Enrico Martin

17 Introduction and thesis outline Aim and outline of this thesis Because of the rare nature and heterogeneous presentation of MPNST many questions remain unanswered. This thesis set out to investigate various knowledge gaps regarding oncological treatment and outcome of MPNST ( Part I ) as well as to explore the field of functional outcomes and reconstructions in these patients ( Part II ). In Part I this thesis will study several questions regarding treatment variation in MPNSTs, risk factors associated with survival, diagnostic accuracy of current imaging techniques, and future possibilities for non-cytotoxic treatment. In Chapter 2 we will investigate the treatment variation and association with survival per tumor site, including rare tumor sites as intracranial and spinal tumors. To obtain enough cases we will use the Surveillance, Epidemiology, and End Result database. As no study has yet been able to investigate a truly nationwide cohort of patients, thus minimizing selection and referral bias, in Chapter 3 and 4 we will investigate overall treatment of MPNST in the Netherlands. We will use the Dutch cancer registry and national pathology database to identify all patients from 1989 onwards. As children and adult patients are generally treated differently, Chapter 3 will focus on adult patients and Chapter 4 on pediatric patients. In Chapter 3 we will further explore differences in treatment and survival between retroperitoneal and non-retroperitoneal MPNST. In Chapter 4 we will investigate differences in treatment and survival between NF1 and non-NF1 associated MPNSTs in children. Also, in Chapter 2-4 we will investigate the association of clinicopathologic and treatment-related factors with survival. As treatment of MPNSTs may vary and different surgical subspecialties treat these patients, we will explore what drives differences in oncological treatment considerations in Chapter 5 by means of an international survey. In Chapter 6 we will investigate diagnostic accuracy of currently available non-invasive tests to detect MPNSTs. Current literature will systematically be reviewed and using Bayesian bivariate meta-analyses the accuracy of several MRI and PET characteristics will be studied. Additionally, the use of liquid biopsies will be assessed. As MPNSTs respond poorly to current cytotoxic systemic treatment regimens, in Chapter 7 we will investigate current literature on possibilities for targeted- and immunotherapies. Literature will systematically be reviewed to assess all in vivo evidence as well as published and ongoing human trials investigating such therapies. In Part II this thesis will investigate functional outcomes andmorbidity after the resection of MPNST as well as exploring the option for the use of functional reconstructions to possibly diminish morbidity. In Chapter 8 and 9 we will systematically review literature to investigate the use and outcomes of functional reconstructions in extremity STS. The effect of radiotherapy and chemotherapy on success rates of reconstructions will be assessed as well. In Chapter 8 all case series describing the reconstruction of tendons, muscles, and nerves will be reviewed. In Chapter 9 all cases, including case reports, of nerve reconstructions specifically will be reviewed in depth. As morbidity is 1