Staging of Alzheimer disease (AD) severity via global assessment measures is commonplace in clinical and research settings and is useful for many reasons. Clinically, knowledge of dementia severity is helpful for rapid communication about the disease, for making management decisions, and for selection of pharmacologic options that have been approved for different levels of disease severity.^1-3 In research settings, staging of dementia severity is valuable for operationally defining homogeneous patient populations for comparison purposes and end points for research studies monitoring progression.² In addition, staging of dementia severity is critical for clinical trials, as outlined by the US Food and Drug Administration's Guidelines for the Clinical Evaluation of Antidementia Drugs,^4(p15) which states that the

Key Points: Recurrent somatic mutations in MAP2K1 were identified in 33% of LCH lesions with wild-type BRAF. The mutant MAPK kinase 1 proteins activate ERK. The ability of MAPK pathway inhibitors to suppress MAPK kinase and ERK phosphorylation in vitro was dependent on the specific LCH mutation.

Langerhans cell histiocytosis (LCH) is a clonal disorder with elusive etiology, characterized by the accumulation of CD207⁺ dendritic cells (DCs) in inflammatory lesions. Recurrent BRAF-V600E mutations have been reported in LCH. In this study, lesions from 100 patients were genotyped, and 64% carried the BRAF-V600E mutation within infiltrating CD207⁺ DCs. BRAF-V600E expression in tissue DCs did not define specific clinical risk groups but was associated with increased risk of recurrence. Strikingly, we found that patients with active, high-risk LCH also carried BRAF-V600E in circulating CD11c⁺ and CD14⁺ fractions and in bone marrow (BM) CD34⁺ hematopoietic cell progenitors, whereas the mutation was restricted to lesional CD207⁺ DC in low-risk LCH patients. Importantly, BRAF-V600E expression in DCs was sufficient to drive LCH-like disease in mice. Consistent with our findings in humans, expression of BRAF-V600E in BM DC progenitors recapitulated many features of the human high-risk LCH, whereas BRAF-V600E expression in differentiated DCs more closely resembled low-risk LCH. We therefore propose classification of LCH as a myeloid neoplasia and hypothesize that high-risk LCH arises from somatic mutation of a hematopoietic progenitor, whereas low-risk disease arises from somatic mutation of tissue-restricted precursor DCs.

Childhood brain tumors are the most common pediatric solid tumor and include several histologic subtypes. Although progress has been made in improving survival rates for some subtypes, understanding of risk factors for childhood brain tumors remains limited to a few genetic syndromes and ionizing radiation to the head and neck. In this report, we review descriptive and analytical epidemiology childhood brain tumor studies from the past decade and highlight priority areas for future epidemiology investigations and methodological work that is needed to advance our understanding of childhood brain tumor causes. Specifically, we summarize the results of a review of studies published since 2004 that have analyzed incidence and survival in different international regions and that have examined potential genetic, immune system, developmental and birth characteristics, and environmental risk factors. Cancer Epidemiol Biomarkers Prev; 23(12); 2716–36. ©2014 AACR.