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The inadequate vascularization seen in fast-growing solid tumors gives rise to hypoxic areas, fostering specific changes in gene expression that bolster tumor cell survival and metastasis, ultimately leading to unfavorable clinical prognoses across different cancer types. Hypoxia-inducible factors (HIF-1 and HIF-2) emerge as druggable pivotal players orchestrating tumor metastasis and angiogenesis, thus positioning them as prime targets for cancer treatment. A range of HIF inhibitors, notably natural compounds originating from marine organisms, exhibit encouraging anticancer properties, underscoring their significance as promising therapeutic options. Bioprospection of the marine environment is now a well-settled approach to the discovery and development of anticancer agents that might have their medicinal chemistry developed into clinical candidates. However, despite the massive increase in the number of marine natural products classified as ‘anticancer leads,’ most of which correspond to general cytotoxic agents, and only a few have been characterized regarding their molecular targets and mechanisms of action. The current review presents a critical analysis of inhibitors of HIF-1 and HIF-2 and hypoxia-selective compounds that have been sourced from marine organisms and that might act as new chemotherapeutic candidates or serve as templates for the development of structurally similar derivatives with improved anticancer efficacy., SCOPUS: re.j, info:eu-repo/semantics/published

Medulloblastoma, an embryonal tumor of the fossa posterior, represents the most common ma- lignant pediatric brain tumors. With the advances in genomics and epigenomics, considerable progress has been made to unravel, to some extent, the biological and molecular mechanisms underlying the spatial heterogeneity in medulloblastoma. Four molecular subgroups (WNT, SHH, Group 3 and Group 4) have been described, each with divergent clinical presentation, genetic drivers and survival out- comes (inter-tumoral heterogeneity), even within the same molecular subgroup (intra-tumoral heterogeneity). The use of multimodal therapy, combining surgical resection, craniospinal irradiation, and chemotherapy regimens has significantly improved the survival of medulloblastoma over time. However, with the emergence of high-risk biological markers (MYC/MYCN amplification, TP53 mutation) and molecular subgroups, these treatment approaches are far from accurate. This not only leads to heterogeneous survival outcomes, but also to unpredictable relapses in 30% of cases diagnosed with medulloblastoma, resulting in a dismal prognosis. Therefore, considerable challenges remain to identify additional clinical-biological predictors of outcome and assess the patterns of relapse. This, will further help improve risk-adapted clinical management and survival outcomes, whilst minimizing treatment-related toxicity and risk of relapse. Chapter 1 summarizes the actual knowledge on childhood medulloblastoma.Since molecular subgroup affiliation is an important predictor factor of outcome, precise and reliable molecular classification and identification of additional high-risk biological features are of utmost importance in determining whether patients are at low or high risk of relapse. In chapter 2 we evaluated the concordance between immunohistochemistry, using four antibodies (YAP1, GAB1, OTX2, and beta-catenin), and DNA-methylation profiling in medulloblastoma subgrouping, which is the current golden st, Le médulloblastome, une tumeur embryonnaire de la fosse postérieure, est la tumeur maligne la plus fréquente chez les enfants. Grâce aux avancées de la génique et de l'épigénétique, d'énormes progrès ont été effectués permettant de mieux comprendre les mécanismes biologiques et moléculaires responsables de l’hétérogénéité tumorale. Des études ont révélé la présence de quatre sous-groupes moléculaires (WNT, SHH, Groupe 3 et Groupe 4) qui se distinguent chacun par leur présentation clinique, leurs facteurs génétiques ainsi que par leurs survies (hétérogénéité inter-tumorale), y compris au sein d'un même sous-groupe moléculaire (hétérogénéité intra-tumorale). L’utilisation d’une thérapie multimodale comportant une résection chirurgicale maximale, une irradiation craniospinale et une chimiothérapie, a permis d’améliorer significativement le taux de survie de ces patients. Néanmoins, face à l'émergence de marqueurs biologiques de haut risque (amplification de MYC/MYCN, mutation TP53) et des sous-groupes moléculaires, ces stratégies thérapeutiques restent imparfaites. Elles aboutissent non seulement à des taux de survies variables, mais également à des rechutes imprévisibles dans 30% des cas et dont le pronostic est sombre. En conséquence, d’importants défis restent à relever afin d'identifier de nouveaux facteurs clinico-biologiques prédictifs de la survie et de mieux comprendre les mécanismes de rechute. Ces données permettront d'améliorer la prise en charge clinique et la survie, tout en réduisant les effets toxiques liés au traitement et le risque de rechute. Un résumé des connaissances actuelles sur le médulloblastome de l'enfant est présenté dans le premier chapitre.Pour évaluer si un patient présente un risque de récidive faible ou élevé, il est essentiel de déterminer l'appartenance à un sous-groupe moléculaire ayant un impact pronostique important sur la survie, d'établir une classification moléculaire précise et fiable ainsi que d'identifier les anomalies biolog, Doctorat en Sciences médicales (Médecine), info:eu-repo/semantics/nonPublished

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The management of primary central nervous system (PCNSL) is one of the most controversial topics in neuro-oncology because of the complexity of the disease and the limited number of controlled studies available. In 2021, given recent advances and the publication of practice-changing randomized trials, the European Association of Neuro-Oncology (EANO) created a multidisciplinary task force to update the previously published evidence-based guidelines for immunocompetent adult patients with PCNSL and added a section on immunosuppressed patients. The guideline provides consensus considerations and recommendations for the treatment of PCNSL, including intraocular manifestations and specific management of the elderly. The main changes from the previous guideline include strengthened evidence for the consolidation with ASCT in first-line treatment, prospectively assessed chemotherapy combinations for both young and elderly patients, clarification of the role of rituximab even though the data remain inconclusive, of the role of new agents, and the incorporation of immunosuppressed patients and primary ocular lymphoma. The guideline should aid the clinicians in everyday practice and decision making and serve as a basis for future research in the field.

Background: Median survival with glioblastoma remains in the range of 12 months on population levels. Only few patients survive for more than 5 years. Patient and disease features associated with long-term survival remain poorly defined. Methods: European Organization for Research and Treatment of Cancer (EORTC) 1419 (ETERNITY) is a registry study supported by the Brain Tumor Funders Collaborative in the US and the EORTC Brain Tumor Group. Patients with glioblastoma surviving at least 5 years from diagnosis were identified at 24 sites in Europe, US, and Australia. In patients with isocitrate dehydrogenase (IDH) wildtype tumours, prognostic factors were analysed using the Kaplan-Meier method and the Cox proportional hazards model. A population-based reference cohort was obtained from the Cantonal cancer registry Zurich. Results: At the database lock of July 2020, 280 patients with histologically centrally confirmed glioblastoma (189 IDH wildtype, 80 IDH mutant, 11 incompletely characterised) had been registered. In the IDH wildtype population, median age was 56 years (range 24–78 years), 96 patients (50.8%) were female, 139 patients (74.3%) had tumours with O6-methylguanine DNA methyltransferase (MGMT) promoter methylation. Median overall survival was 9.9 years (95% confidence interval [95% CI] 7.9–11.9). Patients without recurrence experienced longer median survival (not reached) than patients with one or more recurrences (8.92 years) (p < 0.001) and had a high rate (48.8%) of MGMT promoter-unmethylated tumours. Conclusions: Freedom from progression is a powerful predictor of overall survival in long-term survivors with glioblastoma. Patients without relapse often have MGMT promoter-unmethylated glioblastoma and may represent a distinct subtype of glioblastoma.

Background: Median survival with glioblastoma remains in the range of 12 months on population levels. Only few patients survive for more than 5 years. Patient and disease features associated with long-term survival remain poorly defined. Methods: European Organization for Research and Treatment of Cancer (EORTC) 1419 (ETERNITY) is a registry study supported by the Brain Tumor Funders Collaborative in the US and the EORTC Brain Tumor Group. Patients with glioblastoma surviving at least 5 years from diagnosis were identified at 24 sites in Europe, US, and Australia. In patients with isocitrate dehydrogenase (IDH) wildtype tumours, prognostic factors were analysed using the Kaplan-Meier method and the Cox proportional hazards model. A population-based reference cohort was obtained from the Cantonal cancer registry Zurich. Results: At the database lock of July 2020, 280 patients with histologically centrally confirmed glioblastoma (189 IDH wildtype, 80 IDH mutant, 11 incompletely characterised) had been registered. In the IDH wildtype population, median age was 56 years (range 24-78 years), 96 patients (50.8%) were female, 139 patients (74.3%) had tumours with O6-methylguanine DNA methyltransferase (MGMT) promoter methylation. Median overall survival was 9.9 years (95% confidence interval [95% CI] 7.9-11.9). Patients without recurrence experienced longer median survival (not reached) than patients with one or more recurrences (8.92 years) (p < 0.001) and had a high rate (48.8%) of MGMT promoter-unmethylated tumours. Conclusions: Freedom from progression is a powerful predictor of overall survival in long-term survivors with glioblastoma. Patients without relapse often have MGMT promoter-unmethylated glioblastoma and may represent a distinct subtype of glioblastoma.

Depressive symptoms are common among patients with glioblastoma, but patients are often not treated with antidepressants. There is only limited evidence on the association of antidepressant drug use with survival in glioblastoma. We performed a pooled analysis of patients treated within the CENTRIC, CORE, AVAglio and ACT‐IV trials to explore the relation of antidepressant drug use with progression‐free (PFS) and overall survival (OS) at baseline, at the start of maintenance therapy and at the start of maintenance cycle 4. We further assessed the association of antidepressant drugs with seizure, cognition, fatigue and a diagnosis of depression. Among more than 1700 patients, we found no significant association between the use of antidepressants at baseline or at the start of maintenance therapy and PFS or OS. However, we found OS, but not PFS, to be significantly worse in patients using antidepressants at the start of maintenance cycle 4. After adjustment for antiepileptic drug use and despite showing a trend for increased risk, seizures were not significantly associated with antidepressant drug use, nor was there a change in mini mental state examination (MMSE) scores or fatigue by antidepressant drug use at baseline. However, there was a significant positive association between antidepressant use at the start of maintenance treatment and fatigue during maintenance treatment. The association of antidepressant use at the start of maintenance cycle 4 with inferior OS of glioblastoma patients requires independent confirmation and further study. Further prospective trials should evaluate efficacy, side effects and associations with outcome of antidepressants in glioblastoma.

Importance: A potential relationship between meningioma and breast cancer was suggested 70 years ago. However, to date, no conclusive evidence is available on this topic. Objective: To provide a comprehensive review of the literature on the association of meningioma with breast cancer, supported by a meta-analysis. Data Sources: A systematic PubMed search was performed up to April 2023 to identify articles on the association of meningioma with breast cancer. The following key words were used strategically: meningioma, breast cancer, breast carcinoma, association, relation. Study Selection: All studies reporting women diagnosed with meningioma and breast cancer were identified. The search strategy was not limited by study design or publication date but only included articles in English. Additional articles were identified via citation searching. Studies reporting a complete population of meningiomas or breast cancer patients throughout a specific study period and a proportion of patients with a second pathology could be used for the meta-analysis. Data Extraction and Synthesis: Data extraction was performed by 2 authors in accordance with the Preferred Reporting Items for Systematic Reviews (PRISMA) statement. Meta-analyses regarding both populations were performed using a random-effects model. Risk of bias was assessed. Main Outcomes and Measures: The main measures were whether there was an increased prevalence of breast cancer in female patients with meningioma and whether there was an increased prevalence of meningioma in female patients with breast cancer. Results: A total of 51 retrospective studies (case reports, case series, and cancer registry reports) describing 2238 patients with both diseases were identified; 18 studies qualified for prevalence analyses and meta-analysis. The random-effects meta-analysis (13 studies) revealed a significantly greater prevalence of breast cancer in female patients with meningioma than in the overall population (odds ratio [O, SCOPUS: ar.j, info:eu-repo/semantics/published

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Background: No systemic treatment has been established for meningioma progressing after local therapies. Methods: This randomized, multicenter, open-label, phase II study included adult patients with recurrent WHO grade 2 or 3 meningioma. Patients were 2:1 randomly assigned to intravenous trabectedin (1.5 mg/m2 every 3 weeks) or local standard of care (LOC). The primary endpoint was progression-free survival (PFS). Secondary endpoints comprised overall survival (OS), objective radiological response, safety, quality of life (QoL) assessment using the QLQ-C30 and QLQ-BN20 questionnaires, and we performed tissue-based exploratory molecular analyses. Results: Ninety patients were randomized (n = 29 in LOC, n = 61 in trabectedin arm). With 71 events, median PFS was 4.17 months in the LOC and 2.43 months in the trabectedin arm (hazard ratio [HR] = 1.42; 80% CI, 1.00-2.03; P =. 294) with a PFS-6 rate of 29.1% (95% CI, 11.9%-48.8%) and 21.1% (95% CI, 11.3%-32.9%), respectively. Median OS was 10.61 months in the LOC and 11.37 months in the trabectedin arm (HR = 0.98; 95% CI, 0.54-1.76; P =. 94). Grade ≥3 adverse events occurred in 44.4% of patients in the LOC and 59% of patients in the trabectedin arm. Enrolled patients had impeded global QoL and overall functionality and high fatigue before initiation of systemic therapy. DNA methylation class, performance status, presence of a relevant co-morbidity, steroid use, and right hemisphere involvement at baseline were independently associated with OS. Conclusions: Trabectedin did not improve PFS and OS and was associated with higher toxicity than LOC treatment in patients with non-benign meningioma. Tumor DNA methylation class is an independent prognostic factor for OS.

Meningiomas are the most common intracranial tumors. Yet, only few controlled clinical trials have been conducted to guide clinical decision making, resulting in variations of management approaches across countries and centers. However, recent advances in molecular genetics and clinical trial results help to refine the diagnostic and therapeutic approach to meningioma. Accordingly, the European Association of Neuro-Oncology (EANO) updated its recommendations for the diagnosis and treatment of meningiomas. A provisional diagnosis of meningioma is typically made by neuroimaging, mostly magnetic resonance imaging. Such provisional diagnoses may be made incidentally. Accordingly, a significant proportion of meningiomas, notably in patients that are asymptomatic or elderly or both, may be managed by a watch-and-scan strategy. A surgical intervention with tissue, commonly with the goal of gross total resection, is required for the definitive diagnosis according to the WHO classification. A role for molecular profiling including gene panel sequencing and genomic methylation profiling is emerging. A gross total surgical resection including the involved dura is often curative. Inoperable or recurrent tumors requiring treatment can be treated with radiosurgery, if the size or the vicinity of critical structures allows that, or with fractionated radiotherapy (RT). Treatment concepts combining surgery and radiosurgery or fractionated RT are increasingly used, although there remain controversies regard timing, type, and dosing of the various RT approaches. Radionuclide therapy targeting somatostatin receptors is an experimental approach, as are all approaches of systemic pharmacotherapy. The best albeit modest results with pharmacotherapy have been obtained with bevacizumab or multikinase inhibitors targeting vascular endothelial growth factor receptor, but no standard of care systemic treatment has been yet defined.

Glioblastoma represents the highest grade of brain tumors. Despite maximal resection surgery associated with radiotherapy and concomitant followed by adjuvant chemotherapy with temozolomide (TMZ), patients have a very poor prognosis due to the rapid recurrence and the acquisition of resistance to TMZ. Here, initially considering that TMZ is a prodrug whose activation is pH-dependent, we explored the contribution of glioblastoma cell metabolism to TMZ resistance. Using isogenic TMZ-sensitive and TMZ-resistant human glioblastoma cells, we report that the expression of O6-methylguanine DNA methyltransferase (MGMT), which is known to repair TMZinduced DNA methylation, does not primarily account for TMZ resistance. Rather, fitter mitochondria in TMZ-resistant glioblastoma cells are a direct cause of chemoresistance that can be targeted by inhibiting oxidative phosphorylation and/or autophagy/mitophagy. Unexpectedly, we found that PARP inhibitor olaparib, but not talazoparib, is also a mitochondrial Complex I inhibitor. Hence, we propose that the anticancer activities of olaparib in glioblastoma and other cancer types combine DNA repair inhibition and impairment of cancer cell respiration

Brain metastasis (BM) is a frequent complication of systemic cancer usually associated with poor prognosis. Survival depends on numerous factors, which complicates prognosis and treatment. It has been suggested that BM growing from previously dormant disseminated tumour cells (DTCs) may exhibit a milder phenotype than BM derived from continuously progressing metastatic cells; however, to the best of our knowledge, the prognosis of patients presenting with BM from dormant DTCs is unknown. The present study retrospectively compared survival data, collected from a single neurosurgical centre, between patients presenting with BM from previously dormant DTCs and patients with non-dormant BM. A total of 262 medical records were reviewed. In the univariate Cox regression analysis, the median survival of the dormant BM group was statistically longer than that of the non-dormant group (P=0.048); a trend towards a longer survival persisted after correcting for age, presence of breast cancer and treatment options (P=0.057), which are all factors known to influence outcome. The improved outcome of these patients could be considered in models for prognostication. Moreover, the development of therapies able to eradicate dormant DTCs could provide a new promising strategy to prolong the survival of patients with a favourable prognosis., SCOPUS: ar.j, info:eu-repo/semantics/published

Background: Two concerns with respect to pre-operative task-based motor functional magnetic resonance imaging (fMRI) in patients with brain tumours are inadequate performance due to patients' impaired motor function and head motion artefacts. New method: In the present study we validate the use of a stimulator based on a pneumatic artificial muscle (PAM) for fMRI mapping of the primary sensorimotor (SM1) cortex in twenty patients with rolandic or perirolandic brain tumours. All patients underwent both active and passive motor block-design fMRI paradigms, performing comparable active and passive PAM-induced flexion-extensions of the icontralesional index finger. Results: PAM-induced movements resulted in a significant BOLD signal increase in contralateral primary motor (M1) and somatosensory (S1) cortices in 18/20 and 19/20 (p<.05 FWE corrected in 16/18 and 18/19) patients, versus 18/20 and 16/20 (p<.05 FWE corrected) during active movements. The two patients in whom the PAM-based stimulator failed to induce any significant BOLD signal change in the contralateral M1 cortex differed from the two in whom active motion was conversely ineffective. At the group level, no significant difference in contrast magnitude was observed within the contralateral SM1 cortex when comparing active with passive movements. During passive movements, head motion was significantly reduced. Comparison with existing method(s) As compared to the several robotic devices for passive motion that were introduced in the past decades, our PAM-based stimulator appears smaller, handier, and easier to use. Conclusion: The use of PAM-based stimulators should be included in routine pre-operative fMRI protocols along with active paradigms in such patients' population., info:eu-repo/semantics/published

Glioblastoma represents the highest grade of brain tumors. Despite maximal resection surgery associated with radiotherapy and concomitant followed by adjuvant chemotherapy with temozolomide (TMZ), patients have a very poor prognosis due to the rapid recurrence and the acquisition of resistance to TMZ. Here, initially considering that TMZ is a prodrug whose activation is pH-dependent, we explored the contribution of glioblastoma cell metabolism to TMZ resistance. Using isogenic TMZ-sensitive and TMZ-resistant human glioblastoma cells, we report that the expression of O6-methylguanine DNA methyltransferase (MGMT), which is known to repair TMZ-induced DNA methylation, does not primarily account for TMZ resistance. Rather, fitter mitochondria in TMZ-resistant glioblastoma cells are a direct cause of chemoresistance that can be targeted by inhibiting oxidative phosphorylation and/or autophagy/mitophagy. Unexpectedly, we found that PARP inhibitor olaparib, but not talazoparib, is also a mitochondrial Complex I inhibitor. Hence, we propose that the anticancer activities of olaparib in glioblastoma and other cancer types combine DNA repair inhibition and impairment of cancer cell respiration., SCOPUS: ar.j, info:eu-repo/semantics/published