| 1. |
- Hasni, Muhammad Sharif, et al.
(författare)
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Estrogen receptor beta 1 in diffuse large B-cell lymphoma growth and as a prognostic biomarker
- 2017
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Ingår i: Leukemia and Lymphoma. - : Informa UK Limited. - 1042-8194 .- 1029-2403. ; 58:2, s. 418-427
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Tidskriftsartikel (refereegranskat)abstract
- Diffuse large B-cell lymphoma (DLBCL) shows a higher incidence in males versus females. Epidemiological studies have shown that female gender is a favorable prognostic factor, which may be explained by estrogens. Here we show that when grafting human DLBCL cells to immunocompromised mice, tumor growth in males is faster. When treating mice grafted with either germinal center or activated B-cell like DLBCL cells with the selective estrogen receptor beta (ER beta) agonist diarylpropionitrile, tumor growth was significantly inhibited. Furthermore, nuclear ER beta 1 expression analysis in primary DLBCL's by immunohistochemistry revealed expression in 89% of the cases. Nuclear ERb1 expression was in a univariate and multivariate analysis, an independent prognostic factor for adverse progression-free survival in Rituximab-chemotherapy treated DLBCL (p = 0.02 and p = 0.04, respectively). These results suggest that estrogen signaling through ERb1 is an interesting future therapeutic target for treatment of DLBCL, and that ERb1 expression can be used as a prognostic marker.
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| 2. |
- Lagerlöf, Ingemar, et al.
(författare)
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No excess long-term mortality in stage I-IIA Hodgkin lymphoma patients treated with ABVD and limited field radiotherapy
- 2020
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Ingår i: British Journal of Haematology. - : John Wiley & Sons. - 0007-1048 .- 1365-2141. ; 188:5, s. 685-691
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Tidskriftsartikel (refereegranskat)abstract
- When treating limited stage classical Hodgkin lymphoma (cHL), balancing treatment efficacy and toxicity is important. Toxicities after extended-field radiotherapy are well documented. Investigators have aimed at reducing toxicity without compromising efficacy, mainly by using combined modality treatment (CMT), i.e. chemotherapy and limited-field radiotherapy. In some clinical trials, radiotherapy has been omitted. We evaluated 364 patients with stage I-IIA cHL treated between 1999 and 2005. Patients were treated with two or four cycles of doxorubicin, bleomycin, vinblastine and dacarbazine (ABVD) according to presence of risk factors, followed by 30 Gy limited-field (reduced compared to involved-field) radiotherapy. After a median follow-up of 16 years for survival, freedom from progression at five and ten years was 93% and overall survival at 5 and 10 years was 98% and 96%, respectively. Only two relapses, out of 27, occurred after more than 5 years. There was no excess mortality compared to the general population. Of the analysed subgroups, only patients with progression within five years showed significant excess mortality. The absence of excess mortality questions the concept of omitting radiotherapy after short-term chemotherapy, a strategy that has been associated with an elevated risk of relapse but not yet with a proven reduced long-term excess mortality.
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| 3. |
- Ageberg, Malin, et al.
(författare)
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Inhibition of geranylgeranylation mediates sensitivity to CHOP-induced cell death of DLBCL cell lines.
- 2011
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Ingår i: Experimental Cell Research. - : Elsevier BV. - 1090-2422 .- 0014-4827. ; 317, s. 1179-1191
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Tidskriftsartikel (refereegranskat)abstract
- Prenylation is a post-translational hydrophobic modification of proteins, important for their membrane localization and biological function. The use of inhibitors of prenylation has proven to be a useful tool in the activation of apoptotic pathways in tumor cell lines. Rab geranylgeranyl transferase (Rab GGT) is responsible for the prenylation of the Rab family. Overexpression of Rab GGTbeta has been identified in CHOP refractory diffuse large B cell lymphoma (DLBCL). Using a cell line- based model for CHOP resistant DLBCL, we show that treatment with simvastatin, which inhibits protein farnesylation and geranylgeranylation, sensitises DLBCL cells to cytotoxic treatment. Treatment with the farnesyl transferase inhibitor, FTI-277, or the geranylgeranyl transferase I inhibitor, GGTI-298, indicates that the reduction in cell viability was restricted to inhibition of geranylgeranylation. In addition, treatment with BMS1, a combined inhibitor of farnesyl transferase and Rab GGT, resulted in a high cytostatic effect in WSU-NHL cells, demonstrated by reduced cell viability and decreased proliferation. Co-treatment of BMS1 or GGTI-298 with CHOP showed synergistic effects with regard to markers of apoptosis. We propose that inhibition of protein geranylgeranylation together with conventional cytostatic therapy is a potential novel strategy for treating patients with CHOP refractory DLBCL.
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| 4. |
- Fridberg, Marie, et al.
(författare)
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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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Ingår i: Leukemia and Lymphoma. - : Informa UK Limited. - 1042-8194 .- 1029-2403. ; 48:11, s. 2221-2232
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Tidskriftsartikel (refereegranskat)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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| 5. |
- Glimelius, Ingrid, et al.
(författare)
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Sick leave and disability pension in Hodgkin lymphoma survivors by stage, treatment, and follow-up time-a population-based comparative study
- 2015
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Ingår i: Journal of Cancer Survivorship. - : Springer Science and Business Media LLC. - 1932-2267 .- 1932-2259. ; 9:4, s. 599-609
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Tidskriftsartikel (refereegranskat)abstract
- Purpose This study seeks to investigate the long-term public health burden of Hodgkin lymphoma (HL) in terms of work loss following contemporary treatment protocols and associations with established treatment complications and lymphoma relapse. Methods We identified 1,989 Swedish HL patients (1,082 with clinical information) aged 18-60 (median 33) years at diagnosis 1992-2009, and matched 1:4 to population comparators. Sick leave, disability pension (work loss), and comorbidity were retrieved through September 2013. Relative risks (RR) with 95 % confidence intervals (CI) were calculated using Poisson regression, and mean lost work days were estimated yearly during follow-up. Results The risk of annual work loss was elevated in HL survivors versus comparators up to the 15th year post-diagnosis (RR5th year 1.64, 95 % CI 1.46-1.84; RR10th year 1.33, 95 % CI 1.15-1.34; and RR15th year 1.30, 95 % CI 1.04-1.62). The risk remained elevated up to the 10th year after adjustment for secondary malignancies and cardiovascular disease (RR10th year 1.31, 95 % CI 1.13-1.52). Advanced-stage patients had more lost days than comparators (mean number(5th year) 66 versus 33, mean difference 34, 95 % CI 20-48) as did patients receiving 6-8 chemotherapy courses (62 versus 33, mean difference(5th year) 30, 95 % CI 17-43). Among patients in the first complete remission, a difference was still observed for advanced-stage (51 versus 33, mean difference(5th year) 19, 95 % CI 5-34) but not early-stage disease. Conclusions Advanced-stage HL survivors treated with full-dose chemotherapy were at increased risk of work loss, not only explained by relapse, secondary malignancies, or cardiovascular disease.
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| 6. |
- Jakobsen, Lasse H, et al.
(författare)
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No survival benefit associated with routine surveillance imaging for Hodgkin lymphoma in first remission : a Danish-Swedish population-based observational study
- 2016
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Ingår i: British Journal of Haematology. - : Wiley. - 0007-1048 .- 1365-2141. ; 173:2, s. 236-244
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Tidskriftsartikel (refereegranskat)abstract
- The use of routine imaging for patients with classical Hodgkin lymphoma (HL) in complete remission (CR) is controversial. In a population-based study, we examined the post-remission survival of Danish and Swedish HL patients for whom follow-up practices were different. Follow-up in Denmark included routine imaging, usually for a minimum of 2 years, whereas clinical follow-up without routine imaging was standard in Sweden. A total of 317 Danish and 454 Swedish comparable HL patients aged 18-65 years, diagnosed in the period 2007-2012 and having achieved CR following ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine)/BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, prednisone) therapy, were included in the study. The cumulative progression rates in the first 2 years were 4% (95% confidence interval [CI] 1-7) for patients with stage I-II disease vs. 12% (95% CI 6-18) for patients with stage III-IV disease. An imaging-based follow-up practice was not associated with a better post-remission survival in general (P = 0·2) or in stage-specific subgroups (P = 0·5 for I-II and P = 0·4 for III-IV). Age ≥45 years was the only independent adverse prognostic factor for survival. In conclusion, relapse of HL patients with CR is infrequent and systematic use of routine imaging in these patients does not improve post-remission survival. The present study supports clinical follow-up without routine imaging, as encouraged by the recent Lugano classification.
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| 7. |
- Linderoth, Johan, et al.
(författare)
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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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Ingår i: British Journal of Haematology. - : Wiley. - 0007-1048 .- 1365-2141. ; 141:4, s. 423-32
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Tidskriftsartikel (refereegranskat)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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| 8. |
- Nie, Man, et al.
(författare)
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The dual role of CD70 in B‐cell lymphomagenesis
- 2022
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Ingår i: Clinical and Translational Medicine. - : John Wiley & Sons. - 2001-1326. ; 12:12
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Tidskriftsartikel (refereegranskat)abstract
- BackgroundCD70 is a costimulatory molecule that is transiently expressed on a small set of activated lymphocytes and is involved in T-cell-mediated immunity. However, the role of CD70 in B-cell malignancies remains controversial.MethodsWe investigated the clinical relevance of CD70 genetic alterations and its protein expression in two diffuse large B-cell lymphoma (DLBCL) cohorts with different ethnic backgrounds. We also performed transcriptomic analysis to explore the role of CD70 alterations in tumour microenvironment. We further tested the blockade of CD70 in combination with PD-L1 inhibitor in a murine lymphoma model.ResultsWe showed that CD70 genetic aberrations occurred more frequently in the Chinese DLBCL cohort (56/233, 24.0%) than in the Swedish cohort (9/84, 10.8%), especially in those with concomitant hepatitis B virus (HBV) infection. The CD70 genetic changes in DLBCL resulted in a reduction/loss of protein expression and/or CD27 binding, which might impair T cell priming and were independently associated with poor overall survival. Paradoxically, we observed that over-expression of CD70 protein was also associated with a poor treatment response, as well as an advanced disease stage and EBV infection. More exhausted CD8+ T cells were furthermore identified in CD70 high-expression DLBCLs. Finally, in a murine lymphoma model, we demonstrated that blocking the CD70/CD27 and/or PD1/PD-L1 interactions could reduce CD70+ lymphoma growth in vivo, by directly impairing the tumour cell proliferation and rescuing the exhausted T cells.ConclusionsOur findings suggest that CD70 can play a role in either tumour suppression or oncogenesis in DLBCL, likely via distinct immune evasion mechanisms, that is, impairing T cell priming or inducing T cell exhaustion. Characterisation of specific dysfunction of CD70 in DLBCL may thus provide opportunities for the development of novel targeted immuno-therapeutic strategies.
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| 9. |
- Andersson, Anne, 1966-, et al.
(författare)
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Family history of cancer as a risk factor for second malignancies after Hodgkin's lymphoma
- 2008
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Ingår i: British Journal of Cancer. - : Springer Science and Business Media LLC. - 0007-0920 .- 1532-1827. ; 98:5, s. 1001-1005
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Tidskriftsartikel (refereegranskat)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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| 10. |
- Andreasson, Ulrika, et al.
(författare)
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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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Ingår i: American Journal of Hematology. - : Wiley. - 0361-8609 .- 1096-8652. ; 84:12, s. 803-808
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Tidskriftsartikel (refereegranskat)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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