Single-cell epigenetic analysis reveals principles of chromatin states in H3.3-K27M gliomas.

Cancer cells are highly heterogeneous at the transcriptional level and epigenetic state. Methods to study epigenetic heterogeneity are limited in throughput and information obtained per cell. Here, we adapted cytometry by time-of-flight (CyTOF) to analyze a wide panel of histone modifications in primary tumor-derived lines of diffused intrinsic pontine glioma (DIPG). DIPG is a lethal glioma, driven by a histone H3 lysine 27 mutation (H3-K27M). We identified two epigenetically distinct subpopulations in DIPG, reflecting inherent heterogeneity in expression of the mutant histone. These two subpopulations are robust across tumor lines derived from different patients and show differential proliferation capacity and expression of stem cell and differentiation markers. Moreover, we demonstrate the use of these high-dimensional data to elucidate potential interactions between histone modifications and epigenetic alterations during the cell cycle. Our work establishes new concepts for the analysis of epigenetic heterogeneity in cancer that could be applied to diverse biological systems.

Histone Variant and Cell Context Determine H3K27M Reprogramming of the Enhancer Landscape and Oncogenic State.

Development of effective targeted cancer therapies is fundamentally limited by our molecular understanding of disease pathogenesis. Diffuse intrinsic pontine glioma (DIPG) is a fatal malignancy of the childhood pons characterized by a unique substitution to methionine in histone H3 at lysine 27 (H3K27M) that results in globally altered epigenetic marks and oncogenic transcription. Through primary DIPG tumor characterization and isogenic oncohistone expression, we show that the same H3K27M mutation displays distinct modes of oncogenic reprogramming and establishes distinct enhancer architecture depending upon both the variant of histone H3 and the cell context in which the mutation occurs. Compared with non-malignant pediatric pontine tissue, we identify and functionally validate both shared and variant-specific pathophysiology. Altogether, we provide a powerful resource of epigenomic data in 25 primary DIPG samples and 5 rare normal pediatric pontine tissue samples, revealing clinically relevant functional distinctions previously unidentified in DIPG.

Pathogenic ACVR1R206H activation by Activin A-induced receptor clustering and autophosphorylation.

Fibrodysplasia ossificans progressiva (FOP) and diffuse intrinsic pontine glioma (DIPG) are debilitating diseases that share causal mutations in ACVR1, a TGF-ß family type I receptor. ACVR1R206H is a frequent mutation in both diseases. Pathogenic signaling via the SMAD1/5 pathway is mediated by Activin A, but how the mutation triggers aberrant signaling is not known. We show that ACVR1 is essential for Activin A-mediated SMAD1/5 phosphorylation and is activated by two distinct mechanisms. Wild-type ACVR1 is activated by the Activin type I receptors, ACVR1B/C. In contrast, ACVR1R206H activation does not require upstream kinases, but is predominantly activated via Activin A-dependent receptor clustering, which induces its auto-activation. We use optogenetics and live-imaging approaches to demonstrate Activin A-induced receptor clustering and show it requires the type II receptors ACVR2A/B. Our data provide molecular mechanistic insight into the pathogenesis of FOP and DIPG by linking the causal activating genetic mutation to disrupted signaling.

Click-chemistry mediated synthesis of OTBN-1,2,3-Triazole derivatives exhibiting STK33 inhibition with diverse anti-cancer activities.

There is a continuous and pressing need to establish new brain-penetrant bioactive compounds with anti-cancer properties. To this end, a new series of 4'-((4-substituted-4,5-dihydro-1H-1,2,3-triazol-1-yl)methyl)-[1,1'-biphenyl]-2-carbonitrile (OTBN-1,2,3-triazole) derivatives were synthesized by click chemistry. The series of bioactive compounds were designed and synthesized from diverse alkynes and N3-OTBN, using copper (II) acetate monohydrate in aqueous dimethylformamide at room temperature. Besides being highly cost-effective and significantly reducing synthesis, the reaction yielded 91-98 % of the target products without the need of any additional steps or chromatographic techniques. Two analogues exhibit promising anti-cancer biological activities. Analogue 4l shows highly specific cytostatic activity against lung cancer cells, while analogue 4k exhibits pan-cancer anti-growth activity. A kinase screen suggests compound 4k has single-digit micromolar activity against kinase STK33. High STK33 RNA expression correlates strongly with poorer patient outcomes in both adult and pediatric glioma. Compound 4k potently inhibits cell proliferation, invasion, and 3D neurosphere formation in primary patient-derived glioma cell lines. The observed anti-cancer activity is enhanced in combination with specific clinically relevant small molecule inhibitors. Herein we establish a novel biochemical kinase inhibitory function for click-chemistry-derived OTBN-1,2,3-triazole analogues and further report their anti-cancer activity in vitro for the first time.

The relationship between imaging features, therapeutic response, and overall survival in pediatric diffuse intrinsic pontine glioma.

We aimed to evaluate the relationship between imaging features, therapeutic responses (comparative cross-product and volumetric measurements), and overall survival (OS) in pediatric diffuse intrinsic pontine glioma (DIPG). A total of 134 patients (≤ 18 years) diagnosed with DIPG were included. Univariate and multivariate analyses were performed to evaluate correlations of clinical and imaging features and therapeutic responses with OS. The correlation between cross-product (CP) and volume thresholds in partial response (PR) was evaluated by linear regression. The log-rank test was used to compare OS patients with discordant therapeutic response classifications and those with concordant classifications. In univariate analysis, characteristics related to worse OS included lower Karnofsky, larger extrapontine extension, ring-enhancement, necrosis, non-PR, and increased ring enhancement post-radiotherapy. In the multivariate analysis, Karnofsky, necrosis, extrapontine extension, and therapeutic response can predict OS. A 25% CP reduction (PR) correlated with a 32% volume reduction (R2 = 0.888). Eight patients had discordant therapeutic response classifications according to CP (25%) and volume (32%). This eight patients' median survival time was 13.0 months, significantly higher than that in the non-PR group (8.9 months), in which responses were consistently classified as non-PR based on CP (25%) and volume (32%). We identified correlations between imaging features, therapeutic responses, and OS; this information is crucial for future clinical trials. Tumor volume may represent the DIPG growth pattern more accurately than CP measurement and can be used to evaluate therapeutic response.

MR-guided focused ultrasound in pediatric neurosurgery: current insights, technical challenges, and lessons learned from 45 treatments at Children's National Hospital.

OBJECTIVE: MR-guided focused ultrasound (MRgFUS) is an evolving technology with numerous present and potential applications in pediatric neurosurgery. The aim of this study was to describe the use of MRgFUS, technical challenges, complications, and lessons learned at a single children's hospital. METHODS: A retrospective analysis was performed of a prospectively collected database of all pediatric patients undergoing investigational use of MRgFUS for treatment of various neurosurgical pathologies at Children's National Hospital. Treatment details, clinical workflow, and standard operating procedures are described. Patient demographics, procedure duration, and complications were obtained through a chart review of anesthesia and operative reports. RESULTS: In total, 45 MRgFUS procedures were performed on 14 patients for treatment of diffuse intrinsic pontine glioma (n = 12), low-grade glioma (n = 1), or secondary dystonia (n = 1) between January 2022 and April 2024. The mean age at treatment was 9 (range 5-22) years, and 64% of the patients were male. With increased experience, the total anesthesia time, sonication time, and change in core body temperature during treatment all significantly decreased. Complications affected 4.4% of patients, including 1 case of scalp edema and 1 patient with a postprocedure epidural hematoma. Device malfunction requiring abortion of the procedure occurred in 1 case (2.2%). Technical challenges related to transducer malfunction and sonication errors occurred in 6.7% and 11.1% of cases, respectively, all overcome by subsequent user modifications. CONCLUSIONS: The authors describe the largest series on MRgFUS technical aspects in pediatric neurosurgery at a single institution, comprising 45 total treatments. This study emphasizes potential technical challenges and provides valuable insights into the nuances of its application in pediatric patients.

Clinical outcome, radiological findings, and genetic features of IDH-mutant brainstem glioma in adults.

BACKGROUND: With the recent advent of genetic testing, IDH-mutant glioma has been found among adult brainstem gliomas. However, the clinical outcome and prognosis of IDH-mutant brainstem gliomas in adults have not been elucidated. This study aimed to investigate the clinical outcome, radiological findings, and genetic features of adult patients with IDH-mutant diffuse brainstem gliomas. METHODS: Data from adult patients with brainstem glioma at Hokkaido University Hospital between 2006 and 2022 were retrospectively analyzed. Patient characteristics, treatment methods, genetic features, and prognosis were evaluated. RESULTS: Of 12 patients with brainstem glioma with proven histopathology, 4 were identified with IDH mutation. All patients underwent local radiotherapy with 54 Gray in 27 fractions combined with chemotherapy with temozolomide. Three patients had IDH1 R132H mutation and one had IDH2 R172G mutation. The median progression-free survival and overall survival were 68.4 months and 85.2 months, respectively, longer than that for IDH-wildtype gliomas (5.6 months and 12.0 months, respectively). At the time of initial onset, contrast-enhanced lesions were observed in two of the four cases in magnetic resonance imaging. CONCLUSION: As some adult brainstem gliomas have IDH mutations, and a clearly different prognosis from those with IDH-wildtype, biopsies are proactively considered to confirm the genotype.

Bone Morphogenic Proteins in Pediatric Diffuse Midline Gliomas: How to Make New Out of Old?

The BMP pathway is one of the major signaling pathways in embryonic development, ontogeny and homeostasis, identified many years ago by pioneers in developmental biology. Evidence of the deregulation of its activity has also emerged in many cancers, with complex and sometimes opposing effects. Recently, its role has been suspected in Diffuse Midline Gliomas (DMG), among which Diffuse Intrinsic Pontine Gliomas (DIPG) are one of the most complex challenges in pediatric oncology. Genomic sequencing has led to understanding part of their molecular etiology, with the identification of histone H3 mutations in a large proportion of patients. The epigenetic remodeling associated with these genetic alterations has also been precisely described, creating a permissive context for oncogenic transcriptional program activation. This review aims to describe the new findings about the involvement of BMP pathway activation in these tumors, placing their appearance in a developmental context. Targeting the oncogenic synergy resulting from this pathway activation in an H3K27M context could offer new therapeutic perspectives based on targeting treatment-resistant cell states.

Dimethyl alpha-ketoglutarate inhibits proliferation in diffuse intrinsic pontine glioma by reprogramming epigenetic and transcriptional networks.

Diffuse intrinsic pontine glioma (DIPG) is a highly aggressive pediatric brain tumor with limited therapeutic options. Here, we investigated the potential of dimethyl alpha-ketoglutarate (DMKG) as an anti-proliferative agent against DIPG and unraveled its underlying molecular mechanisms. DMKG exhibited robust inhibition of DIPG cell proliferation, colony formation, and neurosphere growth. Transcriptomic analysis revealed substantial alterations in gene expression, with upregulated genes enriched in hypoxia-related pathways and downregulated genes associated with cell division and the mitotic cell cycle. Notably, DMKG induced G1/S phase cell cycle arrest and downregulated histone H3 lysine 27 acetylation (H3K27ac) without affecting H3 methylation levels. The inhibition of AKT and ERK signaling pathways by DMKG coincided with decreased expression of the CBP/p300 coactivator. Importantly, we identified the c-MYC-p300/ATF1-p300 axis as a key mediator of DMKG's effects, demonstrating reduced binding to target gene promoters and decreased H3K27ac levels. Depletion of c-MYC or ATF1 effectively inhibited DIPG cell growth. These findings highlight the potent anti-proliferative properties of DMKG, its impact on epigenetic modifications, and the involvement of the c-MYC-p300/ATF1-p300 axis in DIPG, shedding light on potential therapeutic strategies for this devastating disease.

11C-methionine PET imaging characteristics in children with diffuse intrinsic pontine gliomas and relationship to survival and H3 K27M mutation status.

PURPOSE: This study aimed to describe 11C-methionine (11C-MET) PET imaging characteristics in patients with paediatric diffuse intrinsic pontine glioma (DIPG) and correlate them with survival and H3 K27M mutation status. METHODS: We retrospectively analysed 98 children newly diagnosed with DIPG who underwent 11C-MET PET. PET imaging characteristics evaluated included uptake intensity, uniformity, metabolic tumour volume (MTV), and total lesion methionine uptake (TLMU). The maximum, mean, and peak of the tumour-to-background ratio (TBR), calculated as the corresponding standardised uptake values (SUV) divided by the mean reference value, were also recorded. The associations between the PET imaging characteristics and clinical outcomes in terms of progression-free survival (PFS) and overall survival (OS) and H3 K27M mutation status were assessed, respectively. RESULTS: In univariate analysis, imaging characteristics significantly associated with shorter PFS and OS included a higher uniformity grade, higher TBRs, larger MTV, and higher TLMU. In multivariate analysis, larger MTV at diagnosis, shorter symptom duration, and no treatment were significantly correlated with shorter PFS and OS. The PET imaging features were not correlated with H3 K27M mutation status. CONCLUSION: Although several imaging features were significantly associated with PFS and OS, only MTV, indicating the size of the active tumour, was identified as a strong independent prognostic factor.

Diffuse intrinsic pontine gliomas: First registry effort in Mexico.

INTRODUCTION: Brainstem tumors comprise 10.9% of all brain tumors, and pediatric diffuse intrinsic pontine gliomas (DIPG) have a fatal prognosis. Some countries have developed national and international register databases to characterize their populations to aid clinical and public policy decisions. This study provides information regarding the clinical characteristics of a retrospective cohort of children with DIPG in México from 2001 to 2021, and assesses the proposed prognostic factors previously described for survival outcome. METHODS: Health institutions from Mexico were invited to contribute to a retrospective electronic registry of patients with DIPG based on the International DIPG Registry. Fisher's exact test was used to compare long- and short-term survivors. Overall survival was estimated using the Kaplan-Meier method. Differences between survival curves were evaluated using the log-rank test and Cox proportional hazard regression analysis. RESULTS: Total 110 patients were included. The median age of the patients at diagnosis was 7 years. Sixty patients (54.5%) presented with symptoms in less than 6 months; the most frequent symptom was ataxia (56.4%). Ninety patients received treatment (81.8%), the overall survival at 4 years was 11.4%, and 16 patients (14.5%) were admitted for palliative end-of-life care. We found no significant survival differences for any of the prognostic factors. CONCLUSION: This study highlights the need to develop strategies to standardize healthcare processes and enhance the quality of care to improve clinical diagnosis in Mexico. We also observed a barrier to the acceptance of palliative end-of-life care in the family and medical teams.

Advances in Treatment of Diffuse Midline Gliomas.

PURPOSE OF REVIEW: Diffuse midline gliomas (DMGs) generally carry a poor prognosis, occur during childhood, and involve midline structures of the central nervous system, including the thalamus, pons, and spinal cord. RECENT FINDINGS: To date, irradiation has been shown to be the only beneficial treatment for DMG. Various genetic modifications have been shown to play a role in the pathogenesis of this disease. Current treatment strategies span targeting epigenetic dysregulation, cell cycle, specific genetic alterations, and the immune microenvironment. Herein, we review the complex features of this disease as it relates to current and past therapeutic approaches.

Fifty years of DIPG: looking at the future with hope.

Diffuse intrinsic pontine glioma (DIPG) is a primary brainstem tumor of childhood that carries a dismal prognosis, with median survival of less than 1 year. Because of the brain stem location and pattern of growth within the pons, Dr. Harvey Cushing, the father of modern neurosurgery, urged surgical abandonment. Such a dismal prognosis remained unchanged for decades, coupled with a lack of understanding of tumor biology and an unchanging therapeutic panorama. Beyond palliative external beam radiation therapy, no therapeutic approach has been widely accepted. In the last one to two decades, however, increased tissue availability, an improving understanding of biology, genetics, and epigenetics have led to the development of novel therapeutic targets. In parallel with this biological revolution, new methods intended to enhance drug delivery into the brain stem are contributing to a surge of exciting experimental therapeutic strategies.

DIPG-like MYB-altered diffuse astrocytoma with durable response to intensive chemotherapy.

Pontine gliomas represent difficult to treat entity due to the location and heterogeneous biology varying from indolent low-grade gliomas to aggressive diffuse intrinsic pontine glioma (DIPG). Making the correct tumor diagnosis in the pontine location is thus critical. Here, we report a case study of a 14-month-old patient initially diagnosed as histone H3 wild-type DIPG. Due to the low age of the patient, the MRI appearance of DIPG, and anaplastic astrocytoma histology, intensive chemotherapy based on the HIT-SKK protocol with vinblastine maintenance chemotherapy was administered. Rapid clinical improvement and radiological regression of the tumor were observed with nearly complete remission with durable effect and excellent clinical condition more than 6.5 years after diagnosis. Based on this unexpected therapeutic outcome, genome-wide DNA methylation array was employed and the sample was classified into the methylation class "Low-grade glioma, MYB(L1) altered." Additionally, RT-PCR revealed the presence of MYB::QKI fusion. Taken together, the histopathological classification, molecular-genetic and epigenetic features, clinical behavior, and pontine location have led us to reclassify the tumor as a pontine MYB-altered glioma. Our case demonstrates that more intensive chemotherapy can achieve long-term clinical effect in the treatment of MYB-altered pontine gliomas compared to previously used LGG-based regimens or radiotherapy. It also emphasizes the importance of a biopsy and a thorough molecular investigation of pontine lesions.

The H3K27M mutation alters stem cell growth, epigenetic regulation, and differentiation potential.

BACKGROUND: Neurodevelopmental disorders increase brain tumor risk, suggesting that normal brain development may have protective properties. Mutations in epigenetic regulators are common in pediatric brain tumors, highlighting a potentially central role for disrupted epigenetic regulation of normal brain development in tumorigenesis. For example, lysine 27 to methionine mutation (H3K27M) in the H3F3A gene occurs frequently in Diffuse Intrinsic Pontine Gliomas (DIPGs), the most aggressive pediatric glioma. As H3K27M mutation is necessary but insufficient to cause DIPGs, it is accompanied by additional mutations in tumors. However, how H3K27M alone increases vulnerability to DIPG tumorigenesis remains unclear. RESULTS: Here, we used human embryonic stem cell models with this mutation, in the absence of other DIPG contributory mutations, to investigate how H3K27M alters cellular proliferation and differentiation. We found that H3K27M increased stem cell proliferation and stem cell properties. It interfered with differentiation, promoting anomalous mesodermal and ectodermal gene expression during both multi-lineage and germ layer-specific cell specification, and blocking normal differentiation into neuroectoderm. H3K27M mutant clones exhibited transcriptomic diversity relative to the more homogeneous wildtype population, suggesting reduced fidelity of gene regulation, with aberrant expression of genes involved in stem cell regulation, differentiation, and tumorigenesis. These phenomena were associated with global loss of H3K27me3 and concordant loss of DNA methylation at specific genes in H3K27M-expressing cells. CONCLUSIONS: Together, these data suggest that H3K27M mutation disrupts normal differentiation, maintaining a partially differentiated state with elevated clonogenicity during early development. This disrupted response to early developmental cues could promote tissue properties that enable acquisition of additional mutations that cooperate with H3K27M mutation in genesis of DMG/DIPG. Therefore, this work demonstrates for the first time that H3K27M mutation confers vulnerability to gliomagenesis through persistent clonogenicity and aberrant differentiation and defines associated alterations of histone and DNA methylation.

Oncolytic virotherapy for the treatment of pediatric brainstem gliomas.

Diffuse intrinsic pontine glioma (DIPG) is the most frequent brainstem glioma and the most lethal brain tumor in childhood. Despite transient benefit with radiotherapy, the prognosis of children with this disease remains dismal with severe neurological morbidity and median survival less than 12months. Oncolytic immunovirotherapy is emerging as a potential therapeutic approach in neuro-oncology. The oncolytic adenovirus Delta-24-RGD has shown efficacy in adult patients with recurrent GBM. Our group has demonstrated that Delta-24-RGD has oncolytic activity and triggers immune response in preclinical models of DIPG, and has a synergistic effect with radiotherapy in animal models of this disease. In this scenario, we conducted a first-in-human phase 1 clinical trial to evaluate the safety and efficacy of intratumoral injection of Delta-24-RGD in pediatric patients with newly diagnosed DIPG prior to standard radiotherapy. The study confirmed the feasibility of this treatment with an acceptable safety profile and encouraging efficacy results. Correlative analyses showed a biological activity from Delta-24-RGD in DIPG. Further advanced trials are needed to validate these results. Meanwhile, plenty of opportunities to increase the potential contribution of oncolytic viruses in the management of devastating tumors with no current effective treatment such as DIPG need to be explored and exploited.

Towards Immunotherapy for Pediatric Brain Tumors.

Pediatric brain tumors are the leading cause of childhood cancer-related death. Immunotherapy is a powerful new approach for treating some refractory cancers; applying this 'fourth pillar' of cancer treatment to pediatric brain tumors is an exciting but challenging prospect. This review offers new perspectives on moving towards successful immunotherapy for pediatric brain tumors, focusing on pediatric high-grade glioma (HGG), a subgroup with universally poor outcomes. We cover chimeric antigen receptor T cell (CAR-T) therapy, vaccine therapy, and checkpoint inhibition in this context, and focus on the need for intimately understanding the growing brain and its immune system. We highlight the challenges associated with the application of immunotherapy in pediatric neuro-oncology, as well as the tissue-specific challenges to be overcome, to achieve improved outcomes.

Infusion-related side-effects during convection enhanced delivery for brainstem-diffuse midline glioma/diffuse intrinsic pontine glioma.

INTRODUCTION: Side-effects during convection enhanced delivery (CED) are poorly understood. We intended to determine the frequency of side-effects during brain stem infusion and determine risk factors for side-effects persisting longer than 24 h. METHODS: Children with a radiological diagnosis of brain stem diffuse midline glioma/Diffuse Intrinsic Pontine Glioma were treated on compassionate grounds with awake infusion of carboplatin and sodium valproate into the brain stem using the 4-catheter (2 trans-cerebellar 2 trans-frontal) chronic, intermittent Renishaw Drug Delivery System. We used change in the Pontine Neurological Observation Score (PONScore), a standardised neurological assessment tool, to identify side-effects during infusion. Recovery was determined by retrospective chart review. RESULTS: 55 infusions were performed in 8 children (3-11 years). Mean PONScore increased during infusion from 3.3 to 5.7 (p-value > 0.001). One hundred and fifty-seven infusion-related side-effects were identified including headache (33/157) and limb weakness (49/157). Fifty-four side-effects persisted > 24 h. Side-effects that had occurred during a previous infusion and those that occurred during infusion via trans-cerebellar catheters were more likely to be persistent with OR 2.333 (95% CI 1.094-4.976; p-value = 0.028) and 2.155 (1.029-4.513; p-value = 0.042) respectively. If infusion was stopped or titrated at onset rather than continued, the side-effect was less likely to persist > 24 h, OR 0.473 (95% CI 0.177-0.948; p-value = 0.037). Most side-effects developed within the first three millilitre of infusion. CONCLUSIONS: Side-effects during brainstem infusion are common, can be transient or persist longer than 24 h. Neurological injury during infusion may be time dependent and accumulative rather than volume dependent.

No wrong decisions in an all-wrong situation. A qualitative study on the lived experiences of families of children with diffuse intrinsic pontine glioma.

BACKGROUND: Diffuse intrinsic pontine glioma (DIPG) is a rare, but lethal pediatric brain tumor with a median survival of less than 1 year. Existing treatment may prolong life and control symptoms, but may cause toxicity and side effects. In order to improve child- and family-centered care, we aimed to better understand the treatment decision-making experiences of parents, as studies on this topic are currently lacking. PROCEDURE: The data for this study came from 24 semistructured interviews with parents whose children were diagnosed with DIPG in two children's hospitals in Switzerland and died between 2000 and 2016. Analysis of the dataset was done using reflexive thematic analysis. RESULTS: For most parents, the decision for or against treatment was relatively straightforward given the fatality of the tumor and the absence of treatment protocols. Most of them had no regrets about their decision for or against treatment. The most distressing factor for them was observing their child's gradual loss of independence and informing them about the inescapability of death. To counter this powerlessness, many parents opted for complementary or alternative medicine in order to "do something." Many parents reported psychological problems in the aftermath of their child's death and coping strategies between mothers and fathers often differed. CONCLUSION: The challenges of DIPG are unique and explain why parental and shared decision-making is different in DIPG compared to other cancer diagnoses. Considering that treatment decisions shape parents' grief trajectory, clinicians should reassure parents by framing treatment decisions in terms of family's deeply held values and goals.

Palliative and end-of-life symptoms management for children with diffuse intrinsic pontine glioma.

Background: This study aimed to investigate diffuse intrinsic pontine glioma-specific symptoms in the last 12 weeks before death and to describe current palliative care. Materials & methods: A retrospective study included 80 pediatric diffuse intrinsic pontine glioma patients diagnosed between January 2018 and December 2019. Results: The most frequently encountered symptoms were headache, gait disturbance, vomiting, dysphagia, sensory loss, seizures and constipation. Steroids were used in 96% of patients with a high success rate, as well as analgesics (67.5%), antiemetics (59%), neuropathic medication (42.5%) and anticonvulsants (37.5%). Re-irradiation improved symptoms in 50% of patients. Conclusion: Steroids were efficient in managing many symptoms, with tolerated side effects. The symptomatic treatment succeeded in relieving end-of-life symptoms. Re-irradiation should be considered a good palliative tool in addition to regular symptomatic treatment.

This study aimed to describe symptoms in 80 patients with aggressive brain tumors in the brain stem, as well as proper management of the symptoms at the end of life. The symptoms encountered were headache, imbalance during walking, vomiting and fits. They were managed successfully with steroids, painkillers, nausea and vomiting medications and anti-fit medication. Giving radiotherapy for a second time improved symptoms in 50% of patients, and steroids can be used efficiently to improve the misery of these patients. These data can help to put a strategy for managing these devastating symptoms in the end-of-life period.