What Is the Rate of Displacement of Occult Posterior Malleolus Fractures in Nailed Tibial Shaft Fractures?

OBJECTIVE: To describe the radiographic consequences of posterior malleolus fractures (PMF) present with tibial shaft fractures fixed with intramedullary nails. DESIGN: Retrospective cohort study. SETTING: Level 1 trauma center. PATIENTS/PARTICIPANTS: Seven hundred thirty-three patients with tibial shaft fractures. INTERVENTION: Intramedullary nail fixation and prophylactic articular fixation. MAIN OUTCOME MEASURE: Displacement of PMF with intramedullary nail insertion. RESULTS: Seven hundred thirty-three patients were identified with tibial shaft fractures treated with intramedullary nail fixation at a Level 1 trauma center without a uniform preoperative computed tomography protocol. One hundred thirty-three patients had an identifiable PMF appreciated on preoperative imaging. Of the 600 remaining patients without a known PMF, 29 had PMF identified after nail insertion: 24 patients with nondisplaced fractures that all healed radiographically at final follow-up, 3 patients had fractures <30% of the articular surface displaced 1-2 mm, and 2 patients had fractures >30% of the joint surface that displaced 1-2 mm. CONCLUSIONS: The incidence of radiographically observable PMF associated with tibial shaft fractures is high, even without a preoperative computed tomography screening protocol in place. In patients without an appreciable PMF on injury films, less than 1% (2/600) had displacement of a large, clinically significant PMF with nail placement. LEVEL OF EVIDENCE: Prognostic Level IV. See Instructions for Authors for a complete description of levels of evidence.

Can Lateral X-Rays Reliably Determine Which Posterior Malleolus Ankle Fractures Need a CT?

BACKGROUND: For rotational ankle fractures with a posterior malleolus fracture (PMF), the decision to further evaluate the ankle injury with computed tomography (CT) is challenging. The objective of this study is to determine how well PMF fracture size on x-rays correlates with size on CT, and how well x-rays can predict which patients receive PMF fixation after CT review. METHODS: This is a retrospective study of adult ankle fractures with PMFs that had preoperative radiographs and CT imaging over a 5-year period. PMF x-ray and CT measurements were recorded, and relationships between x-ray measurements and final PMF fixation plan after CT review were evaluated. RESULTS: A total of 98 patients were identified with both x-rays and preoperative CT imaging. Pearson's rank correlation demonstrated a strong relation between PMF width percentage measured on x-ray and CT (r = 0.724). Of the 45 patients with a PMF size under 20% on x-ray, only one patient (with an apparent incarcerated fragment) underwent PMF fixation after review of the CT. CONCLUSIONS: PMF width on lateral x-ray correlates well with CT size and is sensitive for predicting the need for dedicated posterior malleolus based on one institutional practice pattern. Below 20% fracture width on lateral x-ray, a dedicated CT rarely leads to a decision to perform PMF fixation. Limiting pre-operative CT to those with PMF width >20% could reduce CT utilization by as much as 45% without negatively affecting patient care. LEVELS OF EVIDENCE: Level III: Diagnostic.

Neoadjuvant STING Activation, Extended Half-life IL2, and Checkpoint Blockade Promote Metastasis Clearance via Sustained NK-cell Activation.

Combination immunotherapy treatments that recruit both innate and adaptive immunity have the potential to increase cancer response rates by engaging a more complete repertoire of effector mechanisms. Here, we combined intratumoral STimulator of INterferon Genes (STING) agonist therapy with systemically injected extended half-life IL2 and anti-PD-1 checkpoint blockade (hereafter CIP therapy) to drive innate and adaptive antitumor immunity in models of triple-negative breast cancer. Unlike treatment with the individual components, this trivalent immunotherapy halted primary tumor progression and led to long-term remission for a majority of animals in two spontaneously metastasizing orthotopic breast tumor models, though only as a neoadjuvant therapy but not adjuvant therapy. CIP therapy induced antitumor T-cell responses, but protection from metastatic relapse depended on natural killer (NK) cells. The combination of STING agonists with IL2/anti-PD-1 synergized to stimulate sustained granzyme and cytokine expression by lung-infiltrating NK cells. Type I IFNs generated as a result of STING agonism, combined with IL2, acted in a positive-feedback loop by enhancing the expression of IFNAR-1 and CD25 on lung NK cells. These results suggest that NK cells can be therapeutically targeted to effectively eliminate tumor metastases.See related Spotlight by Demaria, p. 3.

A particulate saponin/TLR agonist vaccine adjuvant alters lymph flow and modulates adaptive immunity.

Saponins are potent and safe vaccine adjuvants, but their mechanisms of action remain incompletely understood. Here, we explored the properties of several saponin formulations, including immune-stimulatory complexes (ISCOMs) formed by the self-assembly of saponin and phospholipids in the absence or presence of the Toll-like receptor 4 agonist monophosphoryl lipid A (MPLA). We found that MPLA self-assembles with saponins to form particles physically resembling ISCOMs, which we termed saponin/MPLA nanoparticles (SMNP). Saponin-containing adjuvants exhibited distinctive mechanisms of action, altering lymph flow in a mast cell­dependent manner and promoting antigen entry into draining lymph nodes. SMNP was particularly effective, exhibiting even greater potency than the compositionally related adjuvant AS01B in mice, and primed robust germinal center B cell, TFH, and HIV tier 2 neutralizing antibodies in nonhuman primates. Together, these findings shed new light on mechanisms by which saponin adjuvants act to promote the immune response and suggest that SMNP may be a promising adjuvant in the setting of HIV, SARS-CoV-2, and other pathogens.

Reprogramming NK cells and macrophages via combined antibody and cytokine therapy primes tumors for elimination by checkpoint blockade.

Treatments aiming to augment immune checkpoint blockade (ICB) in cancer often focus on T cell immunity, but innate immune cells may have important roles to play. Here, we demonstrate a single-dose combination treatment (termed AIP) using a pan-tumor-targeting antibody surrogate, half-life-extended interleukin-2 (IL-2), and anti-programmed cell death 1 (PD-1), which primes tumors to respond to subsequent ICB and promotes rejection of large established tumors in mice. Natural killer (NK) cells and macrophages activated by AIP treatment underwent transcriptional reprogramming; rapidly killed cancer cells; governed the recruitment of cross-presenting dendritic cells (DCs) and other leukocytes; and induced normalization of the tumor vasculature, facilitating further immune infiltration. Thus, innate cell-activating therapies can initiate critical steps leading to a self-sustaining cycle of T cell priming driven by ICB.