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BACKGROUND AND PURPOSE: Vestibular schwannomas are common cerebellopontine angle tumors arising from the vestibulocochlear nerve and can result in cranial nerve dysfunction. Conventional MR imaging does not provide information that could correlate with cranial nerve compression symptoms of hearing loss or imbalance. We used multitensor tractography to evaluate the relationship between the WM microstructural properties of cranial nerves and tumor volume in a cohort of patients with vestibular schwannomas. MATERIALS AND METHODS: A retrospective study was performed in 258 patients with vestibular schwannomas treated at the Gamma Knife clinic at Toronto Western Hospital between 2014 and 2018. 3T MR images were analyzed in 160 surgically naïve patients with unilateral vestibular schwannomas. Multitensor tractography was used to extract DTI-derived metrics (fractional anisotropy and radial, axial, and mean diffusivities of the bilateral facial and vestibulocochlear nerves [cranial nerves VII/VIII]). ROIs were placed in the transition between cisternal and intracanalicular segments, and images were analyzed using the eXtended Streamline Tractography reconstruction method. Diffusion metrics were correlated with 3D tumor volume derived from the Gamma Knife clinic. RESULTS: DTI analyses revealed significantly higher fractional anisotropy values and a reduction in axial diffusivity, radial diffusivity, and mean diffusivity (all P < .001) within the affected cranial nerves VII and VIII compared with unaffected side. All specific diffusivities (axial, radial, and mean diffusivity) demonstrated an inverse correlation with tumor volume (axial, radial, and mean diffusivity, P < .01). CONCLUSIONS: Multitensor tractography allows the quantification of cranial nerve VII and VIII WM microstructural alterations in patients with vestibular schwannomas. Our findings support the hypothesis that tumor volume may cause microstructural alterations of the affected cranial nerves VII and VIII. This type of advanced imaging may represent a possible avenue to correlate diffusivities with cranial nerve function.

Meningiomas are the most common primary intracranial neoplasm. The current World Health Organization (WHO) classification categorizes meningiomas based on histopathological features, but emerging molecular data demonstrate the importance of genomic and epigenomic factors in the clinical behavior of these tumors. Treatment options for symptomatic meningiomas are limited to surgical resection where possible and adjuvant radiation therapy for tumors with concerning histopathological features or recurrent disease. At present, alternative adjuvant treatment options are not available in part due to limited historical biological analysis and clinical trial investigation on meningiomas. With advances in molecular and genomic techniques in the last decade, we have witnessed a surge of interest in understanding the genomic and epigenomic landscape of meningiomas. The field is now at the stage to adopt this molecular knowledge to refine meningioma classification and introduce molecular algorithms that can guide prediction and therapeutics for this tumor type. Animal models that recapitulate meningiomas faithfully are in critical need to test new therapeutics to facilitate rapid-cycle translation to clinical trials. Here we review the most up-to-date knowledge of molecular alterations that provide insight into meningioma behavior and are ready for application to clinical trial investigation, and highlight the landscape of available preclinical models in meningiomas.

Background Few studies have evaluated the health-related quality of life (HRQoL) of patients with meningiomas. Here, we report the largest prospective, longitudinal cross-sectional cohort study of HRQoL in meningiomas to date, in order to identify possible actionable determinants of global HRQoL. Methods Adults who had undergone resection of a grade I intracranial meningioma and were in routine follow-up at a single large tertiary center underwent HRQoL assessment using the QLQ-C30 questionnaire administered opportunistically at follow-up visits. Averaged transformed QLQ-C30 scores at 12-month intervals were compared with scores from a normative reference population, with reference to known minimal clinically meaningful difference (CMD) in scores. To evaluate for possible determinants of changes in global HRQoL, global HRQoL scores were correlated (Spearman's Rho) with subdomain and symptom scores and with interval time from surgical resection. Results A total of 291 postoperative patients with histologically confirmed and surgically treated grade I meningiomas consented to participation and a total of 455 questionnaires were included for analysis. Patients with meningiomas reported reduced global HRQoL at nearly every 12-month interval with clinically and statistically significant impairments at 12, 48, 108, and 120 months postoperative compared with the normative population (P < 0.05). Meningioma patients at the 12-month interval also reported a reduction of each subdomain of HRQoL assessment (P < 0.05); however, a CMD was only seen in cognitive functioning. Physical, emotional, cognitive, and social subdomains, as well as fatigue and sleep/insomnia, were significantly associated with global HRQoL at the first 12-month interval. Overall, there was no significant correlation between time from surgery and global HRQoL or the subdomain functional or symptom sections of the QLQ-C30. Conclusions Meningioma patients report considerable limitations in HRQoL for more than 120 months after surgery, particularly in cognitive, emotional, and social function, as well as suffering significant fatigue and sleep impairment compared with a normative reference population. The majority of these reported functional impairments and symptoms are strongly associated with global HRQoL and thus can be considered determinants of global HRQoL that if treated, have the potential to improve HRQoL for our meningioma patients. This hypothesis requires future study of targeted interventions to determine their efficacy.

Background Variability in standard-of-care classifications precludes accurate predictions of early tumor recurrence for individual patients with meningioma, limiting the appropriate selection of patients who would benefit from adjuvant radiotherapy to delay recurrence. We aimed to develop an individualized prediction model of early recurrence risk combining clinical and molecular factors in meningioma. Methods DNA methylation profiles of clinically annotated tumor samples across multiple institutions were used to develop a methylome model of 5-year recurrence-free survival (RFS). Subsequently, a 5-year meningioma recurrence score was generated using a nomogram that integrated the methylome model with established prognostic clinical factors. Performance of both models was evaluated and compared with standard-of-care models using multiple independent cohorts. Results The methylome-based predictor of 5-year RFS performed favorably compared with a grade-based predictor when tested using the 3 validation cohorts (ΔAUC = 0.10, 95% CI: 0.03–0.018) and was independently associated with RFS after adjusting for histopathologic grade, extent of resection, and burden of copy number alterations (hazard ratio 3.6, 95% CI: 1.8–7.2, P < 0.001). A nomogram combining the methylome predictor with clinical factors demonstrated greater discrimination than a nomogram using clinical factors alone in 2 independent validation cohorts (ΔAUC = 0.25, 95% CI: 0.22–0.27) and resulted in 2 groups with distinct recurrence patterns (hazard ratio 7.7, 95% CI: 5.3–11.1, P < 0.001) with clinical implications. Conclusions The models developed and validated in this study provide important prognostic information not captured by previously established clinical and molecular factors which could be used to individualize decisions regarding postoperative therapeutic interventions, in particular whether to treat patients with adjuvant radiotherapy versus observation alone.

Surgery has long been established as the first-line treatment for the majority of symptomatic and enlarging meningiomas, and evidence for its success is derived from retrospective case series. Despite surgical resection, a subset of meningiomas display aggressive behavior with early recurrences that are difficult to treat. The decision to radically resect meningiomas and involved structures is balanced against the risk for neurological injury in patients. Radiation therapy has largely been used as a complementary and safe therapeutic strategy in meningiomas with evidence primarily stemming from retrospective, single-institution reports. Two of the first cooperative group studies (RTOG 0539 and EORTC 22042) evaluating the outcomes of adjuvant radiation therapy in higher-risk meningiomas have shown promising preliminary results. Historically, systemic therapy has resulted in disappointing results in meningiomas. However, several clinical trials are under way evaluating the efficacy of chemotherapies, such as trabectedin, and novel molecular agents targeting Smoothened, AKT1, and focal adhesion kinase in patients with recurrent meningiomas.

The archetypal imaging characteristics of meningiomas are among the most stereotypic of all central nervous system (CNS) tumors. In the era of plain film and ventriculography, imaging was only performed if a mass was suspected, and their results were more suggestive than definitive. Following more than a century of technological development, we can now rely on imaging to non-invasively diagnose meningioma with great confidence and precisely delineate the locations of these tumors relative to their surrounding structures to inform treatment planning. Asymptomatic meningiomas may be identified and their growth monitored over time; moreover, imaging routinely serves as an essential tool to survey tumor burden at various stages during the course of treatment, thereby providing guidance on their effectiveness or the need for further intervention. Modern radiological techniques are expanding the power of imaging from tumor detection and monitoring to include extraction of biologic information from advanced analysis of radiological parameters. These contemporary approaches have led to promising attempts to predict tumor grade and, in turn, contribute prognostic data. In this supplement article, we review important current and future aspects of imaging in the diagnosis and management of meningioma, including conventional and advanced imaging techniques using CT, MRI, and nuclear medicine.

Introduction The recent advances in regenerative medicine have led to the development of novel experimental therapies, at both the cellular and molecular levels, which aim at reversing the devastating consequences of acute spinal cord injury [1-2]. Several bioactive molecules able to promote regeneration of the injured nervous system show therapeutic potential only when delivered in a controlled and sustained fashion, via appropriate microcarriers. The aim of this work was to evaluate the suitability of poly(lactic-co-glycolic) acid (PLGA)-based microspheres (MS) as a means to deliver therapeutic amounts of either neurotrophic factors (for axonal protection), or inhibitors of bone morphogenetic proteins (for inhibition of the glial scar), following acute spinal cord injury in mice. Several MS formulations were prepared, in order to achieve proper release kinetics of the selected molecule(s), and the effect of the encapsulation technique on the structure and stability of the loaded molecule was assessed. The encapsulation of environmental regulators (ERs) in bioresorbable PLGA-based MS might be a promising approach to promote the regeneration of the injured nervous system. Materials and Methods Microsphere synthesis: PLGA-based MS were synthesized by means of a double emulsion/solvent evaporation technique (water/oil/water), as previously described [3]. The ER (e.g., recombinant mouse chordin) was loaded in the presence of bovine serum albumin (BSA) as stabilizing molecule, and MS were synthesized starting from different PLGA concentrations. Microsphere characterization: The size distribution of MS was evaluated through dynamic laser light scattering, whereas MS morphology was assessed through scanning electron microscopy (SEM). The encapsulation efficiency was evaluated by UV spectrophotometry. Release study: In vitro release of the ER was monitored in PBS at 37°C with gentle shaking, over a period ranging from 72 hours to 30 days, depending on the given MS formulation tested. In order to assess any effects of the presence of BSA on the ER release kinetics, both the total amount of protein (BSA+ER) released at selected time points and the released amount of ER were measured, by UV spectrophotometry (with a BCA-assay protein kit) and ER-specific ELISA assays respectively. Protein/ER stability and bioactivity: The effect of the encapsulation technique on the structure of the loaded molecule(s) was assessed through sodium dodecyl sulphate-polyacrylamide gel electrophoresis (SDS-PAGE) and isoelectrofocalization (IEF), performed at selected time points along the sustained release. Specific bioassays, to assess the biological activity of the released ER, are currently in progress. Results and Discussion The average MS size was found to be significantly affected by the PLGA amount initially dissolved in the organic solvent used to prepare the double emulsion, with lower diameters attained for lower PLGA concentrations. As expected, release kinetics was greatly dependent on the mean MS size. Indeed, for the MS formulations tested, it was possible to modulate the time length of the sustained release of the ER from 3-4 days (for an average MS size of 15 μm, attained for a 10% w/v PLGA concentration) to 35 days (average MS size of 30 μm, attained for a 20% w/v PLGA concentration). The encapsulation efficiency was about 80-90% for all the MS formulations tested. The structural integrity of both BSA and ER was not affected by the encapsulation technique used, as demonstrated by the results of SDS-PAGE and IEF. However, the released fraction of ER as measured by the ELISA assays was found to be significantly lower than the amount expected from the total release study (BSA+ER). Along with in vitro bioactivity assays, specific release studies to understand this discrepancy between the total release of BSA and ER and the release of the only ER are currently being performed. Conclusions ER-loaded PLGA-based MS, possessing different mean diameters, were synthesized by a double emulsion/solvent evaporation technique. This technique yielded MS batches with a small size distribution and a high encapsulation efficiency, and preserved the structural integrity of the loaded molecules. The release kinetics could be tuned by varying the mean MS diameters. Based on these results, PLGA-based MS show potential for the local delivery of ERs to the injured nervous system. However, the suitability of the proposed MS to this purpose will be proved only following in vitro and in vivo bioactivity assays, scheduled in the next future.

3,4-diphenylisoxazolo[3,4-d]pyridazin-7(6H)-one analogs were synthesized and tested for the antiproliferative activity. Study on the cell cycle alteration and on some cellular target (ATM, procaspase-2 proteins and H2AX histone) demonstrate the increase of the cell population in S phase and to induce cellular death by apoptosis by DNA damage with double strand breaks.

The immune mediators in echinoderms can be a potential source of novel antimicrobial peptides (AMPs) applied toward controlling pathogenic staphylococcal biofilms that are intrinsically resistant to conventional antibiotics. The peptide fraction5 kDa from the cytosol of coelomocytes of the sea urchin Paracentrotus lividus (5-CC) was tested against a group of Gram-positive and Gram-negative pathogen reference strains. The 5-CC of P. lividus was active against all planktonic-tested strains but also showed antibiofilm properties against staphylococcal strains. Additionally, we demonstrated the presence of three small peptides in the 5-CC belonging to segment 9-41 of a P. lividusβ-thymosin. The smallest of these peptides in particular, showed the common chemical-physical characteristics of AMPs. This novel AMP from β-thymosin has high potential activity as an antibiofilm agent, acting on slow-growing bacterial cells that exhibit a reduced susceptibility to conventional antibiotics and represent a reservoir for recurrent biofilm-associated infections.

Background: This study evaluated the antitumor efficacy and safety of a novel oxaliplatin/raltitrexed combination in pretreated advanced colorectal cancer patients. Patients and Methods: Forty-five patients with 5-fluorouracil-refractory metastatic colorectal cancer received raltitrexed 3.0 mg/m2 as a 15-minute intravenous (i.v.) infusion, followed 45 min later by l-OHP 130mg/m2 iv as 2-h venous infusion on 1 day every 3 weeks. All patients had histologically proven metastatic colorectal cancer, age 18-75, measurable disease and normal baseline biological values. Most patients (60%) had >2 disease sites. All patients were assessed for safety and also for response according to an intent-to-treat fashion. Results: The overall response rate was 29% (95% CL 16%-44%) including one CR (2%) and 12 PR (27%). Six patients (16%) showed a stabilization of disease for a tumor growth control rate of 45%. The median time to progression was 4 months (range 1-12+) and median overall survival was 9 months (range 1-29+). Conclusion: These data confirm that this oxaliplatin/raltitrexed combination is effective against metastatic colorectal carcinoma, well tolerated with low grade toxicity and easy to administrer. Further evaluation of this regimen seems warranted as an alternative to fluoropyrimidine-based combinations.