Establishment of Synergistic Chemoimmunotherapy for Head and Neck Cancer Using Peritumoral Immature Dendritic Cell Injections and Low-Dose Chemotherapies.

The lack of available tumor antigens with strong immunogenicity, human leukocyte antigen restriction, and immunosuppression via regulatory T-cells (Tregs) and myeloid-derived suppressor cells are limitations for dendritic cell (DC)-based immunotherapy in patients with advanced head and neck cancer (HNC). We sought to overcome these limitations and induce effective antitumor immunity in the host. The effect of low-dose docetaxel (DTX) treatment on DC maturation was examined in an ex vivo study, and a phase I clinical trial of combination therapy with direct peritumoral immature DC (iDC) injection with OK-432 and low-dose cyclophosphamide (CTX) plus DTX was designed. Low-dose DTX did not negatively affect iDC viability and instead promoted maturation and IL-12 production. Five patients with metastatic or recurrent HNC were enrolled for the trial. All patients experienced grade 1 to 3 fevers. Intriguingly, elevated CD8+ effector T-cells and reduced Tregs were observed in four patients who completed two treatment cycles. All patients were judged to have progressive disease, but tumor regressions were observed in a subset of targeted metastatic lesions in two of five patients. Our results show that the combination of direct peritumoral iDC injection with OK-432 and low-dose CTX plus DTX is well tolerated and should give rise to changing the immune profile of T-cell subsets and improvement of immunosuppression in advanced HNC patients. Additionally, our ex vivo data on the effect of low-dose DTX treatment on DC maturation may contribute to developing new combination therapies with low-dose chemotherapy and immunotherapy.

Lower limits of hematocrit and mixed venous oxygen saturation ensuring sufficient cerebral oxygenation during hemodilution in rabbits.

OBJECTIVES: We have assessed clinically systemic tissue oxygenation by monitoring mixed venous oxygen saturation (SvO2) in addition to hematocrit (Hct) during cardiopulmonary bypass. Based on results of experimental studies together with clinical experience, we previously defined the lower limits of the critical range as an Hct of 12% and an SvO2 of 46%. However, these values do not provide direct information about cerebral oxygenation. This study was performed to identify critical values for these variables that would be able to ensure sufficient jugular venous oxygen saturation (SjO2), which reflects global cerebral oxygenation. METHODS: Normovolemic hemodilution was performed in ten rabbits. Hct, SvO2 and SjO2 were measured every 7 minutes. The safety limit for cerebral oxygenation was defined as an SjO2 of 50% based on studies of Croughwell et al. and Cook et al. The limit point was defined as 7 minutes before the time that the SjO2 decreased below 50% for the first time. RESULTS: Minimal values for Hct and SvO2 to maintain SjO2 at 50% or more during normovolemic normothermic hemodilution, expressed as the 95% confidence interval, were Hct of 7.4% to 10.0% and SvO2 of 41.8% to 51.4%. CONCLUSION: Adopting the higher values of these pairs, safety limits for cerebral oxygenation would be an Hct of 10.0% and an SvO2 of 51.4%. In conclusion, our experiments in rabbits suggest new safety limits during normovolemic normothermic hemodilution of Hct of 12% and SvO2 of 52%, taking both whole-body and cerebral oxygenation into consideration.

Critical values of hematocrit and mixed venous oxygen saturation as parameters for a safe cardiopulmonary bypass.

OBJECTIVE: Mixed venous oxygen saturation (SvO2) is high despite a low hematocrit implies that the relationship between oxygen demand and supply is in a safe state. This study was sought to determine the critical values for hematocrit and SvO2 for safe cardiopulmonary bypass. METHODS: Study 1: To evaluate the limit of hemodilution without cardiopulmonary bypass, normovolemic hemodilution with Dextran 40 (10%) was performed in 14 rabbits. SvO2 was monitored from the right atrium, and the hemodynamic parameters were recorded continuously. Study 2: To determine the critical values for hematocrit and SvO2 during cardiopulmonary bypass, normothermic and hypothermic cardiopulmonary bypass were performed in 13 rabbits and hemodynamic parameters were corrected. RESULTS: Study 1: The heart rate decreased to unsafe levels abruptly, when the SvO2 was < or = 43% or the hematocrit was < or = 10%. The lactate concentration increased when the SvO2 was < or = 46% or the hematocrit was < or = 12%. Study 2: When the hematocrit was < or = 12%, the SvO2 decreased gradually. Even when weaning was possible, the animals with a hematocrit < or = 12% collapsed hemodynamically within 40 minutes after cardiopulmonary bypass. Most of the animals could not be weaned from cardiopulmonary bypass during either normothermic or hypothermic cardiopulmonary bypass when the SvO2 was < or = 46%. CONCLUSIONS: Continuous monitoring of hematocrit and SvO2 provides evidence-based guidelines for safe cardiopulmonary bypass. The lower limits of critical range for a safer cardiopulmonary bypass are hematocrit of 12% and SvO2 of 46%.

Preliminary results of intermittent retrograde cerebral perfusion during proximal aortic arch surgery.

OBJECTIVE: Continuous retrograde cerebral perfusion during aortic arch surgery is associated with cerebral edema. In this report, we describe the clinical use of a new type of intermittent retrograde cerebral perfusion. SUBJECTS AND METHODS: Fourteen patients with a Stanford type A dissection were included in this study. With the usual method of retrograde cerebral perfusion, about 2,500 mL venous blood is drained from bicaval cannulae into a hard-shell reservoir, and oxygenated blood is perfused through the superior vena caval cannula. The flow rate is 300 mL/min. After about 15 min, retrograde perfusion is discontinued, and drainage from the bicaval cannulae is restarted. When a bloodless field is necessary, perfusion also is discontinued. RESULTS: Two to seven cycles of intermittent retrograde cerebral perfusion were administered (average, 3.1+/-0.4, mean+/-SD). The total retrograde perfusion time was 36.0+/-1.9 min which was equivalent to 74.8% of the circulatory arrest time. No patient developed edema of the upper body. The time to wake-up was 3 to 14 h (average, 6.5+/-1.0 h). No patient suffered any neurologic complications even though the time of circulatory arrest was greater than 60 min in four cases. Head magnetic resonance imaging or computed tomography was performed in 12 cases, and no evidence of hypoxic brain injury was detected. CONCLUSIONS: Our clinical experience using a moderate amount of intermittent retrograde cerebral perfusion is superior to continuous retrograde cerebral perfusion for protecting the brain during aortic arch surgery.