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Item does not contain fulltext, PURPOSE: To address the role of consolidation treatment for newly diagnosed, transplant eligible patients with multiple myeloma in a controlled clinical trial. PATIENTS AND METHODS: The EMN02/HOVON95 trial compared consolidation treatment with two cycles of bortezomib, lenalidomide, and dexamethasone (VRD) or no consolidation after induction and intensification therapy, followed by continuous lenalidomide maintenance. Primary study end point was progression-free survival (PFS). RESULTS: Eight hundred seventy-eight eligible patients were randomly assigned to receive VRD consolidation (451 patients) or no consolidation (427 patients). At a median follow-up of 74.8 months, median PFS with adjustment for pretreatment was prolonged in patients randomly assigned to VRD consolidation (59.3 v 42.9 months, hazard ratio [HR] = 0.81; 95% CI, 0.68 to 0.96; P = .016). The PFS benefit was observed across most predefined subgroups, including revised International Staging System (ISS) stage, cytogenetics, and prior treatment. Revised ISS3 stage (HR, 2.00; 95% CI, 1.41 to 2.86) and ampl1q (HR, 1.67; 95% CI, 1.37 to 2.04) were significant adverse prognostic factors. The median duration of maintenance was 33 months (interquartile range 13-86 months). Response ≥ complete response (CR) after consolidation versus no consolidation before start of maintenance was 34% versus 18%, respectively (P < .001). Response ≥ CR on protocol including maintenance was 59% with consolidation and 46% without (P < .001). Minimal residual disease analysis by flow cytometry in a subgroup of 226 patients with CR or stringent complete response or very good partial response before start of maintenance demonstrated a 74% minimal residual disease-negativity rate in VRD-treated patients. Toxicity from VRD was acceptable and manageable. CONCLUSION: Consolidation treatment with VRD followed by lenalidomide maintenance improves PFS and depth of response in newly diagnosed patients with multiple myeloma as compared to

Until recently, only retrospective studies had been published on salvage high-dose melphalan (HDM) with autologous stem cell 'transplantation' (ASCT). In a prospective, nonrandomized phase-2 study, we treated 53 bortezomib-naïve patients with bortezomib-dexamethasone as induction and bortezomib included in the conditioning regimen along with the HDM. Median progression-free survival (PFS), time to next treatment (TNT) and overall survival (OS) after start of reinduction therapy were 21.6, 22.8 and 46.6 months, respectively. For 49 patients who completed salvage bortezomib-HDM(II) with ASCT, there was no significant difference of PFS and TNT after HDM (II) compared with after the initial HDM(I), and thus patients were their own controls (PFS (I: 20.1 vs II: 19.3 months (P=0.8)) or TNT (I: 24.4 vs II: 20.7 months (P=0.8)). No significant differences in the response rates after salvage ASCT compared with the initial ASCT. Bortezomib-HDM conditioning combo was feasible, and toxicity was as expected for patients treated with bortezomib and ASCT. In conclusion, in bortezomib-naïve patients treated at first relapse with salvage ASCT including bortezomib, PSF and TNT did not differ significantly from initial ASCT and median OS was almost 5.5 years with acceptable toxicity. A recent prospective randomized study confirms salvage ASCT to be an effective treatment.Bone Marrow Transplantation advance online publication, 29 June 2015; doi:10.1038/bmt.2015.125.

Until recently, only retrospective studies had been published on salvage high-dose melphalan (HDM) with autologous stem cell 'transplantation' (ASCT). In a prospective, nonrandomized phase-2 study, we treated 53 bortezomib-naïve patients with bortezomib-dexamethasone as induction and bortezomib included in the conditioning regimen along with the HDM. Median progression-free survival (PFS), time to next treatment (TNT) and overall survival (OS) after start of reinduction therapy were 21.6, 22.8 and 46.6 months, respectively. For 49 patients who completed salvage bortezomib-HDM(II) with ASCT, there was no significant difference of PFS and TNT after HDM (II) compared with after the initial HDM(I), and thus patients were their own controls (PFS (I: 20.1 vs II: 19.3 months (P=0.8)) or TNT (I: 24.4 vs II: 20.7 months (P=0.8)). No significant differences in the response rates after salvage ASCT compared with the initial ASCT. Bortezomib-HDM conditioning combo was feasible, and toxicity was as expected for patients treated with bortezomib and ASCT. In conclusion, in bortezomib-naïve patients treated at first relapse with salvage ASCT including bortezomib, PSF and TNT did not differ significantly from initial ASCT and median OS was almost 5.5 years with acceptable toxicity. A recent prospective randomized study confirms salvage ASCT to be an effective treatment.

Background: The response to treatment varies among patients with multiple myeloma and markers for prediction of treatment outcome are highly needed. Bioactivation of cyclophosphamide and thalidomide, and biodegradation of bortezomib, is dependent on cytochrome P450 metabolism. We explored the potential influence of different polymorphisms in the CYP enzymes on the outcome of treatment. Methods: Data was analyzed from 348 patients undergoing high-dose treatment and stem cell support in Denmark in 1994 to 2004. Clinical information on relapse treatment in 243 individual patients was collected. The patients were genotyped for the non-functional alleles CYP2C19*2 and CYP2D6*3, *4, *5 (gene deletion), *6, and CYP2D6 gene duplication. Results: In patients who were treated with bortezomib and were carriers of one or two defective CYP2D6 alleles there was a trend towards a better time-to-next treatment. We found no association between the number of functional CYP2C19 and CYP2D6 alleles and outcome of treatment with cyclophosphamide or thalidomide. Neither was the number of functional CYP2C19 and CYP2D6 alleles associated with neurological adverse reactions to thalidomide and bortezomib. Conclusion: There was no association between functional CYP2C19 and CYP2D6 alleles and treatment outcome in multiple myeloma patients treated with cyclophosphamide, thalidomide or bortezomib. A larger number of patients treated with bortezomib are needed to determine the role of CYP2D6 alleles in treatment outcome.

Biomedical science and its allied disciplines are entering a new era in which computational methods and technologies are poised to play a prevalent role in supporting collaborative investigation of the human body. Within Europe, this has its focus in the virtual physiological human (VPH), which is an evolving entity that has emerged from the EuroPhysiome initiative and the strategy for the EuroPhysiome (STEP) consortium. The VPH is intended to be a solution to common infrastructure needs for physiome projects across the globe, providing a unifying architecture that facilitates integration and prediction, ultimately creating a framework capable of describing Homo sapiens in silico. The routine reliance of the biomedical industry, biomedical research and clinical practice on information technology (IT) highlights the importance of a tailor-made and robust IT infrastructure, but numerous challenges need to be addressed if the VPH is to become a mature technological reality. Appropriate investment will reap considerable rewards, since it is anticipated that the VPH will influence all sectors of society, with implications predominantly for improved healthcare, improved competitiveness in industry and greater understanding of (patho)physiological processes. This paper considers issues pertinent to the development of the VPH, highlighted by the work of the STEP consortium., Journal Article, Research Support, Non-U.S. Gov't, SCOPUS: ar.j, info:eu-repo/semantics/published

The physiological significance of serotonin released into the intestinal lumen for the regulation of motility is unknown in humans. The aim of this study was to evaluate the effect of serotonin infused into the lumen of the gastric antrum, duodenum or the jejunum, on antro-duodeno-jejunal contractility in healthy human volunteers. Manometric recordings were obtained and the effects of either a standard meal, continuous intravenous infusion of serotonin (20 nmol/kg/min) or intraluminal bolus infusions of graded doses of serotonin (2.5, 25 or 250 nmol) were compared. In addition, platelet-depleted plasma levels of serotonin, blood pressure, heart rate and electrocardiogram were evaluated. All subjects showed similar results. Intravenous serotonin increased migrating motor complex phase In frequency 3-fold and migrating velocity 2-fold. Intraluminal infusion of serotonin did not change contractile activity. Platelet-depleted-plasma levels of serotonin increased 2-fold following both intravenous and high doses of intraluminal infusions of serotonin. All subjects reported minor short-lived adverse effects following intravenous serotonin stimulation, while only half of the subjects reported minor short-lived adverse effects following intraluminal serotonin stimulations. We conclude that exogenous serotonin in the lumen of the upper part of the small intestine does not seem to change antro-duodeno-jejunal contractility significantly in healthy adult volunteers Udgivelsesdato: 2008

Udgivelsesdato: 2009, Proinflammatory cytokines are suspected to play a role in the pathogenesis of multiple myeloma (MM). Therefore, it is possible that inborn genetic variations leading to a modified expression of these cytokines will influence the outcome for these patients. We investigated 348 MM patients undergoing high-dose melphalan treatment followed by Auto-SCT and examined the influence of single nucleotide polymorphisms (SNPs) in genes involved in the inflammatory response. We found that the polymorphism IL-1beta T-31C significantly influenced overall survival (OS; P=0.02) and that carriers of the variant C-allele had a significantly longer survival than homozygous wild-type allele TT-carriers (relative risk 0.6 (95% CI=0.5-0.9); P=0.008). The polymorphisms IL-6 G-174C, IL-10 C592A, PPARgamma2 Pro(12)Ala, COX-2 A-1195G, COX-2 T8473C and NFKB1 ins/del did not influence the OS in this group of patients. Furthermore, homozygous carriers of the variant allele of IL-1beta T-31C were at 1.37-fold (CI=1.05-1.80) increased risk of MM as compared with population-based controls (P=0.02). Our results indicate that IL-1beta is involved in the pathogenesis of MM.

The aim of this study was to evaluate the effect of mechanical stretch on the expression of ET-1 and ETA- and ETB-receptors in porcine mitral valve leaflets.Leaflet segments from 10 porcine mitral valves were exposed to a static stretch load of 1.5 N for 3.5 h in buffer at 37oC together with matching control segments. Subsequently, the mRNA expression of ET-1, ETA-R and ETB-R was measured by real-time RT-PCR in the chordal insertion areas.The analyses showed an increased transcription of ETB-receptors in stretch-exposed leaflet segments compared to unstretched segments median 2.23 (quartiles 1.37 and 2.70) vs. median 1.56 (quartiles 1.38 and 2.17, P=0.03) whereas the mRNA expression of ETA-receptors (P=0.90) and ET-1 (P=0.51) remained unchanged.Stretch increased the expression of ETB-receptors in porcine mitral valve leaflets. The finding could lead to a better understanding of the pathogenesis of myxomatous mitral valve disease.

Fysiologi/biofysik

Fysiologi, biofysik