Norihiko Hirai

Suppression of T-cell function in gastric cancer patients after total gastrectomy with splenectomy: implications of splenic autotransplantation

Background. In Japan since the 1960s, patients with gastric cancer have routinely had splenectomy combined with gastrectomy to ensure that lymph node dissection is complete. However, the influence of splenectomy on long-term immunity is unclear. Methods. Forty-nine gastric cancer patients who underwent total gastrectomy for cure with (n = 25) and without (n = 24) splenectomy were assessed for immunologic function, including the proportion of lymphocyte subsets, purified protein derivative from tuberculin (PPD) response, natural killer (NK) activity, and phytohemagglutinin (PHA) response. Results. Peripheral T-cell mediated functions, e.g., PPD and PHA response, were significantly suppressed in patients who underwent gastrectomy with splenectomy compared with those who had gastrectomy alone. Decreased T-cell subsets (CD 3+, 4+, 8+) and increased NK cell subsets (CD 16+, 57+) were observed in patients who underwent splenectomy. Patients who did not undergo splenectomy had immunologic responses within the normal range. Conclusions. Splenectomy decreased T-cell mediated responses over the long term. As a potential means to co-rrect this T-cell dysfunction in patients with splenectomy, splenic autotransplantation should be considered in future research.

A series of immune responses leading to the induction ofT cell IL-12/IL-18 responsiveness in patientswith relatively large tumor burdens

Abstract. The induction of interleukin-12 (IL-12) responsiveness in T cells depends on T cell receptor (TCR) triggering, and is regarded as a parameter of recently TCR-sensitized T cells. Here, we investigated whether IL-12 responsiveness could be detected in freshly prepared T cells from tumor-bearing patients, and if so whether such patients exhibited additional immunological parameters related to IL-12 responsiveness. CD4+ and CD8+ T cell populations from an appreciable proportion of tumor-bearing patients exhibited high levels of IL-12 responsiveness as evaluated by IL-12-stimulated interferon-gamma (IFN-γ) production. T cell populations with high IL-12 responsiveness were observed in the group of patients with moderate to large tumor mass or tumor metastases rather than in patients with small tumors. The frequency of such a T cell population was also lower in post-surgery tumor-free patients, showing the correlation between IL-12 responsiveness and the presence of a certain extent of tumor burden. More importantly, a higher incidence of IL-12 responsiveness was observed in tumor-bearing patients exhibiting detectable plasma IL-12 levels, and correlated with IL-18 responsiveness. T cell IL-12 and IL-18 responsiveness is induced by TCR triggering and subsequent IL-12 stimulation respectively. Furthermore, TCR-triggered T cells stimulate antigen-presenting cells (APC) to produce IL-12. Therefore, the present observations suggest that an immune response loop from TCR sensitization to the induction of IL-12/IL-18 responsiveness via IL-12 production operates in tumor-bearing patients, particularly in those with relatively large tumor burdens.

Superiority of hepatic arterial infusion in preventing catabolism of 5-FU compared with portal vein infusion revealed by an in vivo 19F NMR study

Purpose: The aim of this study was to identify the route of administration of 5-FU with the greatest pharmacological advantage in a rat model using noninvasive in vivo 19F nuclear magnetic resonance (NMR) spectroscopy. Methods: 5-FU (50 mg/kg) was administered to anesthetized Wistar rats cannulated into the hepatic artery, portal vein or tail vein and 11 NMR spectra were acquired from the liver region to 60.5 min every 5.5 min. Results: With systemic i.v. (tail vein) infusion, the 19F-NMR signal for 5-FU from the liver region peaked in the first spectrum (0–5.5 min), and then gradually decreased. The signal for the 5-FU catabolite α-fluoro-β-alanine (FBAL) gradually increased to the sixth spectrum (0–33.0 min) and then plateaued. Following portal vein infusion the intensity of the first 5-FU spectrum was twice as high as that following i.v. infusion, but the intensity decreased and the FBAL signal increased gradually in the sixth spectrum as systemic i.v. infusion. In contrast, the intensity of the 5-FU signal following hepatic artery infusion was the same as that following portal vein infusion in the first spectrum, and maintained a strong intensity to the final spectrum (60.5 min). The FBAL signal was detected from the second spectrum following hepatic artery infusion, but its intensity was significantly weaker than that following i.v. or portal vein infusion. Conclusions: Hepatic arterial infusion resulted in the active form of 5-FU being present for a longer time and its degradation in the liver being suppressed compared with the results following portal vein infusion. This catabolic advantage of hepatic areterial infusion could lead to a more potent anti-tumor activity against liver metastases, but could also lead to significant host toxicity including biliary toxicity. We recommend that the dose/schedule of 5-FU administered via the hepatic artery should be adjusted carefully.