Enrico Martin

161 Emerging therapeutic targets target tumors and have limited systemic side-effects. As insights in the differences between STS subtypes are growing, more specific testing to allow for identification and subsequent personalization of treatment is necessary; however, given that MPNST represent a rare sarcoma subtype, such personalization has thus far been challenging. To better understand emerging treatment options, we pooled the available literature and performed a systematic review of non-cytotoxic systemic therapies in MPNST, aiming to guide future research efforts by identifying the most relevant targets and combinations. Methods Literature search A systematic search was performed in both PubMed and Embase databases according to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines, in order to identify all potentially relevant articles published from 2000- 2018. The search string was built with the help of a professional librarian using search terms related to ‘MPNST’ and non-cytotoxic treatments. The exact search syntaxes for PubMed and Embase are provided in Supplemental Table S1. Preclinical studies were included if they studied non-cytotoxic drugs on MPNSTs in vivo . Clinical studies were included if they presented results of non-cytotoxic systemic therapy specifically in MPNST patients. Articles were excluded if they were retrospective or single case studies, reviews, presented non-specific MPNST data, included data on cytotoxic drugs or drugs that were only tested in vitro , or did not provide data on tumor growth, survival, or metastases. Clinicaltrials.gov was also searched with synonyms of ‘MPNST’ to obtain all ongoing non-cytotoxic drug trials enrolling MPNST patients. Cross-referencing of included papers and registered trials was performed, which identified six additional papers. These studies did not include a synonym of MPNST in either their title or abstract. The initial review was carried out by two independent authors (EM, NL). Disagreements were solved through discussion, in which one additional senior author was involved (ID). Data extraction and synthesis Data extracted from preclinical studies included: animal model used, most effective treatment regimen studied, tissues investigated, and treatment effect on tumor growth, survival, and metastasis. The treatment effect on tumor growth was evaluated according to the mean relative tumor volume (RTV) comparing the latest mean volume measurement of the control group (C) to the mean volume of the treatment group (T) at that time point: 23,24 T/C ≤15% represented high effect (black); T/C ≤45% but >15% represented intermediate effect (dark gray); and T/C >45% represented low effect (light gray, Table 1 ). Tumor growth was either assessed by tumor volume, weight, or area. Drugs were categorized as membrane targets, cytoplasmic targets, nuclear targets, 7