Cancer Predisposition Syndromes in Neuro-oncology.

Although most primary central and peripheral nervous system (NS) tumors occur sporadically, there are a subset that may arise in the context of a cancer predisposition syndrome. These syndromes occur due to a pathogenic mutation in a gene that normally functions as a tumor suppressor. With increased understanding of the molecular pathogenesis of these tumors, more people have been identified with a cancer predisposition syndrome. Identification is crucial, as this informs surveillance, diagnosis, and treatment options. Moreover, relatives can also be identified through genetic testing. Although there are many cancer predisposition syndromes that increase the risk of NS tumors, in this review, we focus on three of the most common cancer predisposition syndromes, neurofibromatosis type 1, neurofibromatosis type 2, and tuberous sclerosis complex type 1 and type 2, emphasizing the clinical manifestations, surveillance guidelines, and treatment options.

Past, Present, and Future Therapeutic Strategies for NF-1-Associated Tumors.

PURPOSE OF REVIEW: Neurofibromatosis type 1 (NF-1) is a cancer predisposition syndrome caused by mutations in the NF1 tumor suppressor gene that encodes the neurofibromin protein, which functions as a negative regulator of Ras signaling. We review the past, current, and future state of therapeutic strategies for tumors associated with NF-1. RECENT FINDINGS: Therapeutic efforts for NF-1-associated tumors have centered around inhibiting Ras output, leading to the clinical success of downstream MEK inhibition for plexiform neurofibromas and low-grade gliomas. However, MEK inhibition and similar molecular monotherapy approaches that block Ras signaling do not work for all patients and show limited efficacy for more aggressive cancers such as malignant peripheral nerve sheath tumors and high-grade gliomas, motivating novel treatment approaches. We highlight the current therapeutic landscape for NF-1-associated tumors, broadly categorizing treatment into past strategies for serial Ras pathway blockade, current approaches targeting parallel oncogenic and tumor suppressor pathways, and future avenues of investigation leveraging biologic and technical innovations in immunotherapy, pharmacology, and gene delivery.

An unusual presentation of bilateral optic pathway glioma in Crouzon Syndrome.

Crouzon Syndrome is a genetic craniosynostosis disorder associated with a high risk of ophthalmologic sequelae secondary to structural causes. However, ophthalmologic disorders due to intrinsic nerve aberrations in Crouzon Syndrome have not been described. Optic pathway gliomas (OPGs) are low grade gliomas that are intrinsic to the visual pathway, frequently associated with Neurofibromatosis type 1 (NF-1). OPGs involving both optic nerves without affecting the optic chiasm are rarely seen outside of NF-1. We report an unusual case of bilateral optic nerve glioma without chiasmatic involvement in a 17-month-old male patient with Crouzon Syndrome without any clinical or genetic findings of NF-1. This case suggests that close ophthalmologic follow up and orbital MRIs may benefit patients with Crouzon Syndrome.

Pediatric Gliomas: Molecular Landscape and Emerging Targets.

Next-generation sequencing of pediatric gliomas has revealed the importance of molecular genetic characterization in understanding the biology underlying these tumors and a breadth of potential therapeutic targets. Promising targeted therapies include mTOR inhibitors for subependymal giant cell astrocytomas in tuberous sclerosis, BRAF and MEK inhibitors mainly for low-grade gliomas, and MEK inhibitors for NF1-deficient BRAF:KIAA fusion tumors. Challenges in developing targeted molecular therapies include significant intratumoral and intertumoral heterogeneity, highly varied mechanisms of treatment resistance and immune escape, adequacy of tumor penetrance, and sensitivity of brain to treatment-related toxicities.

Lessons and Challenges from a 6-Month Randomized Pilot Study of Daily Ethanol Consumption: Research Methodology and Study Design.

Background: Observational studies and crossover feeding studies suggest that moderate alcohol use may benefit cardiovascular risk, but we know of no long-term randomized trials that have tested this hypothesis. Objective: We evaluated the feasibility of an efficacy study of daily ethanol use in a 6-mo randomized pilot study in adults at higher cardiovascular risk. Methods: In a double-blind, randomized, controlled parallel-design trial, we screened 67 adults aged ≥55 y and randomly assigned 45 participants to consume 150 mL of an artificially sweetened beverage with or without 10% grain alcohol daily for 6 mo. Participants were asked to consume no other alcohol and returned monthly to receive the beverage and undergo measurement of HDL cholesterol, liver function tests, and complete blood counts. Results: Of the 45 randomly assigned participants, 39 completed the trial; the primary reason cited for attrition was inconvenience. None of the participants reported problem drinking or developed any serious adverse events or abnormal biochemical findings. However, we observed no differences in concentrations of HDL cholesterol, HDL lipoprotein subclasses, aspartate aminotransferase, alanine aminotransferase, γ-glutamyltransferase, mean corpuscular volume, or adiponectin between the alcohol and control arms, suggesting that adherence was poor. Every participant accurately identified their assigned beverage, most with great certainty. Conclusions: In this parallel-design pilot study of daily alcohol use, we observed none of the expected changes in markers of alcohol intake, which suggests poor adherence to this pure alcohol intervention. Our results suggest that long-term trials of alcohol consumption, if they are conducted in light drinkers similar to these, must use pragmatic designs for maximal feasibility. This study was registered at clinicaltrials.gov as NCT01377727.

Circulating irisin, omentin-1, and lipoprotein subparticles in adults at higher cardiovascular risk.

OBJECTIVE: Muscle and fat are now recognized as metabolism-regulating endocrine organs. However, muscle and adipocyte-derived novel cytokines such as irisin and omentin-1 remain understudied in relation to metabolic biomarkers that are associated with cardiovascular risk. SUBJECTS AND METHODS: Thirty-nine subjects with mean (± SD) BMI of 29.2 ± 5.4 kg/m(2) and either diabetes or two other cardiovascular risk factors were enrolled in a 6-month randomized trial of low-dose ethanol. We examined cross-sectional data at baseline, 3-month, and 6-month visits to assess (1) within-person stability of novel cytokines (irisin, omentin-1, visfatin, resistin, and soluble tumor necrosis factor receptor II) and (2) their associations with metabolic parameters, particularly lipoprotein subparticle profile. RESULTS: Repeated measures of irisin and omentin-1 were highly correlated, with intra-class correlations of 0.84 (95% CI: 0.74, 0.91; P < 0.001) and 0.81 (0.70, 0.89; P < 0.001), respectively. Irisin was negatively correlated with omentin-1 (7.4% irisin decrease per a 1-SD increment in omentin-1; 95% CI: 0.5%, 13.9%; P = 0.04). In models adjusted for age, sex, and race, irisin was negatively associated with HDL cholesterol (7.3% decrease per a 10mg/dL increment; 1.0%, 13.3%; P = 0.02) and large HDL particles (15.5% decrease per a 1-SD or 3.5-µmol/L increment; 5.2%, 24.7%; P=0.005). Omentin-1 was positively associated with mean VLDL size (3.8% increase per a 1-SD increment; 0.06%, 7.8%; P = 0.05). Adjustment for alcohol intervention, BMI, and other cytokines did not materially affect these associations. CONCLUSIONS: Irisin and omentin-1 are stable within-person, inversely associated with each other, and closely related to lipoprotein profile. These molecules may be promising markers for cardiovascular risk.