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Solans, M., Benavente, Y., Saez, M., Agudo, A., Naudin, S., Hosnijeh, F. S., . . . Casabonne, D. (2019). Adherence to the mediterranean diet and lymphoma risk in the european prospective investigation into cancer and nutrition. International Journal of Cancer, 145(1), 122-131
Open this publication in new window or tab >>Adherence to the mediterranean diet and lymphoma risk in the european prospective investigation into cancer and nutrition
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2019 (English)In: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 145, no 1, p. 122-131Article in journal (Refereed) Published
Abstract [en]

There is a growing evidence of the protective role of the Mediterranean diet (MD) on cancer. However, no prospective study has yet investigated its influence on lymphoma. We evaluated the association between adherence to the MD and risk of lymphoma and its subtypes in the European Prospective Investigation into Cancer and Nutrition (EPIC) study. The analysis included 476,160 participants, recruited from 10 European countries between 1991 and 2001. Adherence to the MD was estimated through the adapted relative MD (arMED) score excluding alcohol. Cox proportional hazards regression models were used while adjusting for potential confounders. During an average follow-up of 13.9 years, 3,136 lymphomas (135 Hodgkin lymphoma [HL], 2,606 non-HL and 395 lymphoma not otherwise specified) were identified. Overall, a 1-unit increase in the arMED score was associated with a 2% lower risk of lymphoma (95% CI: 0.97; 1.00, p-trend = 0.03) while a statistically nonsignificant inverse association between a high versus low arMED score and risk of lymphoma was observed (hazard ratio [HR]: 0.91 [95% CI 0.80; 1.03], p-trend = 0.12). Analyses by lymphoma subtype did not reveal any statistically significant associations. Albeit with small numbers of cases (N = 135), a suggestive inverse association was found for HL (HR 1-unit increase = 0.93 [95% CI: 0.86; 1.01], p-trend = 0.07). However, the study may have lacked statistical power to detect small effect sizes for lymphoma subtype. Our findings suggest that an increasing arMED score was inversely related to the risk of overall lymphoma in EPIC but not by subtypes. Further large prospective studies are warranted to confirm these findings.

Place, publisher, year, edition, pages
John Wiley & Sons, 2019
Keywords
lymphoma, Mediterranean diet, Europe, prospective studies, risk
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:umu:diva-159047 (URN)10.1002/ijc.32091 (DOI)000466175500012 ()30588620 (PubMedID)
Available from: 2019-05-22 Created: 2019-05-22 Last updated: 2019-05-22Bibliographically approved
Georgiadis, P., Gavriil, M., Rantakokko, P., Ladoukakis, E., Botsivali, M., Kelly, R. S., . . . Kyrtopoulos, S. A. (2019). DNA methylation profiling implicates exposure to PCBs in the pathogenesis of B-cell chronic lymphocytic leukemia. Environment International, 126, 24-36
Open this publication in new window or tab >>DNA methylation profiling implicates exposure to PCBs in the pathogenesis of B-cell chronic lymphocytic leukemia
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2019 (English)In: Environment International, ISSN 0160-4120, E-ISSN 1873-6750, Vol. 126, p. 24-36Article in journal (Refereed) Published
Abstract [en]

OBJECTIVES: To characterize the impact of PCB exposure on DNA methylation in peripheral blood leucocytes and to evaluate the corresponding changes in relation to possible health effects, with a focus on B-cell lymphoma.

METHODS: We conducted an epigenome-wide association study on 611 adults free of diagnosed disease, living in Italy and Sweden, in whom we also measured plasma concentrations of 6 PCB congeners, DDE and hexachlorobenzene.

RESULTS: We identified 650 CpG sites whose methylation correlates strongly (FDR < 0.01) with plasma concentrations of at least one PCB congener. Stronger effects were observed in males and in Sweden. This epigenetic exposure profile shows extensive and highly statistically significant overlaps with published profiles associated with the risk of future B-cell chronic lymphocytic leukemia (CLL) as well as with clinical CLL (38 and 28 CpG sites, respectively). For all these sites, the methylation changes were in the same direction for increasing exposure and for higher disease risk or clinical disease status, suggesting an etiological link between exposure and CLL. Mediation analysis reinforced the suggestion of a causal link between exposure, changes in DNA methylation and disease. Disease connectivity analysis identified multiple additional diseases associated with differentially methylated genes, including melanoma for which an etiological link with PCB exposure is established, as well as developmental and neurological diseases for which there is corresponding epidemiological evidence. Differentially methylated genes include many homeobox genes, suggesting that PCBs target stem cells. Furthermore, numerous polycomb protein target genes were hypermethylated with increasing exposure, an effect known to constitute an early marker of carcinogenesis.

CONCLUSIONS: This study provides mechanistic evidence in support of a link between exposure to PCBs and the etiology of CLL and underlines the utility of omic profiling in the evaluation of the potential toxicity of environmental chemicals.

Keywords
B-cell lymphoma, DNA methylation, Environmental toxicology, Hazard assessment, Molecular epidemiology, Persistent organic pollutants
National Category
Occupational Health and Environmental Health
Identifiers
urn:nbn:se:umu:diva-157883 (URN)10.1016/j.envint.2019.01.068 (DOI)000462597500004 ()30776747 (PubMedID)
Available from: 2019-04-05 Created: 2019-04-05 Last updated: 2019-04-15Bibliographically approved
Thomsen, H., Chattopadhyay, S., Weinhold, N., Vodicka, P., Vodickova, L., Hoffmann, P., . . . Försti, A. (2019). Genome-wide association study of monoclonal gammopathy of unknown significance (MGUS): comparison with multiple myeloma [Letter to the editor]. Leukemia, 33(7), 1817-1821
Open this publication in new window or tab >>Genome-wide association study of monoclonal gammopathy of unknown significance (MGUS): comparison with multiple myeloma
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2019 (English)In: Leukemia, ISSN 0887-6924, E-ISSN 1476-5551, Vol. 33, no 7, p. 1817-1821Article in journal, Letter (Refereed) Published
Place, publisher, year, edition, pages
Nature Publishing Group, 2019
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:umu:diva-156453 (URN)10.1038/s41375-019-0396-x (DOI)000473724900026 ()30737484 (PubMedID)
Available from: 2019-02-15 Created: 2019-02-15 Last updated: 2019-08-05Bibliographically approved
Espín-Pérez, A., Hebels, D. G. A., Kiviranta, H., Rantakokko, P., Georgiadis, P., Botsivali, M., . . . de Kok, T. M. C. (2019). Identification of Sex-Specific Transcriptome Responses to Polychlorinated Biphenyls (PCBs). Scientific Reports, 9, Article ID 746.
Open this publication in new window or tab >>Identification of Sex-Specific Transcriptome Responses to Polychlorinated Biphenyls (PCBs)
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2019 (English)In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 9, article id 746Article in journal (Refereed) Published
Abstract [en]

PCBs are classified as xenoestrogens and carcinogens and their health risks may be sex-specific. To identify potential sex-specific responses to PCB-exposure we established gene expression profiles in a population study subdivided into females and males. Gene expression profiles were determined in a study population consisting of 512 subjects from the EnviroGenomarkers project, 217 subjects who developed lymphoma and 295 controls were selected in later life. We ran linear mixed models in order to find associations between gene expression and exposure to PCBs, while correcting for confounders, in particular distribution of white blood cells (WBC), as well as random effects. The analysis was subdivided according to sex and development of lymphoma in later life. The changes in gene expression as a result of exposure to the six studied PCB congeners were sex- and WBC type specific. The relatively large number of genes that are significantly associated with PCB-exposure in the female subpopulation already indicates different biological response mechanisms to PCBs between the two sexes. The interaction analysis between different PCBs and WBCs provides only a small overlap between sexes. In males, cancer-related pathways and in females immune system-related pathways are identified in association with PCBs and WBCs. Future lymphoma cases and controls for both sexes show different responses to the interaction of PCBs with WBCs, suggesting a role of the immune system in PCB-related cancer development.

Place, publisher, year, edition, pages
Nature Publishing Group, 2019
National Category
Occupational Health and Environmental Health Medical Genetics
Research subject
Epidemiology
Identifiers
urn:nbn:se:umu:diva-155826 (URN)10.1038/s41598-018-37449-y (DOI)000456554600185 ()30679748 (PubMedID)
Available from: 2019-01-28 Created: 2019-01-28 Last updated: 2019-02-26Bibliographically approved
Späth, F., Wibom, C., Krop, E. J., Izarra Santamaria, A., Johansson, A. S., Bergdahl, I., . . . Melin, B. S. (2019). Immune marker changes and risk of multiple myeloma: a nested case-control study using repeated prediagnostic blood samples.. Haematologica, Article ID haematol.2019.216895.
Open this publication in new window or tab >>Immune marker changes and risk of multiple myeloma: a nested case-control study using repeated prediagnostic blood samples.
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2019 (English)In: Haematologica, ISSN 0390-6078, E-ISSN 1592-8721, article id haematol.2019.216895Article in journal (Refereed) Epub ahead of print
Abstract [en]

Biomarkers reliably predicting progression to multiple myeloma are lacking. Myeloma risk has been associated with low blood levels of monocyte chemotactic protein 3, macrophage inflammatory protein 1 alpha, vascular endothelial growth factor, fibroblast growth factor 2, fractalkine, and transforming growth factor alpha. In this study, we aimed to replicate these findings and study the individual dynamics of each marker in a prospective longitudinal cohort, thereby examining their potential as markers of myeloma progression. For this purpose, we identified 65 myeloma cases and 65 matched cancer-free controls each with two donated blood samples within the Northern Sweden Health and Disease Study. Samples from myeloma cases were donated in median 13 and 4 years before myeloma diagnosis. Known risk factors of progression were determined by protein-, and immunofixation electrophoresis, and free light chain assays. We observed lower levels of monocyte chemotactic protein 3, vascular endothelial growth factor, fibroblast growth factor 2, fractalkine, and transforming growth factor alpha in myeloma patients than controls, consistent with previous data. We also observed that these markers decreased among future myeloma patients while remaining stable in controls. Decreasing trajectories were marked for transforming growth factor alpha (P = 2.5 x 10-4) indicating progression to multiple myeloma. Investigating this, we found that low levels of transforming growth factor alpha assessed at time of the repeated sample were independently associated with risk of progression in a multivariable model (hazard ratio = 3.5; P = 0.003). Transforming growth factor alpha can potentially improve early detection of multiple myeloma. .

Keywords
Immune marker change, Monoclonal Gammopathy of Undetermined Significance, Multiple Myeloma, Progression, prospective longitudinal study
Identifiers
urn:nbn:se:umu:diva-158803 (URN)10.3324/haematol.2019.216895 (DOI)30948485 (PubMedID)
Available from: 2019-05-09 Created: 2019-05-09 Last updated: 2019-05-10
Solans, M., Benavente, Y., Saez, M., Agudo, A., Jakszyn, P., Naudin, S., . . . Casabonne, D. (2019). Inflammatory potential of diet and risk of lymphoma in the European Prospective Investigation into Cancer and Nutrition.. European Journal of Nutrition
Open this publication in new window or tab >>Inflammatory potential of diet and risk of lymphoma in the European Prospective Investigation into Cancer and Nutrition.
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2019 (English)In: European Journal of Nutrition, ISSN 1436-6207, E-ISSN 1436-6215Article in journal (Refereed) Epub ahead of print
Abstract [en]

Introduction: Chronic inflammation plays a critical role in lymphomagenesis and several dietary factors seem to be involved its regulation. The aim of the current study was to assess the association between the inflammatory potential of the diet and the risk of lymphoma and its subtypes in the European Investigation into Cancer and Nutrition (EPIC) study.

Methods: The analysis included 476,160 subjects with an average follow-up of 13.9 years, during which 3,136 lymphomas (135 Hodgkin lymphoma (HL), 2606 non-Hodgkin lymphoma (NHL) and 395 NOS) were identified. The dietary inflammatory potential was assessed by means of an inflammatory score of the diet (ISD), calculated using 28 dietary components and their corresponding inflammatory weights. The association between the ISD and lymphoma risk was estimated by hazard ratios (HR) and 95% confidence intervals (CI) calculated by multivariable Cox regression models adjusted for potential confounders.

Results: The ISD was not associated with overall lymphoma risk. Among lymphoma subtypes, a positive association between the ISD and mature B-cell NHL (HR for a 1-SD increase: 1.07 (95% CI 1.01; 1.14), p trend = 0.03) was observed. No statistically significant association was found among other subtypes. However, albeit with smaller number of cases, a suggestive association was observed for HL (HR for a 1-SD increase = 1.22 (95% CI 0.94; 1.57), p trend 0.13).

Conclusions: Our findings suggested that a high ISD score, reflecting a pro-inflammatory diet, was modestly positively associated with the risk of B-cell lymphoma subtypes. Further large prospective studies on low-grade inflammation induced by diet are warranted to confirm these findings.

Place, publisher, year, edition, pages
Springer Berlin/Heidelberg, 2019
Keywords
Chronic inflammation, Inflammatory score of the diet, Lymphoma, Nutrition, Prospective studies
National Category
Nutrition and Dietetics
Identifiers
urn:nbn:se:umu:diva-157844 (URN)10.1007/s00394-019-01947-0 (DOI)30903361 (PubMedID)
Available from: 2019-04-04 Created: 2019-04-04 Last updated: 2019-04-05
Winqvist, M., Andersson, P.-O., Asklid, A., Karlsson, K., Karlsson, C., Lauri, B., . . . Österborg, A. (2019). Long-term real-world results of ibrutinib therapy in patients with relapsed or refractory chronic lymphocytic leukemia: 30-month follow up of the Swedish compassionate use cohort [Letter to the editor]. Haematologica, 104(5), E208-E210
Open this publication in new window or tab >>Long-term real-world results of ibrutinib therapy in patients with relapsed or refractory chronic lymphocytic leukemia: 30-month follow up of the Swedish compassionate use cohort
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2019 (English)In: Haematologica, ISSN 0390-6078, E-ISSN 1592-8721, Vol. 104, no 5, p. E208-E210Article in journal, Letter (Refereed) Published
Place, publisher, year, edition, pages
Ferrata Storti Foundation, 2019
National Category
Hematology
Identifiers
urn:nbn:se:umu:diva-159619 (URN)10.3324/haematol.2018.198820 (DOI)000466305600008 ()30514799 (PubMedID)
Available from: 2019-06-17 Created: 2019-06-17 Last updated: 2019-06-17Bibliographically approved
Späth, F. (2019). Molecular epidemiology approach: nested case-control studies in glioma and lymphoid malignancies. (Doctoral dissertation). Umeå: Umeå universitet
Open this publication in new window or tab >>Molecular epidemiology approach: nested case-control studies in glioma and lymphoid malignancies
2019 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

BACKGROUND: Nested case-control studies aim to link molecular markers with a certain outcome. Repeated prediagnostic samples may improve the evaluation of marker-disease associations. However, data regarding the benefit of repeated samples in such studies are sparse. We aimed to assess the relationship between blood levels of various proteins and risk of glioma, B cell lymphoma, and multiple myeloma to gain further understanding of disease etiology and to evaluate the clinical relevance of the studied markers. To this end, marker-disease associations were evaluated considering the natural history of the studied disease and the time between blood sample collection and diagnosis using both single (I-II) and repeated prediagnostic blood samples (III-IV).

PATIENTS AND METHODS: We conducted four nested case-control studies and one meta-analysis using samples from three prospective cohorts: the Janus Serum Bank, the Northern Sweden Health and Disease study, and the European Prospective Investigation into Cancer and Nutrition study. The following studied endpoints and relationships were included: I) glioma risk and the association with the receptor tyrosine kinases (soluble) sEGFR and sERBB2; II) B cell lymphoma risk and the association with the immune markers sCD27 and sCD30; III) B cell lymphoma risk and the association with immune markers (CXCL13, sTNF-R1, sCD23, sCD27, and sCD30) and their trends over time; and IV) multiple myeloma risk and the association  with ten immune markers and growth factors (MCP-3, MIP-1α, MIP-1β, VEGF, FGF-2, fractalkine, TGF-α, IL-13, TNF-α, and IL-10) and their trends over time.

RESULTS: Risk of developing I) glioma was weakly associated with high blood levels of sERBB2. In addition, high levels of both sEGFR and sERBB2 assessed 15 years before diagnosis were associated with glioblastoma risk.

Risk of II) B cell lymphoma was associated with high levels of sCD30, whereas high levels of sCD27 were particularly associated with risk of chronic lymphocytic leukemia. Meta-analyses showed consistent results for sCD30 across cohorts and lymphoma subtypes, whereas results for sCD27 were less consistent across cohorts and subtypes.

In addition, III) B cell lymphoma risk was associated with levels of CXCL13, sCD23, sCD27, and sCD30 assessed in samples collected 17 years before diagnosis. Marker levels increased in cases closer to diagnosis, particularly for indolent lymphoma with a marked association for chronic lymphocytic leukemia and sCD23. Increasing marker levels closer to diagnosis were also observed for CXCL13 in future diffuse large B cell lymphoma patients.

Risk of IV) multiple myeloma was associated with low levels of MCP-3, VEGF, FGF-2, fractalkine, and TGF-α. Levels of these markers decreased in myeloma cases over time, especially for TGF-α. TGF-α assessed at time of the prediagnostic repeated sample seemed to help predict progression to multiple myeloma.

CONCLUSIONS: Both the natural history of the studied disease and the time between sample collection and diagnosis are crucial for the evaluation of marker-disease associations. Using repeated blood samples improves the understanding of marker-disease associations and might help to identify useful biomarker candidates.

Place, publisher, year, edition, pages
Umeå: Umeå universitet, 2019. p. 53
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 2016
Keywords
Glioma, B cell lymphoma, multiple myeloma, risk, repeated samples, prospective longitudinal study, nested case-control study, circulating sEGFR and sERBB2, circulating immune markers and growth factors, marker disease association, disease progression, NSHDS, Janus, linear mixed modeling
National Category
Cancer and Oncology
Research subject
Epidemiology; Oncology
Identifiers
urn:nbn:se:umu:diva-156421 (URN)978-91-7855-025-8 (ISBN)
Public defence
2019-03-22, Bergasalen, byggnad 27, Norrlands universitetssjukhus, Umeå, 09:00 (English)
Opponent
Supervisors
Available from: 2019-02-22 Created: 2019-02-14 Last updated: 2019-02-21Bibliographically approved
Björkblom, B., Jonsson, P., Späth, F., Melin, B. S. & Antti, H. (2018). PRE-DIAGNOSTIC PLASMA METABOLITES LINKED TO FUTURE BRAIN TUMOR DEVELOPMENT. Paper presented at 13th Meeting of the European-Association-of-Neurooncology (EANO), OCT 10-14, 2018, Stockholm, SWEDEN. Neuro-Oncology, 20, 288-289
Open this publication in new window or tab >>PRE-DIAGNOSTIC PLASMA METABOLITES LINKED TO FUTURE BRAIN TUMOR DEVELOPMENT
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2018 (English)In: Neuro-Oncology, ISSN 1522-8517, E-ISSN 1523-5866, Vol. 20, p. 288-289Article in journal, Meeting abstract (Other academic) Published
Abstract [en]

BACKGROUND: The Northern Sweden Health and Disease Study is a unique population-based biobank linked to the clinical data registries. The samples originate from over 133 000 individuals living in the northern part of Sweden, and primarily collected during health checkups from the age of 40 years. Our project aims to investigate alterations in metabolite signatures in blood plasma of healthy blood donors that later in life developed a tumor. Brain tumors, especially glioblastoma is associated with poor prognosis. To explore early events of metabolic reprograming linked to future diagnosis, we investigated alterations in metabolite concentrations in plasma collected several years before diagnosis with matched healthy controls. MATERIALS AND METHODS: In total 392 analytical samples (256 repeated timepoint and 136 single timepoint, case-control samples) were analyzed using GCTOFMS. Constrained randomization of run order was utilized to maximize information output and minimize the false discovery rate. By use of reference databases, we could with high confidence quantify and identify 150 plasma metabolites. We detected metabolites with significant alterations in concertation between pre-clinical glioma cases and healthy controls by the effect projection approach based on orthogonal partial least squares (OPLSEP). RESULTS AND CONCLUSIONS: For the repeated blood samples, we designed and applied a novel multivariate strategy for high resolution biomarker pattern discovery. We utilize the fact that we have available samples from two repeated time points prior to diagnosis for each future glioma case and their matched controls to construct a small design of experiment (DoE) of four samples for each match pair. The data for each individual DoE was evaluated by OPLS-EP to determine the effect of each individual metabolite in relation to control-case, time and their interaction. Finally, latent significance calculations by means of OPLS were used to extract and evaluate the correct latent biomarker and highlight true significance of individual metabolites. Our study presents an approach to minimize confounding effects due to systematic noise from sampling, the analytical method, as well as take into account personalized metabolic levels over time, enabling biomarker detection within a smaller sample group. We will present and discuss the latest results and biomarkers from this exploratory metabolomics study at the meeting

Place, publisher, year, edition, pages
OXFORD UNIV PRESS INC, 2018
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:umu:diva-157548 (URN)10.1093/neuonc/noy139.277 (DOI)000460645600279 ()
Conference
13th Meeting of the European-Association-of-Neurooncology (EANO), OCT 10-14, 2018, Stockholm, SWEDEN
Available from: 2019-03-26 Created: 2019-03-26 Last updated: 2019-03-26Bibliographically approved
Späth, F., Wibom, C., Krop, E. J. M., Johansson, A.-S., Bergdahl, I. A., Vermeulen, R. & Melin, B. (2017). Biomarker Dynamics in B-cell Lymphoma: A Longitudinal Prospective Study of Plasma Samples Up to 25 Years before Diagnosis. Cancer Research, 77(6), 1408-1415
Open this publication in new window or tab >>Biomarker Dynamics in B-cell Lymphoma: A Longitudinal Prospective Study of Plasma Samples Up to 25 Years before Diagnosis
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2017 (English)In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 77, no 6, p. 1408-1415Article in journal (Refereed) Published
Abstract [en]

The B-cell activation markers CXCL13, sCD23, (S)CD27, and sCD30 are associated with future lymphoma risk. However, a lack of information about the individual dynamics of markerdisease association hampers interpretation. In this study, we identified 170 individuals who had donated two prediagnostic blood samples before B-cell lymphoma diagnosis, along with 170 matched cancer-free controls from the Northern Sweden Health and Disease Study. Lymphoma risk associations were investigated by subtype and marker levels measured at baseline, at the time of the repeated sample, and with the rate of change in the marker level. Notably, we observed strong associations between CXCL13, sCD23, sCD27, and sCD30 and lymphoma risk in blood samples collected 15 to 25 years before diagnosis. B-cell activation marker levels increased among future lympho-ma cases over time, while remaining stable among controls. Associations between slope and risk were strongest for indolent lymphoma subtypes. We noted a marked association of sCD23 with chronic lymphocytic leukemia (ORSlope - 28, Ptrend(-)7.279 x 10 (-10)). Among aggressive lymphomas, the association between diffuse large B-cell lymphoma risk and slope was restricted to CXCL13. B-cell activation seemed to play a role in B-cell lymphoma development at early stages across different subtypes. Furthermore, B-cell activation presented differential trajectories in future lymphoma patients, mainly driven by indolent subtypes. Our results suggest a utility of these markers in predicting the presence of early occult disease and/or the screening and monitoring of indolent lymphoma in individual patients. 

Place, publisher, year, edition, pages
American Association for Cancer Research, 2017
National Category
Cancer and Oncology Hematology
Identifiers
urn:nbn:se:umu:diva-140249 (URN)10.1158/0008-5472.CAN-16-2345 (DOI)000396845600015 ()28108506 (PubMedID)
Available from: 2017-10-17 Created: 2017-10-17 Last updated: 2019-02-20Bibliographically approved
Organisations
Identifiers
ORCID iD: ORCID iD iconorcid.org/0000-0002-0711-0830

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