Real-Life Experience in the Treatment of Intrahepatic Cholangiocarcinoma by 90Y Radioembolization: A Multicenter Retrospective Study.

Limited treatment options in patients with intrahepatic cholangiocarcinoma (iCCA) demand the introduction of new, catheter-based treatment options. Especially, 90Y radioembolization may expand therapeutic abilities beyond surgery or chemotherapy. Therefore, the purpose of this study was to identify factors associated with an improved median overall survival (mOS) in iCCA patients receiving radioembolization in a retrospective study at 5 major tertiary-care centers. Methods: In total, 138 radioembolizations in 128 patients with iCCA (female, 47.7%; male, 52.3%; mean age ± SD, 61.1 ± 13.4 y) were analyzed. Clinical data, imaging characteristics, and radioembolization reports, as well as data from RECIST, version 1.1, analysis performed 3, 6, and 12 mo after radioembolization, were collected. mOS was compared among different subgroups using Kaplan-Meier curves and the log-rank test. Results: Radioembolization was performed as first-line treatment in 25.4%, as second-line treatment in 38.4%, and as salvage treatment in 36.2%. In patients receiving first-line, second-line, and salvage radioembolization, the disease control rate was 68.6%, 52.8%, and 54.0% after 3 mo; 31.4%, 15.1%, and 12.0% after 6 mo; and 17.1%, 5.7%, and 6.0% after 1 y, respectively. In patients receiving radioembolization as first-line, second-line, and salvage treatment, mOS was 12.0 mo (95% CI, 7.6-23.4 mo), 11.8 mo (95% CI, 9.1-16.6 mo), and 8.4 mo (95% CI, 6.3-12.7 mo), respectively. No significant differences among the 3 groups were observed (P = 0.15). Hepatic tumor burden did not significantly influence mOS (P = 0.12). Conclusion: Especially in advanced iCCA, second-line and salvage radioembolization may be important treatment options. In addition to ongoing studies investigating the role of radioembolization as first-line treatment, the role of radioembolization in the later treatment stages of the disease demands further attention.

Purinergic P2X4 receptors and mitochondrial ATP production regulate T cell migration.

T cells must migrate in order to encounter antigen-presenting cells (APCs) and to execute their varied functions in immune defense and inflammation. ATP release and autocrine signaling through purinergic receptors contribute to T cell activation at the immune synapse that T cells form with APCs. Here, we show that T cells also require ATP release and purinergic signaling for their migration to APCs. We found that the chemokine stromal-derived factor-1α (SDF-1α) triggered mitochondrial ATP production, rapid bursts of ATP release, and increased migration of primary human CD4+ T cells. This process depended on pannexin-1 ATP release channels and autocrine stimulation of P2X4 receptors. SDF-1α stimulation caused localized accumulation of mitochondria with P2X4 receptors near the front of cells, resulting in a feed-forward signaling mechanism that promotes cellular Ca2+ influx and sustains mitochondrial ATP synthesis at levels needed for pseudopod protrusion, T cell polarization, and cell migration. Inhibition of P2X4 receptors blocked the activation and migration of T cells in vitro. In a mouse lung transplant model, P2X4 receptor antagonist treatment prevented the recruitment of T cells into allograft tissue and the rejection of lung transplants. Our findings suggest that P2X4 receptors are therapeutic targets for immunomodulation in transplantation and inflammatory diseases.