Salvage Radiotherapy Versus Hormone Therapy for Prostate-specific Antigen Failure After Radical Prostatectomy: A Randomised,Multicentre, Open-label,Phase 3 Trial (JCOG0401)2

BackgroundNo standard therapy has been established for localised prostate cancer patients with prostate-specific antigen (PSA) failure after radical prostatectomy (RP).ObjectiveTo determine whether radiotherapy ± hormone therapy is superior to hormone therapy alone in such patients.Design, setting, and participantsThis study is a multicentre, randomised, open-label, phase 3 trial. Patients with localised prostate cancer whose PSA concentrations had decreased to <0.1 ng/ml after RP, and then increased to 0.4–1.0 ng/ml, were randomised to the salvage hormone therapy (SHT) group (80 mg bicalutamide [BCL] followed by luteinising hormone-releasing hormone agonist in case of BCL failure) or the salvage radiation therapy (SRT) ± SHT group (64.8 Gy of SRT followed by the same regimen as in the SHT group in case of SRT failure). From May 2004 to May 2011, 210 patients (105 in each arm) were registered, with the median follow-up being 5.5 yr.Outcome measurements and statistical analysisThe primary endpoint was time to treatment failure (TTF) of BCL.Results and limitationsTTF of BCL was significantly longer in the SRT ± SHT group (8.6 yr) than in the SHT group (5.6 yr; hazard ratio 0.56, 90% confidence interval [0.40–0.77]; one-sided p = 0.001). Thirty-two of 102 patients (31%) in the SRT ± SHT group did not have SRT treatment failure. However, clinical relapse-free survival and overall survival did not differ between the arms. The most frequent grade 3–4 adverse event was erectile dysfunction (83 patients [80%] in the SHT group vs. 76 [74%] in the SRT ± SHT group). Limitations include the short follow-up periods and surrogate endpoint setting to allow definitive conclusions.ConclusionsInitial SRT prolongs TTF of BCL in patients with post-RP PSA failure, indicating that SRT ± SHT is more beneficial than SHT alone.Patient summaryPatients who have prostate-specific antigen failure after radical prostatectomy benefit from salvage radiation therapy prior to salvage hormone therapy.     

Strain and species effects on the inhibition of hepatocyte intercellular communication by liver tumor promoters

The effect of the liver tumor promoters phenobarbital (PB), 1,1-bis(4-chlorophenyl)-2,2,2-trichlorethane (DDT), and dieldrin on gap junction-mediated intercellular communication between primary cultured hepatocytes from male mice (B6C3F1), C3H, C57BL, and Balb/c strains) and male F344 rats was determined. Intercellular communication was detected autoradiographically as the passage and incorporation of [5-3H]uridine nucleotides from prelabelled donor hepatocytes to donor-contacting recipient hepatocytes. At non-toxic concentrations, PB (20-500 micrograms/ml) inhibited intercellular communication between B6C3F1, C3H, and Balb/c mouse hepatocytes and F344 rat hepatocytes, but not between C57BL mouse hepatocytes. DDT (1-10 micrograms/ml) inhibited intercellular communication between hepatocytes from all 4 strains of mice and the F344 rat. Dieldrin (1-10 micrograms/ml) inhibited intercellular communication between hepatocytes from the 4 strains of mice but not between rat hepatocytes. These findings showed a good correlation with the in vivo liver tumor promoting/hepatocarcinogenic actions of PB, DDT and dieldrin in the 4 mouse strains and the F344 rat strain.     

Infusion of ultrafiltrate from endotoxemic pigs depresses myocardial performance in normal pigs

We previously showed a beneficial effect of hemofiltration on hemodynamics of endotoxic shock pigs. To test the hypothesis that this effect of hemofiltration is caused by convective removal of factors that adversely effect hemodynamics during endotoxemia, we infused ultrafiltrate from endotoxic shock pigs into healthy pigs. Their hemodynamics were compared with those of pigs who were infused with ultrafiltrate from healthy pigs. Twelve anesthetized and ventilated pigs were hemodynamically monitored for 150 minutes following the infusion of 2 L of ultrafiltrate from 12 donor pigs. The acceptor pigs were randomly divided into two groups; group 1 received ultrafiltrate from pigs who were hemofiltered after the infusion of 0.5 mg/kg endotoxin over 30 minutes; group 2 served as a control group, receiving ultrafiltrate from healthy donor pigs. Group 1 showed a decrease in mean arterial pressure of 28 ± 7 mm Hg (mean ± SEM) versus an increase of 17 ± 3 mm Hg in group 2 (P < .04). Mean pulmonary artery pressure increased more in group 1 than in group 2 (9 ± 2 mm Hg versus 1 ± 1 mm Hg, P < .04). The decrease in cardiac output in group 1 was greater than in group 2 (3.3 ± 0.2 L/ min v 0.3 ± 0.3 L /min, P < .02) and was due to a decrease in stroke volume. The decrease in right ventricular ejection fraction was also greater (0.15 ± 0.02 v 0.01 ± 0.00, P < .01). Systemic vascular resistance, right atrial pressure, right ventricular end-diastolic volume, pulmonary wedge pressure and heart rate did not differ between groups. In contrast to ultrafiltrate from healthy pigs, ultrafiltrate from endotoxic shock pigs contains soluble, filtrable factors that increase pulmonary artery pressure and depress cardiac performance.     

Muramyl dipeptide mimicry in the regulation of murine macrophage activation by serotonin

Muramyl peptides (MPs) are regulators of macrophage function. That the activities of MPs may be mediated by serotonin (5-HT) is supported by earlier work that demonstrated specific binding sites for MPs on macrophages that competitively bind 5-HT. Both mediators were also shown to enhance the production of superoxide anion (an antibacterial agent) by these cells. We now report on two additional macrophage activation phenomena affected by 5-HT: phagocytosis and induction of tumor necrosis factorα (TNF) mRNA. Serotonin acts as a muramyl peptide-like agonist by increasing phagocytosis of tubercle bacilli by murine peritoneal macrophages, and as a partial agonist/antagonist in the induction of mRNA for tumor necrosis factor.These observations provide further evidence for a serotonergic involvement in some of the physiological responses to MPs.     

Reduced Lon protease 1 expression in podocytes contributes to the pathogenesis of podocytopathy

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Suppression of macrophage-mediated xenogeneic rejection by the ectopic expression of human CD177

Cellular xenogeneic rejection by the innate immune system is a major immunological obstruction that needs to be overcome for the successful clinical use of xenografts. Our focus has been on macrophage-mediated xenogeneic rejection, since suppressing macrophage function has considerable potential for practical applications in the area of xenotransplantation. We report herein on an investigation of the suppressive effect of human CD177 (hCD177) against macrophage-mediated xenogeneic rejection. Wild type swine aortic endothelial cell (SEC) and an SEC transfectant with hCD177 (SEC/hCD177) were co-cultured with macrophages, and the degree of cytotoxicity was evaluated by WST-8 assays, and phagocytosis was examined using Calcein-AM labeling methods. The expression of anti/pro-inflammatory cytokines was evaluated by RT-qPCR and the phosphorylation of SHP-1 on macrophages in co-culture was evaluated by Western blotting. The result of cytotoxicity assays indicated that hCD177 suppressed M1 macrophage-mediated xenogeneic rejection (vs. SEC, p < 0.0001). Similarly, the result of phagocytosis assays indicated that hCD177 suppressed it (vs. SEC, p < 0.05). In addition, hCD177 significantly suppressed the expression of IL-1β, a pro-inflammatory cytokine, in M1 macrophages (vs. SEC, p < 0.01). Luciferase assays using THP1-Lucia NF-kB also showed a significant difference in NF-kB activation (vs. SEC, p < 0.001). In addition, hCD177 was found to induce the phosphorylation of SHP-1 in M1 macrophages (vs. SEC, p < 0.05). These findings indicate that hCD177 suppresses M1 macrophage-mediated xenogeneic rejection, at least in part via in the phosphorylation of SHP-1.