RESUMEN
The liver's remarkable regenerative capacity is orchestrated by several growth factors and cytokines. Fibroblast growth factor receptor 3 (Fgfr3) is frequently overexpressed in hepatocellular carcinoma and promotes cancer aggressiveness, whereas its role in liver homeostasis, repair and regeneration is unknown. We show here that Fgfr3 is expressed by hepatocytes in the healthy liver. Its major ligand, Fgf9, is mainly expressed by non-parenchymal cells and upregulated upon injury. Mice lacking Fgfr3 in hepatocytes exhibit increased tissue necrosis after acute toxin treatment and more excessive fibrosis after long-term injury. This was not a consequence of immunological alterations in the non-injured liver as revealed by comprehensive flow cytometry analysis. Rather, loss of Fgfr3 altered the expression of metabolic and pro-fibrotic genes in hepatocytes. These results identify a paracrine Fgf9-Fgfr3 signaling pathway that protects from toxin-induced cell death and the resulting liver fibrosis and suggests a potential use of FGFR3 ligands for therapeutic purposes.
RESUMEN
BACKGROUND: Occasional complete responses have been reported in patients with squamous-cell carcinoma of the esophagus treated with carboplatin, and the inferior outcomes seen in early studies might have been the result of underdosing using BSA calculations. Docetaxel was reported to have single-agent activity in squamous-cell carcinoma of the esophagus, with a 50% response rate in a pilot study performed in South Africa. Thus, ECOG investigated the potential role of combination carboplatin using AUC-based dosing and docetaxel in patients with squamous-cell carcinoma of the esophagus. PATIENTS AND METHODS: ECOG 2298 was a multicenter, international, phase II clinical study of docetaxel and carboplatin in patients with histologically confirmed, measurable squamous-cell carcinoma of the esophagus. Docetaxel 75 mg/m(2) was infused over 1 hour on day 1 of each cycle. The carboplatin dose was calculated to an AUC of 6 and infused over 15-30 minutes immediately after the docetaxel. The regimen was repeated every 3 weeks for a total of 6 cycles or until disease progression occurred or unacceptable toxicity developed. RESULTS: A total of 32 patients were accrued, mostly men (78%) with a median age of 64 (range, 41-86). Half the patients were black and half were white. Five patients were not evaluable due to protocol violations. Of the remaining 27 patients, one (3%) achieved a complete clinical response. Four others (13%) achieved partial responses. Thirteen (41%) had stable disease and 9 (28%) had progression of disease. Overall objective response rate was 15.6% (95% CI 5.9% to 36%). The most common grade 3 and 4 toxicities were leukopenia (25/32=78%) and neutropenia (27/32=84%). Most nonhematologic toxicities were infrequent and ≤ grade 3; however, two patients experienced grade 5 toxicities; one died of bowel obstruction and another died of infection with grade 4 neutropenia. CONCLUSIONS: The high toxicity and poor efficacy shown in this study suggest that the combination of carboplatin and docetaxel in squamous-cell carcinoma of the esophagus should not be investigated further. Newer agents need to be investigated in this malignancy.
