Summary Accurate pathological diagnosis is crucial for optimal management of cancer patients. For the ~100 known central nervous system (CNS) tumour entities, standardization of the diagnostic process has been shown to be particularly challenging - with substantial inter-observer variability in the histopathological diagnosis of many tumour types. We herein present the development of a comprehensive approach for DNA methylation-based CNS tumour classification across all entities and age groups, and demonstrate its application in a routine diagnostic setting. We show that availability of this method may have substantial impact on diagnostic precision compared with standard methods, resulting in a change of diagnosis in up to 12% of prospective cases. For broader accessibility we have designed a free online classifier tool (www.molecularneuropathology.org) requiring no additional onsite data processing. Our results provide a blueprint for the generation of machine learning-based tumour classifiers across other cancer entities, with the potential to fundamentally transform tumour pathology.

Clonal composition and T cell receptor (TCR) repertoire of CD4+ and CD8+ T cells infiltrating actively demyelinating multiple sclerosis (MS) lesions were determined with unprecedented resolution at the level of single cells. Individual CD4+ or CD8+ T cells were isolated from frozen sections of lesional tissue by micromanipulation and subjected to single target amplification of TCR-β gene rearrangements. This strategy allows the assignment of a TCR variable region (V region) sequence to the particular T cell from which it was amplified. Sequence analysis revealed that in both cases investigated, the majority of CD8+ T cells belonged to few clones. One of these clones accounted for 35% of CD8+ T cells in case 1. V region sequence comparison revealed signs of selection for common peptide specificities for some of the CD8+ T cells in case 1. In both cases, the CD4+ T cell population was more heterogeneous. Most CD4+ and CD8+ clones were represented in perivascular infiltrates as well as among parenchymal T cells. In case 2, two of the CD8+ clones identified in brain tissue were also detected in peripheral blood. Investigation of the antigenic specificities of expanded clones may help to elucidate their functional properties.

Associazione Italiana del Farmaco, Cancer Research UK, Oncosuisse, and Swiss National Foundation.

The management of primary CNS lymphoma is one of the most controversial topics in neurooncology because of the complexity of the disease and the very few controlled studies available. In 2013, the European Association of Neuro-Oncology created a multidisciplinary task force to establish evidence-based guidelines for immunocompetent adults with primary CNS lymphoma. In this Review, we present these guidelines, which provide consensus considerations and recommendations for diagnosis, assessment, staging, and treatment of primary CNS lymphoma. Specifically, we address aspects of care related to surgery, systemic and intrathecal chemotherapy, intensive chemotherapy with autologous stemcell transplantation, radiotherapy, intraocular manifestations, and management of elderly patients. The guidelines should aid clinicians in their daily practice and decision making, and serve as a basis for future investigations in neuro-oncology. DOI: https://doi.org/10.1016/S1470-2045(15) Posted at the Zurich Open Repository and Archive, University of Zurich ZORA URL: https://doi.org/10.5167/uzh-114449 Accepted Version Originally published at: Hoang-Xuan, K; Bessell, E; Bromberg, J; Hottinger, A F; Preusser, M; Rudà, R; Schlegel, U; Siegal, T; Soussain, C; Abacioglu, U; Cassoux, N; Deckert, M; Dirven, C M; Ferreri, A J; Graus, F; Henriksson, R; Herrlinger, U; Taphoorn, M; Soffietti, R; Weller, M (2015). Diagnosis and treatment of primary CNS lymphoma in immunocompetent patients: guidelines from the European Association for Neuro-Oncology. Lancet Oncology, 16(7):e322-332. DOI: https://doi.org/10.1016/S1470-2045 (15) The management of primary central nervous system (PCNSL) is one of the most controversial topics in neuro-oncology because of the complexity of the disease and the very limited number of controlled studies available. In 2013, the European Association of Neuro-Oncology (EANO) created a multidisciplinary task force to establish evidence-based guidelines for immunocompetent adult patients with PCNSL. The guideline provides consensus considerations and recommendations for diagnosis, staging and treatment of PCNSL, including surgery, systemic and intrathecal chemotherapy, intensive chemotherapy with autologous stem cell transplantation, radiotherapy, intraocular manifestations, and specific management of elderly patients. The guideline should aid the clinicians in everyday practice and decision making and serve as a basis for future research in the field.Dear Editor, Thank you for your suggestions to improve further our paper. Please, find in attached file our revised manuscript which have take into account all your editorial recommendations. You will find below our point by point replies to your editorial comments. We hope that you will find now the manuscript suitable for publication in Lancet Oncology. Kind regardsKhe Hoang-Xuan, MD,PhDResponses to the Editor comments 1) In response to Reviewer 1, comment 2, please revert and move the intraocular lymphoma section back to the appendix as in the original version. RE...

Agenzia Italiana del Farmaco, Cancer Research UK, Oncosuisse, and Swiss National Science Foundation.