Hepatic gene expression during treatment with peginterferon and ribavirin: Identifying molecular pathways for treatment response.

UNLABELLED: The reasons for hepatitis C treatment failure remain unknown but may be related to different host responses to therapy. In this study, we compared hepatic gene expression in patients prior to and during peginterferon and ribavirin therapy. In the on-treatment group, patients received either ribavirin for 72 hours prior to peginterferon alpha-2a injection or peginterferon alpha-2a for 24 hours, prior to biopsy. The patients were grouped into rapid responders (RRs) with a greater than 2-log drop and slow responders (SRs) with a less than 2-log drop in hepatitis C virus RNA by week 4. Pretreatment biopsy specimens were obtained from a matched control group. The pretreatment patients were grouped as RRs or SRs on the basis of the subsequent treatment response. Gene expression profiling was performed with Affymetrix microarray technology. Known interferon-stimulated genes (ISGs) were induced in treated patients. In the pretreatment group, future SRs had higher pretreatment ISG expression than RRs. On treatment, RRs and SRs had similar absolute ISG expression, but when it was corrected for the baseline expression with the pretreatment group, RRs showed a greater fold change in ISGs, whereas SRs showed a greater change in interferon (IFN)-inhibitory pathways. The patients pretreated with ribavirin had heightened induction of IFN-related genes and down-regulation of genes involved in IFN inhibition and hepatic stellate cell activation. CONCLUSION: These data suggest that ISG inducibility is important for the treatment response and that ribavirin may improve outcomes by enhancing hepatic gene responses to peginterferon. Collectively, these mechanisms may provide a molecular basis for the improved efficacy of combination therapy.

A population-based cohort study comparing laparoscopic cholecystectomy and open cholecystectomy.

OBJECTIVES: Laparoscopic cholecystectomy (LC) has become a popular alternative to open cholecystectomy (OC). Previous studies comparing outcomes in LC and OC used small selected cohorts of patients and did not control for comorbid conditions that might affect outcome. The aims of this study were to characterize the morbidity, mortality, and costs of LC and OC in a large unselected cohort of patients. METHODS: We used the population-based North Carolina Discharge Abstract Database (NCHDAD) for January 1, 1991, to September 30, 1994 (n = 850,000) to identify patients undergoing OC and LC. We identified the indications for surgery, complications, and type of perioperative biliary imaging used. We compared length of stay, hospital charges, complications, morbidity, and mortality between OC and LC patients. To account for variations in outcomes from differences in age and comorbidity between the OC and LC groups, we used the age-adjusted Charlson Comorbidity Index in regression analyses quantifying the association between type of surgery and outcome. RESULTS: Our cohort consisted of 43,433 patients (19,662 LC and 23,771 OC). The mean age-adjusted Charlson Comorbidity Index score was slightly higher for the OC compared to the LC group (4.3 vs 4.1, p < 0.05). The OC patients had longer hospitalizations, generated more charges ($12,125 vs $9,139, p < 0.05), and required home care more often. The crude risk ratio comparing risk of death in OC to LC was 5.0 (95% CI = 3.9-6.5). After controlling for age, comorbidity, and sex, the odds of dying in the OC group was still 3.3 times (95% CI = 1.4-7.3) greater than in the LC group. In the LC group, the number of patients with acute cholecystitis rose over the study period, whereas the number of patients with chronic cholecystitis declined. In the OC group, the number of patients with acute and chronic cholecystitis declined. The use of intraoperative cholangiography was greater in the OC group but declined in both groups over the study period. The use of ERCP was greater in the LC group and increased in both groups over time. CONCLUSIONS: The introduction of LC has resulted in a change in the management of cholecystitis. Despite a higher proportion of patients with acute cholecystitis, the risk of dying was significantly less in LC than in OC patients, even after controlling for age and comorbidity. Based on lower costs and better outcomes, LC seems to be the treatment of choice for acute and chronic cholecystitis.