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Korrektur zu 10.1038/s41375-020-0826-9

Background: Maintenance therapy following autologous stem cell transplantation (ASCT) can delay disease progression and prolong survival in patients with multiple myeloma. Ixazomib is ideally suited for maintenance therapy given its convenient once-weekly oral dosing and low toxicity profile. In this study, we aimed to determine the safety and efficacy of ixazomib as maintenance therapy following ASCT. Methods: The phase 3, double-blind, placebo-controlled TOURMALINE-MM3 study took place in 167 clinical or hospital sites in 30 countries in Europe, the Middle East, Africa, Asia, and North and South America. Eligible participants were adults with a confirmed diagnosis of symptomatic multiple myeloma according to International Myeloma Working Group criteria who had achieved at least a partial response after undergoing standard-of-care induction therapy followed by high-dose melphalan (200 mg/m2) conditioning and single ASCT within 12 months of diagnosis. Patients were randomly assigned in a 3:2 ratio to oral ixazomib or matching placebo on days 1, 8, and 15 in 28-day cycles for 2 years following induction, high-dose therapy, and transplantation. The initial 3 mg dose was increased to 4 mg from cycle 5 if tolerated during cycles 1–4. Randomisation was stratified by induction regimen, pre-induction disease stage, and response post-transplantation. The primary endpoint was progression-free survival (PFS) by intention-to-treat analysis. Safety was assessed in all patients who received at least one dose of ixazomib or placebo, according to treatment actually received. This trial is registered with ClinicalTrials.gov, number NCT02181413, and follow-up is ongoing. Findings: Between July 31, 2014, and March 14, 2016, 656 patients were enrolled and randomly assigned to receive ixazomib maintenance therapy (n=395) or placebo (n=261). With a median follow-up of 31 months (IQR 27·3–35·7), we observed a 28% reduction in the risk of progression or death with ixazomib versus placebo (median PFS 26·5 months [95% CI 23·7–33·8] vs 21·3 months [18·0–24·7]; hazard ratio 0·72, 95% CI 0·58–0·89; p=0·0023). No increase in second malignancies was noted with ixazomib therapy (12 [3%] patients) compared with placebo (eight [3%] patients) at the time of this analysis. 108 (27%) of 394 patients in the ixazomib group and 51 (20%) of 259 patients in the placebo group experienced serious adverse events. During the treatment period, one patient died in the ixazomib group and none died in the placebo group. Interpretation: Ixazomib maintenance prolongs PFS and represents an additional option for post-transplant maintenance therapy in patients with newly diagnosed multiple myeloma. Funding: Millennium Pharmaceuticals, a wholly owned subsidiary of Takeda Pharmaceutical Company. © 2019 Elsevier Ltd

Essentials Cancer patients receiving anticoagulants for venous thromboembolism have an elevated bleeding risk. This secondary analysis of CATCH assessed characteristics of clinically relevant bleeding (CRB). CRB occurs in 15% of cancer patients with thrombosis using therapeutic doses of anticoagulation. After multivariate analysis, risk factors for CRB were age >75 years and intracranial malignancy. Summary Background Cancer patients with acute venous thromboembolism (VTE) receiving anticoagulant treatment have an increased bleeding risk. Objectives We performed a prespecified secondary analysis of the randomized, open-label, Phase III CATCH trial (NCT01130025) to assess the rate and sites of and the risk factors for clinically relevant bleeding (CRB). Patients/Methods Patients with active cancer and acute, symptomatic VTE received either tinzaparin 175 IU kg-1 once daily or warfarin (target International Normalized Ratio [INR] of 2.0-3.0) for 6 months. Fisher's exact test was used to screen prespecified clinical risk factors; those identified as being significantly associated with an increased risk of CRB then underwent competing risk regression analysis of time to first CRB. Results Among 900 randomized patients, 138 (15.3%) had 180 CRB events. CRB occurred in 60 patients (81 events) in the tinzaparin group and in 78 patients (99 events) in the warfarin group (hazard ratio [HR] 0.64; 95% confidence interval [CI] 0.45-0.89). Common bleeding sites were gastrointestinal (36.7%; n = 66), genitourinary (22.8%; n = 41), and nasal (10.0%; n = 18). In multivariate analysis, the risk of CRB increased with age > 75 years (HR 1.83, 95% CI 1.14-2.94) and intracranial malignancy (HR 1.97, 95% CI 1.07-3.62). In the warfarin group, 40.4% of CRB events occurred in patients with with an INR of 75 years and intracranial malignancy.

Patients with primary pulmonary hypertension (PPH) benefit from treatment with anticoagulants, and histological findings suggest that in situ thrombosis of pulmonary vessels contributes to the pathogenesis of this disease. The mechanisms that cause a hypercoagulable state in the pulmonary vascular bed have not been fully investigated. This study compared plasminogen plasma activity, protein C and protein S plasma activities, fibrinogen and fibrin degradation products (FGDP and FBDP, respectively), von Willebrand factor antigen (vWF-Ag), prothrombin fragment F1.2, thrombin-antithrombin complexes (TAT), tissue plasminogen activator (tPA), and plasminogen activator inhibitor (PAI) in 16 patients with PPH and in 16 healthy volunteers. In a subset of the PPH patients, these variables were also compared in simultaneously-obtained mixed-venous and arterial blood samples. Proteins C and S, FGDP, FBDP, and plasminogen levels as well as plasma concentrations of prothrombin fragment F1.2 and TAT were normal in the 16 patients with PPH. In contrast, the plasma activity of PAI was significantly elevated (p

Lecithin wet gum with high water content is less stable during storage than dry lecithin. Deoiling and dehydrating the fresh gum can result in a purified lecithin of high quality. The stability of rapeseed wet gum obtained from double-zero rapeseed varieties was determined at various temperatures. The effect of storage time on volatile substances, acetone insolubles, neutral lipids and acid, iodine, and peroxide values were investigated. The rapeseed wet gum stored a little above 20°C is stable for up to ten days, although in the frozen state (−20°C) no changes in general composition, acid, iodine, and peroxide values were observed during 24 mon of storage.

Summary Protein C and its associated cofactor protein S are vitamin K-dependent anticoagulative plasma proteins, that regulate coagulation by inhibiting activated cofactors Va and VIIIa and by stimulating fibrinolysis or inhibition of clot formation. Primary synthesis in the liver may result in a secondary deficiency in patients with impaired liver function, leading to thromboembolic complications. We report a case of Budd-Chiari syndrome, complicated by portal vein thrombosis and incomplete thrombosis of the inferior vena cava, resulting from an acquired protein C deficiency. Effective treatment was achieved by portacaval shunting, supplied by postsurgical substitution of protein C concentrates. Protein C levels raised according to recovering liver function and showed a normal ratio compared with prothrombin time under warfarin therapy. Routine monitoring of proteins C and S should be taken into consideration in all cases of impaired liver synthesis. Acquired protein C deficiency resulting from severe liver disease can effectively be treated by administration of highly purified protein C concentrates.

ZusammenfassungDie intravenöse Thrombolysetherapie kann, insbesondere bei frühzeitigem Einsatz, die Sterblichkeit beim akuten Herzinfarkt wesentlich vermindern. Derzeit stehen vier unterschiedliche Thrombolytika (Streptokinase, APSAC, Urokinase und rt-PA) kommerziell zur Verfügung. Im klinischen Gebrauch unterscheiden sie sich insbesondere in der Geschwindigkeit, mit der sie die Thrombolyse herbeiführen, und in ihrer Fibrinspezifität. Inwieweit diese unterschiedlichen Eigenschaften die Prognose der Patienten wesentlich beeinflussen, wird derzeit noch kontrovers diskutiert.Sofern Urokinase oder rt-PA zum Einsatz kommen, ist eine begleitende Heparintherapie unerläßlich. Um späteren Reinfarkten vorzubeugen, sollte - in Abhängigkeit vom klinischen Verlauf des Patienten - vor der Entlassung aus dem Krankenhaus oder im stabilen Intervall eine invasive Diagnostik mittels Herzkatheter und bei Vorhandensein höhergradiger Stenosen eine Dilatationsbehandlung oder Bypass-Operation durchgeführt werden.

The dissolution profiles of ibuprofen (IB) from solid dispersions prepared by the solvent evaporation method, containing the rapeseed lecithin ethanol soluble fraction (LESF) or rapeseed phosphatidylcholine (RPC) have been determined. The effect of incorporation of PEG 4,000 or PEG 8,000 in the solid dispersions on the controlled-release of IB was also investigated. Dissolution studies conducted in double-distilled water using the paddle dissolution apparatus showed that the initial dissolution rate (IDR) within the first 5 min and the maximum percent of dissolved IB of IB/LESF were double of those of IB/RPC (both in ratio 4:1 w/w). The low amounts of LESF markedly increased dissolution of IB. Increasing of LESF concentration from 0 to 10 and 20% in solid dispersions produced 60 and 100% improvement of IB maximum dissolution level respectively, to compare with that of IB alone. PEG 4,000 caused the slightly decreasing in IB dissolution rate, while PEG 8,000 markedly improved the dissolution of IB in examined conditions.

The raw commercial rapeseed lecithin free of erucic acid and glucosinolate (00-type) was purified by deoiling with acetone and extracting with ethanol. The increasing of phosphatidylcholine (PC) content (from 50 to 70–80%) in obtained rapeseed lecithin extract was performed. It was done by column chromatographic fractionation using a low silica gel–lecithin extract ratio about 2:1 and the various temperatures up to 60°C. The fractions were eluted with 95% ethanol. Effect of rapeseed lecithin column fractionation temperatures is significant and the better purification quality in the higher temperatures was observed. Based on performed investigations it could be summarized that the low silica gel–lecithin extract ratio (2:1) allows to obtain rapeseed lecithin with above 80% content of PC and the best results for temperature 60°C were observed. Herstellung von Rapslecithin mit hohem Phosphatidylcholin-Gehalt Rohes, handelsubliches Rapslecithin, das frei von Erucasaure und Glucosinolaten war (00-Typ), wurde durch Entolung mit Aceton and Extraktion mit Ethanol gereinigt. Der Gehalt an Phosphatidylcholin (PC) im Rapslecithin-Extrakt konnte von 50 auf 70–80% erhoht werden. Dies erfolgte durch Fraktionierung an einer Chromatographiesaule unter Verwendung eines niedrigen Silicagel-Lecithin-Verhaltnisses von 2:1 und verschiedener Temperaturen bis 60°C. Die Fraktionen wurden mit 95%igem Ethanol eluiert. Der Einflus der Temperatur bei der Fraktionierung von Rapslecithin an einer Chromatographiesaule war signifikant. Bei hoheren Temperaturen wurde eine bessere Reinheit erzielt. Die Untersuchungen ergaben. das bei einem niedrigen Silicagel-Lecithin-Verhaltnis von 2:1 ein Rapslecithin mit einem Gehalt von uber 80% erzielt werden kann und die besten Ergebnisse bei einer Temperatur von 60 °C erhalten werden.

Problems relating to the technology of a phospholipid preparation from natural materials, liposome production, and studies into the mechanisms of interaction between metal (trace elements) cations and model bilayer lipid membranes are discussed. The proposed technology of extraction allows for preparation of phospholipids utilizable for liposome formation. The cation specificity of lipid bilayers is found to be determined by the presence of anionic phosphate adsorption sites on their surface.

14021 Background: Active single agents in MGC are 5FU, CDDP, Anthracyclines, Taxanes and irinotecan. Combinations consisting of docetaxel, cisplatin, 5FU (TPF) and epirubicin, cisplatin, 5FU (ECF) have been investigated and both have shown activity and improvement of survival. However, the most efficient regimen is not yet defined. Methods: Chemotherapy-naive Patients with histologically confirmed MGC and measurable lesions were enrolled in this study. They received CDDP 35 mg/m2 iv on day (d) 1, 2, 15 and 16, 5FU 2000 mg/m2 continuous infusion (ci) d 1, 8, 15 and 22, FA 200 mg/m2 iv d 1, 8, 15 and 22 and E 60 mg/m2 d 29 and 43, T 60 mg/m2 d29 and 43 q d 57. Pts with at least one completed cycle were eligible. Objectives of this study were to evaluate the response rate, toxicity, PFS and OAS of CF-ET. Results: Between 2002 and 2005 34 pts (22 male and 9 female) aged 31 - 77 years (median 61) entered. The total number of treatment cycles was 56, mean 1.8 (1 - 5). 31 pts were eligible. 9 pts had complete response; 11 pts had partial response, 4 pts had stable disease, 7 pts had progressive disease and 3 pts were not evaluable. The overall response rate was 64.5%. The median response duration was 6.1 months (2 - 29.4). The overall survival was 11.4 months (2.6 - 43.6). Grade 3/4 toxicities were leukopenia 41/37.5%, neutropenia 16/82%, thrombocytopenia 23.2/0%, neutropenia related fever was observed in 4 cycles. No severe organ toxicities nor toxic death was seen. Conclusions: The alternating CF-ET regimen showed significant efficacy with prolonged survival. The ET-part of the regimen induced severe but manageable haematological toxicities. The results require further evaluation in a randomized phase III - trial. No significant financial relationships to disclose.

The synthesis of polybetaines based on tertiary aliphatic and heterocyclic polyamines is described. Some properties of the obtained polybetaines were determined. It was found that polybetaines are readily soluble in water and other polar solvents. Aminobetaines prepared by quaternization of polyamines in amounts lower than stoichiometric showed similar solubility properties. Some of the obtained compounds show antimicrobial activity. Die Synthese von Polybetainen auf Basis tertiarer aliphatischer und heterocyclischer Polyamine wird beschrieben Einige Eigenschaften der erhaltenen Polybetaine wurden untersucht. Die Polybetaine losen sich leicht in Wasser und anderen polaren Losungsmitteln. Durch unvollstandige Quaternierung von Polyaminen erhaltene Aminobetaine haben ahnliche Loslichkeiten. Einige der erhaltenen Verbindungen zeigten antibakterielle Aktivitat.

In vitro and in vivo formed fibrin clots were investigated by SDS-PAA gel electrophoresis in regard to the amount and distribution of fibrin subunits. It was found that with decreasing factor XIII levels fewer and shorter alpha-polymers were formed in vitro and more so in the exterior than in the core of a clot. Inversely the concentrations of residual alpha-chains rose. These structural changes already began at factor XIII levels of 50%. gamma-dimer formation was not influenced. Nearly all in vivo thrombi, either arterial or venous, consisted of a normal distribution of subunits, but alpha-polymerization was more extensive in the core than in the exterior parts. A significant impairment of alpha polymerization was found in extravasal clots, but not in thrombi formed during anticoagulant therapy.

The combination of generalized broken ("racemose") livedo and cerebrovascular accidents is referred to as "Sneddon's syndrome". Although several pathogenetic factors have been suggested the aetiology of Sneddon's syndrome is unknown. Furthermore, considerable variability of patient characteristics gives rise to the question whether "Sneddon's syndrome" denotes a homogeneous disease entity at all. We hypothesized that the diagnosis "Sneddon's syndrome" can be broken down into different subgroups according to possible aetiologic factors.Thirty-two patients with the combination of generalized broken livedo and cerebrovascular accidents were evaluated by clinical examination, routine diagnostic procedures, MRI of the brain, echocardiography, vascular ultrasound, immunologic and haemostaseologic testing. Patient groups were formed, depending on (1) whether or not an additional feature with a possibly aetiologic role for Sneddon's syndrome was present, and (2) which kind of feature it was.In 16 out of 32 patients, diagnostic features with an implication for the pathogenesis of Sneddon's syndrome could be identified. An autoimmune disorder was diagnosed in six patients. A thrombophilic state was detected in six patients. Three patients had preexisting atherosclerosis. One patient suffered from an embolizing atrial myxoma. Extent and kind of cerebral pathology differed between patient groups as did the kind of cardiac involvement.Sneddon's syndrome is not a homogeneous disease entity. Patients should be classified as "primary Sneddon's syndrome" if no aetiologic factor can be detected. On clinical grounds, this from differs from several varieties of "secondary Sneddon's syndrome" which occurs mainly as part of an autoimmune disorder or in a thrombophilic state.

[Background]: Maintenance therapy following autologous stem cell transplantation (ASCT) can delay disease progression and prolong survival in patients with multiple myeloma. Ixazomib is ideally suited for maintenance therapy given its convenient once-weekly oral dosing and low toxicity profile. In this study, we aimed to determine the safety and efficacy of ixazomib as maintenance therapy following ASCT. [Methods]: The phase 3, double-blind, placebo-controlled TOURMALINE-MM3 study took place in 167 clinical or hospital sites in 30 countries in Europe, the Middle East, Africa, Asia, and North and South America. Eligible participants were adults with a confirmed diagnosis of symptomatic multiple myeloma according to International Myeloma Working Group criteria who had achieved at least a partial response after undergoing standard-of-care induction therapy followed by high-dose melphalan (200 mg/m²) conditioning and single ASCT within 12 months of diagnosis. Patients were randomly assigned in a 3:2 ratio to oral ixazomib or matching placebo on days 1, 8, and 15 in 28-day cycles for 2 years following induction, high-dose therapy, and transplantation. The initial 3 mg dose was increased to 4 mg from cycle 5 if tolerated during cycles 1–4. Randomisation was stratified by induction regimen, pre-induction disease stage, and response post-transplantation. The primary endpoint was progression-free survival (PFS) by intention-to-treat analysis. Safety was assessed in all patients who received at least one dose of ixazomib or placebo, according to treatment actually received. This trial is registered with ClinicalTrials.gov, number NCT02181413, and follow-up is ongoing. [Findings]: Between July 31, 2014, and March 14, 2016, 656 patients were enrolled and randomly assigned to receive ixazomib maintenance therapy (n=395) or placebo (n=261). With a median follow-up of 31 months (IQR 27·3–35·7), we observed a 28% reduction in the risk of progression or death with ixazomib versus placebo (median PFS 26·5 months [95% CI 23·7–33·8] vs 21·3 months [18·0–24·7]; hazard ratio 0·72, 95% CI 0·58–0·89; p=0·0023). No increase in second malignancies was noted with ixazomib therapy (12 [3%] patients) compared with placebo (eight [3%] patients) at the time of this analysis. 108 (27%) of 394 patients in the ixazomib group and 51 (20%) of 259 patients in the placebo group experienced serious adverse events. During the treatment period, one patient died in the ixazomib group and none died in the placebo group. [Interpretation]: Ixazomib maintenance prolongs PFS and represents an additional option for post-transplant maintenance therapy in patients with newly diagnosed multiple myeloma, This study was sponsored by Millennium Pharmaceuticals, a wholly owned subsidiary of Takeda Pharmaceutical Company.