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Objective: To report the median survival time in a contemporary cohort of dogs with primary lung tumors and intrathoracic nodal metastasis. Design: Retrospective Case Series. Animals (or sample): Dogs with primary lung tumors treated with lung lobectomy and lymph node biopsy. Procedures: The medical record database at Colorado State University was queried for dogs with primary lung tumors from January 1, 2005 to December 31, 2017. Patients were identified for inclusion if they had lung lobectomy and an intrathoracic lymph node biopsy performed. The median survival time (MST) for lymph node positive (LN+) and negative dogs (LN-) was calculated as well as the MST in dogs that did or did not receive adjuvant chemotherapy. Differences were compared between groups with significance set at p < 0.05. Results: The MST in LN+ dogs (n = 11) was 167 days which was not statistically different from LN- dogs (n = 29) at 456 days (p = 0.2407). No significant difference in the MST in LN+ dogs was identified between dogs that received adjuvant chemotherapy (n = 4; 110 days) and those that did not receive adjuvant chemotherapy (n = 6; 125 days) (p = 0.4409). There was no difference in survival time in LN- dogs receiving chemotherapy (n = 12; 335 days) as compared to those LN- dogs (n = 10) that did not receive adjuvant chemotherapy (258.5 days; p = 0.6475). Conclusions and Clinical Relevance: The survival of primary pulmonary neoplasia in dogs with intrathoracic nodal metastasis is longer than previously reported in this contemporary cohort. Chemotherapy did not appear to improve survival in LN+ or LN- dogs. The combination of tumor size between 100 and 999 cm3 and positive lymph node status significantly reduced survival.
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BACKGROUND: Mesenchymal stromal cells (MSCs) have been shown in rodent models to promote primary and pulmonary metastatic sarcoma growth when injected in the presence of gross tumor. In theory, this would limit their use in a clinical setting after limb salvage treatment for osteosarcoma. Although concerning, these models do not translate to the clinical setting wherein MSCs could be used after primary tumor resection to aid in bone healing and incorporation of tumor endoprostheses. If we can determine whether the use of MSCs in this setting is safe, it might improve our ability to augment bone healing in patients undergoing limb salvage. QUESTIONS/PURPOSES: The purpose of this study was to determine (1) whether MSCs promote pulmonary metastatic disease progression in a murine osteosarcoma model; and/or (2) whether they affect local disease recurrence in the presence of microscopic residual osteosarcoma. METHODS: An orthotopic model of luciferase-expressing osteosarcoma was developed. At 10 days, resection of the primary tumor was performed. One hundred fourteen female C3H mice were inoculated with DLM8-luc osteosarcoma in the proximal tibia. Ninety-four mice developed orthotopic osteosarcoma with luciferase expression. Mice with bioluminescent evidence of a primary tumor received either a microscopically "clean" amputation at a time when residual microscopic metastatic disease was present in the lungs (pulmonary metastasis group; n = 65) or a "dirty" amputation (local recurrence group; n = 29). Mice were randomized to receive intravenous MSCs, MSCs at the surgical site, or no MSCs. Mice were monitored for development and progression of pulmonary metastasis and local recurrence by bioluminescence imaging and daily measurements at the surgical site. The number of pulmonary nodules, time to first evidence of metastasis, and size of recurrent tumor were compared using Kruskal-Wallis, analysis of variance, Welch's, t-tests, or Mann-Whitney tests as appropriate for the specific data sets with p < 0.05 considered significant. RESULTS: Mice receiving intravenous MSCs had a faster time to first detection of pulmonary metastasis (2.93 ± 1.90 days) compared with mice with local injection of MSCs (6.94 ± 6.78 days) or no MSCs (5.93 ± 4.55 days) (p = 0.022). MSC treatment did not influence whether mice developed local recurrence (p = 0.749) or size of recurrent tumors (p = 0.221). CONCLUSIONS: MSCs delivered to the surgical site did not promote local recurrence or size of recurrent tumors, but intravenous injection of MSCs did hasten onset of detection of pulmonary metastatic disease. Although local administration of MSCs into a surgical site does not appear to promote either pulmonary metastatic disease or local recurrence, large variation within groups and small numbers diminished statistical power such that a Type II error cannot be ruled out. CLINICAL RELEVANCE: If MSCs are to be used to augment bone healing in the postlimb salvage setting in patients with osteosarcoma, it will be important to understand their influence, if any, on pulmonary micrometastsis or residual microscopic local disease. Although murine models do not completely recapitulate the clinical scenario, these results suggest that intravenous delivery of MSCs may promote micrometastatic pulmonary disease. Local administration into a surgical wound, even in the presence of residual microscopic disease, may be safe, at least in this murine model, but further investigation is warranted before considering the use of MSCs for clinical use in patients with osteosarcoma.