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Biomedical subjects

S Zeuzem

Publications and source records attributed to S Zeuzem.

At least 19 recordsLinked to original sources
PubMed2007

Second-line chemotherapy with pemetrexed after gemcitabine failure in patients with advanced pancreatic cancer: a multicenter phase II trial.

BACKGROUND: A standard second-line chemotherapy regimen has yet to be defined for patients with gemcitabine (Gem)-refractory advanced pancreatic cancer (PC). PATIENTS AND METHODS: In this multicenter phase II trial, patients with unresectable or metastatic PC who had progressed on single-agent Gem or a Gem-containing regimen received pemetrexed 500 mg/m(2) as a 10-min infusion every 3 weeks until disease progression or occurrence of unacceptable toxicity. The primary end point was the 3-month survival rate. RESULTS: A total of 192 treatment cycles were given to 52 patients. The overall response rate was 3.8% (two partial responses); 10 patients (19.2%) experienced stable disease, nine of them for >12 weeks. At least one CA 19-9 reduction > or =50% occurred in 12 patients (23.1%). The 3-month survival rate was 75% (95% confidence interval 63.2% to 86.8%), the median time to tumor progression was 7 weeks (range 1-62 weeks) and the median overall survival time was 20 weeks (range 1-84 weeks). Grade 3/4 hematological toxic effects included (percent of patients): neutropenia (17.3%), thrombocytopenia (5.8%) and anemia (3.8%). The most frequent non-hematological toxic effects were diarrhea, nausea and stomatitis/pharyngitis (23.1% each). CONCLUSION: Pemetrexed is a safe treatment option with moderate activity in patients with advanced PC after failure of Gem.

Adult↗
PubMed2007

Impact of hepatic steatosis on viral kinetics and treatment outcome during antiviral treatment of chronic HCV infection.

Liver steatosis is highly prevalent in chronic hepatitis C virus (HCV) infection, especially in patients infected with genotype 3 virus, but its significance for the outcome of antiviral treatment is not fully understood. We have monitored steatosis in liver biopsies from 231 patients with chronic HCV infection who received pegylated recombinant interferon-alpha and ribavirin in a phase III study (DITTO trial). The degree of steatosis, along with relevant metabolic parameters, was correlated with the early disappearance of virus and with the final outcome of treatment. Our data suggest that the presence of steatosis impairs the early reduction of viral load during treatment in patients infected with HCV genotype 3 and non-3. Steatosis negatively affected the final outcome of treatment mainly in patients infected with HCV genotype non-3 virus. Based on these findings, we propose that interventions aiming at reducing hepatic steatosis prior to the onset of antiviral therapy may be of benefit to patients infected with HCV of the non-3 genotypes. Patients infected with genotype 3, on the other hand, should be offered early antiviral treatment.

Adult↗
PubMed2006

Review article: management of patients with chronic hepatitis C virus infection and "normal" alanine aminotransferase activity.

BACKGROUND: Hepatitis C virus infection, a major cause of chronic liver disease, occurs with normal serum alanine aminotransferase activity in approximately 25% of patients. These patients have historically remained untreated but substantial evidence indicates liver damage, progression of disease and impaired quality of life in some individuals. AIM: To review the current management of patients with chronic hepatitis C and normal alanine aminotransferase activity. METHODS: This review represents the summary of discussions at a Clinical Workshop with a comprehensive literature searching of available databases (PubMed and Embase). RESULTS: Current limits defining normal serum alanine aminotransferase activity are not representative of a "healthy" status. Most patients with hepatitis C and normal alanine aminotransferase levels have histologically proven liver damage that, although generally mild, may be significant (> or =F2) in up to 20% of patients and progresses at approximately 50% of the rate in patients with elevated alanine aminotransferase levels. Some patients have persistently normal alanine aminotransferase activity and may have a more benign outcome, but a significant proportion (> or =20%) experience periods of increased serum alanine aminotransferase activity which may be associated with enhanced disease progression. CONCLUSIONS: A treatment approach that considers host and virus-related variables and optimizes patient and cost benefits may therefore provide more effective management of patients with chronic hepatitis C and normal alanine aminotransferase activity.

Alanine Transaminase↗
PubMed2006

Multicenter performance evaluation of a new TaqMan PCR assay for monitoring human immunodeficiency virus RNA load.

A TaqMan real-time PCR assay, the COBAS TaqMan human immunodeficiency virus (HIV) (HPS-CTMHIV) PCR assay, recently developed for the quantification of HIV type 1 RNA in plasma, was evaluated in comparison with the licensed COBAS AMPLICOR HIV-1 MONITOR (CAHIM) assay. In this study, we have analyzed the tests' sensitivities, precisions, and linearities using multiple replicates of a standard panel of HIV RNA covering a 7-logarithm range of concentrations, as well as serial threefold dilutions of high-titer clinical samples. The subtype inclusivity was also investigated, using a panel of subtypes A to H, while a collection of 160 clinical samples was analyzed to assess the tests' specificities and the systems' similarities. The results of these experiments showed that the HPS-CTMHIV assay has a sensitivity of 53 copies/ml (95% hit rate), 100% specificity, and good intra- and interassay precision. The results of the HPS-CTMHIV assay were linear in the 50- to 10(7)-copies/ml range, with a correlation coefficient (R) for expected versus observed results of 0.98. Compared to the CAHIM assay, the HPS-CTMHIV assay showed a high correlation (R=0.99) across the dynamic range of RNA concentrations that, for the CAHIM assay, requires two different sample preparations. Equivalent performances were also observed for the two systems in the detection and quantification of HIV subtypes A to H. These data indicate that the HPS-CTMHIV assay may be one of the tests of choice for monitoring viral load throughout the course of HIV infection and during highly active antiretroviral therapy.

Analysis of Variance↗
PubMed2006

[Difficult-to-treat patients with chronic hepatitis C].

Combination therapy with pegylated interferon-alpha plus ribavirin is the current standard of care. Undetectable HCV-RNA in serum by a sensitive molecular test six months after the end of treatment is the primary aim of antiviral therapy in patients with hepatitis C. The group of "difficult-to-treat" patients is heterogeneous and comprises patients with a difficult indication for antiviral therapy (asymptomatic, minimal histological activity, persistently normal aminotransferase levels, etc.), patients with low chances for achieving a sustained virologic response (HCV genotype 1 infection, high baseline viral load, liver cirrhosis, immunosuppression, HIV coinfection, etc.), patients without sustained virologic response in a previous treatment course (nonresponder, relapser), patients who cannot tolerate interferon-alpha and/or ribavirin, and patients with poor compliance. Councelling in an experienced center is advised in the case of a difficult decision whether to treat or not. Options in patients with low chances for a sustained virologic response and in nonresponders are retreatment with a pegylated interferon and ribavirin at a higher dose and/or a longer treatment duration. Clinical trials with new antiviral agents are highly relevant for this patient population as for those patients who cannot tolerate (peg)interferon-alpha and/or ribavirin. Side effects in patients receiving pegylated interferon-alpha and ribavirin should be actively treated (e.g. serotonine re-uptake inhibitors for depression, erythropoetin for ribavirin-associated anemia, etc.). In addition, optimisation of adherence and compliance is always mandatory.

Antiviral Agents↗
PubMed2006

Review article: predicting response in hepatitis C virus therapy.

The introduction of combination therapy with ribavirin and of pegylated interferons has improved treatment results in patients with chronic hepatitis C. However, overall rates of sustained virologic response following antiviral therapy of chronic hepatitis C still do not exceed 54-63%. Because of several virus- and patient-related factors, treatment is even less successful in some patient subpopulations. The major viral factors associated with impaired response are hepatitis C virus genotype 1 infection and a high viral load. Among patient-related factors cirrhosis is of special importance. Baseline predictive factors for sustained virologic response become less important for prediction of treatment outcome when quantifications of hepatitis C virus RNA during early therapy are taken into account. This article provides a summary of virus- and patient-related parameters, which are prognostic for response to antiviral therapy in chronic hepatitis C and focuses on the prediction of treatment response by quantification of hepatitis C virus RNA concentration during therapy.

Antiviral Agents↗
PubMed2006

[Individualised treatment of chronic hepatitis C].

Patients infected with HCV genotype 1 are treated with a pegylated interferon plus ribavirin for 48 weeks, while HCV-2 or 3 infected patients are treated for 24 weeks. Knowledge of the HCV genotype and fibrosis stage together with baseline viremia and the initial virologic response to therapy enables further individualization of the treatment duration. Non-cirrhotic patients with HCV-1 infection, a baseline viremia < 600,000 U/ml and a rapid virologic response (< 50 U/ml at week 4) can achieve a sustained virologic response rate of almost 90% with only 24 weeks of combination therapy. HCV-2 and HCV-3 infected patients with low baseline viremia can be treated for less than 24 weeks without compromising sustained virologic response rates. A longer treatment duration of up to 72 weeks appears reasonable for HCV-1 infected patients with serum HCV RNA levels of 50-6,000 U/ml at week 12 of therapy.

Antiviral Agents↗
PubMed2006

[Effectiveness of antiviral therapy in patients with chronic hepatitis C treated by private practice gastroenterologists].

The standard treatment for patients with chronic hepatitis C consists of pegylated interferon (PegIFN) alpha in combination with ribavirin. Information on treatment effectiveness outside clinical trials is sparse. To study community-based health care, a regional network supported by the German network of competence for hepatitis (Hep-Net) was created between gastroenterologists in private practice and a tertiary referral centre. A treatment register containing evidence-based guidelines was established and 212 consecutive patients who were treated with either PegIF Nalpha 2a/ribavirin (n = 126) or PegIFNalpha2b/ribavirin (n = 86) for 24 weeks (HCV genotype 2, 3) and 48 weeks (HCV genotype 1, 4, 5), respectively, were included and followed prospectively. Twenty-four weeks after cessation of antiviral treatment a sustained virological response was achieved in 54 % of the patients. By univariate analyses, infection with HCV genotypes 2 or 3 (p < 0.0001), younger age (p < 0.0001), normal gamma-glutamyltransferase levels before initiation of treatment (p = 0.003), and absence of language communication problems (p = 0.023) were associated with a sustained virological response. The presence of liver cirrhosis in patients with HCV genotype 1, 4, 5 infection was associated with lower sustained response rates (p = 0.025). Patients infected with HCV genotype 1 in whom the PegIFNalpha dose was reduced had higher virological relapse rates (p = 0.049). With regard to the treating physician, sustained virological response rates ranged from 26 - 67 % in patients infected with HCV genotype 1. Our study shows that virological response rates similar to those in international randomised clinical trials can be achieved by private practice gastroenterologists. The presented network allows characterization of the treatment outcome in chronic hepatitis C not only with regard to virus- and host-related factors but also on an individual physician basis.

Adult↗
PubMed2006

The economics of treating chronic hepatitis C patients with peginterferon alpha-2a (40 kDa) plus ribavirin presenting with persistently normal aminotransferase.

Peginterferon alpha-2a (40 kDa) plus ribavirin is effective at achieving sustained viral response compared with no treatment in patients with chronic hepatitis C (CHC) and persistently normal aminotransferase levels (PNALT). The cost-effectiveness of treating CHC in the setting of PNALT has not been assessed. Disease progression in patients with PNALT was simulated in a Markov model. The rate of fibrosis progression, quality of life and costs for each health state were based on literature estimates. The perspective of the Italian National Health Service was adopted and costs (euro 2003) and benefits were discounted at 3%. Sensitivity analyses were performed on important parameters. The primary analysis compared combination therapy with peginterferon alpha-2a (40 kDa) plus ribavirin to no treatment in a cohort of patients with mean age 45 years, and was based on findings from a multinational, randomized trial in patients with PNALT. In genotype 1 patients, the risk of cirrhosis at 30 years is forecast to fall from 32% with no treatment to 19% with combination therapy, increasing quality-adjusted life years (QALYs) by 0.74 years at an incremental cost per QALY gained of euro 16,831. The 30-year risk of cirrhosis in genotype 2 or 3 is projected to fall to 9% with combination therapy, an increase in QALYs of 1.34 years, at an incremental cost per QALY gained of euro 3,000. Thus treatment of PNALT with peginterferon alpha-2a (40 kDa) plus ribavirin is projected to reduce the incidence of cirrhosis, increase life expectancy and have an acceptable cost-effectiveness ratio from a societal perspective.

Adult↗
PubMed2006

Impaired health-related quality of life in patients with chronic hepatitis C and persistently normal aminotransferase levels.

A significant impact of hepatitis C virus (HCV) infection on health-related quality of life (HRQOL) has been previously described. However, comprehensive data on the quality of life in patients with chronic hepatitis C and persistently normal aminotransferase levels (PNAL) are currently not available. One hundred fifteen patients with chronic hepatitis C (45 with persistently normal aminotransferases and 70 with elevated aminotransferases) and 50 healthy subjects were enrolled. Emotional and psychological states were assessed by Profile of Mood States (POMS) scale and HRQOL was assessed by the 'Everyday Life' questionnaire (EDLQ), a validated questionnaire related to the SF-36 Health Survey. An impairment in HRQOL was observed in patients with chronic hepatitis C showing PNAL compared with healthy subjects with significant differences for the factor scores depression and anger in the POMS scale as well as for the items body, relationship to partner, self-confidence and zest of life in the EDLQ. No differences in any questionnaire were observed between patients with chronic hepatitis C showing PNAL or elevated aminotransferase levels except of a worse mean level for factor score anger in POMS scale in patients with persistently normal aminotransferases. No association of quality of life with severity of liver disease was found. Impairment of HRQOL by chronic infection with HCV is similar in patients with PNAL and those with elevated aminotransferase levels.

Adult↗
PubMed2005

Increased cytokine transcripts in pouchitis reflect the degree of inflammation but not the underlying entity.

BACKGROUND AND AIMS: After ileopouch anal anastomosis (IPAA), 10-40% of patients with ulcerative colitis (UC) but only 5% of patients with familial adenomatous polyposis (FAP) develop pouchitis. Immunoregulatory abnormalities might be of importance in the pathogenesis of the disease. Therefore, we characterized cytokine and chemokine transcripts in inflamed and non-inflamed pouches in patients with UC compared to those with FAP and Crohn's disease (CD). PATIENTS AND METHODS: Mucosal biopsies were taken from 87 patients with IPAA [UC (n=70), CD (n=8) or FAP (n=9)]. Patients with active ileal CD (n=14), active UC (n=17) and non-inflammatory conditions (n=12) served as controls. The expression of 20 gene transcripts was quantified using real-time polymerase chain reaction. RESULTS AND FINDINGS: Pro-inflammatory cytokines and chemokines are significantly increased in IPAA patients with acute pouchitis. This increase is independent of the underlying disease (UC or CD) and reflects the degree of inflammation. A good correlation between pouchitis activity (using the Pouchitis Disease Activity Index) and the MRP-14, interleukin-8, macrophage inflammatory protein-2alpha and matrix metalloproteinase-1 transcripts was observed. INTERPRETATIONS AND CONCLUSIONS: Our data support the view that pouchitis reflects an inflammatory process that is different from that of underlying inflammatory bowel diseases, as the cytokine and chemokine patterns in pouchitis are neither typical of CD nor of UC, but maybe due to bacterial intestinal microflora overgrowth in the pouch lumen. Quantification of transcript levels allows an estimation of the extent of mucosal inflammation and may become helpful in the evaluation of the disease, especially in clinical trials.

Adolescent↗
PubMed2005

[Treatment of hepatitis C virus infection].

Undetectable hepatitis C virus (HCV)-specific RNA in serum six months after the end of treatment is the primary aim of antiviral therapy in patients with chronic hepatitis C. Long-term studies confirmed that viral eradication is durable in more than 95% of cases. The high chronification rate of acute hepatitis C (50 to 80%) justifies therapeutic strategies to prevent a chronic course of the infection. Monotherapy with interferon-alpha for 24 weeks can prevent chronification in more than 90% of patients with acute hepatitis C. Antiviral therapy should be considered in all patients with chronic hepatitis C, who are symptomatic, or have a considerable risk for the development of liver cirrhosis and its sequelae, if they have no contraindication for therapy. Furthermore, treatment should be considered in all patients who carry a substantial risk to infect others. Combination therapy with a pegylated interferon-alpha plus ribavirin is the current standard of care and achieves sustained virologic response rates of 54 to 61%. Patients chronically infected with genotype HCV-1 isolates should be treated for 48 weeks (independent from baseline viral load), while in patients infected with HCV-2 or -3 isolates 24 weeks of treatment are sufficient. Patients without sustained virologic response can still benefit histologically from an interferon-alpha based therapy. Possibly, interferon-alpha also reduces the risk for patients with chronic hepatitis C to develop hepatocellular carcinoma.

AIDS-Related Opportunistic Infections↗
PubMed2005

The safety of pegylated interferon alpha-2b in the treatment of chronic hepatitis B: predictive factors for dose reduction and treatment discontinuation.

BACKGROUND: Treatment with interferon-alpha has been shown to be effective in one-third of hepatitis B e antigen-positive chronic hepatitis B patients, but is clinically associated with relevant adverse events. AIM: To investigate the safety of pegylated interferon alpha-2b in 300 hepatitis B e antigen-positive patients with compensated liver disease. METHODS: Patients were treated with pegylated interferon alpha-2b for 52 weeks combined with either lamivudine 100 mg/day or placebo. Pegylated interferon alpha-2b was administered for 100 microg once a week for 32 weeks; thereafter, the dose was reduced to 50 microg once a week. Adverse events and their effect on study medication were reported at monthly visits in a standardized way. RESULTS: The most frequently reported side-effects were flu-like syndrome (68%), headache (40%), fatigue (39%), myalgia (29%) and local reaction at the injection site (29%). These symptoms typically occurred within the first month of therapy and subsided during the course of therapy. Neutropenia and thrombocytopenia induced by pegylated interferon alpha-2b increased the risk of infections and bleeding complications, but these complications were rare and mild. The frequency of all side-effects was not different between patients treated with pegylated interferon alpha-2b combined with lamivudine or placebo. In 69 (22%) patients the dose of pegylated interferon alpha-2b was reduced prematurely. Of these dose reductions, 36 (52%) were because of neutropenia. Therapy was discontinued in 28 (8%) patients. The most frequent reasons for early discontinuation were psychiatric side-effects (depression, psychosis) and flu-like symptoms. Multivariate Cox regression analysis showed that low neutrophil count at baseline and cirrhosis were independent predictors of dose reduction or therapy discontinuation. CONCLUSION: We conclude that in patients with chronic hepatitis B and compensated liver disease prolonged pegylated interferon alpha-2b therapy is safe, and that pre-existent cirrhosis and neutropenia are the most important predictors of dose reduction or early treatment discontinuation.

Adult↗
PubMed2005

13C-methacetin breath test as liver function test in patients with chronic hepatitis C virus infection.

BACKGROUND: The 13C-methacetin breath test enables the quantitative evaluation of the cytochrome P450-dependent liver function. AIM: To find out whether this breath test is sensitive in noncirrhotic patients also with chronic hepatitis C in early stages of fibrosis. METHODS: Sixty-one healthy controls and 81 patients with chronic hepatitis C underwent a 13C-methacetin breath test. In all patients, a liver biopsy was performed. The liver histology was classified according to the histology activity index-Knodell score. RESULTS: Delta over baseline values of the patients at 15 min significantly differed from controls (19.2 +/- 9.2 per thousand vs. 24.1 +/- 5.7 per thousand; P < 0.003). The cumulative recovery after 30 min in patients was 11.4 +/- 4.8% and in healthy controls 13.8 +/- 2.8% (P < 0.002). However, patients with early fibrosis (histology activity index IVB) did not differ in delta over baseline values of the patients at 15 min (23.2 +/- 7.9 per thousand vs. 22.6 +/- 7.2 per thousand; P = 0.61) or cumulative recovery (13.6 +/- 3.7% vs. 13.2 +/- 3.8%; P = 0.45) from patients with more advanced fibrosis (histology activity index IVC). Patients with clinically nonsymptomatic cirrhosis (histology activity index IVD; Child A) metabolized 13C-methacetin to a significantly lesser extent (delta over baseline values of the patients at 15 min: 8.3 +/- 4.9 per thousand; P < 0.005 and cumulative recovery after 30 min: 5.6 +/- 3.2%; P < 0.003). The 13C-methacetin breath test identified cirrhotic patients with 95.0% sensitivity and 96.7% specificity. CONCLUSION: The non-invasive 13C-methacetin breath test reliably distinguishes between early cirrhotic (Child A) and noncirrhotic patients, but fails to detect early stages of fibrosis in patients with chronic hepatitis C.

Acetamides↗
PubMed2005

Characterization of the nuclear import of human MutLalpha.

DNA mismatch repair (MMR) is essential for the maintenance of replication fidelity. Its major task is to recognize mismatches as well as insertion/deletion loops of newly synthesized DNA strands. Although different players of human MMR have been identified, the regulation of essential steps of MMR is poorly understood. Because MMR is initiated in the nucleus, nuclear import might be a mechanism to regulate MMR. Nuclear targeting is accomplished by conserved signal sequences called nuclear localization signals (NLS), which represent clusters of positively charged amino acids (aa). hMLH1 contains two clusters of positively charged amino acids, which are candidate NLS sequences (aa 469-472 and 496-499), while hPMS2 contains one (aa 574-580). To study the effect of these clusters on nuclear import, NLS mutants of hMLH1 and hPMS2 were generated and expressed in 293T cells. The subcellular localization of the mutant constructs was monitored by confocal laser microscopy. We demonstrated that missense mutations of two signal sequences, one in hMLH1 and one in hPMS2, lead to impaired nuclear import, which was especially prominent for mutants of the hMLH1 residues K471 and R472; and hPMS2 residues K577 and R578.

Amino Acid Sequence↗