Tumor vaccines have held much promise, but to date have demonstrated little clinical success. This lack of success is conceivably due to poor tumor antigen presentation combined with immuno-suppressive mechanisms exploited by the tumor itself. Knock down of Inhibitor of differentiation protein 2 (Id2-kd) in mouse neuroblastoma whole tumor cells rendered these cells immunogenic. Id2-kd neuroblastoma (Neuro2a) cells (Id2-kd N2a) failed to grow in most immune competent mice and these mice subsequently developed immunity against further wild-type Neuro2a tumor cell challenge. Id2-kd N2a cells grew aggressively in immune-compromised hosts, thereby establishing the immunogenicity of these cells. Therapeutic vaccination with Id2-kd N2a cells alone suppressed tumor growth even in established neuroblastoma tumors and when used in combination with immune checkpoint blockade eradicated large established tumors. Mechanistically, immune cell depletion studies demonstrated that while CD8+ T cells are critical for antitumor immunity, CD4+ T cells are also required to induce a sustained long-lasting helper effect. An increase in number of CD8+ T-cells and enhanced production of interferon gamma (IFNγ) was observed in tumor antigen stimulated splenocytes of vaccinated mice. More importantly, a massive influx of cytotoxic CD8+ T-cells infiltrated the shrinking tumor following combined immunotherapy. These findings show that down regulation of Id2 induced tumor cell immunity and in combination with checkpoint blockade produced a novel, potent, T-cell mediated tumor vaccine strategy.

Noncompressible torso hemorrhage in trauma is particularly lethal. Resuscitative endovascular balloon occlusion of the aorta (REBOA) has the potential to stabilize these patients, but currently is contraindicated for major thoracic bleeding. The goal of this study was to evaluate the effect of REBOA on the hemodynamic and metabolic profile as well as its effect on early survival in a porcine model of thoracic hemorrhage and shock. METHODS Forty-eight male Yorkshire swine (60–80 kg) underwent 30% hemorrhage and were randomized to three thoracic injuries, with and without zone 1 REBOA occlusion: pulmonary parenchymal injury, thoracic venous injury, or subclavian artery injury. Following hemorrhage, thoracic injuries were induced (time of major thoracic injury) and allowed to bleed freely. The REBOA groups had zone 1 occlusion after the thoracic injury, with deflation at the end of prehospital. All groups had whole blood resuscitation at the end of prehospital and were euthanized at end of the hospital care phase. Survival, total blood loss, mean arterial pressure, end-tidal CO2, and arterial blood gas parameters were analyzed. Statistical significance was determined by t tests and two-way repeated-measures analysis of variance. RESULTS The use of REBOA improved the hemodynamics in all three injury patterns, with no differences observed in the outcomes of short-term survival and thoracic blood loss between the REBOA and non-REBOA groups. All groups showed equivalent changes in markers of shock (pH, HCO3, and base excess) prior to resuscitation. CONCLUSION In this animal study of hemorrhage and major thoracic bleeding, the addition of zone 1 REBOA did not significantly affect short-term survival or blood loss, while providing hemodynamic stabilization. Therefore, in noncompressible thoracic bleeding, without immediate surgical capability, long-term outcomes may be improved with REBOA, and thoracic hemorrhage should not be considered contraindications to REBOA use.

Background: Decompensated hemorrhagic shock (DHS) is the leading cause of preventable death in combat casualties. ''Golden hour'' resuscitation effects on cerebral blood flow and perfusion following DHS in prolonged field care (PFC) are not well investigated. Using an established non-human primate model of DHS, we hypothesized noninvasive regional tissue oxygenation (rSO 2 ) and Transcranial Doppler (TCD) would correlate to the invasive measurement of partial pressure of oxygen (PtO 2 ) and mean arterial pressure (MAP) in guiding hypotensive resuscitation in a PFC setting. Methods: Ten rhesus macaques underwent DHS followed by a 2 h PFC phase (T0-T120), and subsequent 4 h hospital resuscitation phase (T120-T360). Invasive monitoring (PtO 2 , MAP) was compared against noninvasive monitoring systems (rSO 2 , TCD). Results were analyzed using t tests and one-way repeated measures ANOVA. Linear correlation was determined via Pearson r. Significance ¼ P < 0.05. Results: MAP, PtO 2 , rSO 2 , and mean flow velocity (MFV) significantly decreased from baseline at T0. MAP and PtO 2 were restored to baseline by T15, while rSO 2 was delayed through T30. At T120, MFV returned to baseline, while the Pulsatility Index significantly elevated by T120 (1.50 AE 0.31). PtO 2 versus rSO 2 (R 2 ¼ 0.2099) and MAP versus MFV (R 2 ¼ 0.2891) shared very weak effect sizes, MAP versus rSO 2 (R 2 ¼ 0.4636) displayed a low effect size, and PtO 2 versus MFV displayed a moderate effect size (R 2 ¼ 0.5540). Conclusions: Though noninvasive monitoring methods assessed here did not correlate strongly enough against invasive methods to warrant a surrogate in the field, they do effectively augment and direct resuscitation, while potentially serving as a substitute in the absence of invasive capabilities.

BackgroundTactical Combat Casualty Care guidelines for hemorrhage recommend resuscitation to systolic blood pressure (SBP) of 85±5 mm Hg during prehospital care. Success depends on transport to definitive care within the ‘golden hour’. As future conflicts may demand longer prehospital/transport times, we sought to determine safety of prolonged permissive hypotension (PH).MethodsAdult male swine were randomized into three experimental groups. Non-shock (NS)/normotensive underwent anesthesia only. NS/PH was bled to SBP of 85±5 mm Hg for 6 hours of prolonged field care (PFC) with SBP maintained via crystalloid, then recovered. Experimental group underwent controlled hemorrhage to mean arterial pressure 30 mm Hg until decompensation (Decomp/PH), followed by 6 hours of PFC. Hemorrhaged animals were then resuscitated with whole blood and observed for 24 hours. Physiologic variables, blood, tissue samples, and neurologic scores were collected.ResultsSurvival of all groups was 100%. Fluid volumes to maintain targeted SBP in PFC were significantly higher in the hemorrhage group than sham groups. After 24 hours’ recovery, no significant differences were observed in neurologic scores or cerebrospinal fluid markers of brain injury. No significant changes in organ function related to treatment were observed during PFC through recovery, as assessed by serum chemistry and histological analysis.ConclusionsAfter 6 hours, a prolonged PH strategy showed no detrimental effect on survival or neurologic outcome despite the increased ischemic burden of hemorrhage. Significant fluid volume was required to maintain SBP—a potential logistic burden for prehospital care. Further work to define maximum allowable time of PH is needed.Study typeTranslational animal model.Level of evidenceN/A.