| 1. |
- Best, Jonathan G., et al.
(författare)
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Optimal timing of anticoagulation after acute ischemic stroke with atrial fibrillation (OPTIMAS) : Protocol for a randomized controlled trial
- 2022
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Ingår i: International Journal of Stroke. - : SAGE Publications. - 1747-4930 .- 1747-4949. ; 17:5, s. 583-589
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Tidskriftsartikel (refereegranskat)abstract
- Rationale: Atrial fibrillation causes one-fifth of ischemic strokes, with a high risk of early recurrence. Although long-term anticoagulation is highly effective for stroke prevention in atrial fibrillation, initiation after stroke is usually delayed by concerns over intracranial hemorrhage risk. Direct oral anticoagulants offer a significantly lower risk of intracranial hemorrhage than other anticoagulants, potentially allowing earlier anticoagulation and prevention of recurrence, but the safety and efficacy of this approach has not been established. Aim: Optimal timing of anticoagulation after acute ischemic stroke with atrial fibrillation (OPTIMAS) will investigate whether early treatment with a direct oral anticoagulant, within four days of stroke onset, is as effective or better than delayed initiation, 7 to 14 days from onset, in atrial fibrillation patients with acute ischemic stroke. Methods and design: OPTIMAS is a multicenter randomized controlled trial with blinded outcome adjudication. Participants with acute ischemic stroke and atrial fibrillation eligible for anticoagulation with a direct oral anticoagulant are randomized 1:1 to early or delayed initiation. As of December 2021, 88 centers in the United Kingdom have opened. Study outcomes: The primary outcome is a composite of recurrent stroke (ischemic stroke or symptomatic intracranial hemorrhage) and systemic arterial embolism within 90 days. Secondary outcomes include major bleeding, functional status, anticoagulant adherence, quality of life, health and social care resource use, and length of hospital stay. Sample size target: A total of 3478 participants assuming event rates of 11.5% in the control arm and 8% in the intervention arm, 90% power and 5% alpha. We will follow a non-inferiority gatekeeper analysis approach with a non-inferiority margin of 2 percentage points. Discussion: OPTIMAS aims to provide high-quality evidence on the safety and efficacy of early direct oral anticoagulant initiation after atrial fibrillation-associated ischemic stroke. Trial registrations: ISRCTN: 17896007; ClinicalTrials.gov: NCT03759938
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| 2. |
- Gunnarsson, Rebeqa, et al.
(författare)
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Array-based genomic screening at diagnosis and during follow-up in chronic lymphocytic leukemia
- 2011
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Ingår i: Haematologica. - : Ferrata Storti Foundation (Haematologica). - 1592-8721 .- 0390-6078. ; 96:8, s. 1161-1169
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Tidskriftsartikel (refereegranskat)abstract
- Background High-resolution genomic microarrays enable simultaneous detection of copy-number aberrations such as the known recurrent aberrations in chronic lymphocytic leukemia [del(11q), del(13q), del(17p) and trisomy 12], and copy-number neutral loss of heterozygosity. Moreover, comparison of genomic profiles from sequential patients' samples allows detection of clonal evolution. Design and Methods We screened samples from 369 patients with newly diagnosed chronic lymphocytic leukemia from a population-based cohort using 250K single nucleotide polymorphism-arrays. Clonal evolution was evaluated in 59 follow-up samples obtained after 5-9 years. Results At diagnosis, copy-number aberrations were identified in 90% of patients; 70% carried known recurrent alterations, including del(13q) (55%), trisomy 12 (10.5%), del(11q) (10%), and del(17p) (4%). Additional recurrent aberrations were detected on chromosomes 2 (1.9%), 4 (1.4%), 8 (1.6%) and 14 (1.6%). Thirteen patients (3.5%) displayed recurrent copy-number neutral loss of heterozygosity on 13q, of whom 11 had concurrent homozygous del(13q). Genomic complexity and large 13q deletions correlated with inferior outcome, while the former was linked to poor-prognostic aberrations. In the follow-up study, clonal evolution developed in 8/24 (33%) patients with unmutated IGHV, and in 4/25 (16%) IGHV-mutated and treated patients. In contrast, untreated patients with mutated IGHV (n=10) did not acquire additional aberrations. The most common secondary event, del(13q), was detected in 6/12 (50%) of all patients with acquired alterations. Interestingly, aberrations on, for example, chromosome 6q, 8p, 9p and 10q developed exclusively in patients with unmutated IGHV. Conclusions Whole-genome screening revealed a high frequency of genomic aberrations in newly diagnosed chronic lymphocytic leukemia. Clonal evolution was associated with other markers of aggressive disease and commonly included the known recurrent aberrations.
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| 3. |
- Hanson, Lars Åke, 1934, et al.
(författare)
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Growth and nutrition: the first six months
- 2008
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Ingår i: Nestlé Nutrition workshop series. Paediatric programme. - Basel : KARGER. - 1661-6677. ; 61, s. 123-34
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- Today the WHO Growth Chart Standards, based on the growth of breastfed infants, are used. These growth curves solve the problem of the deviating observations for breastfed compared to non-breastfed infants using previous growth charts. Presently it is not clear how the mother's diet, especially the fat intake, influences the growth of the offspring. Animal experiments indicate that a low intake of n-3 polyunsaturated fatty acids via the milk may have short- and long-term negative consequences. There is limited information in man. It has been suggested that the mammary glands may have phylogenetically originated from glands providing innate immunity, later developing capacities for providing nutrition. This would agree with the fact that human milk contains so many major components which do not primarily function as nutrients, but seem to protect nutrition and growth. Lactoferrin, oligosaccharides, glycoproteins, secretory IgA antibodies, alpha-lactalbumin and the antisecretory factor have such functions.
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| 4. |
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| 5. |
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| 6. |
- Huledal, Gunilla, et al.
(författare)
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Pharmacokinetics and Metabolism of Melflufen, an Alkylating Peptide-Drug Conjugate, in Patients with Relapsed Refractory Multiple Myeloma
- 2024
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Ingår i: Journal of clinical pharmacology. - : John Wiley & Sons. - 0091-2700 .- 1552-4604. ; 64:2, s. 240-252
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Tidskriftsartikel (refereegranskat)abstract
- Melphalan flufenamide (melflufen) is a novel lipophilic peptide-drug conjugate recently approved in the European Union and the United Kingdom for the treatment of relapsed refractory multiple myeloma. Melflufen rapidly crosses the cell membrane, and inside tumor cells, melflufen utilizes peptidases and esterases to release entrapped hydrophilic metabolites with alkylating activity. In vitro, in whole blood, melflufen was rapidly distributed into blood cells and quickly converted to its main metabolite melphalan, with maximum cellular concentrations of noncovalently bound melflufen and melphalan after 1 and 6 minutes, respectively. Melphalan outflow from blood cells was slow, with peak concentrations in plasma after 25 minutes. The pharmacokinetics of melflufen was best described by a 2-compartment model. Following a 30-minutes intravenous infusion of 40 mg in 27 patients with relapsed refactory multiple myeloma, mean half-life in the alpha phase of the curve was 1.24 minutes, half-life in the beta phase of the curve 26.7 minutes, and clearance 13.4 L/min. Desethyl-melflufen exposure was below 20% compared to melflufen. Based on population analysis (298 patients with relapsed refactory multiple myeloma), the melphalan pharmacokinetics were well characterized by a 3-compartment model with melflufen dosing into a peripheral compartment, assuming instantaneous distribution of melflufen into cells and subsequent rapid metabolism to melphalan. Mean clearance and central and deep peripheral volumes of distribution were 22.4 L/h, 2.70 L, and 51.3 L, respectively. Clearance increased and maximum concentration decreased with increasing body weight and estimated glomerular filtration rate. In conclusion, melflufen administration differs from melphalan administration by a more rapid distribution into cells, which, in conjunction with a rapid intracellular metabolism, allows for higher maximum concentrations of alkylating agents, and by a more extensive distribution of melphalan to peripheral tissues.
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| 7. |
- Norin, Stefan
(författare)
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Clinical prognostic markers in chronic lymphocytic leukemia
- 2011
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Chronic lymphocytic leukemia (CLL) is characterized by the accumulation of mature B lymphocytes in blood, bone marrow and lymphoid tissues. The clinical course for the individual patient is still unpredictable despite decades of research on prognostic markers and staging systems. The aim of this thesis was to review the value of existing prognostic tools in order to develop new clinical prognostic markers for CLL and to assess the impact of clonal evolution and transformation in CLL in relation to biological markers and given therapy. Paper I: This is a long-term follow-up of the first trial of subcutaneous alemtuzumab as first-line therapy in CLL. In order to assess duration of response, infectious complications and incidence of Richter transformation, a comparison was made with historical controls. Median time to treatment failure was 28 months for the alemtuzumab-treated patients compared to 17 months for the control group (not significant). Infectious complications were not more common in the alemtuzumab-treated patients despite profound and prolonged T-cell suppression. The rate of Richter transformation was similar between the groups. Paper II: Clinical data of 77 patients included in five phase II trials at Karolinska University Hospital were analyzed to find out whether the use of computed tomography (CT) could add prognostic information to the Rai and Binet clinical staging systems. A high nodal tumor burden evaluated by CT correlated with a shorter time to next therapy and a trend towards shorter survival. Massive splenomegaly was associated with shorter overall survival and therapy-free survival. Paper III: The expression of the estrogen receptors (ER) α, β1 and its splice variant β2 was evaluated in peripheral blood mononuclear cells (PBMC) from CLL patients and normal controls using immunocytochemistry. The expression of ERα was generally low whereas most PBMCs expressed ERβ1 in both patients and controls. ERβ2 expression was significantly more common in CLL. Patients with high expression (> 50% of PBMC) of ERβ1 and/or ERβ2 were more likely to need therapy during follow-up. Paper IV: Paraffin-embedded splenic tissue samples were obtained from 62 patients with CLL or SLL to assess whether chromosomal aberrations in the spleen have a prognostic impact. The cytogenetic abnormalities 11q-, 13q-, 17p- and trisomy 12 were assessed by interphase FISH and compared with samples from blood and/or bone marrow. Patients with 11q- and 17p- deletions in the spleen had significantly shorter overall and therapy-free survival. Clonal evolution seemed to occur in some cases.
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| 8. |
- Norin, Stefan, et al.
(författare)
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Severe infusion-related reactions are uncommon in rituximab-treated CLL patients in clinical practice: Results from a Swedish national observational study
- 2015
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Ingår i: Leukemia Research. - : Elsevier. - 0145-2126 .- 1873-5835. ; 39:1, s. 33-37
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Tidskriftsartikel (refereegranskat)abstract
- There have been concerns about serious infusion-related adverse drug reactions (ADR) with rituximabin chronic lymphocytic leukemia (CLL). We therefore conducted an observational trial in which CLL patients planned for rituximab-containing therapy were eligible. Ninety-six patients from 19 centers were enrolled. The most common regimen was rituximab, fludarabine and cyclophosphamide. Fifty-six patients experienced ADR during rituximab infusion. Reactions greater than= grade 3 occurred in five patients and no cases of tumor lysis syndrome were recorded. Despite a high number of circulating tumor cells few severe ADR were noted. Thus, rituximab containing regimens can be considered safe for CLL patients in general practice.
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| 9. |
- Sylvan, Sandra Eketorp, et al.
(författare)
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First-line therapy in chronic lymphocytic leukemia : a Swedish nation-wide real-world study on 1053 consecutive patients treated between 2007 and 2013
- 2019
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Ingår i: Haematologica. - : FERRATA STORTI FOUNDATION. - 0390-6078 .- 1592-8721. ; 104:4, s. 797-805
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Tidskriftsartikel (refereegranskat)abstract
- The aim of this study was to investigate long-term outcome following first-line therapy in consecutive chronic lymphocytic leukemia (CLL) patients in a well-defined geographic area: Sweden. All patients diagnosed with CLL (2007-2013) (n=3672) were identified from national registries, screening of patient files identified all (100%) treated first line (n=1053) and for those, an in-depth analysis was performed. End points were overall response rate, progression-free survival (PFS), overall survival (OS), and safety. Median age was 71 years; 53% had Rai stage III-IV and 97% had performance status grade 0-2. Fluorescence in situ hybridization (FISH) was performed in 57% of patients: 15% had del(17p). Chlorambucil + prednisone was used in 39% (5% also received rituximab). Fludarabine+cyclophosphamide+rituximab or fludarabine+cyclophosphamide was used in 43% and bendamustine + rituximab in 6%. Overall response rate was 64%; chlorambucil 43%, fludarabine+cyclophosphamide+rituximab 84%, fludarabine+cyclophosphamide 75% and bendamustine + rituximab 75%. Median PFS and OS was 24 and 58 months, respectively, both were significantly associated (multivariate analysis) with type of treatment, del(17p), performance status, gender, age and geographical region (OS only). Chlorambucil-treated patients had a median PFS and OS of only 9 and 33 months, respectively. Chlorambucil usage declined gradually throughout the study period, but one-third of patients still received chlorambucil + rituximab in 2013. Infections >= grade III were significantly associated with treatment; chlorambucil 19% versus fludarabine+cyclophosphamide+rituximab 30%. Richter transformation occurred in 5.5% of the patients, equally distributed across therapies. This is the largest retrospective, real-world cohort of consecutive first-line treated CLL patients with a complete follow up. In elderly patients, an unmet need for more effective, well-tolerated therapies was identified.
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| 10. |
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| 11. |
- Winqvist, Maria, et al.
(författare)
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Real-world results of ibrutinib in patients with relapsed or refractory chronic lymphocytic leukemia: data from 95 consecutive patients treated in a compassionate use program. A study from the Swedish Chronic Lymphocytic Leukemia Group
- 2016
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Ingår i: Haematologica. - : FERRATA STORTI FOUNDATION. - 0390-6078 .- 1592-8721. ; 101:12, s. 1573-1580
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Tidskriftsartikel (refereegranskat)abstract
- Ibrutinib, a Brutons tyrosine kinase inhibitor is approved for relapsed/refractory and del(17p)/TP53 mutated chronic lymphocytic leukemia. Discrepancies between clinical trials and routine healthcare are commonly observed in oncology. Herein we report real-world results for 95 poor prognosis Swedish patients treated with ibrutinib in a compassionate use program. Ninety-five consecutive patients (93 chronic lymphocytic leukemia, 2 small lymphocytic leukemia) were included in the study between May 2014 and May 2015. The median age was 69 years. 63% had del(17p)/TP53 mutation, 65% had Rai stage III/IV, 28% had lymphadenopathy amp;gt;= 10cm. Patients received ibrutinib 420 mg once daily until progression. At a median follow-up of 10.2 months, the overall response rate was 84% (consistent among subgroups) and 77% remained progression-free. Progression-free survival and overall survival were significantly shorter in patients with del(17p)/TP53 mutation (P=0.017 and P=0.027, log-rank test); no other factor was significant in Cox proportional regression hazards model. Ibrutinib was well tolerated. Hematomas occurred in 46% of patients without any major bleeding. Seven patients had Richters transformation. This real-world analysis on consecutive chronic lymphocytic leukemia patients from a well-defined geographical region shows the efficacy and safety of ibrutinib to be similar to that of pivotal trials. Yet, del(17p)/TP53 mutation remains a therapeutic challenge. Since not more than half of our patients would have qualified for the pivotal ibrutinib trial (RESONATE), our study emphasizes that real-world results should be carefully considered in future with regards to new agents and new indications in chronic lymphocytic leukemia.
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| 12. |
- Yakimchuk, Konstantin, et al.
(författare)
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Up-regulated estrogen receptor β2 in chronic lymphocytic leukemia
- 2012
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Ingår i: Leukemia and Lymphoma. - : Informa UK Limited. - 1042-8194 .- 1029-2403. ; 53:1, s. 139-144
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Tidskriftsartikel (refereegranskat)abstract
- The estrogen receptors alpha (ERα) and beta (ERβ) have been demonstrated in mouse models to be important for immune system regulation, and are differentially expressed in lymphoid organs. One ERβ splice variant, ERβ2, inhibits the ERα-mediated estrogen effect, and expression might predict response to selective estrogen receptor modulators. We studied the expression of ERα, ERβ1 and ERβ2 in peripheral blood mononuclear cells from 26 patients with chronic lymphocytic leukemia (CLL) and 30 normal controls using immunocytochemistry. ERα expression was generally low, while ERβ1 was expressed in 65% of patients with CLL and in 83% of controls (NS). In contrast, nuclear staining for ERβ2 was positive in 69% of patients with CLL, but in only 17% of controls (p < 0.001). In CLL, ERβ2 was found in B- but not in T-lymphocytes. Our data show the expression of ERβ1 and ERβ2 in the majority of patients with CLL, suggesting that the ERs are important in CLL and might be used as therapeutic targets.
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| 13. |
- Ålöw, Tobias, et al.
(författare)
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Recensioner
- 2016
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Ingår i: Svensk Exegetisk Årsbok. - Uppsala : Svenska exegetiska sällskapet. - 1100-2298. ; 81, s. 217-284
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Recension (övrigt vetenskapligt/konstnärligt)abstract
- Book reviews:Herbert W. Basser with Marsha B. CohenThe Gospel of Matthew and Judaic Traditions: A Relevance-based Commentary(Tobias Ålöw)Alicia J. Batten och John S. Kloppenborg (red.)James, 1 & 2 Peter, and Early Jesus Traditions(Leonhard Franke)Bible Works 10 (Bo Krister Ljungberg)Derek R. BrownThe God of This Age: Satan in the Churches and Letters of the Apostle Paul(Torsten Löfstedt)William P. Brown (ed.)The Oxford Handbook of the Psalms (David Willgren)Constantine R. CampbellAdvances in the Study of Greek: New Insights for Reading the New Testament (Jan H. Nylund)Nancy L. deClaissé-Walford (ed.) The Shape and Shaping of the Book of Psalms: The Current State of Scholarship(David Willgren)Nancy L. deClaissé-Walford, Rolf A. Jacobson and Beth Laneel Tanner The Book of Psalms(David Willgren)Thomas B. Dozeman, Konrad Schmid och Baruch J. Schwartz (red.) The Pentateuch: International Perspectives on Current Research(Stig Norin)Ole Jakob FiltvedtThe Identity of God’s People and the Paradox of Hebrews(Mikael Tellbe)David Hellholm, Tor Vegge, Øyvind Norderval and Christer Hellholm (eds.)Ablution, Initiation, and Baptism: Late Antiquity, Early Judaism, and Early Christianity(James A. Kelhoffer)Wesley Hill Paul and the Trinity: Persons, Relations, and the Pauline Letters(Mikael Tellbe)Douglas S. HuffmanVerbal Aspect Theory and the Prohibitions in the Greek New Testament(Jan H. Nylund)Thomas KazenScripture, Interpretation, or Authority? Motives and Arguments in Jesus’ Halakic Conflicts(Cecilia Wassén)Judith M. LieuMarcion and the Making of a Heretic: God and Scripture in the Second Century(James A. Kelhoffer)L. Michael Morales (ed.)Cult and Cosmos: Tilting Toward a Temple-Centered Theology(Stefan Green)Mark D. Nanos och Magnus Zetterholm (red.)Paul within Judaism: Restoring the First-Century Context to the Apostle(Martin Landgren)Carol A. Newsom och Brennan W. BreedDaniel: A Commentary(LarsOlov Eriksson)Maren Niehoff (red.)Homer and the Bible in the Eyes of Ancient Interpreters(Blazenka Scheuer)Kurt L. NollCanaan and Israel in Antiquity: A Textbook on History and Religion(Richard Pleijel)Ken Parry (ed.) The Wiley Blackwell Companion to Patristics(Carl Johan Berglund)Ralf Rothenbusch“... abgesondert zur Tora Gottes hin”: Ethnisch-religiöse Identitäten im Esra/Nehemiabuch(Lena-Sofia Tiemeyer)Michael L. SatlowHow the Bible Became Holy(Martin Wessbrandt)Birke Siggelkow-BernerDie jüdischen Feste im Bellum Judaicum des Flavius Josephus(Birger Olsson)Lena-Sofia Tiemeyer och Hans M. Barstad (red.)Continuity and Discontinuity: Chronological and Thematic Development in Isaiah 40–66(Stefan Green)W. Dennis Tucker Jr.Constructing and Deconstructing Power in Psalms 107–150(David Willgren)Helmut Utzschneider och Wolfgang OswaldExodus 1–15(LarsOlov Eriksson)Urban C. Von WahldeThe Gospel and Letters of John, vol. 1:Introduction, Analysis, and Reference The Gospel and Letters of John, vol. 2: Commentary on the Gospel of JohnThe Gospel and Letters of John, vol. 3: Commentary on the Three Johannine Letters(Birger Olsson)Benjamin L. WhiteRemembering Paul: Ancient and Modern Contests over the Image of the Apostle(Martin Wessbrandt)
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