Prognostic microRNAs in high-grade glioma reveal a link to oligodendrocyte precursor differentiation.

MicroRNA expression can be exploited to define tumor prognosis and stratification for precision medicine. It remains unclear whether prognostic microRNA signatures are exclusively tumor grade and/or molecular subtype-specific, or whether common signatures of aggressive clinical behavior can be identified. Here, we defined microRNAs that are associated with good and poor prognosis in grade III and IV gliomas using data from The Cancer Genome Atlas. Pathway analysis of microRNA targets that are differentially expressed in good and poor prognosis glioma identified a link to oligodendrocyte development. Notably, a microRNA expression profile that is characteristic of a specific oligodendrocyte precursor cell type (OP1) correlates with microRNA expression from 597 of these tumors and is consistently associated with poor patient outcome in grade III and IV gliomas. Our study reveals grade-independent and subtype-independent prognostic molecular signatures in high-grade glioma and provides a framework for investigating the mechanisms of brain tumor aggressiveness

RAD51 Is a Selective DNA Repair Target to Radiosensitize Glioma Stem Cells.

Patients with glioblastoma die from local relapse despite surgery and high-dose radiotherapy. Resistance to radiotherapy is thought to be due to efficient DNA double-strand break (DSB) repair in stem-like cells able to survive DNA damage and repopulate the tumor. We used clinical samples and patient-derived glioblastoma stem cells (GSCs) to confirm that the DSB repair protein RAD51 is highly expressed in GSCs, which are reliant on RAD51-dependent DSB repair after radiation. RAD51 expression and RAD51 foci numbers fall when these cells move toward astrocytic differentiation. In GSCs, the small-molecule RAD51 inhibitors RI-1 and B02 prevent RAD51 focus formation, reduce DNA DSB repair, and cause significant radiosensitization. We further demonstrate that treatment with these agents combined with radiation promotes loss of stem cells defined by SOX2 expression. This indicates that RAD51-dependent repair represents an effective and specific target in GSCs

Expression profiling of single cells and patient cohorts identifies multiple immunosuppressive pathways and an altered NK cell phenotype in glioblastoma.

Glioblastoma (GBM) is an aggressive cancer with a very poor prognosis. Generally viewed as weakly immunogenic, GBM responds poorly to current immunotherapies. To understand this problem more clearly we used a combination of natural killer (NK) cell functional assays together with gene and protein expression profiling to define the NK cell response to GBM and explore immunosuppression in the GBM microenvironment. In addition, we used transcriptome data from patient cohorts to classify GBM according to immunological profiles. We show that glioma stem-like cells, a source of post-treatment tumour recurrence, express multiple immunomodulatory cell surface molecules and are targeted in preference to normal neural progenitor cells by natural killer (NK) cells ex vivo. In contrast, GBM-infiltrating NK cells express reduced levels of activation receptors within the tumour microenvironment, with hallmarks of transforming growth factor (TGF)-β-mediated inhibition. This NK cell inhibition is accompanied by expression of multiple immune checkpoint molecules on T cells. Single-cell transcriptomics demonstrated that both tumour and haematopoietic-derived cells in GBM express multiple, diverse mediators of immune evasion. Despite this, immunome analysis across a patient cohort identifies a spectrum of immunological activity in GBM, with active immunity marked by co-expression of immune effector molecules and feedback inhibitory mechanisms. Our data show that GBM is recognized by the immune system but that anti-tumour immunity is restrained by multiple immunosuppressive pathways, some of which operate in the healthy brain. The presence of immune activity in a subset of patients suggests that these patients will more probably benefit from combination immunotherapies directed against multiple immunosuppressive pathways

Gender balance and suitable positive actions to promote gender equality among healthcare professionals in neuro-oncology:The EANO positive action initiative

Background:The proportion of women among healthcare and biomedical research professionals in neuro-oncology is growing. With changes in cultural expectations and work-life balance considerations, more men aspire to nonfull-time jobs, yet, leadership positions remain dominated by men.Methods:The European Association of Neuro-Oncology (EANO) disparity committee carried out a digital survey to explore gender balance and actions suitable to promote gender equality. The survey was distributed among EANO members in 2021, with responses analyzed descriptively.Results:In total, 262 participants completed the survey (141 women, 53.8%; median age 43). Respondents were neurosurgeons (68, 26.0%); neurologists (67, 25.6%), medical oncologists (43, 16.4%), or other healthcare or research professionals; 208 participants (79.4%) worked full-time. Positive action to enforce the role of women in neuro-oncology was deemed necessary by 180 participants (68.7%), but only 28 participants (10.7%) agreed that women only should be promoted until gender balance is reached. A majority of respondents (162, 61.8%) felt that women with an equivalent CV should be prioritized over men to reach gender balance. If in the future the balance favored women at higher positions, 112 respondents (42.7%) agreed to apply positive action for men. The top indicators considered relevant to measure gender balance were: salary for similar positions (183/228, 80.3%), paid overtime (176/228, 77.2%), number of permanent positions (164/228, 71.9%), protected time for research (161/227, 70.9%), and training opportunities (157/227, 69.2%).Conclusions:Specific indicators may help to measure and promote gender balance and should be considered for implementation among healthcare professionals in neuro-oncology

Non drowsy obstructive sleep apnea as a potential cause of resistant hypertension: a case report

<p>Abstract</p> <p>Background</p> <p>Obstructive sleep apnea (OSA) and arterial hypertension (AH) are common and underrecognized medical disorders. OSA is a potential risk factor for the development of AH and/or may act as a factor complicating AH management. The symptoms of excessive daytime sleepiness (EDS) are considered essential for the initiation of continuous positive airway pressure (CPAP) therapy, which is a first line treatment of OSA. The medical literature and practice is controversial about the treatment of people with asymptomatic OSA. Thus, OSA patients without EDS may be left at increased cardiovascular risk.</p> <p>Case presentation</p> <p>The report presents a case of 42year old Asian woman with symptoms of heart failure and angina like chest pain upon admission. She didnt experience symptoms of EDS, and the Epworth Sleepiness Scale was seven points. Snoring was reported on direct questioning. The patient had prior medical history of three unsuccessful pregnancies complicated by gestational AH and preeclampsia with C-section during the last pregnancy. The admission blood pressure (BP) was 200/120mm Hg. The patients treatment regimen consisted of five hypotensive medications including diuretic. However, a target BP wasnt achieved in about one and half month. The patient was offered to undergo a polysomnography (PSG) study, which she rejected. One month after discharge the PSG study was done, and this showed an apnea-hypopnea index (AHI) of 46 events per hour. CPAP therapy was initiated with a pressure of 11H₂0cm. After 2months of compliant CPAP use, adherence to pharmacologic regimen and lifestyle modifications the patients BP decreased to 134/82mm Hg.</p> <p>Conclusions</p> <p>OSA and AH are common and often underdiagnosed medical disorders independently imposing excessive cardiovascular risk on a diseased subject. When two conditions coexist the cardiovascular risk is likely much greater. This case highlights a possible clinical phenotype of OSA without EDS and its association with resistant AH. Most importantly a good hypotensive response to medical treatment in tandem with CPAP therapy was achieved in this patient. Thus, it is reasonable to include OSA in the differential list of resistant AH, even if EDS is not clinically obvious.</p

Communication in the context of glioblastoma treatment: A qualitative study of what matters most to patients, caregivers and health care professionals

Background: Patients with glioblastoma have a poor prognosis and treatment is palliative in nature from diagnosis. It is therefore critical that the benefits and burdens of treatments are clearly discussed with patients and caregivers. Aim: To explore experiences and preferences around glioblastoma treatment communication in patients, family caregivers and healthcare professionals. Design: Qualitative design. A thematic analysis of semi-structured interviews. Setting/participants: A total of 15 adult patients with glioblastoma, 13 caregivers and 5 healthcare professionals were recruited from Leeds Teaching Hospitals NHS Trust. Results: Four themes were identified: (1) Communication practice and preferences. Risks and side-effects of anti-tumour treatments were explained clearly, with information layered and repeated. Treatment was often understood to be ‘the only option’. Understanding the impact of side-effects could be enhanced, alongside information about support services. (2) What matters most. Patients/caregivers valued being well-supported by a trusted treatment team, feeling involved, having control and quality of life. Healthcare professionals similarly highlighted trust, maintaining independence and emotional support as key. (3) Decision-making. With limited treatment options, trust and control are crucial in decision-making. Patients ultimately prefer to follow healthcare professional advice but want to be involved, consider alternatives and voice what matters to them. (4) Impact of COVID-19. During the pandemic, greater efforts to maintain good communication were necessary. Negative impacts of COVID-19 were limited, caregivers appeared most disadvantaged by pandemic-related restrictions. Conclusions: In glioblastoma treatment communication, where prognosis is poor and treatment will not result in cure, building trusting relationships, maintaining a sense of control and being well-informed are identified as critical

Hydroxychloroquine and short-course radiotherapy in elderly patients with newly diagnosed high-grade glioma: a randomized phase II trial

Background: Effective treatment for patients at least 70 years with newly diagnosed glioblastoma remains challenging and alternatives to conventional cytotoxics are appealing. Autophagy inhibition has shown promising efficacy and safety in small studies of glioblastoma and other cancers. Methods: We conducted a randomized phase II trial to compare radiotherapy with or without hydroxychloroquine (2:1 allocation). Patients aged at least 70 years with newly diagnosed high-grade glioma deemed suitable for short-course radiotherapy with an ECOG performance status of 0–1 were included. Radiotherapy treatment consisted of 30 Gy, delivered as 6 fractions given over 2 weeks (5 Gy per fraction). Hydroxychloroquine was given as 200 mg orally b.d. from 7 days prior to radiotherapy until disease progression. The primary endpoint was 1-year overall survival (OS). Secondary endpoints included progression-free survival (PFS), quality of life, and toxicity. Results: Fifty-four patients with a median age of 75 were randomized between May 2013 and October 2016. The trial was stopped early in 2016. One-year OS was 20.3% (95% confidence interval [CI] 8.2–36.0) hydroxychloroquine group, and 41.2% (95% CI 18.6–62.6) radiotherapy alone, with a median survival of 7.9 and 11.5 months, respectively. The corresponding 6-month PFS was 35.3% (95% CI 19.3–51.7) and 29.4% (95% CI 10.7–51.1). The outcome in the control arm was better than expected and the excess of deaths in the hydroxychloroquine group appeared unrelated to cancer. There were more grade 3–5 events in the hydroxychloroquine group (60.0%) versus radiotherapy alone (38.9%) without any clear common causation. Conclusions: Hydroxychloroquine with short-course radiotherapy did not improve survival compared to radiotherapy alone in elderly patients with glioblastoma

Intensity standardization of MRI prior to radiomic feature extraction for artificial intelligence research in glioma-a systematic review

Objectives Radiomics is a promising avenue in non-invasive characterisation of diffuse glioma. Clinical translation is hampered by lack of reproducibility across centres and difficulty in standardising image intensity in MRI datasets. The study aim was to perform a systematic review of different methods of MRI intensity standardisation prior to radiomic feature extraction. Methods MEDLINE, EMBASE, and SCOPUS were searched for articles meeting the following eligibility criteria: MRI radiomic studies where one method of intensity normalisation was compared with another or no normalisation, and original research concerning patients diagnosed with diffuse gliomas. Using PRISMA criteria, data were extracted from short-listed studies including number of patients, MRI sequences, validation status, radiomics software, method of segmentation, and intensity standardisation. QUADAS-2 was used for quality appraisal. Results After duplicate removal, 741 results were returned from database and reference searches and, from these, 12 papers were eligible. Due to a lack of common pre-processing and different analyses, a narrative synthesis was sought. Three different intensity standardisation techniques have been studied: histogram matching (5/12), limiting or rescaling signal intensity (8/12), and deep learning (1/12)—only two papers compared different methods. From these studies, histogram matching produced the more reliable features compared to other methods of altering MRI signal intensity. Conclusion Multiple methods of intensity standardisation have been described in the literature without clear consensus. Further research that directly compares different methods of intensity standardisation on glioma MRI datasets is required. Key Points • Intensity standardisation is a key pre-processing step in the development of robust radiomic signatures to evaluate diffuse glioma. • A minority of studies compared the impact of two or more methods. • Further research is required to directly compare multiple methods of MRI intensity standardisation on glioma datasets

A phase 1b randomised, placebo-controlled trial of nabiximols cannabinoid oromucosal spray with temozolomide in patients with recurrent glioblastoma

Background Preclinical data suggest some cannabinoids may exert antitumour effects against glioblastoma (GBM). Safety and preliminary efficacy of nabiximols oromucosal cannabinoid spray plus dose-intense temozolomide (DIT) was evaluated in patients with first recurrence of GBM. Methods Part 1 was open-label and Part 2 was randomised, double-blind, and placebo-controlled. Both required individualised dose escalation. Patients received nabiximols (Part 1, n = 6; Part 2, n = 12) or placebo (Part 2 only, n = 9); maximum of 12 sprays/day with DIT for up to 12 months. Safety, efficacy, and temozolomide (TMZ) pharmacokinetics (PK) were monitored. Results The most common treatment-emergent adverse events (TEAEs; both parts) were vomiting, dizziness, fatigue, nausea and headache. Most patients experienced TEAEs that were grade 2 or 3 (CTCAE). In Part 2, 33% of both nabiximols- and placebo-treated patients were progression-free at 6 months. Survival at 1 year was 83% for nabiximols- and 44% for placebo-treated patients (p = 0.042), although two patients died within the first 40 days of enrolment in the placebo arm. There were no apparent effects of nabiximols on TMZ PK. Conclusions With personalised dosing, nabiximols had acceptable safety and tolerability with no drug–drug interaction identified. The observed survival differences support further exploration in an adequately powered randomised controlled trial. Clinical trial registration ClinicalTrials.gov: Part 1– NCT01812603; Part 2– NCT01812616