this.
Any help will be appreciated.
Also if you have any advice on something else we can try kindly let me know.
Many thanks
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