Safety and efficacy of trabectedin when administered in the inpatient versus outpatient setting: Clinical considerations for outpatient administration of trabectedin.

BACKGROUND: The results of the randomized, phase 3 ET743-SAR-3007 trial demonstrated that trabectedin had a significantly longer progression-free survival (PFS) compared with dacarbazine in patients with advanced leiomyosarcoma/liposarcoma after the failure of prior chemotherapy. Patients randomized to trabectedin received a 24-hour intravenous infusion either in an inpatient or outpatient setting. Herein, the authors reported the safety, efficacy, and patient-reported outcomes based on first infusion site of care. METHODS: Patients were randomized 2:1 to trabectedin (at a dose of 1.5 mg/m2 ) or dacarbazine (1 g/m2 over 20-120 minutes) with overall survival (OS) as the primary endpoint and PFS, time to disease progression, objective response rate, duration of response, safety, and patient-reported symptom scoring as secondary endpoints. The setting of the trabectedin infusion was based on institutional preference and categorized based on the setting of the first infusion. RESULTS: Of the 378 patients who were treated with trabectedin, 100 (27%) and 277 (73%), respectively, first received trabectedin in the inpatient and outpatient setting. No differences were observed with regard to PFS or OS based on site of care. The median PFS was 4.1 months versus 4.2 months (hazard ratio, 0.90; P = .49) for inpatients versus outpatients, respectively, and the median OS was 14.3 months versus 13.7 months (hazard ratio, 0.89; P = .40), respectively. Grade 3/4 adverse events (classified according to the National Cancer Institute Common Terminology Criteria for Adverse Events [version 4.0]) were reported in 87 inpatients (87%) compared with 219 outpatients (79%); grade 3/4 serious adverse events were reported in 43 inpatients (43%) and 92 outpatients (33%). Extravasation occurred in 0 inpatients and 5 outpatients (2%), whereas the incidence of catheter-related complications was similar between groups (16% vs 15%). CONCLUSIONS: Although the majority of patients who were randomized to trabectedin received outpatient therapy, the outcomes of the current study suggested equivalent safety and efficacy in either setting.

Pirfenidone is renoprotective in diabetic kidney disease.

Although several interventions slow the progression of diabetic nephropathy, current therapies do not halt progression completely. Recent preclinical studies suggested that pirfenidone (PFD) prevents fibrosis in various diseases, but the mechanisms underlying its antifibrotic action are incompletely understood. Here, we evaluated the role of PFD in regulation of the extracellular matrix. In mouse mesangial cells, PFD decreased TGF-beta promoter activity, reduced TGF-beta protein secretion, and inhibited TGF-beta-induced Smad2-phosphorylation, 3TP-lux promoter activity, and generation of reactive oxygen species. To explore the therapeutic potential of PFD, we administered PFD to 17-wk-old db/db mice for 4 wk. PFD treatment significantly reduced mesangial matrix expansion and expression of renal matrix genes but did not affect albuminuria. Using liquid chromatography with subsequent electrospray ionization tandem mass spectrometry, we identified 21 proteins unique to PFD-treated diabetic kidneys. Analysis of gene ontology and protein-protein interactions of these proteins suggested that PFD may regulate RNA processing. Immunoblotting demonstrated that PFD promotes dosage-dependent dephosphorylation of eukaryotic initiation factor, potentially inhibiting translation of mRNA. In conclusion, PFD is renoprotective in diabetic kidney disease and may exert its antifibrotic effects, in part, via inhibiting RNA processing.

TGF-beta-induced Ca(2+) influx involves the type III IP(3) receptor and regulates actin cytoskeleton.

Ca(2+) influx has been postulated to modulate the signaling pathway of transforming growth factor-beta (TGF-beta); however, the underlying mechanism and functional significance of TGF-beta-induced stimulation of Ca(2+) influx are unclear. We show here that TGF-beta stimulates Ca(2+) influx in mesangial cells without Ca(2+) release. The influx of Ca(2+) is prevented by pharmacological inhibitors of inositol 1,4,5-trisphosphate receptors (IP(3)R) as well as specific antibodies to type III IP(3)R (IP(3)RIII) but not to type I IP(3)R (IP(3)RI). TGF-beta enhances plasma membrane localization of IP(3)RIII, whereas the sarcoplasmic-endoplasmic reticulum Ca(2+)-ATPase (SERCA) preferentially translocates to the nucleus. Untreated mesangial cells exhibit actin filamentous protrusions on the cell surface, and treatment with TGF-beta dramatically reduces this pattern. The alterations in the actin cytoskeleton by TGF-beta are dependent on TGF-beta-induced Ca(2+) influx. These studies identify a novel pathway by which TGF-beta regulates Ca(2+) influx and induces cytoskeletal alterations.