Radiotherapy delays malignant transformation and prolongs survival in patients with IDH-mutant gliomas

Objective:IDH-mutant lower-grade gliomas(LGGs,grade 2 or 3)eventually transform into secondary grade 4 astrocytomas(sAIDHmut/G4).Here,we sought to describe the transformation time,risk factors,and outcomes in malignant transformation of IDHmutant LGGs.Methods:We screened data for 108 patients with sAIDHmut/G4 in the Chinese Glioma Genome Atlas who had initial IDH-mutant LGGs and underwent reoperation during 2005–2021.We evaluated the transformation time from IDH-mutant LGGs to sAIDHmut/G4,and associated risk factors and outcomes.Malignant transformation was defined as pathological confirmation of grade 4 astrocytoma.Results:The median age of the 108 patients with IDH-mutant LGGs was 35 years(range,19–54);the median age at transformation was 40 years(range,25–62);and the median follow-up time for all patients was 146 months(range,121–171).The average transformation time was 58.8 months for all patients with LGGs(range,5.9–208.1);63.5 and 51.9 months for grade 2 and 3 gliomas,respectively;and 58.4 and 78.1 months for IDH-mutant/1p/19q-non-codeleted astrocytomas and IDH-mutant/1p/19q-codeleted oligodendrogliomas,respectively.Univariate and multivariate analysis indicated that radiotherapy[hazard ratio(HR),0.29;95%confidence interval(CI),0.137–0.595;P=0.001]and non-A blood type(HR,0.37;95%CI,0.203–0.680;P=0.001)were protective factors against delayed malignant transformation.Radiotherapy was associated with improved survival after transformation(HR,0.44;95%CI,0.241–0.803;P=0.008),overall survival(HR,0.50;95%CI,0.265–0.972;P=0.041),and progression-free survival(HR,0.25;95%CI,0.133–0.479;P<0.0001)in patients with IDH-mutant gliomas.Conclusions:Radiotherapy is associated with delayed malignant transformation and improved survival in patients with IDHmutant gliomas.

Advances in the Immunotherapeutic Potential of Isocitrate Dehydrogenase Mutations in Glioma

Isocitrate dehydrogenase(IDH)is an essential metabolic enzyme in the tricarboxylic acid cycle(TAC).The high mutation frequency of the IDH gene plays a complicated role in gliomas.In addition to affecting gliomas directly,mutations in IDH can also alter their immune microenvironment and can change immune-cell function in direct and indirect ways.IDH mutations mediate immune-cell infiltration and function by modulating immune-checkpoint gene expression and chemokine secretion.In addition,IDH mutation-derived D2-hydroxyglutarate can be absorbed by surrounding immune cells,also affecting their functioning.In this review,we summarize current knowledge about the effects of IDH mutations as well as other gene mutations on the immune microenvironment of gliomas.We also describe recent preclinical and clinical data related to IDH-mutant inhibitors for the treatment of gliomas.Finally,we discuss different types of immunotherapy and the immunotherapeutic potential of IDH mutations in gliomas.

PTPRZ1-METFUsion GENe(ZM-FUGEN)trial:study protocol for a multicentric,randomized,open-label phase II/III trial

Background PTPRZ1-MET fusion was reported to associate with glioma progression from low-grade to high-grade glioma,which was a target by a MET inhibitor vebreltinib.However,little is known about the further efficacy of vebreltinib among more glioma patients.This trial aims to evaluate the safety and efficacy of vebreltinib enteric-coated capsules in the treatment of sGBM/IDH mutant glioblastoma patients with the ZM fusion gene.Methods This multicentric,randomized,open-label,controlled trial plans to include 19 neurosurgical centers and recruit 84 sGBM or IDH mutant glioblastoma patients with the ZM fusion gene.This trial enrolls sGBM or IDH mutant glioblastoma patients with the inclusion criteria and without the exclusion criteria.It was registered with chinadrugtrials.org.cn(CTR20181664).The primary efficacy endpoint is overall survival(OS).The secondary endpoints are progression-free survival(PFS)and objective response rate(ORR).Discussion If proven effective,this targeted multifaceted intervention protocol will be extended for more glioma patients as a protocol to evaluate the safety and efficacy of MET inhibitors.Trial registration It was registered with chinadrugtrials.org.cn(CTR20181664).