Glioblastoma and Internal Carotid Artery Calcium Score: A Possible Novel Prognostic Partnership?

Purpose: Clinical evidence suggests an association between comorbidities and outcome in patients with glioblastoma (GBM). We hypothesised that the internal carotid artery (ICA) calcium score could represent a promising prognostic biomarker in a competing risk analysis in patients diagnosed with GBM. Methods: We validated the use of the ICA calcium score as a surrogate marker of the coronary calcium score in 32 patients with lung cancer. Subsequently, we assessed the impact of the ICA calcium score on overall survival in GBM patients treated with radio-chemotherapy. Results: We analysed 50 GBM patients. At the univariate analysis, methyl-guanine-methyltransferase gene (MGMT) promoter methylation (p = 0.048), gross total tumour resection (p = 0.017), and calcium score (p = 0.011) were significant prognostic predictors in patients with GBM. These three variables also maintained statistical significance in the multivariate analysis. Conclusions: the ICA calcium score could be a promising prognostic biomarker in GBM patients.

DKK3 Expression in Glioblastoma: Correlations with Biomolecular Markers.

Glioblastoma is the most common malignant primary tumor of the CNS. The prognosis is dismal, with a median survival of 15 months. Surgical treatment followed by adjuvant therapies such as radiotherapy and chemotherapy characterize the classical strategy. The WNT pathway plays a key role in cellular proliferation, differentiation, and invasion. The DKK3 protein, capable of acting as a tumor suppressor, also appears to be able to modulate the WNT pathway. We performed, in a series of 40 patients, immunohistochemical and Western blot evaluations of DKK3 to better understand how the expression of this protein can influence clinical behavior. We used a statistical analysis, with correlations between the expression of DKK3 and overall survival, age, sex, Ki-67, p53, and MGMT and IDH status. We also correlated our data with information included in the cBioPortal database. In our analyses, DKK3 expression, in both immunohistochemistry and Western blot analyses, was reduced or absent in many cases, showing downregulation. To date, no clinical study exists in the literature that reports a potential correlation between IDH and MGMT status and the WNT pathway through the expression of DKK3. Modulation of this pathway through the expression of DKK3 could represent a new tailored therapeutic strategy in the treatment of glioblastoma.

Impact of Heavy Metals on Glioma Tumorigenesis.

Recently, an increase in the incidence of brain tumors has been observed in the most industrialized countries. This event triggered considerable interest in the study of heavy metals and their presence in the environment (air, water, soil, and food). It is probable that their accumulation in the body could lead to a high risk of the onset of numerous pathologies, including brain tumors, in humans. Heavy metals are capable of generating reactive oxygen, which plays a key role in various pathological mechanisms. Alteration of the homeostasis of heavy metals could cause the overproduction of reactive oxygen species and induce DNA damage, lipid peroxidation, and the alteration of proteins. A large number of studies have shown that iron, cadmium, lead, nickel, chromium, and mercury levels were significantly elevated in patients affected by gliomas. In this study, we try to highlight a possible correlation between the most frequently encountered heavy metals, their presence in the environment, their sources, and glioma tumorigenesis. We also report on the review of the relevant literature.

Novel Advances in Treatment of Meningiomas: Prognostic and Therapeutic Implications.

Meningiomas are the most frequent histotypes of tumors of the central nervous system. Their incidence is approximately 35% of all primary brain tumors. Although they have the status of benign lesions, meningiomas are often associated with a decreased quality of life due to focal neurological deficits that may be related. The optimal treatment is total resection. Histological grading is the most important prognostic factor. Recently, molecular alterations have been identified that are specifically related to particular phenotypes and, probably, are also responsible for grading, site, and prognostic trend. Meningiomas recur in 10-25% of cases. In these cases, and in patients with atypical or anaplastic meningiomas, the methods of approach are relatively insufficient. To date, data on the molecular biology, genetics, and epigenetics of meningiomas are insufficient. To achieve an optimal treatment strategy, it is necessary to identify the mechanisms that regulate tumor formation and progression. Combination therapies affecting multiple molecular targets are currently opening up and have significant promise as adjuvant therapeutic options. We review the most recent literature to identify studies investigating recent therapeutic treatments recently used for meningiomas.

Unusual localization and clinical presentation of primary central nervous system extranodal marginal zone B­cell lymphoma: A case report.

Primary central nervous system (CNS) extranodal marginal zone B-cell lymphoma (MZBL) is a rare low-grade non-Hodgkin lymphoma, characterised predominantly by small B cells, plasma cells, monocytoid cells and scattered large immunoblasts. Primary CNS MZBL is a slow-growing tumour that remains localised and is characterised by an excellent clinical prognosis. The present study describes the case of a 48-year-old HIV-negative female patient with a history of head trauma 1 year prior, who presented with worsening neurological symptoms and a magnetic resonance imaging finding of a ~3-cm extra-axial mass within the left lateral ventricle. From histopathology and immunohistochemistry, the lesion was diagnosed as a CNS MZBL; as no other primary lesions were found, the base of the choroid plexuses of the left lateral ventricle was considered the primary site. To the best of our knowledge, the current case is the first study to report on primary CNS MZBL arising in this anatomical site and paves the way for further studies on the role of chronic inflammation (in the present case resulting from trauma) in the pathogenesis not only of primary CNS MZBL but also of lymphoma in general. Additionally, this report could serve as a starting point for studies analysing the role of meningothelial cells in the pathogenesis of primary CNS MZBL.

The impact of survivorship bias in glioblastoma research.

Despite advances in the therapy of Central Nervous System (CNS) malignancies, treatment of glioblastoma (GB) poses significant challenges due to GB resistance and high recurrence rates following post-operative radio-chemotherapy. The majority of prognostic and predictive GB biomarkers are currently developed using tumour samples obtained through surgical interventions. However, the selection criteria adopted by different neurosurgeons to determine which cases are suitable for surgery make operated patients not representative of all GB cases. Particularly, geriatric and frail individuals are excluded from surgical consideration in some cancer centers. Such selection generates a survival (or selection) bias that introduces limitations, rendering the patients or data chosen for downstream analyses not representative of the entire community. In this review, we discuss the implication of survivorship bias on current and novel biomarkers for patient selection, stratification, therapy, and outcome analyses.

Potential Role of Carbon Nanomaterials in the Treatment of Malignant Brain Gliomas.

Malignant gliomas are the most common primary brain tumors in adults up to an extent of 78% of all primary malignant brain tumors. However, total surgical resection is almost unachievable due to the considerable infiltrative ability of glial cells. The efficacy of current multimodal therapeutic strategies is, furthermore, limited by the lack of specific therapies against malignant cells, and, therefore, the prognosis of these in patients is still very unfavorable. The limitations of conventional therapies, which may result from inefficient delivery of the therapeutic or contrast agent to brain tumors, are major reasons for this unsolved clinical problem. The major problem in brain drug delivery is the presence of the blood-brain barrier, which limits the delivery of many chemotherapeutic agents. Nanoparticles, thanks to their chemical configuration, are able to go through the blood-brain barrier carrying drugs or genes targeted against gliomas. Carbon nanomaterials show distinct properties including electronic properties, a penetrating capability on the cell membrane, high drug-loading and pH-dependent therapeutic unloading capacities, thermal properties, a large surface area, and easy modification with molecules, which render them as suitable candidates for deliver drugs. In this review, we will focus on the potential effectiveness of the use of carbon nanomaterials in the treatment of malignant gliomas and discuss the current progress of in vitro and in vivo researches of carbon nanomaterials-based drug delivery to brain.

Atypical meningiomas with an immunohistochemical profile consistent with hypermetabolic or proliferative molecular groups show high mitotic index, chromosomal instability, and higher recurrence risk.

The use of adjuvant radiotherapy is controversial for atypical meningiomas undergoing gross total resection. It has recently been proposed that meningiomas may be classified into four molecular groups (MG): immunogenic (MG1), benign NF2-wildtype (MG2), hypermetabolic (MG3), and proliferative (MG4). The two latter have the worst prognosis, and it has been suggested that they can be identified using ACADL and MCM2 immunostainings. We studied 55 primary atypical meningiomas, treated with gross total resection and no adjuvant therapies, to assess whether ACADL and MCM2 immuno-expression may identify patients at higher recurrence risk, thus requiring adjuvant treatments. Twelve cases resulted ACADL-/MCM2-, 9 ACADL + /MCM2-, 17 ACADL + /MCM2 + , and 17 ACADL-/MCM2 + . MCM2 + meningiomas displayed more frequent atypical features (prominent nucleoli, small cells with high nuclear-to-cytoplasmic ratio) and CDKN2A hemizygous deletion (HeDe) (P = 0.011). The immunoexpression of ACADL and/or MCM2 was significantly associated with higher mitotic index, 1p and 18q deletions, increased recurrence rate (P = 0.0006), and shorter recurrence-free survival (RFS) (P = 0.032). At multivariate analysis, carried out including ACADL/MCM2 immuno-expression, mitotic index, and CDKN2A HeDe as covariates, this latter resulted a significant and independent prognosticator of shorter RFS (P = 0.0003).

Molecular Investigation of DKK3 in Cerebral Ischemic/Reperfusion Injury.

Dickkopf-3 (Dkk3) is an atypical member of the Dkk family of Wnt inhibitors, which has been implicated in the pathophysiology of neurodegenerative disorders. Its role in the mechanisms of cellular degeneration and protection is still unknown. The aim of our work is to investigate the endogenous activation of the DKK3 pathway in a model of transient occlusion of the middle cerebral artery in rats. In particular, the animals were subjected to 1 h of ischemia followed by different reperfusion times (1 h, 6 h, 12 h and 24 h) to evaluate the downstream pathway and the time course of its activation. Western blot analysis showed increased Dkk3 expression in animals with the highest time of reperfusion. The increased levels of Dkk3 were accompanied by reduced Wnt3a, Frz1 and PIWI1a expression in the cytosol while FOXM1 and ß-catenin decreased in the nucleus. These molecular changes led to an increase in the apoptotic pathway, as showed by the increased expression of Caspase 3 and Bax and the reduced levels of Bcl-2, and to a decrease in neurogenesis, as shown by the decreased expression of Tbr2, Ngn2 and Pax6. In the second part of the study, we decided to employ curcumin, an activator of the Wnt/ß-catenin signaling, to investigate its effect on Dkk3. In particular, curcumin was administered 1 and 6 h after ischemia, and animals were sacrificed 24 h later when the expression of Dkk3 was higher. Our data displayed that curcumin administration decreased Dkk3 expression, and increased Wnt3a, Frz1 and PIWI1a levels. Well in line with these data, curcumin administration increased nuclear ß-catenin and FOXM1 expression. The down-regulation of Dkk3 by curcumin led to reduced apoptosis and increased neurogenesis. Summarizing, our results showed that Dkk3 acts as an inhibitor of Wnt/ß-catenin signaling during cerebral ischemia. Additionally, its inhibition and the contextual activation of the Wnt/ß-catenin pathway are protective against ischemic stroke.

The Role of Nanotechnologies in Brain Tumors.

The treatment of glioma remains one of the most interesting topics in neurooncology. Glioblastoma multiforme is the most aggressive and prevalent malignant brain tumor. Nowadays, technologies and new tools are helping the neurosurgeons to define a tailored surgery. However, there are few pharmaceutical strategies in operated and nonoperated patients. There are still few anticancer drugs approved by FDA and EMA. Moreover, these drugs are not so effective and have a lot of side effects due to their toxicity. Nanoparticles are a new strategy which could help to create and carry new drugs. In fact, NPs improve the pharmacokinetic properties of anticancer drugs, reduce side-effects, and increase drug half-life and its selectivity. Nanoparticle drug delivery system has been studied for targeting different molecular biomarkers and signaling pathways. Furthermore, the first problem of anticancer drugs in the treatment of gliomas is penetrating the blood brain barrier which represents an insurmountable wall for most of synthetic and natural particles. In the last 15 years, a lot of researches tried to design a perfect nanoparticle both able to cross blood-brain barrier and to selectively target glioma cells, unfortunately, without great results. In vivo human trials are still ongoing and many of them have already failed. In this chapter we evaluate the effectiveness of nanotechnologies in the treatment of brain tumors. There is not yet, currently, a nanoparticle drug designed for the treatment of gliomas approved by FDA and EMA. Advancements in discovery of molecular characteristics of tumors lead to the development of targeted nanoparticles that are tested in numerous in vitro and in vivo studies on gliomas. Novel and repurposed drugs, as well as novel drug combinations, have also been already studied but those are not included in this chapter because the carried drugs (active substances) are not included among the approved anticancer drug used in the treatment of gliomas.

The Role of Nanotechnology in Spinal Cord Tumors.

The efficacy of current multimodal therapeutic strategies in spinal cord tumors is limited by the lack of specific therapies. Importantly, sufficient amount of therapeutic materials should be concentrated in tumors in order to be efficient. Overcoming the blood-brain barrier is the major obstacle for chemotherapeutics, which cannot reach the tumor bed in efficacious doses. The intrinsic properties of nanoparticles make them suitable for activating numerous processes both at the cellular and subcellular levels, making them good candidates to be used for different purposes in medicine. Furthermore, the adaptability characteristic of NPs may enable them to pass through the blood-brain barrier and transport different pharmacological compounds. Nanoparticle systems provide prolonged drug delivery directly to the tumor or by functionalizing the material surface with peptides and ligands allowing the drug-loaded material to specifically target the tumor cells. In this chapter, various preclinical and/or clinical studies in treatment of spinal cord tumors are discussed.

Overview on Common Genes Involved in the Onset of Glioma and on the Role of Migraine as Risk Factor: Predictive Biomarkers or Therapeutic Targets?

Gliomas are relatively rare but fatal cancers, and there has been insufficient research to specifically evaluate the role of headache as a risk factor. Nowadays, gliomas are difficult to cure due to the infiltrative nature and the absence of specific adjuvant therapies. Until now, mutations in hundreds of genes have been identified in gliomas and most relevant discoveries showed specific genes alterations related to migraine as potential risk factors for brain tumor onset. Prognostic biomarkers are required at the time of diagnosis to better adapt therapies for cancer patients. In this review, we aimed to highlight the significant modulation of CLOCK, BMLA1 and NOTCH genes in glioma onset and development, praising these genes to be good as potentially attractive therapeutic markers for brain tumors. A improved knowledge regarding the role of these genes in triggering or modulating glioma maybe the key to early diagnosing brain tumor onset in patients affected by a simple headache. In addition, investigating on these genes we can suggest potential therapeutic targets for treating brain tumors. These considerations open up the possibility of personalized treatments that can target each brain tumor's specific genetic abnormality.

Cisternostomy for malignant middle cerebral artery infarction: proposed pathophysiological mechanisms and preliminary results.

BACKGROUND: The ischaemic stroke of the territory of the middle cerebral artery represents an event burdened by high mortality and severe morbidity. The proposed medical treatments do not always prove effective. Decompressive craniectomy allows the ischaemic tissue to shift through the surgical defect rather than to the unaffected regions of the brain, thus avoiding secondary damage due to increased intracranial pressure. In this study, we propose a novel treatment for these patients characterised by surgical fenestration of the cisterns of the skull base. METHODS: We have treated 16 patients affected by malignant middle cerebral artery ischaemia and treated with cisternostomy between August 2018 and December 2019. The clinical history, neurological examination findings and neuroradiological studies (brain CT, CT angiography, MRI) were performed to diagnose stroke. Clinical examination was recorded on admission and preoperatively using the Glasgow Coma Scale and the National Institutes of Health Stroke Scale. RESULTS: The study included 16 patients, 10 males and 6 females. The mean age at surgery was 60.1 years (range 19-73). Surgical procedure was performed in all patients. The patients underwent immediate postoperative CT scan and were in the early hours evaluated in sedation window. In total, we recorded two deaths (12.5%). A functional outcome between mRS 0-3, defined as favourable, was observed in 9 (64.2%) patients 9 months after discharge. A functional outcome between mRS 4-6, defined as poor, was observed in 5 (35.7%) patients 9 months after discharge. CONCLUSIONS: The obtained clinical results appear, however, substantially overlapping to decompressive craniectomy. Cisternostomy results in a favourable functional outcome after 9 months. This proposed technique permits that the patient no longer should be undergone cranioplasty thus avoiding the possible complications related to this procedure. The results are certainly interesting but higher case numbers are needed to reach definitive conclusions.

Intraventricular Meningiomas: Clinical-Pathological and Genetic Features of a Monocentric Series.

Intraventricular meningiomas (IVMs) are rare (0.5-5%) and usually low-grade (90% grade I) brain neoplasms. Their recurrence rate is lower than that of extra-axial meningiomas, but their surgical resection can be burdened with life-threatening complications, which represent the major cause of the reported 4% mortality. The aim of this study is to characterize the molecular portrait of IVMs to identify potential therapeutic targets. For this, we explored mutations and copy number variations (CNV) of 409 cancer-related genes and tumor mutational burden (TMB) of six cases, using next-generation sequencing. Five IVMs were grade I and one was grade II; none recurred, in spite of partial surgical resection in one case. NF2 mutation was the only recurring alteration and was present in three of the six IVMs, in association with SMARCB1 mutation in one case. None of the cases was hypermutated (TMB > 10 mutations/Mb). NF2-mutant progressing or recurring IVMs could potentially be treated with targeted therapies applied to other NF2-mutant tumors, as an alternative to surgery or radiosurgery, while in view of their low TMB they are unlikely candidates to immune check-point inhibition.

IDH-wild type glioblastomas featuring at least 30% giant cells are characterized by frequent RB1 and NF1 alterations and hypermutation.

Giant cell glioblastoma (GC-GBM) is a rare variant of IDH-wt GBM histologically characterized by the presence of numerous multinucleated giant cells and molecularly considered a hybrid between IDH-wt and IDH-mutant GBM. The lack of an objective definition, specifying the percentage of giant cells required for this diagnosis, may account for the absence of a definite molecular profile of this variant. This study aimed to clarify the molecular landscape of GC-GBM, exploring the mutations and copy number variations of 458 cancer-related genes, tumor mutational burden (TMB), and microsatellite instability (MSI) in 39 GBMs dichotomized into having 30-49% (15 cases) or ≥ 50% (24 cases) GCs. The type and prevalence of the genetic alterations in this series was not associated with the GCs content (< 50% or ≥ 50%). Most cases (82% and 51.2%) had impairment in TP53/MDM2 and PTEN/PI3K pathways, but a high proportion also featured TERT promoter mutations (61.5%) and RB1 (25.6%) or NF1 (25.6%) alterations. EGFR amplification was detected in 18% cases in association with a shorter overall survival (P = 0.004). Sixteen (41%) cases had a TMB > 10 mut/Mb, including two (5%) that harbored MSI and one with a POLE mutation. The frequency of RB1 and NF1 alterations and TMB counts were significantly higher compared to 567 IDH wild type (P < 0.0001; P = 0.0003; P < 0.0001) and 26 IDH-mutant (P < 0.0001; P = 0.0227; P < 0.0001) GBMs in the TCGA PanCancer Atlas cohort. These findings demonstrate that the molecular landscape of GBMs with at least 30% giant cells is dominated by the impairment of TP53/MDM2 and PTEN/PI3K pathways, and additionally characterized by frequent RB1 alterations and hypermutation and by EGFR amplification in more aggressive cases. The high frequency of hypermutated cases suggests that GC-GBMs might be candidates for immune check-point inhibitors clinical trials.

Immunomodulatory Effect of Microglia-Released Cytokines in Gliomas.

Microglia, a type of differentiated tissue macrophage, are considered to be the most plastic cell population of the central nervous system (CNS). Microglia substantially contribute to the growth and invasion of tumor mass in brain tumors including glioblastoma (GB). In response to pathological conditions, resting microglia undergo a stereotypic activation process and become capable of phagocytosis, antigen presentation, and lymphocyte activation. Considering their immune effector function, it is not surprising to see microglia accumulation in almost every CNS disease process, including malignant brain tumors. Large numbers of glioma associated microglia and macrophages (GAMs) can accumulate within the tumor where they appear to have an important role in prognosis. GAMs constitute the largest portion of tumor infiltrating cells, contributing up to 30% of the entire glioma mass and upon interaction with neoplastic cells. GAMs acquire a unique phenotype of activation, including both M1 and M2 specific markers. It has been demonstrated that microglia possess a dual role: on one hand, microglia may represent a CNS anti-tumor response, which is inactivated by local secretion of immunosuppressive factors by glioma cells. On the other hand, taking into account that microglia are capable of secreting a variety of immunomodulatory cytokines, it is possible that they are attracted by gliomas to promote tumor growth. A better understanding of microglia-glioma interaction will be helpful in designing novel immune-based therapies against these fatal tumors. Concluding, as microglia significantly may contribute to glioma biology, favoring tumor growth and invasiveness, these cells represent a valuable alternative/additional target for the development of more effective treatments for gliomas.

Molecular Profiling of 22 Primary Atypical Meningiomas Shows the Prognostic Significance of 18q Heterozygous Loss and CDKN2A/B Homozygous Deletion on Recurrence-Free Survival.

The use of adjuvant therapy is controversial in atypical meningiomas with gross total resection. Predictors of recurrence risk could be useful in selecting patients for additional treatments. The aim of this study was to investigate whether molecular features are associated with recurrence risk of atypical meningiomas. According to WHO classification, the diagnosis of atypical meningioma was based on the presence of one major criteria (mitotic activity, brain invasion) or three or more minor criteria. The molecular profile of 22 cases (eight mitotically active, eight brain-invasive, and six with minor criteria) was assessed exploring the mutational status and copy number variation of 409 genes using next generation sequencing. Of the 22 patients with a median follow up of 53.5 months, 13 had recurrence of disease within 68 months. NF2 mutation was the only recurrent alteration (11/22) and was unrelated to clinical-pathological features. Recurring meningiomas featured a significantly higher proportion of copy number losses than non-recurring ones (p = 0.027). Chromosome 18q heterozygous loss or CDKN2A/B homozygous deletion was significantly associated with shorter recurrence-free survival (p = 0.008; hazard ratio: 5.3). Atypical meningiomas could be tested routinely for these genetic alterations to identify cases for adjuvant treatment.