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Hofmann, Wolf-Peter ; Mauß, Stefan ; Lutz, Thomas ; Schober, Andreas ; Böker, Klaus ; Moog, Gero ; Baumgarten, Axel ; Pfeiffer-Vornkahl, Heike ; Alshuth, Ulrich ; Hüppe, Dietrich ; Wedemeyer, Heiner ; Manns, Michael P. ; Schott, Eckart
Background and aims: Individualization of treatment with peginterferon alfa and ribavirin in patients with chronic hepatitis C showed benefit in controlled trials and was implemented in treatment guidelines to increase response rates and to reduce side effects and costs. However, it is unknown whether individualization was adopted in routine daily practice and whether it translated into improved outcomes.
Methods: From a large noninterventional cohort study, clinical and virologic response data of 10,262 HCV patients who received peginterferon alfa-2a and ribavirin between 2003-2007 and 2008-2011 were analyzed. To account for treatment individualization, a matched-pair analysis (2,997 matched pairs) was performed. Variation in treatment duration and dosing of ribavirin were analyzed as indicators for individualization.
Results: Sustained virological response (SVR) rates were similar between 2003-2007 and 2008-2011 (62.0% vs. 63.7%). Patients with comorbidities were more abundant in the later period, (44.3% vs. 57.1%). The subsequent matched-pair analysis demonstrated higher SVR rates in the 2008-2011 period (64.3%) than in the 2003-2007 period (61.2%, p=0.008). More patients received abbreviated or extended treatment regimens in the later than the earlier period as an indicator of treatment individualization. To the same end, ribavirin doses were higher in the later period (12.6 versus 11.6 mg/kg/day). Factors independently associated with SVR included HCV genotype, low baseline viral load, younger age, route of infection, absence of concomitant diseases, lower APRI score, normal gamma-GT, higher ribavirin doses, no substitution for drug abuse, treatment duration, and treatment in the 2008-2011 period.
Conclusions: Treatment individualization with peginterferon alfa and ribavirin was implemented in daily routine between 2003-2007 and 2008-2011, SVR rates improved in the same period. These findings may be most relevant in resource-limited settings.
Kröger, Felix Martin ; Weber, Günter ; Herdrich, Marc Oliver ; Glorius, Jan ; Langer, Christoph ; Slavkovská, Zuzana ; Bott, Lukas ; Brandau, Carsten ; Brückner, Benjamin ; Blaum, Klaus ; Chen, Xin ; Dababneh, Saed ; Davinson, Thomas ; Erbacher, Philipp ; Fiebiger, Stefan ; Gaßner, Tobias ; Göbel, Kathrin ; Groothuis, Mathias ; Gumberidze, Alexandre ; Gyürky, György ; Hagmann, Siegbert ; Hahn, Christoph ; Heil, Michael ; Heß, Regina ; Hensch, Roman ; Hillmann, Paula ; Hillenbrand, Pierre-Michel ; Hinrichs, Ole Djürko ; Jurado Apruzzese, Beatriz ; Kausch, Tanja ; Khodaparast, Anahita ; Kisselbach, Timo ; Klapper, Nadine ; Kozhuharov, Christopher ; Kurtulgil, Cem Deniz ; Lane, Gregory J. ; Lederer-Woods, Claudia ; Lestinsky, Michael ; Litvinov, Sergey A. ; Litvinov, Yuri A. ; Löher, Bastian ; Nolden, Fritz ; Petridis, Nikolaos ; Popp, Ulrich ; Reed, Matthew ; Reifarth, René ; Sanjari, Mohammad Shahab ; Simon, Haik ; Spillmann, Uwe ; Steck, Markus ; Stumm, Julia ; Szücs, Tamas ; Nguyen, Thien Tam ; Taremi Zadeh, Ashkan ; Thomas, Benedikt ; Torilov, Sergey Yu. ; Törnqvist, Hans Toshihide ; Trageser, Christian ; Trotsenko, Sergiy ; Volknandt, Meiko ; Weigand, Mario ; Wolf, Clemens ; Woods, Philip John ; Ševelʹko, Vjačeslav P. ; Stöhlker, Thomas
The electron-capture process was studied for Xe54+ colliding with H2 molecules at the internal gas target of the Experimental Storage Ring (ESR) at GSI, Darmstadt. Cross-section values for electron capture into excited projectile states were deduced from the observed emission cross section of Lyman radiation, being emitted by the hydrogenlike ions subsequent to the capture of a target electron. The ion beam energy range was varied between 5.5 and 30.9 MeV/u by applying the deceleration mode of the ESR. Thus, electron-capture data were recorded at the intermediate and, in particular, the low-collision-energy regime, well below the beam energy necessary to produce bare xenon ions. The obtained data are found to be in reasonable qualitative agreement with theoretical approaches, while a commonly applied empirical formula significantly overestimates the experimental findings.
Röhlen, Natascha ; Döring, Claudia ; Hansmann, Martin-Leo ; Grünwald, Frank ; Vorländer, Christian ; Bechstein, Wolf Otto ; Holzer, Katharina ; Badenhoop, Klaus ; Penna Martinez, Marissa
Background: Protective effects of vitamin D have been reported in autoimmune and malignant thyroid diseases, though little is known about the underlying mechanism. Sirtuin 1 histon deacethylase (SIRT1) links the vitamin D pathway with regulation of transcription factor FOXO3a, a key player in cell cycle regulation and apoptosis. Aim of the present study was to investigate common single nucleotide polymorphisms (SNP's) in FOXO3a gene in respect to thyroid diseases, as well as to evaluate the hypothesis of Sirtuin1-FOXO3a interaction being a mediator of anti-proliferative vitamin D effects.
Methods: The SNP's FOXO3a rs4946936/rs4945816/rs9400239 were genotyped in 257 patients with differentiated thyroid carcinoma (DTC), 139 patients with Hashimoto thyroiditis (HT) and 463 healthy controls (HC). Moreover, T-helper cells of HC and papillary thyroid cancer cell line BCPAP were incubated with 1,25(OH)2D3 and/or SIRT1 inhibitor Ex-527 in order to elucidate SIRT1- dependent vitamin D effects on cell proliferation and FOXO3a gene expression in vitro.
Results: Patients with DTC tended to carry more often allele C in FOXO3a rs4946936 in comparison to HC (pcorrected = pc = 0.08). FOXO3a rs9400239T and rs4945816C was more frequent in HT in comparison to HC (pc = 0.02 and pc = 0.01, respectively). In both DTC and HT, we could not find a correlation of FOXO3a SNP's with vitamin D status. However, on in vitro level, 1,25(OH)2D3 showed an anti-proliferative effect in both T-helper cells and BCPAP, that was blocked by SIRT1 inhibition (T-helper cells: p = 0.0059, BCPAP: p = 0.04) and accompanied by elevated FOXO3a gene expression in T-helper cells (p = 0.05).
Conclusions: FOXO3a rs9400239T and rs4945816C may constitute risk factors for HT, independent of the vitamin D status.This indicates the implication of FOXO3a in pathogenesis of autoimmune thyroid diseases. The dependency of anti-proliferative vitamin D effects on SIRT1 activity further suggests a key role of vitamin D-SIRT1-FOXO3a axis for protective vitamin D effects.