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2. Clinical impact of clonal hematopoiesis in patients with lymphoma undergoing ASCT: a national population-based cohort study

Author

Husby, Simon, Favero, Francesco, Nielsen, Christian, Sørensen, Betina S., Bæch, John, Grell, Kathrine, Hansen, Jakob W., Rodriguez-Gonzalez, Francisco G., Haastrup, Eva K., Fischer-Nielsen, Anne, Andersen, Pernille, Arboe, Bente, Sækmose, Susanne G., Hansen, Per B., Christiansen, Ilse, Clasen-Linde, Erik, Meldgaard, Lene, Ebbesen, Lene H., Segel, Erik K., Josefsson, Pär, Thorsgaard, Michael, El-Galaly, Tarec C., Brown, Peter, Weischenfeldt, Joachim, Larsen, Thomas S., and Grønbæk, Kirsten

Published
2020
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4. Treatment strategies, outcomes and prognostic factors in 291 patients with secondary CNS involvement by diffuse large B-cell lymphoma

Author

El-Galaly, Tarec Christoffer, Cheah, Chan Yoon, Bendtsen, Mette Dahl, Nowakowski, Grzegorz S., Kansara, Roopesh, Savage, Kerry J., Connors, Joseph M., Sehn, Laurie H., Goldschmidt, Neta, Shaulov, Adir, Farooq, Umar, Link, Brian K., Ferreri, Andrés J.M., Calimeri, Teresa, Cecchetti, Caterina, Dann, Eldad J., Thompson, Carrie A., Inbar, Tsofia, Maurer, Matthew J., Gade, Inger Lise, Juul, Maja Bech, Hansen, Jakob W., Holmberg, Staffan, Larsen, Thomas S., Cordua, Sabrina, Mikhaeel, N. George, Hutchings, Martin, Seymour, John F., Clausen, Michael Roost, Smith, Daniel, Opat, Stephen, Gilbertson, Michael, Thanarajasingam, Gita, and Villa, Diego

Published
2018
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5. TP53 mutations identify younger mantle cell lymphoma patients who do not benefit from intensive chemoimmunotherapy

Author

Eskelund, Christian W., Dahl, Christina, Hansen, Jakob W., Westman, Maj, Kolstad, Arne, Pedersen, Lone B., Montano-Almendras, Carmen P., Husby, Simon, Freiburghaus, Catja, Ek, Sara, Pedersen, Anja, Niemann, Carsten, Räty, Riikka, Brown, Peter, Geisler, Christian H., Andersen, Mette K., Guldberg, Per, Jerkeman, Mats, and Grønbæk, Kirsten

Published
2017
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6. The number of extranodal sites assessed by PET/CT scan is a powerful predictor of CNS relapse for patients with diffuse large B-cell lymphoma: An international multicenter study of 1532 patients treated with chemoimmunotherapy

Author

El-Galaly, Tarec Christoffer, Villa, Diego, Michaelsen, Thomas Yssing, Hutchings, Martin, Mikhaeel, Nabegh George, Savage, Kerry J., Sehn, Laurie H., Barrington, Sally, Hansen, Jakob W., Smith, Daniel, Rady, Kirsty, Mylam, Karen J., Larsen, Thomas S., Holmberg, Staffan, Juul, Maja B., Cordua, Sabrina, Clausen, Michael R., Jensen, Kristina B., Johnsen, Hans E., Seymour, John F., Connors, Joseph M., de Nully Brown, Peter, Bøgsted, Martin, and Cheah, Chan Y.

Published
2017
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8. Mutations known from B-cell lymphoid malignancies are not found in CD34+ stem cells from patients with lymphoma

Author

Husby, Simon, primary, Favero, Francesco, additional, Rodriguez-Gonzalez, Francisco G., additional, Sutton, Lesley A., additional, Haastrup, Eva K., additional, Ørskov, Andreas Due, additional, Hansen, Jakob W., additional, Arboe, Bente, additional, Aslan, Derya, additional, Clasen-Linde, Erik, additional, Rahbek Gjerdrum, Lise Mette, additional, Gørlev, Jette Sønderskov, additional, Brown, Peter, additional, Fischer-Nielsen, Anne, additional, Rosenquist, Richard, additional, Weischenfeldt, Joachim, additional, and Grønbæk, Kirsten, additional

Published
2021
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9. Mutations known from B-cell lymphoid malignancies are not found in CD34+ stem cells from patients with lymphoma

Author

Husby, Simon, Favero, Francesco, Rodriguez-Gonzalez, Francisco G, Sutton, Lesley A, Haastrup, Eva K, Ørskov, Andreas Due, Hansen, Jakob W, Arboe, Bente, Aslan, Derya, Clasen-Linde, Erik, Rahbek Gjerdrum, Lise Mette, Gørlev, Jette Sønderskov, Brown, Peter, Fischer-Nielsen, Anne, Rosenquist, Richard, Weischenfeldt, Joachim, Grønbæk, Kirsten, Husby, Simon, Favero, Francesco, Rodriguez-Gonzalez, Francisco G, Sutton, Lesley A, Haastrup, Eva K, Ørskov, Andreas Due, Hansen, Jakob W, Arboe, Bente, Aslan, Derya, Clasen-Linde, Erik, Rahbek Gjerdrum, Lise Mette, Gørlev, Jette Sønderskov, Brown, Peter, Fischer-Nielsen, Anne, Rosenquist, Richard, Weischenfeldt, Joachim, and Grønbæk, Kirsten

Published
2021

10. Structural aberrations are associated with poor survival in patients with clonal cytopenia of undetermined significance

Author

Mikkelsen, Stine U, Safavi, Setareh, Dimopoulos, Konstantinos, O'Rourke, Colm J, Andersen, Mette K, Holm, Mette S, Marcher, Claus W, Andersen, Jesper B, Hansen, Jakob W, Grønbæk, Kirsten, Mikkelsen, Stine U, Safavi, Setareh, Dimopoulos, Konstantinos, O'Rourke, Colm J, Andersen, Mette K, Holm, Mette S, Marcher, Claus W, Andersen, Jesper B, Hansen, Jakob W, and Grønbæk, Kirsten

Published
2021

12. Clinical impact of clonal hematopoiesis in patients with lymphoma undergoing ASCT:a national population-based cohort study

Author

Husby, Simon, Favero, Francesco, Nielsen, Christian, Sørensen, Betina S, Bæch, John, Grell, Kathrine, Hansen, Jakob W, Rodriguez-Gonzalez, Francisco G, Haastrup, Eva K, Fischer-Nielsen, Anne, Andersen, Pernille, Arboe, Bente, Sækmose, Susanne G, Hansen, Per B, Christiansen, Ilse, Clasen-Linde, Erik, Meldgaard, Lene, Ebbesen, Lene H, Segel, Erik K, Josefsson, Pär, Thorsgaard, Michael, El-Galaly, Tarec C, Brown, Peter, Weischenfeldt, Joachim, Larsen, Thomas S, Grønbæk, Kirsten, Husby, Simon, Favero, Francesco, Nielsen, Christian, Sørensen, Betina S, Bæch, John, Grell, Kathrine, Hansen, Jakob W, Rodriguez-Gonzalez, Francisco G, Haastrup, Eva K, Fischer-Nielsen, Anne, Andersen, Pernille, Arboe, Bente, Sækmose, Susanne G, Hansen, Per B, Christiansen, Ilse, Clasen-Linde, Erik, Meldgaard, Lene, Ebbesen, Lene H, Segel, Erik K, Josefsson, Pär, Thorsgaard, Michael, El-Galaly, Tarec C, Brown, Peter, Weischenfeldt, Joachim, Larsen, Thomas S, and Grønbæk, Kirsten

Abstract

Clonal hematopoiesis of indeterminate potential (CHIP) is suspected of being a risk factor for patients with cancer. This study aimed to assess the clinical consequences of CHIP in patients with lymphoma intended for high-dose chemotherapy and autologous stem-cell transplantation (ASCT) in a population-based setting. We identified 892 lymphoma patients who had undergone stem cell harvest at all transplant centers in Denmark. A total of 565 patients had an available harvest sample, which was analysed for CHIP by next-generation sequencing, and the median follow-up was 9.1 years. Of the patients who were intended for immediate ASCT, 25.5% (112/440) carried at least one CHIP mutation. In contrast to previous single-center studies CHIP was not associated with inferior overall survival (OS) in multivariate analyses. However, patients with mutations in genes of the DNA repair pathway (PPM1D, TP53, RAD21, BRCC3) had a significant inferior OS (HR after 1 year of follow-up 2.79, 95% confidence interval 1.71-4.56; p < 0.0001), which also was evident in multivariate analysis (p = 0.00067). These patients had also increased rates of therapy-related leukemia and admission to intensive care. Furthermore, in patients who did not undergo immediate ASCT, a significant inferior OS of individuals with DNA repair mutations was also identified (p = 0.003).

Published
2020

13. Mutations known from B-cell lymphoid malignancies are not found in CD34+ stem cells from patients with lymphoma.

Author

Husby, Simon, Favero, Francesco, Rodriguez-Gonzalez, Francisco G., Sutton, Lesley A., Haastrup, Eva K., Ørskov, Andreas Due, Hansen, Jakob W., Arboe, Bente, Aslan, Derya, Clasen-Linde, Erik, Rahbek Gjerdrum, Lise Mette, Gørlev, Jette Sønderskov, Brown, Peter, Fischer-Nielsen, Anne, Rosenquist, Richard, Weischenfeldt, Joachim, and Grønbæk, Kirsten

Subjects
STEM cells, LYMPHOMAS, DIFFUSE large B-cell lymphomas, HODGKIN'S disease, MULTIPOTENT stem cells
Abstract

Future studies in this area are anticipated and will hopefully determine whether rare CD34 SP + sp stem cell clones with lymphoma mutations exists in patients with lymphoma, and whether they have an impact on clinical course and treatment response. Patients were included if they had a diagnosis of lymphoma, were intended to undergo ASCT, had a sufficient stem cell harvest and had at least one additional vial of their stem cell product available for research purposes. However, another possibility is that the methods used in this report (detection limit of VAF >2%, hence able to identify mutations in four out of a 100 CD34 SP + sp cells) are not sensitive enough to detect possible B-cell lymphoma CD34 SP + sp stem cells. [Extracted from the article]

Published
2021
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14. Clinical Impact of Clonal Hematopoiesis after Autologous Stem Cell Transplantation for Lymphoma: A National Population-Based Study

Author

Husby, Simon, Favero, Francesco, Nielsen, Christian, Sørensen, Betina, Bæch, John, Hansen, Jakob W, G.R. Gonzalez, German, Arboe, Bente, Andersen, Lisbeth Pernille, K. Hastrup, Eva, Fischer, Anne, G. Sækmose, Susanne, Hansen, Per Boye, Christiansen, Ilse, Clasen-Linde, Erik, Meldgaard Knudsen, Lene, S. Davids, Matthew, Segel, Erik Kay, Ebbesen, Lene Hyldahl, Thorsgaard, Michael, Josefsson, Pär, El-Galaly, Tarec Christoffer, de Nully Brown, Peter, Weisenfeldt, Joachim, Larsen, Thomas Stauffer, and Grønbæk, Kirsten

Published
2018

15. Oral vitamin C supplementation to patients with myeloid cancer on azacitidine treatment:Normalization of plasma vitamin C induces epigenetic changes

Author

Gillberg, Linn, Ørskov, Andreas D., Nasif, Ammar, Ohtani, Hitoshi, Madaj, Zachary, Hansen, Jakob W., Rapin, Nicolas, Mogensen, Johanne B., Liu, Minmin, Dufva, Inge H., Lykkesfeldt, Jens, Hajkova, Petra, Jones, Peter A., Grønbæk, Kirsten, Gillberg, Linn, Ørskov, Andreas D., Nasif, Ammar, Ohtani, Hitoshi, Madaj, Zachary, Hansen, Jakob W., Rapin, Nicolas, Mogensen, Johanne B., Liu, Minmin, Dufva, Inge H., Lykkesfeldt, Jens, Hajkova, Petra, Jones, Peter A., and Grønbæk, Kirsten

Abstract

BACKGROUND: Patients with haematological malignancies are often vitamin C deficient, and vitamin C is essential for the TET-induced conversion of 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC), the first step in active DNA demethylation. Here, we investigate whether oral vitamin C supplementation can correct vitamin C deficiency and affect the 5hmC/5mC ratio in patients with myeloid cancers treated with DNA methyltransferase inhibitors (DNMTis). RESULTS: We conducted a randomized, double-blinded, placebo-controlled pilot trial (NCT02877277) in Danish patients with myeloid cancers performed during 3 cycles of DNMTi-treatment (5-azacytidine, 100 mg/m2/d for 5 days in 28-day cycles) supplemented by oral dose of 500 mg vitamin C (n = 10) or placebo (n = 10) daily during the last 2 cycles. Fourteen patients (70%) were deficient in plasma vitamin C (< 23 μM) and four of the remaining six patients were taking vitamin supplements at inclusion. Global DNA methylation was significantly higher in patients with severe vitamin C deficiency (< 11.4 μM; 4.997 vs 4.656% 5mC relative to deoxyguanosine, 95% CI [0.126, 0.556], P = 0.004). Oral supplementation restored plasma vitamin C levels to the normal range in all patients in the vitamin C arm (mean increase 34.85 ± 7.94 μM, P = 0.0004). We show for the first time that global 5hmC/5mC levels were significantly increased in mononuclear myeloid cells from patients receiving oral vitamin C compared to placebo (0.037% vs - 0.029%, 95% CI [- 0.129, - 0.003], P = 0.041). CONCLUSIONS: Normalization of plasma vitamin C by oral supplementation leads to an increase in the 5hmC/5mC ratio compared to placebo-treated patients and may enhance the biological effects of DNMTis. The clinical efficacy of oral vitamin C supplementation to DNMTis should be investigated in a large randomized, placebo-controlled clinical trial. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02877277 . Registered on 9 August 2016, retrospectively register

Published
2019

16. An International Collaborative Study of Outcome and Prognostic Factors in Patients with Secondary CNS Involvement By Diffuse Large B-Cell Lymphoma

Author

Tarec Christoffer El-Galaly, Chan Yoon Cheah, Mette Dahl Bendtsen, Gita Thanarasjasingam, Roopesh Kansara, Savage, Kerry J., Connors, Joseph M., Neta Goldschmidt, Adir Shaulov, Umar Farooq, Sehn, Laurie H., Dann, Eldad J., Thompson, Carrie A., Tsofia Inbar, Link, Brian K., Maurer, Matthew J., Inger Lise Gade, Maja Bech Juul, Hansen, Jakob W., Staffan Holmberg, Thomas Stauffer Larsen, Stephen Opat, George Mikhaeel, N., Seymour, John F., Michael Roost Clausen, Daniel Smith, Michael Gilbertson, Nowakowski, Grzegorz S., Sabrina Cordua, Martin Hutchings, and Diego Villa

Subjects
diffuse large B-cell lymphoma, CNS relaps, health care economics and organizations
Abstract

Background: Secondary CNS involvement (SCNS) is a detrimental complication seen in ~5% of patients with diffuse large B-cell lymphoma (DLBCL) treated with modern immunochemotherapy. Data from older series report short survival following SCNS, typically lt;6 months. However, data in patients that develop SCNS following primary therapy that contains a rituximab-based-regimen as well as the impact of more intensified treatment for SCNS are limited.Aims: The aims of this study were to i) describe the natural history of SCNS in a large cohort of patients treated with immunochemotherapy, and ii) determine prognostic factors after SCNS.Patients and methods: We performed a retrospective study of patients diagnosed with SCNS during or after frontline immunochemotherapy (R-CHOP or equivalently effective regimens). SCNS was defined as new involvement of the CNS (parenchymal, leptomeningeal, and/or eye) in patients without known CNS involvement at the time of first pathologic diagnosis of DLBCL. Patients were identified from local databases and/or regional/national registries in Denmark, Canada (British Columbia), Australia, Israel, US (University of Iowa/Mayo Clinic SPORE), and England (Guy's and St. Thomas' Hospital, London). Clinico-pathologic and treatment characteristics at the time of SCNS were collected from medical records.Results: In total, 281 patients with SCNS diagnosed between 2001 and 2016 were included. Median age at SCNS was 64 (range 20-93) years and male:female ratio was 1.3. SCNS occurred as part of first relapse in 244 (87 patients and 112 (40 had documented concurrent systemic disease at the time of SCNS. The median time from initial DLBCL diagnosis to SCNS was 9 months, which was similar for patients treated with (N=76, 27 or without upfront CNS prophylaxis (N=205, 73 (10 vs 9 Mo; P=0.3). The median post-SCNS OS was 4 months (interquartile range 2-13) and the 2yr survival rate was 20% (95% CI 15-25) for the entire cohort. Associations between clinicopathologic features, management strategy, and post-SCNS survival are shown in Table 1, which excludes patients who did not receive any treatment against SCNS, patients treated with steroids alone, and a patient with unavailable treatment information (n=43, 15. In multivariable analysis, performance status gt;1, concurrent leptomeningeal and parenchymal involvement, SCNS developing before completion of 1st line treatment, and combined systemic and CNS involvement by DLBCL were associated with inferior outcomes. Upfront CNS prophylaxis did not influence post-SCNS OS. High-dose methotrexate (HDMTX) and/or platinum based treatment regimens (i.e. ICE, DHAP, or GDP [+/- IT treatment and/or radiotherapy], N=163) for SCNS were associated with reduced risk of death (HR 0.45 [0.32-0.62, Plt;0.01]). The 2yr post-SCNS survival for patients treated with HDMTX and/or platinum-based regimens (N=163) was 29% (95% CI 22-37). For patients with isolated parenchymal SCNS, single modality treatment with radiotherapy resulted in 2-yr OS of 19% (95% CI 8-35). For the subgroup of 49 patients treated with HDMTX- and/or platinum-based regimens for isolated SCNS after 1st line DLBCL treatment and with performance status 0 or 1, the 2yr post-SCNS survival was 46% (95% CI 31-59). Overall, 9% of the patients received HDT with ASCT as part of salvage therapy at the time of SCNS. Amongst 36 SCNS patients without systemic involvement and in CR following intensive treatment (HDMTX and/or platinum-based treatments), 11 patients consolidated with HDT had similar outcomes to 25 patients treated without consolidating HDT (P=0.9, Fig 1)Conclusions: Outcomes for patients with SCNS remain poor in this large international cohort of patients from the immunochemotherapy era. Combined parenchymal and leptomeningeal disease, presence of systemic disease concurrent with SCNS, performance status gt;1, and SCNS developing during first line treatment were independently associated with inferior OS. However, a significant fraction of patients with isolated SCNS after first line DLBCL treatment and with good performance status may achieve long-term remissions after intensive regimens for SCNS.Disclosures El-Galaly: Roche: Consultancy, Other: travel funding. Cheah: Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Gilead Sciences: Membership on an entity's Board of Directors or advisory committees; Janssen-Cilag: Membership on an entity's Board of Directors or advisory committees, Other: Speaker's Bureau. Kansara: Celgene: Honoraria. Connors: Bristol Myers Squib: Research Funding; NanoString Technologies: Research Funding; F Hoffmann-La Roche: Research Funding; Millennium Takeda: Research Funding; Seattle Genetics: Research Funding. Sehn: roche/genentech: Consultancy, Honoraria; amgen: Consultancy, Honoraria; seattle genetics: Consultancy, Honoraria; abbvie: Consultancy, Honoraria; TG therapeutics: Consultancy, Honoraria; celgene: Consultancy, Honoraria; lundbeck: Consultancy, Honoraria; janssen: Consultancy, Honoraria. Opat: Roche: Consultancy, Honoraria, Other: Provision of subsidised drugs, Research Funding. Seymour: Genentech: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Villa: Celgene: Honoraria; Lundbeck: Honoraria; Roche: Honoraria, Research Funding.↵* Asterisk with author names denotes non-ASH members.

Published
2016

17. The number of extranodal sites assessed by PET/CT scan is a powerful predictor of CNS relapse for patients with diffuse large B-cell lymphoma:An international multicenter study of 1532 patients treated with chemoimmunotherapy

Author

El-Galaly, Tarec Christoffer, Villa, Diego, Michaelsen, Thomas Yssing, Hutchings, Martin, Mikhaeel, Nabegh George, Savage, Kerry J., Sehn, Laurie H., Barrington, Sally, Hansen, Jakob W., Smith, Daniel, Rady, Kirsty, Mylam, Karen J., Larsen, Thomas S., Holmberg, Staffan, Juul, Maja B., Cordua, Sabrina, Clausen, Michael R., Jensen, Kristina B., Johnsen, Hans E., Seymour, John F., Connors, Joseph M., de Nully Brown, Peter, Bøgsted, Martin, Cheah, Chan Y., El-Galaly, Tarec Christoffer, Villa, Diego, Michaelsen, Thomas Yssing, Hutchings, Martin, Mikhaeel, Nabegh George, Savage, Kerry J., Sehn, Laurie H., Barrington, Sally, Hansen, Jakob W., Smith, Daniel, Rady, Kirsty, Mylam, Karen J., Larsen, Thomas S., Holmberg, Staffan, Juul, Maja B., Cordua, Sabrina, Clausen, Michael R., Jensen, Kristina B., Johnsen, Hans E., Seymour, John F., Connors, Joseph M., de Nully Brown, Peter, Bøgsted, Martin, and Cheah, Chan Y.

Abstract

Purpose Development of secondary central nervous system involvement (SCNS) in patients with diffuse large B-cell lymphoma is associated with poor outcomes. The CNS International Prognostic Index (CNS-IPI) has been proposed for identifying patients at greatest risk, but the optimal model is unknown. Methods We retrospectively analysed patients with diffuse large B-cell lymphoma diagnosed between 2001 and 2013, staged with PET/CT and treated with R-CHOP(-like) regimens. Baseline clinicopathologic characteristics, treatments, and outcome data were collected from clinical databases and medical files. We evaluated the association between candidate prognostic factors and modelled different risk models for predicting SCNS. Results Of 1532 patients, 62 (4%) subsequently developed SCNS. By multivariate analysis, disease stage III/IV, elevated serum LDH, kidney/adrenal and uterine/testicular involvement were independently associated with SCNS. There was a strong correlation between absolute number of extranodal sites and risk of SCNS; the 144 patients (9%) with >2 extranodal sites had a 3-year cumulative incidence of SCNS of 15.2% (95% confidence interval [CI] 9.2–21.2%) compared with 2.6% (95% CI 1.7–3.5) among those with ≤2 sites (P < 0.001). The 3-year cumulative risks of SCNS for CNS-IPI defined risk groups were 11.2%, 3.1% and 0.4% for high-, intermediate- and low-risk patients, respectively. All risk models analysed had high negative predictive values, but only modest positive predictive values. Conclusions Patients with >2 extranodal sites or high-risk disease according to the CNS-IPI should be considered for baseline CNS staging. Clinical risk prediction models suffer from limited positive predictive ability, highlighting the need for more sensitive biomarkers to identify patients at highest risk of this devastating complication.

Published
2017

18. An International Collaborative Study of Outcome and Prognostic Factors in Patients with Secondary CNS Involvement By Diffuse Large B-Cell Lymphoma

Author

El-Galaly, Tarec Christoffer, primary, Cheah, Chan Yoon, additional, Bendtsen, Mette Dahl, additional, Thanarasjasingam, Gita, additional, Kansara, Roopesh, additional, Savage, Kerry J, additional, Connors, Joseph M., additional, Goldschmidt, Neta, additional, Shaulov, Adir, additional, Farooq, Umar, additional, Sehn, Laurie H, additional, Dann, Eldad J, additional, Thompson, Carrie A, additional, Inbar, Tsofia, additional, Link, Brian K, additional, Maurer, Matthew J, additional, Gade, Inger Lise, additional, Juul, Maja Bech, additional, Hansen, Jakob W, additional, Holmberg, Staffan, additional, Larsen, Thomas S, additional, Opat, Stephen, additional, Mikhaeel, N George, additional, Seymour, John F, additional, Clausen, Michael Roost, additional, Smith, Daniel, additional, Gilbertson, Michael, additional, Nowakowski, Grzegorz S, additional, Cordua, Sabrina, additional, Hutchings, Martin, additional, and Villa, Diego, additional

Published
2016
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19. Targeted Sequencing of Diagnostic Samples Correlated to Clinical Outcome: Data from the Nordic Mantle Cell Lymphoma (MCL2 and MCL3) Studies with Long-Term Follow-up

Author

Eskelund, Christian Winther, primary, Hansen, Jakob W, additional, Westman, Maj Karoline, additional, Freiburghaus, Catja, additional, Ek, Sara, additional, Pedersen, Lone B, additional, Andersen, Mette K, additional, Räty, Riikka, additional, Kolstad, Arne, additional, Jerkeman, Mats, additional, Brown, Peter de Nully, additional, Geisler, Christian H, additional, and Groenbaek, Kirsten, additional

Published
2016
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20. Uterine, but not ovarian, female reproductive organ involvement at presentation by diffuse large B‐cell lymphoma is associated with poor outcomes and a high frequency of secondary CNS involvement

Author

El‐Galaly, Tarec Christoffer, primary, Cheah, Chan Y., additional, Hutchings, Martin, additional, Mikhaeel, Nabegh George, additional, Savage, Kerry J., additional, Sehn, Laurie H., additional, Barrington, Sally, additional, Hansen, Jakob W., additional, Poulsen, Mette Ø., additional, Smith, Daniel, additional, Rady, Kirsty, additional, Mylam, Karen J., additional, Larsen, Thomas S., additional, Holmberg, Staffan, additional, Juul, Maja B., additional, Cordua, Sabrina, additional, Clausen, Michael R., additional, Jensen, Kristina B., additional, Bøgsted, Martin, additional, Johnsen, Hans E., additional, Seymour, John F., additional, Connors, Joseph M., additional, Brown, Peter d. N., additional, and Villa, Diego, additional

Published
2016
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21. Circulating YKL-40 in Patients with Essential Thrombocythemia (ET) and Polycythemia Vera (PV) treated with the Novel Histone Deacetylase Inhibitor Vorinostat

Author

Andersen, Christen Lykkegaard, Bjørn, Mads Emil, McMullin, Mary Frances, Ejerblad, Elisabeth, Zweegman, Sonja, Harrison, Claire, Fernandes, Savio, Bareford, David, Knapper, Steven, Samuelsson, Jan, Löfvenberg, Eva, Linder, Olle, Andreasson, Björn, Ahlstrand, Erik, Jensen, Morten K, Bjerrum, Ole W, Vestergaard, Hanne, Larsen, Herdis, Klausen, Tobias, Mourits-Andersen, Torben, Hansen, Jakob W, Skov, Vibe, Thomassen, Mads, Grønbæk, Kirsten, and Hasselbalch, Hans Carl

Published
2013

22. YKL-40 and genetic status of CHI3L1 in a large group of asthmatics

Author

Hansen, Jakob W, Thomsen, Simon F, Porsbjerg, Celeste, Rasmussen, Linda M, Harmsen, Lotte, Johansen, Julia S, Backer, Vibeke, Hansen, Jakob W, Thomsen, Simon F, Porsbjerg, Celeste, Rasmussen, Linda M, Harmsen, Lotte, Johansen, Julia S, and Backer, Vibeke

Abstract

BACKGROUND: Studies have shown a relationship between asthma, serum YKL-40, and the single nucleotide polymorphism (SNP) (-131 C/G, rs4950928) in the CHI3L1 gene that codes for YKL-40. However, the findings differ. We studied the relationship between clinical asthma phenotypes, serum YKL-40, and SNP (-131 C/G, rs4950928).METHODS: In this study, 1,137 patients with asthma, 415 with rhinitis only, and 275 non-asthmatic controls were included. Assessment included a clinical interview concerning the diagnosis of asthma, severity of asthma, and asthma treatment as well as clinical tests to assess asthma and rhinitis. Serum YKL-40 was measured, and genotyping for the SNP (-131 C/G) was conducted.RESULTS: No significant difference in the serum concentration of YKL-40 was found between patients with asthma, patients with rhinitis, and non-asthmatic controls; however, YKL-40 was increased in patients with severe asthma. No association was found between the SNP (-131 C/G rs4950982) and the risk of having asthma (odds ratio = 0.90, p=0.4). Higher levels of serum YKL-40 were found in all subjects when comparing CC genotype to CG and GG genotypes (45 µg/L vs. 32 µg/L and 19 µg/L, p<0.0001).CONCLUSION: There was no association between polymorphisms of SNP (-131 C/G) and asthma. The highest serum YKL-40 concentrations were seen in severe asthmatics. Individuals with less severe asthma showed a smaller difference against controls, limiting its clinical usefulness. More research is needed to clarify the relationship between different asthma phenotypes, YKL-40, and CHI3L1.

Published
2015

24. Sequence variants affecting eosinophil numbers associate with asthma and myocardial infarction

Author

Gudbjartsson, Daniel F., Bjornsdottir, Unnur S., Halapi, Eva, Helgadottir, Anna, Sulem, Patrick, Jonsdottir, Gudrun M., Thorleifsson, Gudmar, Helgadottir, Hafdis, Steinthorsdottir, Valgerdur, Stefansson, Hreinn, Williams, Carolyn, Hui, Jennie, Beilby, John, Warrington, Nicole M., James, Alan, Palmer, Lyle J., Koppelman, Gerard H., Heinzmann, Andrea, Krueger, Marcus, Boezen, H. Marike, Wheatley, Amanda, Altmuller, Janine, Shin, Hyoung Doo, Uh, Soo-Taek, Cheong, Hyun Sub, Jonsdottir, Brynja, Gislason, David, Park, Choon-Sik, Rasmussen, Linda M., Porsbjerg, Celeste, Hansen, Jakob W., Backer, Vibeke, Werge, Thomas, Janson, Christer, Jönsson, Ulla-Britt, Ng, Maggie C. Y., Chan, Juliana, So, Wing Yee, Ma, Ronald, Shah, Svati H., Granger, Christopher B., Quyyumi, Arshed A., Levey, Allan I., Vaccarino, Viola, Reilly, Muredach P., Rader, Daniel J., Williams, Michael J. A., van Rij, Andre M., Jones, Gregory T., Trabetti, Elisabetta, Malerba, Giovanni, Pignatti, Pier Franco, Boner, Attilio, Pescollderungg, Lydia, Girelli, Domenico, Olivieri, Oliviero, Martinelli, Nicola, Ludviksson, Bjorn R., Ludviksdottir, Dora, Eyjolfsson, Gudmundur I., Arnar, David, Thorgeirsson, Gudmundur, Deichmann, Klaus, Thompson, Philip J., Wjst, Matthias, Hall, Ian P., Postma, Dirkje S., Gislason, Thorarinn, Gulcher, Jeffrey, Kong, Augustine, Jonsdottir, Ingileif, Thorsteinsdottir, Unnur, Stefansson, Kari, Gudbjartsson, Daniel F., Bjornsdottir, Unnur S., Halapi, Eva, Helgadottir, Anna, Sulem, Patrick, Jonsdottir, Gudrun M., Thorleifsson, Gudmar, Helgadottir, Hafdis, Steinthorsdottir, Valgerdur, Stefansson, Hreinn, Williams, Carolyn, Hui, Jennie, Beilby, John, Warrington, Nicole M., James, Alan, Palmer, Lyle J., Koppelman, Gerard H., Heinzmann, Andrea, Krueger, Marcus, Boezen, H. Marike, Wheatley, Amanda, Altmuller, Janine, Shin, Hyoung Doo, Uh, Soo-Taek, Cheong, Hyun Sub, Jonsdottir, Brynja, Gislason, David, Park, Choon-Sik, Rasmussen, Linda M., Porsbjerg, Celeste, Hansen, Jakob W., Backer, Vibeke, Werge, Thomas, Janson, Christer, Jönsson, Ulla-Britt, Ng, Maggie C. Y., Chan, Juliana, So, Wing Yee, Ma, Ronald, Shah, Svati H., Granger, Christopher B., Quyyumi, Arshed A., Levey, Allan I., Vaccarino, Viola, Reilly, Muredach P., Rader, Daniel J., Williams, Michael J. A., van Rij, Andre M., Jones, Gregory T., Trabetti, Elisabetta, Malerba, Giovanni, Pignatti, Pier Franco, Boner, Attilio, Pescollderungg, Lydia, Girelli, Domenico, Olivieri, Oliviero, Martinelli, Nicola, Ludviksson, Bjorn R., Ludviksdottir, Dora, Eyjolfsson, Gudmundur I., Arnar, David, Thorgeirsson, Gudmundur, Deichmann, Klaus, Thompson, Philip J., Wjst, Matthias, Hall, Ian P., Postma, Dirkje S., Gislason, Thorarinn, Gulcher, Jeffrey, Kong, Augustine, Jonsdottir, Ingileif, Thorsteinsdottir, Unnur, and Stefansson, Kari

Abstract

Eosinophils are pleiotropic multifunctional leukocytes involved in initiation and propagation of inflammatory responses and thus have important roles in the pathogenesis of inflammatory diseases. Here we describe a genome-wide association scan for sequence variants affecting eosinophil counts in blood of 9,392 Icelanders. The most significant SNPs were studied further in 12,118 Europeans and 5,212 East Asians. SNPs at 2q12 (rs1420101), 2q13 (rs12619285), 3q21 (rs4857855), 5q31 (rs4143832) and 12q24 (rs3184504) reached genome-wide significance (P = 5.3 x 10(-14), 5.4 x 10(-10), 8.6 x 10(-17), 1.2 x 10(-10) and 6.5 x 10(-19), respectively). A SNP at IL1RL1 associated with asthma (P = 5.5 x 10(-12)) in a collection of ten different populations (7,996 cases and 44,890 controls). SNPs at WDR36, IL33 and MYB that showed suggestive association with eosinophil counts were also associated with atopic asthma (P = 4.2 x 10(-6), 2.2 x 10(-5) and 2.4 x 10(-4), respectively). We also found that a nonsynonymous SNP at 12q24, in SH2B3, associated significantly (P = 8.6 x 10(-8)) with myocardial infarction in six different populations (6,650 cases and 40,621 controls).

Published
2009
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25. Sequence variants affecting eosinophil numbers associate with asthma and myocardial infarction

Author

Gudbjartsson, Daniel F, Bjornsdottir, Unnur S, Halapi, Eva, Helgadottir, Anna, Sulem, Patrick, Jonsdottir, Gudrun M, Thorleifsson, Gudmar, Helgadottir, Hafdis, Steinthorsdottir, Valgerdur, Stefansson, Hreinn, Williams, Carolyn, Hui, Jennie, Beilby, John, Warrington, Nicole M, James, Alan, Palmer, Lyle J, Koppelman, Gerard H, Heinzmann, Andrea, Krueger, Marcus, Boezen, H Marike, Wheatley, Amanda, Altmuller, Janine, Shin, Hyoung Doo, Uh, Soo-Taek, Cheong, Hyun Sub, Jonsdottir, Brynja, Gislason, David, Park, Choon-Sik, Rasmussen, Linda M, Porsbjerg, Celeste, Hansen, Jakob W, Backer, Vibeke, Werge, Thomas, Janson, Christer, Jönsson, Ulla-Britt, Ng, Maggie C Y, Chan, Juliana, So, Wing Yee, Ma, Ronald, Shah, Svati H, Granger, Christopher B, Quyyumi, Arshed A, Levey, Allan I, Vaccarino, Viola, Reilly, Muredach P, Rader, Daniel J, Williams, Michael J A, van Rij, Andre M, Jones, Gregory T, Trabetti, Elisabetta, Malerba, Giovanni, Pignatti, Pier Franco, Boner, Attilio, Pescollderungg, Lydia, Girelli, Domenico, Olivieri, Oliviero, Martinelli, Nicola, Ludviksson, Bjorn R, Ludviksdottir, Dora, Eyjolfsson, Gudmundur I, Arnar, David, Thorgeirsson, Gudmundur, Deichmann, Klaus, Thompson, Philip J, Wjst, Matthias, Hall, Ian P, Postma, Dirkje S, Gislason, Thorarinn, Gulcher, Jeffrey, Kong, Augustine, Jonsdottir, Ingileif, Thorsteinsdottir, Unnur, Stefansson, Kari, Gudbjartsson, Daniel F, Bjornsdottir, Unnur S, Halapi, Eva, Helgadottir, Anna, Sulem, Patrick, Jonsdottir, Gudrun M, Thorleifsson, Gudmar, Helgadottir, Hafdis, Steinthorsdottir, Valgerdur, Stefansson, Hreinn, Williams, Carolyn, Hui, Jennie, Beilby, John, Warrington, Nicole M, James, Alan, Palmer, Lyle J, Koppelman, Gerard H, Heinzmann, Andrea, Krueger, Marcus, Boezen, H Marike, Wheatley, Amanda, Altmuller, Janine, Shin, Hyoung Doo, Uh, Soo-Taek, Cheong, Hyun Sub, Jonsdottir, Brynja, Gislason, David, Park, Choon-Sik, Rasmussen, Linda M, Porsbjerg, Celeste, Hansen, Jakob W, Backer, Vibeke, Werge, Thomas, Janson, Christer, Jönsson, Ulla-Britt, Ng, Maggie C Y, Chan, Juliana, So, Wing Yee, Ma, Ronald, Shah, Svati H, Granger, Christopher B, Quyyumi, Arshed A, Levey, Allan I, Vaccarino, Viola, Reilly, Muredach P, Rader, Daniel J, Williams, Michael J A, van Rij, Andre M, Jones, Gregory T, Trabetti, Elisabetta, Malerba, Giovanni, Pignatti, Pier Franco, Boner, Attilio, Pescollderungg, Lydia, Girelli, Domenico, Olivieri, Oliviero, Martinelli, Nicola, Ludviksson, Bjorn R, Ludviksdottir, Dora, Eyjolfsson, Gudmundur I, Arnar, David, Thorgeirsson, Gudmundur, Deichmann, Klaus, Thompson, Philip J, Wjst, Matthias, Hall, Ian P, Postma, Dirkje S, Gislason, Thorarinn, Gulcher, Jeffrey, Kong, Augustine, Jonsdottir, Ingileif, Thorsteinsdottir, Unnur, and Stefansson, Kari

Abstract

Eosinophils are pleiotropic multifunctional leukocytes involved in initiation and propagation of inflammatory responses and thus have important roles in the pathogenesis of inflammatory diseases. Here we describe a genome-wide association scan for sequence variants affecting eosinophil counts in blood of 9,392 Icelanders. The most significant SNPs were studied further in 12,118 Europeans and 5,212 East Asians. SNPs at 2q12 (rs1420101), 2q13 (rs12619285), 3q21 (rs4857855), 5q31 (rs4143832) and 12q24 (rs3184504) reached genome-wide significance (P = 5.3 x 10(-14), 5.4 x 10(-10), 8.6 x 10(-17), 1.2 x 10(-10) and 6.5 x 10(-19), respectively). A SNP at IL1RL1 associated with asthma (P = 5.5 x 10(-12)) in a collection of ten different populations (7,996 cases and 44,890 controls). SNPs at WDR36, IL33 and MYB that showed suggestive association with eosinophil counts were also associated with atopic asthma (P = 4.2 x 10(-6), 2.2 x 10(-5) and 2.4 x 10(-4), respectively). We also found that a nonsynonymous SNP at 12q24, in SH2B3, associated significantly (P = 8.6 x 10(-8)) with myocardial infarction in six different populations (6,650 cases and 40,621 controls).

Published
2009

26. TP53mutations identify younger mantle cell lymphoma patients who do not benefit from intensive chemoimmunotherapy

Author

Eskelund, Christian W., Dahl, Christina, Hansen, Jakob W., Westman, Maj, Kolstad, Arne, Pedersen, Lone B., Montano-Almendras, Carmen P., Husby, Simon, Freiburghaus, Catja, Ek, Sara, Pedersen, Anja, Niemann, Carsten, Räty, Riikka, Brown, Peter, Geisler, Christian H., Andersen, Mette K., Guldberg, Per, Jerkeman, Mats, and Grønbæk, Kirsten

Abstract

Despite recent advances in lymphoma treatment, mantle cell lymphoma (MCL) remains incurable, and we are still unable to identify patients who will not benefit from the current standard of care. Here, we explore the prognostic value of recurrent genetic aberrations in diagnostic bone marrow (BM) specimens from 183 younger patients with MCL from the Nordic MCL2 and MCL3 trials, which represent current standard-of-care regimens. In the univariate model, mutations of TP53(11%) and NOTCH1(4%), and deletions of TP53(16%) and CDKN2A(20%), were significantly associated with inferior outcomes (together with MIPI, MIPI-c, blastoid morphology, and Ki67 > 30%); however, in multivariate analyses, only TP53mutations (HR, 6.2; P< .0001) retained prognostic impact for overall survival (OS), whereas TP53mutations (HR, 6.9; P< .0001) and MIPI-c high-risk (HR, 2.6; P= .003) had independent prognostic impact on time to relapse. TP53-mutated cases had a dismal outcome, with a median OS of 1.8 years, and 50% relapsed at 1.0 years, compared to a median OS of 12.7 years for TP53-unmutated cases (P< .0001). TP53mutations were significantly associated with Ki67 > 30%, blastoid morphology, MIPI high-risk, and inferior responses to both induction- and high-dose chemotherapy. In conclusion, we show that TP53mutations identify a phenotypically distinct and highly aggressive form of MCL with poor or no response to regimens including cytarabine, rituximab, and autologous stem-cell transplant (ASCT). We suggest patients with MCL should be stratified according to TP53status, and that patients with TP53mutations should be considered for experimental frontline trials exploring novel agents.

Published
2017
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27. Sequence variants affecting eosinophil numbers associate with asthma and myocardial infarction

Author

Gudbjartsson, Daniel F, primary, Bjornsdottir, Unnur S, additional, Halapi, Eva, additional, Helgadottir, Anna, additional, Sulem, Patrick, additional, Jonsdottir, Gudrun M, additional, Thorleifsson, Gudmar, additional, Helgadottir, Hafdis, additional, Steinthorsdottir, Valgerdur, additional, Stefansson, Hreinn, additional, Williams, Carolyn, additional, Hui, Jennie, additional, Beilby, John, additional, Warrington, Nicole M, additional, James, Alan, additional, Palmer, Lyle J, additional, Koppelman, Gerard H, additional, Heinzmann, Andrea, additional, Krueger, Marcus, additional, Boezen, H Marike, additional, Wheatley, Amanda, additional, Altmuller, Janine, additional, Shin, Hyoung Doo, additional, Uh, Soo-Taek, additional, Cheong, Hyun Sub, additional, Jonsdottir, Brynja, additional, Gislason, David, additional, Park, Choon-Sik, additional, Rasmussen, Linda M, additional, Porsbjerg, Celeste, additional, Hansen, Jakob W, additional, Backer, Vibeke, additional, Werge, Thomas, additional, Janson, Christer, additional, Jönsson, Ulla-Britt, additional, Ng, Maggie C Y, additional, Chan, Juliana, additional, So, Wing Yee, additional, Ma, Ronald, additional, Shah, Svati H, additional, Granger, Christopher B, additional, Quyyumi, Arshed A, additional, Levey, Allan I, additional, Vaccarino, Viola, additional, Reilly, Muredach P, additional, Rader, Daniel J, additional, Williams, Michael J A, additional, van Rij, Andre M, additional, Jones, Gregory T, additional, Trabetti, Elisabetta, additional, Malerba, Giovanni, additional, Pignatti, Pier Franco, additional, Boner, Attilio, additional, Pescollderungg, Lydia, additional, Girelli, Domenico, additional, Olivieri, Oliviero, additional, Martinelli, Nicola, additional, Ludviksson, Bjorn R, additional, Ludviksdottir, Dora, additional, Eyjolfsson, Gudmundur I, additional, Arnar, David, additional, Thorgeirsson, Gudmundur, additional, Deichmann, Klaus, additional, Thompson, Philip J, additional, Wjst, Matthias, additional, Hall, Ian P, additional, Postma, Dirkje S, additional, Gislason, Thorarinn, additional, Gulcher, Jeffrey, additional, Kong, Augustine, additional, Jonsdottir, Ingileif, additional, Thorsteinsdottir, Unnur, additional, and Stefansson, Kari, additional

Published
2009
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