The 2016 World Health Organization Classification of Tumors of the Central Nervous System is both a conceptual and practical advance over its 2007 predecessor. For the first time, the WHO classification of CNS tumors uses molecular parameters in addition to histology to define many tumor entities, thus formulating a concept for how CNS tumor diagnoses should be structured in the molecular era. As such, the 2016 CNS WHO presents major restructuring of the diffuse gliomas, medulloblastomas and other embryonal tumors, and incorporates new entities that are defined by both histology and molecular features, including glioblastoma, IDH-wildtype and glioblastoma, IDH-mutant; diffuse midline glioma, H3 K27M-mutant; RELA fusion-positive ependymoma; medulloblastoma, WNT-activated and medulloblastoma, SHH-activated; and embryonal tumour with multilayered rosettes, C19MC-altered. The 2016 edition has added newly recognized neoplasms, and has deleted some entities, variants and patterns that no longer have diagnostic and/or biological relevance. Other notable changes include the addition of brain invasion as a criterion for atypical meningioma and the introduction of a soft tissue-type grading system for the now combined entity of solitary fibrous tumor / hemangiopericytoma-a departure from the manner by which other CNS tumors are graded. Overall, it is hoped that the 2016 CNS WHO will facilitate clinical, experimental and epidemiological studies that will lead to improvements in the lives of patients with brain tumors.

The fourth edition of the World Health Organization (WHO) classiWcation of tumours of the central nervous system, published in 2007, lists several new entities, including angiocentric glioma, papillary glioneuronal tumour, rosette-forming glioneuronal tumour of the fourth ventricle, papillary tumour of the pineal region, pituicytoma and spindle cell oncocytoma of the adenohypophysis. Histological variants were added if there was evidence of a diVerent age distribution, location, genetic proWle or clinical behaviour; these included pilomyxoid astrocytoma, anaplastic medulloblastoma and medulloblastoma with extensive nodularity. The WHO grading scheme and the sections on genetic proWles were updated and the rhabdoid tumour predisposition syndrome was added to the list of familial tumour syndromes typically involving the nervous system. As in the previous, 2000 edition of the WHO 'Blue Book', the classiWcation is accompanied by a concise commentary on clinico-pathological characteristics of each tumour type. The 2007 WHO classiWcation is based on the consensus of an international Working Group of 25 pathologists and geneticists, as well as contributions from more than 70 international experts overall, and is presented as the standard for the deWnition of brain tumours to the clinical oncology and cancer research communities world-wide. Introduction and historical annotation

The new england journal of medicine 1260 n engl j med 351;12 www.nejm.org september 16, 2004 by Schnyder et al. did not include subjects with homocysteine levels higher than 13.5 µmol per liter. Studies are needed that will test the efficacy of homocysteine-lowering vitamin regimens containing betaine instead of folate. EGFR Mutations and Sensitivity to Gefitinibto the editor: The important study by Dr. Lynch and colleagues (May 20 issue) 1 suggests that specific mutations in the epidermal growth factor receptor (EGFR) characterize a subgroup of non-smallcell lung cancers that may be highly responsive to gefitinib therapy. Do these mutations predict a greater sensitivity to chemotherapy as well? The overall objective response rate to first-line combination chemotherapy for metastatic non-small-cell lung cancer is about 20 percent. 2 Only tumors from a small cohort of patients who had a response to gefitinib were studied for the specific mutations, but all patients except one had also received prior chemotherapy. Although the authors describe Patient 6 as "representative" of the cohort, the percentage of other patients who previously had a response to chemotherapy is not reported. If the rate of response to first-line chemotherapy was high for the other patients in the cohort who had a response to gefitinib, the specific mutations may be predictive of either chemotherapy or gefitinib sensitivity, thus identifying a distinct subgroup of patients with non-smallcell lung cancer. to the editor: Lynch et al. and Paez et al. 1 report that mutations in the EGFR kinase domain in lung cancers are associated with responsiveness to gefitinib. We performed a mutational analysis of the EGFR kinase region on tumor tissue from nine patients with an event-free survival of more than 24 weeks in our phase 2 trial of gefitinib in patients with glioblastoma. 2 No mutations affecting the amino acid sequence in the kinase region were detected. However, our experience with EGFR immunolocalization in brain and lung tumors indicates that the cytoplasmic and membranous localization of wild-type EGFR and the constitutively active mutant EGFRvIII in brain tumors as compared with only membranous localization in lung tumors supports additional differences in the biology of EGFR between these tumor systems (McLendon R: personal communication). In summary, EGFR in glioblastoma did not have mutations in the kinase region, and any activity of gefitinib in glioblastoma would occur through an alternative mechanism reflective of important pathophysiological differences between glioblastomas and lung carcinomas.