Marine-Derived Leads as Anticancer Candidates by Disrupting Hypoxic Signaling through Hypoxia-Inducible Factors Inhibition.

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.

Long-term survival with IDH wildtype glioblastoma: first results from the ETERNITY Brain Tumor Funders' Collaborative Consortium (EORTC 1419).

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.

The Association Between Meningioma and Breast Cancer: A Systematic Review and Meta-analysis.

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 [OR], 9.87; 95% CI, 7.31-13.32). Meningioma incidence in patients with breast cancer (11 studies) was greater than that in the baseline population; however, the difference according to the random-effects model was not statistically significant (OR, 1.41; 95% CI, 0.99-2.02). Conclusions and Relevance: This large systematic review and the meta-analysis on the association between meningioma and breast cancer found nearly 10-fold higher odds of breast cancer in female patients with meningioma compared with the general female population. These findings suggest that female patients with meningioma should be screened more intensively for breast cancer. Further research is required to identify the factors causing this association.

BOLD fMRI and DTI fiber tracking for preoperative mapping of eloquent cerebral regions in brain tumor patients: impact on surgical approach and outcome.

PURPOSE: Task-based BOLD fMRI and DTI-fiber tracking have become part of the routine presurgical work-up of brain tumor patients in many institutions. However, their potential impact on both surgical treatment and neurologic outcome remains unclear, in despite of the high costs and complex implementation. METHODS: We retrospectively investigated whether performing fMRI and DTI-ft preoperatively substantially impacted surgical planning and patient outcome in a series of brain tumor patients. We assessed (i) the quality of fMRI and DTI-ft results, by using a scale of 0-2 (0 = failed mapping; 1 = intermediate confidence; 2 = good confidence), (ii) whether functional planning substantially contributed to defining the surgical strategy to be undertaken (i.e., no surgery, biopsy, or resection, with or without ESM), the surgical entry point and extent of resection, and (iii) the incidence of neurological deficits post-operatively. RESULTS: Twenty-seven patients constituted the study population. The mean confidence rating was 1.9/2 for fMRI localization of the eloquent cortex and lateralization of the language function and 1.7/2 for DTI-ft results. Treatment strategy was altered in 33% (9/27) of cases. Surgical entry point was modified in 8% (2/25) of cases. The extent of resection was modified in 40% (10/25). One patient (1/25, 4%) developed one new functional deficit post-operatively. CONCLUSION: Functional MR mapping - which must not be considered an alternative to ESM - has a critical role preoperatively, potentially modifying treatment strategy or increasing the neurosurgeons' confidence in the surgical approach hypothesized based on conventional imaging.

Late-line treatment with bevacizumab alone or in combination with chemotherapy in recurrent high-grade gliomas.

PURPOSE: Bevacizumab's use in recurrent high-grade glioma is controversial. This study evaluates outcomes in recurrent high-grade glioma patients receiving bevacizumab alone or combined with chemotherapy as a late-line treatment. METHODS: We retrospectively analyzed patients treated with bevacizumab alone or combined with chemotherapy for high-grade gliomas who showed tumor progression after multiple treatment attempts. Overall survival (OS) and progression-free survival (PFS) were analyzed with Kaplan-Meier curves. Predictors of PFS according to prognostic variables were assessed with regression analysis. RESULTS: Between 2010 and 2022, 31 consecutive patients received bevacizumab alone or combined with chemotherapy as a late-line treatment for recurrent high-grade gliomas. Of these patients, 14 (45.2%) were responders according to RANO criteria, and 17 (54.8%) showed progressive or stable disease. OS at 3, 6, and 12 months was 80.3%, 62.1%, and 43.5. PFS was 48.4%, 34.3%, and 21.8%, respectively. In the multivariate survival analysis, the only factor independently associated with PFS was smaller 2D tumor size in post-contrast T1-weighted MRI at bevacizumab initiation (p = 0.02). Median time-to-progression was 3 months (95%CI: 1-4) in the unmethylated MGMT promoter group and 6 (95%CI: 1-11) in the methylated MGMT promoter group. This difference was not statistically significant (p = 0.37). CONCLUSIONS: Bevacizumab alone or in combination with chemotherapy could be beneficial as a late-line therapy in a subset of patients with recurrent high-grade glioma. Small 2D tumor size in post-contrast T1 weighted MRI at bevacizumab initiation was independently associated with prolonged time to progression.

Embolization before Gamma Knife radiosurgery for cerebral arteriovenous malformations does not negatively impact its obliteration rate: a series of 190 patients.

PURPOSE: Embolization of arteriovenous malformations (AVMs) before radiosurgery has been reported to negatively impact the obliteration rate. This study aims to assess treatment outcomes in a series of 190 patients treated by Gamma Knife radiosurgery (GKRS) for previously embolized AVMs. METHODS: The institutional database of AVMs was retrospectively reviewed between January 2004 and March 2018. The clinical and radiological data of patients treated with GKRS for previously embolized AVMs were analyzed. Predicting factors of obliteration and hemorrhage following GKRS were assessed with univariate and multivariate regression analyses. RESULTS: The mean AVM size was significantly reduced after embolization (p < 0.001). The obliteration rate was 78.4%. Multivariate analyses showed that a lower Spetzler-Martin grade (p = 0.035) and a higher marginal dose (p = 0.007) were associated with obliteration. Post-GKRS hemorrhages occurred in 14 patients (7.4%). A longer time between diagnosis and GKRS was the only factor associated with post-GKRS hemorrhages in multivariate analysis (p = 0.022). Complications related to the combined treatment were responsible for a new permanent neurological disability in 20 patients (10.5%), and a case of death (0.5%). CONCLUSIONS: This study shows that the embolization of AVMs does not have a negative impact on the obliteration rate after radiosurgery. Embolization reduces the AVM size to a treatable volume by GKRS. However, the combined treatment results in an increased complication rate related to the addition of the risks of each treatment modality.

European Association of Neuro-Oncology (EANO) guidelines for treatment of primary central nervous system lymphoma (PCNSL).

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.

Association of antidepressant drug use with outcome of patients with 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.

Dabrafenib monotherapy for a recurrent BRAFV600E-mutated TTF-1-positive posterior pituitary tumor.

Posterior pituitary tumors (PPT) expressing thyroid transcription factor-1 (TTF-1) are extremely rare low-grade neoplasms. The recent discovery of BRAF mutations in these tumors offers a potential alternative treatment using targeted therapies. We present the case of a 57-year-old female with recurrent BRAFV600E-mutated TTF-1-positive PPT treated with a BRAF inhibitor monotherapy (dabrafenib) leading to tumor regression. After 18 months of uninterrupted treatment, ongoing radiological tumor regression was observed and the patient remained asymptomatic without any significant adverse event. BRAF inhibitor is potentially a valuable treatment option for recurrent TTF-1-positive PPT with BRAF mutation.

Trabectedin for recurrent WHO grade 2 or 3 meningioma: A randomized phase II study of the EORTC Brain Tumor Group (EORTC-1320-BTG).

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.

Olaparib Is a Mitochondrial Complex I Inhibitor That Kills Temozolomide-Resistant Human Glioblastoma Cells.

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.

Transient Receptor Potential (TRP) Ion Channels Involved in Malignant Glioma Cell Death and Therapeutic Perspectives.

Among the most biologically, thus clinically, aggressive primary brain tumors are found malignant gliomas. Despite recent advances in adjuvant therapies, which include targeted and immunotherapies, after surgery and radio/chemotherapy, the tumor is recurrent and always lethal. Malignant gliomas also contain a pool of initiating stem cells that are highly invasive and resistant to conventional treatment. Ion channels and transporters are markedly involved in cancer cell biology, including glioma cell biology. Transient receptor potential (TRP) ion channels are calcium-permeable channels implicated in Ca2+ changes in multiple cellular compartments by modulating the driving force for Ca2+ entry. Recent scientific reports have shown that these channels contribute to the increase in glioblastoma aggressiveness, with glioblastoma representing the ultimate level of glioma malignancy. The current review focuses on each type of TRP ion channel potentially involved in malignant glioma cell death, with the ultimate goal of identifying new therapeutic targets to clinically combat malignant gliomas. It thus appears that cannabidiol targeting the TRPV2 type could be such a potential target.

EANO guideline on the diagnosis and management of meningiomas.

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.

Pneumatic artificial muscle-based stimulator for passive functional magnetic resonance imaging sensorimotor mapping in patients with brain tumours.

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.

Prognosis of patients treated in a single neurosurgical reference centre for brain metastasis caused by dormant disseminated cells.

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.

The Phylum Bryozoa: From Biology to Biomedical Potential.

Less than one percent of marine natural products characterized since 1963 have been obtained from the phylum Bryozoa which, therefore, still represents a huge reservoir for the discovery of bioactive metabolites with its ~6000 described species. The current review is designed to highlight how bryozoans use sophisticated chemical defenses against their numerous predators and competitors, and which can be harbored for medicinal uses. This review collates all currently available chemoecological data about bryozoans and lists potential applications/benefits for human health. The core of the current review relates to the potential of bryozoan metabolites in human diseases with particular attention to viral, brain, and parasitic diseases. It additionally weighs the pros and cons of total syntheses of some bryozoan metabolites versus the synthesis of non-natural analogues, and explores the hopes put into the development of biotechnological approaches to provide sustainable amounts of bryozoan metabolites without harming the natural environment.

EANO guideline on the diagnosis and treatment of vestibular schwannoma.

The level of evidence to provide treatment recommendations for vestibular schwannoma is low compared with other intracranial neoplasms. Therefore, the vestibular schwannoma task force of the European Association of Neuro-Oncology assessed the data available in the literature and composed a set of recommendations for health care professionals. The radiological diagnosis of vestibular schwannoma is made by magnetic resonance imaging. Histological verification of the diagnosis is not always required. Current treatment options include observation, surgical resection, fractionated radiotherapy, and radiosurgery. The choice of treatment depends on clinical presentation, tumor size, and expertise of the treating center. In small tumors, observation has to be weighed against radiosurgery, in large tumors surgical decompression is mandatory, potentially followed by fractionated radiotherapy or radiosurgery. Except for bevacizumab in neurofibromatosis type 2, there is no role for pharmacotherapy.

Marine-Derived Anticancer Agents: Clinical Benefits, Innovative Mechanisms, and New Targets.

The role of the marine environment in the development of anticancer drugs has been widely reviewed, particularly in recent years. However, the innovation in terms of clinical benefits has not been duly emphasized, although there are important breakthroughs associated with the use of marine-derived anticancer agents that have altered the current paradigm in chemotherapy. In addition, the discovery and development of marine drugs has been extremely rewarding with significant scientific gains, such as the discovery of new anticancer mechanisms of action as well as novel molecular targets. Approximately 50 years since the approval of cytarabine, the marine-derived anticancer pharmaceutical pipeline includes four approved drugs and eighteen agents in clinical trials, six of which are in late development. Thus, the dynamic pharmaceutical pipeline consisting of approved and developmental marine-derived anticancer agents offers new hopes and new tools in the treatment of patients afflicted with previously intractable types of cancer.

Neurosurgical Device Implantation for Neurooncologic Patients: What To Avoid?

BACKGROUND: Neurooncologic patients frequently require surgery, and neurosurgical devices are often implanted during neurosurgery. These devices could disturb oncologic follow-up by magnetic resonance imaging. METHODS: The authors describe the use of neurosurgical devices, such as bone substitutes, ventriculoperitoneal shunts, and titanium skull fixations, in neurooncologic patients. RESULTS: Acrylic cement cranioplasty, valve of ventriculoperitoneal shunt, and titanium skull fixations produced magnetic artifacts disturbing postoperative magnetic resonance imaging. CONCLUSIONS: The authors highlight the fact that all these neurosurgical devices implanted during surgery should be carefully evaluated to allow appropriate imaging follow-up for neurooncologic patients, which is a problem that remains underreported in the literature.