State of the Art in Low-Grade Glioma Management: Insights From Isocitrate Dehydrogenase and Beyond.

Low-grade gliomas present a formidable challenge in neuro-oncology because of the challenges imposed by the blood-brain barrier, predilection for the young adult population, and propensity for recurrence. In the past two decades, the systematic examination of genomic alterations in adults and children with primary brain tumors has uncovered profound new insights into the pathogenesis of these tumors, resulting in more accurate tumor classification and prognostication. It also identified several common recurrent genomic alterations that now define specific brain tumor subtypes and have provided a new opportunity for molecularly targeted therapeutic intervention. Adult-type diffuse low-grade gliomas are frequently associated with mutations in isocitrate dehydrogenase 1 and 2 (IDH1/2), resulting in production of 2-hydroxyglutarate, an oncometabolite important for tumorigenesis. Recent studies of IDH inhibitors have yielded promising results in patients at early stages of disease with prolonged progression-free survival (PFS) and delayed time to radiation and chemotherapy. Pediatric-type gliomas have high rates of alterations in BRAF, including BRAF V600E point mutations or BRAF-KIAA1549 rearrangements. BRAF inhibitors, often combined with MEK inhibitors, have resulted in radiographic response and improved PFS in these patients. This article reviews emerging approaches to the treatment of low-grade gliomas, including a discussion of targeted therapies and how they integrate with the current treatment modalities of surgical resection, chemotherapy, and radiation.

Diffuse infiltrating tumour with the molecular profile of an atypical teratoid rhabdoid tumour (AT/RT SHH-1B) in an adult patient.

We describe a 46-year-old patient with an IDH-wildtype diffusely infiltrating atypical teratoid/rhabdoid tumour (AT/RT), SHH-1B molecular subtype. The unusual histology and subsequent diagnosis in an adult patient will be discussed.

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.

H3 K27M-altered glioma and diffuse intrinsic pontine glioma: Semi-systematic review of treatment landscape and future directions.

H3 K27M-mutant diffuse glioma is a recently identified brain tumor associated with poor prognosis. As of 2016, it is classified by the World Health Organization as a distinct form of grade IV glioma. Despite recognition as an important prognostic and diagnostic feature in diffuse glioma, radiation remains the sole standard of care and no effective systemic therapies are available for H3K27M mutant tumors. This review will detail treatment interventions applied to diffuse midline glioma and diffuse intrinsic pontine glioma (DIPG) prior to the identification of the H3 K27M mutation, the current standard-of-care for H3 K27M-mutant diffuse glioma treatment, and ongoing clinical trials listed on www.clinicaltrials.gov evaluating novel therapeutics in this population. Current clinical trials were identified using clinicaltrials.gov, and studies qualifying for this analysis were active or ongoing interventional trials that evaluated a therapy in at least 1 treatment arm or cohort comprised exclusively of patients with DIPG and H3 K27M-mutant glioma. Forty-one studies met these criteria, including trials evaluating H3 K27M vaccination, chimeric antigen receptor T-cell therapy, and small molecule inhibitors. Ongoing evaluation of novel therapeutics is necessary to identify safe and effective interventions in this underserved patient population.

Primary brain tumours in adults.

The most frequent adult-type primary CNS tumours are diffuse gliomas, but a large variety of rarer CNS tumour types exists. The classification of these tumours is increasingly based on molecular diagnostics, which is reflected in the extensive molecular foundation of the recent WHO 2021 classification of CNS tumours. Resection as extensive as is safely possible is the cornerstone of treatment in most gliomas, and is now also recommended early in the treatment of patients with radiological evidence of histologically low-grade tumours. For the adult-type diffuse glioma, standard of care is a combination of radiotherapy and chemotherapy. Although treatment with curative intent is not available, combined modality treatment has resulted in long-term survival (>10-20 years) for some patients with isocitrate dehydrogenase (IDH) mutant tumours. Other rarer tumours require tailored approaches, best delivered in specialised centres. Targeted treatments based on molecular alterations still only play a minor role in the treatment landscape of adult-type diffuse glioma, and today are mainly limited to patients with tumours with BRAFV600E (ie, Val600Glu) mutations. Immunotherapy for CNS tumours is still in its infancy, and so far, trials with checkpoint inhibitors and vaccination studies have not shown improvement in patient outcomes in glioblastoma. Current research is focused on improving our understanding of the immunosuppressive tumour environment, the molecular heterogeneity of tumours, and the role of tumour microtube network connections between cells in the tumour microenvironment. These factors all appear to play a role in treatment resistance, and indicate that novel approaches are needed to further improve outcomes of patients with CNS tumours.

Alternative normalization and analysis pipeline to address systematic bias in NanoString GeoMx Digital Spatial Profiling data.

Spatial transcriptomics is a novel technique that provides RNA-expression data with tissue-contextual annotations. Quality assessments of such techniques using end-user generated data are often lacking. Here, we evaluated data from the NanoString GeoMx Digital Spatial Profiling (DSP) platform and standard processing pipelines. We queried 72 ROIs from 12 glioma samples, performed replicate experiments of eight samples for validation, and evaluated five external datasets. The data consistently showed vastly different signal intensities between samples and experimental conditions that resulted in biased analysis. We evaluated the performance of alternative normalization strategies and show that quantile normalization can adequately address the technical issues related to the differences in data distributions. Compared to bulk RNA sequencing, NanoString DSP data show a limited dynamic range which underestimates differences between conditions. Weighted gene co-expression network analysis allowed extraction of gene signatures associated with tissue phenotypes from ROI annotations. Nanostring GeoMx DSP data therefore require alternative normalization methods and analysis pipelines.

Trotabresib (CC-90010) in combination with adjuvant temozolomide or concomitant temozolomide plus radiotherapy in patients with newly diagnosed glioblastoma.

Background: Standard-of-care treatment for newly diagnosed glioblastoma (ndGBM), consisting of surgery followed by radiotherapy (RT) and temozolomide (TMZ), has improved outcomes compared with RT alone; however, prognosis remains poor. Trotabresib, a novel bromodomain and extraterminal inhibitor, has demonstrated antitumor activity in patients with high-grade gliomas. Methods: In this phase Ib, dose-escalation study (NCT04324840), we investigated trotabresib 15, 30, and 45 mg combined with TMZ in the adjuvant setting and trotabresib 15 and 30 mg combined with TMZ+RT in the concomitant setting in patients with ndGBM. Primary endpoints were to determine safety, tolerability, maximum tolerated dose, and/or recommended phase II dose (RP2D) of trotabresib. Secondary endpoints were assessment of preliminary efficacy and pharmacokinetics. Pharmacodynamics were investigated as an exploratory endpoint. Results: The adjuvant and concomitant cohorts enrolled 18 and 14 patients, respectively. Trotabresib in combination with TMZ or TMZ+RT was well tolerated; most treatment-related adverse events were mild or moderate. Trotabresib pharmacokinetics and pharmacodynamics in both settings were consistent with previous data for trotabresib monotherapy. The RP2D of trotabresib was selected as 30 mg 4 days on/24 days off in both settings. At last follow-up, 5 (28%) and 6 (43%) patients remain on treatment in the adjuvant and concomitant settings, respectively, with 1 patient in the adjuvant cohort achieving complete response. Conclusions: Trotabresib combined with TMZ in the adjuvant setting and with TMZ+RT in the concomitant setting was safe and well tolerated in patients with ndGBM, with encouraging treatment durations. Trotabresib 30 mg was established as the RP2D in both settings.

The effect of dexamethasone on the microenvironment and efficacy of checkpoint inhibitors in glioblastoma: a systematic review.

Background: Checkpoint inhibitor immunotherapy has not proven clinically effective in glioblastoma. This lack of effectiveness may be partially attributable to the frequent administration of dexamethasone in glioblastoma patients. In this systematic review, we assess whether dexamethasone (1) affects the glioblastoma microenvironment and (2) interferes with checkpoint inhibitor immunotherapy efficacy in the treatment of glioblastoma. Methods: PubMed and Embase were systematically searched for eligible articles published up to September 15, 2021. Both in vitro and in vivo preclinical studies, as well as clinical studies were selected. The following information was extracted from each study: tumor model, corticosteroid treatment, and effects on individual immune components or checkpoint inhibitor immunotherapy. Results: Twenty-one preclinical studies in cellular glioma models (n = 10), animal glioma models (n = 6), and glioblastoma patient samples (n = 7), and 3 clinical studies were included. Preclinical studies show that dexamethasone decreases the presence of microglia and other macrophages as well as the number of T lymphocytes in both tumor tissue and periphery. Dexamethasone abrogates the antitumor effects of checkpoint inhibitors on T lymphocytes in preclinical studies. Although randomized studies directly addressing our research question are lacking, clinical studies suggest a negative association between corticosteroids and survival outcomes in glioblastoma patients receiving checkpoint inhibitors after adjustment for relevant prognostic factors. Conclusions: Preclinical research shows that dexamethasone inhibits the antitumor immune response in glioma, thereby promoting a protumorigenic microenvironment. The efficacy of checkpoint inhibitor immunotherapy in glioblastoma patients may therefore be negatively affected by the use of dexamethasone. Future research could investigate the potential of edema-reducing alternatives to dexamethasone.

MicroRNA-575 acts as a novel oncogene via targeting multiple signaling pathways in glioblastoma.

PURPOSE: Glioblastoma (GBM) patients currently face poor survival outcomes with an average survival period of <15 months, while only 3-5% of patients survive longer than 36 months. Although the mechanisms of tumorigenesis are still being elucidated, miRNAs are promising candidates to explore as novel and prognostic biomarkers in GBM. In this study, we identified the association between miR-575 expression and overall survival (OS) of primary GBM patients and undertook functional studies to discern the contribution of miR-575 to GBM tumorigenesis. METHODS: Total RNAs were isolated from 254 FFPE GBM tumor samples and miR expression was assayed (simultaneously) using NanoString Technologies. To determine the association between miR-575 and patients' prognosis, Kaplan-Meier, univariable and multivariable Cox regression analyses were performed. Cell proliferation, colony formation, migration assays were conducted to investigate the function of miR-575 in vitro and in vivo. In silico target gene network analysis was performed to identify the putative targets of miR-575 in GBM, which were further verified by luciferase reporter assay, as well as qPCR and immunoblotting. RESULTS: Our clinical data (n = 254) show that miR-575 is associated with worse GBM OS by univariable analysis (UVA, HR = 1.27, p-value<0.001) and multivariable (MVA, HR = 1.23, p = 0.007) analysis incorporating critical clinical variables. Functional studies indicated that overexpression of miR-575 significantly increased cell proliferation and migration of GBM cells in vitro, as well as tumor growth in vivo. Subsequent in silico target gene network and mechanistic studies identified CDKN1B/p27 and PTEN, as potential targets of miR-575 in GBM. MicroRNA-575 can also regulate the activity of AKT and ERK pathways in GBM. CONCLUSION: miR-575 has prognostic value in GBM, with higher expression associating with worse OS of patients, and contributes to GBM tumorigenesis by regulating multiple signaling pathways in GBM.

Quality of dying after acute stroke.

INTRODUCTION: There is a lack of evidence concerning the palliative needs of patients with acute stroke during end-of-life care. We interviewed relatives of patients who deceased in our stroke unit about the quality of dying and compared their experiences with those of nurses. PATIENTS AND METHODS: Relatives of 59 patients were interviewed approximately 6 weeks after the patient had died. The primary outcome was a score assessing the overall quality of dying on a scale ranging from 0 to 10, with 0 representing the worst quality and 10 the best quality. We investigated the frequency and appreciation of specific aspects of the dying phase with an adapted version of the Quality of Death and Dying Questionnaire. The nurse who was most frequently involved in the end-of-life care of the patient completed a similar questionnaire. RESULTS: Family members were generally satisfied with the quality of dying (median overall score 8; interquartile range, 6-9) as well as with the care provided by nurses (9; 8-10) and doctors (8; 7-9). Breathing difficulties were frequently reported (by 46% of the relatives), but pain was not. Unsatisfactory experiences were related to feeding (69% unsatisfactory), inability to say goodbye to loved ones (51%), appearing not to have control (47%), and not retaining a sense of dignity (41%). Two-thirds of the relatives reported that palliative medication adequately resolved discomfort. There was a good correlation between the experiences of relatives and nurses. DISCUSSION AND CONCLUSION: Most relatives were satisfied with the overall quality of dying. Negative experiences concerned feeding problems, not being able to say goodbye to loved ones, sense of self control and dignity, and breathing difficulties. Experiences of nurses may be a reasonable and practical option when evaluating the quality of dying in acute stroke patients.

Treatment of anaplastic gliomas: evidences and controversies.

PURPOSE OF REVIEW: Evolving molecular data have led to a new and advanced grading system of anaplastic glioma. In everyday practice, physicians have to translate evidence from old clinical trials into evidence meeting the reclassified tumor types. RECENT FINDINGS: New biomarkers allow the identification of anaplastic glioma with relatively poor prognosis and with prognosis similar to glioblastoma. An update with molecular analysis of the phase 3 CATNON trial demonstrates the benefit of adjuvant temozolomide (TMZ) to be dependent on the mutational status of isocitrate dehydrogenase. In the ongoing debate on the optimal chemotherapy regimen, a large retrospective study suggesting a better tumor control with vincristine (PCV) as compared to TMZ is added to the evidence. The best timing for treatment of anaplastic astrocytoma also remains a matter of controversy. A recent study shows that even in selected patients with anaplastic glioma with foci of malignant tumor following (sub)total resection, postponement of medical treatment can be considered. SUMMARY: In clinical practice, the trade-off between efficacy and (acute and long-term) toxicity of treatments needs to be re-evaluated for the newly (molecularly) defined entities. Updates from past clinical trials on anaplastic glioma with molecular analysis and subgroup analyses are needed to further guide treatment decisions.

A basic review on systemic treatment options in WHO grade II-III gliomas.

WHO grade II-III gliomas are rare primary brain tumors occurring at a median age of about 35-55 years. Median survival is longer in WHO grade II-III glioma compared with WHO grade IV glioblastoma as survival times of up to 10 years and longer can be observed. Maximal safe resection and adjuvant therapies including chemotherapy and radiotherapy are the mainstay of treatment. Clinical trials in WHO grade II-III tumors are challenging due to the rarity and the long follow up times. The 2016 WHO Classification of Central Nervous Tumours introduced a new diagnostic framework relying on molecular characteristics, providing the definition of prognostically more homogenous subgroups compared to the histopathological analysis. Most available evidence on the adjuvant treatment of WHO II-III gliomas was generated in the pre-molecular era, challenging the interpretation of study results. The present review therefore summarizes the available data from prospective trials on systemic treatment options in WHO grade II-III glioma, considering molecular markers, recently published results and future outlooks in the field.

A Novel miR-146a-POU3F2/SMARCA5 Pathway Regulates Stemness and Therapeutic Response in Glioblastoma.

Rapid tumor growth, widespread brain-invasion, and therapeutic resistance critically contribute to glioblastoma (GBM) recurrence and dismal patient outcomes. Although GBM stem cells (GSC) are shown to play key roles in these processes, the molecular pathways governing the GSC phenotype (GBM-stemness) remain poorly defined. Here, we show that epigenetic silencing of miR-146a significantly correlated with worse patient outcome and importantly, miR-146a level was significantly lower in recurrent tumors compared with primary ones. Further, miR-146a overexpression significantly inhibited the proliferation and invasion of GBM patient-derived primary cells and increased their response to temozolomide (TMZ), both in vitro and in vivo. Mechanistically, miR-146a directly silenced POU3F2 and SMARCA5, two transcription factors that mutually regulated each other, significantly compromising GBM-stemness and increasing TMZ response. Collectively, our data show that miR-146a-POU3F2/SMARCA5 pathway plays a critical role in suppressing GBM-stemness and increasing TMZ-response, suggesting that POU3F2 and SMARCA5 may serve as novel therapeutic targets in GBM. IMPLICATIONS: miR-146a predicts favorable prognosis and the miR-146a-POU3F2/SMARCA5 pathway is important for the suppression of stemness in GBM.

Treatment Restrictions and the Risk of Death in Patients With Ischemic Stroke or Intracerebral Hemorrhage.

BACKGROUND AND PURPOSE: Do-not-resuscitate (DNR) orders in the first 24 hours after intracerebral hemorrhage have been associated with an increased risk of early death. This relationship is less certain for ischemic stroke. We assessed the relation between treatment restrictions and mortality in patients with ischemic stroke and in patients with intracerebral hemorrhage. We focused on the timing of treatment restrictions after admission and the type of treatment restriction (DNR order versus more restrictive care). METHODS: We retrospectively assessed demographic and clinical data, timing and type of treatment restrictions, and vital status at 3 months for 622 consecutive stroke patients primarily admitted to a Dutch university hospital. We used a Cox regression model, with adjustment for age, sex, comorbidities, and stroke type and severity. RESULTS: Treatment restrictions were installed in 226 (36%) patients, more frequently after intracerebral hemorrhage (51%) than after ischemic stroke (32%). In 187 patients (83%), these were installed in the first 24 hours. Treatment restrictions installed within the first 24 hours after hospital admission and those installed later were independently associated with death at 90 days (adjusted hazard ratios, 5.41 [95% CI, 3.17-9.22] and 5.36 [95% CI, 2.20-13.05], respectively). Statistically significant associations were also found in patients with ischemic stroke and in patients with just an early DNR order. In those who died, the median time between a DNR order and death was 520 hours (interquartile range, 53-737). CONCLUSIONS: The strong relation between treatment restrictions (including DNR orders) and death and the long median time between a DNR order and death suggest that this relation may, in part, be causal, possibly due to an overall lack of aggressive care.

Immunotherapy in Glioblastoma: Current Shortcomings and Future Perspectives.

Glioblastomas are aggressive, fast-growing primary brain tumors. After standard-of-care treatment with radiation in combination with temozolomide, the overall prognosis of newly diagnosed patients remains poor, with a 2-year survival rate of less than 20%. The remarkable survival benefit gained with immunotherapy in several extracranial tumor types spurred a variety of experimental intervention studies in glioblastoma patients. These ranged from immune checkpoint inhibition to vaccinations and adoptive T cell therapies. Unfortunately, almost all clinical outcomes were universally disappointing. In this perspective, we provide an overview of immune interventions performed to date in glioblastoma patients and re-evaluate their performance. We argue that shortcomings of current immune therapies in glioblastoma are related to three major determinants of resistance, namely: low immunogenicity; immune privilege of the central nervous system; and immunosuppressive micro-environment. In this perspective, we propose strategies that are guided by exact shortcomings to sensitize glioblastoma prior to treatment with therapies that enhance numbers and/or activation state of CD8 T cells.