The Lack of Ad Hoc Neuropsychological Assessment in Adults with Neurofibromatosis: A Systematic Review.

Background: Neurofibromatosis Type 1 (NF1) is a genetic autosomal dominant disorder that affects both the central and peripheral nervous systems. Children and adolescents with NF1 commonly experience neuropsychological, motor, and behavioral deficits. The cognitive profile hallmark of this disorder includes visuospatial and executive function impairments. These cognitive disorders may persist into adulthood. This study aims to analyze previous research studies that have described cognitive dysfunctions in adults with NF1. The purpose of this analysis is to review the neuropsychological and psychological assessment methods used. Methods: A total of 327 articles were identified based on the search terms in their titles and abstracts. The evaluation was conducted by scrutinizing each article's title, abstract, and text. Results: Only 16 articles were found to be eligible for inclusion based on the pre-defined criteria. The selected studies primarily focus on the development of diagnostic protocols for individuals with NF1. Conclusions: The management of NF1 disease requires a multidisciplinary approach to address symptoms, preserve neurological functions, and ensure the best possible quality of life. However, cognitive impairment can negatively affect psychological well-being. This study suggested that cognitive functions in NF1 patients were not tested using specific measures, but rather were evaluated through intelligence scales. Additionally, the findings revealed that there is no standardized neuropsychological assessment for adults with NF1. To address this gap, it would be helpful to create a specific neuropsychological battery to study cognitive function in NF1 patients during clinical studies. This battery could also serve as a tool to design models for cognitive rehabilitation by using reliable and sensitive measures of cognitive outcomes.

Fragility Fractures in End-Stage Chronic Kidney Disease (CKD) Population: Patient-Related and CKD-Related Factor Analysis-A Single-Center Experience.

Background: Chronic kidney disease (CKD) stands as a prevalent global health concern, and mineral and bone disease are among the most impactful consequences. A severe complication arising from mineral and bone disease is the occurrence of fragility fractures, which disproportionately affect individuals with CKD compared to the general population. The prevalence of these fractures impacts both survival rates and quality of life. The aims of this study are analyzing and identifying (i) patient-related risk factors and (ii) CKD-related risk factors to contribute to the development of preventive measures for fragility fractures for this population. Methods: A retrospective, single-center observational study was conducted, encompassing patient data from the years 2021 to 2023. Registry data were recorded, including patient-related and CKD-related data. Patients were interviewed about traumatological history, and their answers were recorded. Logistic regression analysis was employed to investigate the association between independent variables and dependent variables. Results: Eighty-four patients, with a mean age of 64.3 ± 15.2 years and a male percentage of 58.3%, were included in this study. Among them, 19.5% exhibited smoking habits. The mean Charlson Comorbidity Index was 3.06 ± 1.21. All patients were diagnosed with end-stage chronic kidney disease, with mean durations of 208 months from the diagnosis and 84.5 months from the beginning of dialysis. The logistic regression analysis, adjusted for age, sex, and CCI, revealed that smoking habits play a significant role as a risk factor for fragility fractures in lower limbs (p: 0.011 *). The incidence of fragility fractures increases directly proportionally to the time since diagnosis (p-value: 0.021 *) and the beginning of dialysis treatment (p-value: 0.001 *). Conclusions: Among patient-related factors, smoking habits seem to significantly affect lower-limb fracture rates (p < 0.05), whereas among CKD-related factors, time since CKD diagnosis and time since the beginning of dialysis treatment are directly related to higher risks of fragility fractures. No relevant correlations emerged in the studied treatments, except for a reduction in proximal femur fracture occurrence when patients underwent a combined treatment of a calcimimetic and a vitamin D analog.

Classical cannabinoid receptors as target in cancer-induced bone pain: a systematic review, meta-analysis and bioinformatics validation.

To test the hypothesis that genetic and pharmacological modulation of the classical cannabinoid type 1 (CB1) and 2 (CB2) receptors attenuate cancer-induced bone pain, we searched Medline, Web of Science and Scopus for relevant skeletal and non-skeletal cancer studies from inception to July 28, 2022. We identified 29 animal and 35 human studies. In mice, a meta-analysis of pooled studies showed that treatment of osteolysis-bearing males with the endocannabinoids AEA and 2-AG (mean difference [MD] - 24.83, 95% confidence interval [95%CI] - 34.89, - 14.76, p < 0.00001) or the synthetic cannabinoid (CB) agonists ACPA, WIN55,212-2, CP55,940 (CB1/2-non-selective) and AM1241 (CB2-selective) (MD - 28.73, 95%CI - 45.43, - 12.02, p = 0.0008) are associated with significant reduction in paw withdrawal frequency. Consistently, the synthetic agonists AM1241 and JWH015 (CB2-selective) increased paw withdrawal threshold (MD 0.89, 95%CI 0.79, 0.99, p < 0.00001), and ACEA (CB1-selective), AM1241 and JWH015 (CB2-selective) reduced spontaneous flinches (MD - 4.85, 95%CI - 6.74, - 2.96, p < 0. 00001) in osteolysis-bearing male mice. In rats, significant increase in paw withdrawal threshold is associated with the administration of ACEA and WIN55,212-2 (CB1/2-non-selective), JWH015 and AM1241 (CB2-selective) in osteolysis-bearing females (MD 8.18, 95%CI 6.14, 10.21, p < 0.00001), and treatment with AM1241 (CB2-selective) increased paw withdrawal thermal latency in males (mean difference [MD]: 3.94, 95%CI 2.13, 5.75, p < 0.0001), confirming the analgesic capabilities of CB1/2 ligands in rodents. In human, treatment of cancer patients with medical cannabis (standardized MD - 0.19, 95%CI - 0.35, - 0.02, p = 0.03) and the plant-derived delta-9-THC (20 mg) (MD 3.29, CI 2.24, 4.33, p < 0.00001) or its synthetic derivative NIB (4 mg) (MD 2.55, 95%CI 1.58, 3.51, p < 0.00001) are associated with reduction in pain intensity. Bioinformatics validation of KEGG, GO and MPO pathway, function and process enrichment analysis of mouse, rat and human data revealed that CB1 and CB2 receptors are enriched in a cocktail of nociceptive and sensory perception, inflammatory, immune-modulatory, and cancer pathways. Thus, we cautiously conclude that pharmacological modulators of CB1/2 receptors show promise in the treatment of cancer-induced bone pain, however further assessment of their effects on bone pain in genetically engineered animal models and cancer patients is warranted.

Abaloparatide is more potent than teriparatide in restoring bone mass and strength in type 1 diabetic male mice.

This study investigated the efficacy of the two FDA-approved bone anabolic ligands of the parathyroid hormone receptor 1 (PTH1R), teriparatide or human parathyroid hormone 1-34 (PTH) and abaloparatide (ABL), to restoring skeletal health using a preclinical murine model of streptozotocin-induced T1-DM. Intermittent daily subcutaneous injections of equal molar doses (12 pmoles/g/day) of PTH (50 ng/g/day), ABL (47.5 ng/g/day), or vehicle, were administered for 28 days to 5-month-old C57Bl/6 J male mice with established T1-DM or control (C) mice. ABL was superior to PTH in increasing or restoring bone mass in control or T1-MD mice, respectively, which was associated with superior stimulation of trabecular and periosteal bone formation, upregulation of osteoclastic/osteoblastic gene expression, and increased circulating bone remodeling markers. Only ABL corrected the reduction in ultimate load, which is a measure of bone strength, induced by T1-DM, and it also increased energy to ultimate load. In addition, bones from T1-DM mice treated with PTH or ABL exhibited increased ultimate stress, a material index, compared to T1-DM mice administered with vehicle. And both PTH and ABL prevented the increased expression of the Wnt antagonist Sost/sclerostin displayed by T1-DM mice. Further, PTH and ABL increased to a similar extent the circulating bone resorption marker CTX and the bone formation marker P1NP in T1-DM after 2 weeks of treatment; however, only ABL sustained these increases after 4 weeks of treatment. We conclude that at equal molar doses, ABL is more effective than PTH in increasing bone mass and restoring the cortical and trabecular bone lost with T1-DM, due to higher and longer-lasting increases in bone remodeling.

Changes in cerebral cortex activity during a simple motor task after MRgFUS treatment in patients affected by essential tremor and Parkinson's disease: a pilot study using functional NIRS.

Objective.Magnetic resonance imaging-guided focused ultrasound surgery (MRgFUS) is a non-invasive thermal ablation method that involves high-intensity focused ultrasound surgery (FUS) and Magnetic Resonance Imaging for anatomical imaging and real-time thermal mapping. This technique is widely employed for the treatment of patients affected by essential tremor (ET) and Parkinson's disease (PD). In the current study, functional near-infrared spectroscopy (fNIRS) was used to highlight hemodynamics changes in cerebral cortex activity, during a simple hand motor task, i.e. unimanual left and right finger-tapping, in ET and PD patients.Approach.All patients were evaluated before, one week and one month after MRgFUS treatment.Main results.fNIRS revealed cerebral hemodynamic changes one week and one month after MRgFUS treatment, especially in the ET group, that showed a significant clinical improvement in tremor clinical scores.Significance.To our knowledge, our study is the first that showed the use of fNIRS system to measure the cortical activity changes following unilateral ventral intermediate nucleus thalamotomy after MRgFUS treatment. Our findings showed that therapeutic MRgFUS promoted the remodeling of neuronal networks and changes in cortical activity in association with symptomatic improvements.

Circulating biomarkers in familial cerebral cavernous malformation.

BACKGROUND: Cerebral Cavernous Malformation (CCM) is a rare cerebrovascular disease, characterized by the presence of multiple vascular malformations that may result in intracerebral hemorrhages (ICHs), seizure(s), or focal neurological deficits (FND). Familial CCM (fCCM) is due to loss of function mutations in one of the three independent genes KRIT1 (CCM1), Malcavernin (CCM2), or Programmed Cell death 10 (PDCD10/CCM3). The aim of this study was to identify plasma protein biomarkers of fCCM to assess the severity of the disease and predict its progression. METHODS: Here, we have investigated plasma samples derived from n = 71 symptomatic fCCM patients (40 female/31 male) and n = 17 healthy donors (HD) (9 female/8 male) of the Phase 1/2 Treat_CCM trial, using multiplexed protein profiling approaches. FINDINGS: Biomarkers as sCD14 (p = 0.00409), LBP (p = 0.02911), CXCL4 (p = 0.038), ICAM-1 (p = 0.02013), ANG2 (p = 0.026), CCL5 (p = 0.00403), THBS1 (p = 0.0043), CRP (p = 0.0092), and HDL (p = 0.027), were significantly different in fCCM compared to HDs. Of note, sENG (p = 0.011), THBS1 (p = 0.011) and CXCL4 (p = 0.011), were correlated to CCM genotype. sROBO4 (p = 0.014), TM (p = 0.026) and CRP (p = 0.040) were able to predict incident adverse clinical events, such as ICH, FND or seizure. GDF-15, FLT3L, CXCL9, FGF-21 and CDCP1, were identified as predictors of the formation of new MRI-detectable lesions over 2-year follow-up. Furthermore, the functional relevance of ang2, thbs1, robo4 and cdcp1 markers was validated by zebrafish pre-clinical model of fCCM. INTERPRETATION: Overall, our study identifies a set of biochemical parameters to predict CCM progression, suggesting biological interpretations and potential therapeutic approaches to CCM disease. FUNDING: Italian Medicines Agency, Associazione Italiana per la Ricerca sul Cancro (AIRC), ERC, Leducq Transatlantic Network of Excellence, Swedish Research Council.

MR-Guided Focused Ultrasound for Refractory Epilepsy: Where Are We Now?

Epilepsy is one of the most common neurological diseases in both adults and children. Despite improvements in medical care, 20 to 30% of patients are still resistant to the best medical treatment. The quality of life, neurologic morbidity, and even mortality of patients are significantly impacted by medically intractable epilepsy. Nowadays, conservative therapeutic approaches consist of increasing medication dosage, changing to a different anti-seizure drug as monotherapy, and combining different antiseizure drugs using an add-on strategy. However, such measures may not be sufficient to efficiently control seizure recurrence. Resective surgery, ablative procedures and non-resective neuromodulatory (deep-brain stimulation, vagus nerve stimulation) treatments are the available treatments for these kinds of patients. However, invasive procedures may involve lengthy inpatient stays for the patients, risks of long-term neurological impairment, general anesthesia, and other possible surgery-related complications (i.e., hemorrhage or infection). In the last few years, MR-guided focused ultrasound (MRgFUS) has been proposed as an emerging treatment for neurological diseases because of technological advancements and the goal of minimally invasive neurosurgery. By outlining the current knowledge obtained from both preclinical and clinical studies and discussing the technical opportunities of this therapy for particular epileptic phenotypes, in this perspective review, we explore the various mechanisms and potential applications (thermoablation, blood-brain barrier opening for drug delivery, neuromodulation) of high- and low-intensity ultrasound, highlighting possible novel strategies to treat drug-resistant epileptic patients who are not eligible or do not accept currently established surgical approaches. Taken together, the available studies support a possible role for lesional treatment over the anterior thalamus with high-intensity ultrasound and neuromodulation of the hippocampus via low-intensity ultrasound in refractory epilepsy. However, more studies, likely conceiving epilepsy as a network disorder and bridging together different scales and modalities, are required to make ultrasound delivery strategies meaningful, effective, and safe.

Coronavirus OC43 and Influenza H3N2 Concomitant Unilateral Parotitis: The Importance of Laboratory Tests in Mumps-Like Parotitis.

Mumps is an acute generalized infection caused by a Paramyxovirus. Infection occurs mainly in school-aged children and adolescents and the most prominent clinical manifestation is nonsuppurative swelling and tenderness of the salivary glands, unilaterally or bilaterally. Negative serology for mumps requires a differential diagnosis with other infectious agents, but it is not routine. An 11-year-old girl presented with fever and right-sided parotitis and a negative serology for Mumps. A respiratory panel revealed the presence of Coronavirus OC43 and influenza virus H3N2. Parotitis may be caused by the parainfluenza virus, Epstein-Barr virus, influenza virus, rhinovirus, adenovirus, or other viruses in addition to noninfectious causes such as drugs, immunologic diseases, or obstruction of the salivary tract as predisposing factors. In this case, Coronavirus OC43 and influenza virus H3N2 were detected. The H3N2 has been already reported in the literature, whereas Coronavirus OC43 has never been associated with parotitis before; although, in the present case, the association of the two viruses does not let us conclude which of the two was responsible for the disease.

Pharmacologic targeting of the p62 ZZ domain enhances both anti-tumor and bone-anabolic effects of bortezomib in multiple myeloma.

Multiple myeloma (MM) is a malignancy of plasma cells whose antibody secretion creates proteotoxic stress relieved by the N-end rule pathway, a proteolytic system that degrades Narginylated proteins in the proteasome. When the proteasome is inhibited, protein cargo is alternatively targeted for autophagic degradation by binding to the ZZ-domain of p62/sequestosome-1. Here, we demonstrate that XRK3F2, a selective ligand for the ZZ-domain, dramatically improved two major responses to the proteasome inhibitor bortezomib by increasing: 1) killing of human MM cells by stimulating both bortezomib mediated apoptosis and necroptosis, a process regulated by p62; and 2) preservation of bone mass by stimulating osteoblasts differentiation and inhibiting osteoclastic bone destruction. Co-administration of bortezomib and XRK3F2 inhibited both branches of the bimodal N-end rule pathway exhibited synergistic anti-MM effects on MM cell lines and CD138+ cells from MM patients, and prevented stromal-mediated MM cell survival. In mice with established human MM, coadministration of bortezomib and XRK3F2 decreased tumor burden and prevented the progression of MM-induced osteolytic disease by inducing new bone formation more effectively than either single agent alone. The results suggest that p62-ZZ ligands enhance the anti-MM efficacy of proteasome inhibitors and can reduce MM morbidity and mortality by improving bone health.

A target discovery pipeline identified ILT3 as a target for immunotherapy of multiple myeloma.

Multiple myeloma (MM) is an incurable malignancy of plasma cells. To identify targets for MM immunotherapy, we develop an integrated pipeline based on mass spectrometry analysis of seven MM cell lines and RNA sequencing (RNA-seq) from 900+ patients. Starting from 4,000+ candidates, we identify the most highly expressed cell surface proteins. We annotate candidate protein expression in many healthy tissues and validate the expression of promising targets in 30+ patient samples with relapsed/refractory MM, as well as in primary healthy hematopoietic stem cells and T cells by flow cytometry. Six candidates (ILT3, SEMA4A, CCR1, LRRC8D, FCRL3, IL12RB1) and B cell maturation antigen (BCMA) present the most favorable profile in malignant and healthy cells. We develop a bispecific T cell engager targeting ILT3 that shows potent killing effects in vitro and decreased tumor burden and prolonged mice survival in vivo, suggesting therapeutic relevance. Our study uncovers MM-associated antigens that hold great promise for immune-based therapies of MM.

Children under 6 years with acute headache in Pediatric Emergency Departments. A 2-year retrospective exploratory multicenter Italian study.

BACKGROUND: Preschool age (i.e. children under six years of age) represents a red flag for requiring neuroimaging to exclude secondary potentially urgent intracranial conditions (PUIC) in patients with acute headache. We investigated the clinical characteristics of preschoolers with headache to identify the features associated with a greater risk of secondary "dangerous" headache. METHODS: We performed a multicenter exploratory retrospective study in Italy from January 2017 to December 2018. Preschoolers with new-onset non-traumatic headache admitted to emergency department were included and were subsequently divided into two groups: hospitalized and discharged. Among hospitalized patients, we investigated the characteristics linked to potentially urgent intracranial conditions. RESULTS: We included 1455 preschoolers with acute headache. Vomiting, ocular motility disorders, ataxia, presence of neurological symptoms and signs, torticollis and nocturnal awakening were significantly associated to hospitalization. Among the 95 hospitalized patients, 34 (2.3%) had potentially urgent intracranial conditions and more frequently they had neurological symptoms and signs, papilledema, ataxia, cranial nerves paralysis, nocturnal awakening and vomiting. Nevertheless, on multivariable logistic regression analysis, we found that only ataxia and vomiting were associated with potentially urgent intracranial conditions. CONCLUSION: Our study identified clinical features that should be carefully evaluated in the emergency department in order to obtain a prompt diagnosis and treatment of potentially urgent intracranial conditions. The prevalence of potentially urgent intracranial conditions was low in the emergency department, which may suggest that age under six should not be considered an important risk factor for malignant causes as previously thought.

Sonodynamic therapy and magnetic resonance-guided focused ultrasound: new therapeutic strategy in glioblastoma.

Glioblastoma (GB) is one of the most aggressive and difficult-to-treat brain tumors, with a poor prognosis and limited treatment options. In recent years, sonodynamic therapy (SDT) and magnetic resonance focused ultrasound (MRgFUS) have emerged as promising approaches for the treatment of GB. SDT uses ultrasound waves in combination with a sonosensitizer to selectively damage cancer cells, while MRgFUS delivers high-intensity ultrasound waves to precisely target tumor tissue and disrupt the blood-brain barrier to enhance drug delivery. In this review, we explore the potential of SDT as a novel therapeutic strategy for GB. We discuss the principles of SDT, its mechanisms of action, and the preclinical and clinical studies that have investigated its use in Gliomas. We also highlight the challenges, the limitations, and the future perspectives of SDT. Overall, SDT and MRgFUS hold promise as novel and potentially complementary treatment modalities for GB. Further research is needed to optimize their parameters and determine their safety and efficacy in humans, but their potential for selective and targeted tumor destruction makes them an exciting area of investigation in the field of brain cancer therapy.

Spring Plates as a Valid Additional Fixation in Comminuted Posterior Wall Acetabular Fractures: A Retrospective Multicenter Study.

BACKGROUND: The posterior wall fracture is the most frequent pattern of acetabular fractures. Many techniques of fixation have been described in the literature and involve plates, screws, or a combination of both. This study aims to investigate the clinical and radiological outcomes of spring plates in the treatment of comminuted posterior wall acetabular fractures. (2) Methods: A retrospective multicenter (four level I trauma centers) observational study was performed. Patients with a comminuted posterior wall acetabular fracture treated with a spring plate (DePuy Synthes, West Chester, PA) were included. Diagnosis was made according to the Judet and Letournel classification. Diagnosis was confirmed with plain radiographs in an antero-posterior view and Judet views, iliac and obturator oblique views, and thin-slice CT with multiplanar reconstructions. (3) Results: Forty-six patients (34 males and 12 females) with a mean age of 51.7 years (range 19-73) were included. The most common mechanism of injury was motor vehicle accident (34 cases). In all cases, spring plates were placed under an overlapping reconstruction plate. The mean follow-up was 33.4 months (range 24-48). The mean period without weight-bearing was 4.9 weeks (range 4-7), and full weight-bearing was allowed at an average of 8.2 weeks (range 7-11) after surgery. (4) Conclusions: According to the present data, spring plates can be considered a viable additional fixation of the posterior wall acetabular fractures.

Global hypo-methylation in a proportion of glioblastoma enriched for an astrocytic signature is associated with increased invasion and altered immune landscape.

We describe a subset of glioblastoma, the most prevalent malignant adult brain tumour, harbouring a bias towards hypomethylation at defined differentially methylated regions. This epigenetic signature correlates with an enrichment for an astrocytic gene signature, which together with the identification of enriched predicted binding sites of transcription factors known to cause demethylation and to be involved in astrocytic/glial lineage specification, point to a shared ontogeny between these glioblastomas and astroglial progenitors. At functional level, increased invasiveness, at least in part mediated by SRPX2, and macrophage infiltration characterise this subset of glioblastoma.

Subgroup-specific roles of primary cilia in medulloblastoma.

Here I discuss the study in this issue of Genes & Development by Youn et al. (pp. 737-751), which describes defined and diverse roles of primary cilia in molecularly distinct medulloblastoma subgroups, highlighting once again the importance of designing subgroup-specific therapeutic approaches for this tumor.

Diagnostic controversies in recurrent painful ophthalmoplegic neuropathy: single case report with a systematic review.

BACKGROUND: Ophthalmoplegic migraine, renamed "Recurrent Painful Ophthalmoplegic Neuropathy" (RPON) in 2013 by the International Headache Society is a rare neurologic disorder characterized by recurrent attacks of ophthalmoplegia associated to ipsilateral headache. The etiology is still unknown. Typical magnetic resonance imaging findings show a focal nerve thickening and contrast enhancement. In the majority of cases, there is a full recovery within days or weeks. There is no evidence supporting a specific treatment. The review defines the characteristics of the recurrent painful ophthalmoplegic neuropathy in patients within 2 years of age underlying the importance of the role of magnetic resonance imaging even in presence of the first attack. Thus, an emblematic case report is presented. CASE PRESENTATION: The authors present a case of third cranial nerve paresis in a 17-month-old male child, presenting a neuroradiological pattern highly suggestive of schwannoma, aneurism or recurrent painful ophthalmoplegic neuropathy. Thus, a review of the literature with the pediatric casuistry of recurrent painful ophthalmoplegic neuropathy occurred within 2 years of age focusing on diagnostic considerations is presented. The authors highlight the importance to consider recurrent painful ophthalmoplegic neuropathy in presence of magnetic resonance imaging findings and clinical symptoms referable to aneurysm or schwannoma. Thus, the review defines the characteristics and the neuroradiological findings at the first RPON attack occurred under 2 years of age. CONCLUSION: Although two attacks are necessary, the review strongly suggests to consider recurrent painful ophthalmoplegic neuropathy even at the first attack, in presence of described characteristics and the aforementioned magnetic resonance imaging findings.

Neuropsychological Disability in the Case of Natalizumab-Related Progressive Multifocal Leukoencephalopathy.

BACKGROUND: Progressive multifocal leukoencephalopathy (PML) is a viral disease characterized by progressive damage or inflammation of the cerebral white matter that can be encountered in patients with multiple sclerosis (MS). There are cases of PML caused by pharmacological agents including natalizumab. Therefore, in patients treated with this drug, early identification of PML allows changes in the treatment plan, reducing the risks of morbidity and mortality. CASE PRESENTATION: We reported the case of a 57-year-old female diagnosed with relapsing-remitting MS, who presented with PML related to natalizumab. The patient presented with change in behavioral, radiological abnormalities in the left parieto-temporal lobes. We described the longitudinal course of PML, from the diagnosis until the patient's death, documenting the progressive deterioration of her cognitive functioning, supported by changes on sequential brain scans and neurophysiological data. CONCLUSION: The neuropsychological impairment documented in this case study expands the range of treatment-related complications associated with natalizumab, and provides evidence that occurrence of "atypical" cognitive deficits in MS may support the early diagnosis of PML.

Combination of BMI1 and MAPK/ERK inhibitors is effective in medulloblastoma.

BACKGROUND: Epigenetic changes play a key role in the pathogenesis of medulloblastoma (MB), the most common malignant pediatric brain tumor. METHODS: We explore the therapeutic potential of BMI1 and MAPK/ERK inhibition in BMI1High;CHD7Low MB cells and in a preclinical xenograft model. RESULTS: We identify a synergistic vulnerability of BMI1High;CHD7Low MB cells to a combination treatment with BMI1 and MAPK/ERK inhibitors. Mechanistically, CHD7-dependent binding of BMI1 to MAPK-regulated genes underpins the CHD7-BMI1-MAPK regulatory axis responsible of the antitumour effect of the inhibitors in vitro and in a preclinical mouse model. Increased ERK1 and ERK2 phosphorylation activity is found in BMI1High;CHD7Low G4 MB patients, raising the possibility that they could be amenable to a similar therapy. CONCLUSIONS: The molecular dissection of the CHD7-BMI1-MAPK regulatory axis in BMI1High;CHD7Low MB identifies this signature as a proxy to predict MAPK functional activation, which can be effectively drugged in preclinical models, and paves the way for further exploration of combined BMI1 and MAPK targeting in G4 MB patients.