13 results on '"Cordua, Sabrina"'
Search Results
2. Clonal haematopoiesis of indeterminate potential and impaired kidney function-A Danish general population study with 11 years follow-up.
- Author
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Larsen MK, Skov V, Kjaer L, Møller-Palacino NA, Pedersen RK, Andersen M, Ottesen JT, Cordua S, Poulsen HE, Dahl M, Knudsen TA, Eickhardt-Dalbøge CS, Koschmieder S, Pedersen KM, Çolak Y, Bojesen SE, Nordestgaard BG, Stiehl T, Hasselbalch HC, and Ellervik C
- Subjects
- Clonal Hematopoiesis genetics, Denmark epidemiology, Follow-Up Studies, Humans, Janus Kinase 2 genetics, Kidney metabolism, Mutation, Calreticulin genetics, Thrombocythemia, Essential genetics
- Abstract
The myeloproliferative neoplasms are associated with chronic kidney disease but whether clonal haematopoiesis of indeterminate potential (CHIP) is associated with impaired kidney function is unknown. In the Danish General Suburban Population Study (N = 19 958) from 2010 to 2013, 645 individuals were positive for JAK2V617F (N = 613) or CALR (N = 32) mutations. Mutation-positive individuals without haematological malignancy were defined as having CHIP (N = 629). We used multiple and inverse probability weighted (IPW)-adjusted linear regression analysis to estimate adjusted mean (95% confidence interval) differences in estimated glomerular filtration rate (eGFR; ml/min/1.73 m
2 ) by mutation status, variant allele frequency (VAF%), blood cell counts, and neutrophil-to-lymphocyte ratio (NLR). We performed 11-year longitudinal follow-up of eGFR in all individuals. Compared to CHIP-negative individuals, the mean differences in eGFR were -5.6 (-10.3, -0.8, p = .02) for CALR, -11.9 (-21.4, -2.4, p = 0.01) for CALR type 2, and -10.1 (-18.1, -2.2, p = .01) for CALR with VAF ≥ 1%. The IPW-adjusted linear regression analyses showed similar results. NLR was negatively associated with eGFR. Individuals with CALR type 2 had a worse 11-year longitudinal follow-up on eGFR compared to CHIP-negative individuals (p = .004). In conclusion, individuals with CALR mutations, especially CALR type 2, had impaired kidney function compared to CHIP-negative individuals as measured by a lower eGFR at baseline and during 11-year follow-up., (© 2022 The Authors. European Journal of Haematology published by John Wiley & Sons Ltd.)- Published
- 2022
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3. [Elevated blood cell counts and vascular disease with the myeloproliferative neoplasms as model diseases].
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Hasselbalch HC, Knudsen TA, Sørensen AL, Christensen SF, Larsen MK, Bak M, El Fassi D, Cordua S, Brabrand M, Thomsen G, Stentoft J, Starklint J, Ellervik C, Wienecke T, Bruun NE, Eickhardt-Dalbøge CE, Kjær L, and Skov V
- Subjects
- Blood Cell Count, Humans, Myeloproliferative Disorders diagnosis, Neoplasms, Vascular Diseases
- Abstract
Recent studies have shown the Philadelphia-negative myeloproliferative neoplasms (MPN) to be massively underdiagnosed and often preceded by a long pre-diagnostic phase of several years, in which many patients suffer serious vascular events. In this review, we focus on the urgent need for earlier diagnosis and treatment of MPN. Such efforts are foreseen to decrease morbidity and mortality for the individual patients and potentially reduce costs for health and social care systems.
- Published
- 2021
4. Elevated levels of oxidized nucleosides in individuals with the JAK2V617F mutation from a general population study.
- Author
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Sørensen AL, Hasselbalch HC, Bjørn ME, Nielsen CH, Cordua S, Skov V, Kjær L, Poulsen HE, and Ellervik C
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- 8-Hydroxy-2'-Deoxyguanosine, Calreticulin genetics, Humans, Janus Kinase 2, Mutation, Myeloproliferative Disorders, Nucleosides
- Abstract
It is unknown if the somatic mutations in chronic myeloproliferative neoplasms (MPNs), JAK2V617F and Calreticulin, are associated with oxidative stress, or impaired mitochondrial defense against reactive oxygen species. In the Danish General Suburban Population Study (GESUS), including 116 JAK2V617F-mutated, 8 CALR-mutated, and 3310 mutation-negative participants without overt MPN, and in a study of 39 patients with myelofibrosis, the most advances type of MPNs, and 179 matched controls, we compared the urinary concentration of oxidized nucleosides - 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG) and 8-oxo-7,8-dihydroguanosine (8-oxoGuo) - as markers of oxidative stress. In GESUS, we performed Mendelian randomization analyses, using the Ala16Val single nucleotide polymorphism in the superoxide dismutase2 (SOD2) gene. In the multivariate analyses in GESUS, the 8-oxodG and 8-oxoGuo concentration were 13% (95%CI: 6-21%, p < 0.001) and 6% (95%CI: 0.4-11%, p = 0.035) higher in mutation-positive than in mutation-negative participants, respectively. Each SOD2 T allele was associated with an odds ratio of being mutation-positive of 1.69 (95%CI: 1.12-2.55, p = 0.013) through 8-oxodG. The 8-oxodG and 8-oxoGuo concentrations were 77% (95%CI: 49-110%, p < 0.001) and 105% (95%CI: 80-133%, p < 0.001) higher in myelofibrosis patients than in controls, respectively. In conclusion, an impaired mitochondrial antioxidative defense, that is causatively associated with markers of oxidative stress, may contribute to the development of mutations associated with MPNs., (Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.)
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- 2021
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5. Evidence of immune elimination, immuno-editing and immune escape in patients with hematological cancer.
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Holmström MO, Cordua S, Skov V, Kjær L, Pallisgaard N, Ellervik C, Hasselbalch HC, and Andersen MH
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- Animals, Antigens, Neoplasm immunology, Biomarkers, Tumor, Calreticulin genetics, Calreticulin metabolism, Cell Transformation, Neoplastic, Disease Models, Animal, Epitopes immunology, Hematologic Neoplasms metabolism, Humans, Mutation, Disease Susceptibility, Hematologic Neoplasms etiology, Immunomodulation genetics, Tumor Escape genetics
- Abstract
There is mounting evidence that the immune system can spontaneously clear malignant lesions before they manifest as overt cancer, albeit this activity has been difficult to demonstrate in humans. The calreticulin (CALR) exon 9 mutations are driver mutations in patients with chronic myeloproliferative neoplasms (MPN), which are chronic blood cancers. The CALR mutations generate a neo-antigen that is recognized by patient T cells, and T cells isolated from a patient with a CALR-mutation can recognize and kill autologous CALR-mutant cells. Surprisingly, healthy individuals display frequent and strong T cell responses to the CALR neo-antigens too. Furthermore, healthy individuals display immune responses to all parts of the mutant CALR epitope, and the CALR neo-epitope specific responses are memory T cell responses. These data suggest that although healthy individuals might acquire a CALR mutation, the mutant cells can be eliminated by the immune system. Additionally, a small fraction of healthy individuals harbor a CALR exon 9 mutation. Four healthy individuals carrying CALR mutations underwent a full medical examination including a bone marrow biopsy after a median follow up of 6.2 years. None of these patients displayed any signs of CALR-mutant MPN. Additionally, all healthy individuals displayed strong CALR neo-epitope specific T cell responses suggesting that these healthy individuals retained their CALR-mutant cells in the editing stage for several years. Thus, we suggest that CALR-mutant MPN could be a disease model of cancer immuno-editing, as we have demonstrated that CALR-mutant MPN displays all three stages described in the theory of cancer immuno-editing.
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- 2020
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6. Prevalence and phenotypes of JAK2 V617F and calreticulin mutations in a Danish general population.
- Author
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Cordua S, Kjaer L, Skov V, Pallisgaard N, Hasselbalch HC, and Ellervik C
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- Adult, Aged, Aged, 80 and over, Alleles, Amino Acid Substitution, Cross-Sectional Studies, Denmark epidemiology, Female, Gene Frequency, Genetic Testing, Humans, Male, Mass Screening, Middle Aged, Population Surveillance, Prevalence, Young Adult, Calreticulin genetics, Genetic Association Studies methods, Genetic Predisposition to Disease, Janus Kinase 2 genetics, Mutation, Phenotype
- Abstract
The JAK2 V617F and calreticulin mutations ( CALR ) are frequent within myeloproliferative neoplasms (MPNs). JAK2 V617F has been detected in the general population, but no studies have previously investigated the CALR prevalence. Thus, we aimed to determine the CALR and JAK2 V617F population prevalence and assess the biochemical profile and lifestyle factors in mutation-positive individuals with and without MPN. 19 958 eligible participants, enrolled from 2010-2013, from the Danish General Suburban Population Study were screened for JAK2 V617F and CALR by droplet digital polymerase chain reaction with (3.2%) mutation positives of which 16 (2.5%) had MPN at baseline. Of 645 participants, 613 were JAK2 V617F positive, and 32 were CALR positive, corresponding to a population prevalence of 3.1% (confidence interval [CI], 2.8-3.3) and 0.16% (CI, 0.11-0.23), respectively. Increasing age, smoking, and alcohol were risk factors for the mutations. JAK2 V617F positives with and without MPN presented elevated odds for prevalent venous thromboembolism. The odds ratio for a diagnosis of MPN per percentage allele burden was 1.14 (95% CI, 1.09-1.18; P = 1.6 × 10
-10 ). Mutation positives displayed higher blood cell counts than nonmutated participants, and 42% of mutation positives without MPN presented elevation of ≥1 blood cell counts; 80 (13%) even presented blood cell counts in accordance with current MPN diagnostic criteria. In conclusion, we present a novel population prevalence of CALR and a JAK2 V617F prevalence that is 3 to 30 times higher compared with less sensitive methods. Mutation-positive non-MPNs with elevated blood cell counts raise concerns of MPN underdiagnosis in the population., (© 2019 by The American Society of Hematology.)- Published
- 2019
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7. JAK2V617F but not CALR mutations confer increased molecular responses to interferon-α via JAK1/STAT1 activation.
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Czech J, Cordua S, Weinbergerova B, Baumeister J, Crepcia A, Han L, Maié T, Costa IG, Denecke B, Maurer A, Schubert C, Feldberg K, Gezer D, Brümmendorf TH, Müller-Newen G, Mayer J, Racil Z, Kubesova B, Knudsen T, Sørensen AL, Holmström M, Kjær L, Skov V, Larsen TS, Hasselbalch HC, Chatain N, and Koschmieder S
- Subjects
- Adult, Aged, Animals, Antiviral Agents pharmacology, Apoptosis, Biomarkers, Tumor genetics, Biomarkers, Tumor metabolism, Cell Proliferation, Female, Follow-Up Studies, Humans, Janus Kinase 1 genetics, Male, Mice, Middle Aged, Myeloproliferative Disorders genetics, Myeloproliferative Disorders metabolism, Myeloproliferative Disorders pathology, Prognosis, Retrospective Studies, STAT1 Transcription Factor genetics, Tumor Cells, Cultured, Calreticulin genetics, Interferon-alpha pharmacology, Janus Kinase 1 metabolism, Janus Kinase 2 genetics, Mutation, Myeloproliferative Disorders drug therapy, STAT1 Transcription Factor metabolism
- Abstract
Pegylated interferon-α (peg-IFNa) treatment induces molecular responses (MR) in patients with myeloproliferative neoplasms (MPNs), including partial MR (PMR) in 30-40% of patients. Here, we compared the efficacy of IFNa treatment in JAK2V617F- vs. calreticulin (CALR)-mutated cells and investigated the mechanisms of differential response. Retrospective analysis of MPN patients treated with peg-IFNa demonstrated that patients harboring the JAK2V617F mutation were more likely to achieve PMR than those with mutated CALR (p = 0.004), while there was no significant difference in hematological response. In vitro experiments confirmed an upregulation of IFN-stimulated genes in JAK2V617F-positive 32D cells as well as patient samples (peripheral blood mononuclear cells and CD34+ hematopoietic stem cells) compared to their CALR-mutated counterparts, and higher IFNa doses were needed to achieve the same IFNa response in CALR- as in JAK2V617F-mutant 32D cells. Additionally, Janus-activated kinase-1 (JAK1) and signal transducers and activators of transcription 1 (STAT1) showed constitutive phosphorylation in JAK2V617F-mutated but not CALR-mutated cells, indicating priming towards an IFNa response. Moreover, IFN-induced growth arrest was counteracted by selective JAK1 inhibition but enhanced by JAK2 inhibition. In conclusion, our data suggest that, clinically, higher doses of IFNa are needed in CALR-mutated vs. JAK2V617F-positive patients and we suggest a model of JAK2V617F-JAK1/STAT1 crosstalk leading to a priming of JAK2V617F-positive cells to IFNa resulting in differential sensitivity.
- Published
- 2019
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8. A comparison of qPCR and ddPCR used for quantification of the JAK2 V617F allele burden in Ph negative MPNs.
- Author
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Link-Lenczowska D, Pallisgaard N, Cordua S, Zawada M, Czekalska S, Krochmalczyk D, Kanduła Z, and Sacha T
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- Adult, Aged, Amino Acid Substitution, Female, Hematologic Neoplasms blood, Hematologic Neoplasms drug therapy, Humans, Janus Kinase 2 blood, Male, Middle Aged, Myeloproliferative Disorders blood, Myeloproliferative Disorders drug therapy, Rituximab administration & dosage, Alleles, Hematologic Neoplasms genetics, Janus Kinase 2 genetics, Mutation, Missense, Myeloproliferative Disorders genetics, Philadelphia Chromosome, Real-Time Polymerase Chain Reaction methods
- Abstract
Philadelphia-negative myeloproliferative neoplasms (MPNs) are a diverse group of diseases whose common feature is the presence of V617F mutation of the JAK2 gene. In the era of novel therapeutic strategies in MPNs, such as JAK-inhibitor therapy, there is a growing need for establishing high sensitive quantitative methods, which can be useful not only at diagnosis but also for monitoring therapeutic outcomes, such as minimal residual disease (MRD). In this study, we compared the qPCR and ddPCR methods and their clinical utility for diagnosis, prognostication, and treatment monitoring of MPNs with JAK2 V617F mutation in 63 MPN patients of which 6 were subjected to ruxolitinib treatment. We show a high conformance between the two methods (correlation coefficient r = 0.998 (p < 0.0001)). Our experiments revealed high analytical sensitivity for both tests, suggesting that they are capable of detecting the JAK2 V617F mutation at diagnosis of MPN with a limit of detection (LoD) of 0.12% for qPCR and 0.01% for ddPCR. The alterations of JAK2 V617F allele burden in patients treated with ruxolitinib were measured by both methods with equal accuracy. The results suggest an advantage of ddPCR in monitoring MRD because of allele burdens below the LoD of qPCR. Overall, the clinical utility of qPCR and ddPCR is very high, and both methods could be recommended for the routine detection of the V617F mutation at diagnosis, though ddPCR will probably supersede qPCR in the future due to cost-effectiveness.
- Published
- 2018
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9. Sorted peripheral blood cells identify CALR mutations in B- and T-lymphocytes.
- Author
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Kjaer L, Holmström MO, Cordua S, Andersen MH, Svane IM, Thomassen M, Kruse TA, Pallisgaard N, Skov V, and Hasselbalch HC
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- Adult, Aged, Cell Separation, DNA Mutational Analysis, Exons genetics, Female, Flow Cytometry, Hematopoietic Stem Cells metabolism, Humans, Male, Middle Aged, Primary Myelofibrosis blood, Primary Myelofibrosis diagnosis, Thrombocythemia, Essential blood, Thrombocythemia, Essential diagnosis, B-Lymphocytes metabolism, Calreticulin genetics, Primary Myelofibrosis genetics, T-Lymphocytes metabolism, Thrombocythemia, Essential genetics
- Published
- 2018
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10. Treatment strategies, outcomes and prognostic factors in 291 patients with secondary CNS involvement by diffuse large B-cell lymphoma.
- Author
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El-Galaly TC, Cheah CY, Bendtsen MD, Nowakowski GS, Kansara R, Savage KJ, Connors JM, Sehn LH, Goldschmidt N, Shaulov A, Farooq U, Link BK, Ferreri AJM, Calimeri T, Cecchetti C, Dann EJ, Thompson CA, Inbar T, Maurer MJ, Gade IL, Juul MB, Hansen JW, Holmberg S, Larsen TS, Cordua S, Mikhaeel NG, Hutchings M, Seymour JF, Clausen MR, Smith D, Opat S, Gilbertson M, Thanarajasingam G, and Villa D
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- Adult, Aged, Aged, 80 and over, Central Nervous System Neoplasms drug therapy, Central Nervous System Neoplasms mortality, Female, Follow-Up Studies, Humans, Lymphoma, Large B-Cell, Diffuse drug therapy, Lymphoma, Large B-Cell, Diffuse mortality, Male, Middle Aged, Neoplasm Recurrence, Local drug therapy, Neoplasm Recurrence, Local mortality, Neoplasms, Second Primary drug therapy, Neoplasms, Second Primary mortality, Prognosis, Retrospective Studies, Survival Rate, Young Adult, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Central Nervous System Neoplasms pathology, Lymphoma, Large B-Cell, Diffuse pathology, Neoplasm Recurrence, Local pathology, Neoplasms, Second Primary pathology
- Abstract
Purpose: Secondary CNS involvement (SCNS) is a profoundly adverse complication of diffuse large B-cell lymphoma. Evidence from older series indicated a median overall survival (OS) < 6 months; however, data from the immunochemotherapy era are limited., Methods: Patients diagnosed with SCNS during or after first-line immunochemotherapy were identified from databases and/or regional/national registries from three continents. Clinical information was retrospectively collected from medical records., Results: In total, 291 patients with SCNS were included. SCNS occurred as part of first relapse in 254 (87%) patients and 113 (39%) had concurrent systemic relapse. With a median post-SCNS follow-up of 48 months, the median post-SCNS OS was 3.9 months and 2-year OS rate was 20% (95% CI: 15-25). In multivariable analysis of 173 patients treated with curative/intensive therapy (such as high-dose methotrexate [HDMTX] or platinum-containing regimens), age ≤60 years, performance status 0-1, absence of combined leptomeningeal and parenchymal involvement, and SCNS occurring after completion of first-line therapy were associated with superior outcomes. Patients ≤60 years with performance status 0-1 and treated with HDMTX-based regimens for isolated parenchymal SCNS had a 2-year OS of 62% (95% CI: 36-80). In patients with isolated SCNS, the addition of rituximab to HDMTX-based regimens was associated with improved OS. Amongst patients with isolated SCNS in CR following intensive treatment, high-dose chemotherapy and autologous stem cell transplantation did not improve OS (P = 0.9)., Conclusions: In this large international cohort of patients treated with first-line immunochemotherapy, outcomes following SCNS remain poor. However, a moderate proportion of patients with isolated SCNS who received intensive therapies achieved durable remissions., (Copyright © 2018 Elsevier Ltd. All rights reserved.)
- Published
- 2018
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11. 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
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El-Galaly TC, Villa D, Michaelsen TY, Hutchings M, Mikhaeel NG, Savage KJ, Sehn LH, Barrington S, Hansen JW, Smith D, Rady K, Mylam KJ, Larsen TS, Holmberg S, Juul MB, Cordua S, Clausen MR, Jensen KB, Johnsen HE, Seymour JF, Connors JM, de Nully Brown P, Bøgsted M, and Cheah CY
- Subjects
- Adolescent, Adult, Aged, Aged, 80 and over, Antibodies, Monoclonal, Murine-Derived administration & dosage, Antineoplastic Combined Chemotherapy Protocols administration & dosage, Central Nervous System Neoplasms prevention & control, Central Nervous System Neoplasms secondary, Combined Modality Therapy, Cyclophosphamide administration & dosage, Doxorubicin administration & dosage, Humans, Lymphoma, Large B-Cell, Diffuse prevention & control, Male, Middle Aged, Neoplasm Recurrence, Local prevention & control, Positron Emission Tomography Computed Tomography, Prednisone administration & dosage, Retrospective Studies, Risk Factors, Rituximab, Treatment Outcome, Vincristine administration & dosage, Young Adult, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Central Nervous System Neoplasms diagnostic imaging, Immunotherapy methods, Lymphoma, Large B-Cell, Diffuse diagnostic imaging, Neoplasm Recurrence, Local diagnostic imaging
- 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., (Copyright © 2017 Elsevier Ltd. All rights reserved.)
- Published
- 2017
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12. 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.
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El-Galaly TC, Cheah CY, Hutchings M, Mikhaeel NG, Savage KJ, Sehn LH, Barrington S, Hansen JW, Poulsen MØ, Smith D, Rady K, Mylam KJ, Larsen TS, Holmberg S, Juul MB, Cordua S, Clausen MR, Jensen KB, Bøgsted M, Johnsen HE, Seymour JF, Connors JM, Brown PD, and Villa D
- Subjects
- Adolescent, Adult, Aged, Aged, 80 and over, Central Nervous System Neoplasms mortality, Central Nervous System Neoplasms secondary, Databases, Factual, Disease-Free Survival, Female, Humans, Lymphoma, Large B-Cell, Diffuse mortality, Middle Aged, Ovarian Neoplasms complications, Ovarian Neoplasms mortality, Ovarian Neoplasms pathology, Prognosis, Retrospective Studies, Rituximab therapeutic use, Survival Rate, Young Adult, Lymphoma, Large B-Cell, Diffuse pathology, Uterine Neoplasms complications, Uterine Neoplasms mortality, Uterine Neoplasms pathology
- Abstract
Involvement of the internal female reproductive organs by diffuse large B-cell lymphoma (DLBCL) is uncommon, and there are sparse data describing the outcomes of such cases. In total, 678 female patients with DLBCL staged with positron emission tomography/computed tomography and treated with rituximab-containing chemotherapy were identified from databases in Denmark, Great Britain, Australia, and Canada. Overall, 27/678 (4%) had internal reproductive organ involvement: uterus (n = 14), ovaries (n = 10) or both (n = 3). In multivariate analysis, women with uterine DLBCL experienced inferior progression-free survival and overall survival compared to those without reproductive organ involvement, whereas ovarian DLBCL was not predictive of outcome. Secondary central nervous system (CNS) involvement (SCNS) occurred in 7/17 (41%) women with uterine DLBCL (two patients with concomitant ovarian DLBCL) and 0/10 women with ovarian DLBCL without concomitant uterine involvement. In multivariate analysis adjusted for other risk factors for SCNS, uterine involvement by DLBCL remained strongly associated with SCNS (Hazard ratio 14·13, 95% confidence interval 5·09-39·25, P < 0·001). Because involvement of the uterus by DLBCL appears to be associated with a high risk of SCNS, those patients should be considered for CNS staging and prophylaxis. However, more studies are needed to determine whether the increased risk of secondary CNS involvement also applies to women with localized reproductive organ DLBCL., (© 2016 John Wiley & Sons Ltd.)
- Published
- 2016
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13. Differential Dynamics of CALR Mutant Allele Burden in Myeloproliferative Neoplasms during Interferon Alfa Treatment.
- Author
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Kjær L, Cordua S, Holmström MO, Thomassen M, Kruse TA, Pallisgaard N, Larsen TS, de Stricker K, Skov V, and Hasselbalch HC
- Subjects
- Adult, Alleles, Blood Cell Count, Female, Follow-Up Studies, Gene Frequency, Genotype, Humans, L-Lactate Dehydrogenase blood, Male, Middle Aged, Mutation, Myeloproliferative Disorders diagnosis, Myeloproliferative Disorders genetics, Prognosis, Thrombocythemia, Essential diagnosis, Thrombocythemia, Essential drug therapy, Thrombocythemia, Essential genetics, Treatment Outcome, Calreticulin genetics, Interferon-alpha therapeutic use, Myeloproliferative Disorders drug therapy
- Abstract
Discovery of somatic mutations in the calreticulin gene (CALR) has identified a subgroup of Philadelphia-negative chronic myeloproliferative neoplasms (MPN) with separate haematological characteristics and prognosis. CALR mutations serve as novel markers both of diagnostic value and as targets for monitoring molecular responses during therapy. Interferon-α (IFN) selectively targets the malignant clone in a subset of MPN patients and can induce both haematological and molecular remissions in CALR mutated essential thrombocythemia (ET) patients. We investigated the response to IFN in a cohort of 21 CALR mutated MPN patients including ET, prefibrotic primary myelofibrosis (pre-PMF), and primary myelofibrosis (PMF) with a median follow-up of 31 months. For evaluation of a molecular response, we developed highly sensitive quantitative PCR (qPCR) assays for monitoring the mutant allele burden of the two most prevalent CALR mutations (type 1 and type 2). Thirteen patients (62%) experienced a decrease in the mutant allele burden with a median decline of 29% from baseline. However, only four patients, including patients with ET, pre-PMF, and PMF diagnosis, achieved molecular responder (MR) status with >50% reduction in mutant allele burden according to European LeukemiaNet (ELN) guidelines. MR patients displayed significant differences in the dynamics of the CALR mutant load with regard to time to response and dynamics in mutant allele burden after discontinuation of IFN treatment. Furthermore, we highlight the prognostic value of the CALR mutant allele burden by showing a close association with leucocyte- and platelet counts, hemoglobin concentration, in addition to plasma lactate dehydrogenase (LDH) irrespective of molecular response and treatment status., Competing Interests: The authors have declared that no competing interests exist.
- Published
- 2016
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