Silvia Sauleda

Pharmacodynamic Studies of the Epidermal Growth Factor Receptor Inhibitor ZD1839 in Skin From Cancer Patients: Histopathologic and Molecular Consequences of Receptor Inhibition

PURPOSE The epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor ZD1839 (Iressa; AstraZeneca Pharmaceuticals, Alderley Park, United Kingdom) is under development as an anticancer agent. We studied the pharmacodynamic effects of ZD1839 on EGFR in the skin, an EGFR-dependent tissue, in cancer patients participating in ZD1839 phase I clinical trials. PATIENTS AND METHODS We studied 104 pre- and/or on-ZD1839 therapy ( approximately at day 28 of therapy) skin biopsies from 65 patients receiving escalating doses of daily oral ZD1839. We measured ZD1839 effects on EGFR activation by immunohistochemistry using an antibody specific for the activated (phosphorylated) EGFR. Effects on receptor signaling (activated mitogen-activated protein kinase [MAPK]), proliferation, p27(KIP1), and maturation were also assessed. RESULTS Histopathologically, the stratum corneum of the epidermis was thinner during therapy (P <.001). In hair follicles, prominent keratin plugs and microorganisms were found in dilated infundibula. ZD1839 suppressed EGFR phosphorylation in all EGFR-expressing cells (P <.001). In addition, ZD1839 inhibited MAPK activation (P <.001) and reduced keratinocyte proliferation index (P <.001). Concomitantly, ZD1839 increased the expression of p27(KIP1) (P <.001) and maturation markers (P <.001) and increased apoptosis (P <.001). These effects were observed at all dose levels, before reaching dose-limiting toxicities. CONCLUSION ZD1839 inhibits EGFR activation and affects downstream receptor-dependent processes in vivo. These effects were profound at doses well below the one producing unacceptable toxicity, a finding that strongly supports pharmacodynamic assessments to select optimal doses instead of a maximum-tolerated dose for definitive efficacy and safety trials.

Phase II and Tumor Pharmacodynamic Study of Gefitinib in Patients with Advanced Breast Cancer

PURPOSE To evaluate the antitumor activity and pharmacodynamic/biologic effect of gefitinib 500 mg/day monotherapy in patients with previously treated, advanced breast cancer. METHODS In this phase II multicenter trial, the primary objective was assessment of the tumor response rate with gefitinib; secondary objectives included analysis of the pharmacodynamic and biologic profiles in healthy and tumor tissue. RESULTS while phosphorylation of mitogen-activated protein kinase was inhibited in both tissues, gefitinib treatment induced p27 and a decrease in Ki67 in skin but not in tumors. Furthermore, gefitinib did not inhibit the activated form of Akt in the tumors. CONCLUSION This study demonstrates a good correlation between the degree of inhibition of EGFR in skin and in breast tumors. The lack of significant clinical activity of gefitinib in our study population is not due to lack of receptor inhibition in these tumors but rather to lack of EGFR dependence in the tested population.

Quality of life and cognitive function in hepatitis C at different stages of liver disease

BACKGROUND/AIMS Hepatitis C has been associated with a decrease in quality of life and with neurological abnormalities. The aim of our study was to investigate the relationship between quality of life and cognitive function. METHODS Quality of life, clinical variables and neuropsychological function were evaluated in 120 patients with hepatitis C (mild chronic hepatitis, compensated cirrhosis and decompensated cirrhosis) and in healthy controls (n=40, in each group). RESULTS Patients with chronic hepatitis or compensated cirrhosis showed a decrease in quality of life, in spite of unimpaired neuropsychological tests. Patients with decompensated cirrhosis exhibited a further decrease in quality of life and neuropsychological abnormalities. The decrease in quality of life was associated with the severity of liver failure, neuropsychological abnormalities and treatment with beta-blockers or diuretics. However, in the multivariable analysis, only treatment with beta-blockers or diuretics (which was limited to decompensated cirrhosis) was independently associated with quality of life. CONCLUSIONS Hepatitis C causes a decrease in quality of life even in the absence of major cognitive impairment. The mechanisms that worsen quality of life are unknown. However, in cirrhotic outpatients with prior decompensations, treatment with beta-blockers or diuretics appears to have an important effect on quality of life.

Seroprevalence of Trypanosoma cruzi infection in at-risk blood donors in Catalonia (Spain)

BACKGROUND: The increasing arrival of Latin Americans to Europe and, particularly, to Spain has led to the appearance of new pathologies, such as Chagas disease, a zoonotic infection endemic to rural areas of Central and South America. In the absence of the triatomid vector, one of the main modes of transmission of Chagas disease in nonendemic regions is through blood transfusion.

epidemiology of hepatitis C virus infection in seven European Union countries: a critical analysis of the literature

Hepatitis C is now recognized as the most common infection causing chronic liver disease in the European population. Our aim was to assess the prevalence of the antibody to hepatitis C virus (HCV), and the incidence of HCV seroconversion in the general population and the main risk groups, namely intravenous drug users, haemodialysis and transfused patients, in seven countries of the European Union, by carrying out a critical analysis of the literature. Data sources used were the Medline database and a manual search using the key words: hepatitis C, prevalence, incidence, transmission, risk factors and epidemiology. Articles published between January 1990 and March 1997 were reviewed. Articles were reviewed according to a critical analysis method regarding title, type of article, study design, period and population, tests, results and their consistency with data. The tests performed were mainly second- or third-generation serological tests. The average prevalence rate in blood donors was 1%, with a north-south gradient ranging from 0.04% to 2%. Prevalence varied from 20% to 30% in haemodialysis patients. The incidence in transfused patients was less than 1% after 1991. The prevalence in intravenous drug users was about 80%. Multicentre studies conducted in larger samples are needed to obtain more accurate and reliable results, in particular. However, the epidemiological studies available allowed us to assess the magnitude of HCV infection in Europe.Eur J Gastroenterol Hepatol12:667-678

Nucleotide and Amino Acid Complexity of Hepatitis C Virus Quasispecies in Serum and Liver

ABSTRACT The quasispecies nature of the hepatitis C virus (HCV) is thought to play a central role in maintaining and modulating viral replication. Several studies have tried to unravel, through the parameters that characterize HCV circulating quasispecies, prognostic markers of the disease. In a previous work we demonstrated that the parameters of circulating viral quasispecies do not always reflect those of the intrahepatic virus. Here, we have analyzed paired serum and liver quasispecies from 39 genotype 1b-infected patients with different degrees of liver damage, ranging from minimal changes to cirrhosis. Viral level was quantified by real-time reverse transcription-PCR, and viral heterogeneity was characterized through the cloning and sequencing of 540 HCV variants of a genomic fragment encompassing the E2-NS2 junction. Although in 95% of patients, serum and liver consensus HCV amino acid sequences were identical, quasispecies complexity varied considerably between the viruses isolated from each compartment. Patients with HCV quasispecies in serum more complex (26%) than, less complex (28%) than, or similarly complex (41%) to those in liver were found. Among the last, a significant correlation between fibrosis and all the parameters that measure the viral amino acid complexity was found. Correlation between fibrosis and serum viral load was found as well (R = 0.7). With regard to the origin of the differences in quasispecies complexity between serum and liver populations, sequence analysis argued against extrahepatic replication as a quantitatively important contributing factor and supported the idea of a differential effect or different selective forces on the virus depending on whether it is circulating in serum or replicating in the liver.

Peginterferon alpha-2b plus ribavirin vs interferon alpha-2b plus ribavirin for chronic hepatitis C in HIV-coinfected patients

Summary.  Treatment of chronic hepatitis C in human immunodeficiency virus (HIV)‐infected patients is associated with low response rates and high incidence of side effects. One hundred twenty‐one hepatitis C virus (HCV)–HIV‐coinfected patients were randomized to receive interferon alpha‐2b (3 MU thrice weekly; n = 61) or peginterferon alpha‐2b (1.5 μg/kg/week; n = 60), plus ribavirin (800 mg daily), for 24 (genotype 2 or 3) or 48 weeks (genotype 1 or 4). We assessed early virological response at 4, 8 and 12 weeks to predict sustained virological response (SVR). Safety assessment included frequent blood lactate measurement and relative quantitation of mitochondrial DNA (mtDNA) content in peripheral blood mononuclear cells. In intention‐to‐treat analysis, the SVR rate was higher in the peginterferon group (55%vs 26%; P = 0.002). The difference for HCV genotypes 1 and 4 was 45%vs 14% (P = 0.009) and 50%vs 27% (P = 0.387), respectively, and for genotype 2 or 3, 71%vs 43% (P = 0.12) Viral response at 4, 8 and 12 weeks of treatment was highly predictive of SVR. Among genotype 3 patients, 17 of 20 (85%) whose HCV RNA was already undetectable at 4 weeks had an SVR after 24 weeks of treatment. Hyperlactataemia occurred in 22 patients and was clinically significant in six, two of whom died. mtDNA decreased significantly 4–12 weeks after the start of treatment in patients developing clinically significant hyperlactataemia. Peginterferon alpha‐2b plus ribavirin was more effective than interferon alpha‐2b plus ribavirin in HIV‐coinfected patients. Frequent monitoring of virological response may be very helpful to optimize treatment compliance, to tailor treatment duration and to minimize side effects.

Seroprevalence of hepatitis E virus (HEV) and detection of HEV RNA with a transcription-mediated amplification assay in blood donors from Catalonia (Spain).

Hepatitis E virus (HEV) is an emerging threat to the safety of blood transfusion. The aim of this study was to determine HEV immunoglobulin (Ig)G and RNA prevalence in Catalan blood donors.

Long-term follow-up of the hepatitis C HENCORE cohort: response to therapy and occurrence of liver-related complications

Summary.  The aims of the study were to verify the long‐term effect of time on viral clearance in hepatitis C virus (HCV) patients and to find out factors possibly associated with disease progression. A total of 1641 patients recruited from eight European centres in 1996–1997 were re‐analysed 5–7 years after inclusion. The occurrence of decompensated cirrhosis, hepatocellular carcinoma (HCC) and liver transplantation was analysed in relation to different host and viral factors. Ninety‐three per cent of the HCV patients who had cleared the virus (spontaneously or after antiviral therapy) remained HCV‐RNA‐negative during follow up and may be considered as ‘cured’. Among patients who were sustained responders at inclusion, 2.3% developed liver complications during follow up, and 31% of non‐responders did. Advanced age at infection and presence of the human leucocyte antigen (HLA) DRB1*1201–3 allele were possibly associated with a higher rate of progression to decompensated cirrhosis or HCC. Decompensated cirrhosis might be further associated with male gender, non‐response to previous therapy, and lack of HLA DRB1*1301 allele, whereas HCC seems to be associated with the presence of the HLA DQ02 allele. Long‐term follow up of HCV patients indicates that virological response persists over time and is associated with a very low incidence of liver complications. Advanced age at inclusion, advanced age at infection, viral genotype 1, non‐response to previous therapy and possibly some specific HLA alleles are factors independently associated with a faster rate of progression towards liver complications. The large proportion of patients lost to follow up stresses the need for a strengthened and optimized management of HCV patients.

Improvements in subcutaneous fat, lipid profile, and parameters of mitochondrial toxicity in patients with peripheral lipoatrophy when stavudine is switched to tenofovir (LIPOTEST study).

Abstract Background: Lipoatrophy is the most stigmatizing side effect of stavudine therapy. We assessed the long-term effects of replacing stavudine with tenofovir in HIV-infected patients with lipoatrophy. Method: Prospective switch study. Sixty-two clinically stable patients with antiretroviral therapy (ART) containing stavudine, HIV-1 RNA <50 copies/mL, and lipoatrophy at least in the face on physical examination were included. All patients switched from stavudine to tenofovir without changing any other drug. Objective (malar ultasonography, bioelectrical impedance analysis) and subjective measures of lipoatrophy were assessed. Results: Median age at baseline was 40 years, 44 patients (71%) were male, and median time on stavudine was 4.8 years. Median malar fat thickness increased 0.8 mm (25%) 24 months after switching. Total fat mass increased 3.9 kg (21%). Plasma lactate levels decreased significantly, mainly in patients with baseline hyperlactatemia (from 3.05 to 1.19 mmol/L). Significant improvement in total cholesterol (−12%), triglycerides (−31%), and total cholesterol/HDL cholesterol ratio (−11%) was observed at Month 24. Conclusions: In this study, switching from stavudine to tenofovir maintained durable virologic suppression when the HAART regimen included a protease inhibitor or a non-nucleoside reverse transcriptase inhibitor, led to a slow improvement of lipoatrophy, and improved the lipid profile and lactate levels with excellent tolerability. These results support the proactive change of stavudine to tenofovir.