Interferon-Stimulated Exonuclease Gene 20 is A Prognosis and Predictive Biomarker and Correlated with Macrophages M2 Polarization in Glioblastoma: A Pan-Cancer Analysis

Background: Since the mutation of isocitrate dehydrogenase 1 was confirmed to be different in the tumor microenvironment of multiple cancer types, several researchers have included it in the study of tumor-infiltrating immune cells. Interferon-stimulated exonuclease gene 20 (ISG20) plays a role in the modulation of immunity and inflammation, and its abnormally high expression is conducive for the progression of tumor malignancy. However, whether ISG20 is associated with isocitrate dehydrogenase 1 mutation during tumorigenesis and cancer progression remains unknown to date. Methods: TIMER2.0, ONCOMINE, GEPIA2, TCGA and CGGA were applied to assess the clinical significance of ISG20 and its correlation with tumor-infiltrating immune cells in glioma. cBioPortal and MethSurv databases were used to observe the genetic and DNA methylation changes of ISG20, respectively. Visualization of data was mostly achieved by R language. Quantitative real-time PCR (qRT-PCR) and Immunohistochemistry (IHC) was performed to evaluate the mRNA and protein expression.Results: ISG20 expression was significantly different in most cancers. However, when we combined ISG20 with isocitrate dehydrogenase 1 mutation, we found significant differences only in glioblastoma (GBM). The clinical values of ISG20 in glioblastoma showed that the ISG20 overexpression was strongly associated with a worse overall survival (OS). Additionally, ISG20 was altered in 9% of samples of patients with GBM, and ISG20 expression was negatively correlated with its DNA methylation level. More importantly, ISG20 expression was associated with macrophage alternatively activated (M2) polarization in glioblastoma. Conclusions: ISG20 overexpression is conducive to malignant phenotype but adverse to OS, suggesting that ISG20 is a potential therapeutic target and prognosis and predictive biomarker in patients with GBM.

IDH1/2 Mutations in Cancer Stem Cells and Their Implications for Differentiation Therapy

Isocitrate dehydrogenase 1 and 2 (IDH1/2) are enzymes recurrently mutated in various types of cancer, including glioma, cholangiocarcinoma, chondrosarcoma, and acute myeloid leukemia. Mutant IDH1/2 induce a block in differentiation and thereby contribute to the stemness and oncogenesis of their cells of origin. Recently, small-molecule inhibitors of mutant IDH1/2 have been Food and Drug Administration–approved for the treatment of IDH1/2-mutated acute myeloid leukemia. These inhibitors decrease the stemness of the targeted IDH1/2-mutated cancer cells and induce their differentiation to more mature cells. In this review, we elucidate the mechanisms by which mutant IDH1/2 induce a block in differentiation and the biological and clinical effects of the release into differentiation by mutant-IDH1/2 inhibitors. (J Histochem Cytochem 70:83–97, 2022)

What to use to treat AML: the role of emerging therapies

The development and approval of novel substances have resulted in substantial improvements in the treatment of acute myeloid leukemia (AML). In the current era of novel treatment options, genetic and molecular testing at the time of diagnosis and relapse becomes increasingly relevant. Midostaurin in combination with intensive chemotherapy is the standard of care as upfront therapy in younger AML patients with mutated fms-related tyrosine kinase 3 (FLT3). Gilteritinib, a second- generation FLT3 inhibitor, represents a key drug for relapsed/refractory (R/R) FLT3-mutated AML patients. Targeted therapy has also been developed for patients with mutated isocitrate dehydrogenase 1 (IDH1) and IDH2. The US Food and Drug Administration (FDA) approved ivosidenib as a monotherapy for newly diagnosed older adult IDH1-mutated patients and enasidenib for R/R IDH2-mutated AML patients. CPX-351, a liposomal formulation of daunorubicin and cytarabine, has become an important upfront treatment strategy for fit patients with therapy-related AML or AML with myelodysplasia-related changes that are generally challenging to treat. The antibody drug conjugate gemtuzumab ozogamicin was approved in combination with intensive therapy for patients with newly diagnosed (FDA/European Medicines Agency [EMA]) as well as R/R CD33+ AML. The combination of venetoclax, an oral selective B-cell leukemia/lymphoma-2 inhibitor, with hypomethylating agents or low-dose AraC (LDAC) has changed the treatment landscape and prognosis for older adult patients very favorably. The addition of glasdegib, a small-molecule hedgehog inhibitor, to LDAC is another example of novel options in older patients. Further substances have shown promising results in early clinical trials.

Role of miR-181c in Diet-induced obesity through regulation of lipid synthesis in liver

We recently identified a nuclear-encoded miRNA (miR-181c) in cardiomyocytes that can translocate into mitochondria to regulate mitochondrial gene mt-COX1 and influence obesity-induced cardiac dysfunction through the mitochondrial pathway. Because liver plays a pivotal role during obesity, we hypothesized that miR-181c might contribute to the pathophysiological complications associated with obesity. Therefore, we used miR-181c/d-/- mice to study the role of miR-181c in hepatocyte lipogenesis during diet-induced obesity. The mice were fed a high-fat (HF) diet for 26 weeks, during which indirect calorimetric measurements were made. Quantitative PCR (qPCR) was used to examine the expression of genes involved in lipid synthesis. We found that miR-181c/d-/- mice were not protected against all metabolic consequences of HF exposure. After 26 weeks, the miR-181c/d-/- mice had a significantly higher body fat percentage than did wild-type (WT) mice. Glucose tolerance tests showed hyperinsulinemia and hyperglycemia, indicative of insulin insensitivity in the miR-181c/d-/- mice. miR-181c/d-/- mice fed the HF diet had higher serum and liver triglyceride levels than did WT mice fed the same diet. qPCR data showed that several genes regulated by isocitrate dehydrogenase 1 (IDH1) were more upregulated in miR-181c/d-/- liver than in WT liver. Furthermore, miR-181c delivered in vivo via adeno-associated virus attenuated the lipogenesis by downregulating these same lipid synthesis genes in the liver. In hepatocytes, miR-181c regulates lipid biosynthesis by targeting IDH1. Taken together, the data indicate that overexpression of miR-181c can be beneficial for various lipid metabolism disorders.

Metabolic Pathways and Targets in Chondrosarcoma

Chondrosarcomas are the second most common primary bone malignancy. Chondrosarcomas are characterized by the production of cartilaginous matrix and are generally resistant to radiation and chemotherapy and the outcomes are overall poor. Hence, there is strong interest in determining mechanisms of cancer aggressiveness and therapeutic resistance in chondrosarcomas. There are metabolic alterations in chondrosarcoma that are linked to the epigenetic state and tumor microenvironment that drive treatment resistance. This review focuses on metabolic changes in chondrosarcoma, and the relationship between signaling via isocitrate dehydrogenase 1 and 2 (IDH1 and IDH2), hedgehog, PI3K-mTOR-AKT, and SRC, as well as histone acetylation and angiogenesis. Also, potential treatment strategies targeting metabolism will be discussed including potential synergy with immunotherapies.

Glioma Imaging by O-(2-18F-Fluoroethyl)-L-Tyrosine PET and Diffusion-Weighted MRI and Correlation With Molecular Phenotypes, Validated by PET/MR-Guided Biopsies

Gliomas exhibit high intra-tumoral histological and molecular heterogeneity. Introducing stereotactic biopsy, we achieved a superior molecular analysis of glioma using O-(2-18F-fluoroethyl)-L-tyrosine (FET)-positron emission tomography (PET) and diffusion-weighted magnetic resonance imaging (DWI). Patients underwent simultaneous DWI and FET-PET scans. Correlations between biopsy-derived tumor tissue values, such as the tumor-to-background ratio (TBR) and apparent diffusion coefficient (ADC)/exponential ADC (eADC) and histopathological diagnoses and those between relevant genes and TBR and ADC values were determined. Tumor regions with human telomerase reverse transcriptase (hTERT) mutation had higher TBR and lower ADC values. Tumor protein P53 mutation correlated with lower TBR and higher ADC values. α-thalassemia/mental-retardation-syndrome-X-linked gene (ATRX) correlated with higher ADC values. 1p/19q codeletion and epidermal growth factor receptor (EGFR) mutations correlated with lower ADC values. Isocitrate dehydrogenase 1 (IDH1) mutations correlated with higher TBRmean values. No correlation existed between TBRmax/TBRmean/ADC/eADC values and phosphatase and tensin homolog mutations (PTEN) or O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation. Furthermore, TBR/ADC combination had a higher diagnostic accuracy than each single imaging method for high-grade and IDH1-, hTERT-, and EGFR-mutated gliomas. This is the first study establishing the accurate diagnostic criteria for glioma based on FET-PET and DWI.

Assessment of Isocitrate Dehydrogenase 1 Genotype and Cell Proliferation in Gliomas Using Multiple Diffusion Magnetic Resonance Imaging

Objectives: To compare the efficacy of parameters from multiple diffusion magnetic resonance imaging (dMRI) for prediction of isocitrate dehydrogenase 1 (IDH1) genotype and assessment of cell proliferation in gliomas.Methods: Ninety-one patients with glioma underwent diffusion weighted imaging (DWI), multi-b-value DWI, and diffusion kurtosis imaging (DKI)/neurite orientation dispersion and density imaging (NODDI) on 3.0T MRI. Each parameter was compared between IDH1-mutant and IDH1 wild-type groups by Mann–Whitney U test in lower-grade gliomas (LrGGs) and glioblastomas (GBMs), respectively. Further, performance of each parameter was compared for glioma grading under the same IDH1 genotype. Spearman correlation coefficient between Ki-67 labeling index (LI) and each parameter was calculated.Results: The diagnostic performance was better achieved with apparent diffusion coefficient (ADC), slow ADC (D), fast ADC (D∗), perfusion fraction (f), distributed diffusion coefficient (DDC), heterogeneity index (α), mean diffusivity (MD), mean kurtosis (MK), and intracellular volume fraction (ICVF) for distinguishing IDH1 genotypes in LrGGs, with statistically insignificant AUC values from 0.750 to 0.817. In GBMs, no difference between the two groups was found. For IDH1-mutant group, all parameters, except for fractional anisotropy (FA) and D∗, significantly discriminated LrGGs from GBMs (P < 0.05). However, for IDH1 wild-type group, only ADC statistically discriminated the two (P = 0.048). In addition, MK has maximal correlation coefficient (r = 0.567, P < 0.001) with Ki-67 LI.Conclusion: dMRI-derived parameters are promising biomarkers for predicting IDH1 genotype in LrGGs, and MK has shown great potential in assessing glioma cell proliferation.

Decreased Expression of Metastasis Suppressor 1 Correlates with Poor Prognosis of Patients with Rectal Adenocarcinoma

Background: Venous thromboembolic events (VTE) are common causes of morbidity and mortality in glioblastoma patients. Mutation in the isocitrate dehydrogenase 1 enzyme (IDH1) is frequent in secondary glioblastoma and results in altered metabolomics. Objectives: This study evaluates whether IDH-1 status correlates with incidence of VTE in glioblastoma patients. Methods: Observational study of 398 cases of patients with glioblastoma, who all underwent surgery in a regional Neurosurgical centre between April 2012 and December 2014. IDH -1 status and Tissue factor (F3) protein expression were assessed by immunohistochemistry. Deep venous thrombosis (DVT) and pulmonary embolism (PE) were diagnosed by Doppler ultrasound and pulmonary CT angiogram respectively. Results: 336 cases were wild type (WT) IDH-1 (94.1%) and 21 cases were IDH-1 mutated (R132H) (5.9%). 51 patients had a thromboembolic event (15.3%), with all cases of VTE in WT IDH-1 tumors, a rate of 21.8% within this group. IDH-1 status had a significant correlation with VTE (p=0.033 Fisher exact test). As expected, mutant IDH was associated with prolonged patient survival (p=0.024 Log rank). The mean expression in IDH-1 wild type GBM was 7.14 and in R132h mutant GBM was 4.87 (log2 scale). This was highly statistically significant with a corrected P value of less than 0.0001. Conclusion: A significant association exists between IDH1 status in glioblastoma patients and the risk of VTE. Patients with wild type IDH-1 appear at high risk of VTE and appropriate precautions should be considered.