Targeting myeloid chemotaxis to reverse prostate cancer therapy resistance.

Inflammation is a hallmark of cancer1. In patients with cancer, peripheral blood myeloid expansion, indicated by a high neutrophil-to-lymphocyte ratio, associates with shorter survival and treatment resistance across malignancies and therapeutic modalities2-5. Whether myeloid inflammation drives progression of prostate cancer in humans remain unclear. Here we show that inhibition of myeloid chemotaxis can reduce tumour-elicited myeloid inflammation and reverse therapy resistance in a subset of patients with metastatic castration-resistant prostate cancer (CRPC). We show that a higher blood neutrophil-to-lymphocyte ratio reflects tumour myeloid infiltration and tumour expression of senescence-associated mRNA species, including those that encode myeloid-chemoattracting CXCR2 ligands. To determine whether myeloid cells fuel resistance to androgen receptor signalling inhibitors, and whether inhibiting CXCR2 to block myeloid chemotaxis reverses this, we conducted an investigator-initiated, proof-of-concept clinical trial of a CXCR2 inhibitor (AZD5069) plus enzalutamide in patients with metastatic CRPC that is resistant to androgen receptor signalling inhibitors. This combination was well tolerated without dose-limiting toxicity and it decreased circulating neutrophil levels, reduced intratumour CD11b+HLA-DRloCD15+CD14- myeloid cell infiltration and imparted durable clinical benefit with biochemical and radiological responses in a subset of patients with metastatic CRPC. This study provides clinical evidence that senescence-associated myeloid inflammation can fuel metastatic CRPC progression and resistance to androgen receptor blockade. Targeting myeloid chemotaxis merits broader evaluation in other cancers.

Evaluation of outflow temperatures generated by a dry heat fluid warmer at low fluid rates.

OBJECTIVE: To evaluate the output temperature of a dry heat fluid warmer at fluid rates typically used in small animal veterinary patients. STUDY DESIGN: Prospective in vitro study. ANIMALS: None. METHODS: Ambient temperature lactated Ringer's (17.9-18.8 °C) was delivered via a dry heat fluid warmer. A temperature probe was used to measure fluid outflow temperature from the compatible giving set at 5, 10, 20, 50, 70, 80, 100, 200, 300, 400 and 500 mL hour-1. Outflow fluid temperature at plateau (two consecutive readings within 0.1 °C) was compared with baseline fluid temperature (fluid warmer turned off) to calculate temperature changes at each rate. Kruskal-Wallis test was used to compare changes in temperature and time to plateau temperature. Dunn's post hoc test was used to test for significant differences in temperature compared to 5 mL hour-1; p value < 0.05. RESULTS: Median plateau outflow temperature increased as fluid rate increased, with temperatures of 18.5, 18.6, 18.7, 18.8, 19.4, 19.4, 21.5, 25.3, 28.5, 30.7 and 32.6 °C, at flow rates of 5, 10, 20, 50, 70, 80, 100, 200, 300, 400 and 500 mL hour-1. Fluid rates > 100 mL hour-1 showed significant increases from baseline (p = 0.021) There was no difference in temperature change from baseline at fluid rates < 100 mL hour-1 (p > 0.05). Compared to plateau temperature at 5 mL hour-1, there was a statistical difference in plateau temperature above 100 mL hour-1(p = 0.0207). Maximum outflow plateau temperature was 32.6 °C at 500 mL hour-1. CONCLUSIONS AND CLINICAL RELEVANCE: A dry heat fluid warmer has significantly decreased efficacy at low fluid rates, with no statistically significant increase in fluid temperature at fluid rates below 100 mL hour-1 at the end of a compatible fluid line. Inline dry heat fluid warmers are ineffective at fluid rates below 100 mL hour-1.