Browsing by Author "Monument, Michael J."

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    Does surgical technique influence the burden of lung metastases in patients with pathologic long bone fractures?
    (2022-01-31) Kendal, Joseph K.; Heard, Bryan J.; Abbott, Annalise G.; Moorman, Scott W.; Saini, Raghav; Puloski, Shannon K. T.; Monument, Michael J.
    Abstract Background The aims of this study are to (1) determine whether fixation of metastatic long bone fractures with an intramedullary nail (IMN) influences the incidence of lung metastasis in comparison to arthroplasty or ORIF (Arthro/ORIF); and (2) assess this relationship in primary tumor types; and (3) to assess survival implications of lung metastasis after surgery. Methods Retrospective cohort study investigating 184 patients (107 IMN, and 77 Arthro/ORIF) surgically treated for metastatic long bone fractures. Patients were required to have a single surgically treated impending or established pathologic fracture of a long bone, pre-operative lung imaging (lung radiograph or computed tomography) and post-operative lung imaging within 6 months of surgery. Primary cancer types included were breast (n = 70), lung (n = 43), prostate (n = 34), renal cell (n = 37). Statistical analyses were conducted using two-tailed Fisher’s exact tests, and Kaplan-Meier survival analyses. Results Patients treated with IMN and Arthro/ORIF developed new or progressive lung metastases following surgery at an incidence of 34 and 26%, respectively. Surgical method did not significantly influence lung metastasis (p = 0.33). Furthermore, an analysis of primary cancer subgroups did not yield any differences between IMN vs Arthro/ORIF. Median survival for the entire cohort was 11 months and 1-year overall survival was 42.7% (95% CI: 35.4–49.8). Regardless of fixation method, the presence of new or progressive lung metastatic disease at follow up imaging study was found to have a negative impact on patient survival (p < 0.001). Conclusions In this study, development or progression of metastatic lung disease was not affected by long bone stabilization strategy. IM manipulation of metastatic long bone fractures therefore may not result in a clinically relevant increase in metastatic lung burden. The results of this study also suggest that lung metastasis within 6 months of surgery for metastatic long bone lesions is negatively associated with patient survival. Level of evidence III, therapeutic study
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    STING Activation as an Immunotherapeutic Strategy for Soft Tissue Sarcoma
    (2020-06-02) Marritt, Kayla Lynn; Monument, Michael J.; Jirik, Frank Robert; Krawetz, Roman J.; Yipp, Bryan G.
    Immunotherapy is an emerging field of cancer treatment that is transforming the management of numerous human cancers. However, there remains a substantial proportion of cancer subtypes that are unresponsive to many modern immunotherapy strategies. Soft tissue sarcomas (STS) are aggressive, connective-tissue derived solid cancers and are notoriously resistant to systemic therapies including immunotherapy. Immunologically, sarcomas are frequently characterized by a paucity of lymphocytic infiltrates, an immune suppressive microenvironment, and resistance to immunotherapies such as immune checkpoint inhibition and oncolytic viruses. Activation of the STING (stimulator of interferon genes) pathway can induce potent innate and adaptive anti-tumour immune responses within immunogenic solid tumours. However, this approach has never been tried in immune-inert sarcomas. Herein, STING activation in STS was analyzed to determine if STING activation could induce therapeutic anti-tumour effects and promote anti-tumour immunity. The long-term therapeutic responses of STING activation via 5,6-dimethylxanthenone-4-acetic acid (DMXAA) injection were assessed using a syngeneic murine model of undifferentiated pleomorphic sarcoma (UPS). Intratumoural DMXAA resulted in a durable cure in 50-60% of UPS-bearing mice. Flow cytometry was used to quantify immune infiltration after STING activation treatment and a higher proportion of CD8+/CD3+ cells was observed seven days post DMXAA treatment compared to the vehicle control treatment. Surviving mice all rejected UPS re-challenge in both the extremity and lung, and the therapeutic effects of DMXAA were mitigated by lymphocyte deficiency suggesting adaptive immunologic pathways are integral to the therapeutic response. This data suggests modulation of the STING pathway can elicit local and systemic anti-tumour immune responses in UPS and deserves further consideration as a novel local and systemic treatment for sarcomas.