Transferability of health cost evaluation across locations in oncology: cluster and principal component analysis as an explorative tool.

BACKGROUND: The transferability of economic evaluation in health care is of increasing interest in today's globalized environment. Here, we propose a methodology for assessing the variability of data elements in cost evaluations in oncology. This method was tested in the context of the European Network of Excellence "Connective Tissues Cancers Network". METHODS: Using a database that was previously aimed at exploring sarcoma management practices in Rhône-Alpes (France) and Veneto (Italy), we developed a model to assess the transferability of health cost evaluation across different locations. A nested data structure with 60 final factors of variability (e.g., unit cost of chest radiograph) within 16 variability areas (e.g., unit cost of imaging) within 12 objects (e.g., diagnoses) was produced in Italy and France, separately. Distances between objects were measured by Euclidean distance, Mahalanobis distance, and city-block metric. A hierarchical structure using cluster analysis (CA) was constructed. The objects were also represented by their projections and area of variability through correlation studies using principal component analysis (PCA). Finally, a hierarchical clustering based on principal components was performed. RESULTS: CA suggested four clusters of objects: chemotherapy in France; follow-up with relapse in Italy; diagnosis, surgery, radiotherapy, chemotherapy, and follow-up without relapse in Italy; and diagnosis, surgery, and follow-up with or without relapse in France. The variability between clusters was high, suggesting a lower transferability of results. Also, PCA showed a high variability (i.e. lower transferability) for diagnosis between both countries with regard to the quantities and unit costs of biopsies. CONCLUSION: CA and PCA were found to be useful for assessing the variability of cost evaluations across countries. In future studies, regression methods could be applied after these methods to elucidate the determinants of the differences found in these analyses.

Short peptide nucleic acids (PNA) inhibit hepatitis C virus internal ribosome entry site (IRES) dependent translation in vitro.

The internal ribosome entry site (IRES) of hepatitis C virus (HCV) which governs the initiation of protein synthesis from viral RNA represents an ideal target for antisense approaches. Using an original bicistronic plasmid, we first established that sequence and translational activity of HCV IRESs cloned from six patients, whether responders or not to combination therapy, were conserved. We then tested the hypothesis that antisense molecules, i.e. short peptide nucleic acids (PNA), could inhibit HCV translation by binding to the highly conserved IIId or IV loop regions of the IRES. Five 6-10mer PNAs were designed. They strongly inhibit HCV IRES-driven translation in a rabbit reticulocyte lysate assay. This inhibition was highly specific since corresponding PNAs with only one mismatch were inactive. Short phosphorothioate oligonucleotides of same sequence were unable to inhibit HCV translation. PNA molecule was shown to have anti-HCV activity in Huh-7.5 cells when electroporated with a full-length HCV genome construct. Using oligonucleotide as carrier, PNA was also transfected in HCV replicon-harboring cells and in JFH1 infected Huh-7.5 cells.

Novel alpha interferon (IFN-alpha) variant with improved inhibitory activity against hepatitis C virus genotype 1 replication compared to IFN-alpha2b therapy in a subgenomic replicon system.

Hepatitis C virus (HCV) treatment is based on the association of pegylated alpha interferon (IFN-alpha) and ribavirin. To improve the level of sustained virological response to treatment, especially in patients infected with HCV genotype 1, new IFNs with improved efficacy and toxicity profiles may be developed. In this report, we show that, in the BM4-5 cell line harboring an HCV subgenomic replicon, a novel and naturally occurring human IFN-alpha17 variant, GEA007.1, which was discovered by using an original population genetics-based drug discovery approach, inhibits HCV genotype 1 RNA replication more efficiently than does IFN-alpha2b. Moreover, we show that complete viral clearance is obtained in BM4-5 cells after long-term treatment with GEA007.1, while HCV subgenomic RNA is still detected in cells treated with other IFN-alpha variants or with standard IFN-alpha2b. Eventually, we demonstrate that the better inhibitory activity of GEA007.1 compared to that of standard IFN-alpha is likely to be due to stronger and faster activation of the JAK-STAT signaling pathway and to broader expression of IFN-alpha-responsive genes in cells. Our results demonstrate a superior inhibitory activity of GEA007.1 over that of IFN-alpha2b in the HCV replicon system. Clinical trials are required to determine whether GEA007.1 could be a potent "next generation" IFN for the treatment of HCV infection, especially in nonresponders or relapsing patients infected with HCV genotype 1 who currently represent a clinical unmet need.

A cyclic PNA-based compound targeting domain IV of HCV IRES RNA inhibits in vitro IRES-dependent translation.

A cyclic molecule 1 constituted by a hepta-peptide nucleic acid sequence complementary to the apical loop of domain IV of hepatitis C virus (HCV) internal ribosome entry site (IRES) RNA has been prepared via a 'mixed' liquid-phase strategy, which relies on easily available protected PNA and poly(2-aminoethylglycinamide) building blocks. This compound 1 has been elaborated to mimic 'loop-loop' interactions. For comparison, its linear analog has also been investigated. Although preliminary biological assays have revealed the ability of 1 to inhibit in vitro the HCV IRES-dependent translation in a dose-dependent manner, the linear analog has shown a slightly higher activity.