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Im wirtschaftlichen Anpassungs- und Aufbauprozes in Ostdeutschland haben kleine und mittlere Industrieunternehmen eine wichtige Rolle. So zeigen die Erfahrungen in Westdeutsch land, das das Zusammenspiel von grosen und kleinen Unternehmen eine wesentliche Voraussetzung fur ein arbeitsteiliges Produzieren auf hohem Niveau ist. Das Deutsche Institut fur Wirtschaftsforschung hat im Auftrag des Bundesministers fur Wirtschaft eine Untersuchung des industriellen Mittelstands in den neuen Bundeslandern durchgefuhrt, die ein Bild dieser Unternehmen im Rahmen der sich neu entwickelnden Industriestruktur zeichnet und auf besondere Probleme hinweist. Auf der Grundlage der empirischen Analyse werden Vorschlage zur besonderen Forderung der mittelstandischen Industrieunternehmen unterbreitet.

Abstract 3316 Background: Patients with refractory or relapsed AML have a poor prognosis and new treatments are needed for this patient population. While younger AML patients might benefit from intensive salvage treatments, a substantial number of elderly patients are considered ineligible for intensive treatment approaches. For these patients, repeated cycles of low-dose cytarabine (LD-Ara-C) are an accepted therapeutic option for palliative treatment. The serine/threonine kinase Polo-like kinase 1 (Plk1) controls several key steps in mitosis. BI 6727 is a first in class, highly selective and potent cell cycle kinase inhibitor targeting Plk1, and has demonstrated antiproliferative activity in multiple cell lines and animal models. Targeting Plk1 with BI 6727 results in cell cycle arrest in prometaphase (referred to as polo arrest) leading to eventual apoptosis. In a phase I dose escalation trial in patients with advanced solid tumors a favorable safety profile and encouraging antitumor activity was reported. BI 6727 has demonstrated a long terminal half life of 111 hours and a high volume of distribution suggesting excellent tissue distribution in patients. Here, we present preliminary results from the Phase I part of an ongoing Phase I/II study of BI 6727 in combination with LD-Ara-C in patients with relapsed or refractory AML considered ineligible for intensive treatment. Methods: This study follows a two stage design: the maximum tolerated dose (MTD) of BI 6727 in combination with fixed dose LD-Ara-C was evaluated in the Phase I dose escalation part of the trial following a 3+3 design with de-escalation. In a second ongoing treatment schedule the MTD of single agent BI 6727 is investigated, the MTD of single agent BI 6727 has not been reached yet. In the planned randomized Phase II part of the study, efficacy of BI 6727 plus LD-Ara-C will be compared to LD-Ara-C alone. BI 6727 was administered as a one hour intravenous infusion on days 1+15 every 28 days in combination with fixed dose LD-Ara-C (20 mg bid s.c). The BI 6727 starting dose was based on the MTD previously determined in solid tumor patients. Patients with no progression after the first cycle were allowed to continue treatment. Results: Patient characteristics were as follows: median age was 71 years (range 40 – 81); ECOG performance score 0: 9 pts; 1: 17 pts; 2: 5 pts. Increasing BI 6727 doses in combination with LD-Ara-C were evaluated in 31 patients (21 males, 10 females). Safety: Drug related adverse events (AEs) were reported in 17 of the 31 patients. The most frequent AEs reported (>5%) were: anemia and febrile neutropenia (each 9.7%), infections (pneumonia), decreased appetite and headache (each 6.5%). Dose-limiting toxicities (DLTs) were reported in 4 patients treated with BI 6727 + LD-Ara-C. DLTs as rated per protocol were: pneumonia, mucositis, hypersensitivity/allergic reaction and myocardial infarction. Based on the preliminary reports on DLTs the MTD for BI 6727 in combination with LD-Ara-C was determined. Preliminary response data of 28 patients with relapsed/refractory AML treated at different BI 6727 doses in combination with LD-Ara-C are available: 5 patients achieved a CRi or CR, 2 patients achieved a PR. Six patients had temporarily stable blood values (“no change” as best response). 10 patients suffered from progression during or at the end of the 1st treatment cycle, and 5 patients were ineligible for response assessment. An update of the phase I part of this trial with further details on patient/disease characteristics, safety and efficacy of BI 6727 in combination with LD-Ara-C will be reported at the meeting. Conclusion: Preliminary results indicate that BI 6727 in combination with LD-Ara-C is well tolerated in patients with relapsed/refractory AML ineligible for intensive treatment. The MTD of BI 6727 in combination with LD-Ara-C was determined. BI 6727 in combination with LD-Ara-C showed first signs of clinical activity in AML patients. Safety and efficacy of BI 6727 + LD-Ara-C will be further explored in the phase II part of the trial. Disclosures: Off Label Use: LD-Ara-C in combination with BI 6727 for treatment of patients with relapsed refractory AML ineligible for intensive treatment. Fleischer:Boehringer Ingelheim Pharma GmbH & Co KG: Employment. Taube:Boehringer Ingelheim Pharma GmbH & Co KG: Employment.

Background: BI 2536 is a potent and selective inhibitor of Plk-1, which plays a crucial role in the regulation of mitosis. Inhibition of Plk-1 leads to mitotic arrest and apoptosis. Therefore, Plk-1 inhibitors are currently in clinical testing as anti-proliferative agents in cancer patients. BI 2536, the first specific Plk-1 inhibitor in clinical testing, demonstrated strong anti-proliferative effects on AML cell lines in vitro and in in vivo models. To investigate target inhibition in the malignant cell, bone marrow samples from patients who participated in a Phase I/II study of BI 2536 single-agent therapy in elderly patients with relapsed or refractory AML were analyzed. Methods: Pharmacodynamic analyses including immunocytochemistry (ICC) and flow cytometry (FACS) of bone marrow (BM) were performed to examine cell morphology, phosphorylation of histone H3 (phospho-H3), and induction of apoptosis. Samples were acquired before and 24 h after the first administration of BI 2536. FACS analysis included propidium iodide (PI)-FACS to determine the percentage of cells residing in various cell cycle stages (G0/1-, S- and G2/M-phases) and Annexin V-Cy5-staining for apoptosis. Immunocytochemistry included staining for phosphorylated histone H3 and TUNEL assay for apoptosis. Results: At the time of analysis, data from 28 patients treated at doses in the range of 50 to 400 mg BI 2536 were available. BM taken after BI 2536 administration showed an increase of phospho-H3 positive cells as compared to baseline prior to treatment. There was a trend toward a positive correlation between phospho-H3 increase and increase in dosage of BI 2536 (p=0.16) when treatment at low doses (50 to 60 mg) of BI 2536 were compared to treatment at higher doses (100 to 400 mg). Furthermore, trends were observed that an increase of phospho-H3 is positively correlated with both a higher percentage of cells in G2/M and an increase in apoptotic cells. The typical morphology of cells in mitotic arrest could be demonstrated by ICC. Interestingly, when patients with progressive disease after one cycle (PD) were compared to patients with disease stabilization or response (nonPD), a statistically significant positive correlation between PD and increase in phospho-H3 compared to baseline was found (p=0.03). Also, there was a clear trend for an increase in the percentage of cells in G2/M phase and apoptosis in patients with PD compared to patients with nonPD. Preliminary evaluation of other disease characteristics including karyotype (normal vs complex), secondary AML, complete response in previous treatments, baseline value for blasts in the bone marrow or in the peripheral blood, did not reveal any signs of correlation with the clinical response to BI 2536 treatment. Conclusion: BI 2536 treatment increases the number of cells in G2/M phase (as detected by FACS analysis and phospho-H3 staining) and the number of apoptotic cells within 24 h after administration. In line with the clinical observation of rapid blast reduction both in the BM and the peripheral blood, these findings indicate that BI 2536 induces mitotic arrest and apoptosis of the malignant target cells in AML patients. The biological meaning of the correlation between the BM findings and the clinical response to BI 2536 is unclear, but if substantiated by more data, these results may suggest a predictive value of BM examinations for the response to BI 2536.

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We propose a mathematical model to describe the microstructure of the gas diffusion layer (GDL) in proton exchange membrane fuel cells (PEMFCs) based on tools from stochastic geometry. The GDL is considered as a stack of thin sections. This assumption is motivated by the production process and the visual appearance of relevant microscopic images. The thin sections are modeled as planar [two-dimensional (2D)] random line tessellations which are dilated with respect to three dimensions. Our 3D model for the GDL consists of several layers of these dilated line tessellations. We also describe a method to fit the proposed model to given GDL data provided by scanning electron microscopy images which can be seen as 2D projections of the 3D morphology. In connection with this, we develop an algorithm for the segmentation of such images which is necessary to obtain the required structural information from the given grayscale images.

NMR and x-ray anal. indicated that pyridazine deriv. I exists in a twist conformation. A ring inversion barrier of 91.5 kJ/mol was found for I.

Background A phase I study to assess the maximum tolerated dose (MTD) of a short course of afatinib in combination with docetaxel for the treatment of solid tumors. Methods Patients with advanced solid malignancies received docetaxel 75 mg/m(2) intravenously on day 1 and oral afatinib once daily on days 2-4, in 3-week treatment cycles. The afatinib dose was escalated in successive cohorts of 3-6 patients until dose-limiting toxicity (DLT). The MTD cohort was expanded to 13 patients. Pharmacokinetic parameters were assessed. Results Forty patients were treated. Afatinib doses were escalated to 160 mg/day in combination with 75 mg/m(2) docetaxel. Three patients had drug-related DLTs during cycle 1. The MTD was defined as 90 mg/day afatinib (days 2-4) with docetaxel 75 mg/m(2). The most frequent drug-related adverse events (all grades) were alopecia, diarrhea, stomatitis (all 50 %) and rash (40 %, all grade ≤2). Three patients had confirmed responses, two patients had unconfirmed responses and nine patients had durable stable disease >6 cycles. No pharmacokinetic interaction was observed. Conclusion Afatinib 90 mg administered for 3 days after docetaxel 75 mg/m(2) is the MTD for this treatment schedule and the recommended phase II/phase III dose. This combination showed anti-tumor activity in phase I, with a manageable adverse-event profile., Journal Article, SCOPUS: ar.j, info:eu-repo/semantics/published

Successful Transformations? contrasts the recent experience of economic development in Eastern Germany and the Czech Republic. It provides a comparative up-to-date account critically assessing the transition from central planning to a free market economy. The book highlights the very different paths that these two economies have taken. Eastern Germany has been absorbed almost entirely into the political and economic framework of West Germany. In contrast the Czech Republic – which is widely acclaimed to have made the speediest transition – has from the outset adopted an independent line.