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  • 1.
    Abdulla, Maysaa
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology. Univ Uppsala Hosp, S-75185 Uppsala, Sweden..
    Laszlo, Sofia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology. Univ Uppsala Hosp, S-75185 Uppsala, Sweden..
    Triumf, Johanna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Univ Uppsala Hosp, S-75185 Uppsala, Sweden..
    Hedström, Gustaf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Univ Uppsala Hosp, S-75185 Uppsala, Sweden..
    Berglund, Mattias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Univ Uppsala Hosp, S-75185 Uppsala, Sweden.;Karolinska Inst, Dept Biosci & Nutr, Huddinge, Sweden..
    Enblad, Gunilla
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Univ Uppsala Hosp, S-75185 Uppsala, Sweden..
    Amini, Rose-Marie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology.
    Core needle biopsies for the diagnosis of diffuse large B-cell lymphoma - a great concern for research2017In: Acta Oncologica, ISSN 0284-186X, E-ISSN 1651-226X, Vol. 56, no 1, p. 106-109Article in journal (Refereed)
  • 2. Ahlin, Cecilia
    et al.
    Fernö, Mårten
    Amini, Rose-Marie
    Karolinska universitetssjukhuset, Stockholm.
    Tolockiene, Egle
    Blomqvist, Carl
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Bergh, Jonas
    Fjällskog, Marie-Louise
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Ki-67 och cyklin A – prognostiska faktorer vid bröstcancer: Dags att införa proliferationsmarkörer i klinisk rutin2010In: Läkartidningen, ISSN 0023-7205, E-ISSN 1652-7518, Vol. 107, no 10, p. 672-675Article in journal (Refereed)
  • 3.
    Amini, Rose-Marie
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Berglund, Mattias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Rosenquist, Richard
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    von Heideman, Anne
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Lagercrantz, Svetlana
    Thunberg, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Bergh, Jonas
    Sundström, Christer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Glimelius, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Enblad, Gunilla
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    A novel B-cell line (U-2932) established from a patient with a diffuse large B-cell lymphoma following Hodgkin lymphoma2002In: Leukemia and Lymphoma, ISSN 1042-8194, E-ISSN 1029-2403, Vol. 43, no 11, p. 2179-2189Article in journal (Refereed)
    Abstract [en]

    Little is known about mechanisms leading to secondary non-Hodgkin lymphomas (NHL) in patients treated for Hodgkin lymphoma (HL). Our aim was to characterise in detail a cell line derived from a diffuse large B-cell lymphoma (DLBCL) that had developed in a patient with relapsing HL. The cell line U-2932 was established from ascites in a patient suffering from DLBCL previously treated for HL with multiple chemotherapy regimens. Characterisation was based on morphology, immunophenotype, Epstein-Barr virus (EBV)-status, IgH gene rearrangement status, tumourigenicity, p53 sequencing, and immunohistochemical expression of p53, BCL-2 and BCL-6. The karyotype was investigated using G-banding, comparative genomic hybridisation (CGH) and spectral karyotype (SKY) analysis. This cell line shows typical morphological features of a DLBCL and grows as colonies in nude mice. It expresses a B-cell phenotype with a somatically hypermutated V(H)4-39 gene and is negative for EBV. The origin of U-2932 was confirmed by demonstrating an identical V(H)4 rearrangement in ascites from the patient. A point mutation of the tumour-suppressor gene p53 was detected in amino acid position 176 and immunohistochemical over-expression of the p53 protein was also demonstrated. U-2932 carries a complex karyotype including high-level amplifications of the chromosomal bands 18q21 and 3q27 and expresses aberrant BCL-2 and BCL-6 immunohistochemically. We were unable to investigate the clonal relationship between the original HL and U-2932. In conclusion, U-2932 is a unique B cell line established from a patient suffering from HL followed by NHL. Overexpression of BCL-2, BCL-6 and p53 may play a role in the tumourigenesis and drug resistance. This cell line may become a useful tool to better understand the mechanisms responsible for development of secondary NHL in patients treated for HL.

  • 4.
    Amini, Rose-Marie
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Enblad, Gunilla
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Engström, Peter
    Christensson, Birger
    Glimelius, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Sundström, Christer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Relapsed Hodgkin's lymphoma: immunostaining patterns in relation to survival2002In: Leukemia and Lymphoma, ISSN 1042-8194, E-ISSN 1029-2403, Vol. 43, no 6, p. 1253-1260Article in journal (Refereed)
    Abstract [en]

    Patients with relapsing Hodgkin's lymphoma (HL) have a rather poor prognosis and mechanisms that lead to resistance to therapy are poorly understood. Our aims were to investigate the immunohistochemical staining patterns of Rb (retinoblastoma protein) and the p53 tumour suppressor protein in HL at initial presentation and at relapse in order to elucidate a possible role in disease progression and resistance to therapy. Further to evaluate the presence and prognostic importance of Epstein-Barr virus (EBV) and anaplastic lymphoma kinase (ALK). Eighty-one cases of relapsing HL were reexamined histopathologically and immunostained for the expression of p53, Rb, ALK and CD30. EBV was detected with LMP-1 stainings and in situ hybridisation for EBER. Clinical data were extracted from the Swedish National Health Care Programme for HL. Median follow-up time was six years (range 0-12) from the date of relapse. The majority of cases were positive for p53 and Rb both at presentation and at relapse, though to a different extent. Both an increase and a decrease in the proportion of stained tumour cells were observed. None of our cases was ALK-positive and 44% were EBV-positive. No specific staining pattern was directly correlated to survival. In 12 patients a switch in HL subtype from diagnosis to relapse was observed and the five-year Hodgkin-specific survival (HLS) was statistically significantly inferior, 37 vs 81% (p = 0.002), in those patients. We found a significant relation between the expression of p53 and EBV at diagnosis and relapse, indicating a clonal relationship. We were unable to find any specific staining pattern of p53 or Rb, affecting survival.

  • 5.
    Amini, Rose-Marie
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Enblad, Gunilla
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Gustavsson, Anita
    Ekman, Tor
    Erlanson, Martin
    Haapaniemi, Eva
    Glimelius, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Treatment outcome in patients younger than 60 years with advanced stages (IIB-IV) of Hodgkin's disease: the Swedish National Health Care Programme experience2000In: European Journal of Haematology, ISSN 0902-4441, E-ISSN 1600-0609, Vol. 65, no 6, p. 379-389Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Despite improved treatment results achieved in Hodgkin's disease (HD), only about 70% of patients with advanced stages are cured. The primary aim of this study was to evaluate the outcome of advanced stages (IIB-IVB) of HD in younger patients in an unselected population-based group of patients. The patients were recommended individualized treatment with respect to number of chemotherapy (CT) courses and post-CT radiotherapy (RT) based on pretreatment characteristics and tumour response. Secondly, we investigated if variables of prognostic importance could be detected.

    PATIENTS AND METHODS: Between 1985-92, 307 patients between 17-59 yr of age (median 36) were diagnosed with HD in stages IIB-IVB in 5/6 health care regions in Sweden. Median follow-up time was 7.8 yr (1.3-13). Retrospectively, laboratory parameters were collected.

    RESULTS: In total, 267 (87%) patients had a complete response (CR). The overall and disease-free 10-yr survivals in the whole cohort were 76% and 67%, respectively. There was no difference in survival between the groups of patients who received 6 or 8 cycles of CT. Survival was not higher for patients in CR after CT when RT was added. For those in PR after CT, additional RT raised the frequencies of CR. A selected group of pathologically staged patients was successfully treated with a short course (2 cycles) of CT + RT. In univariate analyses survival was affected by age, stage IVB, bone-marrow involvement, B-symptoms, S-LDH, S-Alb and reaching CR or not after 2, 4 and 6 cycles of CT. In a multivariate analysis, age and reaching CR after 6 cycles of CT remained statistically significant.

    CONCLUSIONS: The lack of difference in survival between the groups of patients who received 6 versus 8 cycles of CT indicates a successful selection of patients for the shorter treatment. Reaching a rapid CR significantly affected outcome. Whether some patients need less CT than the generally recommended 8 courses can properly only be evaluated in a randomised study. Additional RT may play a role in successful outcome, particularly if residual tumours are present, but its precise role can also only be defined in prospectively randomised studies. Reaching CR after CT was the most important variable affecting survival besides age.

  • 6.
    Amini, Rose-Marie
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology.
    Enblad, Gunilla
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Hollander, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology.
    Laszlo, S.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Eriksson, Emma
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Gustafsson, Kristin Ayoola
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik.
    Loskog, Angelica S.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology. Lokon Pharma, AB,Uppsala, Sweden.
    Thörn, Ingrid
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Altered profile of immune regulatory cells in the peripheral blood of lymphoma patients2019In: BMC Cancer, ISSN 1471-2407, E-ISSN 1471-2407, Vol. 19, article id 316Article in journal (Refereed)
    Abstract [en]

    Background: Regulatory immune cells may modulate the lymphoma microenvironment and are of great interest due to the increasing prevalence of treatment with immunotherapies in lymphoma patients. The aim was to explore the composition of different immune regulatory cell subsets in the peripheral blood of newly diagnosed lymphoma patients in relation to treatment outcome. Methods: Forty-three newly diagnosed patients with lymphoma were included in the study; 24 with high-grade B-cell lymphoma (HGBCL) and 19 with classical Hodgkin lymphoma (cHL). Peripheral blood was prospectively collected and immune regulatory cells were identified by multi-color flow cytometry and analyzed in relation to healthy blood donors and clinical characteristics and outcome. Results: The percentage of CD3-positive T-cells was lower (p=0.03) in the peripheral blood of lymphoma patients at diagnosis compared to healthy blood donors regardless of lymphoma subtype, although statistically, neither the percentage of monocytes (p=0.2) nor the T-cell/monocyte ratio (p=0.055) differed significantly. A significant decrease in the percentage of a subset of regulatory NK cells (CD7(+)/CD3(-)/CD56(bright)/CD16(dim/-)) was identified in the peripheral blood of lymphoma patients compared to healthy blood donors (p=0.003). Lymphoma patients also had more granulocytic myeloid-derived suppressor cells (MDSCs) (p=0.003) compared to healthy blood donors, whereas monocytic MDSCs did not differ significantly (p=0.07). A superior disease-free survival was observed for cHL patients who had an increase in the percentage of granulocytic MDSCs (p=0.04). Conclusions: An altered profile of immune cells in the peripheral blood with a decrease in T-cells and regulatory NK-cells was observed in newly diagnosed lymphoma patients. CHL patients with higher percentages of regulatory NK cells and higher percentages of granulocytic MDSCs might have a better outcome, although the number of patients was low.

  • 7.
    Amini, Rose-Marie
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Pathology.
    Enblad, Gunilla
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Pathology.
    Sundström, Christer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Pathology.
    Glimelius, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Patients suffering from both Hodgkin's disease and non-Hodgkin's lymphoma: a clinico-pathological and immuno-histochemical population-based study of 32 patients1997In: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 71, no 4, p. 510-516Article in journal (Refereed)
    Abstract [en]

    The occurrence of Hodgkin's disease (HD) and non-Hodgkin's lymphoma (NHL) appearing in the same individual indicates a closer relationship between the 2 diseases than previously believed. The purpose of our study was to analyze cases of HD and NHL in a defined population clinically, histopathologically and immunohistochemically to look for similarities indicating a common cellular origin. Between 1974 and 1994, 77 individuals were identified from the Swedish Cancer Registry and the National Health Care Programme for HD as potentially having both diagnoses. Thirty-two patients who had both HD and NHL were available for histo-pathological re-examination and immunohistochemical staining with CD30, CD15, LMP, p53, CD45 (LCA), CD3, CD45R0 (UCHL-1), L26, MB2 and CD45R (4KB5). The most common relation was HD preceding a high-grade malignant NHL (16 of 32 patients), unexpectedly often of T-cell phenotype (7 of 16 patients). The next common association was NHL of B-CLL type followed by HD (7 of 32 patients). At clinical presentation, the first lymphoma did not differ from lymphomas not associated with a second lymphoma, whereas the second one often appeared with a disseminated and aggressive clinical form. There was a significant correlation between the expression of p53 and LMP in first and second lymphomas. CD3 antibody was frequently expressed both in HD and NHL, whereas positivity for B-cell-related antibodies, CD30, CD15 and CD45R0, was less frequent and generally lower than previously described. The occurrence of HD and NHL in an individual is unusual. Tumour biological features common to both HD and NHL may indicate a similar cellular origin, regardless of the time interval between the diagnoses, and may contribute to the understanding of the pathogenesis of lymphoma.

  • 8.
    Amini, Rose-Marie
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Glimelius, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Gustavsson, Anita
    Ekman, Tor
    Erlanson, Martin
    Haapaniemi, Eva
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Enblad, Gunilla
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    A population-based study of the outcome for patients with first relapse of Hodgkin lymphoma2002In: European Journal of Haematology, ISSN 0902-4441, E-ISSN 1600-0609, Vol. 68, no 4, p. 225-232Article in journal (Refereed)
    Abstract [en]

    BACKGROUND:

    Our aims were to evaluate the response to salvage treatment in relation to initial treatment and to evaluate prognostic factors at the time of relapse in an unselected population of relapsing patients with Hodgkin's lymphoma (HL).

    PATIENTS AND METHODS:

    In total, 124 patients younger than 60 yr of age with initial diagnosis of HL in Sweden relapsed between 1985 and 1995.

    RESULTS:

    Fifty-eight patients relapsed after initial treatment with radiotherapy (RT) only, 62 after combination chemotherapy (CT), of whom 30 had received additional involved-field RT, and four after a short course of CT followed by extended-field RT. For 37 patients among the 58 relapsers after initial RT treated according to the recommendations of the National guidelines, the 5-yr Hodgkin-specific survival (HLS) was 85%, overall survival (OS) 73% and event-free survival (EFS) 62%, which is not inferior to survival in patients with primarily advanced stages. It was poorer in the 21 patients who initially had received RT only, even though they had been recommended for more extensive treatment. For patients initially treated with a full course (6-8 cycles) of CT the 5-yr HLS was 60%, OS 58% and EFS 22%. Bulky disease and age at diagnosis strongly affected survival in a multivariate analysis.

    CONCLUSIONS:

    Patients initially treated with RT who relapse have a favourable outcome, provided they have been treated according to the recommendations of the guidelines at the time of diagnosis. Initially bulky disease and, as a consequence, additional RT as part of the initial treatment negatively affect survival at relapse in patients initially treated with a full course of CT.

  • 9.
    Amini, Rose-Marie
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology.
    Sundström, Christer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology.
    [Core needle biopsies for lymphoma diagnosis seriously affect diagnostics, treatment development and research].2017In: Läkartidningen, ISSN 0023-7205, E-ISSN 1652-7518, Vol. 114, article id EMDHArticle in journal (Refereed)
    Abstract [sv]

    Core needle biopsies for lymphoma diagnosis seriously affect diagnostics, treatment development and research Core needle biopsies (CNBs) are widely used in clinical diagnostic labs to aid in the diagnosis of malignant lymphomas and in latter years their use is increasing. CNBs provide a rapid method for obtaining tumour material and may be beneficial when the affected lymph nodes are located deep in the abdominal cavity or mediastinum and surgical excisional biopsies may be difficult to perform. However, according to the Swedish Haematopathology Quality and Standardization Committee, CNBs are insufficient for lymphoma diagnostic purposes and the guidelines state that material from surgical excisional biopsies are mandatory in order to obtain a robust histopathological evaluation of the lymph node architecture, cellular composition and growth pattern. Surgical excision biopsies also ensure that adequate material is available if additional molecular analyses should be required and also to facilitate future research.

  • 10.
    Apollonio, Benedetta
    et al.
    Kings Coll London, Dept Haematooncol, London WC2R 2LS, England..
    Nicholas, Nicole S.
    Kings Coll London, Dept Haematooncol, London WC2R 2LS, England..
    Sutton, Lesley-Ann
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Salisbury, Jon
    Kings Coll Hosp London, London, England..
    Patten, Piers E.
    Kings Coll Hosp London, Haematol, London, England..
    Kassam, Shireen
    Kings Coll Hosp London, London, England..
    Devereux, Stephen
    Kings Coll Hosp London, Haematol, London, England..
    Amini, Rose Marie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Rosenquist, Richard
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Ramsay, Alan G.
    Kings Coll London, Dept Haematooncol, London WC2R 2LS, England..
    Diffuse Large B-Cell Lymphoma (DLBCL) Tumor Cells Reprogram Lymphatic Fibroblasts into Cancer-Associated Fibroblasts (CAFs) That Contribute to Tumor Microenvironment (TME)-Driven Immune Privilege2015In: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 126, no 23Article in journal (Other academic)
  • 11.
    Baliakas, Panagiotis
    et al.
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Uppsala Univ Hosp, Dept Clin Genet, Uppsala, Sweden.
    Kättström, Magdalena
    Orebro Univ Hosp, Dept Med, Sect Hematol, Orebro, Sweden.
    Rossing, Maria
    Copenhagen Univ Hosp, Ctr Genom Med, Copenhagen, Denmark.
    Amini, Rose-Marie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology.
    Refractory chronic "ITP": When platelet size matters2018In: Clinical Case Reports, E-ISSN 2050-0904, Vol. 6, no 9, p. 1779-1780Article in journal (Refereed)
    Abstract [en]

    Key Clinical Message Inherited conditions associated with thrombocytopenia should be included in the differential diagnosis of young patients with refractory immune thrombocytopenia (ITP), even in the absence of a positive family history. Early identification of such conditions is of vital importance in order to reach the right diagnosis and avoid unnecessary or even harmful medication.

  • 12.
    Bergfelt, Emma
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Kozlowski, P.
    Ahlberg, L.
    Hulegardh, E.
    Hägglund, H.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Karlsson, K.
    Markuszewska-Kuczymska, A.
    Tomaszewska-Toporska, B.
    Smedmyr, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Astrom, M.
    Amini, Rose Marie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology.
    Hallböök, Helene
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Minimal Residual Disease in Adults with Philadelphia Negative B-Cell Precursor Acute Lymphoblastic Leukemia a Swedish Population-Based Study2014In: Haematologica (online), ISSN 0390-6078, E-ISSN 1592-8721, Vol. 99, no S1, p. 279-280Article in journal (Other academic)
  • 13.
    Bergfelt, Emma
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Kozlowski, Piotr
    Ahlberg, Lucia
    Hulegardh, Erik
    Hagglund, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Karlsson, Karin
    Markuszewska-Kuczymska, Alicja
    Tomaszewska-Toporska, Beata
    Smedmyr, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Astrom, Maria
    Amini, Rose-Marie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Hallböök, Hélene
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Satisfactory outcome after intensive chemotherapy with pragmatic use of minimal residual disease (MRD) monitoring in older patients with Philadelphia-negative B cell precursor acute lymphoblastic leukaemia: a Swedish registry-based study2015In: Medical Oncology, ISSN 1357-0560, E-ISSN 1559-131X, Vol. 32, no 4, article id 135Article in journal (Refereed)
    Abstract [en]

    The introduction of minimal residual disease (MRD) monitoring, in the Swedish national guidelines for acute lymphoblastic leukaemia, was evaluated in 35 patients aged 46-79 years (median 61), who were diagnosed from 2007 to 2011 and treated with high-intensity, block-based chemotherapy (ABCDV/VABA induction). Both a high complete remission rate (91 %) and acceptable overall survival (OS) rate (47 %) at 5 years were achieved. MRD by flow cytometry was measured in 73 % of the patients reaching complete remission after the first course, but was omitted by the clinicians for eight patients who were either over 70 years of age or already met conventional high-risk criteria. Factors negatively influencing OS were age over 65 years and WHO status >= 2. MRD < 0.1 % after induction had positive impact on continuous complete remission but not on OS. Only five patients were allocated to allogeneic haematopoietic stem cell transplantation in first remission, mainly due to conventional high risk factors. Thus, use of intensive remission induction therapy is effective in a selection of older patients. In a population for whom the possibilities of treatment escalation are limited, the optimal role of MRD monitoring remains to be determined.

  • 14.
    Berglund, Mattias
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Amini, Rose-Marie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology.
    Enblad, Gunilla
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Thunberg, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Is the rs10484561 SNP responsible for differences in age at diagnosis, transformation and death of patients with follicular lymphoma?2013In: International Journal of Hematologic Oncology, ISSN 2045-1407, Vol. 2, no 5, p. 391-396Article, review/survey (Refereed)
    Abstract [en]

    Aim:

    To analyze follicular lymphoma (FL) patients by determining the genotype at SNP rs10484561 (T or G) and comparing the polymorphism with overall survival, time to transformation, time from transformation to death, and age both dependently and independently of gender.

    Materials & methods:A total of 94 patients with FL diagnosed between 1970 and 2000 from a Swedish population were analyzed by PCR–restriction fragment length polymorphism to determine genotypes for rs10484561.

    Results:

    We found that women with FL and the TT genotype of SNP rs10484561 were older at diagnosis, transformation and when they died (p = 0.03, 0.01 and 0.02, respectively) and had a significantly shorter overall survival (p = 0.04) compared with women with the TG or GG genotypes.

    Conclusion:

    It is possible that the SNP rs10484561 polymorphism is responsible for differences in age at diagnosis, transformation and death for patients with follicular lymphoma, particularly in women.

  • 15.
    Berglund, Mattias
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Hedström, Gustaf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Amini, Rose-Marie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology.
    Enblad, Gunilla
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Thunberg, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    High expression of microRNA-200c predicts poor clinical outcome in diffuse large B-cell lymphoma2013In: Oncology Reports, ISSN 1021-335X, E-ISSN 1791-2431, Vol. 29, no 2, p. 720-724Article in journal (Refereed)
    Abstract [en]

    Diffuse large B-cell lymphoma (DLBCL) is a heterogeneous group of B-cell lymphomas. A new and important tool for understanding the biology and clinical course of DLBCL is microRNA expression. This study presents microRNA-200c expression data from 61 DLBCL patients treated with CHOP or R-CHOP. Patients with high microRNA-200c expression had a median survival of 20.3 months and a significantly shorter overall survival (P=0.019) compared to patients with low microRNA-200c expression, who had a median survival of 35.8 months. We also found that patients treated with R-CHOP only and displaying high microRNA-200c expression had a significantly shorter overall survival compared to patients with low microRNA-200c expression, where all patients were still alive at the time of the last follow-up (P=0.0036). Lastly, we found that patients with high microRNA-200c expression had a significantly shorter time from initial diagnosis to the first relapse compared to patients with low microRNA-200c expression (P=0.0001). To our knowledge, this is the first study showing that the expression of microRNA-200c affects the clinical outcome of DLBCL patients, and that microRNA-200c is involved in the biology of DLBCL development, although larger studies are necessary to confirm this. Further investigations may also help to elucidate the biological role of microRNA-200c in DLBCL.

  • 16. Borgquist, Signe
    et al.
    Zhou, Wenjing
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Jirstrom, Karin
    Amini, Rose-Marie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Sollie, Thomas
    Sorlie, Therese
    Blomqvist, Carl
    Butt, Salma
    Wärnberg, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    The prognostic role of HER2 expression in ductal breast carcinoma in situ (DCIS); a population-based cohort study2015In: BMC Cancer, ISSN 1471-2407, E-ISSN 1471-2407, Vol. 15, article id 468Article in journal (Refereed)
    Abstract [en]

    Background: HER2 is a well-established prognostic and predictive factor in invasive breast cancer. The role of HER2 in ductal breast carcinoma in situ (DCIS) is debated and recent data have suggested that HER2 is mainly related to in situ recurrences. Our aim was to study HER2 as a prognostic factor in a large population based cohort of DCIS with long-term follow-up. Methods: All 458 patients diagnosed with a primary DCIS 1986-2004 in two Swedish counties were included. Silver-enhanced in situ hybridisation (SISH) was used for detection of HER2 gene amplification and protein expression was assessed by immunohistochemistry (IHC) in tissue microarrays. HER2 positivity was defined as amplified HER2 gene and/or HER2 3+ by IHC. HER2 status in relation to new ipsilateral events (IBE) and Invasive Breast Cancer Recurrences, local or distant (IBCR) was assessed by Kaplan-Meier survival analyses and Cox proportional hazards regression models. Results: Primary DCIS was screening-detected in 75.5 % of cases. Breast conserving surgery (BCS) was performed in 78.6 % of whom 44.0 % received postoperative radiotherapy. No patients received adjuvant endocrine-or chemotherapy. The majority of DCIS could be HER2 classified (N = 420 (91.7 %)); 132 HER2 positive (31 %) and 288 HER2 negative (69 %)). HER2 positivity was related to large tumor size (P = 0.002), high grade (P < 0.001) and ER-and PR negativity (P < 0.001 for both). During follow-up (mean 184 months), 106 IBCRs and 105 IBEs were identified among all 458 cases corresponding to 54 in situ and 51 invasive recurrences. Eighteen women died from breast cancer and another 114 had died from other causes. The risk of IBCR was statistically significantly lower subsequent to a HER2 positive DCIS compared to a HER2 negative DCIS, (Log-Rank P = 0.03, (HR) 0.60 (95 % CI 0.38-0.94)). Remarkably, the curves did not separate until after 10 years. In ER-stratified analyses, HER2 positive DCIS was associated with lower risk of IBCR among women with ER negative DCIS (Log-Rank P = 0.003), but not for women with ER positive DCIS. Conclusions: Improved prognostic tools for DCIS patients are warranted to tailor adjuvant therapy. Here, we demonstrate that HER2 positive disease in the primary DCIS is associated with lower risk of recurrent invasive breast cancer.

  • 17. Borgquist, Signe
    et al.
    Zhou, Wenjing
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Jirstrom, Karin
    Amini, Rose-Marie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Sollie, Thomas
    Sorlie, Therese
    Butt, Saima
    Blomqvist, Carl
    Wärnberg, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    The prognostic role of HER2 expression in ductal breast carcinoma in situ2015In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 75, no 9, article id P6-13-03Article in journal (Other academic)
  • 18.
    Bremer, Troy
    et al.
    PreludeDx, 26051 Merit Circle Suite 102, Laguna Hills, CA 92653 USA.
    Whitworth, Pat W.
    Nashville Breast Ctr, Nashville, TN USA.
    Patel, Rakesh
    Good Samaritan Canc Ctr, Los Gatos, CA USA.
    Savala, Jess
    PreludeDx, 26051 Merit Circle Suite 102, Laguna Hills, CA 92653 USA.
    Barry, Todd
    Spectrum Pathol Inc, Mission Viejo, CA USA.
    Lyle, Stephen
    Univ Massachusetts, Sch Med, Worcester, MA USA.
    Leesman, Glen
    PreludeDx, 26051 Merit Circle Suite 102, Laguna Hills, CA 92653 USA.
    Linke, Steven P.
    Steven P Linke Consulting, Carlsbad, CA USA.
    Jirstrom, Karin
    Lund Univ, Div Oncol & Pathol, Dept Clin Sci, Lund, Sweden.
    Zhou, Wenjing
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Amini, Rose-Marie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology.
    Wärnberg, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    A Biological Signature for Breast Ductal Carcinoma In Situ to Predict Radiotherapy Benefit and Assess Recurrence Risk2018In: Clinical Cancer Research, ISSN 1078-0432, E-ISSN 1557-3265, Vol. 24, no 23, p. 5895-5901Article in journal (Refereed)
    Abstract [en]

    Purpose: Ductal carcinoma in situ (DCIS) patients and their physicians currently face challenging treatment decisions with limited information about the individual's subsequent breast cancer risk or treatment benefit. The DCI-SionRT biological signature developed in this study provides recurrence risk and predicts radiotherapy (RT) benefit for DCIS patients following breast-conserving surgery (BCS). Experimental Design: A biological signature that calculates an individualized Decision Score (DS) was developed and cross-validated in 526 DCIS patients treated with BCS = RT. The relationship was assessed between DS and 10-year risk of invasive breast cancer (IBC) or any ipsilateral breast event (IBE), including IBC or DCIS. RT benefit was evaluated by risk group and as a function of DS. Results: The DS was significantly associated with IBC and IBE risk, HR (per 5 units) of 4.2 and 3.1, respectively. For patients treated without RT, DS identified a Low Group with 10-year IBC risk of 4% (7% IBE) and an Elevated Risk Group with IBC risk of 15% (23% IBE). In analysis of DS and RT by group, the Elevated Risk Group received significant RT benefit, HR of 0.3 for IBC and IBE. In a clinicopathologically low-risk subset, DS reclassified 42% of patients into the Elevated Risk Group. In an interaction analysis of DS and RT, patients with elevated DS had significant RT benefit over baseline. Conclusions: The DS was prognostic for risk and predicted RT benefit for DCIS patients. DS identified a clinically meaningful low-risk group and a group with elevated 10-year risks that received substantial RT benefit over baseline.

  • 19. Butt, Salma
    et al.
    Butt, Talha
    Jirstrom, Karin
    Hartman, Linda
    Amini, Rose-Marie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Zhou, Wenjing
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Wärnberg, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Borgquist, Signe
    The Target for Statins, HMG-CoA Reductase, Is Expressed in Ductal Carcinoma-In Situ and May Predict Patient Response to Radiotherapy2014In: Annals of Surgical Oncology, ISSN 1068-9265, E-ISSN 1534-4681, Vol. 21, no 9, p. 2911-2919Article in journal (Refereed)
    Abstract [en]

    Background. Patients with ductal carcinoma-in-situ (DCIS) are currently not prescribed adjuvant systemic treatment after surgery and radiotherapy. Prediction of DCIS patients who would benefit from radiotherapy is warranted. Statins have been suggested to exert radio-sensitizing effects. The target for cholesterol-lowering statins is HMG-CoA reductase (HMGCR), the rate-limiting enzyme in the mevalonate pathway. The aim of this study was to examine HMGCR expression in DCIS and study its treatment predictive value. Methods. A population-based cohort including 458 women diagnosed with primary DCIS between 1986 and 2004 were followed until November 2011 to study long-term survival. Tumor tissue microarrays were constructed, and immunohistochemical analyses were performed to detect cytoplasmic protein expression of HMGCR. The association between DCIS HMGCR expression and invasive breast cancer recurrence-free survival (RFSinv) and overall survival (OS) was analyzed by Kaplan-Meier curves, log rank test, and Cox proportional hazard analysis. Results. HMGCR was strongly expressed in 24 % of the assessed DCIS samples, moderately expressed in 46 %, and weakly expressed in 23 %; no expression was detected in 7 % of the samples. During the follow-up time (median 13.8 years), 61 patients were diagnosed with an invasive breast cancer recurrence, and 80 patients died. A crude analysis showed no survival benefit from radiotherapy. However, patients with strong HMGCR expression showed an improved RFSinv (log rank, p = 0.03) and OS (log rank, p = 0.04) after radiotherapy. No statistically significant interaction was observed for HMGCR and radiotherapy (RFSinv p = 0.69 and OS p = 0.29). Conclusions. This study demonstrates HMGCR expression in DCIS and suggests HMGCR as a predictive marker of response to postoperative radiotherapy in DCIS, although the test for interaction was nonsignificant. Future DCIS studies addressing the potential of statin treatment targeting HMGCR are warranted.

  • 20. Caramuta, S.
    et al.
    Lee, L.
    Ozata, D. M.
    Akcakaya, P.
    Georgii-Hemming, Patrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Genetics.
    Xie, H.
    Amini, Rose Marie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology.
    Lawrie, C. H.
    Enblad, G.
    Larsson, C.
    Berglund, M.
    Lui, W-O
    Role of microRNAs and microRNA machinery in the pathogenesis of diffuse large B-cell lymphoma2013In: Blood Cancer Journal, ISSN 2044-5385, E-ISSN 2044-5385, Vol. 3, p. e152-Article in journal (Refereed)
    Abstract [en]

    Deregulation of microRNA (miRNA) expression has been documented in diffuse large B-cell lymphoma (DLBCL). However, the impact of miRNAs and their machinery in DLBCL is not fully determined. Here, we assessed the role of miRNA expression and their processing genes in DLBCL development. Using microarray and RT-qPCR approaches, we quantified global miRNAs and core components of miRNA-processing genes expression in 75 DLBCLs (56 de novo and 19 transformed) and 10 lymph nodes (LN). Differential miRNA signatures were identified between DLBCLs and LNs, or between the de novo and transformed DLBCLs. We also identified subsets of miRNAs associated with germinal center B-cell phenotype, BCL6 and IRF4 expression, and clinical staging. In addition, we showed a significant over-expression of TARBP2 in de novo DLBCLs as compared with LNs, and decreased expression of DROSHA, DICER, TARBP2 and PACT in transformed as compared with de novo cases. Interestingly, cases with high TARBP2 and DROSHA expression had a poorer chemotherapy response. We further showed that TARBP2 can regulate miRNA-processing efficiency in DLBCLs, and its expression inhibition decreases cell growth and increases apoptosis in DLBCL cell lines. Our findings provide new insights for the understanding of miRNAs and its machinery in DLBCL.

  • 21.
    Dahlin, Joakim S.
    et al.
    Karolinska Univ Hosp, Karolinska Inst, Dept Med, Stockholm, Sweden..
    Ekoff, Maria
    Karolinska Univ Hosp, Karolinska Inst, Dept Med, Stockholm, Sweden..
    Grootens, Jennine
    Karolinska Univ Hosp, Karolinska Inst, Dept Med, Stockholm, Sweden..
    Löf, Liza
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular tools. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Amini, Rose-Marie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology.
    Hagberg, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Ungerstedt, Johanna S.
    Karolinska Inst, Dept Med Huddinge, Stockholm, Sweden.;Karolinska Univ Hosp, Hematol Ctr, Stockholm, Sweden..
    Olsson-Strömberg, Ulla
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Nilsson, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology. Karolinska Univ Hosp, Karolinska Inst, Dept Med, Stockholm, Sweden.
    KIT signaling is dispensable for human mast cell progenitor development2017In: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 130, no 16, p. 1785-1794Article in journal (Refereed)
    Abstract [en]

    Human hematopoietic progenitors are generally assumed to require stem cell factor (SCF) and KIT signaling during differentiation for the formation of mast cells. Imatinib treatment, which inhibits KIT signaling, depletes mast cells in vivo. Furthermore, the absence of SCF or imatinib treatment prevents progenitors from developing into mast cells in vitro. However, these observations do not mean that mast cell progenitors require SCF and KIT signaling throughout differentiation. Here, we demonstrate that circulating mast cell progenitors are present in patients undergoing imatinib treatment. In addition, we show that mast cell progenitors from peripheral blood survive, mature, and proliferate without SCF and KIT signaling in vitro. Contrary to the prevailing consensus, our results show that SCF and KIT signaling are dispensable for early mast cell development.

  • 22.
    Enblad, Gunilla
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Karlsson, Hannah
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Gammelgård, Gustav
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Wenthe, Jessica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Lövgren, Tanja
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Amini, Rose-Marie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology.
    Wikstrom, Kristina I.
    Karolinska Univ Hosp Huddinge, VECURA, Stockholm, Sweden.
    Essand, Magnus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Savoldo, Barbara
    Baylor Coll Med, Ctr Cell & Gene Therapy, Houston, TX 77030 USA.
    Hallböök, Helene
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Höglund, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Dotti, Gianpietro
    Baylor Coll Med, Ctr Cell & Gene Therapy, Houston, TX 77030 USA.
    Brenner, Malcolm K.
    Baylor Coll Med, Ctr Cell & Gene Therapy, Houston, TX 77030 USA.
    Hagberg, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Loskog, Angelica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    A Phase I/IIa Trial Using CD19-Targeted Third-Generation CAR T Cells for Lymphoma and Leukemia2018In: Clinical Cancer Research, ISSN 1078-0432, E-ISSN 1557-3265, Vol. 24, no 24, p. 6185-6194Article in journal (Refereed)
    Abstract [en]

    Purpose: The chimeric antigen receptor (CAR) T-cell therapy has been effective for patients with CD19(+) B-cell malignancies. Most studies have investigated the second-generation CARs with either CD28 or 4-1BB costimulatory domains in the CAR receptor. Here, we describe the first clinical phase I/IIa trial using third-generation CAR T cells targeting CD19 to evaluate safety and efficacy.

    Patients and Methods: Fifteen patients with B-cell lymphoma or leukemia were treated with CAR T cells. The patients with lymphoma received chemotherapy during CAR manufacture and 11 of 15 were given low-dose cyclophosphamide and fludarabine conditioning prior to CAR infusion. Peripheral blood was sampled before and at multiple time points after CAR infusion to evaluate the persistence of CAR T cells and for immune profiling, using quantitative PCR, flow cytometry, and a proteomic array.

    Results: Treatment with third-generation CAR T cells was generally safe with 4 patients requiring hospitalization due to adverse reactions. Six of the 15 patients had initial complete responses [4/11 lymphoma and 2/4 acute lymphoblastic leukemia (ALL)], and 3 of the patients with lymphoma were in remission at 3 months. Two patients are still alive. Best predictor of response was a good immune status prior to CAR infusion with high IL12, DC-Lamp, Fas ligand, and TRAIL. Responding patients had low monocytic myeloid-derived suppressor cells (MDSCs; CD14(+)CD33(+)HLA(-)DR(-)) and low levels of IL6, IL8, NAP3, sPDL1, and sPDL2.

    Conclusions: Third-generation CARs may be efficient in patients with advanced B-cell lymphoproliferative malignancy with only modest toxicity. Immune profiling pre- and posttreatment can be used to find response biomarkers.

  • 23.
    Enblad, Gunilla
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Martinsson, Gustaf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Baecklund, Eva
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.
    Hesselager, Göran
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Sundström, Christer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology.
    Amini, Rose-Marie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology.
    Hagberg, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Population-based experience on primary central nervous system lymphoma 2000-2012: the incidence is increasing2017In: Acta Oncologica, ISSN 0284-186X, E-ISSN 1651-226X, Vol. 56, no 4, p. 599-607Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Primary central nervous system lymphomas (PCNSL) are rare lymphomas with a poor prognosis. Recently, an increased incidence has been reported. The present study is a population-based study of all patients with PCNSL in the Uppsala/Örebro region of middle Sweden.

    PATIENTS AND METHODS: All patients diagnosed with a PCNSL at Uppsala University Hospital 2000-2012 were identified. Altogether, 96 patients (50 women and 46 men) were included. The median age at diagnosis was 66 years (17-95).

    RESULTS: There was a statistically significant increase in age-standardized incidence during the study period, 30 patients were diagnosed in the first half and 66 in the second half of the period. No patient had an HIV-infection. Two patients had undergone kidney transplantation and were treated with immunosuppressive drugs. A high proportion of the patients, 29%, had a history of an autoimmune or inflammatory disease. The prognosis was poor with a median survival of only four months. In the 70 (73%) patients treated with curative intention the median survival was 12 months. Patients treated with high-dose methotrexate, radiotherapy and/or temozolomide appeared to have a better survival. There was no improvement in survival during the study period or after the introduction of rituximab. There also was no difference in any of the analyzed variables that could explain the increased incidence.

    CONCLUSION: In this population-based study we could confirm the previously described increased incidence of PCNSL. The prognosis remains poor despite the inclusion of treatment with rituximab during the study period. A high proportion of the patients had a history of an autoimmune or inflammatory disease not previously described but there was no increase during the study period.

  • 24.
    Englund, Annika
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Pediatrics.
    Molin, Daniel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Enblad, Gunilla
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Karlén, Jonas
    Karolinska Inst, Dept Womens & Childrens Hlth, Stockholm, Sweden.
    Glimelius, Ingrid
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Ljungman, Gustaf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Pediatrics.
    Amini, Rose-Marie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology.
    The role of tumour-infiltrating eosinophils, mast cells and macrophages in Classical and Nodular Lymphocyte Predominant Hodgkin Lymphoma in children2016In: European Journal of Haematology, ISSN 0902-4441, E-ISSN 1600-0609, Vol. 97, no 5, p. 430-438Article in journal (Refereed)
    Abstract [en]

    OBJECTIVES: To study Hodgkin lymphoma (HL) microenvironment in a Swedish paediatric population and its relation to clinical parameters.

    METHODS: Tumour tissue from classical HL (cHL) (n=87) and nodular lymphocyte predominant HL (NLPHL) (n=11) was investigated for Epstein-Barr Virus (EBV) and analysed for eosinophils, mast cells and macrophages.

    RESULTS: In cHL, EBV positivity was more common in low age (p<0.001) and in mixed cellularity (MC) (p<0.001). Higher mast cell infiltration was seen in stage III-IV (p<0.001), and with presence of B-symptoms (p=0.01). Cases with high mast cell counts displayed higher erythrocyte sedimentation rate (ESR), lower haemoglobin and albumin levels. Higher macrophage infiltration was seen in stage III-IV (p=0.02) and there was elevated ESR and neutrophil count. All NLPHL cases were EBV negative, had lower rates of inflammatory cells and lower degree of inflammatory reaction in laboratory parameters. There was no difference in survival estimates with regard to infiltration of inflammatory cells.

    CONCLUSIONS: Higher levels of mast cells and macrophages in cHL tumours reflected the clinical presentation in laboratory parameters, B-symptoms and more advanced stages. NLPHL differs from cHL in numbers of inflammatory cells in the tumour, and in laboratory parameters. This article is protected by copyright. All rights reserved.

  • 25.
    Gholiha, Alex R.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Hollander, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology.
    Hedström, Gustaf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Sundström, Christer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology.
    Molin, Daniel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Smedby, Karin E
    Karolinska Inst, Dept Med Solna, Div Clin Epidemiol, Stockholm, Sweden.
    Hjalgrim, Henrik
    Karolinska Inst, Dept Med Solna, Div Clin Epidemiol, Stockholm, Sweden.
    Glimelius, Ingrid
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Amini, Rose-Marie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology.
    Enblad, Gunilla
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    High tumour plasma cell infiltration reflects an important microenvironmental component in classic Hodgkin lymphoma linked to presence of B-symptoms2019In: British Journal of Haematology, ISSN 0007-1048, E-ISSN 1365-2141, Vol. 184, no 2, p. 192-201Article in journal (Refereed)
    Abstract [en]

    Plasma cells are important prognostic actors in different malignancies. The tumour microenvironmental composition in classic Hodgkin lymphoma (cHL) is a major prognostic key element; however, clinicopathological studies regarding plasma cells in cHL are lacking. The aim of this study was to investigate CD138+ (also termed SDC1+) plasma cell and IgG4 producing (IgG4+) plasma cells infiltration in the microenvironment of cHL. Immunohistochemistry with anti-CD138 and IgG4 antibodies was performed on diagnostic tumour biopsies from 124 patients with cHL, on tissue micro array (TMA). In 120 cases, CD138+ plasma cell-infiltration was associated with the presence of B-symptoms (P = 0·028) and advanced stage, IIB-IVB (P = 0·009). In multivariate analysis, CD138+ plasma cells correlated with eosinophil infiltration (P = 0·013). The subgroup of IgG4+ plasma cells was analysed in 122 cases and only correlated to CD138+ plasma cells (P = 0·004). Patients with high proportion of tumour infiltrating CD138+ plasma cells (defined as ≥10%), had a more inferior event-free survival (P = 0·007) and overall survival (P = 0·004) than patients with a low proportion of infiltrating CD138+ plasma cells (<10%), although significance was not maintained in multivariate analysis. In summary, a high proportion of tumour-associated plasma cells in cHL reflect an important component in the microenvironment of cHL.

  • 26.
    Glimelius, Ingrid
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Oncology.
    Edström, Annika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Amini, Rose-Marie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Fischer, Marie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Nilsson, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Sundström, Christer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Enblad, Gunilla
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Oncology.
    Molin, Daniel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Oncology.
    IL-9 expression contributes to the cellular composition in Hodgkin lymphoma2006In: European Journal of Haematology, ISSN 0902-4441, E-ISSN 1600-0609, Vol. 76, no 4, p. 278-283Article in journal (Refereed)
    Abstract [en]

    OBJECTIVES:

    The presence of numerous mast cells or eosinophils in Hodgkin lymphoma (HL) tumours have both been described as negative prognostic factors. One cytokine related to HL is interleukin-9 (IL-9) and it is known to affect both mast cells and eosinophils. The aim of this study was to explore if the expression of IL-9 correlates to the presence of these inflammatory cells in HL tumours.

    METHODS:

    In 131 HL biopsies, immunostainings for IL-9 and IL-9 receptor (IL-9R) were performed. The same material was previously stained for mast cells and eosinophils. These data were correlated to clinical and survival data from all patients.

    RESULTS:

    Fifty-three percent of cases were positive for IL-9 and 19% were positive for IL-9R in the cytoplasm of the tumour cells. The IL-9 positive patients had more eosinophils (P = 0.002) and mast cells (P = 0.02) in their tumours, more often a nodular sclerosis histology (P < 0.0001), a higher white-blood-cell count (P = 0.006) and a higher erythrocyte sedimentation rate (P = 0.003) at the time of diagnosis.

    CONCLUSIONS:

    IL-9 expression is related to the histology, clinical picture and the presence of eosinophils and mast cells in HL. These results indicate that IL-9 is an important part of the cytokine network and inflammatory infiltrate in HL.

  • 27.
    Glimelius, Ingrid
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Oncology.
    Edström, Annika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Fischer, Marie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Nilsson, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Sundström, Christer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Molin, Daniel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Oncology.
    Amini, Rose-Marie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Enblad, Gunilla
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Oncology.
    Angiogenesis and mast cells in Hodgkin lymphoma2005In: Leukemia, ISSN 0887-6924, E-ISSN 1476-5551, Vol. 19, no 12, p. 2360-2362Article in journal (Refereed)
  • 28.
    Glimelius, Ingrid
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Qvarnström, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Simonsson, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Ekwall, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Smedby, Karin E
    Molin, Daniel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Amini, Rose-Marie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology.
    Tissue microarray and digital image analysis: a methodological study with special reference to the microenvironment in Hodgkin lymphoma2012In: Histopathology, ISSN 0309-0167, E-ISSN 1365-2559, Vol. 61, no 1, p. 26-32Article in journal (Refereed)
    Abstract [en]

    Aim:  Cancer research has moved from solely investigating the tumour cells to also including analysis of the tumour microenvironment; however, the methods utilized have not been evaluated for this change. The aim of this study was to compare tissue microarrays (TMA) to whole tissue sections (WS) with regard to cells in the tumour microenvironment. Manual evaluation and digital image analyses (DIA) were utilized and also compared.

    Methods and results:  TMA slides from 117 Hodgkin lymphoma patients were immunostained for forkhead box protein 3 (FoxP3) [identifying regulatory T cells (T(reg) )], and 39 corresponding WS were also analysed. Manual evaluation and DIA were utilized for all patients on both the TMA and the WS. A correlation coefficient of 0.83 was obtained for the proportion of T(reg) in TMA versus WS using manual evaluation and a correlation coefficient of 0.77 with DIA. T(reg) counts using manual evaluation correlated in turn with DIA, with a coefficient of 0.79 for the 117 TMA sections and 0.65 for the 39 WS.

    Conclusion:  Because a high correlation was observed between TMA and WS, TMA can be utilized when evaluating cells in the tumour microenvironment. DIA appears to provide a reliable measurement method, provided that manual control of the tumour slides is conducted.

  • 29.
    Glimelius, Ingrid
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Rubin, Jenny
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Biochemial structure and function.
    Fischer, Marie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Molin, Daniel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Amini, Rose-Marie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology.
    Venge, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Biochemial structure and function.
    Enblad, Gunilla
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    The effect of Eosinophil cationic protein (ECP) on Hodgkin lymphoma cell lines2011In: Experimental Hematology, ISSN 0301-472X, E-ISSN 1873-2399, Vol. 39, no 8, p. 850-858Article in journal (Refereed)
    Abstract [en]

    Background In classical Hodgkin lymphoma (HL), many eosinophils in tumour tissue indicate poor prognosis, probably caused by stimulation of the tumour cells, the Hodgkin Reed Sternberg (HRS) cells. However, eosinophils are primarily known for their role in innate immunity, where one function is to secrete the toxic substances eosinophil cationic protein (ECP), and eosinophil protein X (EPX). The aim of this study was to investigate the effects of ECP on HRS cells in vitro.

    Method The fluorometric microculture cytotoxicity-assay (FMCA) measured survival index (SI) of cells from the HL cell lines HDLM-2, KMH2, and L428 after incubation with ECP or EPX. The gene products of a coding ECP polymorphism, ECP97arg and ECP97thr, and ECPs, with different levels of glycosylation were investigated. Flow cytometry was used to monitor the effects of ECP on markers of cell death.

    Results A concentration dependent reduction of SI was seen after ECP treatment. For the B-cell derived cell lines, KMH2 and L428, ECP was cytotoxic with a dose response relationship similar to a previously investigated small-cell lung cancer cell-line. In contrast, for HDLM-2, which is a cell line of T-cell origin, the cytotoxicity was even more pronounced at the lowest concentrations tested, and then reached a plateau at about 0.018µM. At a concentration of 0.14µM of ECP, an SI of 71%±1.9 was recorded for HDLM-2, which did not accentuate despite higher concentrations of ECP. ECP97arg and ECP97thr displayed similar cytotoxicity, and the level of glycosylation did not affect cytotoxicity for HDLM-2, in contrast to the small-cell lung cancer cell-line. For EPX, no or very limited reduction in SI was seen, compared to ECP (p<0.001). The majority of cells that died from ECP (the HDLM-2 cell line) were PI positive, and only a few were annexin V positive.

    Conclusions ECP is cytotoxic for HRS cells, but heterogeneity between cell lines was seen. The two cell lines of B-cell origin, KMH2 and L428, were sensitive to high ECP concentrations, but for HDLM-2, of T-cell origin, the cytotoxicity reached a plateau at higher concentrations. Thus, even at presumably high concentrations, ECP can be present around HRS cells without eradicating all cells.

  • 30.
    Glimelius, Ingrid
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Rubin, Jenny
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Rostgaard, Klaus
    Department of Epidemiology Research, Statens Serum Institut, Denmark.
    Amini, Rose Marie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Simonsson, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Sorensen, Karina Meden
    Department of Clinical Biochemistry and Immunology, Statens Serum Institut, Denmark.
    Ekström-Smedby, Karin
    Unit of Clinical Epidemiology, Department of Medicine, Karolinska Institut, Sweden.
    Venge, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Hjalgrim, Henrik
    Department of Epidemiology Research, Statens Serum Institut, Denmark.
    Molin, Daniel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Enblad, Gunilla
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Predictors of histology, tissue eosinophilia and mast cell infiltration in Hodgkin's Lymphoma: a population-based study2011In: European Journal of Haematology, ISSN 0902-4441, E-ISSN 1600-0609, Vol. 87, no 3, p. 208-216Article in journal (Refereed)
    Abstract [en]

    Objective:  Classical Hodgkin’s lymphoma (HL) lesions comprise few tumour cells, surrounded by numerous inflammatory cells. Like in other malignancies, the microenvironment is presumed to be clinically important in HL; however, microenvironment predictors remain poorly characterised. The aim of this study was to investigate how selected patient characteristics and genetic factors affect HL phenotype, in particular tissue eosinophilia, mast cell counts and HL histological subtype.

    Methods:  In a population-based study, patients with HL were interviewed about potential HL risk factors. Available tumours, n = 448, were classified histologically; the number of eosinophils and mast cells were estimated, and eosinophil cationic protein (ECP) and eosinophil protein-x (EPX) gene polymorphisms were determined. Associations were assessed in regression models.

    Results:  Self-reported history of asthma was predictive of having tumour eosinophilia [≥200 eosinophils/10 high power fields, univariate odds ratio (OR) = 2.22, 95% CI 1.06–4.64, P = 0.03]. High numbers of eosinophils were predominantly seen in patients carrying the genotype ECP434GG [multivariate relative levels (RLs) = 1.84, 95% CI 1.02–3.30, P = 0.04]. Lower number of eosinophils was seen in Epstein–Barr virus (EBV)-positive tumours (univariate RL = 0.52, 95% CI 0.3–0.9, P = 0.02) and in older patients (univariate RL = 0.85, 95% CI 0.73–0.99, P = 0.03). Well-known factors such as young age, female sex and EBV-negative status predicted nodular sclerosis histology.

    Conclusion:  The number of eosinophils in HL tumours is influenced by patient traits such as asthma, ECP genotype and EBV status. EBV status was predictive of histology.

  • 31.
    Grootens, Jennine
    et al.
    Karolinska Inst, Dept Med Solna, S-17164 Stockholm, Sweden;Karolinska Univ Hosp, S-17164 Stockholm, Sweden.
    Ungerstedt, Johanna S.
    Karolinska Inst, Dept Med Huddinge, S-14186 Stockholm, Sweden;Karolinska Univ Hosp, Hematol Ctr, S-17176 Stockholm, Sweden.
    Ekoff, Maria
    Karolinska Inst, Dept Med Solna, S-17164 Stockholm, Sweden;Karolinska Univ Hosp, S-17164 Stockholm, Sweden.
    Rönnberg, Elin
    Karolinska Inst, Dept Med Solna, S-17164 Stockholm, Sweden;Karolinska Univ Hosp, S-17164 Stockholm, Sweden.
    Klimkowska, Monika
    Karolinska Univ Hosp Huddinge, Dept Clin Pathol & Cytol, S-14186 Stockholm, Sweden.
    Amini, Rose-Marie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology.
    Arock, Michel
    Ecole Normale Super, Mol & Cellular Oncol, F-94235 Cachan, France;Hop La Pitie Salpetriere, Clin Hematol Lab, F-75013 Paris, France.
    Söderlund, Stina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Mattsson, Mattias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Nilsson, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology. Karolinska Inst, Dept Med Solna, S-17164 Stockholm, Sweden;Karolinska Univ Hosp, S-17164 Stockholm, Sweden.
    Dahlin, Joakim S.
    Karolinska Inst, Dept Med Solna, S-17164 Stockholm, Sweden;Karolinska Univ Hosp, S-17164 Stockholm, Sweden.
    Single-cell analysis reveals the KIT D816V mutation in haematopoietic stem and progenitor cells in systemic mastocytosis2019In: EBioMedicine, E-ISSN 2352-3964, Vol. 43, p. 150-158Article in journal (Refereed)
    Abstract [en]

    Background: Systemic mastocytosis (SM) is a haematological disease characterised by organ infiltration by neoplastic mast cells. Almost all SM patients have a mutation in the gene encoding the tyrosine kinase receptor KIT causing a D816V substitution and autoactivation of the receptor. Mast cells and CD34(+) haematopoietic progenitors can carry the mutation: however, in which progenitor cell subset the mutation arises is unknown. We aimed to investigate the distribution of the D816V mutation in single mast cells and single haematopoietic stem and progenitor cells.

    Methods: Fluorescence-activated single-cell index sorting and KIT D816V mutation assessment were applied to analyse mast cells and >10,000 CD34(+) bone marrow progenitors across 10 haematopoietic progenitor subsets. In vitro assays verified cell-forming potential.

    Findings: We found that in SM 60-99% of the mast cells harboured the KIT D816V mutation. Despite increased frequencies of mast cells in SM patients compared with control subjects, the haematopoietic progenitor subset frequencies were comparable. Nevertheless, the mutation could be detected throughout the haematopoietic landscape of SM patients, from haematopoietic stem cells to more lineage-primed progenitors. In addition, we demonstrate that Fc epsilon RI+ bone marrow progenitors exhibit mast cell-forming potential, and we describe aberrant CD45RA expression on SM mast cells for the first time.

    Interpretation: The KIT D816V mutation arises in early haematopoietic stem and progenitor cells and the mutation frequency is approaching 100% in mature mast cells, which express the aberrant marker CD45RA.

  • 32.
    Grönberg, Malin
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine Oncology.
    Amini, Rose-Marie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Stridsberg, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Chemistry. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Biochemical endocrinology.
    Janson, Eva Tiensuu
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine Oncology.
    Saras, Jan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine Oncology.
    Neuroendocrine markers are expressed in human mammary glands2010In: Regulatory Peptides, ISSN 0167-0115, E-ISSN 1873-1686, Vol. 160, no 1-3, p. 68-74Article in journal (Refereed)
    Abstract [en]

    Background

    Regulatory peptides have previously been detected in epithelial cells of human mammary glands. As these peptides are produced by scattered neuroendocrine cells in the epithelium of other tissues the aim of this study was to investigate whether the mammary glands express molecular markers for neuroendocrine cells.

    Material and methods

    Specimens from 28 human mammary glands were retrieved. The distribution of immunoreactive cells was determined using immunohistochemistry with antibodies versus a set of endocrine markers including peptide hormones, chromogranins/secretogranins, vesicular monoamine transporters, synaptophysin, serotonin and synaptic vesicle protein 2.

    Results

    Cells of the luminal epithelium of ducts and lobules of human mammary glands expressed vesicular monoamine transporter 2 and chromogranin B, as well as the previously reported regulatory peptides obestatin, ghrelin, adrenomedullin and apelin. Using consecutive sections, it was revealed that the immunoreactivity patterns of the regulatory peptides and vesicular monoamine transporter 2 were similar. Interestingly, immunoreactivity for secretogranin II, secretogranin III and chromogranin B was identified in myoepithelial cells. No immunoreactivity was detected for chromogranin A or synaptophysin.

    Conclusion

    Specific cells in the epithelium and myoepithelium of mammary glands express neuroendocrine markers suggesting that mammary glands may have neuroendocrine functions.

  • 33.
    Hasni, Muhammad Sharif
    et al.
    Karolinska Inst, Dept Biosci & Nutr, SE-14183 Huddinge, Sweden..
    Berglund, Mattias
    Karolinska Inst, Dept Biosci & Nutr, SE-14183 Huddinge, Sweden..
    Yakimchuk, Konstantin
    Karolinska Inst, Dept Biosci & Nutr, SE-14183 Huddinge, Sweden..
    Guan, Jiyu
    Karolinska Inst, Dept Biosci & Nutr, SE-14183 Huddinge, Sweden..
    Linderoth, Johan
    Lund Univ, Skane Univ Hosp, Div Oncol & Pathol, Dept Clin Sci, Lund, Sweden..
    Amini, Rose-Marie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology.
    Enblad, Gunilla
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Okret, Sam
    Karolinska Inst, Dept Biosci & Nutr, SE-14183 Huddinge, Sweden..
    Estrogen receptor beta 1 in diffuse large B-cell lymphoma growth and as a prognostic biomarker2017In: Leukemia and Lymphoma, ISSN 1042-8194, E-ISSN 1029-2403, Vol. 58, no 2, p. 418-427Article in journal (Refereed)
    Abstract [en]

    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.

  • 34.
    Hedström, Gustaf
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Thunberg, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Amini, Rose-Marie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology.
    Zainuddin, Norafiza
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Enblad, Gunilla
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Berglund, Mattias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    The MDM2 polymorphism SNP309 is associated with clinical characteristics and outcome in diffuse large B-cell lymphoma2014In: European Journal of Haematology, ISSN 0902-4441, E-ISSN 1600-0609, Vol. 93, no 6, p. 500-508Article in journal (Refereed)
    Abstract [en]

    Introduction: The murine double minute 2 (MDM2) gene encodes a regulatory protein of the p53 pathway. A single nucleotide polymorphism (T to G change) at position 309 (SNP309) in the promotor region of MDM2 affects the transcription activity of MDM2 and has been found to be a negative prognostic marker in several cancers. Patients and methods: In this study, the MDM2 SNP309 polymorphism was analysed in 201 patients with diffuse large B-cell lymphoma and analysed in relation to clinical characteristics and prognosis. Results: Patients homozygous for SNP309T had a significantly longer overall survival, lymphoma-specific survival and disease-free survival (P = 0.002; 0.004 and 0.006 respectively) compared to patients carrying a G allele. The longer overall survival was seen in the subgroup of patients not treated with Rituximab, however, not for Rituximab-treated patients (P = 0.01 and 0.2 respectively). The group homozygous for the T allele also had lower age at diagnosis, a tendency towards lower aaIPI and a significantly lower proportion of patients with p53 aberrations compared to the group including at least one G allele. However, the survival differences persisted even after removal of cases with known p53 aberrations from the analysis. Conclusion: Polymorphism in MDM2 SNP309 could be correlated to some clinical characteristics and for patients not treated with immunotherapy, a G allele was correlated to poor survival, whereas no survival differences were found for patients treated with Rituximab. Herewith, we provide additional information about Diffuse large B-cell Lymphoma (DLBCL) biology and highlight the importance of evaluation of molecular markers in relation to treatment.

  • 35.
    Hedström, Gustav
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Thunberg, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Berglund, Mattias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Simonsson, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Amini, Rose-Marie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology.
    Enblad, Gunilla
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Low expression of microRNA-129-5p predicts poor clinical outcome in diffuse large B cell lymphoma (DLBCL)2013In: International Journal of Hematology, ISSN 0925-5710, E-ISSN 1865-3774, Vol. 97, no 4, p. 465-471Article in journal (Refereed)
    Abstract [en]

    Diffuse large B cell lymphoma (DLBCL) is a heterogeneous group of B cell lymphomas. MicroRNA expression provides a new and interesting tool for understanding the biology and clinical course of DLBCL. The present study presents microRNA-129-5p expression data from DLBCL patients treated with CHOP or R-CHOP. Patients with low microRNA-129-5p expression had a median survival of 23 months and a significantly shorter overall survival (P = 0.0042) compared to patients with high microRNA-129-5p expression, who had a median survival of 58 months. We also found that patients treated with R-CHOP only and displaying low microRNA-129-5p expression had a significantly shorter overall survival compared to patients with high microRNA-129-5p expression; all such patients were still alive at the time of last follow-up (P = 0.043). No significant difference was found among microRNA-129-5p expression in tumor tissue, the tissue surrounding the tumor, and normal controls. To our knowledge, this is the first report to show that the expression of microRNA-129-5p can affect the clinical outcome of DLBCL patients and that microRNA-129-5p may be involved in the biology of DLBCL development, although larger studies are necessary to confirm this. Further investigations may also help to elucidate the biological role of microRNA-129-5p in DLBCL.

  • 36.
    Hollander, Peter
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Amini, Rose-Marie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology.
    Ginman, Beatrice
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Enblad, Gunilla
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Glimelius, Ingrid
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    PD-1 and PD-L1 are upregulated in paired consecutive biopsies with classical Hodgkin lymphomaManuscript (preprint) (Other academic)
    Abstract [en]

    Background: High proportions of programmed death receptor 1 (PD-1) and its ligand (PD-L1) in the microenvironment of primary classical Hodgkin lymphoma (cHL) are associated with inferior outcome. However, it is unclear how expression alter during disease progression and if treatment and a subsequent relapse affect their expression. Our aim was to study the heterogeneity of PD-1 and PD-L1 in paired biopsies from untreated and treated cHL patients

    Patients and methods: Patients with multiple biopsies with cHL were identified from three Swedish pathology departments. Eleven patients had a paired diagnostic cHL biopsy and a previous benign lymph node biopsy, which during our review were reclassified as cHL, designated as the untreated group. Thirty patients had a paired primary and a relapse biopsy, designated as the treated group. Cases were immunostained to detect PD-1+ and PD-L1+ leukocytes, and PD-L1+ Hodgkin and Reed-Sternberg (HRS) cells. Differences in expression between biopsies were tested using Wilcoxon signed rank test.

    Results: In the untreated group, 8 of 11 cases (73%) showed an increased proportion of PD-L1+ leukocytes in biopsy 2 compared to biopsy 1, while none of the markers were statistically significantly different when biopsy 1 and 2 were compared. In the treated group, 19 of 30 (63%), 22 of 30 (73%), and 18 of 30 (60%) cases showed increased proportions of PD-1+ leukocytes, PD-L1+ leukocytes and PD-L1+ HRS cells, respectively. When the primary and the relapse biopsies were compared, PD-1+ leukocytes (p=0.04), PD-L1+ leukocytes (p=0.005) and PD-L1+ HRS cells (p=0.009) were statistically significantly different.   

    Conclusion: Our findings indicate that PD-1 and PD-L1 increase both due to longer disease duration and following treatment in relapsed cHL.

  • 37.
    Hollander, Peter
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology.
    Amini, Rose-Marie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology.
    Ginman, Beatrice
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology.
    Molin, Daniel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Enblad, Gunilla
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Glimelius, Ingrid
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Expression of PD-1 and PD-L1 increase in consecutive biopsies in patients with classical Hodgkin lymphoma2018In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 13, no 9, article id e0204870Article in journal (Refereed)
    Abstract [en]

    High expression of programmed death receptor 1 (PD-1) and its ligand (PD-L1) by leukocytes in primary classical Hodgkin lymphoma (cHL) is associated with inferior outcome. However, it is unclear how expression varies during disease progression, and in the event of relapse. Our aim was to study PD-1 and PD-L1 in consecutive biopsies from untreated and treated cHL patients. We screened pathology registries from 3500 cHL patients. Eleven patients had a diagnostic cHL biopsy and a previous benign lymph node biopsy reclassified as cHL when reviewed and designated as the untreated. Thirty patients had a primary and a relapse biopsy, designated as the treated. Biopsies were immunostained to detect PD-1+ and PD-L1+ leukocytes, and PD-L1+ tumor cells. In the untreated, none of the markers were statistically significantly different when biopsies 1 and 2 were compared. In the treated, 19, 22, and 18 of 30 cases had increased proportions of PD-1+ leukocytes, PD-L1+ leukocytes and PD-L1+ tumor cells, respectively, and were all statistically significantly increased when primary and relapse biopsies were compared. PD-1 and PD-L1 most likely increase due to primary treatment with chemotherapy and radiotherapy, which could have implications regarding treatment with PD-1 inhibitors.

  • 38.
    Hollander, Peter
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology.
    Kamper, Peter
    Aarhus Univ Hosp, Dept Hematol, Aarhus, Denmark..
    Smedby, Karin Ekstrom
    Karolinska Inst, Dept Med Solna, Clin Epidemiol Unit, Stockholm, Sweden.;Karolinska Univ Hosp, Hematol Ctr, Stockholm, Sweden..
    Enblad, Gunilla
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Ludvigsen, Maja
    Aarhus Univ Hosp, Dept Hematol, Aarhus, Denmark..
    Mortensen, Julie
    Aarhus Univ Hosp, Dept Hematol, Aarhus, Denmark..
    Amini, Rose-Marie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology.
    Hamilton-Dutoit, Stephen
    Aarhus Univ Hosp, Inst Pathol, Aarhus, Denmark..
    d'Amore, Francesco
    Aarhus Univ Hosp, Dept Hematol, Aarhus, Denmark..
    Molin, Daniel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Glimelius, Ingrid
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Karolinska Inst, Dept Med Solna, Clin Epidemiol Unit, Stockholm, Sweden..
    High proportions of PD-1+ and PD-L1+ leukocytes in classical Hodgkin lymphoma microenvironment are associated with inferior outcome2017In: Blood Advances, ISSN 2473-9529, Vol. 1, no 18, p. 1427-1439Article in journal (Refereed)
    Abstract [en]

    Immune checkpoint inhibition targeting the programmed death receptor (PD)-1 pathway is a novel treatment approach in relapsed and refractory classical Hodgkin lymphoma (cHL). Identifying patients with a high risk of treatment failure could support the use of PD-1 inhibitors as front-line treatment. Our aim was to investigate the prognostic impact of PD-1, programmed death-ligand 1 (PD-L1), and PD-L2 in the tumor microenvironment in diagnostic biopsies of patients with cHL. Patients from Denmark and Sweden, diagnosed between 1990 and 2007 and ages 15 to 86 years, were included. Tissue microarray samples were available from 387 patients. Immunohistochemistry was used to detect PD-1, PD-L1, and PD-L2, and the proportions of positive cells were calculated. Event-free survival (EFS; time to treatment failure) and overall survival (OS) were analyzed using Cox proportional hazards regression. High proportions of both PD-1(+) (hazard ratio [HR], 1.77; 95% confidence interval [CI], 1.10-2.86) and PD-L1(+) (HR 5 1.89; 95% CI, 1.08-3.30) leukocytes in the microenvironment were associated with inferior EFS in a multivariate analysis (adjusted for white blood cell count >15 x 10(9)/L, hemoglobin <105 g/L, albumin <40 g/L, B symptoms, extranodal involvement, stage, bulky tumor, nodular sclerosis subtype, Epstein-Barr virus status, lymphocyte count <0.6 x 10(9)/L, sex, and country). A high proportion of PD-L1(+) leukocytes was also associated with inferior OS in a multivariate analysis (HR, 3.46; 95% CI, 1.15-10.37). This is the first study to show a correlation after multivariate analysis between inferior outcome in cHL and a high proportion of both PD-1(+) and PD-L1(+) leukocytes in the tumor microenvironment.

  • 39.
    Hollander, Peter
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Rostgaard, Klaus
    Ekström-Smedby, Karin
    Molin, Daniel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Loskog, Angelica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    de Nully Brown, Peter
    Enblad, Gunilla
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Amini, Rose-Marie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology.
    Hjalgrim, Henrik
    Glimelius, Ingrid
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    An anergic immune signature in the tumor microenvironment of classical Hodgkin lymphoma is associated with inferior outcome2018In: European Journal of Haematology, ISSN 0902-4441, E-ISSN 1600-0609, Vol. 100, no 1, p. 88-97Article in journal (Refereed)
    Abstract [en]

    Objective: The classical Hodgkin lymphoma (cHL) tumor microenvironment shows anongoing inflammatory response consisting of varying degrees of infiltrating eosinophils,mast cells, macrophages, regulatory T lymphocytes (Tregs), and activated lymphocytes surrounding the malignant cells. Herein, different immune signatures are characterized and correlated with treatment outcome.

    Methods: Tumor-infiltrating leukocytes were phenotyped in biopsies from 459 patients with cHL. Time to progression (TTP) (primary progression, relapse, or death from cHL) and overall survival were analyzed using Cox proportional hazards regression.

    Results: The leukocyte infiltration in the microenvironment was highly diverse between patients and was categorized in 4 immune signatures (active, anergic, innate, or mixed). A high proportion of Tregs (anergic) resulted in shorter TTP (median 12.9-year follow-up) in age-adjusted analyses (hazard ratio = 1.82; 95% confidence interval 1.05-3-15). Epstein-Barrvirus (EBV)-positive cases had higher proportions of macrophages and activated lymphocytes than EBV negative, but neither of those leukocytes predicted prognosis.

    Conclusions: Abundant Tregs (anergic signature) indicate a shorter TTP, particularly in younger patients. This is probably due to a reduced ability of the immune system to attack the tumor cells. Our data warrant further investigation if these suggested immune signatures could predict outcome of immunotherapy such as immune checkpoint inhibitors.

  • 40.
    Hollander, Peter
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology.
    Rostgaard, Klaus
    Statens Serum Inst, Dept Epidemiol Res, DK-2300 Copenhagen S, Denmark..
    Smedby, Karin E.
    Karolinska Inst, Dept Med Solna, Clin Epidemiol Unit, Stockholm, Sweden..
    Chang, Ellen T.
    Stanford Univ, Sch Med, Dept Hlth Res & Policy, Div Epidemiol, Stanford, CA 94305 USA.;Exponent Inc, Hlth Sci, Menlo Pk, CA USA..
    Amini, Rose-Marie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology.
    Brown, Peter de Nully
    Rigshosp, Dept Haematol, DK-2100 Copenhagen, Denmark..
    Glimelius, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Adami, Hans-Olov
    Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden.;Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA..
    Melbye, Mads
    Stanford Univ, Sch Med, Dept Med, Stanford, CA 94305 USA..
    Glimelius, Ingrid
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Hjalgrim, Henrik
    Statens Serum Inst, Dept Epidemiol Res, DK-2300 Copenhagen S, Denmark..
    Autoimmune and Atopic Disorders and Risk of Classical Hodgkin Lymphoma2015In: American Journal of Epidemiology, ISSN 0002-9262, E-ISSN 1476-6256, Vol. 182, no 7, p. 624-632Article in journal (Refereed)
    Abstract [en]

    Results from previous investigations have shown associations between the risk of Hodgkin lymphoma (HL) and a history of autoimmune and atopic diseases, but it remains unknown whether these associations apply to all types of HL or only to specific subtypes. We investigated immune diseases and the risk of classical HL in a population-based case-control study that included 585 patients and 3,187 controls recruited from October 1999 through August 2002. We collected information on immune diseases through telephone interviews and performed serological analyses of specific immunoglobulin E reactivity. Tumor Epstein-Barr virus (EBV) status was determined for 498 patients. Odds ratios with 95% confidence intervals were calculated using logistic regression analysis. Rheumatoid arthritis was associated with a higher risk of HL (odds ratio (OR) = 2.63; 95% confidence interval (CI): 1.47, 4.70), especially EBV-positive HL (OR = 3.18; 95% CI: 1.23, 8.17), and with mixed-cellularity HL (OR = 4.25; 95% CI: 1.66, 10.90). HL risk was higher when we used proxies of severe rheumatoid arthritis, such as ever having received daily rheumatoid arthritis medication (OR = 3.98; 95% CI: 2.08, 7.62), rheumatoid arthritis duration of 6-20 years (OR = 3.80; 95% CI: 1.72, 8.41), or ever having been hospitalized for rheumatoid arthritis (OR = 7.36; 95% CI: 2.95, 18.38). Atopic diseases were not associated with the risk of HL. EBV replication induced by chronic inflammation in patients with autoimmune diseases might explain the higher risk of EBV-positive HL.

  • 41. Kozlowski, Piotr
    et al.
    Astrom, Maria
    Ahlberg, Lucia
    Bernell, Per
    Hulegardh, Erik
    Hägglund, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Karlsson, Karin
    Markuszewska-Kuczymska, Alicja
    Tomaszewska-Toporska, Beata
    Smedmyr, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Amini, Rose-Marie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology.
    Hallböök, Helene
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    High relapse rate of T cell acute lymphoblastic leukemia in adults treated with Hyper-CVAD chemotherapy in Sweden2014In: European Journal of Haematology, ISSN 0902-4441, E-ISSN 1600-0609, Vol. 92, no 5, p. 377-381Article in journal (Refereed)
    Abstract [en]

    Background Hyper-CVAD is widely used to treat acute lymphoblastic leukemia (ALL) and aggressive lymphomas. This multicenter, population-based study assessed the efficacy of Hyper-CVAD as first-line therapy in patients with T-cell ALL (T-ALL). Patients and methods Between October 2002 and September 2006, 24 patients were diagnosed with T-ALL in Sweden; 19 were eligible for treatment with the protocol. Results The median age was 32yr (range 18-72yr). Complete remission (CR) was obtained in 17 of 19 (89%) patients, and the treatment was relatively well tolerated. Allogeneic stem cell transplantation (SCT) was recommended in high-risk disease and was performed in four patients upfront. Two- and 5-yr leukemia-free survivals (LFS) in 17 patients with CR achievement were identical, at 29% (95% confidence interval [CI]: 8-51). Two- and 5-yr overall survival (OS) in whole cohort was 63% (95% CI: 42-85) and 47% (95% CI: 26-69), respectively. The 5-yr LFS for 15 patients who did not receive allogeneic SCT upfront were 20% (95% CI: 0-40), although 14 of 15 completed the protocol (eight cycles). Relapse occurred in 2 of 4 upfront-transplanted patients and in 12 of 15 patients treated with chemotherapy alone, six of whom received allogeneic SCT in CR2. Age >= 35yr influenced OS negatively in univariate analysis (HR 5.1, 95% CI: 1.55-16.7). Conclusions Hyper-CVAD treatment resulted in a high CR rate and appeared safe, but it showed poor efficacy at preventing relapse. Therefore, this treatment is no longer recommended for adults with T-ALL in Sweden.

  • 42.
    Libard, Sylwia
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology.
    Popova, Svetlana N
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology. Department of Pathology, Uppsala University Hospital, Uppsala, Sweden.
    Amini, Rose-Marie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology.
    Kärjä, Vesa
    Department of Clinical Pathology, Kuopio University Hospital, Kuopio, Finland.
    Pietiläinen, Timo
    Department of Clinical Pathology, Kuopio University Hospital, Kuopio, Finland.
    Hämäläinen, Kirsi M
    Department of Clinical Pathology, Kuopio University Hospital, Kuopio, Finland.
    Sundström, Christer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology.
    Hesselager, Göran
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery. Department of Neurosurgery, Uppsala University Hospital, Sweden.
    Bergqvist, Michael
    Department of radiation sciences, Umeå University, Sweden.
    Ekman, Simon
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Zetterling, Maria
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Smits, Anja
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Nilsson, Pelle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Pfeifer, Susan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Pediatrics.
    de Ståhl, Teresita Diaz
    Department of Oncology-Pathology, Karolinska Institutet, Cancer Center Karolinska, Karolinska University Hospital, Stockholm, Sweden.
    Enblad, Gunilla
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Ponten, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology.
    Alafuzoff, Irina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology.
    Human cytomegalovirus tegument protein pp65 is detected in all intra- and extra-axial brain tumours independent of the tumour type or grade2014In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 9, no 9, p. e108861-Article in journal (Refereed)
    Abstract [en]

    Human cytomegalovirus (HCMV) has been indicated being a significant oncomodulator. Recent reports have suggested that an antiviral treatment alters the outcome of a glioblastoma. We analysed the performance of commercial HCMV-antibodies applying the immunohistochemical (IHC) methods on brain sample obtained from a subject with a verified HCMV infection, on samples obtained from 14 control subjects, and on a tissue microarray block containing cores of various brain tumours. Based on these trials, we selected the best performing antibody and analysed a cohort of 417 extra- and intra-axial brain tumours such as gliomas, medulloblastomas, primary diffuse large B-cell lymphomas, and meningiomas. HCMV protein pp65 immunoreactivity was observed in all types of tumours analysed, and the IHC expression did not depend on the patient's age, gender, tumour type, or grade. The labelling pattern observed in the tumours differed from the labelling pattern observed in the tissue with an active HCMV infection. The HCMV protein was expressed in up to 90% of all the tumours investigated. Our results are in accordance with previous reports regarding the HCMV protein expression in glioblastomas and medulloblastomas. In addition, the HCMV protein expression was seen in primary brain lymphomas, low-grade gliomas, and in meningiomas. Our results indicate that the HCMV protein pp65 expression is common in intra- and extra-axial brain tumours. Thus, the assessment of the HCMV expression in tumours of various origins and pathologically altered tissue in conditions such as inflammation, infection, and even degeneration should certainly be facilitated.

  • 43. Linke, Steven P.
    et al.
    Bremer, Troy M.
    Whitworth, Pat
    Lui, Aflred
    Savala, Jess
    Noskina, Yelina
    Barry, Todd
    Lyle, Stephen
    Walters, Stephanie C.
    Taglienti, Cherie
    Simin, Karl
    Zhou, Wenjing
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Jirstrom, Karin
    Amini, Rose-Marie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Warnberg, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    FOXA1 and PR predict ipsilateral event risk and identify a group with strong radiation response in ductal carcinoma in situ (DCIS)2015In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 75, no 9, article id P4-11-18Article in journal (Other academic)
  • 44. Linke, Steven P.
    et al.
    Bremer, Troy M.
    Whitworth, Pat
    Lui, Alfred
    Savala, Jess
    Noskina, Yelina
    Barry, Todd
    Lyle, Stephen
    Walters, Stephanie C.
    Taglienti, Cherie
    Simin, Karl
    Zhou, Wenjing
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Jirstrom, Karin
    Amini, Rose-Marie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Wärnberg, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Validation of a multi-marker test that predicts recurrence in patients diagnosed with ductal carcinoma in situ (DCIS) treated with breast-conserving surgery (BCS)2015In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 75, no 9, article id P4-11-17Article in journal (Other academic)
  • 45.
    Lundgren, Claudia
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Ahlin, Cecilia
    Holmberg, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Amini, Rose-Marie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology.
    Fjällskog, Marie-Louise
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science.
    Blomqvist, Carl
    Cyclin E1 is a strong prognostic marker for death from lymph node negative breast cancer: A population-based case-control study2015In: Acta Oncologica, ISSN 0284-186X, E-ISSN 1651-226X, Vol. 54, no 4, p. 538-544Article in journal (Refereed)
    Abstract [en]

    Background. A large proportion of women with lymph node negative breast cancer treated with systemic adjuvant treatment do not benefit from such therapy since the patient is already cured by local treatment. Several studies have suggested that proliferation markers are strong prognostic factors in early breast cancer. Cyclins are probably the most specific markers of cell proliferation. Previously high expression of cyclin E has been associated with breast cancer recurrence.

    Materials and methods. In this study we investigate the prognostic value of cyclin E1 in node negative breast cancer patients. In a population-based cohort 186 women who died from breast cancer were defined as cases and 186 women alive at the corresponding time as controls. Inclusion criteria were tumour size ≤ 50 mm, no lymph node metastases and no adjuvant chemotherapy. The study was designed to detect an odds ratio of 2.5 with a power of 90% and significance level of 0.05. Cyclin E1 was determined with immunohistochemistry (IHC) on tissue microarray (TMA).

    Results. High expression of cyclin E1 was significantly associated with breast cancer death, in both uni- and multivariate analyses with odds ratios (OR) 2.3 [univariate, 95% confidence interval (CI) 1.5-3.6] and 2.1 (multivariate, 95% CI 1.2-3.5).

    Discussion. Cyclin E1 is a strong prognostic factor for breast cancer death in a population-based and node negative patient cohort and can identify high-risk patients in this group.

  • 46. Löfdahl, Britta
    et al.
    Ahlin, Cecilia
    Holmqvist, Marit
    Holmberg, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Zhou, Wenjing
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Fjällskog, Marie-Louise
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Amini, Rose-Marie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology.
    Inflammatory cells in node-negative breast cancer2012In: Acta Oncologica, ISSN 0284-186X, E-ISSN 1651-226X, Vol. 51, no 5, p. 680-686Article in journal (Refereed)
    Abstract [en]

    Background.

    To study the impact of inflammatory cells in a clinically well-defined cohort of women with node-negative breast cancer in a nested case-control study design.

    Material and methods.

    The cohort was comprised of 190 women who died from breast cancer and 190 women still alive at the date of death for the corresponding breast cancer patients were used as controls. The inclusion criteria included; a tumour size ≤ 50 mm, no lymph node metastases and no initiation of adjuvant chemotherapy. Immunohistochemical stainings for CD3, CD4, CD8, FoxP3, CD20, tryptase and CD68 were performed on TMA blocks, evaluated and correlated to each other and to age, tumour size, histological grade, ER, PgR, Ki67 and cyclin A.

    Results.

    There was no difference regarding the amount or content of inflammatory cells in the cases compared to controls. T- and B-cells were highly correlated to each other but these cell types correlated to a lesser extent to macrophages and not at all to mast cells. A weak tendency of correlations between all the subsets of inflammatory cells and histological grade, Ki67 and cyclin A was observed, although a negative correlation was seen for mast cells.

    Conclusion.

    The amount or content of inflammatory cells in invasive breast cancer did not appear to influence death in node-negative breast cancer.

  • 47.
    Nilsson, Cecilia
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centre for Clinical Research, County of Västmanland. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Johansson, Ida
    Department of Oncology, Clinical Sciences and CREATE Health Strategic Center for Translational Cancer Research, Lund University, Lund.
    Ahlin, Cecilia
    Department of Oncology, Örebro University Hospital, Örebro, Sweden.
    Thorstenson, Sten
    Department of Pathology, Linköping University Hospital, Linköping, Sweden.
    Amini, Rose-Marie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology.
    Holmqvist, Marit
    Uppsala-Örebro Regional Oncologic Center, Uppsala, Sweden .
    Bergkvist, Leif
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centre for Clinical Research, County of Västmanland.
    Hedenfalk, Ingrid
    Department of Oncology, Clinical Sciences and CREATE Health Strategic Center for Translational Cancer Research, Lund University, Lund, Sweden.
    Fjällskog, Marie-Louise
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Molecular subtyping of male breast cancer using alternative definitions and its prognostic impact2013In: Acta Oncologica, ISSN 0284-186X, E-ISSN 1651-226X, Vol. 52, no 1, p. 102-109Article in journal (Refereed)
    Abstract [en]

    Background.

    Male breast cancer (MBC) is an uncommon disease and there is limited information on the prognostic impact of routinely used clinicopathological parameters.

    Material and methods.

    In a retrospective setting, we reviewed 197 MBC patients with accessible paraffin-embedded tumor tissue and clinicopathological data. Immunohistochemical (IHC) stainings were performed on tissue microarrays and histological grading on conventional slides. Cox proportional regression models were applied for uni- and multivariate analyses using breast cancer death as the event.

    Results.

    Estrogen receptor (ER) and progesterone receptor positivity were demonstrated in 93% and 77% of patients, respectively. Nottingham histologic grade (NHG) III was seen in 41% and HER2 positivity in 11%. Classification into molecular subtypes using IHC markers according to three alternative definitions revealed luminal A and luminal B in 81% vs. 11%; 48% vs. 44% and 41% vs. 42% of cases. Two cases of basal-like were identified, but no cases of HER2-like. Factors associated with an increased risk of breast cancer death were node positivity (HR 4.5; 95% CI 1.8-11.1), tumor size > 20 mm (HR 3.3; 95% CI 1.4-7.9) and ER negativity (HR 10.9; 95% CI 3.2-37.9). No difference in breast cancer death between the luminal subgroups was demonstrated, regardless of definition.

    Conclusion.

    MBC tumors were more often of high grade, whereas HER2 overexpression was as frequent as in FBC. Lymph nodes, tumor size and ER status were independent predictors of breast cancer death. The prognostic impact of molecular subtyping in MBC seems to differ from that previously established in FBC.

  • 48. Niméus-Malmström, Emma
    et al.
    Koliadi, Anthoula
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Ahlin, Cecilia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Holmqvist, Marit
    Uppsala-Örebro Regional Oncologic Centre.
    Holmberg, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Amini, Rose-Marie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Jirström, K.
    Wärnberg, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Blomqvist, Carl
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Fernö, M.
    Fjällskog, Marie-Louise
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Cyclin B1 is a prognostic proliferation marker with a high reproducibility in a population-based lymph node negative breast cancer cohort2010In: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 127, no 4, p. 961-967Article in journal (Refereed)
    Abstract [en]

    A large proportion of women with lymph node negative breast cancer treated with chemotherapy do not benefit from such treatment. Proliferation markers have been shown to recognize patients at high risk for recurrence. Ki67 has recently been included in the St Gallen guidelines. We investigated the prognostic importance of cyclin B1 in node negative breast cancer and included a study of reproducibility. In a population-based case-control study 190 women who died from breast cancer were defined as cases and 190 women alive at the time for the corresponding case's death as controls. Inclusion criteria were tumor size < 50 mm, no lymph node metastases, and no adjuvant chemotherapy. Tumor tissue was immunostained for cyclin B1. Two investigators evaluated the staining independently by counting approximately 100, 200, 500, and 1000 cells. Cyclin B1 was statistically significantly associated to breast cancer death, in both uni- and multivariate analyses (adjusted for tumor size, age, and endocrine therapy), with odds ratios 2-3 for both investigators. The agreement between the two investigators was good to very good, regardless of the number of counted cells (kappa values between 0.74 and 0.82).Cyclin B1 is a prognostic factor for breast cancer death in a population-based node negative patient cohort which can identify high-risk patients with a good to very good reproducibility. (c) 2009 UICC.

  • 49.
    Pommerenke, C.
    et al.
    Leibniz Inst DSMZ German Collect Microorganisms &, Braunschweig, Germany..
    Hauer, V.
    Leibniz Inst DSMZ German Collect Microorganisms &, Braunschweig, Germany..
    Zaborski, M.
    Leibniz Inst DSMZ German Collect Microorganisms &, Braunschweig, Germany..
    MacLeod, R. A. F.
    Leibniz Inst DSMZ German Collect Microorganisms &, Braunschweig, Germany..
    Nagel, S.
    Leibniz Inst DSMZ German Collect Microorganisms &, Braunschweig, Germany..
    Amini, Rose-Marie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology.
    Berglund, Mattias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Geffers, R.
    Helmholtz Ctr Infect Res, Genome Analyt Res Grp, Braunschweig, Germany..
    Drexler, H. G.
    Leibniz Inst DSMZ German Collect Microorganisms &, Braunschweig, Germany..
    Quentmeier, H.
    Leibniz Inst DSMZ German Collect Microorganisms &, Braunschweig, Germany..
    Chromosome 11q23 aberrations activating FOXR1 in B-cell lymphoma2016In: Blood Cancer Journal, ISSN 2044-5385, E-ISSN 2044-5385, Vol. 6, article id e433Article in journal (Refereed)
  • 50. Quentmeier, H.
    et al.
    Amini, Rose Marie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology.
    Berglund, Mattias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Dirks, W. G.
    Ehrentraut, S.
    Geffers, R.
    MacLeod, R. A. F.
    Nagel, S.
    Romani, J.
    Scherr, M.
    Zaborski, M.
    Drexler, H. G.
    U-2932: two clones in one cell line, a tool for the study of clonal evolution2013In: Leukemia, ISSN 0887-6924, E-ISSN 1476-5551, Vol. 27, no 5, p. 1155-1164Article in journal (Refereed)
    Abstract [en]

    Genetic heterogeneity is common in tumors, explicable by the development of subclones with distinct genetic and epigenetic alterations. We describe an in vitro model for cancer heterogeneity, comprising the diffuse large B-cell lymphoma cell line U-2932 which expresses two sets of cell surface markers representing twin populations flow-sorted by CD20 vs CD38 expression. U-2932 populations were traced to subclones of the original tumor with clone-specific immunoglobulin IgV(H)4-39 hypermutation patterns. BCL6 was overexpressed in one subpopulation (R1), MYC in the other (R2), both clones overexpressed BCL2. According to the combined results of immunoglobulin hypermutation and cytogenetic analysis, R1 and R2 derive from a mother clone with genomic BCL2 amplification, which acquired secondary rearrangements leading to the overexpression of BCL6 (R1) or MYC (R2). Some 200 genes were differentially expressed in R1/R2 microarrays including transcriptional targets of the aberrantly expressed oncogenes. Other genes were regulated by epigenetic means as shown by DNA methylation analysis. Ectopic expression of BCL6 in R2 variously modulated new candidate target genes, confirming dual silencing and activating functions. In summary, stable retention of genetically distinct subclones in U-2932 models tumor heterogeneity in vitro permitting functional analysis of oncogenes against a syngenic background.

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