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  • 11
    Abstract: Our aim was to explore the impact of the HER2/neu, HER3 receptor as well as their ligands' neuregulin (NRG1) expression on the outcome of patients with metastatic colorectal cancer (mCRC). NRG1, HER2/neu and HER3 expression was evaluated in 208 patients with mCRC receiving 5-FU/LV plus irinotecan or irinotecan plus oxaliplatin as the first-line treatment. Biomarker expression was correlated with the outcome of patients. NRG1 (low: 192 vs. high: 16), HER2/neu (low: 201 vs. high: 7) and HER3 (low: 69 vs. high: 139) expressions were assessed in 208 patients. High versus low NRG1 expression significantly affected progression-free survival (PFS) [4.7 vs. 8.2 months, hazard ratio (HR): 2.45; 95% confidence interval (CI): 1.45-4.13; P=0.001], but not overall survival (OS) (15.5 vs. 20.7 months, HR: 1.33; 95% CI: 0.76-2.35; P=0.32). High versus low HER3 expression (PFS: 7.1 vs. 8.8 months, HR: 1.11; 95% CI: 0.82-1.50; P=0.50; OS: 19.8 vs. 21.1 months, HR: 0.95; 95% CI: 0.70-1.30; P=0.75) and high compared with low HER2/neu expression (PFS: 7.7 vs. 8.0 months, HR: 1.07; 95% CI: 0.71-1.60; P=0.75; OS: 16.6 vs. 21.1 months, HR: 1.13; 95% CI: 0.75-1.71; P=0.57) did not influence outcome. High NRG1 expression was associated with inferior PFS in the FIRE-1 trial. We did not detect a prognostic impact of HER2/neu and HER3 overexpression in mCRC. The frequency of overexpression was comparable with other studies.
    Type of Publication: Journal article published
    PubMed ID: 28582279
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  • 12
    Abstract: Anaplastic lymphoma kinase (ALK) is a receptor tyrosine kinase that is often overexpressed in rhabdomyosarcoma (RMS). However, its oncogenic and functional role in RMS remains unclear. Therefore, we investigated the antitumor activity of LDK378 (ceritinib), a new second-generation ALK inhibitor approved for patients with ALK-positive non-small-cell lung cancers. Here, we report that LDK378 reduces cell viability and induces cell death in RMS cell lines at low micromolar IC50 concentrations irrespective of ALK expression levels or phosphorylation status. Compared with Karpas 299 non-Hodgkin's lymphoma cells carrying the NPM-ALK fusion gene, RMS cell lines proved to be far less sensitive to LDK378. The broad-range caspase inhibitor zVAD.fmk significantly protects RMS cells from LDK378-mediated cell death, indicating that LDK378 induces caspase-dependent apoptotic cell death. Before the onset of apoptosis, LDK378 reduces phosphorylation of AKT, S6 ribosomal protein, STAT3 and - to a lesser extent - phosphorylation of ERK, showing that it suppresses key survival pathways. Importantly, we identify a synergistic induction of cell death by combining subtoxic concentrations of LDK378 with the multitargeting kinase inhibitor sorafenib. Calculation of the combination index confirmed that this interaction is synergistic. Also, LDK378 cooperates with sorafenib to significantly reduce colony formation of RMS cells, showing that this combination affects long-term clonogenic growth. In conclusion, LDK378 induces caspase-dependent apoptotic cell death in RMS cells independent of their ALK status and synergizes at subtoxic concentrations with sorafenib to induce cell death. These findings have important implications for the use of LDK378 in RMS.
    Type of Publication: Journal article published
    PubMed ID: 29045271
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  • 13
    Keywords: CANCER ; tumor ; Germany ; LUNG ; THERAPY ; TOXICITY ; liver ; SURGERY ; PATIENT ; CYCLE ; BREAST ; breast cancer ; BREAST-CANCER ; TRIAL ; EFFICACY ; chemotherapy ; doxorubicin ; CYCLOPHOSPHAMIDE ; RANDOMIZED-TRIAL ; paclitaxel ; GUIDELINES ; PREOPERATIVE CHEMOTHERAPY ; GEMCITABINE ; PHASE ; TOLERABILITY ; PLUS ; EVENTS ; EPIRUBICIN ; darbepoietin ; docetaxel ; dose density ; NEOADJUVANT CHEMOTHERAPY ; pegfilgrastim ; phase I/II study ; pre-operative chemotherapy ; RECOMMENDATIONS
    Abstract: We recruited 50 patients with T2-4 NO-2 MO primary breast cancer into a phase I/II study to define the maximum tolerated dose (MTD), efficacy and tolerability of preoperative gemcitabine (11250 mg/m(2) fixed dose) plus epirubicin (doses escalated from go mg/m(2)) for 5 cycles followed by 4 cycles of docetaxel (scheduled fixed dose 100 mg/m(2) given on day 1 every 2 weeks (q2w) with pegfilgrastim support. The MTD for epirubicin was 100 mg/m(2), but the docetaxel dose had to be reduced to 80 mg/m(2). Dose-limiting toxicities included fatigue, stomatitis, diarrhea and dyspnea (all grade 3) during gemcitabine plus epirubicin, and fatigue (grade 3) and allergic reaction (grade 4) during docetaxel treatment, respectively. A pathologic complete response could be achieved in 13 patients (pTO + pTis, 26%), and in the breast and axilla in 12 patients [(pTO or pTis) + pNO, 24%). Breast-conserving surgery (BCS) was possible in 35 patients (70%). Main grade 3/4 adverse events at MTD were fatigue (57/0%), leukopenia (27/8%), and liver (14/0%) and lung toxicity (14/0%). In conclusion, gemcitabine plus epirubicin 1250/100 mg/m(2) q2w followed sequentially by docetaxel 80 mg/m(2) q2w is highly effective as pre-operative chemotherapy with manageable toxicity. However, response and BCS rates could not be increased by administering gemcitabine plus epirubicin and docetaxel in a dose-dense fashion
    Type of Publication: Journal article published
    PubMed ID: 16162980
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  • 14
    Keywords: CANCER ; EXPRESSION ; IN-VITRO ; INHIBITOR ; proliferation ; AGENTS ; carcinoma ; CELL-PROLIFERATION ; Germany ; INHIBITION ; VITRO ; liver ; DIFFERENTIATION ; LINES ; COMPLEX ; COMPLEXES ; INDUCTION ; RAT ; CELL-LINES ; RAT-LIVER ; ASSAY ; LINE ; acetylation ; SERIES ; rat liver ; HISTONE DEACETYLASE ; cell lines ; TRICHOSTATIN-A ; INHIBITORS ; STANDARD ; AGENT ; CAPACITY ; cell proliferation ; DEACETYLASE ; SUBTYPE ; conversion ; ASSAYS ; PROFILES ; ABILITY ; cell differentiation ; predictive value ; ANALOGS ; ACTIVITY ASSAY ; BENZAMIDE ; benzidine staining ; erythroleukemia ; hydroxamic acid ; K562 ; murine Friend leukemic cell ; TRAPOXIN
    Abstract: Histone deacetylase (HDAC) inhibitors are a novel class of promising anti-cancer agents. Little information is available on the capacity of structurally different HDAC inhibitors to induce terminal cell differentiation in different cell types in relation to enzyme inhibition and subtype selectivity. Consequently, the aim of this study was to provide a comprehensive comparison of these effects. New biarylalanine inhibitors of HDAC were synthesized and compared to a series of standard inhibitors from different laboratories. Chromatographically purified rat liver and immunoprecipitated FLAG-tagged recombinant human HDACs were used as sources of HDAC activity. Enzyme inhibition was studied using a fluorescent substrate and its conversion was monitored by high-performance liquid chromatography. The ability to induce cell differentiation was compared in murine (Friend DS-19) and human (K562) erythroleukemic cell lines, and was quantified by benzidine staining. Inhibition of cell proliferation was evaluated by cell counting. All HDAC inhibitors were identified as potent inhibitors of erythroleukemic cell proliferation. However, we observed a complex pattern of differentiation induction: structurally similar inhibitors resulted in disparate activity profiles, whereas similar profiles were detected within distinct structural classes. Among the newly synthesized biarylalanine compounds, a 3'-methoxy derivative was identified as a very effective inducer of terminal cell differentiation. We conclude that investigation of subtype selectivity of selected HDAC inhibitors does not provide a clear link between selectivity and the observed cellular activity profile. The predictive value of in vitro HDAC inhibition assays for identifying anti-proliferative compounds has been emphasized. (c) 2005 Lippincott Williams & Wilkins
    Type of Publication: Journal article published
    PubMed ID: 15930892
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  • 15
    Keywords: CANCER ; SURVIVAL ; tumor ; carcinoma ; COMBINATION ; Germany ; LUNG ; THERAPY ; TOXICITY ; DISEASE ; liver ; POPULATION ; SITE ; SITES ; TIME ; PATIENT ; 5-FLUOROURACIL ; ACID ; TRIAL ; PROGRESSION ; AGE ; colorectal cancer ; COLORECTAL-CANCER ; EFFICACY ; metastases ; SAFETY ; OXALIPLATIN ; RANDOMIZED-TRIAL ; BOLUS ; REGIMENS ; PHASE-II ; ELDERLY-PATIENTS ; overall survival ; second-line treatment ; intensity ; PHASE ; PLUS ; REMISSION ; phase II ; 2 DIFFERENT SCHEDULES ; capecitabine ; CPT-11 ; FLUOROURACIL-LEUCOVORIN ; irinotecan ; PLUS IRINOTECAN ; salvage chemotherapy
    Abstract: The efficacy of combination therapy with irinotecan and capecitabine has been demonstrated for the first-line treatment of metastatic colorectal cancer (MCRC). The aim of this trial was to evaluate the efficacy and safety of this combination in MCRC as second-line treatment after failure of 24-h infusional 5-fluorouracil (5-FU24h) and folinic acid (FA). Patients pre-treated with 5-FU24h/FA were recruited at two institutions to receive 6 x weekly irinotecan 70 mg/m(2) and capecitabine (1000 mg/m(2) b.i.d. days 1-14 and 22-35). Courses were repeated on day 50. In elderly patients (〉65 years) a 20% dose reduction of both drugs was scheduled. Twenty-eight patients [M/F 20/8; median age 65 years (range 44-79); median ECOG score 1] were enrolled. The most frequent sites of metastases were liver, n = 20, lymph nodes and lungs, n=10, respectively. Half of the patients had two or more metastatic sites. A total of 71 treatment courses (median 2, range 1-8) were administered. Main toxicities [worst per patient (%); CTC grade 1/2/3/4] were: anaemias 18/14/-/-; leukocytopenia 11/21/-/-; thrombocytopenia diarrhea 18/36/21/-; nausea/vomiting 43/29/4/-; mucositis 4/11 /-/-; alopecia 7/25/-/-; hand-foot syndrome 7/21/-/-; fatigue 14/14/-/-; renal insufficiency (caused by diarrhea and exsiccosis) -/-/-/7. Dose intensity in the first course was [median/mean (%)]: irinotecan 92/83; capecitabine 88/82. Twenty-three patients are evaluable for response analysis (five did not complete the first course): three patients showed partial remissions (13%) and 11 patients had stable disease (48%). Median time to progression was 3.0 months for the total population (range 1.4-17.3) and 6.5 months for responders (partial response plus no change). Seventy-four percent of the patients received a third-line therapy. Overall survival was 15.7 months calculated from the start of study treatment. Second-line therapy with irinotecan and capecitabine yielded a tumor control in 61% of patients with MCRC. Efficacy and toxicity data are comparable to 5-FU/irinotecan combinations, although the likelihood of severe diarrhea appears to be higher with capecitabine/irinotecan. (C) 2005 Lippincott Williams Wilkins
    Type of Publication: Journal article published
    PubMed ID: 15613902
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