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The Dutch-Belgian Cooperative Trial Group for Hematology Oncology Group-65/German-speaking Myeloma Multicenter Group-HD4 (HOVON-65/GMMG-HD4) phase III trial compared bortezomib (BTZ) before and after high-dose melphalan and autologous stem cell transplantation (HDM, PAD arm) compared with classical cytotoxic agents prior and thalidomide after HDM (VAD arm) in multiple myeloma (MM) patients aged 18–65 years. Here, the long-term follow-up and data on second primary malignancies (SPM) are presented. After a median follow-up of 96 months, progression-free survival (censored at allogeneic transplantation, PFS) remained significantly prolonged in the PAD versus VAD arm (hazard ratio (HR)=0.76, 95% confidence interval (95% CI) of 0.65–0.89, P=0.001). Overall survival (OS) was similar in the PAD versus VAD arm (HR=0.89, 95% CI: 0.74–1.08, P=0.24). The incidence of SPM were similar between the two arms (7% each, P=0.73). The negative prognostic effects of the cytogenetic aberration deletion 17p13 (clone size ⩾10%) and renal impairment at baseline (serum creatinine >2 mg dl−1) on PFS and OS remained abrogated in the PAD but not VAD arm. OS from first relapse/progression was similar between the study arms (HR=1.02, P=0.85). In conclusion, the survival benefit with BTZ induction/maintenance compared with classical cytotoxic agents and thalidomide maintenance is maintained without an increased risk of SPM.

Chronic myeloid leukemia (CML)-study IV was designed to explore whether treatment with imatinib (IM) at 400 mg/day (n=400) could be optimized by doubling the dose (n=420), adding interferon (IFN) (n=430) or cytarabine (n=158) or using IM after IFN-failure (n=128). From July 2002 to March 2012, 1551 newly diagnosed patients in chronic phase were randomized into a 5-arm study. The study was powered to detect a survival difference of 5% at 5 years. After a median observation time of 9.5 years, 10-year overall survival was 82%, 10-year progression-free survival was 80% and 10-year relative survival was 92%. Survival between IM400 mg and any experimental arm was not different. In a multivariate analysis, risk group, major-route chromosomal aberrations, comorbidities, smoking and treatment center (academic vs other) influenced survival significantly, but not any form of treatment optimization. Patients reaching the molecular response milestones at 3, 6 and 12 months had a significant survival advantage. For responders, monotherapy with IM400 mg provides a close to normal life expectancy independent of the time to response. Survival is more determined by patients’ and disease factors than by initial treatment selection. Although improvements are also needed for refractory disease, more life-time can currently be gained by carefully addressing non-CML determinants of survival.

Tyrosine kinase inhibitors represent today’s treatment of choice in chronic myeloid leukemia (CML). Allogeneic hematopoietic stem cell transplantation (HSCT) is regarded as salvage therapy. This prospective randomized CML-study IIIA recruited 669 patients with newly diagnosed CML between July 1997 and January 2004 from 143 centers. Of these, 427 patients were considered eligible for HSCT and were randomized by availability of a matched family donor between primary HSCT (group A; N=166 patients) and best available drug treatment (group B; N=261). Primary end point was long-term survival. Survival probabilities were not different between groups A and B (10-year survival: 0.76 (95% confidence interval (CI): 0.69–0.82) vs 0.69 (95% CI: 0.61–0.76)), but influenced by disease and transplant risk. Patients with a low transplant risk showed superior survival compared with patients with high- (P<0.001) and non-high-risk disease (P=0.047) in group B; after entering blast crisis, survival was not different with or without HSCT. Significantly more patients in group A were in molecular remission (56% vs 39%; P=0.005) and free of drug treatment (56% vs 6%; P<0.001). Differences in symptoms and Karnofsky score were not significant. In the era of tyrosine kinase inhibitors, HSCT remains a valid option when both disease and transplant risk are considered.

Condensation reactions of cyclopentadienyl silanetriols with titanium alkoxides yield oligomeric titanasiloxanes in high yields. Two types of polyhedral structures can be obtained by small structural modifications at the reactants (Cp^RSi(OH)3, Ti(OR)4) or by variation of reaction parameters. Thus, reaction of the silanetriols 9-(Me3Si)Fluorenyl-Si(OH)3 (1) and Cp*Si(OH)3 (2) with Ti(O^tBu)4 leads to the cubic Ti4O12Si4 polyhedrons [9-(Me3Si)Fluorenyl-Si]4O12[TiO^tBu]4 (3) and [Cp*Si]4O12[TiO^tBu]4 (4), respectively, while co-condensations of 1 with Ti(OⁱPr)4 afford either the polyhedral titanasiloxane [9-(Me3Si)Fluorenyl-Si]4O12[TiOⁱPr]6[μ2-ⁱPrO]2[μ3-O]2 (6) or the cubic polyhedron [9-(Me3Si)Fluorenyl-Si]4O12[TiOⁱPr]4 (5), depending on the choice of temperature and solvent. Substitution reactions with Ph3SiOH, Me2NOH, or acetylacetone at the titanium centers proceed selectively under conservation of the respective TiOSi core structures, whereas substitution reactions at the silicon centers performed with ethanol, HCl, and water are connected with core degradation. Both the novel titanasiloxanes and their titanium-functionalized derivatives have been characterized by IR and NMR spectroscopy as well as by single-crystal X-ray diffraction studies. Thermolysis of 3 leads to quantitative formation of 9-(Me3Si)Fluorene and 2-methylpropene.

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Abstract: Hyperresponsiveness of the bronchi is defined as an excessive reaction of bronchial mucosa to irritants that do no harm to a healthy mucosa. Measures to prevent bronchial hyperreactivity in children with asthma and other diseases remain rather ineffective at present. Though progress has been made in some areas.

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The predictability of maximum oxygen uptake ( max) was tested on 78 male subjects taken from four different age-groups (ages: 9 to 10, 13 to 14, 17 to 18, 20 to 52). max and W170 were measured during the same experiment, both with stepwise respectively continuously increasing loads on the bicycle ergometer. Oxygen uptake and heart rate were measured at submaximal and maximal workloads.

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Abstract 173

Ottmann: Novartis: Honoraria, Research Funding; BMS: Honoraria, Research Funding.

The performance of flow-volume (FV) curves in infants is usually associated with considerable expense, in order to achieve a controlled forced expiration. The inspiratory portion of FV curves is usually neglected.In our lung function laboratory FV curves were recorded in slightly sedated infants during spontaneous breathing. Furthermore, FV curves were recorded immediately after a short artificial interruption of breathing, at the end of inspiration, resp. expiration. In addition, body plethysmography was done.The findings were compared with the results of clinical and - in 18 cases - endoscopical examinations.Tests in 108 infants with and without cardiorespiratory disease showed that the configuration of FV curves allows conclusions on the kind and extent of airways obstruction similar to those in adults: Distinct limitation of inspiratory flow is caused by an extrathoracic stenosis; a low expiratory flow with a very strict linear or a curvilinear course suggests an intrathoracic impairment of airways.The sensitivity in the diagnosis of an airways obstruction is inferior to that of body plethymography. Specifity is high, if the results are compared with clinical and endoscopical findings.Thus, valuable information on ventilation is obtained by means of a simple method.

This study was performed to evaluate the suitability of monitoring theophylline concentrations in the lacrimal fluid for therapy control in asthmatic children.Samples of plasma and lacrimal fluid of 38 children (5 - 16yrs) were collected simultaneously and measured by means of high-performance liquid chromatography. Lacrimal fluid was collected using a small strip of filter paper placed into the conjunctival sac of the lower eyelid.Comparison of theophylline concentrations in plasma and lacrimal samples showed a significant difference. Analysis of the data, however, revealed a close linear correlation (r = 0,83) between theophylline concentrations of the two fluids. The intercept of the regression line is very small (y = 0,55x + 0,26). The mean plasma/lacrimal fluid ratio was 1,79 (± 0,40).It is concluded, that monitoring theophylline concentrations by means of lacrimal fluid analysis is a valuable tool for therapy control.