Search

The androgen receptor (AR) is an established orchestrator of cell metabolism in prostate cancer (PCa), notably by inducing an oxidative mitochondrial program. Intriguingly, AR regulates cytoplasmic isocitrate dehydrogenase 1 (IDH1), but not its mitochondrial counterparts IDH2 and IDH3. Here, we aimed to understand the functional role of IDH1 in PCa. Mouse models, in vitro human PCa cell lines, and human patient‐derived organoids (PDOs) were used to study the expression and activity of IDH enzymes in the normal prostate and PCa. Genetic and pharmacological inhibition of IDH1 was then combined with extracellular flux analyses and gas chromatography–mass spectrometry for metabolomic analyses and cancer cell proliferation in vitro and in vivo. In PCa cells, more than 90% of the total IDH activity is mediated through IDH1 rather than its mitochondrial counterparts. This profile seems to originate from the specialized prostate metabolic program, as observed using mouse prostate and PDOs. Pharmacological and genetic inhibition of IDH1 impaired mitochondrial respiration, suggesting that this cytoplasmic enzyme contributes to the mitochondrial tricarboxylic acid cycle (TCA) in PCa. Mass spectrometry‐based metabolomics confirmed this hypothesis, showing that inhibition of IDH1 impairs carbon flux into the TCA cycle. Consequently, inhibition of IDH1 decreased PCa cell proliferation in vitro and in vivo. These results demonstrate that PCa cells have a hybrid cytoplasmic–mitochondrial TCA cycle that depends on IDH1. This metabolic enzyme represents a metabolic vulnerability of PCa cells and a potential new therapeutic target. [ABSTRACT FROM AUTHOR]

Ivosidenib is an isocitrate dehydrogenase 1 (IDH1) inhibitor that is FDA approved for patients with IDH1 mutation and acute myeloid leukemia and previously treated locally advanced or metastatic cholangiocarcinoma. In the Phase III trial ClarIDHy ivosidenib improved progression-free survival, 2.7 months versus 1.4 months (p < 0.0001) and overall survival (OS), median OS was 10.8 months for ivosidenib and 9.7 months for the placebo arm (p = 0.06) for patients with previously treated and IDH1 mutated cholangiocarcinoma. In this review article, we will address the mechanism of action of ivosidenib and data from early trials and safety from the randomized trial in cholangiocarcinoma. As a conclusion, future perspectives of IDH1 inhibition in IDH1 mutated tumors and possible strategies of sequencing and combinations will be reviewed and discussed. [ABSTRACT FROM AUTHOR]

Reprogramming of energy metabolism is one of the basic characteristics of cancer and has been proved to be an important cancer treatment strategy. Isocitrate dehydrogenases (IDHs) are a class of key proteins in energy metabolism, including IDH1, IDH2, and IDH3, which are involved in the oxidative decarboxylation of isocitrate to yield α-ketoglutarate (α-KG). Mutants of IDH1 or IDH2 can produce d-2-hydroxyglutarate (D-2HG) with α-KG as the substrate, and then mediate the occurrence and development of cancer. At present, no IDH3 mutation has been reported. The results of pan-cancer research showed that IDH1 has a higher mutation frequency and involves more cancer types than IDH2, implying IDH1 as a promising anti-cancer target. Therefore, in this review, we summarized the regulatory mechanisms of IDH1 on cancer from four aspects: metabolic reprogramming, epigenetics, immune microenvironment, and phenotypic changes, which will provide guidance for the understanding of IDH1 and exploring leading-edge targeted treatment strategies. In addition, we also reviewed available IDH1 inhibitors so far. The detailed clinical trial results and diverse structures of preclinical candidates illustrated here will provide a deep insight into the research for the treatment of IDH1-related cancers.

Abstract Acute myeloid leukemia (AML) is the most common acute leukemia in adults. While survival for younger patients over the last several decades has improved nearly sixfold with the optimization of intensive induction chemotherapy and allogeneic stem cell transplantation (alloHSCT), this effect has been largely mitigated in older and less fit patients as well as those with adverse-risk disease characteristics. However, the last 10 years has been marked by major advances in the molecular profiling of AML characterized by a deeper understanding of disease pathobiology and therapeutic vulnerabilities. In this regard, the classification of AML subtypes has recently evolved from a morphologic to a molecular and genetic basis, reflected by recent updates from the World Health Organization and the new International Consensus Classification system. After years of stagnation in new drug approvals for AML, there has been a rapid expansion of the armamentarium against this disease since 2017. Low-intensity induction therapy with hypomethylating agents and venetoclax has substantially improved outcomes, including in those previously considered to have a poor prognosis. Furthermore, targeted oral therapies against driver mutations in AML have been added to the repertoire. But with an accelerated increase in treatment options, several questions arise such as how to best sequence therapy, how to combine therapies, and if there is a role for maintenance therapy in those who achieve remission and cannot undergo alloHSCT. Moreover, certain subtypes of AML, such as those with TP53 mutations, still have dismal outcomes despite these recent advances, underscoring an ongoing unmet need and opportunity for translational advances. In this review, we will discuss recent updates in the classification and risk stratification of AML, explore the literature regarding low-intensity and novel oral combination therapies, and briefly highlight investigative agents currently in early clinical development for high-risk disease subtypes.

Abstract Background DNA methylation is a form of epigenetic modification that regulates gene expression. However, there are limited data on the comprehensive analysis of DNA methylation regulated gene mutations (DMRGM) in acute myeloid leukemia (AML) mainly referring to DNA methyltransferase 3α (DNMT3A), isocitrate dehydrogenase 1 (IDH1), isocitrate dehydrogenase 2 (IDH2), and Tet methylcytidine dioxygenase 2 (TET2). Results A retrospective study of the clinical characteristics and gene mutations in 843 newly diagnosed non-M3 AML patients was conducted between January 2016 and August 2019. 29.7% (250/843) of patients presented with DMRGM. It was characterized by older age, higher white blood cell count, and higher platelet count (P

Dody Priambada,1 Muhamad Thohar Arifin,1 Abdi Saputro,1 Azka Muzakka,1 Vega Karlowee,2 Udadi Sadhana,2 Yuriz Bakhtiar,1 Krisna Tsaniadi Prihastomo,1 Ajid Risdianto,1 Happy Kurnia Brotoarianto,1 Erie Andar,1 Zainal Muttaqin1 1Department of Neurosurgery, Faculty of Medicine, Diponegoro University/Dr. Kariadi Hospital, Semarang, Indonesia; 2Department of Clinical Pathology, Faculty of Medicine, Diponegoro University, Dr. Kariadi Hospital, Semarang, IndonesiaCorrespondence: Muhamad Thohar Arifin, Department of Neurosurgery, Faculty of Medicine, Diponegoro University/Dr. Kariadi Hospital, Dr. Soetomo Street Number 16-18, Semarang, Indonesia, Tel +62 813 2586 1628, Email Thohar@lecturer.undip.ac.idBackground: The current World Health Organization (WHO) 2021 classification of human glioma is based on key molecular biomarkers to define neoplastic entities. This review further delineates mutant IDH (isocitrate dehydrogenase) from wild-type IDH disease, a necessity given the large survival gap between mutant IDH and wild-type IDH tumors. In Indonesia, there are currently few reports on the distribution and significance of these mutations. Therefore, this research aims to determine the relationship between IDH mutations, as well as clinicopathological and prognostic factors in patients with gliomas. Other immunohistochemical markers including ATRX (alpha-thalassemia/mental retardation, X-linked), Ki67 and GFAP (glial fibrillary acidic protein) expression were also evaluated.Methods: Forty-two glioma samples were collected from patients who underwent surgery at Dr. Kariadi General Hospital in Semarang, Central Java, Indonesia. Fresh and paraffin-embedded, formalin-fixed tissue samples were removed and sectioned for hematoxylin and eosin staining, immunohistochemistry, and IDH analysis of mutation. Medical records were used to collect clinicopathological and survival data.Results: IDH1 mutations were discovered in 32 (76,1%) patients, and those with IDH1 mutation had longer overall survival when corresponded to patients with IDH1-wild-type. Lower expression of Ki67 was discovered to be very associated with a better prognosis.Conclusion: IDH1 mutations status showed a significant relationship with prognosis in patients with glioma. Meanwhile, other markers (ATRX, Ki67, and GFAP) did not correlate with the prognosis.Keywords: IDH1, immunohistochemical expression, prognosis, glioma, Indonesia

Simple Summary: Chondrosarcomas are cartilage tumours that often harbour a mutation in one of the isocitrate dehydrogenase (IDH) genes. IDH mutations are important drivers at the beginning of cartilage tumour development, but their role in later stages remains unclear. However, other IDH mutant tumour types do show an influence of this mutation on patient outcomes and therapies that specifically kill these IDH mutant tumour cells. Factors that could explain this discrepancy in the role of IDH mutations are differences in tumour type, elevated oncometabolite levels, the type of model used in preclinical studies (natural vs. introduced IDH mutation), and additional (epi)genetic alterations. The latter influence the downstream biological effects of an IDH mutation, and recent studies have indeed identified subgroups within IDH wildtype and mutant chondrosarcomas. Future studies should build upon these subgroups to improve the identification of effective treatments and biomarkers that predict which patients will benefit from these therapies. Chondrosarcomas are malignant cartilage-producing tumours that frequently harbour isocitrate dehydrogenase 1 and -2 (IDH) gene mutations. Several studies have confirmed that these mutations are key players in the early stages of cartilage tumour development, but their role in later stages remains ambiguous. The prognostic value of IDH mutations remains unclear and preclinical studies have not identified effective treatment modalities (in)directly targeting these mutations. In contrast, the IDH mutation status is a prognostic factor in other cancers, and IDH mutant inhibitors as well as therapeutic strategies targeting the underlying vulnerabilities induced by IDH mutations seem effective in these tumour types. This discrepancy in findings might be ascribed to a difference in tumour type, elevated D-2-hydroxyglutarate levels, and the type of in vitro model (endogenous vs. genetically modified) used in preclinical studies. Moreover, recent studies suggest that the (epi)genetic landscape in which the IDH mutation functions is an important factor to consider when investigating potential therapeutic strategies or patient outcomes. These findings imply that the dichotomy between IDH wildtype and mutant is too simplistic and additional subgroups indeed exist within chondrosarcoma. Future studies should focus on the identification, characterisation, and tailoring of treatments towards these biological subgroups within IDH wildtype and mutant chondrosarcoma. [ABSTRACT FROM AUTHOR]

Objective: The aim of this study was to explore the symptoms, treatment, and pathogenesis of ovarian juvenile granulosa cell tumors with Ollier's disease in children. Methods: From October 2019 to October 2020, clinical data were retrospectively analyzed for one case of ovarian juvenile granulosa cell tumors with Ollier's disease. Whole-exome sequencing and Sanger sequencing were used to detect gene mutation in ovarian tumor and chondroma tissue. NADP-dependent isocitrate dehydrogenase-1 (IDH1) and S6 ribosomal protein expression levels in cells transfected with wild-type or mutant plasmid were analyzed by Western blot. Results: The 4-year-old female showed multiple skeletal deformities, bilateral breast development with chromatosis, and vulvar discharge. Sex hormone assay suggested that estradiol and prolactin were elevated, and the x-ray of limbs suggested enchondroma. Pelvic ultrasound and abdominal CT revealed a right ovarian solid mass. Pathologic examination of the right ovarian solid mass showed a juvenile granulosa cell type. A c.394C>T (p. Arg132Cys) mutation of the IDH1 gene was detected in both the ovarian juvenile granulosa cell tumors and enchondroma. Transfection of HeLa cells with either WT or Mut plasmid caused 4.46- or 3.77-fold overexpression of IDH1 gene compared to nontransfected control cells, respectively. R132C mutation inhibited the phosphorylation of S6 ribosomal protein, which is central to the mTOR pathway. Postoperatively, estradiol and prolactin levels fell to values normal for her age and bilateral breast gradual retraction. Conclusion: The incidence of ovarian juvenile granulosa cell tumors with Ollier's disease in children may be caused by generalized mesodermal dysplasia; IDH1 gene mutation may play a facilitated role in this process. Surgical operation is the main treatment. We suggest that patients with ovarian juvenile granulosa cell tumors and Ollier's disease should undergo regular investigation. [ABSTRACT FROM AUTHOR]

Patients with gliomas, isocitrate dehydrogenase 1 (IDH1) mutation status have been studied as a prognostic indicator. Recent advances in machine learning (ML) have demonstrated promise in utilizing radiomic features to study disease processes in the brain. We investigate whether ML analysis of multiparametric radiomic features from preoperative Magnetic Resonance Imaging (MRI) can predict IDH1 mutation status in patients with glioma. This retrospective study included patients with glioma with known IDH1 status and preoperative MRI. Radiomic features were extracted from Fluid-Attenuated Inversion Recovery (FLAIR) and Diffused Weighted Imaging (DWI). The dataset was split into training, validation, and testing sets by stratified sampling. Synthetic Minority Oversampling Technique (SMOTE) was applied to the training sets. eXtreme Gradient Boosting (XGBoost) classifiers were trained, and the hyperparameters were tuned. Receiver operating characteristic curve (ROC), accuracy, and f1-scores were collected. A total of 100 patients (age: 55 ± 15, M/F 60/40); with IDH1 mutant (n = 22) and IDH1 wildtype (n = 78) were included. The best performance was seen with a DWI-trained XGBoost model, which achieved ROC with Area Under the Curve (AUC) of 0.97, accuracy of 0.90, and f1-score of 0.75 on the test set. The FLAIR-trained XGBoost model achieved ROC with AUC of 0.95, accuracy of 0.90, f1-score of 0.75 on the test set. A model that was trained on combined FLAIR-DWI radiomic features did not provide incremental accuracy. The results show that a XGBoost classifier using multiparametric radiomic features derived from preoperative MRI can predict IDH1 mutation status with > 90% accuracy.

Abstract Background Isocitrate dehydrogenase (IDH) is an appealing target for anticancer therapy, and IDH (IDH1/2) inhibitors have been approved for targeted therapy of acute myeloid leukemia (AML) and Cholangiocarcinoma. The therapeutic potential of IDH inhibitors for non‐small‐cell lung cancer (NSCLC) patients is under active clinical investigation. Thus, it would be necessary and meaningful to study the molecular and clinical characteristics of IDH mutation in NSCLC patients, especially in the Chinese population. Methods A total of 17,978 Chinese patients with NSCLC who underwent next ‐generation sequencing (NGS) testing were retrospectively reviewed. Results We identified 161 unique IDH mutations in 361 of 17,978 patients (2.01%). Common active‐site mutations, including IDH1R100, IDH1R132, IDH2R140, and IDH2R172, were detected in 154 patients (0.86%) and were associated with male sex (p = 0.004) and older age (p = 0.02). The IDH mutation spectra observed in NSCLC were quite different from those in glioma or AML. Patients with IDH active‐site mutations exhibited significantly higher coalterations in KRAS (p. G12/13/61, 22.1% vs. 8.2%, p

Both IDH1 (isocitrate dehydrogenase 1) and IDH2 (isocitrate dehydrogenase 2) mutations play a vital role in the development of gliomas through disruption of normal cellular metabolic processes. Here we describe a case of a patient with an IDH-mutant astrocytoma, in which both IDH1 and IDH2 mutations were detected within the same tumour. The patient remains disease-free, nine and a half years after her initial diagnosis. Interrogation of cancer genomic databases and a systematic review was undertaken, demonstrating the rarity of the co-occurrence of IDH1 and IDH2 mutations in a variety of cancer types, and in glioma specifically. Due to the favourable outcome observed in this patient, the potential effect of concurrent IDH1 and IDH2 mutations on survival was also investigated.

Abstract Background Alternative treatment strategies in melanoma beyond immunotherapy and mutation-targeted therapy are urgently needed. Wild-type isocitrate dehydrogenase 1 (wtIDH1) has recently been implicated as a metabolic dependency in cancer. The enzyme protects cancer cells under metabolic stress, including nutrient limited conditions in the tumor microenvironment. Specifically, IDH1 generates NADPH to maintain redox homeostasis and produces α-ketoglutarate to support mitochondrial function through anaplerosis. Herein, the role of wtIDH1 in melanoma is further explored. Methods The expression of wtIDH1 was determined by qRT-PCR, and Western blot in melanoma cell lines and the effect of wtIDH1 on metabolic reprogramming in melanoma was interrogated by LC-MS. The impact of wtIDH1 inhibition alone and in combination with chemotherapy was determined in cell culture and mouse melanoma models. Results Melanoma patients express higher levels of the wtIDH1 enzyme compared to normal skin tissue, and elevated wtIDH1 expression portends poor patient survival. Knockdown of IDH1 by RNA interference inhibited cell proliferation and migration under low nutrient levels. Suppression of IDH1 expression in melanoma also decreased NADPH and glutathione levels, resulting in increased reactive oxygen species. An FDA-approved inhibitor of mutant IDH1, ivosidenib (AG-120), exhibited potent anti-wtIDH1 properties under low magnesium and nutrient levels, reflective of the tumor microenvironment in natura. Thus, similar findings were replicated in murine models of melanoma. In light of the impact of wtIDH1 inhibition on oxidative stress, enzyme blockade was synergistic with conventional anti-melanoma chemotherapy in pre-clinical models. Conclusions These results demonstrate the clinical potential of wtIDH1 inhibition as a novel and readily available combination treatment strategy for patients with advanced and refractory melanoma. Graphical Abstract Schematic shows increased wild-type IDH1 expression and activity as an adaptive response to metabolic stress induced by chemotherapy.

Grade 4 adult gliomas are IDH-mutant astrocytomas and IDH-wildtype glioblastomas. They have a very high mortality rate, with survival at 5 years not exceeding 5%. We aimed to conduct a clinical imaging and morphogenetic characterization of them, as well as to identify the main negative prognostic factors that give them such aggressiveness. We conducted a ten-year retrospective study. We followed the clinical, imaging, and morphogenetic aspects of the cases. We analyzed immunohistochemical markers (IDH1, Ki-67, and nestin) and FISH tests based on the CDKN2A gene. The obtained results were analyzed using SPSS Statistics with the appropriate parameters. The clinical aspects representing negative prognostic factors were represented by patients’ comorbidities: hypertension (HR = 1.776) and diabetes mellitus/hyperglycemia (HR = 2.159). The lesions were mostly supratentorial, and the temporal lobe was the most affected. The mean volume was 88.05 cm3 and produced a midline shift with an average of 8.52 mm. Subtotal surgical resection was a negative prognostic factor (HR = 1.877). The proliferative index did not influence survival rate, whereas CDKN2A gene mutations were shown to have a major impact on survival. We identified the main negative prognostic factors that support the aggressiveness of grade 4 gliomas: patient comorbidities, type of surgical resection, degree of cell differentiation, and CDKN2A gene mutations.

Adult low-grade gliomas are a rare and aggressive pathology of the central nervous system. Some of their characteristics contribute to the patient’s life expectancy and to their management. This study aimed to characterize and identify the main prognostic factors of low-grade gliomas. The six-year retrospective study statistically analyzed the demographic, imaging, and morphogenetic characteristics of the patient group through appropriate parameters. Immunohistochemical tests were performed: IDH1, Ki-67, p53, and Nestin, as well as FISH tests on the CDKN2A gene and 1p/19q codeletion. The pathology was prevalent in females, with patients having an average age of 56.31 years. The average tumor volume was 41.61 cm3, producing a midline shift with an average of 7.5 mm. Its displacement had a negative impact on survival. The presence of a residual tumor resulted in decreased survival and is an independent risk factor for mortality. Positivity for p53 identified a low survival rate. CDKN2A mutations were an independent risk factor for mortality. We identified that a negative prognosis is influenced by the association of epilepsy with headache, tumor volume, and immunoreactivity to IDH1 and p53. Independent factors associated with mortality were midline shift, presence of tumor residue, and CDKN2A gene deletions and amplifications.

Myelodysplastic syndromes (MDSs) are a heterogeneous group of clonal hematopoietic stem cell disorders with treatment approaches tailored to the presence of cytopenias, disease risk, and molecular mutation profile. In higher-risk MDSs, the standard of care are DNA methyltransferase inhibitors, otherwise referred to as hypomethylating agents (HMAs), with consideration for allogeneic hematopoietic stem cell transplantation in appropriate candidates. Given modest complete remission rates (15%–20%) with HMA monotherapy and median overall survival of approximately 18 months, there is much interest in the investigation of combination and targeted treatment approaches. Furthermore, there is no standard treatment approach in patients with progression of disease after HMA therapy. In this review, we aim to summarize the current evidence for the B-cell lymphoma-2 inhibitor, venetoclax, and a variety of isocitrate dehydrogenase inhibitors in the treatment of MDSs along with discussing their potential role in the treatment paradigm of this disease. [ABSTRACT FROM AUTHOR]

Myelodysplastic syndrome (MDS) is a clonal disorder characterized by ineffective hematopoiesis and variable cytopenias with a considerable risk of progression to acute myeloid leukemia. Epidemiological assessment of MDS remains challenging because of evolving classification systems, but the overall incidence in the United States is estimated to be approximately 4 per 100,000 and increases with age. The sequential accumulation of mutations drives disease evolution from asymptomatic clonal hematopoiesis (CH) to CH of indeterminate potential, clonal cytopenia of unknown significance, to frank MDS. The molecular heterogeneity seen in MDS is highly complex and includes mutations of genes involved in splicing machinery, epigenetic regulation, differentiation, and cell signaling. Recent advances in the understanding of the molecular landscape of MDS have led to the development of improved risk assessment tools and novel therapies. Therapies targeting the underlying pathophysiology will hopefully further expand the armamentarium of MDS therapeutics, bringing us closer to a more individualized therapeutic approach based on the unique molecular profile of each patient and eventually improving the outcomes of patients with MDS. We review the epidemiology of MDS and the newly described MDS precursor conditions CH, CH of indeterminate potential, and CCUS. We then discuss central aspects of MDS pathophysiology and outline specific strategies targeting hallmarks of MDS pathophysiology, including ongoing clinical trials examining the efficacy of these therapeutic modalities. [ABSTRACT FROM AUTHOR]

Context: IDH1 is a pheochromocytoma/paraganglioma (PPGL) susceptibility gene; however, its role, especially in the Chinese population, has not been characterized. Objective: To determine the prevalence of somatic IDH1 hotspot variants in a large cohort of Chinese patients with PPGLs and to summarize associated phenotypes. Methods: This retrospective cross-sectional study was based on a main cohort of 1141 patients with PPGLs from 2 tertiary-care centers in China. We included 50 cases with urinary bladder paragangliomas (UBPGLs), of whom 29 were part of the main cohort and 21 were from other centers. Two additional cases with IDH1 hotspot variants not part of the main cohort were also included for summarizing IDH1- associated phenotypes. Next-generation sequencing of tumor DNA was used to analyze a customized panel of genes. Results: The overall prevalence of IDH1 hotspot variants in the main cohort was 0.5% (6/1141). Among those PPGLs without mutations in 15 common driver genes, the prevalence of IDH1 variants was 0.9% (4/455). When restricted to paraganglioma (PGL) without mutations, the prevalence reached 4.7% (4/86). Among UBPGLs, IDH1 hotspot variants accounted for 8% (4/50). Together, all 10 patients (9 PGLs and 1 pheochromocytoma) with IDH1 hotspot variants, including 3 females with concurrent EPAS1 hotspot variants, had apparently sporadic tumors, without metastasis or recurrence. There were 3 patients with biochemical data, all showing a non-adrenergic phenotype. Conclusions: The somatic IDH1 hotspot variants cause PPGL development in some Chinese patients, especially among those apparently sporadic PGLs with a non-adrenergic phenotype and without mutations in major PPGL driver genes. [ABSTRACT FROM AUTHOR]

Reprogramming of energy metabolism is one of the basic characteristics of cancer and has been proved to be an important cancer treatment strategy. Isocitrate dehydrogenases (IDHs) are a class of key proteins in energy metabolism, including IDH1, IDH2, and IDH3, which are involved in the oxidative decarboxylation of isocitrate to yield α -ketoglutarate (α -KG). Mutants of IDH1 or IDH2 can produce d -2-hydroxyglutarate (D-2HG) with α -KG as the substrate, and then mediate the occurrence and development of cancer. At present, no IDH3 mutation has been reported. The results of pan-cancer research showed that IDH1 has a higher mutation frequency and involves more cancer types than IDH2 , implying IDH1 as a promising anti-cancer target. Therefore, in this review, we summarized the regulatory mechanisms of IDH1 on cancer from four aspects: metabolic reprogramming, epigenetics, immune microenvironment, and phenotypic changes, which will provide guidance for the understanding of IDH1 and exploring leading-edge targeted treatment strategies. In addition, we also reviewed available IDH1 inhibitors so far. The detailed clinical trial results and diverse structures of preclinical candidates illustrated here will provide a deep insight into the research for the treatment of IDH1-related cancers. Isocitrate dehydrogenase 1 (IDH1) is a potential target for cancer treatment. Mutant IDH1 promotes the occurrence and development of cancer by influencing metabolism, immune microenvironment, epigenetics, and phenotype. [Display omitted] [ABSTRACT FROM AUTHOR]

Oligodendrogliomas are a type of rare and incurable gliomas whose metabolic profiles have yet to be fully examined. The present study examined the spatial differences in metabolic landscapes underlying oligodendrogliomas and should provide unique insights into the metabolic characteristics of these uncommon tumors. Single-cell RNA-sequencing expression profiles from 4044 oligodendroglioma cells derived from tumors resected from four locations frontal, temporal, parietal, and frontotemporoinsular) and in which 1p/19q co-deletion and IDH1 or IDH2 mutations were confirmed were computationally analyzed through a robust workflow to elucidate relative differences in metabolic pathway activities among the different locations. Dimensionality reduction using metabolic expression profiles exhibited clustering corresponding to each location subgroup. From the 80 metabolic pathways examined, over 70 pathways had significantly different activity scores between location subgroups. Further analysis of metabolic heterogeneity suggests that mitochondrial oxidative phosphorylation accounts for considerable metabolic variation within the same locations. Steroid and fatty acid metabolism pathways were also found to be major contributors to heterogeneity. Oligodendrogliomas display distinct spatial metabolic differences in addition to intra-location metabolic heterogeneity. [ABSTRACT FROM AUTHOR]

Aim: To review clinical evidence for current and emerging treatments for patients with acute myeloid leukemia (AML) who are ineligible for first-line induction chemotherapy. Methods: A systematic literature review was performed (28 October 2021) to identify clinical outcomes including overall survival (OS), event-free survival (EFS), relapse-free survival (RFS) and adverse events (AEs). Results: Of 233 references that met prespecified criteria, 26 studies were included. Adding targeted therapies (venetoclax/ivosidenib) to hypomethylating agents (HMAs) yielded better OS hazard ratios (HRs) (0.44–0.66) and EFS HRs (0.33–0.63) compared with other agents. AEs were more frequent with combination therapies than control arms, except with ivosidenib plus azacitidine. Conclusion: Targeted therapy combined with a HMA shows the most promising results in this difficult-to-treat population. Acute myeloid leukemia (AML) is a type of cancer of the bone marrow and blood that leads to overproduction of immature white blood cells. High-dose (intensive) chemotherapy is usually the first treatment option for AML. However, more than half of people newly diagnosed with AML cannot receive the recommended initial intensive chemotherapy due to older age or poor health. Treatment with low-dose cytarabine (LDAC) and hypomethylating agents (HMAs), such as azacitidine, is key for such people. We reviewed 26 clinical trials looking into available and developing treatment options for people who cannot have the recommended initial chemotherapy. The review found evidence that combining LDAC or HMA with a targeted therapy can improve survival. In AML, new therapies (such as ivosidenib, venetoclax and glasdegib) 'target' specific changes in the genes of cancer cells to slow or stop their division and growth. The greatest improvement in survival was seen in clinical trials where targeted therapies were added to azacitidine or LDAC. Targeted therapies may result in certain side effects that require regular monitoring. To provide patients with the benefits of targeted therapies they need to undergo genetic testing at the time of diagnosis. Tests to determine an individual's specific gene changes allows clinicians to develop personalised treatment plans with available targeted therapies. This shows promise in improving survival for people with AML who cannot receive initial intensive chemotherapy. [ABSTRACT FROM AUTHOR]

Background: DNA methylation is a form of epigenetic modification that regulates gene expression. However, there are limited data on the comprehensive analysis of DNA methylation regulated gene mutations (DMRGM) in acute myeloid leukemia (AML) mainly referring to DNA methyltransferase 3α (DNMT3A), isocitrate dehydrogenase 1 (IDH1), isocitrate dehydrogenase 2 (IDH2), and Tet methylcytidine dioxygenase 2 (TET2). Results: A retrospective study of the clinical characteristics and gene mutations in 843 newly diagnosed non-M3 AML patients was conducted between January 2016 and August 2019. 29.7% (250/843) of patients presented with DMRGM. It was characterized by older age, higher white blood cell count, and higher platelet count (P < 0.05). DMRGM frequently coexisted with FLT3-ITD, NPM1, FLT3-TKD, and RUNX1 mutations (P < 0.05). The CR/CRi rate was only 60.3% in DMRGM patients, significantly lower than in non-DMRGM patients (71.0%, P = 0.014). In addition to being associated with poor overall survival (OS), DMRGM was also an independent risk factor for relapse-free survival (RFS) (HR: 1.467, 95% CI: 1.030–2.090, P = 0.034). Furthermore, OS worsened with an increasing burden of DMRGM. Patients with DMRGM may be benefit from hypomethylating drugs, and the unfavorable prognosis of DMRGM can be overcome by hematopoietic stem cell transplantation (HSCT). For external validation, the BeatAML database was downloaded, and a significant association between DMRGM and OS was confirmed (P < 0.05). Conclusion: Our study provides an overview of DMRGM in AML patients, which was identified as a risk factor for poor prognosis. [ABSTRACT FROM AUTHOR]

Acute myeloid leukemia (AML) is the most common acute leukemia in adults. While survival for younger patients over the last several decades has improved nearly sixfold with the optimization of intensive induction chemotherapy and allogeneic stem cell transplantation (alloHSCT), this effect has been largely mitigated in older and less fit patients as well as those with adverse-risk disease characteristics. However, the last 10 years has been marked by major advances in the molecular profiling of AML characterized by a deeper understanding of disease pathobiology and therapeutic vulnerabilities. In this regard, the classification of AML subtypes has recently evolved from a morphologic to a molecular and genetic basis, reflected by recent updates from the World Health Organization and the new International Consensus Classification system. After years of stagnation in new drug approvals for AML, there has been a rapid expansion of the armamentarium against this disease since 2017. Low-intensity induction therapy with hypomethylating agents and venetoclax has substantially improved outcomes, including in those previously considered to have a poor prognosis. Furthermore, targeted oral therapies against driver mutations in AML have been added to the repertoire. But with an accelerated increase in treatment options, several questions arise such as how to best sequence therapy, how to combine therapies, and if there is a role for maintenance therapy in those who achieve remission and cannot undergo alloHSCT. Moreover, certain subtypes of AML, such as those with TP53 mutations, still have dismal outcomes despite these recent advances, underscoring an ongoing unmet need and opportunity for translational advances. In this review, we will discuss recent updates in the classification and risk stratification of AML, explore the literature regarding low-intensity and novel oral combination therapies, and briefly highlight investigative agents currently in early clinical development for high-risk disease subtypes. [ABSTRACT FROM AUTHOR]

Purpose: Isocitrate dehydrogenase enzyme 1 (IDH1) mutations at 132nd amino acid residue (R132*) result in the cellular accumulation of the oncometabolite, 2-hydroxyglutarate (2-HG). IDH305 is an orally bioavailable, brain-penetrant, mutant-selective allosteric IDH1 inhibitor demonstrating target engagement in preclinical models. This first-in human study was designed to identify the recommended dose for expansion/maximum tolerated dose of IDH305 in patients with IDH1R132-mutant acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). Methods: IDH305 was given at doses 75–750 mg twice daily in 41 patients with IDH1R132-mutant AML/MDS. Dose escalation was designed using Bayesian hierarchical model with overdose control principle and relationship with dose-limiting toxicity. Results: IDH305 exhibited rapid absorption with mean T1/2 approximately 4–10 h across doses. Interpatient variability was moderate and exposure increased with dose in a less than dose proportional manner. Most patients (35/41) demonstrated target engagement with reduction in 2-HG concentration at all doses. Complete remission (CR) or CR with incomplete count recovery occurred in 10/37 (27%) patients with AML and 1/ 4 patients with MDS. Adverse events (AEs) suspected to be related to study drug were reported in 53.7% of patients: increased blood bilirubin (14.6%), nausea (14.6%), increased alanine aminotransferase and aspartate aminotransferase (12.2%, each); most frequent grade 3 or 4 AEs were differentiation syndrome and tumor lysis syndrome (n = 3; 7.3%, each). Hepatotoxicity was manageable with dose modification. Conclusion: Due to potentially narrow therapeutic window, the study was prematurely halted and recommended phase 2 dose could not be declared. Trial registration: Clinicaltrials.gov identifier: NCT02381886. [ABSTRACT FROM AUTHOR]

Abstract Background Central conventional chondrosarcoma (CS) is the most common subtype of primary malignant bone tumour in adults. Treatment options are usually limited to surgery, and prognosis is challenging. These tumours are characterised by the presence and absence of IDH1 and IDH2 mutations, and recently, TERT promoter alterations have been reported in around 20% of cases. The effect of these mutations on clinical outcome remains unclear. The purpose of this study was to determine if prognostic accuracy can be improved by the addition of genomic data, and specifically by examination of IDH1, IDH2, and TERT mutations. Methods In this study, we combined both archival samples and data sourced from the Genomics England 100,000 Genomes Project (n = 356). Mutations in IDH1, IDH2, and TERT were profiled using digital droplet PCR (n = 346), whole genome sequencing (n=68), or both (n = 64). Complex events and other genetic features were also examined, along with methylation array data (n = 84). We correlated clinical features and patient outcomes with our genetic findings. Results IDH2-mutant tumours occur in older patients and commonly present with high-grade or dedifferentiated disease. Notably, TERT mutations occur most frequently in IDH2-mutant tumours, although have no effect on survival in this group. In contrast, TERT mutations are rarer in IDH1-mutant tumours, yet they are associated with a less favourable outcome in this group. We also found that methylation profiles distinguish IDH1- from IDH2-mutant tumours. IDH wild-type tumours rarely exhibit TERT mutations and tend to be diagnosed in a younger population than those with tumours harbouring IDH1 and IDH2 mutations. A major genetic feature of this group is haploidisation and subsequent genome doubling. These tumours evolve less frequently to dedifferentiated disease and therefore constitute a lower risk group. Conclusions Tumours with IDH1 or IDH2 mutations or those that are IDHwt have significantly different genetic pathways and outcomes in relation to TERT mutation. Diagnostic testing for IDH1, IDH2, and TERT mutations could therefore help to guide clinical monitoring and prognostication.

The present study intends to clarify the hypothesis that isocitrate dehydrogenase 1 (IDH1) mutation in cholangiocarcinoma impairs tumor progression by sensitizing cells to ferroptosis through the in vitro and in vivo experiments. Cholangiocarcinoma RBE cell line was transfected with IDH1 R132C mutation plasmids and treated with erastin to induce ferroptosis, which were then microscopically photographed. Cell viability rate was calculated by trypan blue staining. The lipid ROS level was determined by using flow cytometer. The BALB/c nude mice were injected subcutaneously with IDH1 knockout (KO), WT, or R132C mutation cell line, followed by injecting erastin intraperitoneally. The tumor tissue was surgically separated for the measurement of tumor volume and weight. The results showed that IDH1 mutant RBE cell line are sensitive to erastin-induced ferroptosis, evidenced by the increased number of propidium iodide-positive cells, the decreased cell viability, and increased lipid ROS level. However, current targeted inhibitors of IDH1 mutation (AG120 and IDH305) reversed these effects caused by IDH1 mutation. The in vivo experiment showed that IDH1 mutation in cholangiocarcinoma impairs tumor progression by sensitizing cells to erastin-induced ferroptosis. This study indicated that IDH1 mutation in cholangiocarcinoma impairs tumor progression by sensitizing cells to erastin-induced ferroptosis.

Neomorphic mutations in NADP-dependent isocitrate dehydrogenases (IDH1 and IDH2) contribute to tumorigenesis in several cancers. Although significant research has focused on the hypermethylation phenotypes associated with (D)2-hydroxyglutarate (D2HG) accumulation, the metabolic consequences of these mutations may also provide therapeutic opportunities. Here we apply flux-based approaches to genetically engineered cell lines with an endogenous IDH1 mutation to examine the metabolic impacts of increased D2HG production and altered IDH flux as a function of IDH1 mutation or expression. D2HG synthesis in IDH1-mutant cells consumes NADPH at rates similar to de novo lipogenesis. IDH1-mutant cells exhibit increased dependence on exogenous lipid sources for in vitro growth, as removal of medium lipids slows growth more dramatically in IDH1-mutant cells compared with those expressing wild-type or enzymatically inactive alleles. NADPH regeneration may be limiting for lipogenesis and potentially redox homeostasis in IDH1-mutant cells, highlighting critical links between cellular biosynthesis and redox metabolism.

Neomorphic mutations in NADP-dependent isocitrate dehydrogenases (IDH1 and IDH2) contribute to tumorigenesis in several cancers. Although significant research has focused on the hypermethylation phenotypes associated with (D)2-hydroxyglutarate (D2HG) accumulation, the metabolic consequences of these mutations may also provide therapeutic opportunities. Here we apply flux-based approaches to genetically engineered cell lines with an endogenous IDH1 mutation to examine the metabolic impacts of increased D2HG production and altered IDH flux as a function of IDH1 mutation or expression. D2HG synthesis in IDH1-mutant cells consumes NADPH at rates similar to de novo lipogenesis. IDH1-mutant cells exhibit increased dependence on exogenous lipid sources for in vitro growth, as removal of medium lipids slows growth more dramatically in IDH1-mutant cells compared with those expressing wild-type or enzymatically inactive alleles. NADPH regeneration may be limiting for lipogenesis and potentially redox homeostasis in IDH1-mutant cells, highlighting critical links between cellular biosynthesis and redox metabolism.

BackgroundRare multicentric lower-grade gliomas (LGGs) represent a unique opportunity to study the heterogeneity among distinct tumor foci in a single patient and to infer their origins and parallel patterns of evolution.MethodsIn this study, we integrate clinical features, histology, and immunohistochemistry for 4 patients with multicentric LGG, arising both synchronously and metachronously. For 3 patients we analyze the phylogeny of the lesions using exome sequencing, including one case with a total of 8 samples from the 2 lesions.ResultsOne patient was diagnosed with multicentric isocitrate dehydrogenase 1 (IDH1) mutated diffuse astrocytomas harboring distinct IDH1 mutations, R132H and R132C; the latter mutation has been associated with Li-Fraumeni syndrome, which was subsequently confirmed in the patient's germline DNA and shown in additional cases with The Cancer Genome Atlas data. In another patient, phylogenetic analysis of synchronously arising grade II and grade III diffuse astrocytomas demonstrated a single shared mutation, IDH1 R132H, and revealed convergent evolution via non-overlapping mutations in ATRX and TP53. In 2 cases, there was divergent evolution of IDH1-mutated and 1p/19q-codeleted oligodendroglioma and IDH1-mutated and 1p/19q-intact diffuse astrocytoma, occurring synchronously in one case and metachronously in a second.ConclusionsEach tumor in multicentric LGG cases may arise independently or may diverge very early in their development, presenting as genetically and histologically distinct tumors. Comprehensive sampling of these lesions can therefore significantly alter diagnosis and management. Additionally, somatic IDH1 R132C mutation in either multicentric or solitary LGG identifies unsuspected germline TP53 mutation, validating the limited number of published cases.

Atomic force microscopy (AFM) recently burst into biomedicine, providing morphological and functional characteristics of cancer cells and their microenvironment responsible for tumor invasion and progression, although the novelty of this assay needs to coordinate the malignant profiles of patients' specimens to diagnostically valuable criteria. Applying high-resolution semi-contact AFM mapping on an extended number of cells, we analyzed the nanomechanical properties of glioma early-passage cell cultures with a different IDH1 R132H mutation status. Each cell culture was additionally clustered on CD44+/− cells to find possible nanomechanical signatures that differentiate cell phenotypes varying in proliferative activity and the characteristic surface marker. IDH1 R132H mutant cells compared to IDH1 wild-type ones (IDH1wt) characterized by two-fold increased stiffness and 1.5-fold elasticity modulus. CD44+/IDH1wt cells were two-fold more rigid and much stiffer than CD44-/IDH1wt ones. In contrast to IDH1 wild-type cells, CD44+/IDH1 R132H and CD44-/IDH1 R132H did not exhibit nanomechanical signatures providing statistically valuable differentiation of these subpopulations. The median stiffness depends on glioma cell types and decreases according to the following manner: IDH1 R132H mt (4.7 mN/m), CD44+/IDH1wt (3.7 mN/m), CD44-/IDH1wt (2.5 mN/m). This indicates that the quantitative nanomechanical mapping would be a promising assay for the quick cell population analysis suitable for detailed diagnostics and personalized treatment of glioma forms. [ABSTRACT FROM AUTHOR]

Introduction: Amino-acid positron emission tomography (PET) is a validated metabolic imaging approach for the diagnostic work-up of gliomas. This study aimed to evaluate sex-specific radiomic characteristics of L-[S-methyl-11Cmethionine (MET)-PET images of glioma patients in consideration of the prognostically relevant biomarker isocitrate dehydrogenase (IDH) mutation status. Methods: MET-PET of 35 astrocytic gliomas (13 females, mean age 41 ± 13 yrs. and 22 males, mean age 46 ± 17 yrs.) and known IDH mutation status were included. All patients underwent radiomic analysis following imaging biomarker standardization initiative (IBSI)-conform guidelines both from standardized uptake value (SUV) and tumor-to-background ratio (TBR) PET values. Aligned Monte Carlo (MC) 100-fold split was utilized for SUV and TBR dataset pairs for both sex and IDH-specific analysis. Borderline and outlier scores were calculated for both sex and IDHspecificMC folds. Feature ranking was performed by R-squared ranking and Mann- Whitney U-test together with Bonferroni correction. Correlation of SUV and TBR radiomics in relation to IDH mutational status in male and female patients were also investigated. Results: There were no significant features in either SUV or TBR radiomics to distinguish female and male patients. In contrast, intensity histogram coefficient of variation (ih.cov) and intensity skewness (stat.skew) were identified as significant to predict IDH +/-. In addition, IDH+ females had significant ih.cov deviation (0.031) and mean stat.skew (-0.327) differences compared to IDH+ male patients (0.068 and -0.123, respectively) with two-times higher standard deviations of the normal brain background MET uptake as well. Discussion: We demonstrated that female and male glioma patients have significantly different radiomic profiles in MET PET imaging data. Future IDH prediction models shall not be built on mixed female-male cohorts, but shall rely on sex-specific cohorts and radiomic imaging biomarkers. [ABSTRACT FROM AUTHOR]

Metabolism reprogramming plays an important role in tumorigenesis and osteosarcoma metastasis. Sine oculis homeobox 4 (SIX4) is reported to be a key transcription factor that is involved in glycolysis reprogramming of cancer cells. However, the role of SIX4 in osteosarcoma progression remains unknown. The expression profile of SIX4 in OS was evaluated in surgery samples of osteosarcoma patients. Functional studies were performed in vitro and in vivo. We found that SIX4 is significantly overexpressed in osteosarcoma and related to the undesirable prognosis of osteosarcoma patients. SIX4 promotes progression of osteosarcoma via upregulating isocitrate dehydrogenase 1 (IDH1), which provides novel prognostic biomarkers and promising therapeutic targets for osteosarcoma patients. [ABSTRACT FROM AUTHOR]

BACKGROUND: The finding of an undifferentiated osteoclastic giant cell carcinoma in liver tissue is rare. The coexistence of this neoplasm in the absence of other primary liver tumors is exceptional. CLINICAL CASE: 72-year-old male patient with weight loss, asthenia, adynamia and hyporexia. The physical examination revealed: abnormal vascular patterns in the abdomen and abundant ascitic fluid. Laboratory studies reported: alpha-fetoprotein 571 ng/mL and Ca 19-9 antigen 156 ng/mL. The computed tomography reported multiple lesions in the right hepatic lobe, with peripheral lymphadenopathy. The histopathological study showed: pleomorphic cells, with abundant cytoplasm and osteoclastic phenotype; Immunohistochemistry reported negative expression of markers Hepar-1, Arginase-1, Glypican-3, CK7 and CK20, and positive expression of markers IDH1, CD163, CD68 and PD-L1. CONCLUSION: The expression of IDH1 and CD163 coincides with the diagnosis of poorly differentiated carcinoma with osteoclastic phenotype in the absence of other primary liver neoplasms. However, since the immunohistochemistry results were complex, it is important to perform the most exhaustive marker analysis in order to verify the accurate diagnosis. [ABSTRACT FROM AUTHOR]

Introduction: In the last decade, several molecular pathways in gliomagenesis have been discovered, with each involving a unique set of molecular alterations. IDH1 has become a diagnostic tool in the latest 2016 WHO Classification. The tumour protein, p53, is involved in the IDH-mutant arm, observed in astrocytoma and oligodendroglioma (grades II and III), and secondary glioblastoma. Meanwhile, EGFR and c-erbB2/HER2 were postulated to be expressed in higher-grade glioma as the disease progresses. Methods: A retrospective cross-sectional study was conducted to evaluate the association of IDH1, EGFR, p53 and c-erbB2/HER2 protein expression in astrocytic and oligodendroglial tumours with clinicopathological data in HUSM, Kota Bharu, Kelantan, Malaysia. This study examined 61 archived formalin-fixed paraffin-embedded (FFPE) tissue blocks of patients diagnosed with glioma. The immunohistochemistry (IHC) test was performed using antibodies, IDH1, EGFR, p53 and c-erbB2/HER2, and the protein expressions were evaluated microscopically. Finally, the association between IDH1, p53, EGFR and c-erbB2/HER with the clinicopathology variables were statistically analysed. Results: A total of 61 glioma cases consisting of 36 (59%) males and 25 (41%) females were included in this study. The IDH1 protein was positively expressed in 14 cases (23%), P53 was highly expressed in 26 cases (42.6%), and EGFR was substantially observed in 34 cases (55.7%). For glioblastoma cases, IDH1 was expressed in two cases (11.1%), EGFR in 14 cases (77.7%), p53 in 12 cases (66.7%) and c-erbB2 in 1 case (5.6%). Significant associations exist between IDH1, p53 and EGFR expressions in astrocytoma and oligodendroglial tumours with the histological types and WHO tumour grades. Conclusion: Recently, our knowledge regarding the genetics of central nervous system (CNS) tumors has expanded; hence, newer antibodies or molecular markers, which can be used in IHC, are continuously being developed. These antibodies, IDH1, p53 and EGFR markers are useful for diagnostic, prognostication and therapeutic. In addition, help to clarify the nature of cellular maturation, tissue differentiation, and tumor progression to be considered as an integral part of WHO classification of CNS tumours. [ABSTRACT FROM AUTHOR]

Neurotrophic tyrosine receptor kinase (NTRK) rearrangements are oncogenic drivers of various types of adult and pediatric tumors, including gliomas. However, NTRK rearrangements are extremely rare in glioneuronal tumors. Here, we report a novel NTRK2 rearrangement in a 24-year-old female with dysembryoplastic neuroepithelial tumor (DNT), a circumscribed WHO grade I benign tumor associated with epilepsy. By utilizing targeted RNA next-generation sequencing (NGS), fluorescence in situ hybridization (FISH), reverse transcriptasePCR (RT-PCR), and Sanger sequencing, we verified an in-frame fusion between NTRK2 and the lipomaHMGIC fusion partner-like 3 (LHFPL3). This oncogenic gene rearrangement involves 5' LHFPL3 and 3' NTRK2, retaining the entire tyrosine kinase domain of NTRK2 genes. Moreover, thetargetedDNANGSanalysis revealed an IDH1(p.R132H) mutation, a surprising finding in this type of tumor. The pathogenic mechanism of theLHFPL3::NTRK2 in this case likely involves aberrantdimerization and constitutive activation of RTK signaling pathways. [ABSTRACT FROM AUTHOR]

Recent years have seen some breakthroughs in the therapeutic landscape of advanced biliary tract cancer (BTC). Firstly, a better understanding of the molecular background of BTC has led to important improvements in the management of these hepatobiliary malignancies, with the advent of targeted agents representing an unprecedented paradigm shift, as witnessed by the FDA approval of pemigatinib and infigratinib for FGFR2-rearranged and ivosidenib in IDH1-mutant cholangiocarcinoma. In addition, several novel treatments are under assessment, including immune checkpoint inhibitors and combination chemotherapies. In the current review, we provide an overview of systemic treatment for metastatic BTC, summarizing recent clinical data on chemotherapy as well as the main results of targeted therapies and immunotherapy.

Chondrosarcoma (CS) is a rare tumour type and the most common primary malignant bone cancer in adults. The prognosis, currently based on tumour grade, imaging and anatomical location, is not reliable, and more objective biomarkers are required. We aimed to determine whether the level of circulating tumour DNA (ctDNA) in the blood of CS patients could be used to predict outcome. In this multi‐institutional study, we recruited 145 patients with cartilaginous tumours, of which 41 were excluded. ctDNA levels were assessed in 83 of the remaining 104 patients, whose tumours harboured a hotspot mutation in IDH1/2 or GNAS. ctDNA was detected pre‐operatively in 31/83 (37%) and in 12/31 (39%) patients postoperatively. We found that detection of ctDNA was more accurate than pathology for identification of high‐grade tumours and was associated with a poor prognosis; ctDNA was never associated with CS grade 1/atypical cartilaginous tumours (ACT) in the long bones, in neoplasms sited in the small bones of the hands and feet or in tumours measuring less than 80 mm. Although the results are promising, they are based on a small number of patients, and therefore, introduction of this blood test into clinical practice as a complementary assay to current standard‐of‐care protocols would allow the assay to be assessed more stringently and developed for a more personalised approach for the treatment of patients with CS.

IntroductionAmino-acid positron emission tomography (PET) is a validated metabolic imaging approach for the diagnostic work-up of gliomas. This study aimed to evaluate sex-specific radiomic characteristics of L-[S-methyl-11Cmethionine (MET)-PET images of glioma patients in consideration of the prognostically relevant biomarker isocitrate dehydrogenase (IDH) mutation status.MethodsMET-PET of 35 astrocytic gliomas (13 females, mean age 41 ± 13 yrs. and 22 males, mean age 46 ± 17 yrs.) and known IDH mutation status were included. All patients underwent radiomic analysis following imaging biomarker standardization initiative (IBSI)-conform guidelines both from standardized uptake value (SUV) and tumor-to-background ratio (TBR) PET values. Aligned Monte Carlo (MC) 100-fold split was utilized for SUV and TBR dataset pairs for both sex and IDH-specific analysis. Borderline and outlier scores were calculated for both sex and IDH-specific MC folds. Feature ranking was performed by R-squared ranking and Mann-Whitney U-test together with Bonferroni correction. Correlation of SUV and TBR radiomics in relation to IDH mutational status in male and female patients were also investigated.ResultsThere were no significant features in either SUV or TBR radiomics to distinguish female and male patients. In contrast, intensity histogram coefficient of variation (ih.cov) and intensity skewness (stat.skew) were identified as significant to predict IDH +/-. In addition, IDH+ females had significant ih.cov deviation (0.031) and mean stat.skew (-0.327) differences compared to IDH+ male patients (0.068 and -0.123, respectively) with two-times higher standard deviations of the normal brain background MET uptake as well.DiscussionWe demonstrated that female and male glioma patients have significantly different radiomic profiles in MET PET imaging data. Future IDH prediction models shall not be built on mixed female-male cohorts, but shall rely on sex-specific cohorts and radiomic imaging biomarkers.

Grade II and III gliomas are heterogeneous and aggressive diseases. More efficient prognosis models and treatment methods are needed. This study aims to construct a new risk model and propose a new strategy for grade II and III gliomas. The data were downloaded from The Cancer Genome Atlas (TCGA), the Gene Expression Omnibus (GEO), gene set enrichment analysis (GSEA), and the EMTome website for analysis. The Human Cell Landscape website and the Genomics of Drug Sensitivity in Cancer website were used for single-cell analysis and drug susceptibility analysis. Gene set enrichment analysis, gene function enrichment analysis, univariate and multivariate Cox regression analyses, Pearson’s correlation analysis, log-rank test, Kaplan–Meier survival analysis, and ROC analysis were performed. We constructed an immune-related prognostic model associated with the isocitrate dehydrogenase 1 (IDH1) mutation status. By analyzing the immune microenvironment of patients with different risk scores, we found that high-risk patients were more likely to have an inflammatory immune microenvironment and a higher programmed death ligand-1 (PD-L1) expression level. Epithelial–mesenchymal transition (EMT)-related gene sets were significantly enriched in the high-risk group, and the epithelial–mesenchymal transition phenotype was associated with a decrease in CD8+ T cells and an increase in M2 macrophages. Transforming growth factor-β (TGF-β) signaling was the most important signaling in inducing epithelial–mesenchymal transition, and TGFB1/TGFBR1 was correlated with an increase in CD8+ T cytopenia and M2 macrophages. Survival analysis showed that simultaneous low expression of TGFBR1 and PD-L1 had better survival results. Through single-cell analysis, we found that TGFB1 is closely related to microglia and macrophages, especially M2 macrophages. Finally, we discussed the sensitivity of TGFB1 inhibitors in gliomas using cell line susceptibility data. These results demonstrated a potential immunotherapy strategy in combination with the TGFB1/TGFBR1 inhibitor and PD-1/PD-L1 inhibitor for grade II and III gliomas.

Background: Isocitrate dehydrogenase (IDH) is an appealing target for anticancer therapy, and IDH (IDH1/2) inhibitors have been approved for targeted therapy of acute myeloid leukemia (AML) and Cholangiocarcinoma. The therapeutic potential of IDH inhibitors for non‐small‐cell lung cancer (NSCLC) patients is under active clinical investigation. Thus, it would be necessary and meaningful to study the molecular and clinical characteristics of IDH mutation in NSCLC patients, especially in the Chinese population. Methods: A total of 17,978 Chinese patients with NSCLC who underwent next ‐generation sequencing (NGS) testing were retrospectively reviewed. Results: We identified 161 unique IDH mutations in 361 of 17,978 patients (2.01%). Common active‐site mutations, including IDH1R100, IDH1R132, IDH2R140, and IDH2R172, were detected in 154 patients (0.86%) and were associated with male sex (p = 0.004) and older age (p = 0.02). The IDH mutation spectra observed in NSCLC were quite different from those in glioma or AML. Patients with IDH active‐site mutations exhibited significantly higher coalterations in KRAS (p. G12/13/61, 22.1% vs. 8.2%, p < 0.001) or BRAF (p. V600E, 6.5% vs. 1.0%, p < 0.001), but significantly lower coalterations in activating EGFR (e18–e20, 22.7 vs. 37.9%, p < 0.001) than IDH wild‐type patients. Furthermore, we found that active‐site IDH mutations were correlated with a short PFS (2–5.6 months) and short OS (2–9.5 months), which may arise as a resistance mechanism against common targeted drugs. In vitro, we experimentally observed that the combination of an IDH inhibitor and EGFR TKI could better inhibit lung cancer cell proliferation than an EGFR TKI alone. Conclusions: Taken together, this study reveals the molecular and clinical characteristics of IDH mutations in Chinese NSCLC patients and provides a theoretical basis for IDH‐directed treatment. The potential of IDH mutations as response markers for targeted therapy warrants further investigation. [ABSTRACT FROM AUTHOR]

IDH1 is a key metabolic enzyme for cellular respiration in the tricarboxylic acid (TCA) cycle that can convert isocitrate into α-ketoglutarate (α-KG) and generate NADPH. The reduction of IDH1 may affect dioxygenase activity and damage the body's detoxification mechanism. Many studies have shown that IDH1 is closely related to the occurrence and development of tumors, and the changes in IDH1 expression levels or gene mutations have appeared in many tumor tissues and produced a series of metabolic and immunity changes at the same time. To better understand the relationship between IDH1 and tumor development, this article reviews the latest advances in IDH1 and tumor metabolism, tumor immunity, IDH1 regulatory mechanisms and IDH1 target inhibitors. IDH1 is a key metabolic enzyme for cellular respiration. The changes in IDH1 expression or gene mutations may affect enzyme activity and damage the body's detoxification mechanism. Studies have shown that IDH1 is closely related to the occurrence and development of tumors, and the changes in IDH1 also produced a series of metabolic and immunity changes. To better understand the relationship between IDH1 and tumor development, this article reviews the latest advances in IDH1 and tumor metabolism, tumor immunity, IDH1 regulatory mechanisms and IDH1 target inhibitors. [ABSTRACT FROM AUTHOR]

A single-institution observational study with 43 newly diagnosed diffuse gliomas defined the isocitrate dehydrogenase 1 and 2 (IDH1/2) gene mutation status and evaluated the prognostic relevance of the methylation status of the epigenetic marker O6-methylguanine-DNA methyltransferase (MGMT). Younger patients (<50 years) with surgically resected glioma and temozolomide (TMZ) adjuvant chemotherapy were associated with better prognosis, consistent with other studies. The methylation status depends on the chosen method and the cut-off value determination. Methylation-specific PCR (MSP) established the methylation status for 36 glioma patients (19 (52.8%) positively methylated and 17 (47.2%) unmethylated) without relevancy for the overall survival (OS) (p = 0.33). On the other side, real-time methylation-specific PCR (qMSP) revealed 23 tumor samples (54%) that were positively methylated without association with OS (p = 0.15). A combined MSP analysis, which included the homogenous cohort of 24 patients (>50 years with surgical resection and IDH1/2-wildtype diffuse glioma), distinguished 10 (41.6%) methylated samples from 14 (58.4%) unmethylated samples. Finally, significant correlation between OS and methylation status was noticed (p ≈ 0.05). The OS of the hypermethylated group was 9.6 ± 1.77 months, whereas the OS of the unmethylated group was 5.43 ± 1.04 months. Our study recognized the MGMT promoter methylation status as a positive prognostic factor within the described homogenous cohort, although further verification in a larger population of diffuse gliomas is required. [ABSTRACT FROM AUTHOR]

Isocitrate dehydrogenase (IDH)1/2 mutations are the most frequent druggable alterations in intrahepatic cholangiocarcinoma (iCCA), reported in ~20% of cases. Preclinical evidence indicates that these mutations are associated with homologous recombination deficiency (HRD), which could be exploited as a target for platinum chemotherapy (ChT) and PARP inhibitors. However, the role of IDH1/2 mutations as surrogate biomarkers for platinum efficacy is unknown. We conducted a multicenter, propensity score‐matched analysis to investigate the impact of IDH1/2 mutations on progression‐free survival (PFS), overall response rate (ORR) and disease control rate (DCR) in patients with iCCA treated with platinum‐based ChT. An exploratory comparison of complex HRD estimates between IDH1/2 mutated and wild‐type tumors from TCGA was also performed. A total of 120 cases were matched in a 1:1 ratio (60 IDH1/2 mutant and 60 wild‐type). No differences were observed for platinum‐based PFS (7.7 vs 7.3 months, P =.970), DCR (66.1% vs 74.1%, P =.361) and ORR (27.8% vs 25.0%, P =.741). IDH1/2 mutations showed mutual exclusivity with genomic alterations in ATM, BRCA2, MST1R, NF1, FGFR2 and CDKN2A/B losses, respectively, with no clear survival and response differences. Among TCGA tumors, IDH1/2 mutated CCA did not show higher HRD compared to wild‐type cases. IDH1/2 mutations are not associated with increased sensitivity to platinum‐based ChT in iCCA patients. Deeper genomic sequencing is needed to elucidate the HRD phenotype in IDH1/2 mutant iCCA and exploit its therapeutic vulnerabilities. [ABSTRACT FROM AUTHOR]

Simple Summary: In our study, the involvement of IDH1 in atherosclerotic foam cells was explored. Inhibiting macrophage ferroptosis and foam cell formation by knocking down IDH1 is a promising study direction for better understanding the occurrence and progression of atherosclerosis, as well as the treatment targets for atherosclerosis. A distinctive feature of ferroptosis is intracellular iron accumulation and the impairment of antioxidant capacity, resulting in a lethal accumulation of lipid peroxides leading to cell death. This study was conducted to determine whether inhibiting isocitrate dehydrogenase 1 (IDH1) may help to prevent foam cell formation by reducing oxidized low-density lipoprotein (ox-LDL)-induced ferroptosis in macrophages and activating nuclear factor erythroid 2-related factor 2 (NRF2). Gene expression profiling (GSE70126 and GSE70619) revealed 21 significantly different genes, and subsequent bioinformatics research revealed that ferroptosis and IDH1 play essential roles in foam cell production. We also confirmed that ox-LDL elevates macrophage ferroptosis and IDH1 protein levels considerably as compared with controls. Ferrostatin-1 (Fer-1), a ferroptosis inhibitor, reduced ox-LDL-induced elevated Fe2+ levels, lipid peroxidation (LPO) buildup, lactate dehydrogenase (LDH) buildup, glutathione (GSH) depletion, glutathione peroxidase 4 (GPX4), ferritin heavy polypeptide 1 (FTH1), and solute carrier family 7 member 11 (SLC7A11) protein downregulation. More crucially, inhibiting IDH1 reduced Fe2+ overload, lipid peroxidation, LDH, and glutathione depletion, and elevated GPX4, FTH1, and SLC7A11 protein expression, resulting in a reduction in ox-LDL-induced macrophage ferroptosis. IDH1 inhibition suppressed ox-LDL-induced macrophage damage and apoptosis while raising NRF2 protein levels. We have demonstrated that inhibiting IDH1 reduces ox-LDL-induced ferroptosis and foam cell formation in macrophages, implying that IDH1 may be an important molecule regulating foam cell formation and may be a promising molecular target for the treatment of atherosclerosis. [ABSTRACT FROM AUTHOR]