A variable-frequency HFQPO in GRS 1915+105 as observed with Astrosat

From the analysis of more than 92 ks of data obtained with the laxpc instrument on board Astrosat we have detected a clear high-frequency QPO whose frequency varies between 67.4 and 72.3 Hz. In the classification of variability classes of GRS 1915+105, at the start of the observation period the source was in class omega and at the end the variability was that of class mu: both classes are characterized by the absence of hard intervals and correspond to disk-dominated spectra. After normalization to take into account time variations of the spectral properties as measured by X-ray hardness, the QPO centroid frequency is observed to vary along the hardness-intensity diagram, increasing with hardness. We also measure phase lags that indicate that HFQPO variability at high energies lags that at lower energies and detect systematic variations with the position on the hardness-intensity diagram. This is the first time that (small) variations of the HFQPO frequency and lags are observed to correlate with other properties of the source. We discuss the results in the framework of existing models, although the small (7%) variability observed is too small to draw firm conclusions.Comment: 7 pages, 9 figures; Accepted in MNRAS. Some figures are at lower resolution than journal versio

381pdcomprehensive geriatric assessment cga for outcome prediction in elderly patients pts with glioblastoma gbm a mono institutional experience

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Mismatch-repair protein expression in high-grade gliomas: A large retrospective multicenter study

Background: DNA mismatch repair (MMR) is a system for repairing errors in DNA replication. Cancer cells with MMR deficiency can have immunohistochemical loss of MMR protein expression leading to a hypermutable phenotype that may correlate with anti-PD1 efficacy. Scant data exist about immunohistochemical loss of MMR protein expression in high-grade gliomas (HGG). Materials and Methods: We performed a large multicenter retrospective study to investigate the frequency and the prognostic role of immunohistochemical loss of MMR protein expression in HGG patients; we nevertheless evaluated the association between this status and clinical or molecular characteristics. Immunohistochemical loss of MMR protein expression was recorded as partial or complete loss of at least 1 MMR protein. Results: We analyzed the expression of MMR proteins in tumor tissue of 355 consecutive patients. Partial and complete immunohistochemical loss of MMR proteins was found in 43/355 samples (12.1%) and among these, 15 cases (4.2%) showed a complete loss of at the least one MMR protein. Alteration of MSH2 expression was found in 55.8%, MSH6 in 46.5%, PMS2 in 34.9%, and MLH1 in 30.2%. Alteration of MMR protein expression was statistically more frequent in anaplastic gliomas, in recurrent disease, in patients treated with temozolomide, and in IDH-mut gliomas. Immunohistochemical loss of MMR proteins was not associated with survival, adjusting for clinically relevant confounders. Conclusions: MMR protein expression status did not affect survival in HGG patients. We identified clinical and molecular characteristics correlating with immunohistochemical loss of MMR proteins expression. A large study should be performed to analyze its predictive role of immune checkpoint inhibitor efficacy in these subgroups of patients

mismatch repair deficiency mmrd in glioma patients pts frequency and correlation with clinical histological and molecular characteristics

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PET/MR in recurrent glioblastoma patients treated with regorafenib: [18F]FET and DWI-ADC for response assessment and survival prediction

Objective: The use of regorafenib in recurrent glioblastoma patients has been recently approved by the Italian Medicines Agency (AIFA) and added to the National Comprehensive Cancer Network (NCCN) 2020 guidelines as a preferred regimen. Given its complex effects at the molecular level, the most appropriate imaging tools to assess early response to treatment is still a matter of debate. Diffusion-weighted imaging and O-(2-18F-fluoroethyl)-L-tyrosine positron emission tomography ([18F]FET PET) are promising methodologies providing additional information to the currently used RANO criteria. The aim of this study was to evaluate the variations in diffusion-weighted imaging/apparent diffusion coefficient (ADC) and [18F]FET PET-derived parameters in patients who underwent PET/MR at both baseline and after starting regorafenib. Methods: We retrospectively reviewed 16 consecutive GBM patients who underwent [18F]FET PET/MR before and after two cycles of regorafenib. Patients were sorted into stable (SD) or progressive disease (PD) categories in accordance with RANO criteria. We were also able to analyze four SD patients who underwent a third PET/MR after another four cycles of regorafenib. [18F]FET uptake greater than 1.6 times the mean background activity was used to define an area to be superimposed on an ADC map at baseline and after treatment. Several metrics were then derived and compared. Log-rank test was applied for overall survival analysis. Results: Percentage difference in FET volumes correlates with the corresponding percentage difference in ADC (R = 0.54). Patients with a twofold increase in FET after regorafenib showed a significantly higher increase in ADC pathological volume than the remaining subjects (p = 0.0023). Kaplan-Meier analysis, performed to compare the performance in overall survival prediction, revealed that the percentage variations of FET- and ADC-derived metrics performed at least as well as RANO criteria (p = 0.02, p = 0.024 and p = 0.04 respectively) and in some cases even better. TBR Max and TBR mean are not able to accurately predict overall survival. Conclusion In recurrent glioblastoma patients treated with regorafenib, [18F]FET and ADC metrics, are able to predict overall survival and being obtained from completely different measures as compared to RANO, could serve as semi-quantitative independent biomarkers of response to treatment. Advances in knowledge Simultaneous evaluation of [18F]FET and ADC metrics using PET/MR allows an early and reliable identification of response to treatment and predict overall survival

Association between thyroid function and regorafenib efficacy in patients with relapsed wild-type IDH glioblastoma: a large multicenter study

Purpose: Regorafenib demonstrated encouraging results in recurrent glioblastoma patients. Some studies showed that changes in circulating thyroid hormones (fT3, fT4, fT3/fT4 ratio) can be considered as prognostic factors in patients with various types of tumors. We designed this study to investigate the relationship between baseline thyroid variables and outcome in IDH-wild type GBM patients who were treated with regorafenib. Methods: This multicenter retrospective study included recurrent IDH-wild-type glioblastoma patients treated with regorafenib. Only patients with baseline thyroid function values (TSH, fT3, fT4, fT3/fT4 ratio) available were evaluated. RANO criteria were used to analyze neuroradiological response. Survival curves were estimated using the Kaplan–Meier method. The relationships between baseline thyroid variables (TSH, fT3, fT4, fT3/fT4) and survival (PFS, OS) were investigated with Cox regression models. Results: From November 2015 to April 2022, 134 recurrent IDH-wildtype GBM patients were treated with regorafenib and 128 of these had information on baseline thyroid function value. Median follow-up was 8 months (IQR 4.7–14.0). Objective Response Rate was 9% and Disease Control Rate was 40.9%. Median PFS was 2.7 months (95%CI 2.2–3.6) and median OS was 10.0 months (95%CI 7.0–13.0). Lower baseline TSH value in the blood was correlated with a higher rate of disease progression to regorafenib (p = 0.04). Multivariable analyses suggested a non-linear relationship between PFS (p = 0.01) and OS (p = 0.03) with baseline fT3/fT4 ratio. Conclusion: In recurrent wild-type IDH glioblastoma patients, baseline fT3/fT4 ratio showed a non-linear relationship with survival, with different impacts across the spectrum of fT3/fT4 ratio. Moreover, baseline TSH may be a predictor of regorafenib activity

preliminary results of principe predictors of resistance to immunotherapy with nivolumab niv study in advanced pretreated non small cell lung cancer apnsclc investigating the role of an immune genomic signature igs including jak2 jak3 pias4 ptpn2 stat3 ifnar2 alterations

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Microbiologic characteristics and predictors of mortality in bloodstream infections in intensive care unit patients: A 1-year, large, prospective surveillance study in 5 Italian hospitals

Bloodstream infections (BSIs) from multidrug-resistant (MDR) bacteria cause morbidity and mortality in intensive care unit (ICU) patients worldwide. This study investigated the incidence of BSIs in 5 adult general ICUs in Rome, Italy, and evaluated the mortality rate and risk factors associated with these infections

Definition of the Prognostic Role of MGMT Promoter Methylation Value by Pyrosequencing in Newly Diagnosed IDH Wild‐Type Glioblastoma Patients Treated with Radiochemotherapy: A Large Multicenter Study

Background. O6‐methylguanine (O6‐MeG)‐DNA methyltransferase (MGMT) methylation status is a predictive factor for alkylating treatment efficacy in glioblastoma patients, but its prognostic role is still unclear. We performed a large, multicenter study to evaluate the association between MGMT methylation value and survival. Methods. We evaluated glioblastoma patients with an assessment of MGMT methylation status by pyrosequencing from nine Italian centers. The inclusion criteria were histological diagnosis of IDH wild‐type glioblastoma, Eastern Cooperative Oncology Group Performance Status (ECOG‐PS) ≤2, and radio‐chemotherapy treatment with temozolomide. The relationship between OS and MGMT was investigated with a time‐dependent Receiver Operating Characteristics (ROC) curve and Cox regression models. Results. In total, 591 newly diagnosed glioblastoma patients were analyzed. The median OS was 16.2 months. The ROC analysis suggested a cut‐off of 15% for MGMT methylation. The 2‐year Overall Survival (OS) was 18.3% and 51.8% for MGMT methylation <15% and ≥15% (p < 0.0001). In the multivariable analysis, MGMT methylation <15% was associated with impaired survival (p <0.00001). However, we also found a non‐linear association between MGMT methylation and OS (p = 0.002): median OS was 14.8 months for MGMT in 0–4%, 18.9 months for MGMT in 4–40%, and 29.9 months for MGMT in 40– 100%. Conclusions. Our findings suggested a non‐linear relationship between OS and MGMT promoter methylation, which implies a varying magnitude of prognostic effect across values of MGMT promoter methylation by pyrosequencing in newly diagnosed IDH wild‐type glioblastoma patients treated with chemoradiotherapy

Recurrent glioblastoma: From molecular landscape to new treatment perspectives

Glioblastoma is the most frequent and aggressive form among malignant central nervous system primary tumors in adults. Standard treatment for newly diagnosed glioblastoma consists in maximal safe resection, if feasible, followed by radiochemotherapy and adjuvant chemotherapy with temozolomide; despite this multimodal treatment, virtually all glioblastomas relapse. Once tumors progress after first-line therapy, treatment options are limited and management of recurrent glioblastoma remains challenging. Loco-regional therapy with re-surgery or re-irradiation may be evaluated in selected cases, while traditional systemic therapy with nitrosoureas and temozolomide rechallenge showed limited efficacy. In recent years, new clinical trials using, for example, regorafenib or a combination of tyrosine kinase inhibitors and immunotherapy were performed with promising results. In particular, molecular targeted therapy could show efficacy in selected patients with specific gene mutations. Nonetheless, some molecular characteristics and genetic alterations could change during tumor progression, thus affecting the efficacy of precision medicine. We therefore reviewed the molecular and genomic landscape of recurrent glioblastoma, the strategy for clinical management and the major phase I-III clinical trials analyzing recent drugs and combination regimens in these patients