| 1. |
- Nikkarinen, Anna, et al.
(författare)
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Soluble CD163 predicts outcome in both chemoimmunotherapy and targeted therapy-treated mantle cell lymphoma
- 2023
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Ingår i: Blood Advances. - : American Society of Hematology. - 2473-9529 .- 2473-9537. ; 7:18, s. 5304-5313
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Tidskriftsartikel (refereegranskat)abstract
- The outcome for patients with mantle cell lymphoma (MCL) has drastically improved with new treatments directed toward the tumor immune microenvironment, where macrophages play an important role. In MCL, the presence of M2 macrophages defined by CD163 expression in diagnostic biopsies has been associated with a worse prognosis. An alternative way to assess the abundance of M2 macrophages is by measuring the level of soluble CD163 in serum (sCD163). We aimed to investigate the prognostic value of sCD163 in 131 patients with MCL. We found that high sCD163 at diagnosis was associated with shorter progression-free survival (PFS) and shorter overall survival (OS) in 81 patients who were newly diagnosed and subsequently treated with chemoimmunotherapy. The same was seen in a cohort of 50 patients with relapsed MCL that were mainly treated within the phase 2 Philemon-trial with rituximab, ibrutinib, and lenalidomide. In patients who were newly diagnosed and had low levels of sCD163, 5-year survival was 97%. There was a moderate correlation between sCD163 and tissue CD163. The association with a poor prognosis was independent of MCL international prognostic index, Ki67, p53 status, and blastoid morphology, as assessed in a multivariable Cox proportional hazards model. In this study, high sCD163 was associated with both shorter PFS and shorter OS, showing that high levels of the M2 macrophage marker sCD163 is an independent negative prognostic factor in MCL, both in the chemoimmunotherapy and ibrutinib/lenalidomide era. In addition, low sCD163 levels identify patients with MCL with a very good prognosis.
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| 2. |
- Rodrigues, Joana M., et al.
(författare)
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Infiltration of CD163-, PD-L1-and FoxP3-positive cells adversely affects outcome in patients with mantle cell lymphoma independent of established risk factors
- 2021
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Ingår i: British Journal of Haematology. - : John Wiley & Sons. - 0007-1048 .- 1365-2141. ; 193:3, s. 520-531
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Tidskriftsartikel (refereegranskat)abstract
- We characterised patients with mantle cell lymphoma (MCL) with poor prognosis based on differences in immune infiltration. Different expressions of the tumour cell markers Cyclin D1 and sex-determining region Y-box transcription factor 11 (SOX11), and the immune markers cluster of differentiation 3 (CD3), CD4, CD8, CD25, forkhead box protein P3 (FoxP3), T-box transcription factor TBX21 (T-bet), programmed cell death protein 1 (PD-1), programmed-death ligand 1 (PD-L1) and CD163 were investigated for all-cause mortality in 282 patients with MCL and time-to-progression (TTP) in 106 clinical trial patients. With increasing age, a significantly lower infiltration of CD3(+) T lymphocytes was seen. T-cell infiltration was independent of cellular tumour antigen p53 (p53) expression, Ki-67, morphology and frequency of tumour cells. The all-cause mortality was higher in patients with PD-L1-expression above cut-off [hazard ratio (HR) 1 center dot 97, 95% confidence interval (CI) 1 center dot 18-3 center dot 25, adjusted for sex and MCL International Prognostic Index (MIPI)] and a higher frequency of CD163(+) cells (continuously, HR 1 center dot 51, 95% CI 1 center dot 03-2 center dot 23, adjusting for age, sex, morphology, Ki-67 and p53). In patients treated within the Nordic Lymphoma Group MCL2/3 trials, TTP was shorter in patients with a higher frequency of FoxP3(+) cells (HR 3 center dot 22, 95% CI 1 center dot 40-7 center dot 43) and CD163(+) cells (HR 6 center dot 09, 95% CI 1 center dot 84-20 center dot 21), independent of sex and MIPI. When combined a higher frequency of CD163(+) macrophages and PD-L1(+) cells or high CD163(+) macrophages and FoxP3(+) regulatory T cells indicated worse outcome independent of established risk factors. The T-cell infiltrate was in turn independent of molecular characteristics of the malignant cells and decreased with age.
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| 3. |
- Rodrigues, Joana M., et al.
(författare)
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p53 is associated with high-risk and pinpoints TP53 missense mutations in mantle cell lymphoma
- 2020
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Ingår i: British Journal of Haematology. - : Wiley. - 0007-1048 .- 1365-2141. ; 191:5, s. 796-805
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Tidskriftsartikel (refereegranskat)abstract
- Survival for patients diagnosed with mantle cell lymphoma (MCL) has improved drastically in recent years. However, patients carrying mutations in tumour protein p53 (TP53) do not benefit from modern chemotherapy-based treatments and have poor prognosis. Thus, there is a clinical need to identify missense mutations through routine analysis to enable patient stratification. Sequencing is not widely implemented in clinical practice for MCL, and immunohistochemistry (IHC) is a feasible alternative to identify high-risk patients. The aim of the present study was to investigate the accuracy of p53 as a tool to identify patients with TP53 missense mutations and the prognostic impact of overexpression and mutations in a Swedish population-based cohort. In total, 317 cases were investigated using IHC and 255 cases were sequenced, enabling analysis of p53 and TP53 status among 137 cases divided over the two-cohort investigated. The accuracy of predicting missense mutations from protein expression was 82%, with sensitivity at 82% and specificity at 100% in paired samples. We further show the impact of p53 expression and TP53 mutations on survival (hazard ratio of 3·1 in univariate analysis for both), and the association to risk factors, such as high MCL International Prognostic Index, blastoid morphology and proliferation, in a population-based setting.
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| 4. |
- Rodrigues, Joana M., et al.
(författare)
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p53 is associated with high-risk and pinpointsTP53missense mutations in mantle cell lymphoma
- 2020
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Ingår i: British Journal of Haematology. - : WILEY. - 0007-1048 .- 1365-2141. ; 191:5, s. 796-805
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Tidskriftsartikel (refereegranskat)abstract
- Survival for patients diagnosed with mantle cell lymphoma (MCL) has improved drastically in recent years. However, patients carrying mutations in tumour protein p53 (TP53) do not benefit from modern chemotherapy-based treatments and have poor prognosis. Thus, there is a clinical need to identify missense mutations through routine analysis to enable patient stratification. Sequencing is not widely implemented in clinical practice for MCL, and immunohistochemistry (IHC) is a feasible alternative to identify high-risk patients. The aim of the present study was to investigate the accuracy of p53 as a tool to identify patients withTP53missense mutations and the prognostic impact of overexpression and mutations in a Swedish population-based cohort. In total, 317 cases were investigated using IHC and 255 cases were sequenced, enabling analysis of p53 andTP53status among 137 cases divided over the two-cohort investigated. The accuracy of predicting missense mutations from protein expression was 82%, with sensitivity at 82% and specificity at 100% in paired samples. We further show the impact of p53 expression andTP53mutations on survival (hazard ratio of 3 center dot 1 in univariate analysis for both), and the association to risk factors, such as high MCL International Prognostic Index, blastoid morphology and proliferation, in a population-based setting.
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| 5. |
- Sandström Gerdtsson, Anna, et al.
(författare)
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Overexpression of the key metabolic protein CPT1A defines mantle cell lymphoma patients with poor response to standard high dose chemotherapy independent of MIPI and complement established high-risk factors
- 2023
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Ingår i: Haematologica. - : Ferrata Storti Foundation (Haematologica). - 0390-6078 .- 1592-8721. ; 108:4, s. 1092-1104
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Tidskriftsartikel (refereegranskat)abstract
- The variable outcome to standard immunochemotherapy for mantle cell lymphoma (MCL) patients is a clinical challenge. Established risk factors, including high MCL international prognostic index (MIPI), high proliferation (Ki-67), non-classic (blastoid/pleomorphic) morphology, and mutated TP53, only partly identify patients in need of alternative treatment. Deepened understanding of biological factors that influence time to progression and relapse would allow for an improved stratification, and identification of novel targets for high-risk patients. We performed gene expression analyses to identify pathways and genes associated with outcome in a cohort of homogeneously treated patients. In addition to deregulated proliferation, we show that thermogenesis, fatty acid degradation and oxidative phosphorylation are altered in patients with poor survival, and that high expression of carnitine palmitoyltransferase 1A (CPT1A), an enzyme involved in fatty acid degradation, can specifically identify high-risk patients independent of the established high-risk factors. We suggest that complementary investigations of metabolism may increase the accuracy of patient stratification and that immunohistochemistry-based assessment of CPT1A can contribute to defining high-risk MCL.
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| 6. |
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| 7. |
- Béné, Marie C., et al.
(författare)
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Mixed Phenotype/Lineage Leukemia : Has Anything Changed for 2021 on Diagnosis, Classification, and Treatment?
- 2022
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Ingår i: Current Oncology Reports. - : Springer Science and Business Media LLC. - 1523-3790 .- 1534-6269. ; 24:8, s. 1015-1022
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Forskningsöversikt (refereegranskat)abstract
- Purpose of Review: Recent advances in the small field of the rare mixed phenotype acute leukemias (MPAL) are presented focusing on a better understanding of their pathophysiology and search for better therapeutic approaches. Recent Findings: Three aspects of respective classification, therapy, and immunophenotype of MPAL are reviewed. New proposals have been made to segregate MPAL subtypes based on their genomic landscape. In parallel, it was found that a large array of therapeutic approaches has been tested in the past few years with increasingly good results. Finally, we explored the use of unsupervised flow cytometry analysis to dissect subtle variations in markers expression to better characterize the variegating aspect of MPALs. Summary: Genomic and immunophenotypic aspects more clearly link MPAL subtypes with bona fide acute myeloblastic of lymphoblastic leukemias. This is likely to impact therapeutic strategies, towards a better management and outcome.
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| 8. |
- Béné, Marie C., et al.
(författare)
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Unsupervised flow cytometry analysis in hematological malignancies : A new paradigm
- 2021
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Ingår i: International Journal of Laboratory Hematology. - : Wiley. - 1751-5521 .- 1751-553X. ; 43:S1, s. 54-64
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Forskningsöversikt (refereegranskat)abstract
- Ever since hematopoietic cells became “events” enumerated and characterized in suspension by cell counters or flow cytometers, researchers and engineers have strived to refine the acquisition and display of the electronic signals generated. A large array of solutions was then developed to identify at best the numerous cell subsets that can be delineated, notably among hematopoietic cells. As instruments became more and more stable and robust, the focus moved to analytic software. Almost concomitantly, the capacity increased to use large panels (both with mass and classical cytometry) and to apply artificial intelligence/machine learning for their analysis. The combination of these concepts raised new analytical possibilities, opening an unprecedented field of subtle exploration for many conditions, including hematopoiesis and hematological disorders. In this review, the general concepts and progress achieved in the development of new analytical approaches for exploring high-dimensional data sets at the single-cell level will be described as they appeared over the past few years. A larger and more practical part will detail the various steps that need to be mastered, both in data acquisition and in the preanalytical check of data files. Finally, a step-by-step explanation of the solution in development to combine the Bioconductor clustering algorithm FlowSOM and the popular and widely used software Kaluza® (Beckman Coulter) will be presented. The aim of this review was to point out that the day when these progresses will reach routine hematology laboratories does not seem so far away.
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| 9. |
- Gupta, Monali, et al.
(författare)
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Radar plots facilitate differential diagnosis of acute promyelocytic leukemia and NPM1+ acute myeloid leukemia by flow cytometry
- 2021
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Ingår i: Cytometry Part B - Clinical Cytometry. - : Wiley. - 1552-4949 .- 1552-4957. ; 100:4, s. 409-420
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Tidskriftsartikel (refereegranskat)abstract
- Background: Acute promyelocytic leukemia (APL) is one of the most life-threatening hematological emergencies and requires a prompt correct diagnosis by cytomorphology and flow cytometry (FCM) with later confirmation by cytogenetics/molecular genetics. However, nucleophosmin 1 muted acute myeloid leukemia (NPM1+ AML) can mimic APL, especially the hypogranular variant of APL. Our study aimed to develop a novel, Radar plot-based FCM strategy to distinguish APLs and NPM1+ AMLs quickly and accurately. Method: Diagnostic samples from 52 APL and 32 NPM1+ AMLs patients were analyzed by a 3-tube panel of 10-color FCM. Radar plots combining all markers were constructed for each tube. Percentages of positive leukemic cells and mean fluorescence intensity were calculated for all the markers. Results: APL showed significantly higher expression of CD64, CD2, and CD13, whereas more leukemic cells were positive for CD11b, CD11c, CD15, CD36, and HLA-DR in NPM1+ AMLs. Radar plots featured CD2 expression, a lack of a monocytic component, lack of expression of HLA-DR and CD15, and a lack of a prominent CD11c+ population as recurring characteristics of APL. The presence of blasts with low SSC, presence of at least some monocytes, some expression of HLA-DR and/or CD15, and a prominent CD11c population were recurrent characteristics of NPM1+ AMLs. Radar plot analysis could confidently separate all hypergranular APL cases from any NPM1+ AML and in 90% of cases between variant APL and blastic NPM1+ AML. Conclusion: Radar plots can potentially add to differential diagnostics as they exhibit characteristic patterns distinguishing APL and different types of NPM1+ AMLs.
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| 10. |
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