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Mutations in the genes encoding the cytoplasmic and mitochondrial forms of isocitrate dehydrogenase (IDH1 and IDH2, respectively; collectively referred to as IDH) are frequently detected in cancers of various origins, including but not limited to acute myeloid leukaemia (20%), cholangiocarcinoma (20%), chondrosarcoma (80%) and glioma (80%). In all cases, neomorphic activity of the mutated enzyme leads to production of the oncometabolite D-2-hydroxyglutarate, which has profound cell-autonomous and non-cell-autonomous effects. The broad effects of IDH mutations on epigenetic, differentiation and metabolic programmes, together with their high prevalence across a variety of cancer types, early presence in tumorigenesis and uniform expression in tumour cells, make mutant IDH an ideal therapeutic target. Herein, we describe the current biological understanding of IDH mutations and the roles of mutant IDH in the various associated cancers. We also present the available preclinical and clinical data on various methods of targeting IDH-mutant cancers and discuss, based on the underlying pathogenesis of different IDH-mutated cancer types, whether the treatment approaches will converge or be context dependent.

The presence of mutations in the gene encoding isocitrate dehydrogenase (IDH1), parameters of pro- and antioxidant activity in glioma tumor tissue, and their correlation were studied using bioinformatic analysis using STRING, IntAct, BioGrid, UniProt, SwissProt databases. The rate of detection of IDH1 gene mutations varied in different degree of anaplasia, being maximum in grade III gliomas. The intensity of free radical oxidation and activities of superoxide dismutase and catalase in the tumor tissue were significantly higher than in the control. The dependence of these parameters on the degree of anaplasia was shown. Mutations in IDH1 are associated with a decrease in antioxidant activity in the tissues of gliomas, which is critically important for the initial diagnosis, the choice of treatment options, and prediction of patient survival.

Mutations in isocitrate dehydrogenase genes (IDH1 and IDH2) are common in acute myeloid leukemia (AML), occurring in up to 30% of AML cases. Mutations in IDH leads to abnormal epigenetic regulation in AML cells and blocks differentiation. Inhibitors of mutated IDH1 and IDH2, ivosidenib and enasidenib, respectively, were recently approved by the FDA for relapsed/refractory AML; ivosidenib is also approved for newly diagnosed AML patients not fit for standard chemotherapy. Here, we discuss the clinical development of IDH inhibitors, their unique side effects, and outline future combination approaches in AML. IDH inhibitors are well-tolerated but can induce differentiation of AML cells, which leads to the on-target side effect of differentiation syndrome in up to 20% of patients. Although IDH inhibitors demonstrate efficacy as monotherapy, recent trials have shown that they have higher response rates in combination with hypomethylating agents (HMAs). Current trials of IDH inhibitors include combination with standard induction chemotherapy, as maintenance therapy, and in combination with venetoclax-based regimens. IDH inhibitors are active and have a favorable toxicity profile in AML therapy. Current clinical trials are evaluating how to best incorporate IDH inhibitors into combination therapy to optimize outcomes and duration of response for AML patients with IDH mutations.

Isocitrate dehydrogenase (IDH) is an important enzyme that oxidatively decarboxylates isocitrate to α-ketoglutarate, and three isoforms (IDH1-3) have been identified. Overexpression and/or downregulation of IDH isoforms was reported in several human malignancies, suggesting importance of IDH in oncogenesis. However, significance of IDH isoforms remains largely unclear in the breast carcinoma. We immunolocalized IDH1, IDH2 and IDH3α in 226 breast carcinomas and evaluated their clinical significance. Subsequently, we examined effects of IDH2 on proliferation in breast carcinoma cells. Immunoreactivity of IDH1-3α was detected in 53%, 38% and 41% of breast carcinomas, and the non-neoplastic epithelium was IDH1-positive, IDH2-negative and IDH3α-positive. IDH1 immunoreactivity was inversely associated with pathological T factor (pT) and Ki-67 in the breast carcinoma, while IDH3α immunoreactivity was not significantly associated with clinicopathological factors. IDH2 status was positively correlated with stage, pT, histological grade, HER2, Ki-67 and microvessel density. Moreover, IDH2 status was significantly associated with worse prognosis of the patients, and it turned out an independent prognostic factor for estrogen-receptor (ER) positive patients. These findings were more evident in the IDH1-negative / IDH2-positive/IDH3α-negative subgroup which is the opposite immunohistochemical IDH phenotype of normal mammary epithelium. In vitro studies demonstrated that RNA interference of IDH2 significantly decreased proliferation activity of T47D and SKBR-3 cells. These results suggest that IDH2 is associated with an aggressive phenotype of breast carcinoma through increasing cell proliferation, different from IDH1 and IDH3α, and immunohistochemical IDH2 status is a potent prognostic factor especially in ER-positive breast cancer patients.

Cholangiocarcinoma (CCA) is an aggressive biliary tract malignancy and overall prognosis remains poor, with a median survival of less than 24 months. Sequencing studies have revealed a high prevalence of genomic alterations in CCA, with multiple potential therapeutic targets. Next-generation sequencing (NGS) can identify actionable mutations such as FGFR, IDH, BRAF, ERBB2, ROS1, or microsatellite instability (MSI-H), among others.We conducted a retrospective multicenter study in Spain in 2019. Thirty consecutive patients from 15 centers were included. All patients were diagnosed with advanced CCA and underwent NGS (FoundationOne®) in 2019. Twenty-four patients underwent tissue-based NGS (FoundationOne® CDx), and 6 patients underwent blood-based NGS (FoundationOne®Liquid) with sequencing panels of 324 and 70 genes, respectively RESULTS: We identified 12 patients (40%) with an actionable genetic alteration in tissue: 2 FGFR2 fusions, 6 IDH1 mutations, 1 ERBB2 mutation, 1 ROS1 fusion, 1 PIK3CA mutation, and 1 MSI-H.Comprehensive genomic profiling (CGP) in cholangiocarcinoma can identify, in a high proportion of patients, clinically relevant genomic alterations that can lead to targeted therapies, expanding treatment options.

BACKGROUND: Despite surgical resection and chemoradiation, all patients with GBM invariably recur. Radiological imaging is limited in differentiating tumor recurrence (TR) from treatment-related changes (TRC); therefore, re-resection is often needed. Few studies have assessed the relationship between re-resection histopathology and overall survival (OS). We performed a large retrospective study to analyze the clinical significance of histopathology following re-resection and its influence on genomic sequencing results. METHODS: Clinical, radiographic, and histological information was compiled from 675 patients with GBM (2005–2017). 137-patients met the inclusion criteria. IDH1 p.R132H immunohistochemistry was performed in all patients. Next-generation sequencing interrogating 205 tumor-related genes was performed in 68-patients. Molecular alterations from initial and subsequent resections were compared in a subset of cases. RESULTS: There were no differences in OS (17.3-months TRC vs. 21-months TR, p = 0.881) and survival from progression (9.0 vs. 11.7-months, p = 0.778) between patients with TR and TRC on re-resection. TR patients were more likely to receive salvage radiotherapy (26% vs. 0%) and tumor-treating fields (25% vs. 5%,) after the 2nd surgery than the TRC group (p = < 0.045). There was no correlation between mutations and TRC. IDH status was not predictive of TRC. Fifteen-patients had sequencing results from multiple surgeries without evident differences in genomic alterations. CONCLUSIONS: Histopathologic findings following chemoradiation do not correlate with clinical outcomes. Such findings should be considered during patient management and clinical trial enrollment. Standardization of tissue sampling and interpretation following reoperation is urgently needed. Future work is required to understand the relationship between the mutation profile following TRC and outcomes.

Despite substantial advances in understanding of the molecular features of gliomas, the therapeutic options for these aggressive tumors remain scarce. Rich, Mitchell and colleagues provide their views about a phase 1 clinical trial testing the safety and efficacy of vaccines against cancer expressing mutant metabolic enzyme IDH1 in patients with high-grade glioma.

Approximately 10% of IDH-mutant gliomas harbour non-canonical IDH mutations (non-p.R132H IDH1 and IDH2 mutations). The aim of this study was to analyse the characteristics of non-canonical IDH-mutant gliomas. We retrospectively analysed the characteristics of 166 patients with non-canonical IDH mutant gliomas and compared them to those of 155 consecutive patients with IDH1 p.R132H mutant gliomas. The median age at diagnosis was 38 years in patients with non-canonical IDH mutant gliomas and 43 years in glioma patients with IDH1 p.R132H-mutant tumours. Family history of cancer was more frequent among glioma patients harbouring non-canonical IDH mutations than in patients with IDH1 p.R132H mutations (22.2% vs 5.1%; P

To assess whether the main genetic differences observed in high-grade gliomas (HGG) will present different MR imaging and MR spectroscopy correlates that could be used to better characterize lesions in the clinical setting. Seventy-nine patients with histologically confirmed HGG were recruited. Immunohistochemistry analyses for isocitrate dehydrogenase gene 1 (IDH1), alpha thalassemia mental retardation X-linked gene (ATRX), Ki-67, and p53 protein expression were performed. Tumour radiological features were examined on MR images. Metabolic profile and infiltrative pattern were assessed with MR spectroscopy. MR features were analysed to identify imaging-molecular associations. The Kaplan-Meier method and the Cox regression model were used to identify survival prognostic factors. In total, 17.7% of the lesions were IDH1-mutated, 8.9% presented ATRX-mutated, 70.9% presented p53 unexpressed, and 22.8% had Ki-67 > 5%. IDH1 wild-type tumours had higher levels of mobile lipids (p = 0.001). The tumour-infiltrative pattern was higher in HGG with unexpressed p53 (p = 0.009). Mutated ATRX tumours presented higher levels of glutamate and glutamine (Glx) (p = 0.001). An association was observed between Glx tumour levels (p = 0.038) and Ki-67 expression (p = 0.008) with the infiltrative pattern. Survival analyses identified IDH1 status, age, and tumour choline levels as independent predictors of prognostic significance. Our results suggest that IDH1-wt tumours are more necrotic than IDH1-mut. And that the presence of an infiltrative pattern in HGG is associated with loss of p53 expression, Ki-67 index, and Glx levels. Finally, tumour choline levels could be used as a predictive factor in survival in addition to the IDH1 status to provide a more accurate prediction of survival in HGG patients. • IDH1-wt tumours present higher levels of mobile lipids than IDH1-mut. • Mutated ATRX tumours exhibit higher levels of glutamate and glutamine. • Loss of p53 expression, Ki-67 expression, and glutamate and glutamine levels may contribute to the presence of an infiltrative pattern in HGG.

Pediatric cerebellar glioblastomas (pcGBMs) are rare and their characteristics remain ill-defined. We conducted a retrospective analysis of pediatric cerebellar glioblastomas who underwent surgery from 2008 to 2019 in our department. Besides, we performed a literature review of the literature data on pcGBMs. Ten children with mean age of 9.4 years were included. During the follow-up, six patients died with mean survival time of 11.7 months, four patients survived with mean follow-up of 28 months. Seven patients underwent molecular analysis, no patients detected IDH1 mutations, four patients (57.1%) had H3K27M mutations, and two patients (28.6%) had MGMT promoter methylation. The literature review identified 38 pcGBMs cases (including ours), with mean age of 8.84 ± 4.20 years (range, 1–16 years). Increased ICP was the commonest sign. Eighteen (47.4%) patients underwent GTR and fifteen (45.5%) patients received STR. Postoperative radiation (RT) was conducted in 28 patients (75.7%) and 23 patients (65.7%) received chemotherapy. During the follow-up, 25 patients died with mean survival time of 12.21 months and 11 patients survived with average follow-up of 29.3 months. Kaplan-Meier survival depicted chemotherapy (P

Despite tremendous progress in understanding the pathobiology of astrocytoma, major gaps remain in our knowledge of the molecular basis underlying the aggressiveness of high-grade astrocytoma (glioblastoma - GBM). Recently, we and others have shown nuclear respiratory factor 1 (NRF1) transcription factor being highly active in human cancers, but its role in astrocytoma remains unknown. Therefore, the purpose of this study was to uncover the role of NRF1 in the progression of GBM. NRF1 has higher mRNA expression and transcription factor activity in astrocytoma compared to non-tumor brain tissue. NRF1 activity also correlated with the aggressiveness of cancer. Increased NRF1 TF activity coupled with overexpression of RHOG was associated with poor survival of GBM patients. NRF1 activity was associated with transcriptomic signatures of neurogenesis, cell stemness, epithelial-mesenchymal transition and cell cycle progression. Overexpression of CDK4, AKT1, APAF1, HDAC1, NBN, TGFB1, & TNFRSF1A and downregulation of CASP3, IL7, STXBP1 and OPA1 predicted GBM malignancy in high expressors of NRF1 activity. Increased expression of the NRF1 motif containing genes, H6PD, NAT10, NBEAL2, and RNF19B predicted poor survival of IDH1 wild-type GBM patients. Poor survival outcomes and resistance to Temozolomide therapy were associated with higher NRF1 expression including its targets - LDHA, ZMAT3, NSUN2, ARMC5, NDEL1, CLPTM1L, ALKBH5, YIPF5, PPP2CA, and TFG. These findings suggest that aberrant NRF1 activity may contribute to the pathogenesis of GBM and severity of astrocytoma. Further analyses of NRF1 gene signatures will pave the way for next generation targeted therapies and drug combination strategies for GBM patients.

We report a rare case of oligodendroglioma with gangliocytic differentiation. A 31-year-old male without a past medical history was admitted with a sudden seizure. On magnetic resonance imaging, an approximately 7-cm mass with necrosis was noted in the right frontal lobe. The patient underwent surgical resection. On microscopy, two morphologically distinct areas with oligodendroglioma- and ganglioglioma-like features were found. Immunohistochemistry showed an absence of CD34 expression, whereas isocitrate dehydrogenase 1 (IDH1) was positive in the glial component. Moreover, IDH1 was positive in the ganglion-like cells as well as in the glial component. Subsequent 1p/19q co-deletion was confirmed by fluorescence in situ hybridization. Finally, a diagnosis of oligodendroglioma with gangliocytic differentiation was made. IDH1/2 molecular test would be basic and essential diagnostic tool in central nervous system tumor of young patients.

Isocitrate dehydrogenase (IDH) mutations lead to formation of the oncometabolite 2-hydroxyglutarate (2-HG), which is elevated in several solid and liquid tumors. Ivosidenib (AG-120) is a targeted, potent, oral inhibitor of the mutant IDH1 protein. We describe detailed pharmacokinetics and pharmacodynamics of ivosidenib in patients with advanced hematologic malignancies with an IDH1 mutation treated in a phase I study (ClinicalTrials.gov NCT02074839). Patients received single and multiple oral doses of ivosidenib from 100 mg twice daily to 1200 mg once daily (QD) in 28-day continuous cycles. Concentrations of ivosidenib and 2-HG in plasma, and 2-HG in bone marrow, were assessed at routine intervals. Plasma 4β-hydroxycholesterol/cholesterol ratios were assessed as a marker of CYP3A activity. Ivosidenib was rapidly absorbed and slowly eliminated (half-life 72–138 h) after single and multiple dosing. Ivosidenib exhibited dose- and time-dependent pharmacokinetics, with exposure increasing sub-proportionally to dose, and clearance increasing with increasing dose. Plasma 2-HG concentrations were maximally and persistently inhibited in the majority of patients receiving 500-mg QD ivosidenib, to concentrations close to those observed in healthy subjects. Ivosidenib pharmacokinetics were not affected by mild or moderate renal impairment, mild hepatic impairment, age, weight, sex, race, or co-administration of weak CYP3A4 inhibitors or inducers. Moderate-to-strong CYP3A4 inhibitors decreased ivosidenib clearance. Ivosidenib also induced CYP3A enzyme activity, with increases in 4β-hydroxycholesterol/cholesterol ratios of 119–168% at 500-mg QD ivosidenib. Ivosidenib 500-mg QD has favorable pharmacokinetic and pharmacodynamic profiles in patients with advanced hematologic malignancies with an IDH1 mutation. ClinicalTrials.gov NCT02074839.

According to the 2016 World Health Organization (WHO) classification of central nervous system tumors, diffuse astrocytic and oligodendroglial tumors are differentiated by the presence of isocitrate dehydrogenase 1 or 2 (IDH1/2) mutation and the combined loss of the short arm of chromosome 1 and the long arm of chromosome 19 (1p/19q co-deletion). IDH-mutant astrocytoma often has p53 and alpha-thalassemia/mental retardation syndrome X-linked (ATRX) mutation, showing the alternative lengthening of telomeres (ALT) phenotype, while IDH-mutant and 1p/19q-co-deleted oligodendroglioma often have wild-type p53 and telomerase reverse transcriptase (TERT) promoter mutation, showing telomerase activation. This study analyzed IDH, ATRX, and TERT promoter mutations, and the correlation between them. Immortalized cells overcome the telomere-related crisis by activating telomerase or ALT. In glioma, telomerase is mainly activated by TERT promoter mutation, while ALT is usually associated with ATRX mutation. Although the mechanism of how ATRX mutation induces ALT remains unclear, ATRX loss alone is believed to be insufficient to induce ALT. Treatments targeting telomere maintenance are promising.

Introduction Advanced therapy-refractory biliary tract cancer (BTC) has poor prognosis and constitutes a major challenge for adequate treatment strategies. By mapping the molecular profiles of advanced BTC patients, precision cancer medicine may provide targeted therapies for these patients. Objective In this analysis, we aimed to show the potential of PCM in metastatic BTC. Methods In this single-center, real-world retrospective analysis of our PCM platform, we describe the molecular profiling of 30 patients diagnosed with different types of metastatic BTC. Tumor samples of the patients were examined using a 161-gene next-generation sequencing panel, immunohistochemistry (IHC), and fluorescence in situ hybridization for chromosomal translocations. Results In total, we identified 35 molecular aberrations in 30 patients. The predominant mutations were KRAS (n = 8), TP53 (n = 7), IDH2 (n = 4), and IDH1 (n = 3) that accounted for the majority of all molecular alterations (62.86%). BRAF mutations were observed in two patients. Less frequent alterations were noted in ARID1A, CTNNB1, ESR1, FBXW7, FGFR2, MET, NOTCH2, PIK3CA, PTCH1, SMAD4, and SRC1, each in one case. FGFR fusion gene was detected in one patient. No mutations were detected in eight patients. IHC revealed EGFR and p-mTOR expression in 28 patients. Applying these results to our patients, targeted therapy was recommended for 60% of the patients (n = 18). One patient achieved stable disease. Conclusions PCM is a feasible treatment approach and may provide molecular-guided therapy recommendations for metastatic BTC.

SummaryThe treatment options for newly diagnosed and relapsed/refractory acute myeloid leukemia (AML) have substantially improved over the last 5 years. However, even though novel targeted agents (e.g. venetoclax, IDH1/2 and novel FLT-3 inhibitors; cytosolic isocitrate dehydrogenase 1/2 and fms-like tyrosine kinase 3 inhibitor) and improved chemotherapeutics (e.g. CPX-351; liposomale Daunorubicin/Cytarabine) are entering clinics, physicians are still confronted with high relapse and treatment failure rates. Thus, novel new strategies are required to improve AML therapy. Application of genetically engineered T cells (i.e. chimeric antigen receptor T cells, CAR-T cells) has proven to be highly effective in B cell-derived neoplasia and early data suggest also a high potential in the treatment of AML. This short review highlights the current approaches but also limitations of CAR-T cell therapy in AML precluding their current routine clinical use. Among a plethora of problems to be overcome, a critical issue will be to find relatively selective actionable targets in AML.

We previously reported that CD133 expression correlated with the recurrence pattern of glioblastoma (GBM). Subventricular zone (SVZ) involvement may also be associated with distant recurrence in GBM. Therefore, we herein investigated whether the combined analysis of SVZ involvement and CD133 expression is useful for predicting the pattern of GBM recurrence. We retrospectively analyzed 167 cases of GBM. Tumors were divided into four groups based on spatial relationships between contrast-enhanced lesions (CEL) and the SVZ or cortex (Ctx) on MRI. The initial recurrence pattern (local/distant) was obtained from medical records. To identify factors predictive of recurrence, we examined CD133 expression by immunohistochemical, clinical (age, sex, KPS, Ki-67 labeling index, surgery, and MRI characteristics), and genetic (IDH1, MGMT, and BRAF) factors. The CD133 expression rate was higher in SVZ-positive tumors than in SVZ-negative tumors (P = 0.046). Distant recurrence was observed in 21% of patients, and no significant difference was noted in recurrence patterns among the four groups. However, strong CD133 expression was associated with a shorter time to distant recurrence in univariate, multivariate, and propensity-matched scoring analyses (P

Somatic mutations of the isocitrate dehydrogenase 1 (IDH1) gene, mostly substituting Arg132 with histidine, are associated with better patient survival, but glioma recurrence and progression are nearly inevitable, resulting in disproportionate morbidity and mortality. Our previous studies demonstrated that in contrast to hemizygous IDH1R132H (loss of wild-type allele), heterozygous IDH1R132H is intrinsically glioma suppressive but its suppression of three-dimensional (3D) growth is negated by extracellular glutamate and reducing equivalent. This study sought to understand the importance of 3D culture in IDH1R132H biology and the underlying mechanism of the glutamate effect. RNA sequencing data of IDH1R132H-heterozygous and IDH1R132H-hemizygous glioma cells cultured under two-dimensional (2D) and 3D conditions were subjected to unsupervised hierarchal clustering and gene set enrichment analysis. IDH1R132H-heterozygous and IDH1R132H-hemizygous tumor growth were compared in subcutaneous and intracranial transplantations. Short-hairpin RNA against glutamate dehydrogenase 2 gene (GLUD2) expression was employed to determine the effects of glutamate and the mutant IDH1 inhibitor AGI-5198 on redox potential in IDH1R132H-heterozygous cells. In contrast to IDH1R132H-heterozygous cells, 3D-cultured but not 2D-cultured IDH1R132H-hemizygous cells were clustered with more malignant gliomas, possessed the glioblastoma mesenchymal signature, and exhibited aggressive tumor growth. Although both extracellular glutamate and AGI-5198 stimulated redox potential for 3D growth of IDH1R132H-heterozygous cells, GLUD2 expression was required for glutamate, but not AGI-5198, stimulation. 3D culture is more relevant to IDH1R132H glioma biology. The importance of redox homeostasis in IDH1R132H glioma suggests that metabolic pathway(s) can be explored for therapeutic targeting, whereas IDH1R132H inhibitors may have counterproductive consequences in patient treatment.

Tumor microenvironment (TME) cells are important elements in tumor tissue. There is increasing evidence that they have important clinical pathological significance in predicting tumor clinical outcomes and therapeutic effects. However, no systematic analysis of TME cell interactions in glioblastoma (GBM) has been reported. We systematically analyzed the transcriptional sequencing data of GBM to find an immune gene marker to predict the clinical results of GBM. First, we downloaded the expression profiles and clinical follow-up information of GBM from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO). CIBERSORT was used to evaluate the infiltration mode of TME in 757 patients, systematically correlated TME phenotype with genomic characteristics and clinicopathological characteristics of GBM, defined four TME phenotypes, and TMEScore was constructed using algorithms such as random forest and principal component analysis. There is a significant correlation between TMEScore and age of onset. High TMEScore samples are characterized by immune activation, TGF pathway activation, and high expression of immune checkpoint genes, while low TMEScore samples are characterized by high-frequency IDH1 and MET mutations. Therefore, a comprehensive landscape depicting the TME characteristics of GBM may help explain GBM's response to immunotherapy and provide new strategies for cancer treatment. In this study, TMEScore can be used as a new prognostic marker to predict the survival of GBM patients, and as a potential predictor of immune checkpoint inhibitor response.

Chondrosarcomas are rare cancers of bone that arise from the malignant transformation of cells of chondrocytic lineage. They are known to be resistant to systemic cytotoxic chemotherapy and radiotherapy. The mainstay of management of localised disease is en bloc surgical resection with curative intent. Metastatic chondrosarcoma has a dismal prognosis, and to date, there are no proven effective systemic therapies in the advanced setting. Genomic studies have demonstrated that 50 to 80% of chondrosarcomas harbour a mutation in either the IDH1 or IDH2 gene. IDH inhibitors are currently under investigation in clinical trials, after showing promising results in phase 1 studies in IDH mutated cancers. In chondrosarcoma, IDH mutations represent an attractive target, however, early results with IDH inhibitors in IDH mutated chondrosarcoma are modest and the final results of ongoing trials are eagerly awaited.

Congenital glioblastomas (cGBMs) are uncommon tumors presenting in early infancy, variably defined as diagnosed at birth or at age less than 3 months by strict criteria, or more loosely, as occurring in very young children less than 12 months of age. Previous studies have shown that cGBMs are histologically indistinguishable from GBMs in older children or adults, but may have a more favorable clinical outcome, suggesting biological differences between congenital versus other GBMs. Due to the infrequency of cGBMs, especially when employing strict inclusion criteria, molecular features have not been sufficiently explored. Archer FusionPlex Solid Tumor Kit, Archer VariantPlex Solid Tumor Kit, Illumina RNAseq were utilized to study cGBMs seen at our institution since 2002. A strict definition for cGBM was utilized, with only infants less than age 3 months at clinical presentation sought for this study. Of the 8 cGBM cases identified in our files, 7 had sufficient materials for molecular analyses, and 3 of 7 cases analyzed showed fusions of the ALK gene (involving MAP4, MZT2Bex2 and EML4 genes as fusion partners). One case showed ROS1 fusion. Somatic mutations in TSC22D1, BMG1 and DGCR6 were identified in 1 case. None of the cases showed alterations in IDH1/2, histone genes, or the TERT gene, alterations which can be associated with GBMs in older children or adults. Our results show that cGBMs are genetically heterogeneous and biologically different from pediatric and adult GBMs. Identification of ALK and ROS1 raise the possibility of targeted therapy with FDA-approved targeted inhibitors.

The introduction of the 2016 WHO classification of CNS tumors has made the combined molecular and histopathological characterization of tumors a pivotal part of glioma patient management. Recent publications on radiogenomics-based prediction of the mutational status have demonstrated the predictive potential of imaging-based, non-invasive tissue characterization algorithms. Hence, the aim of this study was to assess the potential of multiparametric 18F-FET PET-MRI including MR fingerprinting accelerated with machine learning and radiomic algorithms to predict tumor grading and mutational status of patients with cerebral gliomas. 42 patients with suspected primary brain tumor without prior surgical or systemic treatment or biopsy underwent an 18F-FET PET-MRI examination. To differentiate the mutational status and the WHO grade of the cerebral tumors, support vector machine and random forest were trained with the radiomics signature of the multiparametric PET-MRI data including MR fingerprinting. Surgical sampling served as a gold standard for histopathological reference and assessment of mutational status. The 5-fold cross-validated area under the curve in predicting the ATRX mutation was 85.1%, MGMT mutation was 75.7%, IDH1 was 88.7%, and 1p19q was 97.8%. The area under the curve of differentiating low-grade glioma vs. high-grade glioma was 85.2%. 18F-FET PET-MRI and MR fingerprinting enable high-quality imaging-based tumor decoding and phenotyping for differentiation of low-grade vs. high-grade gliomas and for prediction of the mutational status of ATRX, IDH1, and 1p19q. These initial results underline the potential of 18F-FET PET-MRI to serve as an alternative to invasive tissue characterization.

Background The present study tested the possible utility of fractal analysis from l-[methyl-11C]-methionine (MET) uptake in patients with newly diagnosed gliomas for differentiating glioma, especially in relation to isocitrate dehydrogenase 1 (IDH1) mutation status, and as compared with the conventional standardized uptake value (SUV) parameters. Methods Investigations of MET PET/CT were performed retrospectively in 47 patients with newly diagnosed glioma. Tumors were divided into three groups: lower grade glioma (IDH1-mutant diffuse astrocytoma and IDH1-mutant anaplastic astrocytoma), higher grade glioma (IDH1-wildtype diffuse astrocytoma and IDH1-wildtype anaplastic astrocytoma), and glioblastoma. The fractal dimension for tumor, maximum SUV (SUVmax) for tumor (T) and mean SUV for normal contralateral hemisphere (N) were calculated, and the tumor-to-normal (T/N) ratio was determined. Metabolic tumor volume (MTV) and total lesion MET uptake (TLMU) were also measured. Results There were significant differences in SUVmax (p = 0.006) and T/N ratio (p = 0.02) between lower grade glioma and glioblastoma. There were no significant differences among any of the three groups in MTV or TLMU. Significant differences were obtained in the fractal dimension between lower grade glioma and higher grade glioma (p = 0.006) and glioblastoma (p Conclusions The results of this preliminary study in a small patient population suggest that the fractal dimension using MET PET in patients with newly diagnosed gliomas is useful for differentiating glioma, especially in relation to IDH1 mutation status, which has not been possible with SUV parameters.

Primary liver cancer, consisting of both cholangiocarcinoma (CCA) and hepatocellular carcinoma (HCC), is the second leading cause of cancer deaths worldwide. Our goal is to genomically characterize rare HCC subclasses to provide insight into disease biology. Leveraging The Cancer Genome Atlas (TCGA) to perform a combined analysis of CCA (n = 36) and HCC (n = 275), we integrated multiple genomic platforms, to assess transcriptional profiles, mutational signatures, and copy number patterns to uncover underlying etiology and linage specific patterns. We identified two molecular classes distinct from prototypical HCC tumors. The first, CCA-Like, although histologically indistinguishable from HCC, had enrichment of CCA mutations (IDH1, BAP1), mutational signatures, and transcriptional patterns (SOX9, KRT19). CCA-Like, however, retained a copy number landscape similar to HCC, suggesting a hepatocellular linage. The second, Blast-Like, is enriched in TP53 mutations, HBV infection, exposure related mutational signatures and transcriptionally similar to hepatoblasts. Although these subclasses are molecularly distinct, they both have a worse progression-free survival compared to classical HCC tumors, yet are clinically treated the same. The identification of and characterization of CCA-Like and Blast-Like subclasses advance our knowledge of HCC as well as represents an urgent need for the identification of class specific biomarkers and targeted therapy., Jeffrey Damrauer, Markia Smith et al. used existing datasets from cholangiocarcinoma (CCA) and hepatocellular carcinoma (HCC) to characterize two subsets of HCC distinct from prototypical HCC tumors, based on comprehensive analysis of molecular data. The two classes differed from HCC by their copy number, gene expression and mutational signature and exhibited worse progression free survival, highlighting the need to identify class-specific biomarkers and develop targeted therapies for these forms of cancer.

Long-term complications such as radiation-induced second malignancies occur in a subset of patients following radiation-therapy, particularly relevant in pediatric patients due to the long follow-up period in case of survival. Radiation-induced gliomas (RIGs) have been reported in patients after treatment with cranial irradiation for various primary malignancies such as acute lymphoblastic leukemia (ALL) and medulloblastoma (MB). We perform comprehensive (epi-) genetic and expression profiling of RIGs arising after cranial irradiation for MB (n = 23) and ALL (n = 9). Our study reveals a unifying molecular signature for the majority of RIGs, with recurrent PDGFRA amplification and loss of CDKN2A/B and an absence of somatic hotspot mutations in genes encoding histone 3 variants or IDH1/2, uncovering diagnostic markers and potentially actionable targets., Radiation-induced gliomas (RIGs) have been reported in patients after treatment with cranial irradiation for various primary malignancies but their origin are still unclear. Here, the authors define the genomic, epigenetic and transcriptional landscape of 32 RIGs cases.

Purpose. The oncological and functional outcomes in glioblastoma (GBM) patients following supratotal resection (SupTR), involving complete resection of contrast-enhancing enhanced (CE) tumors and areas of methionine (Met) uptake on 11C-met positron emission tomography (Met-PET), are unknown.Methods. We conducted a retrospective review in newly diagnosed, IDH1 wild-type GBM patients, comparing SupTR with gross total resection (GTR), in which only CE tumor tissue was resected. All patients underwent standard radiotherapy and temozolomide treatment, and were followed for tumor recurrence and overall survival (OS).Results. Among the 30 patients included in this study, 7 underwent SupTR and 23 underwent GTR. Awake craniotomy with cortical and subcortical mapping was more frequently performed in the SupTR group than in the GTR group. During the follow-up period, significantly different patterns of disease progression were observed between groups. Although more than 80% of recurrences were local in the GTR group, all recurrences in the SupTR group were distant. Median OS in the GTR and SupTR groups was 18.5 months (95% confidence interval [CI], 14.2-35.1) and not reached (95% CI, 30.5-not estimable), respectively; this difference was statistically significant (p=0.03 by log-rank test). No postoperative neurocognitive decline was evident in patients who underwent SupTR.Conclusion. Compared to GTR alone, aggressive resection of both CE tumors and areas with Met uptake (SupTR) under awake craniotomy with functional mapping results in a survival benefit associated with better local control and neurocognitive preservation.

No abstract

Mutations in the isocitrate dehydrogenase (IDH) 1 gene are commonly found in human glioma, with the majority of low-grade gliomas harboring a recurrent point mutation (IDH1 R132H). Mutant IDH reveals an altered enzymatic activity leading to the synthesis of 2-hydroxyglutarate, which has been implicated in epigenetic mechanisms of oncogenesis. Nevertheless, it is unclear exactly how IDH mutations drive glioma initiation and progression, and it is also not clear why tumors with this mutation generally have a better prognosis than IDH wild-type tumors. Recognition of the high frequency of IDH mutations in glioma [and also in other malignancies, including acute myeloid leukemia (AML) and cholangiocarcinoma] have led to the development of a number of targeted agents that can inhibit these enzymes. Enasidenib and ivosidenib have both gained regulatory approval for IDH mutant AML. Both agents are still in early clinical phases for glioma therapy, as are a number of additional candidates (including AG-881, BAY1436032, and DS1001). A marked clinical problem in the development of these agents is overcoming the blood-brain barrier. An alternative approach to target the IDH1 mutation is by the induction of synthetic lethality with compounds that target poly (ADP-ribose) polymerase (PARP), glutamine metabolism, and the Bcl-2 family of proteins. We conclude that within the last decade, several approaches have been devised to therapeutically target the IDH1 mutation, and that, potentially, both IDH1 inhibitors and synthetic lethal approaches might be relevant for future therapies.

Therapy-related myeloid neoplasms (tMN) following successful treatment of acute myeloid leukemia (AML) are rare and poorly characterized. To evaluate the presence of a common ancestral clone, we performed whole-exome sequencing of 25 patients at AML diagnosis, tMN diagnosis (tMDS: 13; tAML: 12), and matched remission samples, identifying 607 mutations affecting 504 different genes (46 recurrently mutated). Number of mutations was higher in tAML vs. tMDS cases (median 19 vs 13 mutations, p = 0.05). Focusing on 24 genes commonly mutated in hematological malignancies, 19/25 (76%) patients were found to share mutations between AML and tMN, mostly affecting epigenetic modifiers (21/32; 66%), splicing factors (6/32; 19%), and chromatin modifiers (3/32; 9%). Analysis of remission samples identified 13 persisting mutations in 10/22 patients, affecting DNMT3A (n = 6), TET2 (n = 5), IDH1 and SRSF2 (n = 1, each). Comparison of cytogenetics revealed that 9/12 patients with a normal karyotype (NK) in AML harbored aberrations in tMN, four aberrant AML cases presented with NK in tMN, four other patients showed unrelated cytogenetic aberrations. Our study provides novel insights into the pathogenesis of tMN, hypothesizing the presence of a common ancestral clone in AML and tMN. Mutations mostly affected epigenetic modifiers, which have previously been linked to clonal hematopoiesis.

Recently, the potential value of isocitrate dehydrogenase (IDH) mutation as a prognostic marker in glioblastomas has been established. Glioblastomas are classified by their IDH mutation status under the 2016 WHO classification system. However, noninvasive diagnostic methods for the mutation status in glioblastoma patients have not been established so far. The purpose of this study was to evaluate the difference of acetate metabolism between in glioblastomas with wild-type IDH and in those with IDH mutation by comparing the uptake of 14C-acetate using genetically engineered glioblastoma cell lines in vitro and in vivo. We established glioblastoma cells (U251) expressing IDH1 R132H and examined the cell uptake of [1-14C]acetate. Biodistribution studies and an autoradiographic study for U251 cell tumor-bearing mice (BALB/c-nu/nu) with or without the IDH1 mutation were performed 1 h after [1-14C]acetate administration. Significantly higher uptake of [1-14C]acetate was observed in U251/IDH1 R132H cells than in U251/IDH1 wild-type cells both in vitro (10.11 ± 0.94 vs. 4.26 ± 0.95%dose/mg, p = 0.0047) and in vivo (0.97 ± 0.14 vs. 0.66 ± 0.05%ID/g; p = 0.0037). Tumor-to-muscle ratios were also significantly higher in U251/IDH1 R132H tumors (3.36 ± 0.41 vs. 1.88 ± 0.59, p = 0.0030). The autoradiographic study shows the entirely higher radioactivity of the U251/IDH1 R132H tumor tissue section than that of the U251/IDH1 Wild-type tumor. In vitro and in vivo studies demonstrated that the uptake of radiolabeled acetate was significantly higher in IDH-mutated cells than in IDH-wild-type cells.

Molecular and clinical research based on isocitrate dehydrogenase (IDH) mutations is much sought after in glioma research since a decade of its discovery in 2008. IDH enzyme normally catalyzes isocitrate to α-keto-glutarate (α-KG), but once the gene is mutated it produces an 'oncometabolite', 2-hydroxyglutarate (2-HG). 2-HG is proposed to inhibit α-KG-dependent dioxygenases and also blocks cellular differentiation. Here, we discuss the role of the IDH1 mutation in gliomagenesis. The review also focuses on the effect of 2-HG on glioma epigenetics, the cellular signaling involved in IDH1 mutant glioma cells and the therapeutic response seen in mutant IDH1(mIDH1) harboring glioma patients in comparison to the patients with wild-type IDH1. The review encompasses the debatable impacts of the mutation on immune microenvironment a propos of various mIDH1 inhibitors in practice or in trials. Recent studies revealing the relation of IDH mutation with the immune microenvironment and inflammatory status in untreated versus treated glioblastoma patients are highlighted with respect to prospective therapeutic targets. Also at the molecular level, the association of mIDH1/2-HG with the intracellular components such as mitochondria and other neighboring cells is discussed.

Chondrosarcoma is the second most common malignant bone tumor. It is characterized by low vascularity and an abundant extracellular matrix, which confer these tumors resistance to chemotherapy and radiotherapy. There are currently no effective treatment options for relapsed or dedifferentiated chondrosarcoma, and new targeted therapies need to be identified. Isocitrate dehydrogenase (IDH) mutations, which are detected in ~50% of chondrosarcoma patients, contribute to malignant transformation by catalyzing the production of 2-hydroxyglutarate (2-HG), a competitive inhibitor of α-ketoglutarate-dependent dioxygenases. Mutant IDH inhibitors are therefore potential novel anticancer drugs in IDH mutant tumors. Here, we examined the efficacy of the inhibition of mutant IDH1 as an antitumor approach in chondrosarcoma cells in vitro and in vivo, and investigated the association between the IDH mutation and chondrosarcoma cells. DS-1001b, a novel, orally bioavailable, selective mutant IDH1 inhibitor, impaired the proliferation of chondrosarcoma cells with IDH1 mutations in vitro and in vivo, and decreased 2-HG levels. RNA-seq analysis showed that inhibition of mutant IDH1 promoted chondrocyte differentiation in the conventional chondrosarcoma L835 cell line and caused cell cycle arrest in the dedifferentiated JJ012 cell line. Mutant IDH1-mediated modulation of SOX9 and CDKN1C expression regulated chondrosarcoma tumor progression, and DS-1001b upregulated the expression of these genes via a common mechanism involving the demethylation of H3K9me3. DS-1001b treatment reversed the epigenetic changes caused by aberrant histone modifications. The present data strongly suggest that inhibition of mutant IDH1 is a promising therapeutic approach in chondrosarcoma, particularly for the treatment of relapsed or dedifferentiated chondrosarcoma.

Relapsed acute myeloid leukemia (AML) after an allogeneic hematopoietic cell transplant (allo-HCT) entails a poor prognosis. Treating these cases is challenging due to lack of effective therapies and, in some cases, poor performance status and/or presence of graft-versus-host disease (GVHD), among others. No randomized controlled trial (RCT) has ever been conducted comparing a second allo-HCT against other treatments. Existing data are mainly from observational studies or registries. Success of a second allo-HCT is dependent on appropriately selecting patients who might achieve best outcomes with reasonable non-relapse mortality (NRM) risk. Several factors are associated with worse outcomes, namely a shorter time from first allo-HCT to relapse or to the second allo-HCT, and AML not being in complete hematologic remission (CR). Patients relapsing earlier than 6 months or having active/persistent disease should be enrolled in clinical trials. Limitations of the published literature include retrospective small size studies, a heterogeneous population, and absence of information on somatic mutations, among others. Future studies assessing the role of a second allo-HCT should evaluate the impact of IDH1, IDH2, or others on outcomes; and the feasibility and efficacy of targeted therapies in the pre-, peri-, or post-second allo-HCT setting.

Pediatric glioblastoma (pGBM) tumors have been identified as an entity distinct and different from the adult variety of GBM not only with respect to pathogenesis, genetics, and molecular alterations but also in clinical outcomes and overall survival. This study aims to evaluate the immunohistochemical profile of molecular markers in pediatric GBM and correlate them with clinical features and prognosis. We retrospectively analyzed 29 pGBMs (age range 3 to 18 years), operated at our institute between 2009 and 2014, and evaluated their clinical and histopathological features along with the immunohistochemical expression of clinically relevant molecular markers: H3K27M, p53, ATRX, and IDH1 (R132H), and correlated their expression with clinical features. We further assessed the prognostic value of these markers in our cohort of patients. The median overall survival (OS) of the cohort was 6.00 ± 0.882 months. The mean overall survival was 7.571 ± 1.118 months which was lower than in most studies. Preoperative Karnofsky Performance Score (KPS), extent of surgical resection, and adjuvant radiotherapy were found to be the clinical factors strongly influencing median survival (p

We evaluated the usefulness of 11C-methionine (MET) positron emission tomography/computed tomography (PET/CT) for grading cerebral gliomas according to the 2016 WHO classification with special emphasis on the presence of the isocitrate dehydrogenase 1 (IDH1) gene mutation and 1p/19q codeletion. In total, 144 patients underwent MET PET/CT before surgery. The ratios of the maximum standardized uptake value (SUV) of the gliomas to the mean SUV of the contralateral cortex on MET PET/CT (MET TNR) were calculated. The median MET TNRs in IDH1-mutant and IDH1-wildtype tumours were 1.95 and 3.35, respectively. From among 74 IDH1-mutant tumours, the oligodendrogliomas showed a higher median MET TNR than the astrocytic tumours (2.90 vs. 1.40, P

The current study aimed to assess patterns of failure (PoF) in anaplastic glioma (AG) patients managed with intensity-modulated radiation therapy (IMRT) and their relationship to molecular subtype. The outcomes of AG patients managed between 2008 and 2014 and entered into a prospective database were assessed, including PoF. AG was initially defined using the WHO 2007 classification, but for analysis, patients were subsequently recategorised based on WHO 2016 as anaplastic oligodendroglioma (AOD), astrocytoma isocitrate dehydrogenase (IDH) mutant (AAmut) or astrocytoma IDH wildtype (AAwt). Management involved IMRT and temozolomide (TMZ), including from 2011 patients with an IDH mutation (IDHmut) planned with 18F-fluoroethyltyrosine (FET) and 18F-fluorodeoxyglucose (FDG) positron-emission tomography (PET). PoF was local, marginal or distant in relation to the IMRT volume. Relapse-free survival (RFS) was calculated from the start of IMRT. A total of 156 patients were assessed, with median follow-up of 5.1 years. Of these patients, 75% were IDHmut, 44% were managed at first or later relapse and 73% received TMZ. Relapse occurred in 68 patients, with 6‑year RFS of 75.0, 48.8 and 2.5% for AOD, AAmut and AAwt, respectively (p

Diffuse astrocytic and oligodendroglial gliomas are the most common neuroepithelial tumors. Their classification is based on the integration of histological and molecular findings according to the classification of tumors of the central nervous system published by the World Health Organization (WHO) in 2016. This review describes the different entities and variants of diffuse gliomas and summarizes the current diagnostic criteria for these tumors. Based on the 2016 WHO classification and selected other publications, the histomolecular diagnostics of diffuse gliomas is presented and illustrated. Diffuse gliomas are divided into isocitrate dehydrogenase (IDH)-mutant or IDH-wildtype gliomas by detection of mutations in the IDH1 or IDH2 genes. Among the IDH-mutant gliomas, oligodendroglial tumors are characterized by combined losses of chromosome arms 1p and 19q. Loss of nuclear expression of the ATRX protein is a marker of IDH- mutant astrocytic gliomas. Glioblastoma, IDH-wildtype, is the most common diffuse glioma. Diffuse and anaplastic astrocytic gliomas without IDH mutation should be further evaluated for molecular features of glioblastoma, IDH-wildtype. Diffuse gliomas in the thalamus, brainstem, or spinal cord carrying a histone 3 (H3)-K27M mutation are classified as diffuse midline gliomas, H3-K27M-mutant. By determining the IDH and 1p/19q status, oligoastrocytomas can be stratified into either astrocytic or oligodendroglial gliomas. Gliomatosis cerebri is no longer regarded as a distinct glioma entity. Diffuse gliomas can today be classified accurately and reproducibly by means of histological, immunohistochemical, and molecular analyses.

Tumour-associated angiogenesis is associated with the malignancy and poor prognosis of glioma. Isocitrate dehydrogenase (IDH) mutations are present in the majority of lower-grade (WHO grade II and III) and secondary glioblastomas, but their roles in tumour angiogenesis remain unclear. Using magnetic resonance imaging (MRI), the cerebral blood flow (CBF) of IDH-mutated glioma was measured and compared with the IDH-wildtype glioma. The densities of microvessels in IDH-mutated and wildtype astrocytoma and glioblastoma were assessed by immunohistochemical (IHC) staining with CD34, and the pericytes were labelled with α-smooth muscle antigen (α-SMA), neural-glial antigen 2 (NG2) and PDGF receptor-β (PDGFR-β), respectively. Furthermore, glia-specific mutant IDH1 knock-in mice were generated to evaluate the roles of mutant IDH1 on brain vascular architectures. The transcriptions of the angiogenesis-related genes were assessed in TCGA datasets, including ANGPT1, PDGFB and VEGFA. The expressions of these genes were further determined by western blot in U87-MG cells expressing a mutant IDH1 or treated with 2-HG. The MRI results indicated that CBF was reduced in the IDH-mutated gliomas. The IHC staining showed that the pericyte coverages of microvessels were significantly decreased, but the microvessel densities (MVDs) were only slightly decreased in IDH-mutated glioma. The mutant IDH1 knock-in also impeded the pericyte coverage of brain microvessels in mice. Moreover, the TCGA database showed the mRNA levels of angiogenesis factors, including ANGPT1, PDGFB and VEGFA, were downregulated, and their promoters were also highly hyper-methylated in IDH-mutated gliomas. In addition, both mutant IDH1 and D-2-HG could downregulate the expression of these genes in U87-MG cells. Our results suggested that IDH mutations could reduce the pericyte coverage of microvessels in astrocytic tumours by inhibiting the expression of angiogenesis factors. As vascular pericytes play an essential role in maintaining functional blood vessels to support tumour growth, our findings imply a potential avenue of therapeutic strategy for IDH-mutated gliomas.

Purpose H3 K27 mutations, most commonly in H3F3A, are common in diffuse midline glioma. The exact frequency of these mutations in adults with gliomas in the midline location is unknown. This study was conducted to define the incidence of H3 K27M mutations in this location and to compare clinicopathological features with those of patients who do not harbor this mutation. Methods Consecutive glioma cases from 2007 to 2017 were screened for gliomas in the midline location. Immunohistochemistry was performed on all available tissue for mutations of H3 K27M, IDH1, and ARTX. Results Of 850 gliomas screened, 163 cases had midline glioma on MRI. Sufficient FFPE tissue was available for 123 cases (75%). H3 K27M mutation was identified in 18 of 123 cases (15%). All except one H3 K27M-mutant tumors were WHO grade III or IV on histology, while non-mutant tumors encompassed all four grades. The most common midline locations for H3 K27M-mutated tumors were midbrain (2/3; 67%), pons (4/11; 36%), and cerebellum (6/24; 25%). As compared to H3 K27M-wildtype tumors, there were no differences in age at diagnosis, sex, tumor grade, contrast enhancement on MRI, extent of resection, or treatment received. In this cohort, median survival was longer for patients with H3 K27M-mutated tumors (n = 18; 17.6 months) compared with high-grade wildtype tumors (n = 74; 7.7 months, p = 0.03). Conclusions H3 K27M mutations are common in midline gliomas in adults and can present in all midline locations. Survival comparison between H3 K27M-mutant and wildtype midline gliomas suggests that survival may be similar or possibly improved if the mutation is present.

Ivosidenib (Tibsovo®), a first-in-class, small molecule inhibitor of mutant isocitrate dehydrogenase 1 (IDH1), is an important new therapeutic option in the USA for treating adults with relapsed or refractory acute myeloid leukemia who have a susceptible IDH1 gene mutation. In such patients, oral ivosidenib is effective and generally well tolerated, producing encouraging rates and durations of complete remission (CR), CR or CR with partial hematologic recovery (CR/CRh), overall response, and overall survival. CR/CRh rates are consistent across most baseline characteristics. Ivosidenib also provides additional clinical benefits, including transfusion independence, improvements in hematologic variables, and deep molecular responses as measured by IDH1 mutation clearance in patients who achieve CR/CRh.

Diffuse leptomeningeal glioneuronal tumors (DLGNTs) are newly recognized as an entity in the 2016 revision of the WHO Classification of tumors of the central nervous system. They typically present as diffuse leptomeningeal infiltrates along the neuraxis with focal and superficial involvement of the parenchyma. Here, we report a DLGNT with unusual radiological and histological features. A 13-year-old girl presented with scoliosis and back pain. Magnetic resonance imaging demonstrated a syrinx from C2 to T11 and an intramedullary mass from T6 to T9-10. No leptomeningeal involvement was recognized. Histological examination of the gross total resection specimen revealed a low-grade neuroepithelial neoplasm predominantly infiltrating the spinal cord and only focally involving the leptomeninges. Chromosome microarray identified co-deletion of the short arm of chromosome 1 and the long arm of chromosome 19 as well as fusion of the KIAA1549 and BRAF genes. Next-generation sequencing demonstrated wild-type alleles at the mutational hotspots of IDH1 (R132) and IDH2 (R140 and R172). In contrast to most reported DLGNTs, the tumor described in this manuscript was characterized by a predominant parenchymal component and only minor leptomeningeal involvement both radiographically and histologically. Our case, therefore, expands the spectrum of radiological and histopathological features of this new entity. It also highlights the critical role of molecular genetic testing in establishing the diagnosis of DLGNT in unusual cases.

Oligodendrogliomas are defined by mutation in isocitrate dehydrogenase (NADP(+)) (IDH)1/2 genes and chromosome 1p/19q codeletion. World Health Organisation diagnosis endorses testing for 1p/19q codeletion to distinguish IDH mutant (Mut) oligodendrogliomas from astrocytomas because these gliomas require different treatments and they have different outcomes. Several methods have been used to identify 1p/19q status; however, these techniques are not routinely available and require substantial infrastructure investment. Two recent studies reported reduced immunostaining for trimethylation at lysine 27 on histone H3 (H3K27me3) in IDH Mut 1p/19q codeleted oligodendroglioma. However, the specificity of H3K27me3 immunostaining in this setting is controversial. Therefore, we developed an easy-to-implement immunohistochemical surrogate for IDH Mut glioma subclassification and evaluated a validated adult glioma cohort. We screened 145 adult glioma cases, consisting of 45 IDH Mut and 1p/19q codeleted oligodendrogliomas, 30 IDH Mut astrocytomas, 16 IDH wild-type (Wt) astrocytomas, and 54 IDH Wt glioblastomas (GBMs). We compared immunostaining with DNA sequencing and fluorescent in situ hybridization analysis and assessed differences in H3K27me3 staining between oligodendroglial and astrocytic lineages and between IDH1-R132H and non-canonical (non-R132H) IDH1/2 Mut oligodendroglioma. A loss of H3K27me3 was observed in 36/40 (90%) of IDH1-R132H Mut oligodendroglioma. In contrast, loss of H3K27me3 was never seen in IDH1-R132L or IDH2-mutated 1p/19q codeleted oligodendrogliomas. IDH Mut astrocytoma, IDH Wt astrocytoma and GBM showed preserved nuclear staining in 87%, 94%, and 91% of cases, respectively. A high recursive partitioning model predicted probability score (0.9835) indicated that the loss of H3K27me3 is frequent to IDH1-R132H Mut oligodendroglioma. Our results demonstrate H3K27me3 immunohistochemical evaluation to be a cost-effective and reliable method for defining 1p/19q codeletion along with IDH1-R132H and ATRX immunostaining, even in the absence of 1p/19q testing. Supplementary Information The online version contains supplementary material available at 10.1186/s40478-021-01194-7.

Background Acute myeloid leukemia (AML) remains one of the most common hematological malignancies, posing a serious challenge to human health. HSPA8 is a chaperone protein that facilitates proper protein folding. It contributes to various activities of cell function and also is associated with various types of cancers. To date, the role of HSPA8 in AML is still undetermined. Methods In this study, public datasets available from the TCGA (Cancer Genome Atlas) and GEO (Gene Expression Omnibus) were mined to discover the association between the expression of HSPA8 and clinical phenotypes of CN-AML. A series of bioinformatics analysis methods, including functional annotation and miRNA-mRNA regulation network analysis, were employed to investigate the role of HSPA8 in CN-AML. Results HSPA8 was highly expressed in the AML patients compared to the healthy controls. The high HSPA8 expression had lower overall survival (OS) rate than those with low HSPA8 expression. High expression of HSPA8 was also an independent prognostic factor for overall survival (OS) of CN-AML patients by multivariate analysis. The differential expressed genes (DEGs) associated with HSPA8 high expression were identified, and they were enriched PI3k-Akt signaling, cAMP signaling, calcium signaling pathway. HSPA8 high expression was also positively associated with micro-RNAs (hsa-mir-1269a, hsa-mir-508-3p, hsa-mir-203a), the micro-RNAs targeted genes (VSTM4, RHOB, HOBX7) and key known oncogenes (KLF5, RAN, and IDH1), and negatively associated with tumor suppressors (KLF12, PRKG1, TRPS1, NOTCH1, RORA). Conclusions Our research revealed HSPA8 as a novel potential prognostic factor to predict the survival of CN-AML patients. Our data also revealed the possible carcinogenic mechanism and the complicated microRNA-mRNA network associated with the HSPA8 high expression in AML.

Background The goal of this study is to disclose the clinically significant genomic alterations in the Chinese and Western patients with intrahepatic cholangiocarcinoma. Methods A total of 86 Chinese patients were enrolled in this study. A panel of 579 pan-cancer genes was sequenced for the qualified samples from these patients. Driver genes, actionability, and tumor mutational burden were inferred and compared to a cohort of Western patients. Results Totally, 36 and 12 driver genes were identified in the Chinese and Western cohorts, respectively. Of them, seven driver genes (IDH1, KRAS, TP53, BAP1, PBRM1, ARID1A, and NRAS) were shared by the two cohorts. Four driver genes (SPTA1, ARID2, TP53, and GATA1) were found significantly correlated with the tumor mutational burden. For both cohorts, half of the patients had actionable mutations. The two cohorts shared the most actionable genes but differed much in their frequency. Though KRAS mutations were at the first and second actionable rank respectively for the Chinese and Western populations, they were still at a relatively low level of actionable evidence. Conclusions The study on the clinical significance of genomic alterations directs the future development of precision medicine for intrahepatic cholangiocarcinoma treatment.

The 2016 World Health Organization classification of central nervous system tumor firstly introduces molecular diagnosis to glioma, while the molecular features of adult thalamic gliomas (ATGs) in a relatively large sample have not been reported. We aimed at exploring molecular characteristics in ATGs. The data of 97 and 575 newly diagnosed ATGs and superficial gliomas (SGs) patients were collected, and we performed a comparative analysis of molecular characteristics between them. We analyzed expressions of molecules as follow: H3 K27M, isocitrate dehydrogenase1 (IDH1), Ki-67, O6-Methylguanine-DNA methyltransferase (MGMT) promoter, EGFR, p53, ATRX, GFAP, Oligo2, PTEN, MGMT, and MMP9 by immunohistochemistry. Direct gene sequencing was performed to test the H3 K27M, IDH1, and TERT promoter mutation. The median age at diagnosis of ATGs was 36.0 years, and majority of them were high-grade glioma. We found a significant difference in H3 K27M mutation (P = 0.003), IDH1 mutation (P 0.001), MGMT promoter methylation (P = 0.005), and Ki67 0.1 (P 0.001) between ATGs and SGs. The statuses of IDH1 (P 0.001), MGMT promoter (P 0.001), and Ki67 (P 0.001) were significantly different between these two groups in lower-grade gliomas. And statuses of IDH1 (P 0.001), Ki67 (P 0.001), and EGFR (P = 0.032) were different between these two groups in high-grade gliomas. Only Ki67 0.1 was differentially expressed between lower- and high-grade gliomas in ATGs (P = 0.014). The high occurrence of H3 K27M mutation and Ki67 0.1, rare occurrence of IDH1 mutation, and MGMT promoter methylation in ATGs suggested that ATGs may be a distinct type of glioma entity.

Osteosarcoma (OS) is the most common primary malignant bone tumor in children and adolescents. Although activator of HSP90 ATPase activity 1 (AHA1) is reported to be a potential oncogene, its role in osteosarcoma progression remains largely unclear. Since metabolism reprogramming is involved in tumorigenesis and cancer metastasis, the relationship between AHA1 and cancer metabolism is unknown. In this study, we found that AHA1 is significantly overexpressed in osteosarcoma and related to the prognosis of osteosarcoma patients. AHA1 promotes the growth and metastasis of osteosarcoma both in vitro and in vivo. Mechanistically, AHA1 upregulates the metabolic activity to meet cellular bioenergetic needs in osteosarcoma. Notably, we identified that isocitrate dehydrogenase 1 (IDH1) is a novel client protein of Hsp90-AHA1. Furthermore, the IDH1 protein level was positively correlated with AHA1 in osteosarcoma. And IDH1 overexpression could partially reverse the effect of AHA1 knockdown on cell growth and migration of osteosarcoma. Moreover, high IDH1 level was also associated with poor prognosis of osteosarcoma patients. This study demonstrates that AHA1 positively regulates IDH1 and metabolic activity to promote osteosarcoma growth and metastasis, which provides novel prognostic biomarkers and promising therapeutic targets for osteosarcoma patients.

Intrahepatic cholangiocarcinoma (ICC) is a rare but fatal tumor. The isocitrate dehydrogenase 1 and 2 (IDH1/2) genes are known to be mutated in ICC. IDH1/2 mutations tend to be accompanied by enhanced hypermethylation at a subset of genomic loci. We sought to clarify the clinicopathological features, including prognostic value, of ICCs with IDH1/2 mutation-associated hypermethylation at a subset of genes. The mutation status of IDH1/2 and methylation status of 30 gene CpG island loci were analyzed in 172 cases of ICC using pyrosequencing and the MethyLight assay, respectively. The mutation status of IDH1/2 was correlated with clinicopathological features and the DNA methylation status at 30 gene loci. Then, the clinicopathological characteristics were analyzed regarding three-tiered methylation statuses in genes showing IDH1/2 mutation-associated methylation. IDH1/2 mutations were found in 9.3% of ICCs, and IDH1/2-mutated tumors were associated with the histological subtype, including the bile ductular type and small duct type, and poor differentiation. Eight DNA methylation markers showed associations with IDH1/2 mutations, and ICCs with > 5/8 methylated markers were associated with the bile ductular type or small duct type, absence of mucin production, absence of biliary intraepithelial neoplasia, and presence of chronic liver disease. > 5/8 methylated markers were an independent prognostic marker associated with better survival in both cancer-specific survival and recurrence-free survival. In summary, by analyzing the association between IDH1/2 mutations and DNA methylation in individual genes, we developed a panel of DNA methylation markers that were significantly associated with IDH1/2 mutations and were able to identify a subset of ICC with better clinical outcomes.

Inter- and intratumoral heterogeneity is a hallmark of glioblastoma (GBM) that facilitates recurrence, treatment resistance, and worse prognosis. O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation is a significant prognostic marker for Temozolomide (TMZ) resistance in GBM patients. YKL-40 is a molecular marker for the mesenchymal subtype of GBMs and is responsible for TMZ resistance. However, underlying mechanisms by which MGMT epigenetics impacts patient outcomes and the function of YKL-40 are not fully determined. Herein, we performed in vitro and in vivo experiments, six human IDH1/2 wild-type glioblastoma stem-like cells (GSCs) were established and studied to further determine a potential interaction of YKL-40 and MGMT promoter methylation. We demonstrated that YKL-40 functioned differently in human IDH1/2 wild-type GSCs. In MGMT promoter-methylated (MGMT-m) GSCs, it acted as a tumor suppressor gene. On the other hand, in MGMT promoter-unmethylated (MGMT-um) GSCs, it promoted tumorigenesis. Notably, the reason that YKL-40 played different roles in GSCs could not be interpreted by the molecular classification of each GSCs, but is a function of MGMT promoter methylation status and involves the RAS–MEK–ERK pathway. YKL-40 mediated TMZ sensitivity by activating DNA damage responses (DDRs) in MGMT-m GSCs, and it mediated resistance to TMZ by inhibiting DDRs in MGMT-um GSCs. Our report demonstrated that MGMT promoter methylation status might influence a gene’s function in human cancer. Moreover, our data also highlight the point that gene function should be investigated not only according to the molecular tumor classification, but also the epigenetic signature.

A case of a true dual-genotype IDH-mutant oligoastrocytoma with two different cell types within a single mass in a young woman is presented. Imaging findings of the left frontal infiltrating glioma predicted the two neoplastic components that were identified upon resection. Tissue examination demonstrated areas of tumor with contrasting histologic and molecular features, including specific IDH1, ATRX, TP53, TERT and CIC mutational profiles, consistent with oligodendroglioma and astrocytoma, respectively. The clinical and radiological course over 17 months from first diagnosis included three surgical resections with slow progression of the astrocytic component, and ultimately chemotherapy and radiation treatments were commenced. Reports of the clinical courses for these rare cases of dual-genotype oligoastrocytomas will inform therapy choices, to optimize benefit while minimizing side effects. The steadily increasing number of cases suggests that the neoplasm might be reconsidered as an official entity by the WHO.