Proteins of the VEGFR and EGFR pathway as predictive markers for adjuvant treatment in patients with stage II/III colorectal cancer: results of the FOGT-4 trial
Jens Martin Kittner
Johannes Wilhelm Rey
Peter Robert Galle
Unlike metastatic colorectal cancer (CRC) there are to date few reports concerning the predictive value of molecular biomarkers on the clinical outcome in stage II/III CRC patients receiving adjuvant chemotherapy. Aim of this study was to assess the predictive value of proteins related with the EGFR- and VEGFR- signalling cascades in these patients.
The patients' data examined in this study were from the collective of the 5-FU/FA versus 5-FU/FA/irinotecan phase III FOGT-4 trial. Tumor tissues were stained by immunohistochemistry for VEGF-C, VEGF-D, VEGFR-3, Hif-1 α, PTEN, AREG and EREG expression and evaluated by two independent, blinded investigators. Survival analyses were calculated for all patients receiving adjuvant chemotherapy in relation to expression of all makers above.
Patients with negative AREG and EREG expression on their tumor had a significant longer DFS in comparison to AREG/EREG positive ones (p< 0.05). The benefit on DFS in AREG-/EREG- patients was even stronger in the group that received 5-FU/FA/irinotecan as adjuvant treatment (p=0.002). Patients with strong expression of PTEN profited more in terms of OS under adjuvant treatment containing irinotecan (p< 0.05). Regarding markers of the VEGFR- pathway we found no correlation of VEGF-C- and VEGFR-3 expression with clinical outcome. Patients with negative VEGF-D expression had a trend to live longer when treated with 5-FU/FA (p=0.106). Patients who were negative for Hif-1 α, were disease-free in more than 50% at the end of the study and showed significant longer DFS-rates than those positive for Hif-1 α (p=0.007). This benefit was even stronger at the group treated with 5-FU/FA/irinotecan (p=0.026). Finally, AREG-/EREG-/PTEN+ patients showed a trend to live longer under combined treatment combination.
The addition of irinotecan to adjuvant treatment with 5-FU/FA does not provide OS or DFS benefit in patients with stage II/III CRC. Nevertheless, AREG/EREG negative, PTEN positive and Hif-1 α negative patients might profit significantly in terms of DFS from a treatment containing fluoropyrimidines and irinotecan. Our results suggest a predictive value of these biomarkers concerning adjuvant chemotherapy with 5-FU/FA +/− irinotecan in stage II/III colorectal cancer.
Fatigue during treatment for hepatitis C virus: results of self-reported fatigue severity in two Phase IIb studies of simeprevir treatment in patients with hepatitis C virus genotype 1 infection
Donna M. Evon
Fatigue is a common symptom of chronic hepatitis C virus (HCV) infection and a frequent side-effect of peginterferon/ribavirin (PR) therapy for HCV. This study evaluated the impact of adding the oral HCV NS3/4A protease inhibitor simeprevir to PR on patient-reported fatigue and health status among patients with chronic HCV genotype 1 infection enrolled in the Phase IIb PILLAR and ASPIRE trials [NCT00882908; NCT00980330].
Treatment-naïve patients (PILLAR, n = 386) and treatment-experienced patients (ASPIRE, n = 462) were randomized to simeprevir plus PR (simeprevir/PR) or placebo plus PR (placebo/PR). In PILLAR, duration of PR treatment in the simeprevir/PR groups was determined using response-guided therapy (RGT) criteria. PR could be terminated at Week 24, instead of Week 48, if HCV RNA was <25 IU/mL by Week 4 and then undetectable at Weeks 12, 16, and 20. In both studies, patients completed the Fatigue Severity Scale (FSS) and EQ-5D quality-of-life questionnaire in their native language at baseline and throughout the studies up until Week 72.
During the first 24 weeks of treatment, mean FSS total score was increased to a similar degree compared with baseline among patients receiving simeprevir/PR or placebo/PR in both studies indicating increased fatigue severity. Mean FSS scores returned to values comparable with baseline among patients receiving simeprevir/PR after Week 24 in PILLAR (after treatment completion for the majority of patients) and in ASPIRE (after Week 48), consistent with RGT enabling early termination of all treatment at Week 24 in 82.2% of simeprevir/PR-treated patients in the PILLAR study. Similar results were observed for EQ-5D, with simeprevir/PR-treated patients experiencing less time with worse health problems according to EQ-5D scores compared with placebo/PR groups in both studies, and more rapid improvement in health status associated with shorter treatment duration in the PILLAR study.
Combination of simeprevir with PR did not increase patient-reported fatigue severity or health status impairments beyond that reported by patients treated with PR alone. Many patients treated with simeprevir/PR returned to pretreatment fatigue and health status levels sooner due to increased treatment efficacy that enabled shorter duration of all therapy, compared with PR alone.
Treatment of unresectable stage IV metastatic melanoma with aviscumine after anti-neoplastic treatment failure: a phase II, multi-centre study
Katharina C. Kähler
Aviscumine, a recombinant plant protein, is an immune modulator that induces ribotoxic stress at the 28S ribosomal RNA subunit. In this way cytokine release and T-cell responses are enhanced. This phase II trial was conducted to test the efficacy and safety of aviscumine in patients with systemically pre-treated metastatic melanoma stage IV.
A total of 32 patients with progressive stage IV melanoma after failure of standard therapy were enrolled onto a single-arm, multi-centre, open-label, phase II trial. All patients had an ECOG performance status of 0 or 1. Patients received 350 ng aviscumine twice weekly by subcutaneous injection until progression. The primary end points were progression-free survival (PFS) and overall survival (OS). Safety was assessed as adverse events (AEs). Tumor response was assessed every eight weeks and survival of patients was followed up to one year after the end of therapy. Thirty one patients (intent-to-treat population (ITT)) were assessed for efficacy; safety was assessed in the whole population.
One patient achieved a partial response (PR) and 10 patients showed stable disease/no change (SD). The median progression-free survival (mPFS) was 63 days (95% CI 57–85) and median overall survival (mOS) was 335 days (95% CI 210–604). In total 210 treatment-emergent adverse events were recorded. Grade 1 or 2 AEs occurred in 72% of patients and were mostly application-site effects such as pruritus Grade 3–4 treatment-emergent drug-related adverse events occurred in 9% of patients.
These results suggest that aviscumine may have a clinical impact in patients with previously treated metastatic melanoma and provide rationale for further clinical evaluation of this agent. In the light of effective new immune checkpoint blockers it might be a candidate for combinations with these agents.
Burden of carbapenem-resistant organisms in the Frankfurt/Main Metropolitan Area in Germany 2012/2013 – first results and experiences after the introduction of legally mandated reporting
Volkhard A.J. Kempf
In silico analysis of regulatory networks underlines the role of miR-10b-5p and its target BDNF in huntington’s disease
- Non-coding RNAs (ncRNAs) play various roles during central nervous system development. MicroRNAs (miRNAs) are a class of ncRNAs that exert their function together with argonaute proteins by post-transcriptional gene silencing of messenger RNAs (mRNAs). Several studies provide evidence for alterations in miRNA expression in patients with neurodegenerative diseases. Among these is huntington‘s disease (HD), a dominantly inherited fatal disorder characterized by deregulation of neuronal-specific mRNAs as well as miRNAs. Recently, next-generation sequencing (NGS) miRNA profiles from human HD and neurologically normal control brain tissues were reported. Five consistently upregulated miRNAs affect the expression of genes involved in neuronal differentiation, neurite outgrowth, cell death and survival. We re-analyzed the NGS data publicly available in array express and detected nineteen additional differentially expressed miRNAs. Subsequently, we connected these miRNAs to genes implicated in HD development and network analysis pointed to miRNA-mediated downregulation of twenty-two genes with roles in the pathogenesis as well as treatment of the disease. In silico prediction and reporter systems prove that levels of BDNF, a central node in the miRNA-mRNA regulatory network, can be post-transcriptionally controlled by upregulated miR-10b-5p and miR-30a-5p. Reduced BDNF expression is associated with neuronal dysfunction and death in HD. Moreover, the 3’UTR of CREB1 harbors a predicted binding site for these two miRNAs. CREB1 is similarly downregulated in HD and overexpression decreased susceptibility to 3-nitropropionic-induced toxicity in a cell model. In contradiction to these observations, it is presumed that miR-10b-5p upregulation in HD exerts a neuroprotective role in response to the mutation in the huntingtin gene. Therefore, the function of miR-10b-5p and especially its effect on BDNF expression in HD requires further academic research.
Editorial: (Micro)Plastics and the environment
- (Micro)Plastics in the aquatic environment are an issue of emerging concern. However, to date, there is considerable lack of knowledge on the abundance and toxicity of plastic debris in aquatic ecosystems, especially with regard to the freshwater situation. In this editorial, we briefly discuss important aspects of the research on environmental (micro)plastics to stimulate research and call for papers.
Effects of flavonoid-induced oxidative stress on anti-H5N1 influenza a virus activity exerted by baicalein and biochanin A
Jindrich Cinatl Jr
Different flavonoids are known to interfere with influenza A virus replication. Recently, we showed that the structurally similar flavonoids baicalein and biochanin A inhibit highly pathogenic avian H5N1 influenza A virus replication by different mechanisms in A549 lung cells. Here, we investigated the effects of both compounds on H5N1-induced reactive oxygen species (ROS) formation and the role of ROS formation during H5N1 replication.
Baicalein and biochanin A enhanced H5N1-induced ROS formation in A549 cells and primary human monocyte-derived macrophages. Suppression of ROS formation induced by baicalein and biochanin A using the antioxidant N-acetyl-L-cysteine strongly increased the anti-H5N1 activity of both compounds in A549 cells but not in macrophages.
These findings emphasise that flavonoids induce complex pharmacological actions some of which may interfere with H5N1 replication while others may support H5N1 replication. A more detailed understanding of these actions and the underlying structure-activity relationships is needed to design agents with optimised anti-H5N1 activity.
Aeshna viridis (Eversmann, 1836) - Grüne Mosaikjungfer
- Aeshna viridis hat wie alle Aeshniden einen mosaikartig gemusterten Hinterleib. Die Brustseiten sind grün mit dünnen braunen Nahten. Die Farbe der Hinterleibseiten der Weibchen ist ebenfalls grün. Auf den Hinterleibsegmenten zwei bis neun der Männchen befinden sich blaue Flecken, so dass Verwechslungsgefahr mit Aeshna cyanea besteht.
Hans Ulrich Gumbrechts Begriff der Präsenz und die Literatur
Die Mehrheit will das nicht hören : Gilles Deleuze' Konzept der 'littérature mineure'
- Literatur ist revolutionär. Nicht im Sinne einer littérature engagée, sondern als Äußerung, als Sprechakt, als eine bestimmte Konfiguration von Sprache. In ihrer Studie 'Kafka. Pour une littérature mineure' entwickeln Gilles Deleuze und Félix Guattari diesen Gedanken einer Kleinen Literatur. Sie setzen dabei bei einigen Tagebucheinträgen Kafkas an, in denen dieser Skizzen zu einem Konzept einer kleinen Literatur entwickelt. Als deutschsprachiger Jude in Prag gehörte Kafka einer doppelten Minderheit an: der der Deutschsprechenden und der der Juden. Daher stellt sich für Kafka die Frage, in was für einer Sprache er schreiben soll: auf Tschechisch, Deutsch oder Jiddisch? Kafka hat sich bekanntermaßen für das Deutsche entschieden. Doch wie kann man auf Deutsch, der Sprache der übergroßen Literaturdenkmäler Goethe und Schiller, schreiben? Auf welche Art und Weise nähert man sich als Minderheitensprecher einer solchen Sprache? Schließlich ist das Deutsche eine große Sprache, eine Sprache einer Mehrheit, in der literarische Wege vermeintlich vorgezeichnet sind. Beispielsweise durch die oben genannten Vorbilder, die man in Zuspitzung der These für die ganze Literatur nehmen kann und die damit zur Imitation auffordern. In diesem Kontext entwickelte Kafka jenes Konzept der kleinen Literatur, deren drei Pfeiler Deleuze und Guattari folgendermaßen benennen: "Les trois caractères de la littérature mineure sont la déterritorialisation de la langue, le branchement de l‘individuel sur l‘immédiat-politique, l‘agencement collectif d‘énonciation". Dieser Essay soll diese drei Punkte verknüpft mit Deleuze's Konzepten der Sprache und des Werdens genauer ausführen. Zunächst muss jedoch der Begriff der Minderheit im Deleuze'schen Sinne konkretisiert werden.