Soft tissue sarcomas (STS) are rare, aggressive malignancies derived from connective tissues such as muscle and fat. Undifferentiated pleomorphic sarcoma (UPS) is one of the most common STS in adults. UPS is an aggressive, highly metastatic sarcoma, and is resistant to chemotherapy. New therapies for UPS are desperately needed. STS have an immune desert tumour immune microenvironment (TIME), characterized by a paucity of tumour infiltrating lymphocytes and subsequent resistance to immunotherapies such as immune checkpoint inhibitors. Strategies capable of creating an immune-rich, inflamed TIME may improve immunotherapy efficacies for sarcoma. Activation of the STING (stimulator of interferon genes) receptor can induce potent innate and adaptive immune responses within immunogenic solid tumours. However, this approach has never been attempted in immune-inert sarcomas. Purpose: To determine the therapeutic anti-tumour effects of STING activation in UPS tumours. We have developed an inducible, immune-competent mouse model of UPS. We evaluated intra-tumoural injection of the murine STING receptor agonist, DMXAA, into UPS-bearing immune-competent mice. DMXAA was injected into palpable UPS tumours of the hindlimb. Tumour volume and bioluminescence imaging was recorded bi-weekly. DMXAA treated UPS tumours were also evaluated for necrosis and immune infiltration at defined time points. UPS tumours developed necrosis and lymphocytic infiltration 72 hours after DMXAA treatment. A single intra-tumoural dose of DMXAA into UPS tumours resulted in durable cure in 50% of mice. All survivors rejected a re-challenge of the UPS tumours in both the contralateral hindlimb and lung, suggesting adaptive immunity. The therapeutic effects of DMXAA were mitigated in lymphocyte deficient Rag2 knockout mice. STING therapy is a promising immunotherapeutic opportunity for immune-inert sarcomas. Our data warrants further preclinical investigations in other sarcoma models and in combination with other immune-based therapies

The histopathology of periprosthetic tissues has been important to understanding the relationship between wear debris and arthroplasty outcome. In a landmark 1977paper, Willert and Semlitsch (1) used a semiquantitative rating to show that tissue reactions largely reflected the extent of particulate debris. Notably, small amounts of debris, including metal, could be eliminated without “overstraining the tissues” but excess debris led to deleterious changes. Currently, a plethora of terms is used to describe tissues from metal-on-metal (M-M) hips and corroded modular connections. We reviewed the evaluation and reporting of local tissue reactions over time, and asked if a dose response has been found between metal and tissue features, and how the use of more standardized terms and quantitative methodologies could reduce the current confusion in terminology. Methods. The PubMed database was searchedbetween 2000 and 2015 for papers using “metal sensitivity /allergy /hypersensitivity, Adverse Local Tissue Reaction (ALTR): osteolysis, metallosis, lymphocytic infiltration, Aseptic Lymphocytic Vasculitis-Associated Lesions (ALVAL), Adverse Reaction to Metal Debris (ARMD) or pseudotumor/ pseudotumour” as well as metal-on-metal / metal-metal AND hip arthroplasty/replacement. Reports lacking soft tissue histological analysis were excluded. Results. 131 articles describing M-M tissue histology were found. In earlier studies, the terms metal sensitivity / hypersensitivity /allergy implied or stated the potential for a Type IV delayed type hypersensitivity response as a reason for revision. More recently those terms have largely been replaced by broader terms such as ALTR, ALVAL and ARMD. ALVAL and metal hypersensitivity were often used interchangeably, both as failure modes and histological findings. Several histology scoring systems have been published but were only used in a limited number of studies. Correlations of histological features with metal levels or component wear were inconclusive, typically because of a high degree of variability. Interestingly, there were very few descriptions that concluded that the observed reactions were benign / normal or anticipated i.e. regardless of the histological features, extent of debris or failure mode, the histology was interpreted as showing an adverse reaction. Discussion. There is now an expanded set of terms to describe tissues but they lack clear definitions and typically do not use quantitative histological data to describe a wide range of periprosthetic reactions to metal. Lower limits of inflammation, necrosis or re-organization that represent a “normal” reaction to surgery and/or small amounts of wear debris are not clearly defined and are rarely discussed. The widespread adoption of the term “adverse” in the present tissue lexicon implies a cause and effect relationship between metal wear and corrosion products and histological features even though this has yet to be determined. The use of quantitative histological scores rather than subjective histological descriptions is imperative to improve the understanding and reporting of the range of periprosthetic reactions. In particular, a new lexicon that allows for a level of tissue reaction that is not misinterpreted as adverse is required