Search Results (444)

Background/Objectives: Non-invasive motor mapping with navigated transcranial magnetic stimulation (nTMS) is an established diagnostic tool to identify spatial relationships between functional and tumor areas and to characterize motor excitability. Recently, nTMS has been used to analyze the impact of different brain tumor entities on motor excitability. However, entity-specific excitability patterns are not sufficiently validated yet. Methods: We retrospectively analyzed nTMS motor mapping data of 800 motor-eloquent brain tumor patients in this observational study. The motor excitability profile consisted of four nTMS parameters (resting motor threshold (RMT), cortical motor area, amplitude and latency) measured on both hemispheres. The relationship between motor excitability parameters and tumor entity, glioma subtype and motor status were assessed using multiple regressions analyses. Regression models included patient- and tumor-specific factors. Results: Gliomas had more frequent pathologic RMT ratios (OR 1.76, 95%CI: 1.06–2.89, p = 0.030) compared to benign entities. In the subgroup of gliomas, pathologic RMT ratios were more associated with the isocitrate dehydrogenase (IDH)-wildtype status (OR 0.43, 95%CI: 0.23–0.79, p = 0.006) and less so with higher WHO grades (OR 1.61, 95%CI: 0.96–2.71, p = 0.074). This was true for both IDH-mutant astrocytomas (OR 0.43, 95%CI: 0.20–0.91, p = 0.027) and IDH-mutant oligodendrogliomas (OR 0.43, 95%CI: 0.20–0.93, p = 0.031). Motor area enlargement on the tumor hemisphere was more frequently observed in lower WHO-graded gliomas (OR 0.87, 95%CI: 0.78–0.97, p = 0.019). Interestingly, a larger cortical motor area was additionally found for oligodendrogliomas on the healthy hemisphere (OR 1.18, 95%CI: 1.01–1.39, p = 0.041). Motor deficits were related with higher RMT (OR 1.12, 95%CI: 1.05–1.21, p = 0.001), reduced amplitude (OR 0.78, 95%CI: 0.64–0.96, p = 0.019) and prolonged latency (OR 1.12, 95%CI: 1.02–1.24, p = 0.025) in the tumor hemisphere. Conclusions: Neuroplastic phenomena such as adjustment of the motor excitability level and an enlargement of the nTMS-positive motor area were more frequently observed in benign tumors and in IDH-mutated gliomas. Consequently, patients experienced motor deficits less often, suggesting a differentiated susceptibility to resection-related paresis. Future studies will analyze which stimulation paradigms are most effective in stimulating and optimizing neuroplasticity processes to improve the functional outcomes (and thus the quality of life) for patients. Full article

Background/Objectives: This PETHEMA PCR-LMA study aimed to evaluate whether mutations detected by NGS (VAF cut-off of ≥5%) correlate with NPM1, FLT3-ITD, FLT3-TKD, IDH1, and IDH2 mutations detected using conventional PCR (analytical sensitivity 3%) in a nationwide network of seven reference laboratories. Methods: Between 2019 and 2021, 1685 adult AML patients with at least one centralized sample (NGS or PCR) at primary diagnosis or relapse/refractory episode were included. Results: During this period, 1288 paired NGS/PCR samples (1094 at diagnosis, 103 at relapse and 88 at refractoriness) were analyzed. Considering PCR the gold-standard, for NPM1 NGS sensitivity was 98.5% and specificity 98.9%, for FLT3-ITD 73.8% and 99.6%, for FLT3-TKD 84.5% and 99.3%, for IDH1 98.7% and 98.7%, and for IDH2 99.1% and 97.7%, respectively. Overall concordance rate of positive results between NGS (and PCR was 95% (262/276) for NPM1, 72% (149/206) for FLT3-ITD, 74% (49/66) for FLT3-TKD, 87% (77/89) for IDH1 and 84% (107/127) for IDH2. Overall, median days from sample reception until report were 7 for PCR and 28 for NGS. Conclusions: This study shows high concordance between NPM1 and IDH results using PCR and NGS. However, sensible important discrepancies are observed for FLT3 mutations. In our context, rapid screening for these druggable mutations should be performed by conventional PCR. Full article

Background: Oligodendrogliomas are a molecularly distinct subtype of glioma according to the WHO 2021 tumor classification, defined as isocitrate dehydrogenase (IDH) mutations and 1p/19q co-deletion. This updated classification has changed the approach to glioma management by emphasizing the critical role of molecular diagnostics. This study explores current therapeutic strategies for adult oligodendrogliomas and contextualizes findings with a patient with a Grade 3 oligodendroglioma of the hippocampus. Methods: A systematic review was conducted, synthesizing evidence from 36 studies published between 2021 and 2024. The review focuses on surgical resection, PCV chemotherapy (procarbazine, lomustine, vincristine), and radiotherapy, with progression-free survival (PFS) and overall survival (OS) as primary outcomes. Moreover, a 45-year-old woman diagnosed with an IDH-mutant, 1p/19q-co-deleted Grade 3 oligodendroglioma is presented to illustrate clinical management. Results: The review highlights the significance of molecular profiling in personalizing treatment strategies. The findings highlight that maximal safe surgical resection combined with PCV chemotherapy and radiotherapy optimizes PFS and OS. However, our case underwent chemotherapy and radiotherapy after a multidisciplinary consultation, demonstrating favorable initial outcomes. These findings reaffirm the importance of integrating molecular insight into clinical decision-making. Conclusions: Advancements in molecular diagnostics have profoundly enhanced the personalization of therapy for oligodendrogliomas, yielding improved survival outcomes. Optimal management should entail a multidisciplinary approach incorporating surgery, chemotherapy, and radiotherapy, guided by molecular features. This study reinforces the necessity of molecular-driven strategies to improve survival and quality of care for patients with oligodendroglioma. Full article

Background: Cholangiocarcinoma, a malignancy originating from the bile ducts, poses significant treatment challenges due to its typically late diagnosis and limited therapeutic options. However, recent advances in molecular genetics enable more personalized treatment approaches. A notable breakthrough in this context is the identification of isocitrate dehydrogenase (IDH) mutations, particularly IDH1 and IDH2, which occur in a subset of cholangiocarcinoma patients. Those with IDH1/2 mutations may benefit from targeted therapies. For instance, Ivosidenib, an IDH1 inhibitor, has shown efficacy in clinical trials, offering a new therapeutic option for patients with IDH1-mutant cholangiocarcinoma. Developing and implementing standardized protocols for testing and reporting mutation status are crucial for consistency and accuracy in clinical practice. Both the Idylla™ IDH1-2 Mutation Assay Kit as a FastTrack method and Next-Generation Sequencing (NGS) panels play critical roles in molecular characterization of cholangiocarcinoma. Methods: Under this aspect, a set of cholangiocarcinomas was tested using the Idylla™ platform regarding the respective recommended guidelines and standards of DIN EN ISO:17020 and DIN EN ISO:15198. Results: Overall, 25 clinically diagnosed intrahepatic cholangiocarcinomas or Adeno-CUPs were analyzed. IDH1/2 mutations were identified in 68% (17/25) of cases using both methods, with high concordance between NGS and Idylla™ results. Discrepancies were observed in two samples, where Idylla™ detected no mutations, but NGS reported IDH1 and IDH2 mutations, respectively. Conclusions: Idylla^TM offers a rapid, user-friendly, and specific method for detecting IDH1/2 mutations, ideal for immediate clinical needs. NGS, while more time-consuming and costly, provides comprehensive genetic profiles valuable for personalized medicine and research. The choice between these methods should be guided by the clinical context, resource availability, and individual patient needs. For routine diagnostics, we recommend an algorithmic approach starting with the FastTrack method followed by NGS for wildtype cases. Full article

Introduction: Glioma Grade 4 (GG4) tumors, which include both IDH-mutated and IDH wild-type astrocytomas, are the most prevalent and aggressive form of primary brain tumor. Radiomics is gaining ground in neuro-oncology. The integration of this data into machine learning models has the potential to improve the accuracy of prognostic models for GG4 patients. Karnofsky Performance Status (KPS), an established preoperative prognostic factor for survival, is commonly used in these patients. In this study, we developed a nomogram to identify patients with improved functional performance as indicated by an increase in KPS after surgery by analyzing radiomic features from preoperative 3D MRI scans. Methods: Quantitative imaging features were extracted from the -3D T1 GRE sequence of 157 patients from a single center and were used to develop the machine learning (ML) model. To improve applicability and create a nomogram, multivariable logistic regression analysis was performed to build a model incorporating clinical characteristics and radiomics features. Results: We labeled 55 cases in which KPS was improved after surgery (35%, KPS-flag = 1). The resulting model was evaluated according to test series results. The best model was obtained by XGBoost using the features extracted by pyradiomics, with a Matthew coefficient score (MCC) of 0.339 (95% CI: 0.330–0.3483) in cross-validation. The out-of-sample evaluation on the test set yielded an MCC of 0.302. A nomogram evaluating the improvement of KPS post-surgery was built based on statistically significant variables from multivariate logistic regression including clinical and radiomics data (c-index = 0.760, test set). Conclusions: MRI radiomic analysis represents a powerful tool to predict postoperative functional outcomes, as evaluated by KPS. Full article

Chondrosarcoma (CS), the second most common malignant bone tumor after osteosarcoma, accounts for 20–30% of all malignant bone tumors. It mainly affects adults, middle-aged, and elderly people. The CS family includes various entities displaying peculiar biological, genetic, and epigenetic characteristics and clinical behaviors. Conventional CS is the most common subtype. High-grade, dedifferentiated, and mesenchymal CS, as well as unresectable and metastatic CS, exhibit poor prognoses due to their intrinsic resistance to radiotherapy and chemotherapy, underscoring the urgent need for novel therapeutic strategies. CS research is dealing with several challenges. Experimental studies can rely on animal and patient-derived models, but the paucity of representative near-patient preclinical models has hampered predictive drug screening research. This review describes the main clinical and molecular features of CS subtypes, discussing recent data on the genetic alterations and molecular mechanisms involved in CS pathogenesis and progression. The review provides an overview of the current in vitro and in vivo CS models, discusses their advantages and limitations, and highlights the recent efforts in the development of new targeted therapies against CS dependencies, including IDH1/2 mutations, NAD⁺ dependency, and SIRT1-HIF-2α axis, or exploring DR5 targeting, antiangiogenic therapies, epigenetic drugs, and immunological approaches. All such strategies, in combination with advanced preclinical modeling and personalized multi-omic profiling, hold promise for improving the survival of patients with advanced CS. Full article

Gliomas within the insular region represent one of the most challenging problems in neurosurgical oncology. There are two main surgical approaches to address the complex vascular network and functional areas around the insula: the transsylvian approach and the transcortical approach. In the literature, there is not a clear consensus on the best approach in terms of safety and efficacy. The purpose of this study is to evaluate the effectiveness of these approaches and to analyze prognostic factors on the natural history of insular gliomas. Patients with newly diagnosed high-grade insular gliomas who underwent surgery between January 2019 and June 2024 were analyzed. The series was analyzed according to the classification of Berger–Sanai and Yaşargil. The Karnofsky performance score (KPS), extent of resection (EOR), progression-free survival (PFS), and overall survival (OS) were considered the outcome measures. A total of 58 primary high-grade insular glioma patients were enrolled in this study. The IDH mutation was found in 13/58 (22.4%); specifically, 3/13 (23.1%) were grade 4, and 10/13 (76.9%) were grade 3. Furthermore, 40/58 patients (69%) underwent gross total resection (GTR), 15 patients (26%) subtotal resection, and 3 patients (5%) partial resection. Middle cerebral artery encasement negatively affected the OS. GTR, radiotherapy, KPS, and autonomous deambulation at a month after surgery positively affected the OS. The surgical approach used was transsylvian and transcortical in 11 and 47 cases, respectively. The comparison between the two different approaches did not display differences in terms of neurological deficits and OS (p > 0.05). The transcortical approach was related to the greater achievement of GTR (p = 0.031). According to the Berger–Sanai classification, the transcortical approach has higher EOR and postoperative KPS when the lesion is in zone III-IV (p = 0.029). Greater resection of insular gliomas can be achieved with an acceptable morbidity profile and is predictive of improved OS. Both the transsylvian and transcortical corridors to the insula are associated with low morbidity profiles. The transcortical approach with intraoperative mapping is more favorable for achieving greater EOR, particularly in gliomas within the inferior border of the Sylvian fissure. Full article

Background and Objectives: Primary central nervous system (CNS) tumors are often associated with relatively poor outcomes. Data on the epidemiology and outcome of CNS tumors in Jordan are scarce. We aim to report the epidemiology and outcome of primary CNS tumors of patients managed at a comprehensive cancer care center in Jordan. Methods: We performed a retrospective chart review of all Jordanian patients with a primary CNS tumor diagnosis who were managed at the center between July 2003 and June 2019. We included all entities described in the 2021 CNS WHO classification system, in addition to pituitary neuroendocrine tumors (PitNETs). We used the Kaplan–Meier method to estimate the 1-year, 2-year, and 5-year overall survival (OS) rates for each entity. Results and Findings: We included 2094 cases. The numbers of pediatrics and adults were 652 (31.1%) and 1442 (68.9%), respectively. The three most common groups of tumors were “gliomas, glioneuronal tumors, and neuronal tumors” (n = 1200 [57.30%]), followed by meningiomas (n = 261 [12.5%]), embryonal tumors (n = 234 [11.2%]). The three most common tumor families were adult-type diffuse gliomas (n = 709 [33.8%]), medulloblastoma (n = 199 [9.5%]), and circumscribed astrocytic gliomas (n = 183 [8.7%]). The median survival for the entire cohort was 97 months (95CI; 81–112). Survival was significantly worse for males and adults compared to their respective counterparts. Among the most common tumor group, “gliomas, glioneuronal tumors, and neuronal tumors”, OS rates for adult-type diffuse gliomas were significantly lower than all other types. Overall, adult gliomas with IDH-mutations had a survival advantage over wildtype cases (IDH-mutant 1-year OS, 89% [82–97%] vs. IDH-wildtype 1-year OS, 60% [52–70%]; p < 0.001). Conclusions: We present a detailed analysis of the primary CNS tumors diagnosed in the largest cancer center in Jordan between 2003 and 2019. We compared the epidemiology and overall survival of these patients to worldwide estimates and found the epidemiology and outcome of these tumors comparable to worldwide trends. Full article

Purpose: This study aimed to investigate the efficacy and the clinical and molecular predictors of response and survival following venetoclax plus hypomethylating agents (VEN + HMAs) in adult relapsed/refractory acute myeloid leukemia (R/R AML) patients. Methods: We retrospectively analyzed 197 adult R/R AML patients who received the VEN + HMAs regimen. Molecular profiling was performed using targeted next-generation sequencing (NGS) of 139 genes to explore potential response and survival genetic predictors. Results: The median treatment cycle was 1 (1–4) cycle. The composite complete remission (CRc) rate, encompassing complete remission (CR) and CR with incomplete hematologic recovery (CRi), was 44.7%, while the overall response rate (ORR) reached 59.9%. With a median follow-up period of 14.0 months (range: 0.7–54.0 months), the 1-year and 2-year overall survival (OS) rates were 55.4% and 40.2%, respectively. Multivariate analyses revealed that mutations in NPM1 and SRSF2 were significantly associated with improved response rates. Conversely, prior exposure to HMA therapy, early relapse, and the presence of GATA2 mutations were linked to lower response rates. Regarding survival outcomes, the CBFB-MYH11 fusion gene, as well as mutations in NPM1 and IDH1/2, were found to be favorable prognostic factors for OS, whereas mutations in FLT3-ITD, TP53, DNMT3A, and GATA2 were associated with worse OS. Conclusions: The VEN + HMAs regimen demonstrated considerable efficacy in the treatment of R/R AML patients, with both response rates and overall survival being influenced by distinct genetic features. These findings provide valuable insights into optimizing personalized treatment strategies for this challenging patient population. Full article

Mutations in isocitrate dehydrogenase (IDH) genes are among the most frequently encountered molecular alterations in cholangiocarcinoma (CCA). These neomorphic point mutations endow mutant IDH (mIDH) with the ability to generate an R-enantiomer of 2-hydroxyglutarate (R2HG), a metabolite that drives malignant transformation through aberrant epigenetic signaling. As a result, pharmacologic inhibition of mIDH has become an attractive therapeutic strategy in CCAs harboring this mutation. One such inhibitor, ivosidenib, has already undergone clinical validation and received FDA approval in this disease, but there is still much work to be done to improve outcomes in mIDH CCA patients. In this publication we will review the pathogenesis and treatment of mIDH CCA with special emphasis on novel agents and combinations currently under investigation. Full article

Background: Some evidence of the value of 18F-fluorodesoxyglucose ([18F]FDG) positron emission tomography (PET) imaging for the assessment of gliomas and glioblastomas (GBMs) is emerging. The aim of this systematic review was to assess the role of [18F]FDG PET-based radiomics and machine learning (ML) in the evaluation of these neoplasms. Methods: A wide literature search of the PubMed/MEDLINE, Scopus, and Cochrane Library databases was made to find relevant published articles on the role of [18F]FDG PET-based radiomics and ML for the assessment of gliomas and GBMs. Results: Eight studies were included in the systematic review. Signatures, including radiomics analysis and ML, generally demonstrated a possible diagnostic value to assess different characteristics of gliomas and GBMs, such as the methylation status of the O6-methylguanine-DNA methyltransferase (MGMT) promoter, the isocitrate dehydrogenase (IDH) genotype, alpha thalassemia/mental retardation X-linked (ATRX) mutation status, proliferative activity, differential diagnosis with solitary brain metastases or primary central nervous system lymphoma, and prognosis of these patients. Conclusion: Despite some intrinsic limitations of radiomics and ML affecting the studies included in the review, some initial insights on the promising role of these technologies for the assessment of gliomas and GBMs are emerging. Validation of these preliminary findings in multicentric studies is needed to translate radiomics and ML approaches in the clinical setting. Full article

Cholangiocarcinoma (CCA) represents approximately 3% of all gastrointestinal cancers and is a highly heterogeneous and aggressive malignancy originating from the epithelial cells of the biliary tree. CCA is classified by anatomical location into intrahepatic (iCCA), extrahepatic (eCCA), gallbladder cancer (GBC), and ampullary cancers. Although considered a rare tumor, CCA incidence has risen globally, particularly due to the increased diagnosis of iCCA. Genomic and immune profiling studies have revealed significant heterogeneity within CCA, leading to the identification of molecular subtypes and actionable genetic alterations in 40–60% of cases, particularly in iCCA. Among these, FGFR2 rearrangements or fusions (7–15%) and IDH1 mutations (10–20%) are common in iCCA, while HER2 amplifications/overexpression are more frequent in eCCA and GBC. The tumor-immune microenvironment (TIME) of CCAs plays an active role in the pathogenesis and progression of the disease, creating a complex and plastic environment dominated by immune-suppressive populations. Among these, cancer-associated fibroblasts (CAFs) are a key component of the TIME and are associated with worse survival due to their role in maintaining a poorly immunogenic landscape through the deposition of stiff extracellular matrix and release of pro-tumor soluble factors. Improved understanding of CCA tumor biology has driven the development of novel treatments. Combination therapies of cisplatin and gemcitabine with immune checkpoint inhibitors (ICIs) have replaced the decade-long standard doublet chemotherapy, becoming the new standard of care in patients with advanced CCA. However, the survival improvements remain modest prompting research into more effective ways to target the TIME of CCAs. As key mechanisms of immune evasion in CCA are uncovered, novel immune molecules emerge as potential therapeutic targets. Current studies are exploring strategies targeting multiple immune checkpoints, angiogenesis, and tumor-specific antigens that contribute to immune escape. Additionally, the success of ICIs in advanced CCA has led to interest in their application in earlier stages of the disease, such as in adjuvant and neoadjuvant settings. This review offers a comprehensive overview of the immune biology of CCAs and examines how this knowledge has guided clinical drug development, with a focus on both approved and emergent treatment strategies. Full article

Background/Objectives: Anaplastic oligodendrogliomas (AOs) are central nervous system (CNS) World Health Organization (WHO) grade 3 gliomas characterized by isocitrate dehydrogenase (IDH) mutation (m)IDH and 1p/19q codeletion. AOs are typically treated with surgery and chemoradiation. However, chemoradiation can cause detrimental late neurocognitive morbidities and an accelerated disease course. The recently regulatory-approved vorasidenib, a brain-penetrating oral inhibitor of IDH1/2, has altered the treatment paradigm for recurrent/residual non-enhancing surgically resected CNS WHO grade 2 mIDH gliomas. Though vorasidenib can delay the time to chemoradiation for grade 2 gliomas, the implications for vorasidenib in non-grade 2 mIDH gliomas are not well understood. Results: We present a case of a 71-year-old male with a grade 3 non-enhancing oligodendroglioma successfully treated with vorasidenib with an 11% reduction in residual tumor volume. Vorasidenib was well tolerated in our patient with a mild elevation in his liver transaminases that resolved following a brief interruption in treatment. Conclusions: Our case suggests that vorasidenib may impart therapeutic benefits in this setting. This case illustrates the need for further investigation into these less commonly addressed scenarios and treatment strategies that extend beyond current guidelines. Full article

Glioblastoma (GBM) is an aggressive brain tumor characterized by extensive metabolic reprogramming that drives tumor growth and therapeutic resistance. Key metabolic pathways, including glycolysis, lactate production, and lipid metabolism, are upregulated to sustain tumor survival in the hypoxic and nutrient-deprived tumor microenvironment (TME), while glutamine and tryptophan metabolism further contribute to the aggressive phenotype of GBM. These metabolic alterations impair immune cell function, leading to exhaustion and stress in CD8+ and CD4+ T cells while favoring immunosuppressive populations such as regulatory T cells (Tregs) and M2-like macrophages. Recent studies emphasize the role of slow-cycling GBM cells (SCCs), lipid-laden macrophages, and tumor-associated astrocytes (TAAs) in reshaping GBM’s metabolic landscape and reinforcing immune evasion. Genetic mutations, including Isocitrate Dehydrogenase (IDH) mutations, Epidermal Growth Factor Receptor (EGFR) amplification, and Phosphotase and Tensin Homolog (PTEN) loss, further drive metabolic reprogramming and offer potential targets for therapy. Understanding the relationship between GBM metabolism and immune suppression is critical for overcoming therapeutic resistance. This review focuses on the role of metabolic rewiring in GBM, its impact on the immune microenvironment, and the potential of combining metabolic targeting with immunotherapy to improve clinical outcomes for GBM patients. Full article

The latest World Health Organization (WHO) classification of central nervous system tumors (WHO2021/5th) has incorporated molecular information into the diagnosis of each brain tumor type including diffuse glioma. Therefore, an artificial intelligence (AI) framework for learning histological patterns and predicting important genetic events would be useful for future studies and applications. Using the concept of multiple-instance learning, we developed an AI framework named GLioma Image-level and Slide-level gene Predictor (GLISP) to predict nine genetic abnormalities in hematoxylin and eosin sections: IDH1/2, ATRX, TP53 mutations, TERT promoter mutations, CDKN2A/B homozygous deletion (CHD), EGFR amplification (EGFRamp), 7 gain/10 loss (7+/10−), 1p/19q co-deletion, and MGMT promoter methylation. GLISP consists of a pair of patch-level GLISP-P and patient-level GLISP-W models, each pair of which is for a genetic prediction task, providing flexibility in clinical utility. In this study, the Cancer Genome Atlas whole-slide images (WSIs) were used to train the model. A total of 108 WSIs from the Tokyo Women’s Medical University were used as the external dataset. In cross-validation, GLISP yielded patch-level/case-level predictions with top performances in IDH1/2 and 1p/19q co-deletion with average areas under the curve (AUCs) of receiver operating characteristics of 0.75/0.79 and 0.73/0.80, respectively. In external validation, the patch-level/case-level AUCs of IDH1/2 and 1p/19q co-deletion detection were 0.76/0.83 and 0.78/0.88, respectively. The accuracy in diagnosing IDH-mutant astrocytoma, oligodendroglioma, and IDH-wild-type glioblastoma was 0.66, surpassing the human pathologist average of 0.62 (0.54–0.67). In conclusion, GLISP is a two-stage AI framework for histology-based prediction of genetic events in adult gliomas, which is helpful in providing essential information for WHO 2021 molecular diagnoses. Full article