Enrico Martin

280 Chapter 12 Surgical margins This thesis further emphasizes the need for macroscopic complete resections as it is the only treatment strategy proven to increase survival. 1,3,21 As seen in Chapter 3 , it was even the most important predictor of survival in localized disease. When tumors are not amenable to complete resection, prognosis is almost similar to metastatic cases. Achieving R1 resections were nevertheless not associated with decreased survival in any of the cohorts studied in this thesis. Similar conclusions have been drawn in other studies as well. 1,3,21 Chapter 5 did indicate that most surgeons are hesitant to perform less extensive resections in order to preserve function and one third never considers preservation of function before resection. As mentioned earlier, the MPNSTs have a high propensity to recur albeit free surgical margins and the use of radiotherapy. Some researchers have argued that due to their perineural origin and possibility of skip lesions an MPNST may stretch along the nerve of origin. 22 In Chapter 5 half of all respondents felt that it may be beneficial to resect more of the nerve of origin whenever possible to decrease the rate of local recurrences. Additionally, obtaining multiple fresh frozen coupes of nerve endings may be indicated as well to ascertain complete resection. 2,3,22 These beliefs are not routine practice and demand further research. Future perspectives It goes without saying that careful planning by a comprehensive dedicated multidisciplinary team is necessary to weigh out all available options for oncological treatment in MPNST. In order to further enhance our understanding of treatment effects on outcomes, large international collaborations like the MONACO study are necessary to facilitate enough patients. Although disease-free survival was not studied in this thesis it should definitely be taken into account for optimal treatment allocation. Studies should be encouraged to establish safety and efficacy of radiotherapy in pediatric and NF1-associated MPNSTs. Similarly, the non-inferiority of less extensive R1 resections should be validated. As recurrence rates are high despite clear margins and the use of radiotherapy, it is of interest to investigate recurrence patterns along the nerve of origin. This could provide a foundation to perform more extensive resections of the originating nerve if it is already to be sacrificed. The use of chemotherapy in localized disease needs further investigation as well and may require a search for MPNST patients at highest risk of metastasis. At the same time a different approach to chemotherapy use between sporadic and NF1-associated MPNST requires further research. Evidently, new systemic therapies are needed and should include multiple targets because of high biologic heterogeneity in MPNST. Most preclinical evidence points towards mTOR and vascularization pathway targets, but other combinations are definitely possible. The use of immunotherapy and oncolytic viruses can be interesting as well, but also requires further investigation of MPNSTs’ immune environment. Enrolling sufficient patients will be the bottleneck for any trial in MPNSTs specifically and therefore requires large multi-institutional collaborations.