A phase I/II study of gemcitabine during radiotherapy in children with newly diagnosed diffuse intrinsic pontine glioma

The purpose of this phase I/II, open-label, single-arm trial is to investigate the safety, tolerability, maximum tolerated dose and preliminary efficacy of the potential radiosensitizer gemcitabine, administered concomitantly to radiotherapy, in children with newly diagnosed diffuse intrinsic pontine glioma (DIPG). Six doses of weekly gemcitabine were administered intravenously, concomitantly to 6 weeks of hyperfractionated radiotherapy. Successive cohorts received increasing doses of 140, 175 and 200 mg/m2 gemcitabine, respectively, following a 3 + 3 dose-escalation schedule without expansion cohort. Dose-limiting toxicities (DLT) were monitored during treatment period. Clinical response was assessed using predefined case report forms and radiological response was assessed using the modified RANO criteria. Quality of life (QoL) was assessed using PedsQL questionnaires. Between June 2012 and December 2016, nine patients were enrolled. Treatment was well tolerated, and no DLTs were observed up to the maximum dose of 200 mg/m2. All patients experienced reduction of tumor-related symptoms. QoL tended to improve during treatment. PFS and MOS were 4.8 months (95% CI 4.0–5.7) and 8.7 months (95% CI 7.0–10.4). Classifying patients according to the recently developed DIPG survival prediction model, intermediate risk patients (n = 4),

The STELLAR trial:a phase II/III randomized trial of high-dose, intermittent sunitinib in patients with recurrent glioblastoma

Previously, the tyrosine kinase inhibitor sunitinib failed to show clinical benefit in patients with recurrent glioblastoma. Low intratumoural sunitinib accumulation in glioblastoma patients was reported as a possible explanation for the lack of therapeutic benefit. We designed a randomized phase II/III trial to evaluate whether a high-dose intermittent sunitinib schedule, aimed to increase intratumoural drug concentrations, would result in improved clinical benefit compared to standard treatment with lomustine. Patients with recurrent glioblastoma were randomized 1:1 to high-dose intermittent sunitinib 300 mg once weekly (Q1W, part 1) or 700 mg once every two weeks (Q2W, part 2) or lomustine. The primary end-point was progression-free survival. Based on the pre-planned interim analysis, the trial was terminated for futility after including 26 and 29 patients in parts 1 and 2. Median progression-free survival of sunitinib 300 mg Q1W was 1.5 months (95% CI 1.4–1.7) compared to 1.5 months (95% CI 1.4–1.6) in the lomustine arm (P = 0.59). Median progression-free survival of sunitinib 700 mg Q2W was 1.4 months (95% CI 1.2–1.6) versus 1.6 months (95% CI 1.3–1.8) for lomustine (P = 0.70). Adverse events (≥grade 3) were observed in 25%, 21% and 31% of patients treated with sunitinib 300 mg Q1W, sunitinib 700 mg Q2W and lomustine, respectively (P = 0.92). To conclude, high-dose intermittent sunitinib treatment failed to improve the outcome of patients with recurrent glioblastoma when compared to standard lomustine therapy. Since lomustine remains a poor standard treatment strategy for glioblastoma, innovative treatment strategies are urgently needed.</p

MRI and Molecular Characterization of Pediatric High-Grade Midline Thalamic Gliomas: The HERBY Phase II Trial

Background: Diffuse midline gliomas (DMG) are characterized by a high incidence of H3 K27 mutations and poorer outcome. The HERBY trial has provided one of the largest cohorts of pediatric DMGs with available radiologic, histologic-genotypic, and survival data. / Purpose: To define MRI and molecular characteristics of DMG. / Materials and Methods: This study is a secondary analysis of a prospective trial (HERBY; ClinicalTrials.gov identifier, NCT01390948) undertaken between October 2011 and February 2016. Among 121 HERBY participants, 50 had midline nonpontine-based tumors. Midline high-grade gliomas were reclassified into DMG H3 K27 mutant, H3 wild type with enhancer of zest homologs inhibitory protein overexpression, epidermal growth factor receptormutant, or not otherwise stated. The epicenter of each tumor and other radiologic characteristics were ascertained from MRI and correlated with the new subtype classification, histopathologic characteristics, surgical extent, and outcome parameters. Kaplan-Meier curves and log-rank tests were applied to determine and describe survival differences between groups. / Results: There were 42 participants (mean age, 12 years ± 4 [SD]; 23 girls) with radiologically evaluable thalamic-based DMG. Eighteen had partial thalamic involvement (12 thalamopulvinar, six anteromedial), 10 involved a whole thalamus, nine had unithalamic tumors with diffuse contiguous extension, and five had bithalamic tumors (two symmetric, three partial). Twenty-eight participants had DMG H3 K27 mutant tumors; there were no differences in outcome compared with other DMGs (n = 4). Participants who underwent major debulking or total or near-total resection had longer overall survival (OS): 18.5 months vs 11.4 months (P = .02). Enrolled participants who developed leptomeningeal metastatic dissemination before starting treatment had worse outcomes (event-free survival, 2.9 months vs 8.0 months [P = .02]; OS, 11.4 months vs 18.5 months [P = .004]). / Conclusion: Thalamic involvement of diffuse midline gliomas ranged from localized partial thalamic to holo- or bithalamic with diffuse contiguous spread and had poor outcomes, irrespective of H3 K27 subtype alterations. Leptomeningeal dissemination and less than 50% surgical resection were adverse risk factors for survival. / Clinical trial registration no. NCT0139094

Early postoperative MRI overestimates residual tumour after resection of gliomas with no or minimal enhancement

Standards for residual tumour measurement after resection of gliomas with no or minimal enhancement have not yet been established. In this study residual volumes on early and late postoperative T2-/FLAIR-weighted MRI are compared. A retrospective cohort included 58 consecutive glioma patients with no or minimal preoperative gadolinium enhancement. Inclusion criteria were first-time resection between 2007 and 2009 with a T2-/FLAIR-based target volume and availability of preoperative, early (<48 h) and late (1-7 months) postoperative MRI. The volumes of non-enhancing T2/FLAIR tissue and diffusion restriction areas were measured. Residual tumour volumes were 22% smaller on late postoperative compared with early postoperative T2-weighted MRI and 49% smaller for FLAIR-weighted imaging. Postoperative restricted diffusion volume correlated with the difference between early and late postoperative FLAIR volumes and with the difference between T2 and FLAIR volumes on early postoperative MRI. We observed a systematic and substantial overestimation of residual non-enhancing volume on MRI within 48 h of resection compared with months postoperatively, in particular for FLAIR imaging. Resection-induced ischaemia contributes to this overestimation, as may other operative effects. This indicates that early postoperative MRI is less reliable to determine the extent of non-enhancing residual glioma and restricted diffusion volumes are imperativ

Hyperoxemia and excess oxygen use in early acute respiratory distress syndrome : Insights from the LUNG SAFE study

Publisher Copyright: © 2020 The Author(s). Copyright: Copyright 2020 Elsevier B.V., All rights reserved.Background: Concerns exist regarding the prevalence and impact of unnecessary oxygen use in patients with acute respiratory distress syndrome (ARDS). We examined this issue in patients with ARDS enrolled in the Large observational study to UNderstand the Global impact of Severe Acute respiratory FailurE (LUNG SAFE) study. Methods: In this secondary analysis of the LUNG SAFE study, we wished to determine the prevalence and the outcomes associated with hyperoxemia on day 1, sustained hyperoxemia, and excessive oxygen use in patients with early ARDS. Patients who fulfilled criteria of ARDS on day 1 and day 2 of acute hypoxemic respiratory failure were categorized based on the presence of hyperoxemia (PaO2 > 100 mmHg) on day 1, sustained (i.e., present on day 1 and day 2) hyperoxemia, or excessive oxygen use (FIO2 ≥ 0.60 during hyperoxemia). Results: Of 2005 patients that met the inclusion criteria, 131 (6.5%) were hypoxemic (PaO2 < 55 mmHg), 607 (30%) had hyperoxemia on day 1, and 250 (12%) had sustained hyperoxemia. Excess FIO2 use occurred in 400 (66%) out of 607 patients with hyperoxemia. Excess FIO2 use decreased from day 1 to day 2 of ARDS, with most hyperoxemic patients on day 2 receiving relatively low FIO2. Multivariate analyses found no independent relationship between day 1 hyperoxemia, sustained hyperoxemia, or excess FIO2 use and adverse clinical outcomes. Mortality was 42% in patients with excess FIO2 use, compared to 39% in a propensity-matched sample of normoxemic (PaO2 55-100 mmHg) patients (P = 0.47). Conclusions: Hyperoxemia and excess oxygen use are both prevalent in early ARDS but are most often non-sustained. No relationship was found between hyperoxemia or excessive oxygen use and patient outcome in this cohort. Trial registration: LUNG-SAFE is registered with ClinicalTrials.gov, NCT02010073publishersversionPeer reviewe

Brain miliary enhancement

Purpose: Miliary enhancement refers to the presence of multiple small, monomorphic, enhancing foci on T1-weighted post-contrast MRI images. In the absence of a clear clinical presentation, a broad differential diagnosis may result in invasive procedures and possibly brain biopsy for diagnostic purposes. Methods: An extensive review of the literature is provided for diseases that may present with miliary enhancement on T1-weighted brain MR images. Additional disease-specific findings, both clinical and radiological, are summarized and categorized by the presence or absence of perivascular space involvement. Results: Miliary pattern of enhancement may be due to a variety of underlying causes, including inflammatory, infectious, nutritional or neoplastic processes. The recognition of disease spread along the perivascular spaces in addition to the detection or exclusion of disease-specific features on MRI images, such as leptomeningeal enhancement, presence of haemorrhagic lesions, spinal cord involvement and specific localisation or systemic involvement, allows to narrow the potential differential diagnoses. Conclusion: A systematic approach to disease-specific findings from both clinical and radiological perspectives might facilitate diagnostic work-up, and recognition of disease spread along the perivascular spaces may help narrowing down differential diagnoses and may help to minimize the use of invasive diagnostic procedures

Validation of an MRI Rating Scale for Amyloid-Related Imaging Abnormalities

INTRODUCTION: Immunotherapeutic agents against amyloid beta (Aβ) are associated with adverse events, including amyloid-related imaging abnormalities with edema and effusion (ARIA-E). Recently, a magnetic resonance imaging (MRI) rating scale was developed for ARIA-E detection and classification. The aim of this study was to validate the use of this rating scale in a larger patient group with multiple raters. METHODS: MRI scans of 75 patients (29 with known ARIA-E and 46 control subjects) were analyzed by five neuroradiologists with different degrees of expertise, according to the ARIA-E rating scale. For each patient, we included a baseline and a follow-up fluid-attenuated inversion recovery image. Interrater agreement was calculated using intraclass correlation coefficient (ICC). RESULTS: On average, 4.1% of the ARIA-E cases were missed. We observed a high interrater agreement for scores of sulcal hyperintensity (SH; ICC =.915; 95% CI 85–95) and for the combined scores of the 2 ARIA-E findings, parenchymal hyperintensity (PH) and SH (ICC =.878; 95% CI 79–93). A slightly lower agreement for PH (ICC =.678; 95% CI 51–81) was noted. CONCLUSION: The ARIA-E rating scale is a simple tool to evaluate the extent of ARIA-E in patients recruited into Aβ-lowering therapeutic trials. It shows high interrater agreement among raters with different degrees of expertise

A twenty-year review of diagnosing and treating children with diffuse intrinsic pontine glioma in The Netherlands

Children with diffuse intrinsic pontine glioma (DIPG) face a dismal prognosis, with a median overall survival of 9 months. Our aims are to determine the incidence of DIPG in the Netherlands and to identify points for improvement in clinical research, a prerequisite for increasing the chance to find a cure. We performed a population-based retrospective cohort study by evaluating all children diagnosed with DIPG in the Netherlands between 1990 and 2010. The incidence of DIPG in the Netherlands corresponds with international literature. Between 1990 and 2010, a large heterogeneity of treatment schedules was applied and only a minority of patients was included in clinical trials. Given the rarity of DIPG, we emphasize the need for (inter-)national trials to facilitate the identification of potentially effective therapeutics in the future. This can be supported by the recent development of a European DIPG registry enabling international study collaboration

The association between preoperative edema and postoperative cognitive functioning and health-related quality of life in WHO grade I meningioma patients

Background: Studies on the associations between preoperative cerebral edema, cognitive functioning, and health-related quality of life (HRQOL) in WHO grade I meningioma patients are virtually lacking. We studied the association between preoperative cerebral edema on postoperative cognitive functioning and HRQOL 6 months postoperatively in WHO grade I meningioma patients. Methods: Twenty-one consecutive WHO grade I meningioma patients, who underwent surgery, were matched individually for age, gender, and educational level to healthy controls. Tumor and edema volume were assessed on preoperative T1- and T2-weighted MRI images, respectively. At least 5 months postoperatively, functional status, cognitive functioning, and HRQOL, using a cognitive test battery and the Short-Form Health Survey (SF-36), were determined. The correlation between preoperative tumor and cerebral edema volume with postoperative cognitive functioning and HRQOL was investigated using Kendall’s tau coefficients. Results: Compared to healthy controls, patients had lower verbal memory capacity (p =.012), whereas HRQOL was similar to matched healthy controls. In all cognitive domains, postoperative functioning was much lower in patients with preoperative cerebral edema than in those without. There were significant correlations between preoperative cerebral edema and tumor volume and postoperative cognitive functioning. Preoperative cerebral edema and/or tumor volume were not associated with HRQOL. Conclusions: Our results suggest that WHO grade I meningioma patients with larger volumes of preoperative cerebral edema are more at risk of experiencing limitations in longer-term cognitive functioning than patients with no or less edema preoperatively. This is an important knowledge for neurologists and neurosurgeons treating patients with a meningioma. More studies regarding the effect of peritumoral edema on cognitive functioning in meningioma patients are necessary