Peltomaiden kalkitustarve ja kalkituksen vaikutus viljan ja nurmen satoon

vokKirjasto Aj-kEffect of liming on yield of cereals and gras

Lymfoomat

Ajankohtaista Lääkärin käsikirjast

Itraconazole Increases Ibrutinib Exposure 10-Fold and Reduces Interindividual Variation-A Potentially Beneficial Drug-Drug Interaction

The oral bioavailability of ibrutinib is low and variable, mainly due to extensive first-pass metabolism by cytochrome P450 (CYP) 3A4. The unpredictable exposure can compromise its safe and effective dosing. We examined the impact of itraconazole on ibrutinib pharmacokinetics. In a randomized crossover study, 11 healthy subjects were administered itraconazole 200 mg or placebo twice on day 1, and once on days 2-4. On day 3, 1 hour after itraconazole (placebo) and breakfast, ibrutinib (140 mg during placebo; 15 mg during itraconazole) was administered. Itraconazole increased the dose-adjusted geometric mean area under the concentration-time curve from zero to infinity (AUC(0-infinity)) of ibrutinib 10.0-fold (90% confidence interval (CI) 7.2-13.9; P <0.001) and peak plasma concentration (C-max) 8.8-fold (90% CI 6.3-12.1; P <0.001). During itraconazole, the intersubject variation for the AUC(0-infinity) (55%) and C-max (53%) was around half of that during placebo (104%; 99%). In conclusion, itraconazole markedly increases ibrutinib bioavailability and decreases its interindividual variability, offering a possibility to improved dosing accuracy and cost savings.Peer reviewe

Copy number alterations define outcome in Philadelphia chromosome-positive acute lymphoblastic leukemia

Funding Information: NGS library preparation, sequencing and sequence analysis were performed by the Institute for Molecular Medicine Finland (FIMM) Technology Center, University of Helsinki. We thank laboratory technicians Jay Klievink in Hematology Research Unit Helsinki (HRUH) and Minna Suvela in FIMM for technical support with the DNA extractions and laboratory coordinator Minna Tuominen in FIMM for technical support with multiplex ligation-dependent probe amplification. We are grateful to the members of the HRUH for discussions and technical help. We thank research nurses Anne Gesterberg, Jenni Raali and Susanna Helkkula for help with clinical data. We thank Dr Veli Kairisto in Tykslab, Dr Taru Kuittinen in Kuopio University Hospital and clinical laboratory geneticists Anne Juvonen and Tarja Salonen in HUSLAB for help with clinical samples. The samples of this project were provided by Finnish University Hospital clinical laboratories and the Finnish Hematology Registry and Clinical Biobank (FHRB) with appropriate ethics approval (Dnro 202/06.01.00/2013). We thank all the patients for their generous participation. The FHRB Biobank is supported by the Finnish Association of Hematology, the Finnish Red Cross Blood Service, Institute for Molecular Medicine Finland, and the participating hospitals in Finland. This study was supported by the Doctoral Program in Clinical Research at the University of Helsinki and personal grants (to HH) from Emil Aaltonen Foundation, Ida Montin Foundation, Blood Disease Research Foundation, Finnish Hematology Association, Finnish Medical Foundation, Biomedicum Helsinki Foundation, Paulo Foundation, (to SM) Finnish Cancer Organizations, Sigrid Juselius Foundation, Signe and Ane Gyllenberg Foundation, Relander Foundation, and state funding for university-level health research in Finland. The laboratory analytics costs of this study were funded by Incyte. Funding Information: TS (not related to this study) is a member of the advisory board of Celgene and AbbVie; is a member of the advisory board of and received lecture fees from Pfizer and Janssen-Cilag; received lecture fees from Bristol Myers Squibb; received congress fees from and is a member of the advisory board of Novartis; received congress fees from Amgen. MP (not-related to this study) is a member of the advisory board of Pfizer and AbbVie; received lecture and congress fees from Novartis. OB received consultancy fees from Novartis and Sanofi. SM (not related to this study) received research funding from Novartis, BMS, Janpix, and Pfizer. All other authors have no conflicts of interest to disclose. Funding Information: NGS library preparation, sequencing and sequence analysis were performed by the Institute for Molecular Medicine Finland (FIMM) Technology Center, University of Helsinki. We thank laboratory technicians Jay Klievink in Hematology Research Unit Helsinki (HRUH) and Minna Suvela in FIMM for technical support with the DNA extractions and laboratory coordinator Minna Tuominen in FIMM for technical support with multiplex ligation-dependent probe amplification. We are grateful to the members of the HRUH for discussions and technical help. We thank research nurses Anne Gesterberg, Jenni Raali and Susanna Helkkula for help with clinical data. We thank Dr Veli Kairisto in Tykslab, Dr Taru Kuittinen in Kuopio University Hospital and clinical laboratory geneticists Anne Juvonen and Tarja Salonen in HUSLAB for help with clinical samples. The samples of this project were provided by Finnish University Hospital clinical laboratories and the Finnish Hematology Registry and Clinical Biobank (FHRB) with appropriate ethics approval (Dnro 202/06.01.00/2013). We thank all the patients for their generous participation. The FHRB Biobank is supported by the Finnish Association of Hematology, the Finnish Red Cross Blood Service, Institute for Molecular Medicine Finland, and the participating hospitals in Finland.Non peer reviewe

Abnormal expression of apoptosis-related genes in haematological malignancies: Overexpression of MYC is poor prognostic sign in mantle cell lymphoma

The expression of apoptosis-related genes BCL2, BAX, BCL2L1, BCL2A1, MCL1, DAPK1 and MYC was studied by quantitative real-time polymerase chain reaction on total RNA samples from patients with acute lymphoblastic leukaemia (ALL, n = 16), acute myeloid leukaemia (AML, n = 27). chronic myeloid leukaemia (CML, n = 12), mantle cell lymphoma (MCL, n = 19) and chronic lymphoid leukaemia (CLL. n = 32). BCL2, BAX, BCL2A1, MCL1, DAPK1 and MYC were overexpressed in all patient groups. BCL2L1 was underexpressed in CLL and CML, but not in AML, ALL and MCL. MCL1 levels were significantly higher in CD13 and CD33-positive ALL, and in CD56-positive AML samples. BCL2, BCL2L1, BCL2A1 and MCL1 were overexpressed and DAPK1 was underexpressed in CLL samples with a 11q23 deletion. MYC overexpression was significantly associated with shorter overall survival in MCL (P ≤ 0.01). AML patients with a normal karyotype showed a higher frequency of BCL2A1 overexpression (P ≤ 0.001) than those with an abnormal karyotype.Facultad de Ciencias Naturales y Muse

Copy number alterations define outcome in Philadelphia chromosome-positive acute lymphoblastic leukemia

</p

Molecular Monitoring after Autologous Stem Cell Transplantation and Preemptive Rituximab Treatment of Molecular Relapse; Results from the Nordic Mantle Cell Lymphoma Studies (MCL2 and MCL3) with Median Follow-Up of 8.5 Years

The main objectives of the present study were to monitor minimal residual disease (MRD) in the bone marrow of patients with mantle cell lymphoma (MCL) to predict clinical relapse and guide preemptive treatment with rituximab. Among the patients enrolled in 2 prospective trials by the Nordic Lymphoma Group, 183 who had completed autologous stem cell transplantation (ASCT) and in whom an MRD marker had been obtained were included in our analysis. Fresh samples of bone marrow were analyzed for MRD by a combined standard nested and quantitative real-time PCR assay for Bcl-1/immunoglobulin heavy chain gene (IgH) and clonal IgH rear-rangements. Significantly shorter progression-free survival (PFS) and overall survival (OS) was demonstrated for patients who were MRD positive pre-ASCT (54 patients) or in the first analysis post-ASCT (23 patients). The median PFS was only 20 months in those who were MRD-positive in the first sample post-ASCT, compared with 142 months in the MRD-negative group (PPeer reviewe

Dasatinib crosses the blood-brain barrier and is an efficient therapy for central nervous system philadelphia chromosome positive leukemia

Although imatinib, a BCR-ABL tyrosine kinase inhibitor, is used to treat acute Philadelphia chromosome-positive (Ph+) leukemia, it does not prevent central nervous system (CNS) relapses resulting from poor drug penetration through the blood-brain barrier. Imatinib and dasatinib (a dual-specific SRC/BCR-ABL kinase inhibitor) were compared in a pre-clinical mouse model of intracranial Ph+ leukemia. Clinical dasatinib treatment in patients with CNS Ph+ leukemia was assessed. In preclinical studies, dasatinib increased survival, whereas imatinib failed to inhibit intracranial tumor growth. Stabilization and regression of CNS disease were achieved with continued dasatinib administration. The drug also demonstrated substantial activity in 11 adult and pediatric patients with CNS Ph+ leukemia. Eleven evaluable patients had clinically significant, long-lasting responses, which were complete in 7 patients. In 3 additional patients, isolated CNS relapse occurred during dasatinib therapy; and in 2 of them, it was caused by expansion of a BCR-ABL-mutated dasatinib-resistant clone, implying selection pressure exerted by the compound in the CNS. Dasatinib has promising therapeutic potential in managing intracranial leukemic disease and substantial clinical activity in patients who experience CNS relapse while on imatinib therapy. This study is registered at ClinicalTrials. gov as CA180006 (#NCT00108719) and CA180015 (#NCT00110097)

15-year follow-up of the Second Nordic Mantle Cell Lymphoma trial (MCL2) : prolonged remissions without survival plateau

In recent decades, the prognosis of Mantle Cell Lymphoma (MCL) has been significantly improved by intensified first-line regimens containing cytarabine, rituximab and consolidation with high-dose-therapy and autologous stem cell transplantation. One such strategy is the Nordic MCL2 regimen, developed by the Nordic Lymphoma Group. We here present the 15-year updated results of the Nordic MCL2 study after a median follow-up of 114years: For all patients on an intent-to-treat basis, the median overall and progression-free survival was 127 and 85years, respectively. The MCL International Prognostic Index (MIPI), biological MIPI, including Ki67 expression (MIPI-B) and the MIPI-B including mIR-18b expression (MIPI-B-miR), in particular, significantly divided patients into distinct risk groups. Despite very long response durations of the low and intermediate risk groups, we observed a continuous pattern of relapse and the survival curves never reached a plateau. In conclusion, despite half of the patients being still alive and 40% in first remission after more than 12years, we still see an excess disease-related mortality, even among patients experiencing long remissions. Even though we consider the Nordic regimen as a very good choice of regimen, we recommend inclusion in prospective studies to explore the benefit of novel agents in the frontline treatment of MCL.Peer reviewe