Search

Chondrosarcoma (CS) is a malignant tumor that produces cartilaginous matrix and is the second most common primary bone sarcoma. CS encompasses a range of histological subtypes, with high-grade conventional central CS being particularly rare, occurring at a rate of 1.81 cases per 1 million person-years. Complete surgical resection is the standard curative treatment for this subtype, as radiation therapy and chemotherapy have proven ineffective. High-grade conventional central CS is highly metastatic and prone to recurrence, resulting in a poor prognosis. Therefore, effective multidisciplinary treatment strategies are urgently needed. Patient-derived cell lines offer promising tools for exploring new therapeutic approaches. However, only two cell lines of high-grade CSs are currently available in public cell banks. In this study, we aimed to establish a novel cell line for high-grade conventional central CS. We successfully developed the NCC-CS1-C1 cell line using surgically resected tumor tissues from a patient with conventional central grade 3 CS. This cell line harbored an IDH1 mutation (p.R132S), commonly found in 50% of CS cases, and exhibited complex copy number variants. A high-throughput screening of 221 anti-cancer drugs identified five candidates—bortezomib, carfilzomib, doxorubicin, panobinostat, and romidepsin—that demonstrated low IC50 values, indicating potential efficacy in treating CS. These findings suggest that NCC-CS1-C1 is a valuable tool for both preclinical and basic research on high-grade conventional central CS. [ABSTRACT FROM AUTHOR]

Summary Acute myeloid leukaemia (AML) arising from a myeloproliferative neoplasm (MPN) is more aggressive and less responsive to therapies compared to de novo AML. Olutasidenib, an oral small‐molecule inhibitor of mutated IDH1 (mIDH1), showed encouraging and durable responses in a phase 1/2 study of adults with post‐MPN mIDH1 AML. Patients received olutasidenib 150 mg BID monotherapy or in combination with azacitidine. Primary end‐points: safety and best response defined as complete remission (CR), CR with partial haematological recovery or morphological leukaemia‐free state (MLFS). Analysis included 15 patients with post‐MPN mIDH1 AML; 10 had relapsed or refractory AML and five had newly diagnosed AML. Six were treated with olutasidenib monotherapy and nine in combination with azacitidine. Treatment emergent adverse events occurred in 15 patients, three of whom discontinued therapy. CR: 40% (n = 6/15); median duration of response: 15.6 months (range: 1.7–44.3); CR with incomplete haematological recovery: 13% (n = 2/15); MLFS: 7% (n = 1/15); composite complete remission (CRc): 53% (n = 8/15); and overall response rate (ORR): 60% (9/18). Median duration of CRc and ORR: 13.15 (range: 2.4–48.7) and 14.3 months (range: 2.4–48.7), respectively, and median overall survival: 13.8 months (95% confidence interval: 3.70–23.7). Olutasidenib demonstrated encouraging response rates with a manageable safety profile for patients with post‐MPN mIDH1 AML. [ABSTRACT FROM AUTHOR]

Background: Molecular profiles can predict which patients will respond to current standard treatment and new targeted therapy regimens. Using data from a highly diverse population of approximately three million in Southeast London and Kent, this study aims to evaluate the prevalence of IDH1 mutation and MGMT promoter methylation in the gliomas diagnosed in adult patients and to explore correlations with patients' demographic and clinicopathological characteristics. Methods: Anonymised data on 749 adult patients diagnosed with a glioma in 2015–2019 at King's College Hospital were extracted. Univariable and multivariable logistic regressions were used to estimate odds ratios (ORs) for expressing IDH1 mutation and MGMT promoter methylation, based on each patient's age, sex, ethnicity, histology, tumour location and extent of resection. The Kaplan–Meier method was used to estimate the overall survival functions. Results: A total of 19.5% of cases were IDH1-mutated. Being 39 years and younger (OR 5.48, 95% CI 3.17–9.47), from Asian/Asian British background (OR 3.68, 95% CI 1.05–12.97), having MGMT methylation (OR 15.92, 95% CI 7.30–34.75), an oligodendroglioma diagnosis (OR 7.45, 95% CI 2.90–19.13) and receiving a gross total/total microscopic resection (OR 1.95, 95% CI 1.24–3.08) were each univariately correlated with IDH1 mutation. MGMT methylation association persisted on adjustment (OR 14.13, 95% CI 3.88–51.43). MGMT promoter methylation was seen in 54.3% of gliomas. In the univariate adjusted ORs, being younger than 39 years (OR 2.56, 95% CI 1.48–4.43), female (OR 1.52, 95% CI 1.11–2.08), having IDH1 mutation (OR 15.92, 95% CI 7.30–34.75) and an oligodendroglioma diagnosis (OR 6.20, 95% CI 1.33–28.88) were associated with MGMT methylation. Being female (OR 1.75, 95% CI 1.22–2.51) and having an IDH1 mutation (OR 15.54, 95% CI 4.73–51.05) persisted after adjustment for age, sex, ethnicity, histology, tumour location and extent of resection. IDH1 mutant and MGMT methylated gliomas were associated with frontal lobe location. Survival analysis showed that patients with both IDH1 mutation and MGMT methylation had significantly better survival than those with either molecular marker alone. Over a 3-year period, women with unmethylated MGMT promoters generally had better survival than men with unmethylated MGMT. Conclusion: This study showed that the molecular markers of IDH1 mutation and MGMT promoter methylation were associated with age, sex, Asian/Asian British ethnic group, tumour histology, anatomical location and extent of resection. This study has demonstrated the importance of assessing glioma molecular markers in the clinical setting and the need to stratify patients according to their clinicopathological characteristics. [ABSTRACT FROM AUTHOR]

Objective: To study clinical efficacy of isocitrate dehydrogenase 1 (IDH1) mutation on temozolomide chemotherapy for glioma patients and its impact on immune cytokines and prognosis. Methods; A total of 134 patients with glioma who underwent surgical resection and were confirmed by pathology in Dushu Lake Hospital Affiliated to Sooehow University from October 2021 to October 2022 were selected as research subjects. 1DH1 mutation status was measured by direct sequencing method, and 1DH1 expression rate in glioma tissue was determined by immunohistochemistry. All patients with brain glioma were treated with temozolomide chemotherapy. Effects of 1DH1 mutation on clinical efficacy, immune cytokines (IFN-γ, IL-2, 1L-4, IL-10) and prognosis of glioma were analyzed. Results; Seventy-nine cases out of 134 cases of glioma tissue had IDH1 mutations, mostly at R132, with a mutation rate of 58.96%, significantly higher than normal brain tissue (χ²=48.066, P<0.05). Immunohistochemistry showed strong positive expression of 1DH1 in 56 out of 134 glioma tissues. Proportion of WHO grade IV in IDH1 mutant group was lower than 1DH1 wild type group [11.39% (9/79) vs 63.64% (35/55),Z=41.020, P<0.05], Proportion of low differentiation in IDH1 mutant group was higher than IDH1 wild type group [50.63%(40/79) vs 20.00%(11/55),/=12.907,P<0.05], Total effective rate in IDH1 mutant group was higher than IDH1 wild type group [91.14%(72/79) ps 76.36%(42/55),χ²=5.575,P<0.05], IFN-γ and IL-2 levels were higher than IDH1 wild type group [ (28.98±3.25) pg/ml vs (20.15±2.54) pg/ml, (33.42±4.25) pg/ml ts (25.23±3.52) pg/ml, 1=16.870, 11.750, P< 0.05], IL-4 and 1L-10 levels were lower than 1DH1 wild type group [ (7.90±1.02) pg/ml t;s (12.38+1.66) pg/ml, (8.79+1.00) pg/ml vs (15.26+1.23) pg/ml,f=19.330,33.500,P<0.05], 1DH1 mutation was positively correlated with IFN-γ and IL-2 levels after temozolo- mide chemotherapy (r=0.845, 0.772, P<0.05), and negatively correlated with IL-4 and IL-10 levels after temozolomide chemotherapy (r=-0.786,-0.685, P<0.05). Survival rate after chemotherapy in IDH1 mutant group was higher than 1DH1 wild type group [89.87% (71/79) vs 72.70%(40/55), Log Rank test χ²=5.208,P<0.05], Cox regression analysis found that WHO grade III (RR= 1.342), poorly differentiated (RR=1.783), IFN-γ III (RR= 1.808), IL-2 (RR=2.112), IL-4 (RR=2.342), IL-10 (RR=1.342) as risk factors, temozolomide chemotherapy efficacy (RR=0.653), IDH1 mutation (RR=0.895) as protective factors affect prognosis of temozolomide chemotherapy in glioma patients (P<0.05). Conclusion; IDH1 mutation is related to disease grade and differentiation degree of glioma patients, and can affect efficacy of temozolomide chemotherapy and expressions of immune cytokines, which is a protective factor for prognosis and survival after temozolomide chemotherapy. [ABSTRACT FROM AUTHOR]

Olutasidenib, a potent, selective, oral, mutant isocitrate dehydrogenase 1 (mIDH1) inhibitor, is FDA-approved for relapsed/refractory (R/R) acute myeloid leukemia (AML). Here we report efficacy and safety of olutasidenib in 18 patients with mIDH1 AML who were relapsed (10), refractory (6) or had complete remission with incomplete hematologic recovery (CRi; 2) to a venetoclax combination. Of the 16 patients who were R/R, 4 (25%) achieved complete remission (CR), one (6.3%) achieved CR with partial hematologic recovery (CRh), and 7 (43.8%) achieved a composite complete remission (CRc). Median time to CRc was 1.9 months (range 1–2.8). As of data cutoff (18 June 2021), median duration of CRc was not reached (range, 1.2-NR, ongoing at 30.4+ months). Both patients with CRi at study entry achieved a CR. Safety was consistent with the overall profile of olutasidenib. Olutasidenib offers a valuable treatment option for patients with mIDH1 AML previously treated with venetoclax. [ABSTRACT FROM AUTHOR]

Background Isocitrate dehydrogenase 1 (IDH1) missense mutations occur at a frequency of 10%-15% in intrahepatic cholangiocarcinoma (iCCA). IDH1 mutations result in accumulation of (R)-2-hydroxyglutarate, an oncometabolite that leads to DNA hypermethylation and impairment of homologous recombination (HR). Impairment of HR results in a "BRCAness" phenotype which may confer sensitivity to poly(ADP ribose) polymerase (PARP) inhibition. Methods We conducted a retrospective cohort review to identify patients with advanced, IDH1 mutated iCCA treated with a PARP inhibitor (PARPi) at the University of Michigan between 2018 and 2023. Patients are described with respect to prior lines of therapy, response to platinum-based chemotherapy, and progression-free survival (PFS) and overall survival (OS) from the time of PARPi initiation. Results Between 2018 and 2023 we identified 40 patients with IDH1 mutated iCCA of which 6 patients were treated with a PARPi as monotherapy or in combination with an ATR inhibitor or anti-PD-1 immune checkpoint inhibitor. Majority of patients (n  = 5) carried an IDH1 R132C mutation per tissue-based next generation sequencing. All patients had previously received at least one line of cisplatin-based systemic therapy for advanced disease prior to treatment with PARPi. PFS and OS from time of PARPi initiation ranged from 1.4 to 18.5 months and 2.8 to 42.4 months, respectively. Best response on PARPi therapy included 2 partial responses. Conclusion This is the first case series to describe PARPi treatment in IDH1 mutated iCCA. Results underscore the limitation of PARPi monotherapy, potentially support combined PARPi therapies, and highlight a need for effective treatment options for patients with IDH1 mutated iCCA. [ABSTRACT FROM AUTHOR]

Metastatic cholangiocarcinoma (CCA) has poor prognosis. Chemotherapy in this indication demonstrated a limited benefit. Adding immunotherapy to standard chemotherapy is associated with an increase in median progressio.- free survival (mPFS) and increase in the response rate. An interesting therapeutic option for patients who have experienced progression during first line of treatment are targeted therapies. It is estimated that in over 50% of patients with CCA molecular tests based on next-generation sequencing (NGS) make it possible to identify genomic disorders, potentially enabling the use of targeted treatment. The most frequently reported disorders are fusions in the gene encoding fibroblast growth factor receptor 2 (FGFR2) and mutations in the IDH1 gene encoding isocitrate dehydrogenase (IDH). Ivosidenib is an oral reversible inhibitor of the abnormal form of IDH1 enzyme. The use of ivosidenib in patients with CCA and the IDH1 gene mutation after failure of previous therapy was evaluated in a phase III ClarIDHy study. The results of the trial confirmed its beneficial effect in terms of both PFS and overall survival (OS). [ABSTRACT FROM AUTHOR]

Abstract Background Mutations in isocitrate dehydrogenase 1 and 2 (IDH1 and IDH2), are present in most gliomas. IDH1 mutation is an important prognostic marker in glioma. However, its regulatory mechanism in glioma remains incompletely understood. Results miR-182-5p expression was increased within IDH1-mutant glioma specimens according to TCGA, CGGA, and online dataset GSE119740, as well as collected clinical samples. (R)-2-hydroxyglutarate ((R)-2HG) treatment up-regulated the expression of miR-182-5p, enhanced glioma cell proliferation, and suppressed apoptosis; miR-182-5p inhibition partially eliminated the oncogenic effects of R-2HG upon glioma cells. By direct binding to Cyclin Dependent Kinase Inhibitor 2 C (CDKN2C) 3’UTR, miR-182-5p inhibited CDKN2C expression. Regarding cellular functions, CDKN2C knockdown promoted R-2HG-treated glioma cell viability, suppressed apoptosis, and relieved cell cycle arrest. Furthermore, CDKN2C knockdown partially attenuated the effects of miR-182-5p inhibition on cell phenotypes. Moreover, CDKN2C knockdown exerted opposite effects on cell cycle check point and apoptosis markers to those of miR-182-5p inhibition; also, CDKN2C knockdown partially attenuated the functions of miR-182-5p inhibition in cell cycle check point and apoptosis markers. The engineered CS-NPs (antagomir-182-5p) effectively encapsulated and delivered antagomir-182-5p, enhancing anti-tumor efficacy in vivo, indicating the therapeutic potential of CS-NPs(antagomir-182-5p) in targeting the miR-182-5p/CDKN2C axis against R-2HG-driven oncogenesis in mice models. Conclusions These insights highlight the potential of CS-NPs(antagomir-182-5p) to target the miR-182-5p/CDKN2C axis, offering a promising therapeutic avenue against R-2HG’s oncogenic influence to glioma.

Background: Mutations in isocitrate dehydrogenase 1 and 2 (IDH1 and IDH2), are present in most gliomas. IDH1 mutation is an important prognostic marker in glioma. However, its regulatory mechanism in glioma remains incompletely understood. Results: miR-182-5p expression was increased within IDH1-mutant glioma specimens according to TCGA, CGGA, and online dataset GSE119740, as well as collected clinical samples. (R)-2-hydroxyglutarate ((R)-2HG) treatment up-regulated the expression of miR-182-5p, enhanced glioma cell proliferation, and suppressed apoptosis; miR-182-5p inhibition partially eliminated the oncogenic effects of R-2HG upon glioma cells. By direct binding to Cyclin Dependent Kinase Inhibitor 2 C (CDKN2C) 3'UTR, miR-182-5p inhibited CDKN2C expression. Regarding cellular functions, CDKN2C knockdown promoted R-2HG-treated glioma cell viability, suppressed apoptosis, and relieved cell cycle arrest. Furthermore, CDKN2C knockdown partially attenuated the effects of miR-182-5p inhibition on cell phenotypes. Moreover, CDKN2C knockdown exerted opposite effects on cell cycle check point and apoptosis markers to those of miR-182-5p inhibition; also, CDKN2C knockdown partially attenuated the functions of miR-182-5p inhibition in cell cycle check point and apoptosis markers. The engineered CS-NPs (antagomir-182-5p) effectively encapsulated and delivered antagomir-182-5p, enhancing anti-tumor efficacy in vivo, indicating the therapeutic potential of CS-NPs(antagomir-182-5p) in targeting the miR-182-5p/CDKN2C axis against R-2HG-driven oncogenesis in mice models. Conclusions: These insights highlight the potential of CS-NPs(antagomir-182-5p) to target the miR-182-5p/CDKN2C axis, offering a promising therapeutic avenue against R-2HG's oncogenic influence to glioma. [ABSTRACT FROM AUTHOR]

Background: Molecular profiles can predict which patients will respond to current standard treatment and new targeted therapy regimens. Using data from a highly diverse population of approximately three million in Southeast London and Kent, this study aims to evaluate the prevalence of IDH1 mutation and MGMT promoter methylation in the gliomas diagnosed in adult patients and to explore correlations with patients’ demographic and clinicopathological characteristics. Methods: Anonymised data on 749 adult patients diagnosed with a glioma in 2015–2019 at King’s College Hospital were extracted. Univariable and multivariable logistic regressions were used to estimate odds ratios (ORs) for expressing IDH1 mutation and MGMT promoter methylation, based on each patient’s age, sex, ethnicity, histology, tumour location and extent of resection. The Kaplan–Meier method was used to estimate the overall survival functions. Results: A total of 19.5% of cases were IDH1-mutated. Being 39 years and younger (OR 5.48, 95% CI 3.17–9.47), from Asian/Asian British background (OR 3.68, 95% CI 1.05–12.97), having MGMT methylation (OR 15.92, 95% CI 7.30–34.75), an oligodendroglioma diagnosis (OR 7.45, 95% CI 2.90–19.13) and receiving a gross total/total microscopic resection (OR 1.95, 95% CI 1.24–3.08) were each univariately correlated with IDH1 mutation. MGMT methylation association persisted on adjustment (OR 14.13, 95% CI 3.88–51.43). MGMT promoter methylation was seen in 54.3% of gliomas. In the univariate adjusted ORs, being younger than 39 years (OR 2.56, 95% CI 1.48–4.43), female (OR 1.52, 95% CI 1.11–2.08), having IDH1 mutation (OR 15.92, 95% CI 7.30–34.75) and an oligodendroglioma diagnosis (OR 6.20, 95% CI 1.33–28.88) were associated with MGMT methylation. Being female (OR 1.75, 95% CI 1.22–2.51) and having an IDH1 mutation (OR 15.54, 95% CI 4.73–51.05) persisted after adjustment for age, sex, ethnicity, histology, tumour location and extent of resection. IDH1 mutant and MGMT methylated gliomas were associated with frontal lobe location. Survival analysis showed that patients with both IDH1 mutation and MGMT methylation had significantly better survival than those with either molecular marker alone. Over a 3-year period, women with unmethylated MGMT promoters generally had better survival than men with unmethylated MGMT. Conclusion: This study showed that the molecular markers of IDH1 mutation and MGMT promoter methylation were associated with age, sex, Asian/Asian British ethnic group, tumour histology, anatomical location and extent of resection. This study has demonstrated the importance of assessing glioma molecular markers in the clinical setting and the need to stratify patients according to their clinicopathological characteristics.

Glioblastoma multiforme (GBM) remains one of the most challenging solid cancers to treat due to its highly aggressive and drug-resistant nature. Flavopiridol is synthetic flavone that was recently approved by the FDA for the treatment of acute myeloid leukemia. Flavopiridol exhibits antiproliferative activity in several solid cancer cells and currently evaluated in clinical trials in several solid and hematological cancers. In this study, we investigated the molecular mechanisms underlying antiproliferative effects of flavopiridol in GBM cell lines with wild-type and mutant encoding isocitrate dehydrogenase 1 (IDH1). We found that flavopiridol inhibits proliferation, colony formation, and migration and induces apoptosis in IDH1 wild-type and IDH-mutant cells through inhibition of FOXM1 oncogenic signaling. Furthermore, flavopiridol treatment also inhibits of NF-KB, mediators unfolded protein response (UPR), including, GRP78, PERK and IRE1α, and DNA repair enzyme PARP, which have been shown to be potential therapeutic targets by downregulating FOXM1 in GBM cells. Our findings suggest for the first time that flavopiridol suppresses proliferation, survival, and migration and induces apoptosis in IDH1 wild-type and IDH1-mutant GBM cells by targeting FOXM1 oncogenic signaling which also regulates NF-KB, PARP, and UPR response in GBM cells. Flavopiridol may be a potential novel therapeutic strategy in the treatment of patients IDH1 wild-type and IDH1-mutant GBM. [ABSTRACT FROM AUTHOR]

Traditional treatment strategies for acute myeloid leukemia (AML) have primarily relied on standard chemotherapy regimens for four decades. Indeed, the landscape of AML therapy has evolved substantially in recent years, mainly due to the introduction of hypomethylating agents and small molecules. Bcl2 inhibitor venetoclax, Fms-like tyrosine kinase 3 (FLT3) inhibitors such as midostaurin and gilteritinib, and isocitrate dehydrogenases 1 and 2 (IDH1 and IDH2) inhibitors ivosidenib and enasidenib, as well as hedgehog (HH) pathway inhibitor glasdegib represented a significant step forward in AML therapeutic armamentarium. Smoothened (SMO) inhibitor in combination with low-dose cytarabine marks a recent milestone. Ivosidenib, the first-in-class, selective, allosteric IDH1R132 inhibitor, showed the capability to induce in vitro differentiation of primary mIDH1 AML blasts. Clinical data highlighted its exceptional safety profile, as a standalone therapy and in combination strategy. Additionally, comprehensive studies consistently demonstrated its effectiveness, both in monotherapy and in association with chemotherapy. The identified ivosidenib's strengths, including its remarkable safety record and ability to yield positive therapeutic outcomes, position it as an ideal partner for both classic chemotherapy and biological treatments, i.e. hypometilant agents and/or venetoclax. Further studies are warranted to explore strategies for overcoming the occurrence of ivosidenib resistance. [ABSTRACT FROM AUTHOR]

High grade gliomas are associated with cognitive problems. The aim of the study was to investigate cognitive functioning in a cohort of patients with high grade glioma, according to isocitrate dehydrogenase (IDH) and methyl guanine methyl transferase (MGMT) status and other clinical characteristics.

Simple Summary: Biliary tract cancers (BTCs) are rare tumours associated with poor prognosis. In advanced-stage disease, two treatment lines are approved: gemcitabine-cisplatin in combination with checkpoint inhibitors, and 5-FU-oxaliplatin, with a median overall survival of approximately one year. About 40% of BTC bear a targetable molecular alteration, the most frequent being FGFR2 fusions and IDH1 mutations in about 15% of intrahepatic cholangiocarcinomas. In this review, we will describe the different molecular targetable alterations in BTC (including FGFR2 and NTRK fusions, IDH1 mutation, BRAFV600E mutation, HER2 amplification, BRCA1/2 mutation and KRASG12C mutation), the targeted therapies that these patients can receive and the expected benefit. Biliary tract cancers (BTCs) are rare tumours, most often diagnosed at an unresectable stage, associated with poor prognosis, with a 5-year survival rate not exceeding 10%. Only first- and second-line treatments are well codified with the combination of cisplatin-gemcitabine chemotherapy and immunotherapy followed by 5-FU and oxaliplatin chemotherapy, respectively. Many studies have shown that BTC, and more particularly intrahepatic cholangiocarcinoma (iCCA), have a high rate of targetable somatic alteration. To date, the FDA has approved several drugs. Ivosidenib targeting IDH1 mutations, as well as futibatinib and pemigatinib targeting FGFR2 fusions, are approved for pre-treated advanced CCA. The combination of dabrafenib and trametinib are approved for BRAFV600E mutated advanced tumours, NTRK inhibitors entrectinib and larotrectinib for tumours bearing NTRK fusion and prembrolizumab for MSI-H advanced tumours, involving a small percentage of BTC in these three settings. Several other potentially targetable alterations are found in BTC, such as HER2 mutations or amplifications or KRASG12C mutations and mutations in genes involved in DNA repair mechanisms. This review aims to clarify the specific diagnostic modalities for gene alterations and to summarize the results of the main trials and developments underway for the management of advanced BTC with targetable alterations. [ABSTRACT FROM AUTHOR]

Mutations in isocitrate dehydrogenase 1 (IDH1) induce extensive transcriptional alterations to promote glioma development. However, IDH1 mutation contributes the better clinical outcomes of glioma. Further understanding the transcriptional and DNA methylation changes mediated by IDH1 mutation will provide new therapeutic targets for glioma. Public glioma cohorts were collected and processed using R software. The transcriptional changes mediated by IDH1 mutation were determined and presented using heatmap. The differentially expressed genes in IDH1 mutant glioma were overlapped using TBtools. The prognostic effects of IDH1 regulated genes were determined by Kaplan-Meier survival analysis. Retinoic acid receptor responder 2 (RARRES2) was upregulated in IDH1 wild type lower-grade glioma (LGG) patients, and higher expression levels of RARRES2 were associated with worse clinical outcomes of LGG. Moreover, IDH1 wild type LGG patients with higher expression levels of RARRES2 had even worse overall survival. Compared with LGG, RARRES2 was upregulated in grade IV glioma (glioblastoma multiforme, GBM). Also, RARRES2 represented an unfavorable prognostic factor of glioma. In GBM, RARRES2 was also associated with IDH1 mutation. In both LGG and GBM, IDH1 mutation induced extensive DNA hypermethylation, and more than half genes that were downregulated in IDH1 mutant glioma were contributed by DNA hypermethylation. RARRES2 was also hypermethylated in IDH1 mutant LGG or GBM patients. Furthermore, RARRES2 hypomethylation was an unfavorable prognostic factor in patients with LGG. RARRES2 was downregulated by IDH1 mutation and served as an unfavorable prognostic factor in glioma. [ABSTRACT FROM AUTHOR]

Background: The results of the phase III ClarIDHy trial led to the FDA approval of ivosidenib as a therapeutic option for patients with locally advanced or metastatic cholangiocarcinoma (CCA) harboring isocitrate dehydrogenase 1 (IDH1) mutations. We recently published the first data on the use of ivosidenib in a real-world setting. Objective: Here we report the updated survival results of 11 patients with locally advanced or metastatic IDH1-mutated CCA who received ivosidenib in clinical practice. Patients and methods: Patients treated with ivosidenib as second- and third-line treatments for advanced CCA have been collected with the aim to evaluate the survival outcomes. A molecular study has been performed by next generation sequencing essay. Results: Overall, 11 patients were included. After a median follow-up of 13.7 months, median progression-free survival from the start of treatment with ivosidenib was 4.4 months (95% CI: 2.0–5.8), whereas median overall survival was 15 months (95% CI: 6.6–15.0) regardless of treatment line. Disease control rate was 63%, with two patients achieving a partial response (18%). Eighteen percent of patients experienced at least one treatment-related adverse events (AEs), but no grade ⩾3 was reported. The most frequently observed grade 2 AEs were prolonged QT interval and hypomagnesemia. A molecular profiling was performed on 8 out of 11 patients, highlighting TP53, BAP1, CDKN2A, and CDKN2B as the most common co-altered genes in these patients. Conclusion: The present update confirms the results of our previous real-world experience on the use of ivosidenib in IDH1-mutated CCA. Real-world evidence on larger numbers of patients is needed to confirm our findings. [ABSTRACT FROM AUTHOR]

Purpose: To investigate the associations of MRI radiological features and prognosis of glioma with the status of isocitrate dehydrogenase 1 (IDH1). Material and Methods: A total of 116 patients with gliomas were retrospectively recruited from January 2013 to December 2015. All patients were undergone routine MRI (T1WI, T2WI, T2-FLAIR) scanning and contrast-enhanced MRI T1WI before surgery. The following imaging features were included: tumor location, diameter, the pattern of growth, boundary, the degree of enhancement, mass effect, edema, cross the middle line, under the ependyma. χ2 and Fisher's exact probability tests were used to determine the significance of associations between MRI features and IDH1 mutation of glioma. The survival distributions were estimated using Kaplan-Meier compared by Log-rank test. Univariate and multivariate analyses were performed using Cox regression. Results: Gliomas with IDH1 mutant were significantly more likely to exhibit homogeneous signal intensity (p = 0.009) on non-contrast MRI protocols and less contrast enhancement (p = 0.000) on contrast enhanced T1WI. IDH1 mutant type glioma was more inclined to cross the midline to invade contralateral hemisphere (p = 0.001). The overall survival between IDH1 mutated and wild type glioma were significantly different (p = 0.000), age ≤ 40 (p = 0.003), KPS scores > 80 before operation (p = 0.000) and low grade glioma (p = 0.000). Conclusions: Our results suggest IDH1 mutant in gliomas is more likely to exhibit homogeneous signal intensity, less contrast enhancement and more inclined to cross the midline. Patients with IDH1 mutated, age ≤ 40, KPS scores > 80 before operation and low-grade glioma may have a longer life and better prognosis.

Mutations in isocitrate dehydrogenase 1 (IDH1mut) are reported in 70-90% of low-grade gliomas and secondary glioblastomas. IDH1mut catalyzes the reduction of α-ketoglutarate (α-KG) to 2-hydroxyglutarate (2-HG), an oncometabolite which drives tumorigenesis. Inhibition of IDH1mut is therefore an emerging therapeutic approach, and inhibitors such as AG-120 and AG-881 have shown promising results in phase 1 and 2 clinical studies. However, detection of response to these therapies prior to changes in tumor growth can be challenging. The goal of this study was to identify non-invasive clinically translatable metabolic imaging biomarkers of IDH1mut inhibition that can serve to assess response. Methods: IDH1mut inhibition was confirmed using an enzyme assay and 1H- and 13C- magnetic resonance spectroscopy (MRS) were used to investigate the metabolic effects of AG-120 and AG-881 on two genetically engineered IDH1mut-expressing cell lines, NHAIDH1mut and U87IDH1mut. Results:1H-MRS indicated a significant decrease in steady-state 2-HG following treatment, as expected. This was accompanied by a significant 1H-MRS-detectable increase in glutamate. However, other metabolites previously linked to 2-HG were not altered. 13C-MRS also showed that the steady-state changes in glutamate were associated with a modulation in the flux of glutamine to both glutamate and 2-HG. Finally, hyperpolarized 13C-MRS was used to show that the flux of α-KG to both glutamate and 2-HG was modulated by treatment. Conclusion: In this study, we identified potential 1H- and 13C-MRS-detectable biomarkers of response to IDH1mut inhibition in gliomas. Although further studies are needed to evaluate the utility of these biomarkers in vivo, we expect that in addition to a 1H-MRS-detectable drop in 2-HG, a 1H-MRS-detectable increase in glutamate, as well as a hyperpolarized 13C-MRS-detectable change in [1-13C] α-KG flux, could serve as metabolic imaging biomarkers of response to treatment.

Gliomas are the most common primary malignant brain tumors in adults. The fifth edition of the WHO Classification of Tumors of the Central Nervous System, published in 2021, provided molecular and practical approaches to CNS tumor taxonomy. Currently, molecular features are essential for differentiating the histological subtypes of gliomas, and recent studies have emphasized the importance of isocitrate dehydrogenase (IDH) mutations in stratifying biologically distinct subgroups of gliomas. IDH plays a significant role in gliomagenesis, and the association of IDH status with prognosis is very clear. Recently, there has been much progress in conventional MR imaging (cMRI), advanced MR imaging (aMRI), and radiomics, which are widely used in the study of gliomas. These advances have resulted in an improved correlation between MR signs and IDH mutation status, which will complement the prediction of the IDH phenotype. Although imaging cannot currently substitute for genetic tests, imaging findings have shown promising signs of diagnosing glioma subtypes and evaluating the efficacy and prognosis of individualized molecular targeted therapy. This review focuses on the correlation between MRI and MRI-based radiomics and IDH gene-phenotype prediction, discussing the value and application of these techniques in the diagnosis and evaluation of the prognosis of gliomas.

The AFEF and ESMO 2022 symposia have outlined one of the three recent developments in the management of biliary tract cancers, along with the definition of standard chemotherapies and the entry of immune checkpoint inhibitors into the therapeutic arsenal, namely, the contribution of precision medicine. Biliary tract cancers, and particularly intrahepatic cholangiocarcinomas, are rich in targetable molecular alterations. This fact imposes a more marked attention to the quantity and quality of tumor samples and a multidisciplinary work with samplers, pathologists and molecular biologists in order to advance jointly and as soon as possible in the diagnosis and the molecular characterization of these cancers. Among the targets of interest, IDH1 mutations and FGFR2 fusions are the more frequent ones, for which inhibitors are already available. [ABSTRACT FROM AUTHOR]

Background High-grade glioma (HGG) patients present with variable impairment in neurocognitive function (NCF). Based on that, isocitrate dehydrogenase 1 (IDH1) wild-type HGGs are more aggressive than IDH1 mutant-type ones, we hypothesized that patients with IDH1 wild-type HGG would exhibit more severe NCF deficits than their IDH1 mutant counterparts. Methods NCF was assessed by Mini Mental Status Exam (MMSE), Trail Making Test (TMT), Digit Span (DS), and Controlled Word Association Test (COWAT) tests in 147 HGG patients preoperatively. Results Analyses between IDH1 groups revealed a significant difference on MMSE concentration component (p ≤.01), DS (p ≤.01), TMTB (p ≤.01), and COWAT (p ≤.01) scores, with the IDH1 wild group performing worse than the IDH1 mutant one. Age and tumor volume were inversely correlated with MMSE concentration component (r = −4.78, p <.01), and with MMSE concentration (r = −.401, p <.01), TMTB (r = −.328, p <.01), and COWAT phonemic scores (r = −.599, p <.01), respectively, but only for the IDH1 wild-type group. Analyses between age-matched subsamples of IDH1 groups revealed no age effect on NCF. Tumor grade showed nonsignificance on NCF (p >.05) between the 2 IDH1 mutation subgroups of grade IV tumor patients. On the contrary, grade III group showed a significant difference in TMTB (p <.01) and DS backwards (p <.01) between IDH1 subgroups, with the mutant one outperforming the IDH1 wild one. Conclusions Our findings indicate that IDH1 wild-type HGG patients present greater NCF impairment, in executive functions particularly, compared to IDH1 mutant ones, suggesting that tumor growth kinetics may play a more profound role than other tumor and demographic parameters in clinical NCF of HGG patients. [ABSTRACT FROM AUTHOR]

Laser interstitial thermal therapy (LITT) has become an increasingly utilized alternative to surgical resection for the treatment of glioma in patients. However, treatment outcomes in isocitrate dehydrogenase 1 and 2 (IDH1/2) mutant glioma, specifically, have not been reported. The objective of this study was to characterize a single institution’s cohort of IDH1/2 mutant grade 2/3 glioma patients treated with LITT. We collected data on patient presentation, radiographic features, tumor molecular profile, complications, and outcomes. We calculated progression-free survival (PFS) and tested factors for significant association with longer PFS. Overall, 22.7% of our cohort experienced progression at a median follow up of 1.8 years. The three- and five-year estimates of PFS were 72.5% and 54.4%, respectively. This is the first study to characterize outcomes in patients with IDH1/2 mutant glioma after LITT. Our results suggest that LITT is an effective treatment option for IDH1/2 mutant glioma.

BackgroundMagnetic resonance spectroscopy (MRS) studies have identified elevated levels of the phospholipid precursor phosphocholine (PC) and phosphoethanolamine (PE) as metabolic hallmarks of cancer. Unusually, however, PC and PE levels are reduced in mutant isocitrate dehydrogenase 1 (IDHmut) gliomas that produce the oncometabolite 2-hydroxyglutarate (2-HG) relative to wild-type IDH1 (IDHwt) gliomas. The goal of this study was to determine the molecular mechanism underlying this unusual metabolic reprogramming in IDHmut gliomas.MethodsSteady-state PC and PE were quantified using 31P-MRS. To quantify de novo PC and PE synthesis, we used 13C-MRS and measured flux to 13C-PC and 13C-PE in cells incubated with [1,2-13C]-choline and [1,2-13C]-ethanolamine. The activities of choline kinase (CK) and ethanolamine kinase (EK), the enzymes responsible for PC and PE synthesis, were quantified using 31P-MR-based assays. To interrogate the role of 2-HG, we examined IDHwt cells incubated with 2-HG and, conversely, IDHmut cells treated with the IDHmut inhibitor AGI-5198. To examine the role of hypoxia-inducible factor 1-α (HIF-1α), we silenced HIF-1α using RNA interference. To confirm our findings in vivo and in the clinic, we studied IDHwt and IDHmut orthotopic tumor xenografts and glioma patient biopsies.ResultsDe novo synthesis of PC and PE was reduced in IDHmut cells relative to IDHwt. Concomitantly, CK activity and EK activity were reduced in IDHmut cells. Pharmacological manipulation of 2-HG levels established that 2-HG was responsible for reduced CK activity, EK activity, PC and PE. 2-HG has previously been reported to stabilize levels of HIF-1α, a known regulator of CK activity. Silencing HIF-1α in IDHmut cells restored CK activity, EK activity, PC and PE to IDHwt levels. Our findings were recapitulated in IDHmut orthotopic tumor xenografts and, most importantly, in IDHmut patient biopsies, validating our findings in vivo and in the clinic.ConclusionsThis study identifies, to our knowledge for the first time, a direct role for 2-HG in the downregulation of CK and EK activity, and thereby, PC and PE synthesis in IDHmut gliomas. These results highlight the unusual reprogramming of phospholipid metabolism in IDHmut gliomas and have implications for the identification of MRS-detectable metabolic biomarkers associated with 2-HG status.

Cholangiocarcinoma is a deadly cancer comprising very heterogenous subtypes with a limited therapeutic arsenal in all comers. However, recent significant advances were made with immunotherapy in the first-line treatment of advanced cholangiocarcinoma, with the addition of durvalumab to cisplatin–gemcitabine chemotherapy showing a survival benefit. In the second line setting, only FOLFOX (5FU/folinic acid-oxaliplatin) is validated by a phase 3 trial, yet with a very modest benefit on survival; new options using 5FU with nanoliposomal-irinotecan may emerge in the next few years. The advent of molecular profiling in advanced cholangiocarcinoma in the last decade revealed frequent targetable alterations such as IDH1 mutations, FGFR2 fusions or rearrangements, HER2 amplification, BRAF V600E mutation and others. This strategy opened the way to personalised medicine for patients which are still fit after first-line treatment and the use of targeted inhibitors in first line constitutes a huge challenge with many ongoing trials to improve patients' care. This review exposes the recent clinical trial findings in non-molecularly selected advanced cholangiocarcinoma, offers a focus on how systematic molecular screening should be structured to allow patients to access to personalised medicine, and details which are the therapeutic options accessible in case of actionable alteration. • CISGEM-durvalumab is a new standard in advanced cholangiocarcinoma in first line. • Actionable alterations are present in up to 40–50% of patients, especially in iCCA. • Molecular profiling should be proposed to every ECOG 0–1 patients from the diagnosis. • Molecular profiling should integrate DNA and RNA next-generation sequencing techniques. [ABSTRACT FROM AUTHOR]

Mutations in IDH1 (isocitrate dehydrogenases) such as R132H/Q/C, are frequently found in intrahepatic cholangiocarcinoma (IHCC). Mutant IDH1 proteins obtain an abnormal activity converting α-ketoglutarate (αKG) to 2-hydroxyglutarate (2-HG), inhibiting the activity of multiple αKG-dependent dioxygenases, leading to metabolism disorder. Here, we depict a molecular network leading by mutant IDH1, that regulates hepatic lipid embolism using mouse model (KI) with IDH1 R132Q specifically knocked in liver. KI mice appear small and have notably reduced hepatic TG and FFA levels. Technically, mutant IDH1-mediated 2-HG can stabilize PTEN mRNA level probably depending on miR-32, activate Akt-SEBP1c signaling, leading to lipogenesis defect. Our study identifies a new role of oncometabolite 2-HG in inhibiting hepatic lipid metabolism. • IDH1 R132Q knock-in mice show hepatic lipogenesis defect. • Mutant IDH1 curbs hepatic lipogenesis via PTEN-dependent pathway. • 2-HG elevates PTEN mRNA level probably relying on miR-32. [ABSTRACT FROM AUTHOR]

Background: Lipoblastoma-like tumors (LLTs) are uncommon lipogenic neoplasms that predominantly occur in the vulva of female individuals. This study presents a novel case of LLT located on the tongue with an IDH1 mutation. Both the site of occurrence and molecular alterations are reported for the first time., Case Presentation: A 65-year-old female patient presented to the hospital 1 month ago with an incidental finding of a multinodular mass at the right lingual margin. We performed an incision along the outer edge of the mass and completely excised it 0.5 cm beyond its periphery. The final pathological diagnosis after routine examination confirmed a lipoblastoma-like tumor. Furthermore, Next-generation sequencing revealed the presence of mutations in IDH1., Conclusions: This study presents the first documented case of LLT, thereby expanding its anatomical site of tongue and confirming the presence of a significant IDH1 mutation, thus enhancing our understanding of the molecular alterations in LLT., (© 2025 Wiley Periodicals LLC.)

Objective In order to establish a connection between programmed death-ligand 1 (PD-L1) expression and glioma grades as well as the presence of IDH1 mutations, it is necessary to investigate the expression of PD-L1 and isocitrate dehydrogenase-1 (IDH1) in glioma patients and assess their potential as predictive markers for glioblastoma multiforme (GBM) immunotherapy. We analyzed the frequency of PD-L1 expression in glioma samples. Methodology In this two-year retrospective study, 45 glioma cases of varying grades (grades 2 to 4) were examined at a tertiary care hospital. Tumor samples that were formalin-fixed, paraffin-embedded (FFPE) were obtained from the pathology archives of the hospital. According to the WHO Classification of Central Nervous System Tumors, 5th edition, tumor grading and histopathological subtyping were carried out. PD-L1 antibody (clone 28-8) and IDH1 (R132H, clone QM002, Quartett Immunodiagnostika, 1:100 dilution) markers were used for immunohistochemistry (IHC). The sections underwent deparaffinization, rehydration, and antigen retrieval using Leica bond III staining platform. Based on the tumor proportion score (TPS), which is the proportion of viable tumor cells with membranous staining, PD-L1 expression was assessed. The literature's standardized cut-off values were used to determine positive expression. Staining intensity and tumor cell location were used to determine the status of IDH1 mutations. Age, sex, and tumor location were among the clinical and demographic information gathered about the patient. The association between PD-L1 expression, glioma grades, and IDH1 (R132H) mutation status was assessed statistically using SPSS software and a Chi-square test. The threshold for statistical significance was p < 0.05. For every IHC run, positive and negative controls were used as part of the quality control procedures. To reduce bias and guarantee consistency, two pathologists and post graduate residents independently reviewed the results. Results PD-L1 expression was found in 27 out of 36 (75%) grade 4 glioblastoma multiforme cases and six out of nine (66.7%) grade 2 gliomas. Overall, 33/45 (73.3%) of the gliomas had PD-L1 expression. However, PD-L1 expression and glioma grade did not correlate in a statistically significant way. IDH1 (R132H) expression and PD-L1 were found to be inversely correlated (p < 0.05). Conclusion The findings suggest that PD-L1 may be a promising therapeutic target, even in the absence of significant grade-specific trends by demonstrating PD-L1 presence in the majority of glioma cases, highlighting its potential as a therapeutic target in GBM immunotherapy. The results provide insight into the immune landscape of gliomas and pave the way for future research into effective combination therapies for GBM, despite the lack of a significant correlation between glioma grade and PD-L1 expression., Competing Interests: Human subjects: All authors have confirmed that this study did not involve human participants or tissue. Animal subjects: All authors have confirmed that this study did not involve animal subjects or tissue. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2025, Mushir et al.)

Abstract Maffucci syndrome (MS, OMIM 166000) is an extremely unusual, nonhereditary, multisystemic disorder that is characterized with multiple enchondromas and vascular lesions, most of which are spindle cell hemangiomas. Complications of MS, such as bone deformities and dysfunction caused by enchondromas, usually increase during childhood and adolescence. Malignant transformation of enchondromas and other malignancies are the most severe complications. MS is caused by somatic mosaic IDH1/2 mutations, 65% of which are the IDH1 p.Arg132Cys variant. Due to its rarity, there is no international consensus for the most appropriate treatment option of MS. Here, we report a case of a female patient presenting with multiple enchondromas and spindle cell hemangiomas (SCHs) on bilateral hand and feet diagnosed as MS. A detailed clinical, pathological and genetic diagnosis of MS was rendered. Integrative Genomics Viewer (IGV) visualization of next-generation sequencing (NGS) data revealed the consistent detection of the low-frequency somatic IDH1 p.Arg132Cys mutation between SCH tissue and cystic blood-derived cfDNA. This is the first successful molecular diagnosis of MS complicated with SCH utilizing minimally invasive cfDNA techniques. We suggest that cfDNA sequencing could potentially be used as an alternative, reliable and sensitive method to identify molecular information for genetic diagnosis and for future targeted therapies of MS.

Objective: To investigate whether extending adjuvant temozolomide (TMZ) improved the prognosis of newly diagnosed glioblastoma (GBM) patients with different mutation statuses of O6-methylguanine DNA methyltransferase (MGMT), isocitrate dehydrogenase 1 (IDH1), p53 and different expression level of Ki67. Methods: This study was a retrospective cohort study that postoperative patients with newly diagnosed GBM who did not progress after receiving radiotherapy with concomitant and 6 cycles of adjuvant TMZ were enrolled in control group, and those received more than 6 cycles of adjuvant TMZ were incorporated in extended group. Patients were stratified by MGMT expression, IDH1 mutation, p53 mutation and expression level of Ki67. The primary endpoints were overall survival (OS) and progression-free survival (PFS). Result: A total of 93 postoperative patients with newly diagnosed GBM were included in this study, 40 and 53 cases were included in control group and extended group, respectively. On the whole, extended adjuvant TMZ chemotherapy significantly prolonged OS and PFS of patients with newly diagnosed GBM [median OS (mOS): 29.00 months vs. 16.70 months, P < 0.001; median PFS (mPFS): 13.80 months vs. 9.60 months, P = 0.002]. The results of subgroup analysis showed that patients with methylated MGMT in extended group had significantly longer OS and PFS than those in control group; patients with IDH1 mutation benefited more from extended adjuvant TMZ chemotherapy than those with wild-type IDH1; there was no significant difference in the effect of extended TMZ chemotherapy on OS between GBM patients with wild-type p53 and those with mutant p53; compared with GBM patients with lower expression of Ki67, extended adjuvant TMZ treatment dramatically improved the OS and PFS of those with higher expression of Ki67. Conclusion: The therapeutic schedule of extended adjuvant TMZ significantly prolonged OS and PFS of patients with newly diagnosed GBM regardless of p53 mutation status, and patients with different MGMT methylation, IDH1 mutation and Ki67 expression level benefited differently from extended adjuvant TMZ chemotherapy. [ABSTRACT FROM AUTHOR]

IDH1 -mutated intrahepatic cholangiocarcinomas (IDH1 m iCCAs) could be treated with anti-IDH1 drugs, although the high heterogeneity in this class of tumours could limit treatment efficacy. We selected 125 IDH1 m iCCAs that were treated as resectable, locally advanced, or metastatic and were screened by the NGS-based FoundationOne gene panel. We conducted a mutation-based clustering of tumours and survival analysis. Three main clusters were identified. The most altered pathways in cluster 1 were cell cycle and apoptosis, RTK/RAS, PI3K, and chromatin modification. Of note, CDKN2A/2B were mutated in 41/44 patients of this cluster. In cluster 2, the most affected pathways were as follows: Chromatin modification, DNA damage control, PI3K, and RTK/RAS. In this cluster, the most frequently mutated genes were ARID1A and PBRM1. The most altered pathways in cluster 3 were as follows: Cell cycle and apoptosis, DNA damage control, TP53, and chromatin modification. Importantly, TP53 was mutated only in cluster 3 patients. In the cohort of patients treated with surgery, cluster 2 showed statistically significant better disease-free survival (DFS) and overall survival (OS) compared with patients in cluster 3 and cluster 1 (p = 0.0014 and p = 0.0003, respectively). In the advanced setting, cluster 2 experienced a statistically significant better PFS (p = 0.0012), a tendency toward a better OS from first-line treatment, and a better OS from first-line progression compared with patients in cluster 1 and cluster 3 (p = 0.0017). We proposed an easy-to-use algorithm able to stratify patients in the three clusters on the basis of the genomic profile. We highlighted three different mutation-based clusters with prognostic significance in a cohort of IDH1 m iCCAs. • IDH1-mutated cholangiocarcinomas are a heterogeneous group of neoplasia. • We performed a mutation-based clustering on a sample of 125 IDH1-mutated iCCAs. • Three main clusters have been highlighted, and an easy-to-use algorithm has been proposed. • From the survival analysis, the three clusters resulted to have a prognostic role. [ABSTRACT FROM AUTHOR]

ABCB1 belongs to a superfamily of membrane transporters that use ATP hydrolysis to efflux various endogenous compounds and drugs outside the cell. Cancer cells upregulate ABCB1 expression as an adaptive response to evade chemotherapy-mediated cell death. On the other hand, several reports highlight the role of the epigenetic regulation of ABCB1 expression. In fact, the promoter methylation of ABCB1 was found to be methylated in several tumor types, including gliomas, but its role as a biomarker is not fully established yet. Thus, the aim of this study was to analyze the methylation of the ABCB1 promoter in tumor tissues from 50 glioma patients to verify its incidence and to semi-quantitively detect ABCB1 methylation levels in order to establish its utility as a potential biomarker. The results of this study show a high interindividual variability in the ABCB1 methylation level of the samples derived from gliomas of different grades. Additionally, a positive correlation between ABCB1 methylation, the WHO tumor grade, and an IDH1 wild-type status has been observed. Thus, ABCB1 methylation can be regarded as a potential diagnostic or prognostic biomarker for glioma patients, indicating more aggressive tumors. [ABSTRACT FROM AUTHOR]

Gliomas are the most common primary malignant brain tumors in adults. The fifth edition of the WHO Classification of Tumors of the Central Nervous System, published in 2021, provided molecular and practical approaches to CNS tumor taxonomy. Currently, molecular features are essential for differentiating the histological subtypes of gliomas, and recent studies have emphasized the importance of isocitrate dehydrogenase (IDH) mutations in stratifying biologically distinct subgroups of gliomas. IDH plays a significant role in gliomagenesis, and the association of IDH status with prognosis is very clear. Recently, there has been much progress in conventional MR imaging (cMRI), advanced MR imaging (aMRI), and radiomics, which are widely used in the study of gliomas. These advances have resulted in an improved correlation between MR signs and IDH mutation status, which will complement the prediction of the IDH phenotype. Although imaging cannot currently substitute for genetic tests, imaging findings have shown promising signs of diagnosing glioma subtypes and evaluating the efficacy and prognosis of individualized molecular targeted therapy. This review focuses on the correlation between MRI and MRI-based radiomics and IDH gene-phenotype prediction, discussing the value and application of these techniques in the diagnosis and evaluation of the prognosis of gliomas. [ABSTRACT FROM AUTHOR]

Objectives:(a) The objective of the study was to assess the control of seizure in glioblastoma patients receiving anti-epileptic drugs and chemotherapies after total resection and its association with O-methylguanine-DNA methyltransferase (MGMT) promoter methylation and the isocitrate dehydrogenase 1 (IDH1) mutation; (b) to determine which anti-epileptic drug exerts the best effective control on glioblastoma-associated epilepsy; and (c) to identify the relationship between seizure control and anti-epileptic drugs with recurrence interval.Methods:This was a retrospective cohort study of patients with postoperative glioblastoma-associated epilepsy. The correlation between IDH1 mutation and MGMT methylation with anti-epileptic drugs, chemotherapy type, seizure control, and recurrence interval was analyzed.Results:The study included 53 patients with glioblastoma-associated epilepsy. IDH1 mutation was present in 20 patients, and MGMT methylation was present in 13 patients. 37 cases received chemoradiotherapy while 16 cases received only radiotherapy. Levetiracetam was the most prescribed anti-epileptic drug (n=36, 60%), and 36 and 16 patients had controlled and uncontrolled seizures, respectively. IDH1 mutation and unmethylated MGMT were significantly present in cases with controlled epilepsy (p

Isocitrate dehydrogenase (IDH1) is frequently mutated in glioma tissues, and this mutation mediates specific tumor-promoting mechanisms in glioma cells. We aimed to identify specific immune biomarkers for IDH1-mutation (IDH1mt) glioma. The Cancer Genome Atlas (TCGA) and Chinese Glioma Genome Atlas (CGGA) were used to obtain RNA sequencing data and clinical characteristics of glioma tissues, while the stromal and immune scores of TCGA glioma tissues were determined using the ESTIMATE algorithm. Differentially expressed genes (DEGs), the protein–protein interaction(PPI) network, and least absolute shrinkage and selection operator (LASSO) and Cox regression analyses were used to select hub genes associated with stroma and immune scores and the prognoses of patients and to construct the risk model. The practicability and specificity of the risk model in both IDH1mt and IDH1-wildtype (wtIDH1) gliomas in TCGA and CGGA were evaluated. Molecular mechanisms, immunological characteristics and benefits of immune checkpoint blockade therapy in glioma tissues with IDH1mt were analyzed using GSEA, immunohistochemical staining, CIBERSORT, and T-cell dysfunction and exclusion (TIDE) analysis. The overall survival rate for IDH1mt-glioma patients with high stroma/immune scores was lower than that for those with low stroma/immune scores. A total of 222 DEGs were identified in IDH1mt glioma tissues with high stroma/immune scores. Among them, 72 genes had interactions in the PPI network, while three genes, HLA-DQA2, HOXA3, and SAA2, were selected as hub genes and used to construct risk models classifying patients into high- and low-risk score groups, followed by LASSO and Cox regression analyses. This risk model showed prognostic value in IDH1mt glioma in both TCGA and CCGA; nevertheless, the model was not suitable for wtIDH1 glioma. The risk model may act as an independent prognostic factor for IDH1mt glioma. IDH1mt glioma tissues from patients with high-risk scores showed more infiltration of M1 and CD8 T cells than those from patients with low-risk scores. Moreover, TIDE analysis showed that immune checkpoint blockade(ICB) therapy was highly beneficial for IDH1mt patients with high-risk scores. The risk model showed specific potential to predict the prognosis of IDH1mt-glioma patients, as well as guide ICB, contributing to the diagnosis and therapy of IDH1mt-glioma patients.

Maher Kurdi,1 Nadeem Shafique Butt,2 Saleh Baeesa,3 Abudukadeer Kuerban,4 Yazid Maghrabi,5 Anas Bardeesi,5 Rothaina Saeedi,3 Badrah S Alghamdi,6 Ahmed I Lary,7 Fawaz Mohamed,1 Sahar Hakamy8 1Department of Pathology, Faculty of Medicine in Rabigh, King Abdulaziz University, Jeddah, Kingdom of Saudi Arabia; 2Department of Family and Community Medicine, Faculty of Medicine in Rabigh, King Abdulaziz University, Jeddah, Kingdom of Saudi Arabia; 3Division of Neurosurgery, Faculty of Medicine, King Abdulaziz University, Jeddah, Kingdom of Saudi Arabia; 4Department of Biochemistry, Faculty of Science, King Abdulaziz University, Jeddah, Kingdom of Saudi Arabia; 5Department of Neuroscience, King Faisal Specialist Hospital and Research Center, Jeddah, Kingdom of Saudi Arabia; 6Department of Physiology, Faculty of Medicine, King Abdulaziz University, Jeddah, Kingdom of Saudi Arabia; 7Section of Neurosurgery, Department of Surgery, King Abdulaziz Medical City, Jeddah, Kingdom of Saudi Arabia; 8Center of Excellence in Genomic Medicine Research, King Abdulaziz University, Jeddah, Kingdom of Saudi ArabiaCorrespondence: Maher KurdiDepartment of Pathology, Faculty of Medicine in Rabigh, King Abdulaziz University, Jeddah, Kingdom of Saudi ArabiaTel +966 556655467Email Ahkurdi@kau.edu.saPurpose: Wilms tumor 1 (WT1) gene has recently shown a role in gliomagenesis, making it a potential immunotherapy target in glioblastomas. We aimed to investigate the most sensitive method to detect WT1 expression in glioblastoma and explore the relationship between WT1 expression, IDH1 mutation and recurrence interval.Patients and Methods: Clinical data were collected from 44 patients with glioblastomas, treated with adjuvant therapies. WT1 expression was assessed in all cases using immunohistochemistry (IHC), while its gene expression was assessed in 13 clustered samples using polymerase chain reaction (qPCR). IDH1 mutation was assessed using IHC. The sensitivity between IHC and RT-qPCR was examined. Kaplan–Meier curves were used to compare the recurrence-free interval (RFI) between IDH1 and WT1 expression groups.Results: IDH1wildtype was found in 26 cases (59.1%) and the remaining 18 cases (40.9%) were IDH1mutant. Through IHC, WT1 was overexpressed in 32 cases (72.7%), partially expressed in 9 cases (20.5%) and not expressed in only 3 cases. For the 13 cases tested by qPCR, 6 cases showed WT1 upregulation and 7 cases showed WT1 downregulation. There was no significant difference in WT1 expression among cases with different RNA concentrations regardless the testing method (p-value > 0.05). However, the difference between IHC and qPCR was significant. IDH1mutant cases with WT1 overexpression showed significant difference in RFI (p-value =0.048).Conclusion: Parallel testing for WT1 expression using IHC and qPCR is not reliable. However, IHC provides more accurate results. Moreover, IDH1mutant glioblastomas with WT1 overexpression are associated with late RFI particularly if temozolomide with additional chemotherapies are used.Keywords: glioblastoma, IDH1 mutation, WT1 expression, chemotherapies, PCR sensitivity

Gliomas are tumors that originate from glial cells and the most common neoplasms in the central nervous system. The World Health Organization (WHO) has classified glioma into four grades, I to IV, with multidisciplinary therapies required for the management of high-grade gliomas (grades III and IV). Molecular pathology has become increasingly critical in guiding the treatment and predicting the prognosis of patients with gliomas. A 35-year-old man diagnosed with WHO grade III diffuse astrocytic glioma initially underwent surgical resection, followed by immunohistochemical and molecular diagnosis. The patient was administered adjuvant radiotherapy and chemotherapy based on the molecular characteristics of the tumor. Long term follow-up showed a relatively satisfactory therapeutic response. Molecular classification may help guide decisions on the comprehensive treatment of patients with WHO grade III diffuse astrocytic glioma. This study was approved by the Ethics Committee of Zhongda Hospital of Southeast University, China (approval No. 20211015001, approval date: October 15, 2021).

Background: Acute myeloid leukemia (AML) is heterogeneous myeloid disorder with multifactorial pathogenic mechanisms and a broad range of prognosis. AML is characterized by clonal proliferation of poorly differentiated cells of the myeloid lineage. Objective: This study aimed to detect Isocitrate Dehydrogenase 1 (IDH1) mutation in adult Egyptian AML patients and to find correlation between the mutation and prognosis & survival in those patients after intensive chemotherapy. Patients and Methods: Our study included 98 subjects with newly diagnosed AML. They all presented to Ain Shams University Hospital (Hematology Unit). All Patients included in the study were subjected to: History taking and clinical examination, laboratory investigations including routine investigations and cytogenetic studies for detection of IDH 1 mutation. All patients were followed up for their response to treatment for a period of 6 months. Results: IDH1 mutation occurs in a considerable percentage of Egyptian AML patients that shows independent bad prognostic impact on the clinical outcome. Conclusion: IDH1 mutation occurred in a considerable percentage of Egyptian AML patients that showed independent bad prognostic impact on the clinical outcome. [ABSTRACT FROM AUTHOR]

Abstract Background Glioblastoma is the most frequent and high-grade adult malignant central nervous system tumor. The prognosis is still poor despite the use of combined therapy involving maximal surgical resection, radiotherapy, and chemotherapy. Metabolic reprogramming currently is recognized as one of the hallmarks of cancer. Glutamine metabolism through glutaminolysis has been associated with tumor cell maintenance and survival, and with antioxidative stress through glutathione (GSH) synthesis. Methods In the present study, we analyzed the glutaminolysis-related gene expression levels in our cohort of 153 astrocytomas of different malignant grades and 22 non-neoplastic brain samples through qRT-PCR. Additionally, we investigated the protein expression profile of the key regulator of glutaminolysis (GLS), glutamate dehydrogenase (GLUD1), and glutamate pyruvate transaminase (GPT2) in these samples. We also investigated the glutathione synthase (GS) protein profile and the GSH levels in different grades of astrocytomas. The differential gene expressions were validated in silico on the TCGA database. Results We found an increase of glutaminase isoform 2 gene (GLSiso2) expression in all grades of astrocytoma compared to non-neoplastic brain tissue, with a gradual expression increment in parallel to malignancy. Genes coding for GLUD1 and GPT2 expression levels varied according to the grade of malignancy, being downregulated in glioblastoma, and upregulated in lower grades of astrocytoma (AGII–AGIII). Significant low GLUD1 and GPT2 protein levels were observed in the mesenchymal subtype of GBM. Conclusions In glioblastoma, particularly in the mesenchymal subtype, the downregulation of both genes and proteins (GLUD1 and GPT2) increases the source of glutamate for GSH synthesis and enhances tumor cell fitness due to increased antioxidative capacity. In contrast, in lower-grade astrocytoma, mainly in those harboring the IDH1 mutation, the gene expression profile indicates that tumor cells might be sensitized to oxidative stress due to reduced GSH synthesis. The measurement of GLUD1 and GPT2 metabolic substrates, ammonia, and alanine, by noninvasive MR spectroscopy, may potentially allow the identification of IDH1 mut AGII and AGIII progression towards secondary GBM.

Background: Gliomas are highly invasive brain tumors that evade accurate geographic assessment by conventional MRI due to microscopic invasion along white matter (WM) tracts. Advanced diffusion MRI techniques are needed to assess occult WM involvement., Purpose: To evaluate peak width of skeletonized mean diffusivity (PSMD) and peak width of skeletonized free water (PSFW), and axonal water fraction (AWF) for assessing glioma-induced alterations in normal-appearing WM and their relationship with isocitrate dehydrogenase 1 (IDH1) mutation., Study Type: Retrospective., Population: One hundred five glioma patients (46 ± 13 years), 53 healthy controls (HCs) (46 ± 9 years)., Field Strength/sequence: 3.0 T, T1WI, T1-CE, T2WI, T2FLAIR, and DKI., Assessment: PSMD and PSFW were compared between lesion and contralateral sides in glioma patients and between patients and HCs. The associations between these metrics and clinical variables, including IDH1 mutation, was assessed. Corpus callosum (CC) injury, quantified by the AWF, was evaluated for its mediated effect of IDH1 mutation on contralesional PSMD and PSFW., Statistical Tests: Paired-t tests, ANCOVA, univariate and multivariate linear regression, and mediation analysis with significance set at P < 0.05., Results: Contralateral PSMD and PSFW were significantly higher in left-sided gliomas (PSMD: 0.206 ± 0.027 vs. 0.193 ± 0.023; PSFW: 0.119 ± 0.019 vs. 0.106 ± 0.020) than in HCs, with similar increases in right-sided gliomas (PSMD: 0.219 ± 0.036 vs. 0.195 ± 0.023; PSFW: 0.129 ± 0.031 vs. 0.109 ± 0.020). IDH1 wild-type gliomas were associated with higher contralateral PSMD and PSFW (β = -0.302 and -0.412). AWF of CC mediated the impact of IDH1 mutations on contralesional PSMD and PSFW (mediated proportion: 42.7% and 53.7%)., Data Conclusion: PSMD and PSFW are effective biomarkers for assessing WM integrity in gliomas, significantly associated with IDH1 mutation status. AWF of CC mediates the relationship between IDH1 mutation and contralesional PSMD and PSFW., Evidence Level: 4 TECHNICAL EFFICACY: Stage 2., (© 2024 International Society for Magnetic Resonance in Medicine.)

Background Several molecular markers have important roles in glioma management. Mutations in the isocitrate dehydrogenase ( IDH) gene are associated with the grading and prognosis of glioma. Methylation in the promoter region of the O (6)-methylguanine-DNA methyltransferase ( MGMT) gene is an important determinant of glioma sensitivity to alkylating agents. Studies in various cancers indicated that IDH1 mutations and MGMT promoter methylations were associated with smoking habits. However, these associations in gliomas are still unclear. Accordingly, this study aimed to examine the association among smoking, IDH1 mutations, MGMT promoter methylation, and grading in glioma patients. Methods Patients were recruited from Dr. Sardjito General Hospital (a referral hospital in Yogyakarta and Central Java region) and its network hospitals. Genomic DNA was extracted from formalin-fixed paraffin-embedded samples or fresh glioma tissues. Identification of IDH1 mutation was performed using Polymerase Chain Reaction-Restriction Fragment Length Polymorphism (PCR-RFLP) or DNA sequencing. Methylation-specific real-time PCR was performed to identify MGMT promoter methylation status. Smoking status was obtained by history taken from the patient or family members. Results In total, 122 patients were included in this study. As many as 35 patients (28.7%) had a smoking history. Most smokers (57.1%) smoke less than ten cigarettes per day. However, most of them (68.8%) have been smoking for more than 20 years. Smoking patients have a significantly higher proportion of high-grade glioma than non-smokers (80% vs. 55.2%, p=0.01). Among 122 patients, 24 (19.7%) of them carried IDH1 mutation. Smoking patients have a significantly higher proportion of IDH1 mutation compared with non-smokers (31.4% vs. 14.9%, pIDH1 mutations and glioma grading. No significant association was found between smoking and MGMT promoter methylation. Conclusions In glioma patients, smoking is associated with IDH1 mutations and grading but not with MGMT promoter methylation.

Adult brainstem gliomas are rare central nervous system tumors that represent a heterogeneous group of tumors. Somatic IDH mutations are uncommon in adult brainstem gliomas and there are few relevant clinical studies. Here, we reported five patients with IDH1 mutations associated with brainstem gliomas, including four cases of IDH1 R132H mutations and one case of R132G mutation. All patients were treated with focal intensity-modulated radiation therapy (IMRT) with concurrent temozolomide (TMZ). One patient died, one relapsed, and three survived to date. All these cases carried a pathogenic variant of TP53, among whom 1 harbored ATRX mutation and 1 had H3K27M mutation. Moreover, we also found some genes related to a worse prognosis, such as CDK4/6 amplification. These findings demonstrate that the specific characteristics of IDH-mutant brainstem gliomas should be considered in diagnostic workflows to make therapeutic regimens and improve the prognosis.

Mutations in IDH1 and IDH2 drive the development of gliomas. These genetic alterations promote tumor cell renewal, disrupt differentiation states, and induce stem-like properties. Understanding how this phenotypic reprogramming occurs remains an area of high interest in glioma research. Previously, we showed that IDH mutation results in the development of a CD24-positive cell population in gliomas. Here, we demonstrate that this CD24-positive population possesses striking stem-like properties at the molecular and phenotypic levels. We found that CD24 expression is associated with stem-like features in IDH-mutant tumors, a patient-derived gliomasphere model, and a neural stem cell model of IDH1-mutant glioma. In orthotopic models, CD24-positive cells display enhanced tumor initiating potency compared to CD24-negative cells. Furthermore, CD24 knockdown results in changes in cell viability, proliferation rate, and gene expression that closely resemble a CD24-negative phenotype. Our data demonstrate that induction of a CD24-positive population is one mechanism by which IDH-mutant tumors acquire stem-like properties. These findings have significant implications for our understanding of the molecular underpinnings of IDH-mutant gliomas.

The IDH1R132H mutation in glioma results in the neoenzymatic function of IDH1, leading to the production of the oncometabolite 2-hydroxyglutarate (2-HG), alterations in energy metabolism and changes in the cellular redox household. Although shifts in the redox ratio NADPH/NADP+ were described, the consequences for the NAD+ synthesis pathways and potential therapeutic interventions were largely unexplored. Here, we describe the effects of heterozygous IDH1R132H on the redox system in a CRISPR/Cas edited glioblastoma model and compare them with IDH1 wild-type (IDH1wt) cells. Besides an increase in 2-HG and decrease in NADPH, we observed an increase in NAD+ in IDH1R132H glioblastoma cells. RT-qPCR analysis revealed the upregulation of the expression of the NAD+ synthesis enzyme nicotinamide phosphoribosyltransferase (NAMPT). Knockdown of NAMPT resulted in significantly reduced viability in IDH1R132H glioblastoma cells. Given this dependence of IDH1R132H cells on NAMPT expression, we explored the effects of the NAMPT inhibitors FK866, GMX1778 and GNE-617. Surprisingly, these agents were equally cytotoxic to IDH1R132H and IDH1wt cells. Altogether, our results indicate that targeting the NAD+ synthesis pathway is a promising therapeutic strategy in IDH mutant gliomas; however, the agent should be carefully considered since three small-molecule inhibitors of NAMPT tested in this study were not suitable for this purpose. [ABSTRACT FROM AUTHOR]

As the traditional treatment for glioma, the most common central nervous system malignancy with poor prognosis, the efficacy of high-intensity surgery combined with radiotherapy and chemotherapy is not satisfactory. The development of individualized scientific treatment strategy urgently requires the guidance of signature with clinical predictive value. In this study, five prognosis-related differentially expressed immune-related genes (PR-DE-IRGs) (CCNA2, HMGB2, CASP3, APOBEC3C, and BMP2) highly associated with glioma were identified for a prognostic model through weighted gene co-expression network analysis, univariate Cox and lasso regression. Kaplan-Meier survival curves, receiver operating characteristic curves and other methods have shown that the model has good performance in predicting the glioma patients' prognosis. Further combined nomogram provided better predictive performance. The signature's guiding value in clinical treatment has also been verified by multiple analysis results. We also constructed a comprehensive competing endogenous RNA (ceRNA) regulatory network based on the protective factor BMP2 to further explore its potential role in glioma progression. Numerous immune-related biological functions and pathways were enriched in a high-risk population. Further multi-omics integrative analysis revealed a strong correlation between tumor immunosuppressive environment/IDH1 mutation and signature, suggesting that their cooperation plays an important role in glioma progression. [ABSTRACT FROM AUTHOR]

Laser interstitial thermal therapy (LITT) has become an increasingly utilized alternative to surgical resection for the treatment of glioma in patients. However, treatment outcomes in isocitrate dehydrogenase 1 and 2 (IDH1/2) mutant glioma, specifically, have not been reported. The objective of this study was to characterize a single institution's cohort of IDH1/2 mutant grade 2/3 glioma patients treated with LITT. We collected data on patient presentation, radiographic features, tumor molecular profile, complications, and outcomes. We calculated progression-free survival (PFS) and tested factors for significant association with longer PFS. Overall, 22.7% of our cohort experienced progression at a median follow up of 1.8 years. The three- and five-year estimates of PFS were 72.5% and 54.4%, respectively. This is the first study to characterize outcomes in patients with IDH1/2 mutant glioma after LITT. Our results suggest that LITT is an effective treatment option for IDH1/2 mutant glioma. [ABSTRACT FROM AUTHOR]

Effect of isocitr ate dehydrogenase 1 (IDH1) mutation in neovascularization might be linked with tissue perfusion in gliomas. At present, the need of injection of contrast agent and the increasing scanning time limit the application of perfusion techniques. We used a simplified intravoxel incoherent motion (IVIM)-derived perfusion fraction (SPF) calculated from diffusion-weighted imaging (DWI) using only three b-values to quantitatively assess IDH1-linked tissue perfusion changes in WHO grade II-III gliomas (LGGs). Additionally, by comparing accuracy with dynamic contrast-enhanced (DCE) and full IVIM MRI, we tried to find the optimal imaging markers to predict IDH1 mutation status.

Abstract Background The molecular features of isocitrate dehydrogenase (IDH) mutation and chromosome 1p and 19q (1p/19q) codeletion status have pivotal role for differentiating gliomas and have been integrated in the World Health Organization (WHO) classification in 2016. Positron emission tomography (PET) with 3′-deoxy-3′-[18F]fluorothymidine (FLT) has been used to evaluate tumour grade and proliferative activity and compared with l-[methyl-11C]-methionine (MET) in glioma patients. Herein, we evaluated tracer uptakes of MET-PET/CT and FLT-PET/CT for differentiating glioma based on the 2016 WHO classification especially in relation to IDH1 mutation status. Methods In total, 81 patients with newly diagnosed supratentorial glioma were enrolled in this study. They underwent PET/CT studies with MET and FLT before surgery. The molecular features and histopathological diagnosis based on the 2016 WHO classification were determined using surgical specimens. The ratios of the maximum standardized uptake value (SUV) of the tumours to the mean SUV of the contralateral cortex (T/N ratios) were calculated on MET-PET/CT and FLT-PET/CT images. Results The mean T/N ratios of MET-PET/CT and FLT-PET/CT in IDH1-wildtype tumours were significantly higher than those in IDH1-mutant tumours (P < 0.001 and P < 0.001, respectively). Receiver operating characteristic analysis for differentiating IDH1 mutation status showed that the area under the curve of the FLT T/N ratio was significantly larger than that of the MET T/N ratio (P < 0.01). The mean T/N ratio of FLT-PET/CT in IDH1-wildtype tumours was significantly higher than that in IDH1-mutant tumours among grade II and III gliomas (P = 0.005), but this was not the case for MET-PET/CT. Both MET-PET/CT and FLT-PET/CT were able to distinguish between grade II and III gliomas in IDH1-mutant tumours (P = 0.002 and P < 0.001, respectively), but only FLT-PET/CT was able to distinguish between grade III and IV gliomas in IDH1-wildtype tumours (P = 0.029). Conclusion This study showed that FLT-PET/CT can be used to determine the IDH1 mutation status and evaluate glioma grade more accurately than MET-PET/CT. FLT-PET/CT can improve glioma differentiation based on the 2016 WHO classification, but caution must be paid for tumours without contrast enhancement and further studies should be conducted with more cases.