We previously reported (Bell, D., P. Chomarat, D. Broyles, G. Netto, G.M. Harb, S. Lebecque, J. Valladeau, J. Davoust, K.A. Palucka, and J. Banchereau. 1999. J. Exp. Med. 190: 1417–1426) that breast cancer tumors are infiltrated with mature dendritic cells (DCs), which cluster with CD4+ T cells. We now show that CD4+ T cells infiltrating breast cancer tumors secrete type 1 (interferon γ) as well as high levels of type 2 (interleukin [IL] 4 and IL-13) cytokines. Immunofluorescence staining of tissue sections revealed intense IL-13 staining on breast cancer cells. The expression of phosphorylated signal transducer and activator of transcription 6 in breast cancer cells suggests that IL-13 actually delivers signals to cancer cells. To determine the link between breast cancer, DCs, and CD4+ T cells, we implanted human breast cancer cell lines in nonobese diabetic/LtSz-scid/scid β2 microglobulin–deficient mice engrafted with human CD34+ hematopoietic progenitor cells and autologous T cells. There, CD4+ T cells promote early tumor development. This is dependent on DCs and can be partially prevented by administration of IL-13 antagonists. Thus, breast cancer targets DCs to facilitate its development.

The mda-7 gene (approved gene symbol IL24) is a novel tumor suppressor gene with tumor-apoptotic and immune-activating properties. We completed a Phase I dose-escalation clinical trial, in which a nonreplicating adenoviral construct expressing the mda-7 transgene (INGN 241; Ad-mda7) was administered intratumorally to 22 patients with advanced cancer. Excised tumors were evaluated for vector-specific DNA and RNA, transgenic MDA-7 expression, and biological effects. Successful gene transfer as assessed by DNA- and RT-PCR was demonstrated in 100% of patients evaluated. DNA analyses demonstrated a dose-dependent penetration of INGN 241 (up to 4 x 10(8) copies/mug DNA at the 2 x 10(12) vp dose). A parallel distribution of vector DNA, vector RNA, MDA-7 protein expression, and apoptosis induction was observed in all tumors, with signals decreasing with distance away from the injection site. Additional evidence for bioactivity of INGN 241 was illustrated via regulation of the MDA-7 target genes beta-catenin, iNOS, and CD31. Transient increases (up to 20-fold) of serum IL-6, IL-10, and TNF-alpha were observed. Significantly higher elevations of IL-6 and TNF-alpha were observed in patients who responded clinically to INGN 241. Patients also showed marked increases of CD3+CD8+ T cells posttreatment, suggesting that INGN 241 increased systemic TH1 cytokine production and mobilized CD8+ T cells. Intratumoral delivery of INGN 241 induced apoptosis in a large volume of tumor and elicited tumor-regulatory and immune-activating events that are consistent with the preclinical features of MDA-7/IL-24.

Key Points Question Compared with sorafenib, is atezolizumab plus bevacizumab cost-effective as first-line treatment of unresectable hepatocellular carcinoma? Findings In this economic evaluation using a partitioned survival model, therapy with atezolizumab plus bevacizumab generated incremental benefit over sorafenib as measured by quality-adjusted life-years but was not cost-effective at a willingness-to-pay threshold of $150 000 per quality-adjusted life-year. However, some patients may achieve preferred economic outcomes from atezolizumab plus bevacizumab therapy by tailoring the regimen based on individual patient factors. Meaning The findings suggest that atezolizumab plus bevacizumab may be a valuable therapy for unresectable hepatocellular carcinoma but may become more cost-effective with price reductions.

A study on bioavailability and pharmacokinetics of cefquinome in piglets was conducted after intravenous (i.v.) and intramuscular (i.m.) administrations of 2.0 mg/kg of body weight, respectively. Plasma concentrations were measured by high-performance liquid chromatography assay with UV detector at 268-nm wavelength. Plasma concentration-time data after i.v. administration were best fit by a two-compartment model. The pharmacokinetic values were distribution half-life 0.27 +/- 0.21 h, elimination half-life 1.85 +/- 1.11 h, total body clearance 0.26 +/- 0.08 L/kg.h, area under curve 8.07 +/- 1.91 microg x h/mL and volume of distribution at steady state 0.46 +/- 0.10 L/kg. Plasma concentration-time data after i.m. administration were also best fit by a two-compartment model. The pharmacokinetic parameters were distribution half-life 0.88 +/- 0.42 h, elimination half-life 4.36 +/- 2.35 h, peak concentration 4.01 +/- 0.57 microg/mL and bioavailability 95.13 +/- 9.93%.

What is already known about this subject • Schisandra sphenanthera extract (SchE) and tacrolimus are often co‐administrated in treating renal and liver transplant recipients in China. • We discovered occasionally that blood tacrolimus concentrations are markedly increased in some patients who receive tacrolimus and concomitant SchE. • This is the first study to investigate the effects of SchE on the pharmacokinetics of tacrolimus. What this study adds • Following administration of SchE in healthy volunteers, the mean AUC, AUMC and Cmax of tacrolimus substantially increases, whereas its CL/F and V/F decreases significantly. • Blood tacrolimus concentrations need to be closely monitored and dose adjustments of tacrolimus have to be made accordingly in the presence of SchE. Aim To assess the effect of Schisandra sphenanthera extract (SchE) on the pharmacokinetics of tacrolimus in healthy volunteers. Methods Twelve healthy male volunteers were orally treated with SchE, three capsules twice daily for 13 days. Pharmacokinetic investigations of oral tacrolimus administration at 2 mg were performed both before and at the end of the SchE treatment period. Whole blood tacrolimus concentrations were determined by enzyme‐linked immunosorbent assay. Estimated pharmacokinetic parameters before and with SchE were calculated with noncompartmental techniques. Results Following administration of SchE, the average percentage increases of individual increases in AUC, AUMC and Cmax of tacrolimus were 164.2% [95% confidence interval (CI) 70.1, 258.4], 133.1% (95% CI 49.5, 261.3) and 227.1% (95% CI 155.8, 298.4), respectively (P < 0.01 or 0.05). On average, there was a 36.8% (95% CI 13.4, 60.2) increase in tacrolimus tmax (P < 0.01). The average percentage decreases in CL/F and V/F were 49.0% (95% CI 31.1, 66.9) and 53.7% (95% CI 40.1, 67.4), respectively (P < 0.01). Conclusions SchE can increase the oral bioavailability of tacrolimus. The results of this study will add important information to the interaction area between drugs and herbal products.