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  • 1
    Keywords: GROWTH-FACTOR RECEPTOR ; chemotherapy ; GEFITINIB ; tyrosine kinase inhibitors ; erlotinib ; OPEN-LABEL ; 1ST-LINE TREATMENT ; RANDOMIZED PHASE-3 TRIAL ; CARBOPLATIN-PACLITAXEL ; PROLONGED SURVIVAL
    Abstract: BACKGROUND: Most patients with non-small-cell lung cancer tumours that have EGFR mutations have deletion mutations in exon 19 or the Leu858Arg point mutation in exon 21, or both (ie, common mutations). However, a subset of patients (10%) with mutations in EGFR have tumours that harbour uncommon mutations. There is a paucity of data regarding the sensitivity of these tumours to EGFR inhibitors. Here we present data for the activity of afatinib in patients with advanced non-small-cell lung cancer that have tumours harbouring uncommon EGFR mutations. METHODS: In this post-hoc analysis, we used prospectively collected data from tyrosine kinase inhibitor-naive patients with EGFR mutation-positive advanced (stage IIIb-IV) lung adenocarcinomas who were given afatinib in a single group phase 2 trial (LUX-Lung 2), and randomised phase 3 trials (LUX-Lung 3 and LUX-Lung 6). Analyses were done in the intention-to-treat population, including all randomly assigned patients with uncommon EGFR mutations. The type of EGFR mutation (exon 19 deletion [del19], Leu858Arg point mutation in exon 21, or other) and ethnic origin (LUX-Lung 3 only; Asian vs non-Asian) were pre-specified stratification factors in the randomised trials. We categorised all uncommon mutations as: point mutations or duplications in exons 18-21 (group 1); de-novo Thr790Met mutations in exon 20 alone or in combination with other mutations (group 2); or exon 20 insertions (group 3). We also assessed outcomes in patients with the most frequent uncommon mutations, Gly719Xaa, Leu861Gln, and Ser768Ile, alone or in combination with other mutations. Response was established by independent radiological review. These trials are registered with ClinicalTrials.gov, numbers NCT00525148, NCT00949650, and NCT01121393. FINDINGS: Of 600 patients given afatinib across the three trials, 75 (12%) patients had uncommon EGFR mutations (38 in group 1, 14 in group 2, 23 in group 3). 27 (71.1%, 95% CI 54.1-84.6) patients in group 1 had objective responses, as did two (14.3%, 1.8-42.8) in group 2 and two (8.7%, 1.1-28.0) in group 3. Median progression-free survival was 10.7 months (95% CI 5.6-14.7) in group 1, 2.9 months (1.2-8.3) in group 2; and 2.7 months (1.8-4.2) in group 3. Median overall survival was 19.4 months (95% CI 16.4-26.9) in group 1, 14.9 months (8.1-24.9) in group 2, and 9.2 months (4.1-14.2) in group 3. For the most frequent uncommon mutations, 14 (77.8%, 95% CI 52.4-93.6) patients with Gly719Xaa had an objective response, as did nine (56.3%, 29.9-80.2) with Leu861Gln, and eight (100.0%, 63.1-100.0) with Ser768Ile. INTERPRETATION: Afatinib was active in non-small-cell lung cancer tumours that harboured certain types of uncommon EGFR mutations, especially Gly719Xaa, Leu861Gln, and Ser768Ile, but less active in other mutations types. Clinical benefit was lower in patients with de-novo Thr790Met and exon 20 insertion mutations. These data could help inform clinical decisions for patients with non-small-cell lung cancer harbouring uncommon EGFR mutations. FUNDING: Boehringer Ingelheim.
    Type of Publication: Journal article published
    PubMed ID: 26051236
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  • 2
    Abstract: INTRODUCTION: Metastatic spread to the brain is common in patients with non-small cell lung cancer (NSCLC), but these patients are generally excluded from prospective clinical trials. The studies, phase III study of afatinib or cisplatin plus pemetrexed in patients with metastatic lung adenocarcinoma with EGFR mutations (LUX-Lung 3) and a randomized, open-label, phase III study of BIBW 2992 versus chemotherapy as first-line treatment for patients with stage IIIB or IV adenocarcinoma of the lung harbouring an EGFR activating mutation (LUX-Lung 6) investigated first-line afatinib versus platinum-based chemotherapy in epidermal growth factor receptor gene (EGFR) mutation-positive patients with NSCLC and included patients with brain metastases; prespecified subgroup analyses are assessed in this article. METHODS: For both LUX-Lung 3 and LUX-Lung 6, prespecified subgroup analyses of progression-free survival (PFS), overall survival, and objective response rate were undertaken in patients with asymptomatic brain metastases at baseline (n = 35 and n = 46, respectively). Post hoc analyses of clinical outcomes was undertaken in the combined data set (n = 81). RESULTS: In both studies, there was a trend toward improved PFS with afatinib versus chemotherapy in patients with brain metastases (LUX-Lung 3: 11.1 versus 5.4 months, hazard ratio [HR] = 0.54, p = 0.1378; LUX-Lung 6: 8.2 versus 4.7 months, HR = 0.47, p = 0.1060). The magnitude of PFS improvement with afatinib was similar to that observed in patients without brain metastases. In combined analysis, PFS was significantly improved with afatinib versus with chemotherapy in patients with brain metastases (8.2 versus 5.4 months; HR, 0.50; p = 0.0297). Afatinib significantly improved the objective response rate versus chemotherapy in patients with brain metastases. Safety findings were consistent with previous reports. CONCLUSIONS: These findings lend support to the clinical activity of afatinib in EGFR mutation-positive patients with NSCLC and asymptomatic brain metastases.
    Type of Publication: Journal article published
    PubMed ID: 26823294
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  • 3
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    German Medical Science GMS Publishing House; Düsseldorf
    In:  87. Jahresversammlung der Deutschen Gesellschaft für Hals-Nasen-Ohren-Heilkunde, Kopf- und Hals-Chirurgie; 20160504-20160507; Düsseldorf; DOC16hnod635 /20160330/
    Publication Date: 2016-03-31
    Keywords: ddc: 610
    Language: English
    Type: conferenceObject
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  • 4
    Abstract: BACKGROUND: In the Phase III LUX-Lung 3/6 (LL3/LL6) trials in epidermal growth factor receptor (EGFR) mutation-positive lung adenocarcinoma patients, we evaluated feasibility of EGFR mutation detection using circulating cell-free DNA (cfDNA) and prognostic and predictive utility of cfDNA positivity (cfDNA+). METHODS: Paired tumour and blood samples were prospectively collected from randomised patients. Mutations were detected using cfDNA from serum (LL3) or plasma (LL6) by a validated allele-specific quantitative real-time PCR kit. RESULTS: EGFR mutation detection rates in cfDNA were 28.6% (serum) and 60.5% (plasma). Mutation detection in blood was associated with advanced disease characteristics, including higher performance score, number of metastatic sites and bone/liver metastases, and poorer prognosis. In patients with common EGFR mutations, afatinib improved progression-free survival vs chemotherapy in cfDNA+ (LL3: HR, 0.35; P=0.0009; LL6: HR, 0.25; P〈0.0001) and cfDNA- (LL3: HR, 0.46; P〈0.0001; LL6: HR, 0.12; P〈0.0001) cohorts. A trend towards overall survival benefit with afatinib was observed in cfDNA+ patients. CONCLUSIONS: Plasma cfDNA is a promising alternative to biopsy for EGFR testing. Detectable mutation in blood was associated with more advanced disease and poorer prognosis. Afatinib improved outcomes in EGFR mutation-positive patients regardless of blood mutation status.
    Type of Publication: Journal article published
    PubMed ID: 28006816
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  • 5
    Abstract: The effect of inhibitors of RNA (actinomycin D, Act. D) and protein synthesis (cycloheximide, CH) on induction of Epstein-Barr virus (EBV) antigens by the tumour promoter TPA and by EBV superinfection has been analysed. The data indicate that (i) concomitant treatment of cells with Act. D and TPA leads to complete suppression of virus antigen induction. Subsequent treatment of the cells with Act. D after prior exposure to TPA results in some virus antigen induction, the amount depending on the time of TPA treatment. (ii) Simultaneous treatment of the cells with TPA and CH blocks antigen expression completely. Removal of the inhibitor results in antigen expression at a comparable rate to that of CH-untreated cells. (iii) If Ch treatment is followed by addition of Act. D, virus antigen induction by TPA is completely inhibited. In contrast, superinfection of the cells with P3HR-1 EBV in the presence of CH for the same period followed by removal of the inhibitor and addition of Act. D leads to virus antigen expression by 3 h after Act. D addition. (iv) Concomitant treatment with CH and TPA followed by addition of either iododeoxyuridine or n-butyric acid results in 'superinduction'. Virtually all cells exhibit EBV-specified antigens. This implies that induction of virus antigens by tumour promoters requires the synthesis of a specific RNA, that this RNA increases in concentration during the induction period and that the same RNA is not required for EBV transcription after exogenous infection.
    Type of Publication: Journal article published
    PubMed ID: 6262437
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  • 6
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    German Medical Science; Düsseldorf, Köln
    In:  33rd International Congress on Electrocardiology; 20060628-20060701; Cologne; DOC06ice080 /20070208/
    Publication Date: 2007-02-09
    Keywords: ddc: 610
    Language: English
    Type: conferenceObject
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  • 7
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    German Medical Science GMS Publishing House; Düsseldorf
    In:  GMS Current Posters in Otorhinolaryngology - Head and Neck Surgery; VOL: 12; DOC038 /20160411/
    Publication Date: 2016-04-12
    Description: Introduction: Induced pluripotent stem cells allow us to confirm the results from animal experiments on human cells in a safe and convenient way. This give us the opportunity to investigate their role in the field of regenerative medicine for inner ear diseases.Methods: The effect of BDNF, NT-3 and IGF-1 on neurite outgrowth of human induced pluripotent stem (hiPS) cell-derived neurons was examined. First, human iPS cell line 201B7-GFP was differentiated into neural progenitor cells. Neurospheres were prepared from neural progenitor cells by floating culture on U-bottom low adhesion plate. After that the neurospheres were transferred on Matrigel-coated plates and underwent neuronal differentiation for 7 days with or without additional neurotrophic or growth factors. Results: Immunocytochemistry showed betaIII-tubulin and neurofilament positive cells in the neurospheres. The neurites of each neurosphere were counted. No significant difference was observed between the different groups. Conclusions: Previous studies demonstrate the effect of BDNF, NT-3 and IGF-1 on neurite outgrowth. In our study for the first time this assessment is done by using human iPS cells. Our results differ from the results previously reported. This could be due to the genetic instability of iPS cells.Der Erstautor gibt keinen Interessenkonflikt an.
    Keywords: ddc: 610
    Language: English
    Type: article
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  • 8
    ISSN: 1662-9779
    Source: Scientific.Net: Materials Science & Technology / Trans Tech Publications Archiv 1984-2008
    Topics: Physics
    Type of Medium: Electronic Resource
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  • 9
    ISSN: 0942-0940
    Keywords: Keywords: Cerebral vasospasm; interleukin-6; interleukin-8; subarachnoid haemorrhage (SAH).
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary  The authors characterized the role of interleukins in the cerebrospinal fluid (CSF) in the development of vasospasm after subarachnoid haemorrhage (SAH), particularly interleukin-6 (IL-6).  Concentrations of interleukin-1β (IL-1 β), IL-6, and interleukin-8 (IL-8) were measured serially in CSF of 24 patients and in serum of 9 patients with SAH and correlated clinically. Additionally, the effects of the same cytokines on the cerebral arteries of dogs were analyzed on angiograms after intracisternal injection. Changes in levels of eicosanoids, angiogenic factors, and soluble cell adhesion molecules were investigated in the CSF of injected dogs.  CSF concentrations of IL-6 and IL-8 were elevated significantly above control levels from the acute stage of SAH until the chronic stage. Patients with symptomatic vasospasm had significantly higher levels of IL-6 as well as IL-8 in CSF on days 5 and 7. Intracisternal injection of IL-6 induced long-lasting vasoconstriction in five out of eight dogs, while IL-8 did not. The diameter of canine basilar artery after IL-6 was reduced 29±5% from pretreatment diameter at 8 hours. Prostaglandins E2 and I2 were elevated in CSF for the first 4.5 hour of this IL-6-induced vasospasm. Neither angioenic factors such as platelet-derived growth factor-AB and vascular endothelial growth factor nor soluble cell adhesion molecules were significantly elevated in CSF.  IL-6, which increases to very high concentrations in CSF after SAH, may be important in inducing vasospasm, as IL-6 produced long-lasting vasoconstriction in the canine cerebral artery, which may be partly related to activation of the prostaglandin cascade.
    Type of Medium: Electronic Resource
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  • 10
    ISSN: 1573-0794
    Keywords: C2 ; Production rate ; asymmetrical coma ; C/1996 B2 ; C/1995 O1
    Source: Springer Online Journal Archives 1860-2000
    Topics: Geosciences , Physics
    Notes: Abstract In order to monitor the various phenomena of comets, we continuously made the near-nucleus imaging observations of comets at National Astronomical Observatory, Mitaka. Here we report on the results of the observations of two spectacular comets. One is the analysis of photometry of C2 emission images in the coma of comet Hyakutake (C/1996 B2). By comparing the production rates of C2 radicals with C2H2 molecules, we conclude that the most C2 radicals were originated from C2H2, while some of them might be produced from other parents. The second item is the analysis of the morphology of C2 emission images in the coma of comet Hale-Bopp(C/1995 O1). By applying a ring masking technique, we detected asymmetrical distribution of the C2 molecules. The results of these two comets might suggest that a portion of C2 radicals were formed by the disintegration of the small organic dust grains, like the so-called CHON particles.
    Type of Medium: Electronic Resource
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