[備份] 腦瘤研究系列 @ Montpellier
Fb設計與介面是用來快速分享、更新與瀏覽，但對於記性不太好的我，對於不能「累積」這件事情，使用起來並不是太舒服。搬回來 Blogger之後，覺得踏實許多。
以下是備份 2019/10-12 這段期間，到法國Montpellier進修時的讀書心得，統整在一起方便查閱。
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[腦瘤研究系列1] Co-deleted anaplastic oligodendroglioma怎麼治療？
https://n.neurology.org/cont…/…/16_Supplement/PL02.005.short
CODEL trial (2016):
RT+ TMZ or RT alone is better than TMZ alone as adjuvant therapy for newly diagnosed anaplastic 1p/19q codeleted oligodendroglioma.
-> follow the "two-arm comparison of RT+adjuvant PCV vs. RT+concomitant/adjuvant TMZ"
[腦瘤研究系列2] - Non-co-deleted anaplastic glioma怎麼治療？
https://www.thelancet.com/…/PIIS0140-6736(17)31442…/fulltext
CATNON trial 1st interim analysis (2017):
Adjuvant temozolomide chemotherapy was associated with a significant survival benefit in patients with newly diagnosed non-co-deleted anaplastic glioma. (5yr OS: 55.9% vs 44.1%; HR of adjuvant TMZ: 0.65(0.45-0.93), p=0.0014)
https://ascopubs.org/…/abs/10.1200/JCO.2019.37.15_suppl.2000
CATNON trial 2nd interim analysis (2019):
concTMZ did not increase OS. However, in IDHmt tumors a trend towards benefit of concTMZ is present.
(HR for IDH mt: 0.67(0.44-1.03), p=0.06)
[腦瘤研究系列3] TMZ rechallenge in recurrent GBM?
https://onlinelibrary.wiley.com/doi/full/10.1002/cncr.23813
Perry(2008), retrospective, total 49 pts(A:21,B:14,C:14), metronomical regimen (50mg/m2/d -> 1400mg/m2/m), via antiangiogenic and dose intensity, also to overcome TMZ resistance
-> clinical benefit in A: 47%, PFS-6: 17%; in B: 78%, PFS-6: 57%; in C: 57%, PFS-6: 42%
[criticism: small number, no molecular]
https://www.ncbi.nlm.nih.gov/pubmed/20308655
Perry(2010), RESCUE trial, prospective non-randomized phase II trial, total 120 pts(A:29,B1:33,B2:39,B3:29; A:anaplastic, B1:early, B2:extended, B3:rechanllenge), continuous dose-intense TMZ 50mg/m2/d for 1yr or PD.
-> Patients who experience progression during the first six cycles of conventional adjuvant TMZ therapy or after a treatment-free interval get the most benefit from therapy.
(B1,B3 better than B2); PFS-6(A,35.7%; B1,27.3%; B2,7.4%; B3,35.7%); 1yr-OS(A,60.7%; B1,27.3%; B2,14.8%; B3,28.6%)
=> PFS-6 and time to progression was similar in mMGMT and umMGMT
[*pseudoprogression has been rule out: not include PD within post-CCRT-3m; **15.8% grIII lymphopenia]
https://clincancerres.aacrjournals.org/content/…/9/2057.long
Weller(2015), DIRECTOR trial, prospective, randomized, two-arm trial for GBM first relapse after CCRT+at least 2cycles of TMZ, study dosing-regimen. 7-on-7-off vs. 21-on-7-off (both 1680mg/m2/m), total 105 pts(A:52,B:53)
-> prematurely closed, no efficacy, safety and tolerability differences. OS:A,9.8m;B10.6m.
=> median TTF(time-to-treatment failure): umMGMT,1.8m vs. mMGMT,3.2m. PFS-6: umMGMT, 6.9% vs. mMGMT, 39.7% (HR 1.76 (1.11-2.82), p=0.017)
[*. Profound lymphopenia was the most common hematologic toxicity, 19% in Arm A and 29% in Arm B]
[criticism: not compare with RESCUE trial]
[腦瘤研究4] What is G-CIMP?
https://www.ncbi.nlm.nih.gov/pubmed/26824661
Ceccarelli(2016), 1122 samples, from TCGA dataset, grade II,III gliomas and GBM. Complete genomic, transcriptomic and epigenomic(methylation) analysis.
* G-CIMP (Glioma-CpG island methylator phenotype): highly associate with IDH mutation (reifenberger,2016,nat rev)
-> methylation profile: high DNA methylation associate with IDH1/2 mut (99%) vs. low methylation with IDH wt (99%) and GBM (80%)
=> G-CIMP low subset: activation of cell cycle genes mediated by SOX binding at hypomethylated functional genomic elements, unfavorable outcome
=> G-CIMP high can emerge as G-CIMP low glioma at recurrence (role of methylation in disease progression?)
=> IDH-wt glioma revealed the PA-like LGG subset that harbors a silent genomic landscape: favorable prognosis
** in gliomas, increased telomere length is associated with ATRX mut, not TERTp mut, suggesting an alternative lengthening of telomeres (ALT) mechanism.
** issues associate with MT
-> compared with the G-CIMP GBM, IDH mut-non-codel LGG in LGr3 were characterized by enrichment of genes associated with neuro-glial functions such as ion transport and synaptic transmission, possibly suggesting a more differentiated nature.
-> GBM versus the LGG component of LGr4 (IDH-wt), identified an inflammation and immunologic response signature characterized by the activation of several chemokines (CCL18, CXCL13, CXCL2, and CXCL3) and interleukins (IL8 and CXCR2) enriching sets involved in inflammatory and immune response, negative regulation of apoptosis, cell cycle and proliferation, and the IKB/NFKB kinase cascade.(microglia?)
Resembling the functional enrichment for LGG within LGr3, functional enrichment of LGG IDH-wt in comparison to GBM within LGr4 showed activation in LGG of special glial-neuronal functions involved in ion transport, synaptic transmission, and nervous system development.
-> Master regulator analysis comparing the IDH-wt group to the IDH mut group revealed transcription factors that were upregulated in IDH-wild-type gliomas and showed an increase in expression of target genes, including NKX2-5, FOSL1, ETV4, ETV7, RUNX1, CEBPD, NFE2L3, ELF4, RUNX3, NR2F2, PAX8, and IRF1. No transcription factors were found to be upregulated in IDH mutant gliomas relative to IDH-wild-type gliomas
[腦瘤研究5] GBM TME
https://www.ncbi.nlm.nih.gov/pubmed/27088132
Heterogeneity of GBM: clonal evolution (the stochastic model) vs. cancer stem cell (hierarchical model)
Three tumor niches:
**tumor niches undergo dynamic alterations in a temporal and spatial manner
1) Perivascular niche: VEGF/FGF/PDGF -> chronic vascular hyperplasia (CVH); role of EC and pericyte or CSC?; BBB breakdown -> increase interstitial pressure; monocyte, neurotrophil, MDSC => immunosuppressive
* TAM and microglias compose 30-40% of cells in GBM; CSC may recruit TAM more efficiently; TAM release TGFb, induce MMP9 expression and CSC invasiveness; CSC release periostin attract TAMs
2) Hypoxic niche: local hypoxia -> pseudopalisading necrosis(angiopoietin-2-mediated EC apoptosis, vassel regression, intravascular thrombosis) and microvascular hyperplasia: predict poor prognosis and MT
* hypoxia: CSCs enriched, hypoxia promote stemness: CD133, SOX2, OCT4, nestin, KLF4, HIF1,2
* hypoxia enhances transdifferentiation of CSCs into endothelial-like cells -> microvascular hyperplasia -> vicious cycle
3) Invasive niche: move along whit matter tracts and basement membrane (blood vessels).
* GBM cells disrupt astrocyte-vasculature interaction, even seize control of the regulation of vascular tone; astrocytosis -> in turn affect gliomagenesis.
* Microglia: glioma cell secrete CSF1, recruit blood-derived monocyte into immunosuppressive and angiogenic macrophage
* Neuron: perineuronal satellitosis (surround by tumor cells); NLGN3 & glutamate
-----------------------------------------------------------------------------------------------
CODEL trial (2016):
RT+ TMZ or RT alone is better than TMZ alone as adjuvant therapy for newly diagnosed anaplastic 1p/19q codeleted oligodendroglioma.
-> follow the "two-arm comparison of RT+adjuvant PCV vs. RT+concomitant/adjuvant TMZ"
[腦瘤研究系列2] - Non-co-deleted anaplastic glioma怎麼治療？
https://www.thelancet.com/…/PIIS0140-6736(17)31442…/fulltext
CATNON trial 1st interim analysis (2017):
Adjuvant temozolomide chemotherapy was associated with a significant survival benefit in patients with newly diagnosed non-co-deleted anaplastic glioma. (5yr OS: 55.9% vs 44.1%; HR of adjuvant TMZ: 0.65(0.45-0.93), p=0.0014)
CATNON trial 1st interim analysis (2017):
Adjuvant temozolomide chemotherapy was associated with a significant survival benefit in patients with newly diagnosed non-co-deleted anaplastic glioma. (5yr OS: 55.9% vs 44.1%; HR of adjuvant TMZ: 0.65(0.45-0.93), p=0.0014)
https://ascopubs.org/…/abs/10.1200/JCO.2019.37.15_suppl.2000
CATNON trial 2nd interim analysis (2019):
concTMZ did not increase OS. However, in IDHmt tumors a trend towards benefit of concTMZ is present.
(HR for IDH mt: 0.67(0.44-1.03), p=0.06)
CATNON trial 2nd interim analysis (2019):
concTMZ did not increase OS. However, in IDHmt tumors a trend towards benefit of concTMZ is present.
(HR for IDH mt: 0.67(0.44-1.03), p=0.06)
[腦瘤研究系列3] TMZ rechallenge in recurrent GBM?
https://onlinelibrary.wiley.com/doi/full/10.1002/cncr.23813
Perry(2008), retrospective, total 49 pts(A:21,B:14,C:14), metronomical regimen (50mg/m2/d -> 1400mg/m2/m), via antiangiogenic and dose intensity, also to overcome TMZ resistance
Perry(2008), retrospective, total 49 pts(A:21,B:14,C:14), metronomical regimen (50mg/m2/d -> 1400mg/m2/m), via antiangiogenic and dose intensity, also to overcome TMZ resistance
-> clinical benefit in A: 47%, PFS-6: 17%; in B: 78%, PFS-6: 57%; in C: 57%, PFS-6: 42%
[criticism: small number, no molecular]
[criticism: small number, no molecular]
https://www.ncbi.nlm.nih.gov/pubmed/20308655
Perry(2010), RESCUE trial, prospective non-randomized phase II trial, total 120 pts(A:29,B1:33,B2:39,B3:29; A:anaplastic, B1:early, B2:extended, B3:rechanllenge), continuous dose-intense TMZ 50mg/m2/d for 1yr or PD.
Perry(2010), RESCUE trial, prospective non-randomized phase II trial, total 120 pts(A:29,B1:33,B2:39,B3:29; A:anaplastic, B1:early, B2:extended, B3:rechanllenge), continuous dose-intense TMZ 50mg/m2/d for 1yr or PD.
-> Patients who experience progression during the first six cycles of conventional adjuvant TMZ therapy or after a treatment-free interval get the most benefit from therapy.
(B1,B3 better than B2); PFS-6(A,35.7%; B1,27.3%; B2,7.4%; B3,35.7%); 1yr-OS(A,60.7%; B1,27.3%; B2,14.8%; B3,28.6%)
=> PFS-6 and time to progression was similar in mMGMT and umMGMT
(B1,B3 better than B2); PFS-6(A,35.7%; B1,27.3%; B2,7.4%; B3,35.7%); 1yr-OS(A,60.7%; B1,27.3%; B2,14.8%; B3,28.6%)
=> PFS-6 and time to progression was similar in mMGMT and umMGMT
[*pseudoprogression has been rule out: not include PD within post-CCRT-3m; **15.8% grIII lymphopenia]
https://clincancerres.aacrjournals.org/content/…/9/2057.long
Weller(2015), DIRECTOR trial, prospective, randomized, two-arm trial for GBM first relapse after CCRT+at least 2cycles of TMZ, study dosing-regimen. 7-on-7-off vs. 21-on-7-off (both 1680mg/m2/m), total 105 pts(A:52,B:53)
Weller(2015), DIRECTOR trial, prospective, randomized, two-arm trial for GBM first relapse after CCRT+at least 2cycles of TMZ, study dosing-regimen. 7-on-7-off vs. 21-on-7-off (both 1680mg/m2/m), total 105 pts(A:52,B:53)
-> prematurely closed, no efficacy, safety and tolerability differences. OS:A,9.8m;B10.6m.
=> median TTF(time-to-treatment failure): umMGMT,1.8m vs. mMGMT,3.2m. PFS-6: umMGMT, 6.9% vs. mMGMT, 39.7% (HR 1.76 (1.11-2.82), p=0.017)
=> median TTF(time-to-treatment failure): umMGMT,1.8m vs. mMGMT,3.2m. PFS-6: umMGMT, 6.9% vs. mMGMT, 39.7% (HR 1.76 (1.11-2.82), p=0.017)
[*. Profound lymphopenia was the most common hematologic toxicity, 19% in Arm A and 29% in Arm B]
[criticism: not compare with RESCUE trial]
[criticism: not compare with RESCUE trial]
[腦瘤研究4] What is G-CIMP?
https://www.ncbi.nlm.nih.gov/pubmed/26824661
Ceccarelli(2016), 1122 samples, from TCGA dataset, grade II,III gliomas and GBM. Complete genomic, transcriptomic and epigenomic(methylation) analysis.
* G-CIMP (Glioma-CpG island methylator phenotype): highly associate with IDH mutation (reifenberger,2016,nat rev)
-> methylation profile: high DNA methylation associate with IDH1/2 mut (99%) vs. low methylation with IDH wt (99%) and GBM (80%)
=> G-CIMP low subset: activation of cell cycle genes mediated by SOX binding at hypomethylated functional genomic elements, unfavorable outcome
=> G-CIMP high can emerge as G-CIMP low glioma at recurrence (role of methylation in disease progression?)
=> IDH-wt glioma revealed the PA-like LGG subset that harbors a silent genomic landscape: favorable prognosis
** in gliomas, increased telomere length is associated with ATRX mut, not TERTp mut, suggesting an alternative lengthening of telomeres (ALT) mechanism.
Ceccarelli(2016), 1122 samples, from TCGA dataset, grade II,III gliomas and GBM. Complete genomic, transcriptomic and epigenomic(methylation) analysis.
* G-CIMP (Glioma-CpG island methylator phenotype): highly associate with IDH mutation (reifenberger,2016,nat rev)
-> methylation profile: high DNA methylation associate with IDH1/2 mut (99%) vs. low methylation with IDH wt (99%) and GBM (80%)
=> G-CIMP low subset: activation of cell cycle genes mediated by SOX binding at hypomethylated functional genomic elements, unfavorable outcome
=> G-CIMP high can emerge as G-CIMP low glioma at recurrence (role of methylation in disease progression?)
=> IDH-wt glioma revealed the PA-like LGG subset that harbors a silent genomic landscape: favorable prognosis
** in gliomas, increased telomere length is associated with ATRX mut, not TERTp mut, suggesting an alternative lengthening of telomeres (ALT) mechanism.
** issues associate with MT
-> compared with the G-CIMP GBM, IDH mut-non-codel LGG in LGr3 were characterized by enrichment of genes associated with neuro-glial functions such as ion transport and synaptic transmission, possibly suggesting a more differentiated nature.
-> GBM versus the LGG component of LGr4 (IDH-wt), identified an inflammation and immunologic response signature characterized by the activation of several chemokines (CCL18, CXCL13, CXCL2, and CXCL3) and interleukins (IL8 and CXCR2) enriching sets involved in inflammatory and immune response, negative regulation of apoptosis, cell cycle and proliferation, and the IKB/NFKB kinase cascade.(microglia?)
Resembling the functional enrichment for LGG within LGr3, functional enrichment of LGG IDH-wt in comparison to GBM within LGr4 showed activation in LGG of special glial-neuronal functions involved in ion transport, synaptic transmission, and nervous system development.
-> Master regulator analysis comparing the IDH-wt group to the IDH mut group revealed transcription factors that were upregulated in IDH-wild-type gliomas and showed an increase in expression of target genes, including NKX2-5, FOSL1, ETV4, ETV7, RUNX1, CEBPD, NFE2L3, ELF4, RUNX3, NR2F2, PAX8, and IRF1. No transcription factors were found to be upregulated in IDH mutant gliomas relative to IDH-wild-type gliomas
-> compared with the G-CIMP GBM, IDH mut-non-codel LGG in LGr3 were characterized by enrichment of genes associated with neuro-glial functions such as ion transport and synaptic transmission, possibly suggesting a more differentiated nature.
-> GBM versus the LGG component of LGr4 (IDH-wt), identified an inflammation and immunologic response signature characterized by the activation of several chemokines (CCL18, CXCL13, CXCL2, and CXCL3) and interleukins (IL8 and CXCR2) enriching sets involved in inflammatory and immune response, negative regulation of apoptosis, cell cycle and proliferation, and the IKB/NFKB kinase cascade.(microglia?)
Resembling the functional enrichment for LGG within LGr3, functional enrichment of LGG IDH-wt in comparison to GBM within LGr4 showed activation in LGG of special glial-neuronal functions involved in ion transport, synaptic transmission, and nervous system development.
-> Master regulator analysis comparing the IDH-wt group to the IDH mut group revealed transcription factors that were upregulated in IDH-wild-type gliomas and showed an increase in expression of target genes, including NKX2-5, FOSL1, ETV4, ETV7, RUNX1, CEBPD, NFE2L3, ELF4, RUNX3, NR2F2, PAX8, and IRF1. No transcription factors were found to be upregulated in IDH mutant gliomas relative to IDH-wild-type gliomas
[腦瘤研究5] GBM TME
https://www.ncbi.nlm.nih.gov/pubmed/27088132
Heterogeneity of GBM: clonal evolution (the stochastic model) vs. cancer stem cell (hierarchical model)
https://www.ncbi.nlm.nih.gov/pubmed/27088132
Heterogeneity of GBM: clonal evolution (the stochastic model) vs. cancer stem cell (hierarchical model)
Three tumor niches:
**tumor niches undergo dynamic alterations in a temporal and spatial manner
1) Perivascular niche: VEGF/FGF/PDGF -> chronic vascular hyperplasia (CVH); role of EC and pericyte or CSC?; BBB breakdown -> increase interstitial pressure; monocyte, neurotrophil, MDSC => immunosuppressive
* TAM and microglias compose 30-40% of cells in GBM; CSC may recruit TAM more efficiently; TAM release TGFb, induce MMP9 expression and CSC invasiveness; CSC release periostin attract TAMs
**tumor niches undergo dynamic alterations in a temporal and spatial manner
1) Perivascular niche: VEGF/FGF/PDGF -> chronic vascular hyperplasia (CVH); role of EC and pericyte or CSC?; BBB breakdown -> increase interstitial pressure; monocyte, neurotrophil, MDSC => immunosuppressive
* TAM and microglias compose 30-40% of cells in GBM; CSC may recruit TAM more efficiently; TAM release TGFb, induce MMP9 expression and CSC invasiveness; CSC release periostin attract TAMs
2) Hypoxic niche: local hypoxia -> pseudopalisading necrosis(angiopoietin-2-mediated EC apoptosis, vassel regression, intravascular thrombosis) and microvascular hyperplasia: predict poor prognosis and MT
* hypoxia: CSCs enriched, hypoxia promote stemness: CD133, SOX2, OCT4, nestin, KLF4, HIF1,2
* hypoxia enhances transdifferentiation of CSCs into endothelial-like cells -> microvascular hyperplasia -> vicious cycle
* hypoxia: CSCs enriched, hypoxia promote stemness: CD133, SOX2, OCT4, nestin, KLF4, HIF1,2
* hypoxia enhances transdifferentiation of CSCs into endothelial-like cells -> microvascular hyperplasia -> vicious cycle
3) Invasive niche: move along whit matter tracts and basement membrane (blood vessels).
* GBM cells disrupt astrocyte-vasculature interaction, even seize control of the regulation of vascular tone; astrocytosis -> in turn affect gliomagenesis.
* Microglia: glioma cell secrete CSF1, recruit blood-derived monocyte into immunosuppressive and angiogenic macrophage
* Neuron: perineuronal satellitosis (surround by tumor cells); NLGN3 & glutamate
* GBM cells disrupt astrocyte-vasculature interaction, even seize control of the regulation of vascular tone; astrocytosis -> in turn affect gliomagenesis.
* Microglia: glioma cell secrete CSF1, recruit blood-derived monocyte into immunosuppressive and angiogenic macrophage
* Neuron: perineuronal satellitosis (surround by tumor cells); NLGN3 & glutamate
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