Overview of Curcumin and Piperine Effects on Glucose Metabolism: The Case of an Insulinoma Patient's Loss of Consciousness.

The hypoglycemic properties of curcumin supplements in therapeutic doses are well-known and may represent a useful tool for the treatment of chronic diseases such as metabolic syndrome, insulin resistance and type 2 diabetes. The poor bioavailability of curcumin can be improved with the concomitant administration of piperine, with no severe adverse effects on glycemia reported so far in the literature. In this article, we further discuss a previously reported case of a helicopter pilot, affected by grade I obesity who, under curcumin and piperine treatment, experienced a transient loss of consciousness (TLOC), during a low-altitude flight. This episode led to a diagnosis of insulinoma, previously asymptomatic. We hypothesized that the combined effects of curcumin and piperine might have caused a severe hypoglycemic episode and subsequent TLOC. Therefore, further studies should be conducted to evaluate the safety of curcumin and piperine supplementation in subjects with impaired glucose metabolism and insulin secretion.

Role of Luteolin as Potential New Therapeutic Option for Patients with Glioblastoma through Regulation of Sphingolipid Rheostat.

Glioblastoma (GBM) is the most aggressive brain tumor, still considered incurable. In this study, conducted on primary GBM stem cells (GSCs), specifically selected as the most therapy-resistant, we examined the efficacy of luteolin, a natural flavonoid, as an anti-tumoral compound. Luteolin is known to impact the sphingolipid rheostat, a pathway regulated by the proliferative sphingosine-1-phosphate (S1P) and the proapoptotic ceramide (Cer), and implicated in numerous oncopromoter biological processes. Here, we report that luteolin is able to inhibit the expression of SphK1/2, the two kinases implicated in S1P formation, and to increase the expression of both SGPL1, the lyase responsible for S1P degradation, and CERS1, the ceramide synthase 1, thus shifting the balance toward the production of ceramide. In addition, luteolin proved to decrease the expression of protumoral signaling as MAPK, RAS/MEK/ERK and PI3K/AKT/mTOR and cyclins involved in cell cycle progression. In parallel, luteolin succeeded in upregulation of proapoptotic mediators as caspases and Bcl-2 family and cell cycle controllers as p53 and p27. Furthermore, luteolin determined the shutdown of autophagy contributing to cell survival. Overall, our data support the use of luteolin as add-on therapy, having demonstrated a good ability in impairing GSC viability and survival and increasing cell sensitivity to TMZ.

A Targeted Next-Generation Sequencing Panel to Genotype Gliomas.

Gliomas account for the majority of primary brain tumors. Glioblastoma is the most common and malignant type. Based on their extreme molecular heterogeneity, molecular markers can be used to classify gliomas and stratify patients into diagnostic, prognostic, and therapeutic clusters. In this work, we developed and validated a targeted next-generation sequencing (NGS) approach to analyze variants or chromosomal aberrations correlated with tumorigenesis and response to treatment in gliomas. Our targeted NGS analysis covered 13 glioma-related genes (ACVR1, ATRX, BRAF, CDKN2A, EGFR, H3F3A, HIST1H3B, HIST1H3C, IDH1, IDH2, P53, PDGFRA, PTEN), a 125 bp region of the TERT promoter, and 54 single nucleotide polymorphisms (SNPs) along chromosomes 1 and 19 for reliable assessment of their copy number alterations (CNAs). Our targeted NGS approach provided a portrait of gliomas' molecular heterogeneity with high accuracy, specificity, and sensitivity in a single workflow, enabling the detection of variants associated with unfavorable outcomes, disease progression, and drug resistance. These preliminary results support its use in routine diagnostic neuropathology.

A Frailty-Adjusted Stratification Score to Predict Surgical Risk, Post-Operative, Long-Term Functional Outcome, and Quality of Life after Surgery in Intracranial Meningiomas.

Object: To investigate those parameters affecting early and follow-up functional outcomes in patients undergoing resection of meningiomas and to design a dedicated predictive score, the Milan Bio(metric)-Surgical Score (MBSS) is hereby presented. Methods: Patients undergoing transcranial surgery for intracranial meningiomas were included. The most significant parameters in the regression analyses were implemented in a patient stratification score and were validated by testing its classification consistency with a clinical−radiological grading scale (CRGS), Milan complexity scale (MCS), and Charlson Comorbidity Index (CCI) scores. Results: The ASA score, Frailty index, skull base and posterior cranial fossa locations, a diameter of >25 mm, and the absence of a brain−tumour interface were predictive of early post-operative deterioration and were collected in MBSS Part A (AUC: 0.965; 95%C.I. 0.890−1.022), while the frailty index, posterior cranial fossa location, a diameter of >25 mm, a edema/tumour volume index of >2, dural sinus invasion, DWI hyperintensity, and the absence of a brain−tumour interface were predictive of a long-term unfavourable outcome and were collected in MBSS Part B (AUC: 0.877; 95%C.I. 0.811−0.942). The score was consistent with CRGS, MCS, and CCI. Conclusion: Patients' multi-domain evaluation and the implementation of frailty indexes might help predict the perioperative complexity of cases; the functional, clinical, and neurological early outcomes; survival; and overall QoL after surgery.

Space flight and central nervous system: Friends or enemies? Challenges and opportunities for neuroscience and neuro-oncology.

Space environment provides many challenges to pilots, astronauts, and space scientists, which are constantly subjected to unique conditions, including microgravity, radiations, hypoxic condition, absence of the day and night cycle, etc. These stressful stimuli have the potential to affect many human physiological systems, triggering physical and biological adaptive changes to re-establish the homeostatic state. A particular concern regards the risks for the effects of spaceflight on the central nervous system (CNS), as several lines of evidence reported a great impact on neuroplasticity, cognitive functions, neurovestibular system, short-term memory, cephalic fluid shift, reduction in motor function, and psychological disturbances, especially during long-term missions. Aside these potential detrimental effects, the other side of the coin reflects the potential benefit of applicating space-related conditions on Earth-based life sciences, as cancer research. Here, we focused on examining the effect of real and simulated microgravity on CNS functions, both in humans and in cellular models, browsing the different techniques to experience or mime microgravity on-ground. Increasing evidence demonstrate that cancer cells, and brain cancer cells in particular, are negatively affected by microgravity, in terms of alteration in cell morphology, proliferation, invasion, migration, and apoptosis, representing an advancing novel side of space-based investigations. Overall, deeper understandings about the mechanisms by which space environment influences CNS and tumor biology may be promisingly translated into many clinical fields, ranging from aerospace medicine to neuroscience and oncology, representing an enormous pool of knowledge for the implementation of countermeasures and therapeutic applications.

Basal serum level of Δ4-androstenedione reflects the ovaries' ability to respond to stimulation in IVF cycles: setting up a new reliable index of both ovarian reserve and response.

PURPOSE: Adequate androgen levels are necessary for regular follicular growth, progression beyond the pre-antral stage, and prevention of follicular atresia. The main purpose of this study was to investigate whether baseline androgen levels had a predictive value on stimulation outcomes in IVF cycles. The secondary purpose was to compare the possible predictive value of androgens with that of already known markers. METHODS: The study included 91 infertile patients aged 30-45 years awaiting the first IVF cycle. All women underwent the same stimulation protocol and the same starting dose of recombinant FSH. As stimulation outcomes, the number of follicles recruited, estradiol and progesterone levels on the day of trigger, the total dose of gonadotropins administered, and the number of oocytes collected were recorded. Multiple linear regression and multivariate logistic regression were used to evaluate the significant predictive value of the variables for response to controlled ovarian stimulation (COS). By studying the reliability of different markers, an attempt was made to develop a single index with the highest predictive value. RESULTS: Pearson's correlation revealed a statistically significant inverse correlation between oocytes collected and age (r = - 0.333, p < 0.001) and a positive correlation with AMH (anti-müllerian hormone) (r = 0.360, p < 0.001), antral follicle count (AFC) (r = 0.639, p < 0.001), and androstenedione (Δ4-A) (r = 0.359, p < 0.001). No significant correlation was reported with FSH (r = - 0.133, p = 0.207) and total testosterone (r = 0.180, p = 0.088). In COS good responders, the G-index (= AMH ng/mL*AFC/Δ4-A ng/dL) revealed a significantly higher level (p < 0.001) than AMH, AFC, and Δ4-A alone. CONCLUSION: Baseline serum Δ4-A, presumably crucial for ensuring a regular follicular growth, is a reliable marker of ovarian response to stimulation. Since the ovarian capacity to respond to gonadotropins does not depend exclusively on the presence of follicles, we suggest a new index, the G-index, able to contemplate both the ovarian reserve and the Δ4-A level.

Effects of Metformin as Add-On Therapy against Glioblastoma: An Old Medicine for Novel Oncology Therapeutics.

BACKGROUND: Glioblastoma is the most aggressive primary brain malignancy in adults, with a poor prognosis of about 14 months. Recent evidence ascribed to metformin (MET), an antihyperglycemic drug, the potential to reduce cancer incidence and progression, but the molecular mechanisms underlying these effects need to be better investigated. METHODS: Here, we tested the efficacy of MET on n = 10 primary glioblastoma endothelial cells (GECs), by viability and proliferation tests, as MTT and Live/Dead assays, apoptosis tests, as annexin V assay and caspase 3/7 activity, functional tests as tube-like structure formation and migration assay and by mRNA and protein expression performed by quantitative real-time PCR analysis (qRT-PCR) and Western Blot, respectively. RESULTS: Data resulting revealed a time- and µ-dependent ability of MET to decrease cell viability and proliferation, increasing pro-apoptotic mechanisms mediated by caspases 3/7. Also, MET impacted GEC functionality with a significant decrease of angiogenesis and invasiveness potential. Mechanistically, MET was able to interfere with sphingolipid metabolism, weakening the oncopromoter signaling promoted by sphingosine-1-phosphate (S1P) and shifting the balance toward the production of the pro-apoptotic ceramide. CONCLUSIONS: These observations ascribed to MET the potential to serve as add-on therapy against glioblastoma, suggesting a repurposing of an old, totally safe and tolerable drug for novel oncology therapeutics.

Loss of consciousness in a helicopter pilot as plausible first sign of insulinoma: a case report.

A 50-year-old man who worked as a helicopter rescue pilot transiently lost consciousness while piloting a helicopter rescue. In the diagnostic process, all tests for the main possible differential diagnoses of loss of consciousness (cardiological and neurological) were performed and yielded normal results. Blood chemistry tests revealed recurrent fasting hypoglycemia and Chromogranin A was at the upper limit of normal. Fine needle aspiration guided by endoscopic ultrasonography was used to diagnose insulinoma-type neuroendocrine tumor of the pancreas. According to the Italian policies, the occupational physician aims to maintain professional skills without neglecting flight safety. A careful analysis of the relationship between the characteristics of the state of health of the aviator and his specific work needs was carried out, and he was given the opportunity to continue working as a rescue pilot thanks to medical therapies associated with organizational interventions in the workplace.

Hyperandrogenism and menstrual imbalance are the best predictors of metformin response in PCOS patients.

BACKGROUND: Moving from the correlation between insulin-resistance and PCOS, metformin has been administered in some PCOS women improving ovulatory and metabolic functions and decreasing androgen levels. Inconsistency and unpredictability of response to metformin limit its extensive use. Aim of this study was to identify reliable predictors of response to metformin therapy for weight loss and reduction in plasma androgen levels using ANNs (artificial neural networks). METHODS: One hundred eight consecutive women with PCOS (ESHRE/ASRM 2003 Rotterdam criteria) treated with metformin 1500 mg/day, at inclusion and every 6 months underwent to a complete clinical, endocrine/metabolic assessment and ultrasonographic evaluation. Therapy outcomes were BMI reduction (≥1 kg/m2) in overweight/obese and free-androgen-index (FAI) decrease (≥1%) in hyperandrogenemic women. Semantic connectivity maps (SCMs) were obtained through Auto-CM, a fourth generation ANN, to compare patients' baseline clinical features to the treatment outcomes. Multivariate logistic regression analysis was used to assess the major predictor in drop-out patients and the associated risk. RESULTS: At 6 months 54 out of 103 (52,4%) obese patients showed BMI reduction and 45 out of 89 (50,6%) hyperandrogenemic women showed FAI decrease. The further response rates at 12 months were 30,6 and 47%, respectively. SCMs showed a clear polarization for both the outcomes with elevated accuracy. Treatment responsiveness resulted strictly related to oligo-amenorrhea and hyperandrogenemia at baseline. In addition, lower serum testosterone levels at baseline were found to be the major predictor of treatment discontinuation. CONCLUSIONS: In women with PCOS, menstrual pattern imbalance and ovarian androgens excess are the best predictors of metformin response. They may pave the way for a rethinking of the criteria for evaluating hyperandrogenism in order to better define the large population included in the diagnosis of PCOS. Baseline plasma testosterone level can serve as a sensitive marker to predict treatment compliance.

The "Parachute" Technique for the Endoscopic Repair of High-Flow Anterior Skull-Base CSF Leaks.

OBJECTIVE: This study aims to assess the feasibility and reliability of our endoscopic trans-nasal technique for the repair of cribriform and sellar high-flow cerebrospinal fluid (CSF) leaks. METHODS: A comparison between patients suffering from high-flow rhinorrhea and treated through a free grafting endoscopic technique or the "parachute" technique, our nasal packing proposal, was performed. RESULTS: Thirty-three patients were included. The mean age was 52 years (range: 36-68 years). The etiology of the CSF leaks was iatrogenic in 16 cases (48.5%), traumatic in 5 cases (15.2%), spontaneous in 11 cases (33.3%), and related to anterior skull base tumors in 1 case (3%). The bone defect affected the sphenoidal sinus in 20 cases (60.6%), the cribriform plate of the ethmoid in 10 cases (30.3%), and both the sphenoid and ethmoid in 3 cases (9.1%). The mean size of bone defects was 8.5 ± 3.9 mm. The median follow-up was 28 (64) months. A CSF leak recurrence occurred in no cases treated with the parachute technique and in 3 cases that underwent conventional endoscopic treatments. The CSF leak recurrences were associated with 2 iatrogenic and 1 post-traumatic fistula. All the CSF leak recurrences underwent the parachute technique, not showing second recurrences. CONCLUSIONS: Our results suggest that the parachute technique is simple, safe, and effective. We recommend it as an alternative treatment to vascular flaps for the treatment of high-flow and recurrent fistulas.

Inflammatory interactions between degenerated intervertebral discs and microglia: Implication of sphingosine-1-phosphate signaling.

The etiology of intervertebral disc degeneration is largely unknown, but local neuroinflammation may exert a crucial role through activation of cells as microglia and pro-inflammatory cytokines production. We aimed to compare the effect of degenerated and normal intervertebral disc microenvironment on microglial cells and the potential role of sphingosine-1-phosphate, a pro-inflammatory sphingolipid, in their crosstalk. Human degenerated intervertebral discs (Pfirrmann grade IV) were obtained at surgery for spondylolisthesis. Normal intervertebral discs were collected from cadaveric normal lumbar spines. Normal and degenerated-intervertebral discs were kept in culture to obtain media conditioning. Then, microglial cells were cocultured with conditioned media and viability, proliferation, migration, chemotaxis, and inflammatory gene expression were evaluated. The results demonstrate that conditioned media from degenerated intervertebral discs activate microglial cells, increasing chemotaxis, migration, and pro-inflammatory mediators release to a great extent than normal discs. In addition, we show that the administration of sphingosine-1-phosphate to normal intervertebral disc/microglia coculture mimicked degenerative effects. Interestingly, sphingosine-1-phosphate content in conditioned media from degenerated discs was significantly higher than that from normal ones. In addition, FTY720, a functional antagonist of sphingosine-1-phosphate, potently inhibited the effect of degenerated intervertebral discs on microglial inflammatory factor transcription and migration. Our data report, for the first time, that sphingosine-1-phosphate is involved as signal in the microenvironment of human degenerated intervertebral discs. Sphingosine-1-phosphate signaling modulation by FTY720 may induce beneficial effects in counteracting microglial activation during intervertebral disc degeneration.

Frontiers in Anti-Cancer Drug Discovery: Challenges and Perspectives of Metformin as Anti-Angiogenic Add-On Therapy in Glioblastoma.

Glioblastoma is the most common primitive tumor in adult central nervous system (CNS), classified as grade IV according to WHO 2016 classification. Glioblastoma shows a poor prognosis with an average survival of approximately 15 months, representing an extreme therapeutic challenge. One of its distinctive and aggressive features is aberrant angiogenesis, which drives tumor neovascularization, representing a promising candidate for molecular target therapy. Although several pre-clinical studies and clinical trials have shown promising results, anti-angiogenic drugs have not led to a significant improvement in overall survival (OS), suggesting the necessity of identifying novel therapeutic strategies. Metformin, an anti-hyperglycemic drug of the Biguanides family, used as first line treatment in Type 2 Diabetes Mellitus (T2DM), has demonstrated in vitro and in vivo antitumoral efficacy in many different tumors, including glioblastoma. From this evidence, a process of repurposing of the drug has begun, leading to the demonstration of inhibition of various oncopromoter mechanisms and, consequently, to the identification of the molecular pathways involved. Here, we review and discuss metformin's potential antitumoral effects on glioblastoma, inspecting if it could properly act as an anti-angiogenic compound to be considered as a safely add-on therapy in the treatment and management of glioblastoma patients.

Personalized and translational approach for malignant brain tumors in the era of precision medicine: the strategic contribution of an experienced neurosurgery laboratory in a modern neurosurgery and neuro-oncology department.

Personalized medicine (PM) aims to optimize patient management, taking into account the individual traits of each patient. The main purpose of PM is to obtain the best response, improving health care and lowering costs. Extending traditional approaches, PM introduces novel patient-specific paradigms from diagnosis to treatment, with greater precision. In neuro-oncology, the concept of PM is well established. Indeed, every neurosurgical intervention for brain tumors has always been highly personalized. In recent years, PM has been introduced in neuro-oncology also to design and prescribe specific therapies for the patient and the patient's tumor. The huge advances in basic and translational research in the fields of genetics, molecular and cellular biology, transcriptomics, proteomics, and metabolomics have led to the introduction of PM into clinical practice. The identification of a patient's individual variation map may allow to design selected therapeutic protocols that ensure successful outcomes and minimize harmful side effects. Thus, clinicians can switch from the "one-size-fits-all" approach to PM, ensuring better patient care and high safety margin. Here, we review emerging trends and the current literature about the development of PM in neuro-oncology, considering the positive impact of innovative advanced researches conducted by a neurosurgical laboratory.

Sphingosine-1-Phosphate in the Tumor Microenvironment: A Signaling Hub Regulating Cancer Hallmarks.

As a key hub of malignant properties, the cancer microenvironment plays a crucial role intimately connected to tumor properties. Accumulating evidence supports that the lysophospholipid sphingosine-1-phosphate acts as a key signal in the cancer extracellular milieu. In this review, we have a particular focus on glioblastoma, representative of a highly aggressive and deleterious neoplasm in humans. First, we highlight recent advances and emerging concepts for how tumor cells and different recruited normal cells contribute to the sphingosine-1-phosphate enrichment in the cancer microenvironment. Then, we describe and discuss how sphingosine-1-phosphate signaling contributes to favor cancer hallmarks including enhancement of proliferation, stemness, invasion, death resistance, angiogenesis, immune evasion and, possibly, aberrant metabolism. We also discuss the potential of how sphingosine-1-phosphate control mechanisms are coordinated across distinct cancer microenvironments. Further progress in understanding the role of S1P signaling in cancer will depend crucially on increasing knowledge of its participation in the tumor microenvironment.

Tumor-Educated Platelets and Angiogenesis in Glioblastoma: Another Brick in the Wall for Novel Prognostic and Targetable Biomarkers, Changing the Vision from a Localized Tumor to a Systemic Pathology.

: Circulating platelets (PLTs) are able to affect glioblastoma (GBM) microenvironment by supplying oncopromoter and pro-angiogenic factors. Among these mediators, sphingosine-1-phophate (S1P) has emerged as a potent bioactive lipid enhancing cell proliferation and survival. Here, we investigated the effect of "tumor education", characterizing PLTs from GBM patients in terms of activation state, protein content, and pro-angiogenic potential. PLTs from healthy donors (HD-PLTs) and GBM patients (GBM-PLTs) were collected, activated, and analyzed by flow cytometry, immunofluorescence, and Western blotting. To assess the pro-angiogenic contribution of GBM-PLTs, a functional cord formation assay was performed on GBM endothelial cells (GECs) with PLT-releasate. GBM-PLTs expressed higher positivity for P-selectin compared to HD-PLTs, both in basal conditions and after stimulation with adenosine triphosphate (ADP) and thrombin receptor activating peptide (TRAP). PLTs showed higher expression of VEGFR-1, VEGFR-2, VWF, S1P, S1PR1, SphK1, and SPNS. Interestingly, increased concentrations of VEGF and its receptors VEGFR1 and VEGFR2, VWF, and S1P were found in GBM-PLT-releasate with respect to HD-PLTs. Finally, GBM-PLT-releasate showed a pro-angiogenic effect on GECs, increasing the vascular network's complexity. Overall, our results demonstrated the contribution of PLTs to GBM angiogenesis and aggressiveness, advancing the potential of an anti-PLT therapy and the usefulness of PLT cargo as predictive and monitoring biomarkers.

Increased VEGF levels in a case of papillary tumor of the pineal region with intracranial hemorrhage: a potential surrogate indicator of tumor angiogenesis and aggressiveness?

Pineal tumors are rare, about 1% of all intracranial tumors. At variance with pineocytomas, usually characterized by a good prognosis, papillary tumors behave more aggressively. Owing to their rarity, little is known about their biology and clinical behavior, moreover conflicting data on prognosis have been reported. Here we present an unusual case of papillary neuroepithelial tumor of the pineal region in a 40-year-old man who was admitted in a state of unconsciousness due to the presence of intracranial hemorrhage. After 21 days from admission, he underwent third ventriculostomy for hydrocephalus and biopsy of the lesion. Since bleeding manifestations are uncommonly associated with this kind of tumors, we performed some additional non routine laboratory tests in order to identify biological indicators of disease course and abnormal angiogenesis. Coagulation screening tests were performed to rule out the presence of coagulopathy and vascular endothelial growth factor (VEGF ) levels were measured in plasma as marker of tumor angiogenic potential. Histologic evaluation confirmed the diagnosis of a papillary tumor of the pineal region with the presence of tiny vessel lumens that may account for increased angiogenesis Coagulation screening was normal and VEGF levels were extremely high if compared to healthy individuals. After 20 months of follow-up the tumor mass, radiotherapy treated, appeared dramatically reduced at MRI evaluation, and, interestingly, VEGF levels, although still higher than in healthy individuals, resulted significantly decreased as compared to those measured at time of first hospital admission suggesting a role for VEGF as indicator of tumor aggressiveness. In conclusion, measurement of angiogenesis circulating soluble markers could have an additional feedback in the diagnosis, therapy and monitoring the disease in patients with very rare CNS tumors as papillary tumors of pineal region that have non univocal clinical behavior and prognosis.

Anterolateral Approach for Retrostyloid Superior Parapharyngeal Space Schwannomas Involving the Jugular Foramen Area: A 20-Year Experience.

BACKGROUND: Schwannomas encompassing the superior parapharyngeal space are challenging lesions because of the anatomical complexity of this region and the frequent involvement of the neurovascular structures of the jugular foramen. The purpose of this study is to report the technical aspects and the advantages of the anterolateral approach, here proposed for schwannomas of this complex area. METHODS: The main steps of the anterolateral approach are described in detail, along with the results of a consecutive series of 38 patients with a retrostyloid superior parapharyngeal schwannoma involving the jugular foramen operated on by means of this route between 1999 and 2019. RESULTS: The supine position is generally preferred. The medial border of the sternocleidomastoid muscle, mastoid tip, and superior nuchal line are the landmarks for the hockey-stick skin incision. The accessory nerve is retrieved and mobilized cranially. Detachment of the sternocleidomastoid, digastric, and nuchal muscles allows for a 180° exposure of the extracranial side of the jugular foramen. Three working corridors, namely the pre-carotid, pre-jugular, and retro-jugular, allow access to the deeper part of the jugular foramen area and the superior parapharyngeal space. In the present series, a gross total resection was achieved in 89.4% of the patients. Three recurrences occurred after an average follow-up of 80.5 ± 51 months. CONCLUSIONS: The anterolateral approach is highly effective in the treatment of retrostyloid superior parapharyngeal space schwannomas involving the jugular foramen. Its simplicity of execution, versatility, and very low morbidity are among its main strengths.

The Genetic Landscape of Human Glioblastoma and Matched Primary Cancer Stem Cells Reveals Intratumour Similarity and Intertumour Heterogeneity.

Glioblastoma (GBM) is the most malignant human brain tumour, characterized by rapid progression, invasion, intense angiogenesis, high genomic instability, and resistance to therapies. Despite countless experimental researches for new therapeutic strategies and promising clinical trials, the prognosis remains extremely poor, with a mean survival of less than 14 months. GBM aggressive behaviour is due to a subpopulation of tumourigenic stem-like cells, GBM stem cells (GSCs), which hierarchically drive onset, proliferation, and tumour recurrence. The morbidity and mortality of this disease strongly encourage exploring genetic characteristics of GSCs. Here, using array-CGH platform, we investigated genetic and genomic aberration profiles of GBM parent tumour (n = 10) and their primarily derived GSCs. Statistical analysis was performed by using R software and complex heatmap and corrplot packages. Pearson correlation and K-means algorithm were exploited to compare genetic alterations and to group similar genetic profiles in matched pairs of GBM and derived GSCs. We identified, in both GBM and matched GSCs, recurrent copy number alterations, as chromosome 7 polysomy, chromosome 10 monosomy, and chromosome 9p21deletions, which are typical features of primary GBM, essential for gliomagenesis. These observations suggest a condition of strong genomic instability both in GBM as GSCs. Our findings showed the robust similarity between GBM mass and GSCs (Pearson corr.≥0.65) but also highlighted a marked variability among different patients. Indeed, the heatmap reporting Gain/Loss State for 21022 coding/noncoding genes demonstrated high interpatient divergence. Furthermore, K-means algorithm identified an impairment of pathways related to the development and progression of cancer, such as angiogenesis, as well as pathways related to the immune system regulation, such as T cell activation. Our data confirmed the preservation of the genomic landscape from tumour tissue to GSCs, supporting the relevance of this cellular model to test in vitro new target therapies for GBM.

Correlation of Preoperative Von Willebrand Factor with Magnetic Resonance Imaging Perfusion and Permeability Parameters as Predictors of Prognosis in Glioblastoma.

BACKGROUND: Angiogenesis has been shown to be strictly related to tumor malignancy. Glioblastoma (GBM) is highly vascularized and von Willebrand Factor (VWF) plays a potent proangiogenic role. Dynamic contrast-enhanced and dynamic susceptibility contrast magnetic resonance imaging (MRI) represent a widely accepted method to assess GBM microvasculature. Our aim was to investigate the correlation between plasma VWF:Ag, permeability, and perfusion MRI parameters and examine their potential in predicting GBM patient prognosis. METHODS: We retrospectively analyzed preoperative dynamic contrast-enhanced, dynamic susceptibility contrast MRI, and VWF:Ag level of 26 patients with GBM. We assessed the maximum values of relative cerebral blood flow and volume, volume transfer constant Ktrans, plasma volume (Vp) and reflux rate constant between fractional volume of the extravascular space and blood plasma (Kep). Nonparametric Mann-Whitney test and Kaplan-Meier survival analyses were conducted and a P value < 0.05 was considered statistically significant. RESULTS: The median VWF:Ag value was 248 IU/dL and the median follow-up duration was about 13 months. We divided patients according to low-VWF:Ag and high-VWF:Ag and we found significant differences in the median follow-up duration (19 months vs. 10 months; P = 0.04) and in Ktrans (0.31/minute vs. 0.53/minute; P = 0.02), and Kep (1.79/minute vs. 3.89/minute; P = 0.005) values. The cumulative 1-year survival was significantly shorter in patients with high-VWF:Ag and high-Kep compared with patients with low-VWF:Ag and low-Kep (37.5% vs. 68%; P = 0.05). CONCLUSIONS: These findings, in a small group of patients, suggest a role for VWF:Ag, similar to Ktrans, and Kep as a prognostic indicator of postoperative survival of patients with GBM.

Significance and Prognostic Value of The Coagulation Profile in Patients with Glioblastoma: Implications for Personalized Therapy.

BACKGROUND: Coagulation is an important aspect of the vascular microenvironment in which brain tumors evolve. Patients with tumor often show aberrant coagulation and fibrinolysis activation. In particular, glioblastoma (GBM), the most aggressive primary brain tumor, is associated with a state of hypercoagulability, and venous thromboembolism is a common complication of this cancer and its treatment. Our study aims to investigate the clinical and prognostic significance of routine laboratory tests to assess the coagulative state of patients with brain tumors, to identify potential new prognostic factors and targets for personalized therapy. METHODS: Blood samples were collected from patients with GBM (n = 58) and patients with meningioma (MNG, n = 22), before any treatment. The parameters analyzed were prothrombin time (PT), activated partial thromboplastin time (aPTT), D dimer (DD), fibrinogen, von Willebrand factor (VWF), leukocyte count, and hemoglobin levels. RESULTS: Plasma levels of PT and aPTT were significantly reduced in GBMs compared with MNGs (P < 0.05), whereas DD, VWF:Ag levels, and leukocyte count were significantly higher in GBMs than in MNGs (P < 0.01). Furthermore, we observed that patients with GBM with reduced PT and aPTT and high levels of DD and VWF, defined as hypercoagulable patients, showed reduced overall survival (P < 0.05) compared with nonhypercoagulable patients. CONCLUSIONS: Our data support the assumption that patients with GBM show a plasma hypercoagulable profile and that coagulation profile is related to adverse outcome in patients with GBM. If confirmed, hypercoagulability could play an important role as a prognostic factor of the disease and in the decision of an antithrombotic prophylaxis.