Desmoid-type fibromatosis is a rare and locally aggressive monoclonal, fibroblastic proliferation characterized by a variable and often unpredictable clinical course. Currently, there is no established or evidence-based treatment approach available for this disease. Therefore, in 2015 the European Desmoid Working Group published a position paper giving recommendations on the treatment of this intriguing disease. Here, we present an update of this consensus approach based on professionals’ AND patients’ expertise following a round table meeting bringing together sarcoma experts from the European Organization for Research and Treatment of Cancer/Soft Tissue and Bone Sarcoma Group with patients and patient advocates from Sarcoma PAtients EuroNet. In this paper, we focus on new findings regarding the prognostic value of mutational analysis in desmoid-type fibromatosis patients and new systemic treatment options.

Desmoid tumor (DT; other synonymously used terms: Desmoid-type fibromatosis, aggressive fibromatosis) is a rare and locally aggressive monoclonal, fibroblastic proliferation characterised by a variable and often unpredictable clinical course. Previously surgery was the standard primary treatment modality; however, in recent years a paradigm shift towards a more conservative management has been introduced and an effort to harmonise the strategy amongst clinicians has been made. We present herein an evidence-based, joint global consensus guideline approach to the management of this disease focussing on: molecular genetics, indications for an active treatment, and available systemic therapeutic options. This paper follows a one-day consensus meeting held in Milan, Italy, in June 2018 under the auspices of the European Reference Network for rare solid adult cancers, EURACAN, the European Organisation for Research and Treatment of Cancer (EORTC) Soft Tissue and Bone Sarcoma Group (STBSG) as well as Sarcoma Patients Euro-Net (SPAEN) and The Desmoid tumour Research Foundation (DTRF). The meeting brought

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Tumor necrosis factor-stimulated gene-6 (TSG-6) is a hyaluronan (HA)-binding protein that plays important roles in inflammation and ovulation. TSG-6-mediated cross-linking of HA has been proposed as a functional mechanism (e.g. for regulating leukocyte adhesion), but direct evidence for cross-linking is lacking, and we know very little about its impact on HA ultrastructure. Here we used films of polymeric and oligomeric HA chains, end-grafted to a solid support, and a combination of surface-sensitive biophysical techniques to quantify the binding of TSG-6 into HA films and to correlate binding to morphological changes. We find that full-length TSG-6 binds with pronounced positive cooperativity and demonstrate that it can cross-link HA at physiologically relevant concentrations. Our data indicate that cooperative binding of full-length TSG-6 arises from HA-induced protein oligomerization and that the TSG-6 oligomers act as cross-linkers. In contrast, the HA-binding domain of TSG-6 (the Link module) alone binds without positive cooperativity and weaker than the full-length protein.Both the Link module and full-length TSG-6 condensed and rigidified HA films, and the degree of condensation scaled with the affinity between the TSG-6 constructs and HA. We propose that condensation is the result of protein-mediated HA crosslinking. Our findings firmly establish that TSG-6 is a potent HA cross-linking agent and might hence have important implications for the mechanistic understanding of the biological function of TSG-6 (e.g. in inflammation). Hyaluronan (HA)3 is a structurally simple and linear polysaccharide. It is ubiquitous in the extracellular matrix of vertebrates and plays important roles in numerous physiological and pathological processes, such as inflammation, fertilization, embryogenesis, tumor development, osteoarthritis, and atherosclerosis (1, 2). HA is considered a "pericellular cue" (3) (i.e. it serves as a versatile scaffold within which other molecules are organized and regulated). A number of proteins, called hyaladherins (4), can bind to the flexible HA chains and engender self-assembly into large and hydrated multimolecular complexes (5-7).The secreted product of tumor necrosis factor-stimulated gene-6 (TSG-6) (8, 9) is of particular importance for the formation and remodeling of HA-rich pericellular coats (10, 11) and extracellular matrices (12). There is little or no constitutive expression of TSG-6 in most adult tissues (with the exception of bone marrow (13) and epidermis (14)). Expression is elevated in response to stimulation with proinflammatory mediators or certain growth factors (8, 9, 15-18), and TSG-6 is detected in the context of many inflammatory diseases (19,20) and in inflammation-like processes, such as ovulation (21,22). TSG-6 is composed mainly of two contiguous domains, a Link module and a CUB module (8,17,23,24). The Link module is conserved among members of the hyaladherin family (4) and is essential for binding to HA (23). Administration of recombinant human TSG-6 Link module (L...