Cellular senescence in gliomas is a complex process that is induced by aging and replication, ionizing radiation, oncogenic stress, and the use of temozolomide. However, the escape routes that gliomas must evade senescence and achieve cellular immortality are much more complex, in which the expression of telomerase and the alternative lengthening of telomeres, as well as the mutation of some proto-oncogenes or tumor suppressor genes, are involved. In gliomas, these molecular mechanisms related to cellular senescence can have a tumor-suppressing or promoting effect and are directly involved in tumor recurrence and progression. From these cellular mechanisms related to cellular senescence, it is possible to generate targeted senostatic and senolytic therapies that improve the response to currently available treatments and improve survival rates. This review aims to summarize the mechanisms of induction and evasion of cellular senescence in gliomas, as well as review possible treatments with therapies targeting pathways related to cellular senescence.

BACKGROUND: Classification of gliomas based on tumor histology remains the gold standard in the diagnosis and prognosis of gliomas. However, the recent World Health Organization (WHO) classification has included molecular studies for diagnosis and prognostication. Immunohistochemical markers such as isocitrate dehydrogenase 1 (IDH1) and alpha thalassemia/mental retardation syndrome X-linked (ATRX) can be used for the diagnosis and prognosis of the majority of gliomas.
OBJECTIVE: We aim to study the frequencies of IDH1 and ATRX mutations in diffuse gliomas using surrogate immunohistochemical markers and correlate histopathological findings of gliomas with immunohistochemical findings.
METHODS: This was a retrospective study of one-year duration from January 2022 to December 2022, conducted in the department of pathology. Relevant data was retrieved from medical records. Histopathology blocks were collected and sent for immunohistochemical studies using tissue microarray for IDH1 and ATRX.
METHODS: Qualitative data were expressed in percentages and proportions. The difference in proportion was calculated using the chi-square test, and a p-value of <0.005 was taken as significant.
RESULTS: A total of 51 cases of diffuse gliomas were included in the study. The frequency of IDH1-positive diffuse astrocytomas was 33 (64.7%), and loss of ATRX was seen in 12 (23.5%) cases.
CONCLUSIONS: Immunohistochemistry serves as a surrogate marker to detect molecular alterations in diffuse gliomas.

BACKGROUND: The T2-FLAIR mismatch sign is a characteristic imaging biomarker for astrocytoma, isocitrate dehydrogenase (IDH)-mutant. However, investigators have provided varying interpretations of the positivity/negativity of this sign given for individual cases the nature of qualitative visual assessment. Moreover, MR sequence parameters also influence the appearance of the T2-FLAIR mismatch sign. To resolve these issues, we used synthetic MR technique to quantitatively evaluate and differentiate astrocytoma from oligodendroglioma.
METHODS: This study included 20 patients with newly diagnosed non-enhanced IDH-mutant diffuse glioma who underwent preoperative synthetic MRI using the Quantification of Relaxation Times and Proton Density by Multiecho acquisition of a saturation-recovery using Turbo spin-Echo Readout (QRAPMASTER) sequence at our institution. Two independent reviewers evaluated preoperative conventional MR images to determine the presence or absence of the T2-FLAIR mismatch sign. Synthetic MRI was used to measure T1, T2 and proton density (PD) values in the tumor lesion. Receiver operating characteristic (ROC) curve analysis was performed to evaluate the diagnostic performance.
RESULTS: The pathological diagnoses included astrocytoma, IDH-mutant (n = 12) and oligodendroglioma, IDH-mutant and 1p/19q-codeleted (n = 8). The sensitivity and specificity of T2-FLAIR mismatch sign for astrocytoma were 66.7% and 100% [area under the ROC curve (AUC) = 0.833], respectively. Astrocytoma had significantly higher T1, T2, and PD values than did oligodendroglioma (p < 0.0001, < 0.0001, and 0.0154, respectively). A cutoff lesion T1 value of 1580 ms completely differentiated astrocytoma from oligodendroglioma (AUC = 1.00).
CONCLUSIONS: Quantitative evaluation of non-enhanced IDH-mutant diffuse glioma using synthetic MRI allowed for better differentiation between astrocytoma and oligodendroglioma than did conventional T2-FLAIR mismatch sign. Measurement of T1 and T2 value by synthetic MRI could improve the differentiation of IDH-mutant diffuse gliomas.

BACKGROUND: Recent evidence suggests that the tumor stem cells that are responsible for the pathogenesis of gliomas have similar properties to those of neural stem cells. We have studied two of the most consistently expressed stem cell markers in gliomas, i.e., CD133 and Nestin, and compared them with respect to p53 expression and IDH status.
OBJECTIVE: To assess the level of expression of Nestin and CD133, and identify a correlation among various grades of diffuse glioma with IDH status and expression of p53.
METHODS: A cross-sectional retrospective study with 102 subjects for the expression of cancer stem cell markers; CD133 and Nestin and the correlation of their expression with that of p53 and IDH1 status in adult diffuse glioma. The study was conducted in the Departments of Pathology and Neurosurgery. The expression was assessed by immunohistochemistry on formalin-fixed paraffin-embedded sections. The scoring of expression of CD133 and Nestin was adapted from Zhang et al. The scoring for p53 was adopted from Aruna et al. Results: The diffuse gliomas were graded based on WHO into grade II (30.3%), grade III (28.4%), and grade IV (41.3%). Among WHO grade IV, 59.4% were primary, and 40.4% were secondary glioblastomas. 73% of the diffuse gliomas were IDH mutant, and p53 showed an overall expression of 76.4%. The expression of CD133 and Nestin were compared with the increasing grades of diffuse gliomas, which, when plotted on ROC curves, had AUCs of 0.6806 and 0.6119, respectively. Their expression showed a positive correlation with the IDH status of the tumor.
CONCLUSIONS: Cancer stem cell markers CD133 and Nestin are expressed in diffuse glioma and have a higher expression with increasing WHO grade of malignancy. These cancer stem cell markers have shown significant association with the IDH-1 mutant status of diffuse gliomas. Hence, it can be inferred that diffuse gliomas with a higher expression of CD133 and Nestin have a poorer prognosis. Further, these cancer stem cell markers may be used as therapeutic targets in the future.

OBJECTIVE: The T2-FLAIR mismatch sign is a highly specific diagnostic imaging biomarker for astrocytoma, IDH-mutant. However, a definitive prognostic imaging biomarker has yet to be identified. This study investigated imaging prognostic markers, specifically analyzing T2-weighted and FLAIR images of this tumor.
METHODS: We retrospectively analyzed 31 cases of non-enhancing astrocytoma, IDH-mutant treated at our institution, and 30 cases from The Cancer Genome Atlas (TCGA)/The Cancer Imaging Archive (TCIA). We defined \"super T2-FLAIR mismatch sign\" as having a significantly strong low signal comparable to cerebrospinal fluid at non-cystic lesions rather than just a pale FLAIR low-signal tumor lesion as in conventional T2-FLAIR mismatch sign. Cysts were defined as having a round or oval shape and were excluded from the criteria for the super T2-FLAIR mismatch sign. We evaluated the presence or absence of the T2-FLAIR mismatch sign and super T2-FLAIR mismatch sign using preoperative MRI and analyzed the progression-free survival (PFS) and overall survival (OS) by log-rank test.
RESULTS: The T2-FLAIR mismatch sign was present in 17 cases (55%) in our institution and 9 cases (30%) within the TCGA-LGG dataset without any correlation with PFS or OS. However, the super T2-FLAIR mismatch sign was detected in 8 cases (26%) at our institution and 13 cases (43%) in the TCGA-LGG dataset. At our institution, patients displaying the super T2-FLAIR mismatch sign showed significantly extended PFS (122.7 vs. 35.9 months, p = 0.0491) and OS (not reached vs. 116.7 months, p = 0.0232). Similarly, in the TCGA-LGG dataset, those with the super T2-FLAIR mismatch sign exhibited notably longer OS (not reached vs. 44.0 months, p = 0.0177).
CONCLUSIONS: The super T2-FLAIR mismatch is a promising prognostic imaging biomarker for non-enhancing astrocytoma, IDH-mutant.

Supplemental material is available for this article.

Background: Primary spinal cord diffuse gliomas (SpDG) are rare tumors that may harbor, like diffuse intrinsic pontine gliomas (DIPG), H3K27M mutations. According to the WHO (2021), SpDGs are included in diffuse midline H3K27-altered gliomas, which occur more frequently in adults and show unusual clinical presentation, neuroradiological features, and clinical behavior, which differ from H3 G34-mutant diffuse hemispheric glioma. Currently, homogeneous adult-only case series of SpDG, with complete data and adequate follow-up, are still lacking. Methods: We conducted a qualitative systematic review, focusing exclusively on adult and young adult patients, encompassing all studies reporting cases of primitive, non-metastatic SpDG with H3K27 mutation. We analyzed the type of treatment administered, survival, follow-up duration, and outcomes. Results: We identified 30 eligible articles published between 1990 and 2023, which collectively reported on 62 adult and young adult patients with primitive SpDG. Postoperative outcomes were assessed based on the duration of follow-up, with outcomes categorized as either survival or mortality. Patients who underwent surgery were followed up for a mean duration of 17.37 months, while those who underwent biopsy had a mean follow-up period of 14.65 months. Among patients who were still alive, the mean follow-up duration was 18.77 months. The radiological presentation of SpDG varies widely, indicating its lack of uniformity. Conclusion: Therefore, we presented a descriptive scenario where SpDG was initially suspected to be a meningioma, but was later revealed to be a malignant SpDG with H3K27M mutation.

OBJECTIVE: Circulating tumor cell (CTC) detection is a promising noninvasive technique that can be used to diagnose cancer, monitor progression, and predict prognosis. In this study, the authors aimed to investigate the clinical utility of CTCs in the management of diffuse glioma.
METHODS: Sixty-three patients with newly diagnosed diffuse glioma were included in this multicenter clinical cohort. The authors used a platform based on isolation by size of epithelial tumor cells (ISET) to detect and analyze CTCs and circulating tumor microemboli (CTMs) in the peripheral blood of patients both before and after surgery. Least absolute shrinkage and selector operation (LASSO) and Cox regression analyses were used to verify whether CTCs and CTMs are independent prognostic factors for diffuse glioma.
RESULTS: CTC levels were closely related to the degree of malignancy, WHO grade, and pathological subtypes. Receiver operating characteristic curve analysis revealed that a high CTC level was a predictor for glioblastoma. The results also showed that CTMs originate from the parental tumor rather than from the circulation and are an independent prognostic factor for diffuse glioma. The postoperative CTC level is related to the peripheral immune system and patient survival. Cox regression analysis showed that postoperative CTC levels and CTM status are independent prognostic factors for diffuse glioma, and CTC- and CTM-based survival models had high accuracy in internal validation.
CONCLUSIONS: The authors revealed a correlation between CTCs and clinical characteristics and demonstrated that CTCs and CTMs are independent predictors for the diagnosis and prognosis of diffuse glioma. Their CTC- and CTM-based survival models can enable clinicians to evaluate patients\' response to surgery as well as their outcomes.

Biomarker-driven therapeutic clinical trials require the implementation of standardized, evidence-based practices for sample collection. In diffuse glioma, phosphatidylinositol 3 (PI3)-kinase/AKT/mTOR (PI3/AKT/mTOR) signaling is an attractive therapeutic target for which window-of-opportunity clinical trials could facilitate the identification of promising new agents. Yet, the relevant preanalytic variables and optimal tumor sampling methods necessary to measure pathway activity are unknown. To address this, we used a murine model for isocitrate dehydrogenase (IDH)-wildtype glioblastoma (GBM) and human tumor tissue, including IDH-wildtype GBM and IDH-mutant diffuse glioma. First, we determined the impact of delayed time-to-formalin fixation, or cold ischemia time (CIT), on the quantitative assessment of cellular expression of 6 phosphoproteins that are readouts of PI3K/AK/mTOR activity (phosphorylated-proline-rich Akt substrate of 40 kDa (p-PRAS40, T246), -mechanistic target of rapamycin (p-mTOR; S2448); -AKT (p-AKT, S473); -ribosomal protein S6 (p-RPS6, S240/244 and S235/236), and -eukaryotic initiation factor 4E-binding protein 1 (p-4EBP1, T37/46). With CITs ≥ 2 hours, typical of routine clinical handling, all had reduced or altered expression with p-RPS6 (S240/244) exhibiting relatively greater stability. A similar pattern was observed using patient tumor samples from the operating room with p-4EBP1 more sensitive to delayed fixation than p-RPS6 (S240/244). Many clinical trials utilize unstained slides for biomarker evaluation. Thus, we evaluated the impact of slide storage conditions on the detection of p-RPS6 (S240/244), p-4EBP1, and p-AKT. After 5 months, storage at -80°C was required to preserve the expression of p-4EBP1 and p-AKT, whereas p-RPS6 (240/244) expression was not stable regardless of storage temperature. Biomarker heterogeneity impacts optimal tumor sampling. Quantification of p-RPS6 (240/244) expression in multiple regionally distinct human tumor samples from 8 patients revealed significant intratumoral heterogeneity. Thus, the accurate assessment of PI3K/AKT/mTOR signaling in diffuse glioma must overcome intratumoral heterogeneity and multiple preanalytic factors, including time-to-formalin fixation, slide storage conditions, and phosphoprotein of interest.

To construct an optimal prognostic model to assess the prognosis of patients with diffuse glioma.
Preoperative magnetic resonance imaging and clinical data were retrospectively collected from 266 patients (training cohort: validation cohort=7:3) with pathologically confirmed diffuse gliomas. A radiomics prognostic model (R-model) based on the radiomics features was constructed. A prognostic model based on clinical factors (C-model) and a fusion model (F-model) was also constructed. Based on the optimal model of three models, the nomogram was constructed. Finally, a \"Prognosis Calculator for Diffuse Glioma\" was constructed based on the nomogram.
The c-index of the R-, C-, and F-models in the validation cohort was 0.742, 0.796, and 0.814, respectively. In the validation cohort, the 1-year area under the curve of the R-, C-, and F-models was 0.749, 0.806, and 0.836, respectively; the 3-year area under the curve was 0.896, 0.966, and 0.963, respectively. In the training cohort, validation cohort, all cohorts, and different grades of glioma cohorts, F-model (optimal model) could identify low- and high-risk groups well. The \"Prognosis Calculator for Diffuse Glioma\" was available at https://github.com/HDCurry/prognosis.
Among the three models, the F-model (radiomics combined with clinical factors) had optimal predictive efficacy and could more accurately assess the prognosis of diffuse glioma. The \"Prognosis Calculator for Diffuse Glioma\" constructed based on this model could assist clinicians in more easily and accurately assessing the prognosis of patients with diffuse glioma, thus enabling them to make more reasonable treatment strategies.