UNASSIGNED: Evaluation of molecular markers (IDH, pTERT, 1p/19q codeletion, and MGMT) in adult diffuse gliomas is crucial for accurate diagnosis and optimal treatment planning. Dynamic Susceptibility Contrast (DSC) and Arterial Spin Labeling (ASL) perfusion MRI techniques have both shown good performance in classifying molecular markers, however, their performance has not been compared side-by-side.
UNASSIGNED: Pretreatment MRI data from 90 patients diagnosed with diffuse glioma (54 men/36 female, 53.1 ± 15.5 years, grades 2-4) were retrospectively analyzed. DSC-derived normalized cerebral blood flow/volume (nCBF/nCBV) and ASL-derived nCBF in tumor and perifocal edema were analyzed in patients with available IDH-mutation (n = 67), pTERT-mutation (n = 39), 1p/19q codeletion (n = 33), and MGMT promoter methylation (n = 31) status. Cross-validated uni- and multivariate logistic regression models assessed perfusion parameters\' performance in molecular marker detection.
UNASSIGNED: ASL and DSC perfusion parameters in tumor and edema distinguished IDH-wildtype (wt) and pTERT-wt tumors from mutated ones. Univariate classification performance was comparable for ASL-nCBF and DSC-nCBV in IDH (maximum AUROCC 0.82 and 0.83, respectively) and pTERT (maximum AUROCC 0.70 and 0.81, respectively) status differentiation. The multivariate approach improved IDH (DSC-nCBV AUROCC 0.89) and pTERT (ASL-nCBF AUROCC 0.8 and DSC-nCBV AUROCC 0.86) classification. However, ASL and DSC parameters could not differentiate 1p/19q codeletion or MGMT promoter methylation status. Positive correlations were found between ASL-nCBF and DSC-nCBV/-nCBF in tumor and edema.
UNASSIGNED: ASL is a viable gadolinium-free replacement for DSC for molecular characterization of adult diffuse gliomas.

UNASSIGNED: Based on preclinical studies showing that IDH-mutant (IDHm) gliomas could be vulnerable to PARP inhibition we launched a multicenter phase 2 study to test the efficacy of olaparib monotherapy in this population.
UNASSIGNED: Adults with recurrent IDHm high-grade gliomas (HGGs) after radiotherapy and at least one line of alkylating chemotherapy were enrolled. The primary endpoint was a 6-month progression-free survival rate (PFS-6) according to response assessment in neuro-oncology criteria. Pre-defined threshold for study success was a PFS-6 of at least 50%.
UNASSIGNED: Thirty-five patients with recurrent IDHm HGGs were enrolled, 77% at ≥ 2nd recurrence. Median time since diagnosis and radiotherapy were 7.5 years and 33 months, respectively. PFS-6 was 31.4% (95% CI [16.9; 49.3%]). Two patients (6%) had an objective response and 14 patients (40%) had a stable disease as their best response. Median PFS and median overall survival were 2.05 and 15.9 months, respectively. Oligodendrogliomas (1p/19q codeleted) had a higher PFS-6 (53.4% vs. 15.7%, P = .05) than astrocytomas while an initial diagnosis of grade 4 astrocytoma tended to be associated with a lower PFS-6 compared to grade 2/3 gliomas (0% vs 31.4%, P = .16). A grade 2 or 3 treatment-related adverse event was observed in 15 patients (43%) and 5 patients (14%), respectively. No patient definitively discontinued treatment due to side effects.
UNASSIGNED: Although it did not meet its primary endpoint, the present study shows that in this heavily pretreated population, olaparib monotherapy was well tolerated and resulted in some activity, supporting further PARP inhibitors evaluation in IDHm HGGs, especially in oligodendrogliomas.

BACKGROUND: Novel effective treatments are needed for recurrent IDH mutant high-grade gliomas (IDHm HGGs). The aim of the multicentric, single-arm, phase II REVOLUMAB trial (NCT03925246) was to assess the efficacy and safety of the anti-PD1 Nivolumab in patients with recurrent IDHm HGGs.
METHODS: Adult patients with IDHm WHO grade 3-4 gliomas recurring after radiotherapy and ≥ 1 line of alkylating chemotherapy were treated with intravenous Nivolumab until end of treatment (12 months), progression, unacceptable toxicity, or death. The primary endpoint was the 24-week progression-free survival rate (24w-PFS) according to RANO criteria.
RESULTS: From July 2019 to June 2020, 39 patients with recurrent IDHm HGGs (twenty-one grade 3, thirteen grade 4, five grade 2 with radiological evidence of anaplastic transformation; 39% 1p/19q codeleted) were enrolled. Median time since diagnosis was 5.7 years, and the median number of previous systemic treatments was two. The 24w-PFS was 28.2% (11/39, CI95% 15-44.9%). Median PFS and OS were 1.84 (CI95% 1.81-5.89) and 14.7 months (CI95% 9.18-NR), respectively. Four patients (10.3%) achieved partial response according to RANO criteria. There were no significant differences in clinical or histomolecular features between responders and non-responders. The safety profile of Nivolumab was consistent with prior studies.
CONCLUSIONS: We report the results of the first trial of immune checkpoint inhibitors in IDHm gliomas. Nivolumab failed to achieve its primary endpoint. However, treatment was well tolerated, and long-lasting responses were observed in a subset of patients, supporting further evaluation in combination with other agents (e.g. IDH inhibitors).

Background Oligodendrogliomas, rare brain tumors in the frontal lobe\'s white matter, are reshaped by molecular markers like isocitrate dehydrogenase mutations and 1p/19q co-deletion, influencing treatment outcomes. Despite the initial indolence, these tumors pose a significant risk, with a median survival of 10-12 years. Non-invasive alternatives, such as magnetic resonance imaging (MRI) for assessing T2-fluid-attenuated inversion recovery (FLAIR) mismatch and calcifications, provide insights into molecular subtypes and aid prognosis. Our study explored these features to predict the oligodendroglioma status and refine patient management to improve outcomes. Methods In this retrospective study, patient data identified patients with suspected central nervous system tumors undergoing MRI, revealing low-grade gliomas. Surgical biopsy and 1p/19q fluorescence in situ hybridization confirmed the co-deletion status. MRI was used to assess various morphological features. Statistical analyses included x2 tests, Fisher\'s exact tests, Kruskal-Wallis tests, and binary logistic regression models, with significance set at p < 0.05. Results Seventy-three patients (median age, 37 years) were stratified according to 1p/19q co-deletion. Most (61.6%) were 18-40 years old and mostly male (67.1%). Co-deletion cases, primarily frontal lobe lesions (67.6%), were unilateral (88.2%), with 55.9% non-circumscribed margins and 58.8% ill-defined contours. Smooth contrast enhancement and no necrosis were observed in 48.1% of 1p/19q co-deletion cases. Logistic regression analysis showed a significant association between ill-defined/irregular contours and 1p/19q co-deletion. Fisher\'s exact test confirmed this but raised concerns about the small sample size influencing the conclusions. Conclusions This study established a significant link between glioma tumor contour characteristics, particularly irregular and ill-defined contours, and the likelihood of 1p/19q co-deletion. Our findings underscore the clinical relevance of using tumor contours in treatment decisions and prognosis assessments.

Isocitrate dehydrogenase-wildtype (IDHwt) glioblastoma (GBM) is one of the most aggressive primary brain tumors. The recurrence of GBM is almost inevitable. As an adjuvant option to surgery, intraoperative radiotherapy (IORT) is gaining increasing attention in the treatment of glioma. This study is aimed to evaluate the therapeutic efficacy of IORT on recurrent IDHwt GBM.
In total, 34 recurrent IDHwt GBM patients who received a second surgery were included in the analysis (17 in the surgery group and 17 in the surgery + IORT group).
The progression-free survival and overall survival after the second surgery were defined as PFS2 and OS2, respectively. The median PFS2 was 7.3 months (95% CI: 6.3-10.5) and 10.6 months (95% CI: 9.3-14.6) for those patients who received surgery and surgery + IORT, respectively. Patients in the surgery + IORT group also had a longer OS2 (12.8 months, 95% CI: 11.4-17.2) than those in the surgery group (9.3 months, 95% CI: 8.9-12.9). The Kaplan-Meier survival curves, analyzed by log-rank test, revealed a statistically significant difference in PFS2 and OS2 between both groups, suggesting that IORT plays an active role in the observed benefits for PFS2 and OS2. The effects of IORT on PFS2 and OS2 were further confirmed by multivariate Cox hazards regression analysis. Two patients in the surgery group developed distant glioma metastases, and no radiation-related complications were observed in the IORT group.
This study suggests that low-dose IORT may improve the prognosis of recurrent IDHwt GBM patients. Future prospective large-scale studies are needed to validate the efficacy and safety of IORT.

Background: Hypertension can be classified into different phenotypes based on systolic and diastolic blood pressure (BP) that carry a different prognosis and may therefore be differently associated with sympathetic activity. We assessed the association between cardiac autonomic function determined from continuous finger BP recordings and hypertensive phenotypes. Methods: We included 10,221 individuals aged between 18-70 years from the multi-ethnic HELIUS study. Finger BP was recorded continuously for 3-5 minutes from which cross-correlation baroreflex sensitivity (xBRS) and heart rate variability (HRV) were determined. Hypertension was classified into isolated systolic (ISH; ≥140/<90), diastolic (IDH; <140/≥90) and combined systolic and diastolic hypertension (SDH; ≥140/≥90). Differences were assessed after stratification by age (younger: ≤40, older: >40 years) and sex, using regression with correction for relevant covariates. For xBRS, values were log-transformed. Results: In younger adults with ISH, xBRS was comparable to normotensive individuals in men (ratio 0.92; 95%CI 0.84-1.01) and women (1.00; 95%CI 0.84-1.20), while xBRS was significantly lower in IDH and SDH (ratios between 0.67 and 0.80). In older adults, all hypertensive phenotypes had significantly lower xBRS compared to normotensives. We found a similar pattern for HRV in men, while in women HRV did not differ between phenotypes. Conclusions: In younger men and women ISH is not associated with a shift towards increased sympathetic control, while IDH and SDH in younger and all hypertensive phenotypes in older participants were associated with increased sympathetic control. This suggests that alterations in autonomic regulation could be a contributing factor to known prognostic disparities between hypertensive phenotypes.
Hypertension can be classified into different phenotypes based on systolic and diastolic blood pressure (BP) that carry a different prognosis. Impaired autonomic regulation is important in the pathogenesis of hypertension and independently associated with adverse cardiovascular outcomes.We analyzed 3-5 minutes continuous non-invasive finger blood pressure recordings performed in over 10.000 individuals participating in the HELIUS cohort study. From these measurements, short term heart rate variability (HRV) and cross correlation baroreflex sensitivity (xBRS) were determined using an automatic algorithm.In our analysis we observed pronounced differences in the relation between autonomic regulation and hypertensive phenotypes that depend on age and sex.Younger men and women (age 18-40 years) with isolated systolic hypertension had similar values for xBRS and HRV compared to normotensives, while isolated diastolic hypertension was associated with a shift towards increased sympathetic control. In contrast to our findings in younger individuals, all hypertensive phenotypes were associated with increased sympathetic control in older participants (age 40-70 years).This supports earlier studies showing prognostic differences and suggests that alterations in sympathovagal balance could be a contributing factor to the disparities between phenotypes.

Glioblastoma (GBM) is the most common primary malignant brain tumour in adults and frequently relapses. The aim of this study was to assess the efficacy and safety of metronomic temozolomide (TMZ) in the recurrent GBM population.
All patients treated at our centre between September 2013 and March 2021 were retrospectively reviewed. The main inclusion criteria were first-line therapy with the Stupp protocol, relapse after the first or subsequent line of therapy, treatment with a metronomic TMZ schedule (50 mg/m2 continuously) and histological diagnosis of isocitrate dehydrogenase wild-type GBM according to World Health Organization 2016 classification.
In total, 120 patients were enrolled. The median follow-up was 15.6 months, the median age was 59 years, Eastern Cooperative Oncology Group performance status (ECOG-PS) was 0-2 in 107 patients (89%). O6-methylguanine-DNA-methyltransferase (MGMT) was methylated in 66 of 105 (62%) evaluable patients. The median number of prior lines of treatment was 2 (range 1-7). Three (2%) patients showed a partial response; 48 (40%) had stable disease; 69 (57%) had progressive disease. The median overall survival from the start of metronomic TMZ was 5.4 months (95% confidence interval 4.3-6.4), whereas the median progression-free survival (PFS) was 2.6 months (95% confidence interval 2.3-2.8). At univariate analysis, MGMT methylated and unmethylated patients had a median PFS of 2.9 and 2.1 months (P = 0.001) and a median overall survival of 5.6 and 4.4 months (P = 0.03), respectively. At multivariate analysis, the absence of MGMT methylation (hazard ratio = 2.3, 95% confidence interval 1.3-3.9, P = 0.004) and ECOG-PS ≤ 2 (hazard ratio = 0.5, 95% confidence interval 0.3-0.9, P = 0.017) remained significantly associated with PFS, whereas ECOG-PS ≤ 2 (hazard ratio = 0.4, 95% confidence interval 0.3-07, P = 0.001) was the only factor associated with overall survival. The most common grade 3-4 toxicities were haematological (lymphopenia 10%, thrombocytopenia 3%).
Rechallenge with metronomic TMZ is a well-tolerated option for recurrent GBM, even in pretreated patients. Patients with methylated MGMT disease and good ECOG-PS seem to benefit the most from this treatment.

We aimed to summarize the clinicopathological characteristics and prognostic features of various molecular subtypes of diffuse gliomas (DGs) in the Chinese population.
In total, 1,418 patients diagnosed with DG between 2011 and 2017 were classified into 5 molecular subtypes according to the 2016 WHO classification of central nervous system tumors. The IDH mutation status was determined by immunohistochemistry and/or DNA sequencing, and 1p/19q codeletion was detected with fluorescence in situ hybridization. The median clinical follow-up time was 1,076 days. T-tests and chi-square tests were used to compare clinicopathological characteristics. Kaplan-Meier and Cox regression methods were used to evaluate prognostic factors.
Our cohort included 15.5% lower-grade gliomas, IDH-mutant and 1p/19q-codeleted (LGG-IDHm-1p/19q); 18.1% lower-grade gliomas, IDH-mutant (LGG-IDHm); 13.1% lower-grade gliomas, IDH-wildtype (LGG-IDHwt); 36.1% glioblastoma, IDH-wildtype (GBM-IDHwt); and 17.2% glioblastoma, IDH-mutant (GBM-IDHm). Approximately 63.3% of the enrolled primary gliomas, and the median overall survival times for LGG-IDHm, LGG-IDHwt, GBM-IDHwt, and GBM-IDHm subtypes were 75.97, 34.47, 11.57, and 15.17 months, respectively. The 5-year survival rate of LGG-IDHm-1p/19q was 76.54%. We observed a significant association between high resection rate and favorable survival outcomes across all subtypes of primary tumors. We also observed a significant role of chemotherapy in prolonging overall survival for GBM-IDHwt and GBM-IDHm, and in prolonging post-relapse survival for the 2 recurrent GBM subtypes.
By controlling for molecular subtypes, we found that resection rate and chemotherapy were 2 prognostic factors associated with survival outcomes in a Chinese cohort with DG.

UNASSIGNED: Abnormal glycolipid metabolism plays a crucial role in hypertension. While an elevated triglyceride-glucose (TyG) index has been recognized as a risk factor for developing hypertension, the associations between the TyG index and different hypertension subtypes, namely, isolated systolic hypertension (ISH), isolated diastolic hypertension (IDH), and systolic-diastolic hypertension (SDH), remain unclear. This study was designed to investigate the associations between the TyG index and hypertension subtypes in a general Chinese population.
UNASSIGNED: In a sample of 16,793 participants from Shandong Province, China, multivariate logistic regression analyses were performed to examine the associations between the TyG index and different hypertension subtypes. Loess smooth curves were fitted to visualize the trends. Stratified analyses were conducted to further assess the potential interactions in the associations between the TyG index and different hypertension subtypes.
UNASSIGNED: A higher TyG index was associated with an increased odds of having IDH (OR = 2.94, 95% CI: 1.66-5.23) and SDH (OR = 1.82, 95% CI: 1.33-2.49), whereas no apparent relationship was observed between TyG index and ISH. With respect to sex, the effect of TyG index on having IDH and SDH was significant in women, but not in men. Participants with lower lipid profiles and glucose levels demonstrated a stronger strength of association between the TyG index and IDH as compared with the TyG index-SDH association. Stratified analysis showed that participants with a higher TyG index were more than 3 times more likely to have IDH and SDH among persons aged 18-42 years. Significant interactions were observed between TyG index and sex, age, and high-density lipoprotein cholesterol (HDL-C) in the SDH group, and a significant interaction was also found between TyG index and body mass index (BMI) in the ISH group.
UNASSIGNED: Triglyceride-glucose index may potentially serve as a novel indicator for IDH and SDH. Our findings could also inform the development and implementation of targeted screening for hypertension.

OBJECTIVE: Glioblastoma Multiforme (GBM), a devastating the most common primary malignant intracranial brain tumors. In India, the incidence of this malignancy is escalating, however, there are very few studies on this tumor entity from Indian population. The present study sought to investigate the prevalence and prognostic significance of Signal Transducer and Activator of Transcription 3 (STAT3) gene expression in GBM patients from Western India.
METHODS: STAT3 gene expression using real-time PCR was detected in total 55 GBM patients. The impact of STAT3 aberrant expression on progression-free survival (PFS) and overall (OS) was analysed using univariate and multivariate survival analysis. The data were analysed using SPSS statistical software and p value ≤0.05 was considered as significant.
RESULTS: The aberrant STAT3 expression was found in 85% (47/55) of patients with -1.12 fold change down-regulation in 49% (23/47) and 3.36 fold change up-regulation was noted in 51% (24/47) of patients. In wild type IDH tumors (n=30), down regulation and up regulation of STAT3 was noted in 63% and 27% of patients, respectively, whereas, for IDH mutant GBM tumors (n=25), the incidence of low expression and high expression of STAT3 was noted in 16% and 68% of patients, respectively. Thus, we found that incidence of STAT3 down regulation was significantly high in patients with IDH wild type tumors, whereas, in IDH mutant GBM tumors, the incidence of up-regulated STAT3 was significantly high (P=0.021, χ2=12.81, r=+0.310). In Kaplan-Meier univariate survival analysis, a part from age (P=0.006), tumor location (P=0.025), and KPS score (P=0.002), co-detection of STAT3 up regulation and presence of IDH mutation (P=0.030) remained significant prognostic factors for PFS and OS. In multivariate survival analysis also, co-detection of STAT3 high expression and presence of IDH mutation remained independent prognosticators for PFS (HR=6.45, 95% CI=1.32-31.40, P=0.021) and OS (HR=8.69, 95% CI=1.66-45.51, P=0.010).
CONCLUSIONS: For GBM tumors, STAT3 up-regulation and presence of IDH mutations together predicts better survival. This reflects unique molecular etiology for GBM patients. Therefore, they would be useful in the future for targeted therapy and for clinicians they would be useful for better patient management. However, study on a larger sample size is required for validation.