| 1. |
- Andersson, Anne, 1966-, et al.
(author)
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Family history of cancer as a risk factor for second malignancies after Hodgkin's lymphoma
- 2008
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In: British Journal of Cancer. - : Springer Science and Business Media LLC. - 0007-0920 .- 1532-1827. ; 98:5, s. 1001-1005
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Journal article (peer-reviewed)abstract
- This study estimated the risk of second primary malignancies after Hodgkin's lymphoma (HL) in relation to family history of cancer, age at diagnosis and latency, among 6946 patients treated for HL in Sweden in 1965–1995 identified through the Swedish Cancer Register (SCR). First-degree relatives (FDRs) to the HL patients and their malignancies were then ascertained together with their malignancies through the Multi-Generation Registry and SCR. The HL patient cohort was stratified on the number of FDRs with cancer, and standardised incidence ratios (SIRs) of developing SM were analysed. In the HL cohort, 781 SM were observed 1 year or longer after HL diagnosis. The risk for developing SM increased with the number of FDRs with cancer, SIRs being 2.26, 3.01, and 3.45 with 0, 1, or ≥2 FDRs with cancer, respectively. Hodgkin's lymphoma long-term survivors treated at a young age with a family history of cancer carry an increased risk for developing SM and may represent a subgroup where standardised screening for the most common cancer sites could be offered in a stringent surveillance programme.
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| 2. |
- Andreasson, Ulrika, et al.
(author)
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Identification of molecular targets associated with transformed diffuse large B cell lymphoma using highly purified tumor cells
- 2009
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In: American Journal of Hematology. - : Wiley. - 0361-8609 .- 1096-8652. ; 84:12, s. 803-808
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Journal article (peer-reviewed)abstract
- Follicular lymphoma (FL) frequently transforms into the more aggressive diffuse large B cell lymphoma (DLBCL-tr), but no protein biomarkers have been identified for predictive or early diagnosis. Gene expression analyses have identified genes changing on transformation but have failed to be reproducible in different studies, reflecting the heterogeneity within the tumor tissue and between tumor samples. Gene expression analyses on Affymetrix Human Genome U133 Plus 2.0 arrays were performed, using flow cytometry sorted tumor cells derived from FL and transformed DLBCL. To identify molecular targets associated with the transformation, subsequent immunohistochemistry (IHC) analyses of the corresponding proteins were performed. Using highly purified cells, this study identified 163 genes, which were significantly deregulated during the transformation in a majority of cases. Among the upregulated transcripts, 13 genes were selected for validation using IHC, based on the availability of commercial antibodies, and galectin-3 and NEK2 proteins specifically identify DLBCL-tr, when compared with FL. We demonstrate that by purifying tumor cells through cell sorting, thereby reducing the heterogeneity due to infiltrating cells, it was possible to identify distinct differences between tumor entities rather than variations due to cellular composition. Galectin-3 and NEK2 both identified a subgroup of DLBCL-tr, and the function of these protein markers also suggests a biological role in the transformation process.
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| 3. |
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| 4. |
- Ehinger, Mats, et al.
(author)
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A Subset of CD5- Diffuse Large B-Cell Lymphomas Expresses Nuclear Cyclin D1 With Aberrations at the CCND1 Locus.
- 2008
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In: American Journal of Clinical Pathology. - 1943-7722 .- 0002-9173. ; 129:4, s. 630-638
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Journal article (peer-reviewed)abstract
- In 231 diffuse large B-cell lymphomas, the expression of cyclin D1 and CD5 was evaluated. All cases were CD5-. Ten (4.3%) were positive for cyclin D1 and were subjected to fluorescence in situ hybridization at the CCND1 locus. One case showed the t(11;14). In another case, the telomeric probe signal for cyclin D1 was lost in most tumor cells, and in a small proportion of the cells, there were fluorescence signals indicative of the t(11;14). Two other cases displayed additional cyclin D1 signals in the absence of the t(11;14). All cases but 1 were positive for bcl-6 or MUM1, disfavoring the possibility of misdiagnosed blastoid variants of CD5- mantle cell lymphomas. Thus, contrary to the current view, there seems to exist a certain number of cyclin D1+ and CD5- diffuse large B-cell lymphomas, some of which have structural aberrations at the CCND1 locus, including the t(11;14).
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| 5. |
- Fridberg, Marie, et al.
(author)
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Protein expression and cellular localization in two prognostic subgroups of diffuse large B-cell lymphoma : higher expression of ZAP70 and PKC-beta II in the non-germinal center group and poor survival in patients deficient in nuclear PTEN
- 2007
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In: Leukemia and Lymphoma. - : Informa UK Limited. - 1042-8194 .- 1029-2403. ; 48:11, s. 2221-2232
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Journal article (peer-reviewed)abstract
- Patients diagnosed with diffuse large B-cell lymphoma (DLBCL) show varying responses to conventional therapy, and this might be contributed to the differentiation stage of the tumor B-cells. The aim of the current study was to evaluate a panel of kinases (ZAP70, PKC-β I and II and phosphorylated PKB/Akt) and phosphatases (PTEN, SHP1 and SHP2) known to be frequently deregulated in lymphoid malignancies. De novo DLBCL cases were divided into two subgroups, the germinal center (GC) group (14/28) and the non-germinal center (non-GC) or activated B-cell (ABC) group (14/28). ZAP70 and PKC-β II were expressed in a significantly higher percentage of tumor cells in the clinically more aggressive non-GC group compared with the prognostically favourable GC group. Also, the subcellular localization of PKC-β I and II differed in DLBCL cells, with the PKC-β I isoform being expressed in both the cytoplasm and nucleus, while PKC-β II was found exclusively in the cytoplasm. Loss of nuclear PTEN correlated with poor survival in cases from both subgroups. In addition, five cell lines of DLBCL origin were analyzed for protein expression and for mRNA levels of PTEN and SHP1. For the first time, we show that ZAP70 is expressed in a higher percentage of tumor cells in the aggressive non-GC subgroup of DLBCL and that PKC-β I and II are differently distributed in the two prognostic subgroups of de novo DLBCL.
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| 6. |
- Linderoth, Johan, et al.
(author)
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CD40 expression identifies a prognostically favourable subgroup of diffuse large B-cell lymphoma
- 2007
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In: Leukemia and Lymphoma. - : Informa UK Limited. - 1042-8194 .- 1029-2403. ; 48:9, s. 1774-1779
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Journal article (peer-reviewed)abstract
- In order to confirm our earlier findings of the prognostic effects of CD23 and CD40 expression in diffuse large B-cell lymphoma (DLBCL), possibly due to association with the germinal center (GC) phenotype and/or an increased autologous tumour response, tumour specimens from 125 patients with de novo DLBCL were investigated for immunohistochemical expression of CD23, CD40, BCL6, CD10, MUM1, CD4 and CD8. CD40 was positive in 64% and was associated with improved overall survival (p = 0.03). A GC phenotype was present in 47%, and was also associated with a better overall survival (p = 0.006) but did not correlate with CD40-expression. There was no correlation between amount of tumour infiltrating T-cells and CD40-positivity. CD23 was positive in 10% and expression did not correlate with prognosis. In conclusion, the prognostic effect of CD40 expression was confirmed, but did not correlate with GC-phenotype or T-cell infiltration.
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| 7. |
- Linderoth, Johan
(author)
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Diffuse large B-cell lymphoma - tumour characteristics on RNA and protein level associated with prognosis
- 2007
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Doctoral thesis (other academic/artistic)abstract
- Diffuse large B-cell lymphoma (DLBCL) is the most frequent lymphoma subtype. In Sweden 450 new cases are diagnosed annually. With modern anthracycline-containing chemotherapy DLBCL is potentially curable, with an estimated overall cure rate of approximately 50% for patients with advanced stage disease. Through molecular profiling of DLBCL the ?cell-of-origin concept? has been established: patients with tumours expressing genes characteristic of germinal center B-cells, ?GC-profile? has a significantly better survival than patients with tumors expressing genes normally induced during in vitro activation of peripheral blood B-cells, ?ABC-profile?. The first study (n=125) aimed to identify a protein pattern that could be used for discriminating germinal center derived (GC) and activated B-cell like (ABC)/non-GC DLBCL, using immunohistochemistry (IHC). BCL6, CD10 and CD40 were chosen as markers of a GC-phenotype, CD23 as a marker of pre/early GC-origin and CD138 as a marker of post-GC origin (i.e non-GC). No prognostically different subgroups, corresponding to GC or ABC (non-GC) could be identified. A new finding was the positive prognostic impact of CD23 and CD40 expression. In the second study (n=125) the prognostic effect of CD40, but not CD23, was confirmed. The effect of CD40 effect could not be explained by association with the GC-phenotype or by an enhanced autologous tumour response, as detected by tumour infiltrating helper and cytotoxic T-lymphocytes. The prognostic effect of a GC versus non-GC phenotype according to Hans et al (Blood 2004) was confirmed. The third study (n=122) identified the tissue microarray technique to be unreliable for immunohistochemical detection in GC vs. non-GC phenotypes, mostly due to difficulties interpreting BCL6 status. In the fourth study tumours from patients with cured (n=24) versus primary chemotherapy-refractory DLBCL (n=13), were investigated with respect to gene expression profiles, using spotted 55K oligonucleotide arrays produced in Lund. The genes that most differed between chemotherapy sensitive and refractory tumours mainly coded for proteins expressed by cells in the tumour microenvironment, and not by the tumour cells themselves. Confirmative IHC showed that the frequency of tumour infiltrating lymphocytes, macrophages and reactive cells expressing proteolytic and pro-inflammatory proteins were higher in the chemo-sensitive cohort, indicating that the microenvironment has an impact on the response to chemotherapy in DLBCL.
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| 8. |
- Linderoth, Johan, et al.
(author)
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Genes associated with the tumour microenvironment are differentially expressed in cured versus primary chemotherapy-refractory diffuse large B-cell lymphoma
- 2008
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In: British Journal of Haematology. - : Wiley. - 0007-1048 .- 1365-2141. ; 141:4, s. 423-32
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Journal article (peer-reviewed)abstract
- In order to identify genes associated with primary chemotherapy-resistance, gene expression profiles (GEP) in tumour tissue from 37 patients with de novo diffuse large B-cell lymphoma (DLBCL), stage II-IV, either in continuous complete remission (n = 24) or with progressive disease during primary treatment (n = 13), were examined using spotted 55K oligonucleotide arrays. Immunohistochemistry was used for confirmation at the protein level. The top 86 genes that best discriminated between the two cohorts were chosen for further analysis. Only seven of 86 genes were overexpressed in the refractory cohort, e.g. RABGGTB and POLE, both potential targets for drug intervention. Seventy-nine of 86 genes were overexpressed in the cured cohort and mainly coded for proteins expressed in the tumour microenvironment, many of them involved in proteolytic activity and remodelling of extra cellular matrix. Furthermore, major histocompatibility complex class I molecules, CD3D and ICAM1 were overexpressed, indicating an enhanced immunological reaction. Immunohistochemistry confirmed the GEP results. The frequency of tumour infiltrating lymphocytes, macrophages, and reactive cells expressing ICAM-1, lysozyme, cathepsin D, urokinase plasminogen activator receptor, signal transducer and activator of transcription 1, and galectin-3 was higher in the cured cohort. These findings indicate that a reactive microenvironment has an impact on the outcome of chemotherapy in DLBCL.
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| 9. |
- Linderoth, Johan, et al.
(author)
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Tissue microarray is inappropriate for analysis of BCL6 expression in diffuse large B-cell lymphoma
- 2007
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In: European Journal of Haematology. - : Wiley. - 0902-4441 .- 1600-0609. ; 79:2, s. 146-149
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Journal article (peer-reviewed)abstract
- Objective: In this study, our aim was to investigate how different immunohistochemical techniques may influence the result of BCL6 positivity and categorization in germinal center (GC) and non-GC derived diffuse large B-cell lymphoma (DLBCL), as it has been proposed that classification of DLBCL according to cell-of-origin by immunohistochemistry may be performed as a routine procedure in the diagnostic work-up. However, a number of technical issues need to be solved before introducing this as a standard technique. Methods: Tumor specimens from 122 patients with de novo stage II–IV disease, adequately treated with anthracycline-containing chemotherapy regimens were collected. Immunohistochemical expression of BCL6, CD10, and MUM-1/IRF4 was examined using a tissue microarray (TMA) technique. BCL6 and CD10 were also evaluated on whole tissue sections. Results: Due to profound tissue heterogeneity, BCL6 showed a wide range of positivity, with a high number of false negative results by TMA (25% positive), compared to 53% on whole tissue sections (WTS). CD10 was more homogeneously expressed, and TMA results corresponded better to WTS. Consequently, the results from categorization into GC and non-GC DLBCL differed considerably by use of the two methods, and resulted in very different outcome in terms of overall survival. Conclusion: Immunohistochemical GC-status determined on TMA is not reliable enough to be used for individual treatment decisions in DLBCL, mostly due to difficulties in interpreting BCL6 status.
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| 10. |
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