Effectiveness of regional hyperthermia with chemotherapy for high-risk retroperitoneal and abdominal soft-tissue sarcoma after complete surgical resection: a subgroup analysis of a randomized phase-III multicenter study.

OBJECTIVE: To determine whether regional hyperthermia (RHT) in addition to chemotherapy improves local tumor control after macroscopically complete resection of abdominal or retroperitoneal high-risk sarcomas. BACKGROUND: Within the prospectively randomized EORTC 62961 phase-III trial, RHT and systemic chemotherapy significantly improved local progression-free survival (LPFS) and disease-free survival (DFS) in patients with abdominal and extremity sarcomas. That trial included macroscopically complete and R2 resections. METHODS: A subgroup analysis of the EORTC trial was performed and long-term survival determined. From 341 patients, 149 (median age 52 years, 18-69) were identified with macroscopic complete resection (R0, R1) of abdominal and retroperitoneal soft-tissue sarcomas (median diameter 10 cm, G2 48.3%, G3 51.7%). Seventy-six patients were treated with EIA (etoposide, ifosfamide, doxorubicin)+RHT (≥5 cycles: 69.7%) versus 73 patients receiving EIA alone (≥5 cycles: 52.1%, P=0.027). LPFS and DFS as well as overall survival were determined. RESULTS: RHT and systemic chemotherapy significantly improved LPFS (56% vs 45% after 5 years, P=0.044) and DFS (34% vs 27% after 5 years, P=0.040). Overall survival was not significantly improved in the RHT group (57% vs 55% after 5 years, P=0.82). Perioperative morbidity and mortality were not significantly different between groups. CONCLUSIONS: In patients with macroscopically complete tumor resection, RHT in addition to chemotherapy resulted in significantly improved local tumor control and DFS without increasing surgical complications. Within a multimodal therapeutic concept for abdominal and retroperitoneal high-risk sarcomas, RHT is a treatment option beside radical surgery and should be further evaluated in future trials.

Monocyte-Dependent Suppression of T-Cell Function in Postoperative Patients and Abdominal Sepsis.

INTRODUCTION: Surgical trauma causes inflammation and postoperative immunosuppression. Previous studies have shown a T-cell-dependent suppression of MHC II expression and other functions of antigen-presenting cells. The aim of this study was to determine which immune cell initiates postoperative immunosuppression and consecutive sepsis. METHODS: We separated T-cells and monocytes in human abdominal surgery (n = 11) patients preoperatively as well as 24 h postoperatively and in patients who developed postoperative sepsis (n = 6). We analyzed their surface markers and then coincubated these cells with naïve preoperative cells of the other cell type, respectively. Cytokine secretion from naïve cells was measured by a multiplex immunoassay, serving as a bioassay for the function of the stimulating postoperative cell. RESULTS: Surface marker analysis showed a postoperative suppression of CD3 cells and the activation marker CD28 (P = 0.02), which was further reduced in septic patients. FACS analysis revealed a significant increase in CD14 monocytes (P = 0.02) and CD14CD86, CD14HLA-DR subpopulations 2 h postoperatively. In sepsis patients, HLA-DR expression was reduced compared with postoperative levels (P < 0.01). After coincubation with postoperative T-cells, secretion of IL-6 (P < 0.01) and IL-10 (P < 0.01) from naïve monocytes was increased, whereas T-cells from sepsis patients resulted in suppressed cytokine secretion. After coincubation with postoperative monocytes, secretion of IFN-gamma (P < 0.01) and IL-10 (P < 0.01) from naïve T-cells was significantly diminished, whereas monocytes from septic patients triggered only insignificant IL-10 secretion from naïve and septic T-cells. CONCLUSIONS: Our results show that in the early postoperative period, T-cells are suppressed but able to trigger the release of cytokines from monocytes, whereas activated monocytes seem to induce T-cell suppression. In sepsis patients, a global suppression of both cell types in terms of absolute numbers and function seems to occur.

Dehydroepiandrosterone restores depressed peripheral blood mononuclear cell function following major abdominal surgery via the estrogen receptors.

OBJECTIVE: Peripheral blood mononuclear cell (PBMC) dysfunction occurs following major abdominal surgery and correlates with an increased rate of septic complications. Studies have shown that dehydroepiandrosterone (DHEA) restores cell-mediated immune responses after trauma-hemorrhage in mice. Nonetheless, it remains unknown whether DHEA has any salutary effects on depressed PBMC function in surgical patients. DESIGN: Laboratory experiment. SETTING: University laboratory. PATIENTS: Fifteen patients undergoing major abdominal surgery. INTERVENTIONS: Blood samples were obtained preoperatively and 2 hrs postoperatively. MEASUREMENTS AND MAIN RESULTS: PBMCs were cultured with 33% plasma in the presence or absence of DHEA (10(-10) M, 10(-8) M physiologic concentration, 10(-6) M, 10(-5) M). In an additional set of samples, the estrogen receptor antagonist tamoxifen (10(-6) M) was added. The release of proinflammatory cytokines (interleukin-1beta, interleukin-6, and tumor necrosis factor-alpha) was measured in the supernatants by enzyme-linked immunosorbent assay. Abdominal surgery resulted in depressed interleukin-1beta and tumor necrosis factor-alpha release by PBMC. Addition of DHEA to the culture medium, however, significantly improved the release of interleukin-1beta and tumor necrosis factor-alpha and stimulated the interleukin-6 release capacity of PBMC. This effect was most pronounced for a concentration of 10(-5)M DHEA. The immunomodulatory effect of DHEA on PBMC cytokine release was completely blocked by tamoxifen. In contrast, the modulatory effect of DHEA was enhanced by the addition of postoperative plasma. CONCLUSIONS: DHEA stimulates proinflammatory cytokine release capacities of human PBMCs following major abdominal surgery. The estrogen receptor appears to be involved in mediating the immunomodulatory effect of DHEA. Thus, DHEA might be a useful adjunct for preventing immunosuppression in surgical patients.