Phase II study of oral vinorelbine in combination with carboplatin followed by consolidation therapy with oral vinorelbine as single-agent in unresectable localized or metastatic non-small cell lung carcinoma.

INTRODUCTION: This phase II study assessed the efficacy and safety of oral vinorelbine given weekly in combination with carboplatin (CBDCA) AUC 5 once every 3 weeks for four cycles in chemonaive patients with advanced non-small cell lung carcinoma (NSCLC), followed by consolidation therapy with single-agent oral vinorelbine in non-progressive patients. METHODS: Chemonaive advanced NSCLC patients received four cycles of combination therapy with CBDCA AUC 5 day 1 and oral vinorelbine, 60 mg/m2 on days 1, 8 and 15 (cycle 1), dose increased to 80 mg/m2 (cycles 2-4) in absence of grades 3-4 neutropenia (NCI-CTCv2). Consolidation therapy with oral vinorelbine was continued (cycle 5) at same dosage; if dose was decreased during combination therapy, it was given at 60 mg/m2, then increased at 80 mg/m2 (cycle 6) in absence of grades 3-4 neutropenia until PD, toxicity or patient's refusal. RESULTS: A total of 57 patients were registered and 56 patients were treated (ITT population), median age was 61 years (37-71). Objective response evaluated by RECIST was 17.9% (95% confidence interval, CI [8.9-30.4]) and disease control (CR, PR, NC) 73.2% (95% CI [59.7-84.2]), median progression-free survival 4.3 months (95% CI [3.1-5.1]) with median overall survival 9.7 months (95% CI [7.7-11.9]) and 1-year survival 37.1% (95% CI [24.4, 49.9]). Grades 3-4 neutropenia occurred in 67.9% of patients during combination and 20% during consolidation; febrile neutropenia occurred in 4 patients (7.1%) during combination therapy. Non-hematological toxicities occurred primarily during combination (grade 3 nausea and grade 3 vomiting in 7.1% of patients). CONCLUSIONS: The combination of oral vinorelbine given weekly in 3-week cycles in combination with carboplatin followed by consolidation therapy with oral vinorelbine as a single-agent was able to achieve efficacy results in line with other doublets including carboplatin in terms of response as well as survival. This regimen reported a good profile of tolerability in the treatment of advanced NSCLC, allowing that this combination can be easily proposed for the palliative care of NSCLC patients where the advantages of carboplatin over cisplatin are still appreciated.

Functional expression of AQP3 in human skin epidermis and reconstructed epidermis.

The purpose of this study was to examine the presence of aquaporin water channels in human skin and to assess their functional role. On western blots of human epidermis obtained from plastic surgery, a strong signal was obtained with polyclonal anti-aquaporin-3 antibodies. By indirect immunofluorescence on 5 microm cryosections, anti-aquaporin-3 antibodies strongly stained keratinocyte plasma membranes in human epidermis, whereas no staining was observed in the dermis or the stratum corneum or when anti-aquaporin-3 antibodies were preabsorbed with the peptide used for immunization. Similarly, a strong signal with anti-aquaporin-3 antibodies was observed in keratinocyte plasma membranes of reconstructed human epidermis in culture at the air-liquid interface for up to 3 wk. The keratinocyte plasma membrane localization of aquaporin-3 was confirmed at the electron microscope level in prickle cells. In addition an intracellular localization of aquaporin-3 was also detected in epidermis basal cells. Osmotically induced transepidermal water permeability was measured on stripped human skin and on reconstructed epidermis. Water transport across both stripped human skin and 2-3 wk reconstructed epidermis was comparable, inhibited by > 50% by 1 mM HgCl2 and fully inhibited by acid pH. By stopped-flow light scattering, keratinocyte plasma membranes, where aquaporin-3 is localized, exhibited a high, pH-sensitive, water permeability. Although human skin is highly impermeable to water, this is primarily accounted for by the stratum corneum, where a steep water content gradient was demonstrated. In contrast, the water content of viable strata of the epidermis is remarkably constant. Our results suggest that the human epidermis, below the stratum corneum, exhibits a high, aquaporin-3-mediated, water permeability. We propose that the role of aquaporin-3 is to water-clamp viable layers of the epidermis in order to improve the hydration of the epidermis below the stratum corneum.