Isocitrate Dehydrogenase Gene Research Articles

Advancing Systemic Therapy in Chondrosarcoma: New Horizons.

The systemic treatment landscape for advanced and metastatic chondrosarcoma, a malignancy with limited responsiveness to conventional therapies, has always been notoriously challenging. While standard chemotherapy offers minimal benefits, certain subtypes, such as mesenchymal and dedifferentiated chondrosarcomas, have shown some response to systemic therapies initially developed for other sarcomas. Investigational strategies are focusing on molecular targets, including mutations in the isocitrate dehydrogenase gene (IDH), signaling pathways, such as hedgehog and death receptor 5 (DR5) and immune modulation. IDH mutations, notably found in conventional and dedifferentiated chondrosarcomas, have prompted the evaluation of IDH inhibitors, which have demonstrated promising efficacy in preclinical and early clinical trials, despite limited data in chondrosarcoma. Additionally, the hedgehog pathway, implicated in chondrosarcoma progression, has been targeted with inhibitors, although clinical translation has shown mixed results. Immunotherapy, including programmed cell death 1 (PD-1) checkpoint inhibitors and chimeric antigen receptor-T (CAR-T) cells, is also being investigated but faces challenges due to the immunosuppressive tumour microenvironment. Among new approaches, DR5 agonists such as INBRX-109 have shown single-agent efficacy, with minimal toxicity, opening possibilities for use in combination therapies to improve outcomes. Given the heterogenous and treatment-resistant nature of chondrosarcoma, we highlight the need for multi-omics and genetic profiling to guide personalized, combination therapies that target multiple carcinogenic pathways. The integration of multi-targeted approaches could enhance efficacy, address tumour heterogeneity, and overcome resistance, presenting a hopeful direction for systemic therapy in this challenging cancer. The investigation of combination regimens with IDH inhibitors, immunotherapy and DR5 agonists hold promise for transforming the management of advanced chondrosarcoma.

Acute myeloid leukemia treatment outcomes with isocitrate dehydrogenase mutations: A systematic review and meta-analysis.

Isocitrate dehydrogenase (IDH) gene alterations and acute myeloid leukemia (AML) treatment results remain controversial. This study reviews the literature on IDH mutations in AML to determine the foundation of individualized therapy and improve effectiveness, survival time, and recurrence rate. Seven English and 2 Chinese databases were searched for literature on IDH mutations and AML outcomes. Pooled hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated. Twenty studies were included in this analysis. For the prognostic influence of IDH mutation on AML patients, the pooled HRs of overall survival in AML patients were 0.76 (95% CI, 0.63-0.93); the pooled HRs of event-free survival were 1.34 (95% CI, 1.15-1.57; heterogeneity: I2 = 52.2%, P = .027 < 0.05); the pooled HRs of recurrence free survival were 0.79 (95% CI, 0.61-1.02). The pooled HRs of overall survival in AML patients with mutant IDH1 were 1.62 (95% CI, 1.42-1.86) and of mutant IDH2 were 1.07 (95% CI, 0.89-1.29). The pooled HRs for event-free survival in AML patients with mutant IDH1 were 1.71 (95% CI, 1.40-2.08) and of mutant IDH2 were 0.93 (95% CI, 0.65-1.34). No evidence of publication bias was observed. Different subtypes of IDH mutations may lead to different AML prognoses, suggesting the feasibility of personalized treatment for AML patients.

Prevalence of SPOP and IDH Gene Mutations in Prostate Cancer in a Jordanian Population.

Speckle-type POZ (SPOP) is described as an essential tumor suppressor factor in gastric cancer, colorectal cancer, and prostate cancer (PCa). SPOP gene mutations were reported in primary human PCa. Isocitrate dehydrogenase-1 (IDH1) oncogene mutations were detected in gliomas, acute myeloid leukemia, some benign and malignant cartilaginous tumors, and only 1% of PCa. This study aimed to investigate the prevalence of mutations of SPOP and IDH1 genes in PCa in the Jordanian population. One hundred formalin-fixed paraffin-embedded tissue samples were collected from patients diagnosed with prostate adenocarcinoma. The obtained specimens were subjected to genomic DNA extraction, PCR amplification, and direct sequencing of exons 4, 5, 6, and 7 of the SPOP gene and exon 6 of the IDH1 gene. SPOP gene mutations were found in 17% of PCa cases, while no mutation was detected in the screened exon 6 of the IDH1 gene. Clinicopathological data demonstrated a strong correlation between prostate-specific antigen (PSA) levels and both Gleason score (GS) and the International Society of Urological Pathology (ISUP) grade group (GG). There was no significant correlation between PSA levels and age (p = 0.816) nor there were significant associations for SPOP mutational status with age (p = 0.659), PSA levels (p = 0.395), GS (p = 0.259), and ISUP GG (p = 0.424) in the tested population. The study found a strong correlation between PSA levels and both GS and ISUP GG. It also identified a high frequency (17%) of SPOP gene mutations in Jordanian Arab PCa patients, mainly in exon 7. No IDH1 mutations were detected in exon 6.

Genetic variants in mitochondrial sirtuins associated with brain tumor risk: a case-control study.

Previous studies on brain tumors have been performed on the nuclear genome, but limited studies have been reported on the mitochondrial genome. The mitochondrial sirtuin (SIRT3/SIRT4/SIRT5) has been mutated in different cancers. Limited studies have been performed on brain tumors. Isocitrate dehydrogenase (IDH) is an important marker, and polymorphism in the IDH gene has been reported to differentiate the brain tumor subtypes. The present study was designed to screen mitochondrial sirtuins and IDH polymorphisms in brain tumor patients. One thousand blood samples were collected (500 brain tumor patients and 500 controls). Two SNPs for each gene SIRT3 (rs12226697, rs570591), SIRT4 (rs184496260, 1925909), SIRT5 (rs2841522, rs2841523), and one SNP for IDH (rs11554137) was screened using Tetra-ARMS PCR. Logistic regression showed that the mutant genotype of selected SNPs was associated with increased disease incidence compared to wild type. Haplotype analysis and linkage disequilibrium (LD) showed a strong LD in brain tumor patients. Kaplan-Meier analysis showed that mutant allele frequency was found to be associated with a significant decrease in the survival of brain tumor patients. The present study showed that the mutant allele of selected mitochondrial sirtuins' SNP was associated with increased brain tumor risk.

IDH1/2 Mutations in Cancer: Unifying Insights and Unlocking Therapeutic Potential for Chondrosarcoma.

Chondrosarcomas, a rare form of bone sarcomas with multiple subtypes, pose a pressing clinical challenge for patients with advanced or metastatic disease. The lack of US Food and Drug Administration (FDA)-approved medications underscores the urgent need for further research and development in this area. Patients and their families face challenges as there are no systemic therapeutic options available with substantial effectiveness. A significant number (50-80%) of chondrosarcomas have a mutation in the isocitrate dehydrogenase (IDH) genes. This review focuses on IDH-mediated pathogenesis and recent pharmacological advances with novel IDH inhibitors, explores their potential therapeutic value, and proposes potential future avenues for clinical trials combining IDH inhibitors with other systemic agents for chondrosarcomas.

The Correlation Patterns of miRNA Expression with Targeted mRNA Transcripts in Glioma Patients with Wild-Type and Mutated Isocitrate Dehydrogenase (IDH) Genotypes.

Low-grade gliomas are divided into two main genetic phenotypes based on the presence or absence of mutations in the isocitrate dehydrogenase (IDH) genes. The mutated IDH phenotype (IDHmut), in contrast to the wild-type phenotype (IDHwt), is characterized by a more positive response to pharmacological intervention and a significantly longer survival time. In this study, we analyzed the differential co-expression of 225,000 microRNA-mRNA pairs at the level of correlations between microRNA levels and their potential mRNA targets. Analysis of the associative relationships of individual representatives of the selected pairs revealed that the level of mRNAs encoded by the ELN, ARL4C, C9orf64, PLAT, and FKBP9 genes associated with aggressive progression of glioma was increased in the IDHwt group. Meanwhile, the levels of miRNA-182, miRNA-455, and miRNA-891a associated with the negative prognosis in glioma were generally increased in the IDHmut group. Most (16/21) of the detected 21 microRNA-mRNA pairs with significant difference in regulation between IDHwt and IDHmut glioma samples had a weak or moderate positive correlation in IDHmut samples and a negative correlation in IDHwt samples. Therefore, our findings indicate that glioma samples from the IDHmut group with a positive prognosis potentially have a significantly less pronounced ability to microRNA-mediated regulation. We further suggest that such physiological disorders can lead to reduced tumor viability, resulting in an increased ability of the host to resist the spread of a malignant transformation of this genetic phenotype.

Dual phenotypes in recurrent astrocytoma, IDH-mutant; coexistence of IDH-mutant and IDH-wildtype components: a case report with genetic and epigenetic analysis

Mutations in the isocitrate dehydrogenase (IDH) gene are recognized as the key drivers in the oncogenesis of astrocytoma and oligodendroglioma. However, the significance of IDH mutation in tumor maintenance and malignant transformation has not been elucidated. We encountered a unique case of IDH-mutant astrocytoma that, upon malignant transformation, presented two distinct intratumoral components: one IDH-wildtype and one IDH-mutant. The IDH-wild-type component exhibited histological findings similar to those of small cell-type glioblastoma with a higher Ki-67 index than the IDH-mutant component. Despite their genetic divergence, both components exhibited similar comprehensive methylation profiles within the CpG island and were classified into methylation class of “Astrocytoma, IDH-mutant; High Grade” by the German Cancer Center (DKFZ) classifier v11.4. Phylogenetic analysis demonstrated that the IDH-wildtype component emerged as a subclonal component of the primary tumor. Detailed molecular analyses revealed that the loss of the IDH mutation was induced by the hemizygous loss of the entire arm of chromosome 2, on which IDH1 gene is located. Notably, the IDH-wild-type subclones uniquely acquired CDKN2A/B homozygous deletion and PDGFRA amplification, which is a marker of the aggressive phenotype of astrocytoma, IDH-mutant. Because these genetic abnormalities can drive oncogenic pathways, such as the PI3K/AKT/mTOR and RB signaling pathway, IDH-mutant gliomas that acquired these mutations were no longer dependent on the initial driver mutation, the IDH mutation. Molecular analysis of this unique case provides insight that in a subset of astrocytoma, IDH-mutant that acquired these genetic abnormalities, IDH mutation may not play a pivotal role in tumor growth and acquisition of these genetic abnormalities may contribute to the acquisition of resistance to IDH inhibitors.

A multi-center, clinical analysis of IDH-mutant gliomas, WHO Grade 4: implications for prognosis and clinical trial design.

Mutations in the Isocitrate Dehydrogenase (IDH) genes, IDH1 or IDH2, define a group of adult diffuse gliomas associated with a younger age at diagnosis and better prognosis than IDH wild-type glioblastoma. Within IDH mutant gliomas, a small fraction of astrocytic tumors present with grade 4 histologic features and poor prognosis. In molecular studies, homozygous deletion of CDKN2A/B is independently predictive of poor prognosis and short survival. As a consequence, 2021 WHO classification now also recognizes this molecular feature, CDKN2A/B deletion, as sufficient for classifying an astrocytoma as IDH-mutant, WHO Grade 4, regardless of histological grading. Here, we investigate outcomes of patients with WHO Grade 4 IDH-mutant astrocytoma both with and without CDKN2A/B deletion, to compare these groups and evaluate clinical and radiographic factors that contribute to survival. We retrospectively identified 79 patients with IDH-mutant astrocytoma with CDKN2A/B deletion detected at initial diagnosis across five international institutions as well as a comparison group of 51 patients with IDH-mutant, astrocytoma, histologically Grade 4 without detectable CDKN2A/B deletion. We assembled clinical and radiographic features for all patients. We find that CDKN2A/B deletion was associated with significantly worse overall survival (OS; p = 0.0004) and progression-free survival (PFS; p = 0.0026), with median OS of 5.0 years and PFS of 3.0 years, compared to 10.1 and 5.0 years for tumors with a grade 4 designation based only on histologic criteria. Multivariate analysis confirmed CDKN2A/B deletion as a strong negative prognosticator for both OS (HR = 3.51, p < 0.0001) and PFS (HR = 2.35, p = 0.00095). In addition, in tumors with CDKN2A/B deletion, preoperative contrast enhancement is a significant predictor of worse OS (HR 2.19, 95% CI 1.22-3.93, p = 0.0090) and PFS (HR = 1.74, 95% CI = 1.02-2.97, p = 0.0420). These findings underscore the severe prognostic impact of CDKN2A/B deletion in IDH-mutant astrocytomas and highlight the need for further refinement of tumor prognostic categorization. Our results provide a key benchmark of baseline patient outcomes for therapeutic trials, underscoring the importance of CDKN2A/B status assessment, in addition to histologic grading, in clinical trial design and therapeutic decision-making for IDH-mutant astrocytoma patients.

Molecular detection and phylogeny analysis of Coxiella burnetii detected from cattle and buffalo milk based on plasmid cbhE gene in West Azerbaijan of Iran

Humans and animals may get Q fever, which is caused by the Gram-negative coccobacillus Coxiella burnetii. The symptoms of Q fever may include a self-limiting febrile illness, pneumonia, endocarditis, or hepatitis. Infections are classified as either acute or persistent. Cattle, sheep, and goats are the most prevalent reservoir animals for this zoonosis. This research was conducted to identify C. burnetii using transposable and isocitrate dehydrogenase genes (IS1111, icd) and QpH1 plasmids. A total of 142 samples of raw buffalo and cow milk were collected from various locations within the West Azerbaijan region (see map). We used "nested" PCR techniques using primers based on the IS1111 and icd genes of C. burnetii, as well as conserved and variable portions of plasmid sequences, to identify C. burnetii and their plasmids in milk samples from buffalo and calves. Out of 142 milk samples that were positive for the chromosomal transposable genes (IS1111 and icd) at a rate of 16.9 percent (95 percent CI: 14.5 percent to 19.6 percent) and 7.1 % (95 percent CI: 5.59 percent to 9.08 percent), respectively, 86 samples were positive for the QpH1 plasmid at a rate of 60.5 percent (95 percent CI: 52.35 percent to 68.2 percent). Based on a phylogenetic study of the icd and QpH1 genes, the majority of the isolates had a similarity of 99.45–99.9 percent. Conclusion: It was determined that the buffalo population in West Azerbaijan province represents a significant epidemiological factor with respect to Q fever and consequently public health.

Sex differences in the molecular profile of adult diffuse glioma are shaped by IDH status and tumor microenvironment.

Sex differences in adult diffuse glioma (ADG) are well-established clinically, yet the underlying molecular mechanisms remain inadequately understood. Here, we aim to reveal molecular features and cellular compositions unique to each sex in ADG to comprehend the role of sex in disease etiology. We quantified sex differences in transcriptome of ADG using multiple independent glioma patient datasets. Next, we delved into the single-cell landscape to examine sex differences in gene expression and cellular composition. To explore how sex influences disease progression, we analyzed paired samples from primary and recurrent ADG cases, aiming to identify sex-specific differences in molecular and cellular features. Our analysis revealed that mutations in isocitrate dehydrogenase (IDH) genes and the tumor microenvironment emerged as primary influencers of sex-differential molecular enrichments. In IDHwt tumors, genes in neuronal signaling pathway are found to be enriched in male tumors, while genes in hypoxia and inflammatory response pathways are enriched in female tumors. This pattern was reversed in IDHmut gliomas. We hypothesized that these distinctions could be attributed to heterogeneous cellular composition between sexes. Using single-cell data, we observed distinctive patterns of sex differences in cell states, cell composition and cell-cell interaction in IDHwt and IDHmut tumors separately. Further, by comparing molecular changes in paired primary and recurrent ADG samples, we identified sex-specific differences in molecular characteristics and cellular compositions of recurrent tumors. Our results provide a comprehensive multi-level characterization of sex differences in ADG, such findings provide novel insights into glioma disease progression in each sex.

Fractal dimension and lacunarity measures of glioma subcomponents are discriminative of the grade of gliomas and IDH status.

Since the overall glioma mass and its subcomponents-enhancing region (malignant part of the tumor), non-enhancing (less aggressive tumor cells), necrotic core (dead cells), and edema (water deposition)-are complex and irregular structures, non-Euclidean geometric measures such as fractal dimension (FD or "fractality") and lacunarity are needed to quantify their structural complexity. Fractality measures the extent of structural irregularity, while lacunarity measures the spatial distribution or gaps. The complex geometric patterns of the glioma subcomponents may be closely associated with the grade and molecular landscape. Therefore, we measured FD and lacunarity in the glioma subcomponents and developed machine learning models to discriminate between tumor grades and isocitrate dehydrogenase (IDH) gene status. 3D fractal dimension (FD3D) and lacunarity (Lac3D) were measured for the enhancing, non-enhancing plus necrotic core, and edema-subcomponents using preoperative structural-MRI obtained from the The Cancer Genome Atlas (TCGA) and University of California San Francisco Preoperative Diffuse Glioma MRI (UCSF-PDGM) glioma cohorts. The FD3D and Lac3D measures of the tumor-subcomponents were then compared across glioma grades (HGGs: high-grade gliomas vs. LGGs: low-grade gliomas) and IDH status (mutant vs. wild type). Using these measures, machine learning platforms discriminative of glioma grade and IDH status were developed. Kaplan-Meier survival analysis was used to assess the prognostic significance of FD3D and Lac3D measurements. HGG exhibited significantly higher fractality and lower lacunarity in the enhancing subcomponent, along with lower fractality in the non-enhancing subcomponent compared to LGG. This suggests that a highly irregular and complex geometry in the enhancing-subcomponent is a characteristic feature of HGGs. A comparison of FD3D and Lac3D between IDH-wild type and IDH-mutant gliomas revealed that mutant gliomas had ~2.5-fold lower FD3D in the enhancing-subcomponent and higher FD3D with lower Lac3D in the non-enhancing subcomponent, indicating a less complex and smooth enhancing subcomponent, and a more continuous non-enhancing subcomponent as features of IDH-mutant gliomas. Supervised ML models using FD3D from both the enhancing and non-enhancing subcomponents together demonstrated high-sensitivity in discriminating glioma grades (~97.9%) and IDH status (~94.4%). A combined fractal estimation of the enhancing and non-enhancing subcomponents using MR images could serve as a non-invasive, precise, and quantitative measure for discriminating glioma grade and IDH status. The combination of 2-hydroxyglutarate-magnetic resonance spectroscopy (2HG-MRS) with FD3D and Lac3D quantification may be established as a robust imaging signature for glioma subtyping.

Therapeutic inhibition of isocitrate dehydrogenase mutations in glioma and cholangiocarcinoma: new insights and promises-a narrative review.

The identification of mutation hot spots in the isocitrate dehydrogenase (IDH) genes is one of the most important cancer genome-wide sequencing discoveries with relevant impact in the treatment of some orphan tumors. These genes were mostly found mutated in lower-grade gliomas (LGGs), acute myeloid leukaemia (AML), myelodysplastic syndromes (MDS) and myeloproliferative neoplasms (MPNs) and in cholangiocarcinoma. This aberrant genomic condition represents a therapeutic target of great interest in cancer research, especially in AML, given the limitations of currently approved therapies in this field. In this review, we investigate the role of IDH mutation and the mutant IDH (mIDH)-targeted therapies for cholangiocarcinoma and glioma. Here, we provide an overview of the IDH mutation role and discuss its role in tumorigenesis and progression of some solid cancers, in which the therapeutic strategy can be completely changed thanks to these brand-new therapeutic options. The encouraging early clinical data demonstrated to be a proof of concept for investigational mIDH1/2 inhibitors in tumors with a paucity of therapeutic possibilities. Moreover, we list the most important randomised clinical trials still active with their preliminary results.

Mutant IDH Modulates Suppressive Myeloid Populations in Malignant Glioma.

Mutations in the isocitrate dehydrogenase (IDH) genes IDH1 and IDH2 have critical diagnostic and prognostic significance in diffuse gliomas. Neomorphic mutant IDH activity has been previously implicated in T-cell suppression; however, the effects of IDH mutations on intratumoral myeloid populations remain underexplored. In this study, we investigate the influence of IDH status on the myeloid compartment using human glioma specimens and preclinical models. We performed RNA sequencing and quantitative immunofluorescence on newly diagnosed, treatment-naive IDH-mutant grade 4 astrocytoma and IDH-wild-type (IDH-WT) glioblastoma (GBM) specimens. We also generated a syngeneic murine model, comparing transcriptomic and cell-level changes in paired isogenic glioma lines that differ only in IDH mutational status. Among patient samples, IDH-mutant tumors displayed an underrepresentation of suppressive myeloid transcriptional signatures, which was confirmed at the cellular level with decreased numbers of intratumoral M2-like macrophages and myeloid-derived suppressor cells. Introduction of the mutant IDH enzyme into murine glioma was sufficient to recapitulate the transcriptomic and cellular shifts observed in patient samples. We provide transcriptomic and cellular evidence that mutant IDH is associated with a quantitative reduction of suppressive myeloid cells in gliomas and that introduction of the mutant enzyme is sufficient to result in corresponding cellular changes using an in vivo preclinical model. These data advance our understanding of high-grade gliomas by identifying key myeloid cell populations that are reprogrammed by mutant IDH and may be targetable through therapeutic approaches.

Low-Grade Gliomas: A New Mutation, New Targeted Therapy, and Many Questions.

The discovery in 2008 that many adult gliomas harbor a hitherto unknown mutation in the metabolic gene isocitrate dehydrogenase (IDH) initiated revolutionary advances in our understanding of the biology, and correspondingly our classification, of gliomas. IDH mutations are found in most nonglioblastoma adult gliomas and portend a better prognosis. Massive efforts have unraveled many of the pleiotropic cellular effects of these mutations and spawned several lines of investigation to target the effect to therapeutic benefit. In this article are reviewed the implications of the IDH mutation in gliomas, in particular focusing on recent studies that have culminated in a rare positive phase 3 trial in these generally refractory tumors.

The Leukemic Isocitrate Dehydrogenase (IDH) 1/2 Mutations Impair Myeloid and Erythroid Cell Differentiation of Primary Human Hematopoietic Stem and Progenitor Cells (HSPCs).

How hematopoietic stem and progenitor cell (HSPC) fate decisions are affected by genetic alterations acquired during AML leukemogenesis is poorly understood and mainly explored in animal models. Here, we study isocitrate dehydrogenase (IDH) gene mutations in the human model of HSPC and discuss the available literature on this topic. IDH1/2 mutations occur in ~20% of AML cases, are recognized among the mutations earliest acquired during leukemogenesis, and are targets of specific inhibitors (ivosidenib and enasidenib, respectively). In order to investigate the direct effects of these mutations on HSPCs, we expressed IDH1-R132H or IDH2-R140Q mutants into human CD34+ healthy donor cells via lentiviral transduction and analyzed the colony-forming unit (CFU) ability. CFU ability was dramatically compromised with a complete trilineage block of differentiation. Strikingly, the block was reversed by specific inhibitors, confirming that it was a specific effect induced by the mutants. In line with this observation, the CD34+ leukemic precursors isolated from a patient with IDH2-mutated AML at baseline and during enasidenib treatment showed progressive and marked improvements in their fitness over time, in terms of CFU ability and propensity to differentiate. They attained clonal trilinear reconstitution of hematopoiesis and complete hematological remission.

Roles of α-1,3-glucosyltransferase in growth and polysaccharides biosynthesis of Ganoderma lucidum

Ganoderma lucidum polysaccharides are valuable natural compounds possessing significant biological activity, with glycosyltransferases playing a crucial role in their biosynthesis. Although the function of β-1,3-glucosyltransferase in polysaccharides production is well understood, the role of α-1,3-glucosyltransferase in edible fungi remains unclear. In this study, over-expression of the α-1,3-glucosyltransferase gene in G. lucidum (glagt) was found to suppress the growth, with the maximum biomass and mycelial growth rate decreasing by 21.78 % and 79.61 %, respectively, a behavior distinct from β-1,3-glucosyltransferase. The fungal pellet diameter decreased by 38 % and the cell-wall thickness by 32.44 %, whereas intracellular and extracellular polysaccharides production increased by 27.58 % and 66.08 %, respectively. In the transcription level, overexpressing the glagt gene i) downregulated the citrate synthase and isocitrate dehydrogenase gene in the TCA cycle, disrupting energy metabolism and fungal growth; ii) upregulated key enzymes involved in UDP-glucose synthesis and glycosyltransferases (gl24465, gl24971, and gl22535); and iii) universally increased the transcriptional level of glucosidases gl21451, gl30087, and gl24581 by 22 %–397 %, contributing to cell-wall thinning to facilitate polysaccharides export. Conversely, the glagt gene downregulation promoted G. lucidum growth and decreased polysaccharides production. The results elucidate the roles of GLAGT and are expected to inspire in-depth exploration of polysaccharides biosynthesis pathways.

Molecular mechanisms of thrombotic complications in glial tumors

Cancer patients are at increased risk of venous thromboembolic complications (VTE), which are the second leading cause of death in these patients. Moreover, the maximum incidence of VTE occurs in tumors of the central nervous system [1]. Research is being conducted to identify laboratory biomarkers of increased risk of VTE, but to date data on their role are ambiguous. Patients with a mutation in the isocitrate dehydrogenase (IDH) gene are at lower risk of VTE, and the IDH mutation is associated with suppression of the production of tissue factor (TF) and podoplanin, the most studied molecules responsible for the occurrence of thromboembolic complications [2]. The main specific markers of VTE are based on immunohistochemical methods, which are possible only with histological examination of the tumor material. Therefore, it is important to find noninvasive biomarkers that could be used to assess the risk of venous thromboembolic complications. In this review, we will focus on highlighting the accumulated knowledge on this theme.

Lomustine with or without reirradiation for first progression of glioblastoma, LEGATO, EORTC-2227-BTG: study protocol for a randomized phase III study

BackgroundChemotherapy with lomustine is widely considered as standard treatment option for progressive glioblastoma. The value of adding radiotherapy to second-line chemotherapy is not known.MethodsEORTC-2227-BTG (LEGATO, NCT05904119) is an investigator-initiated, pragmatic (PRECIS-2 score: 34 out of 45), randomized, multicenter phase III trial in patients with first progression of glioblastoma. A total of 411 patients will be randomized in a 1:1 ratio to lomustine (110 mg/m2 every 6 weeks) or lomustine (110 mg/m2 every 6weeks) plus radiotherapy (35 Gy in 10 fractions). Main eligibility criteria include histologic confirmation of glioblastoma, isocitrate dehydrogenase gene (IDH) wild-type per WHO 2021 classification, first progression at least 6 months after the end of prior radiotherapy, radiologically measurable disease according to RANO criteria with a maximum tumor diameter of 5 cm, and WHO performance status of 0–2. The primary efficacy endpoint is overall survival (OS) and secondary endpoints include progression-free survival, response rate, neurocognitive function, health-related quality of life, and health economic parameters. LEGATO is funded by the European Union’s Horizon Europe Research program, was activated in March 2024 and will enroll patients in 43 sites in 11 countries across Europe with study completion projected in 2028.DiscussionEORTC-2227-BTG (LEGATO) is a publicly funded pragmatic phase III trial designed to clarify the efficacy of adding reirradiation to chemotherapy with lomustine for the treatment of patients with first progression of glioblastoma.Trial registrationClinicalTrials.gov NCT05904119. Registered before start of inclusion, 23 May 2023

Multidisciplinary Management of Isocitrate Dehydrogenase-Mutated Gliomas in a Contemporary Molecularly Defined Era.

Mutations in isocitrate dehydrogenase (IDH) genes, an early step in the ontogeny of lower-grade gliomas, induce global epigenetic changes characterized by a hypermethylation phenotype and are critical to tumor classification, treatment decision making, and estimation of patient prognosis. The introduction of IDH inhibitors to block the oncogenic neomorphic function of the mutated protein has resulted in new therapeutic options for these patients. To appreciate the implications of these recent IDH inhibitor results, it is important to juxtapose historical outcomes with chemoradiotherapy. Herein, we rationally evaluate recent IDH inhibitor data within historical precedents to guide contemporary decisions regarding the role of observation, maximal safe resection, adjuvant therapies, and the import of patient and tumor variables. The biological underpinnings of the IDH pathway and the mechanisms, impact, and limitations of IDH inhibitors, the actual magnitude of tumor regression and patient benefit, and emergence of resistance pathways are presented to guide future trial development. Management in the current, molecularly defined era will require careful patient selection and risk factor assessment, followed by an open dialog about the results of studies such as INDIGO, as well as mature data from legacy trials, and a discussion about risk-versus-benefit for the choice of treatment, with multidisciplinary decision making as an absolute prerequisite.

Beyond The Tumor: A Review of Standard Procedures and Emerging Advancements in Treatments for Glioblastomas

Glioblastomas are a type of brain tumor, which–according to the Glioblastoma Research Organization–affects more than 241,000 people across the globe. While the causes of glioblastomas are largely unknown, research has shown that some glioblastomas arise likely due to genetic factors such as mutations in isocitrate dehydrogenase (IDH) gene or a 9p/13q deletion. Glioblastomas are extremely hard to treat because they rapidly proliferate, and spread into nearby brain tissues. Surgery has long been used to remove glioblastomas, in order to minimize the intracranial pressure due to the growth of tumor and to reduce tumor bulk for other therapies. However, surgical removal has been tough, since it is very hard to remove all the cancerous cells, and there is a high chance of tumor recurrence. In 2005, the FDA approved the drug temozolomide to be used in glioblastoma treatment following surgical removal. However, temozolomide is minimally effective and causes adverse effects in many patients. As of now, there is no real cure for glioblastoma. Therefore, there is a need to explore new treatments in order to increase the lifespan of glioblastoma patients, as well as to reduce unwarranted effects due to treatment. Newer treatments such as tumor treating fields and nanobots have shown to be promising for glioblastoma treatments. These new advancements have shown to be more precise, which reduces the concern of toxicity to healthy tissues. By researching various treatments for glioblastomas, this paper’s main goal is to explore alternative ways to treat glioblastomas effectively.