Significance of tibial MRI findings of special forces recruits at the onset of their training.

INTRODUCTION: MRI is commonly used to evaluate medial tibial stress syndrome (MTSS), based on grading assessments developed in civilian populations. When MTSS represents stress fracture, rest is required to allow for bone remodelling to occur. False positive evaluations can lead to unnecessary recruit attrition. METHODS: Thirty randomly selected new recruits to a special forces training unit underwent MRI of their tibias using the T2-Dixon sequence at the onset of training. Evaluation was according to the Fredericson MTSS grading system. Prior to undergoing MRI, anthropomorphic measurements, a survey of sports history and an orthopaedic examination of subject tibias were performed. Orthopaedic follow-up was through 11 weeks of training. RESULTS: Medial periosteal oedema without the presence of bone marrow oedema, corresponding to a grade 1 stress reaction, was present on MRI in 10 recruits (17 tibias). In only one case did the periosteal oedema include the posterior aspect of the medial cortex where medial tibial stress fractures usually occur. Tibial tenderness was present in seven tibias on examination done just prior to the MRI studies, but none were symptomatic and only one had periosteal oedema present on MRI, but without anatomical correlation between the site of the tenderness and the periosteal oedema. During subsequent training, five tibias in four recruits developed pain and tenderness. Two had periosteal oedema in their prior MRIs, but the location did not coincide anatomically with that of the tibial tenderness. The time from stopping sports before induction and the presence of periosteal oedema was not significant. CONCLUSION: Periosteal oedema, one of the hallmarks used in MRI grading systems to evaluate MTSS, was found to have a 37.7% false positive rate for anatomically corresponding tibial tenderness at the time of the examination and during subsequent training, indicating the grading systems' low utility for the military.

Response of patients with melanoma to immune checkpoint blockade - insights gleaned from analysis of a new mathematical mechanistic model.

Immune checkpoint inhibitors (ICI) are becoming widely used in the treatment of metastatic melanoma. However, the ability to predict the patient's benefit from these therapeutics remains an unmet clinical need. Mathematical models that predict melanoma patients' response to ICI can contribute to better informed clinical decisions. Here, we developed a simple mathematical population model for pembrolizumab-treated advanced melanoma patients, and analyzed the local and global dynamics of the system. Our results show that zero, one, or two steady states of the mathematical system exist in the phase plane, depending on the parameter values of individual patients. Without treatment, the simulated tumors grew uncontrollably. At increased efficacy of the immune system, e.g., due to immunotherapy, two steady states were found, one leading to uncontrollable tumor growth, and the other resulting in tumor size stabilization. Model analysis indicates that a sufficient increase in the activation of CD8+ T cells results in stable disease, whereas a significant reduction in T-cell exhaustion, another process contributing CD8+ T cell activity, temporarily reduces the tumor mass, but fails to control disease progression in the long run. Importantly, the initial tumor burden influences the response to treatment: small tumors respond better to treatment than larger tumors. In conclusion, our model suggests that disease progression and response to ICI depend on the ratio between activation and exhaustion rates of CD8+ T cells. The analysis of the model provides a foundation for the use of computational methods to personalize immunotherapy.