106 results on '"Klaus, Beiske"'
Search Results
2. Amplification of CDK4 and MDM2: a detailed study of a high-risk neuroblastoma subgroup
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Angela Martinez-Monleon, Hanna Kryh Öberg, Jennie Gaarder, Ana P. Berbegall, Niloufar Javanmardi, Anna Djos, Marek Ussowicz, Sabine Taschner-Mandl, Inge M. Ambros, Ingrid Øra, Bengt Sandstedt, Klaus Beiske, Ruth Ladenstein, Rosa Noguera, Peter F. Ambros, Lena Gordon Murkes, Gustaf Ljungman, Per Kogner, Susanne Fransson, and Tommy Martinsson
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Medicine ,Science - Abstract
Abstract In neuroblastoma, MYCN amplification and 11q-deletion are important, although incomplete, markers of high-risk disease. It is therefore relevant to characterize additional alterations that can function as prognostic and/or predictive markers. Using SNP-microarrays, a group of neuroblastoma patients showing amplification of one or multiple 12q loci was identified. Two loci containing CDK4 and MDM2 were commonly co-amplified, although amplification of either locus in the absence of the other was observed. Pharmacological inhibition of CDK4/6 with ribociclib or abemaciclib decreased proliferation in a broad set of neuroblastoma cell lines, including CDK4/MDM2-amplified, whereas MDM2 inhibition by Nutlin-3a was only effective in p53wild-type cells. Combined CDK4/MDM2 targeting had an additive effect in p53wild-type cell lines, while no or negative additive effect was observed in p53mutated cells. Most 12q-amplified primary tumors were of abdominal origin, including those of intrarenal origin initially suspected of being Wilms’ tumor. An atypical metastatic pattern was also observed with low degree of bone marrow involvement, favoring other sites such as the lungs. Here we present detailed biological data of an aggressive neuroblastoma subgroup hallmarked by 12q amplification and atypical clinical presentation for which our in vitro studies indicate that CDK4 and/or MDM2 inhibition also could be beneficial.
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- 2022
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3. Whole exome sequencing of high-risk neuroblastoma identifies novel non-synonymous variants.
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Weronika Przybyła, Kirsti Marie Gjersvoll Paulsen, Charitra Kumar Mishra, Ståle Nygård, Solveig Engebretsen, Ellen Ruud, Gunhild Trøen, Klaus Beiske, and Lars Oliver Baumbusch
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Medicine ,Science - Abstract
Neuroblastoma (NBL), one of the main death-causing cancers in children, is known for its remarkable genetic heterogeneity and varied patient outcome spanning from spontaneous regression to widespread disease. Specific copy number variations and single gene rearrangements have been proven to be associated with biological behavior and prognosis; however, there is still an unmet need to enlarge the existing armamentarium of prognostic and therapeutic targets. We performed whole exome sequencing (WES) of samples from 18 primary tumors and six relapse samples originating from 18 NBL patients. Our cohort consists of 16 high-risk, one intermediate, and one very low risk patient. The obtained results confirmed known mutational hotspots in ALK and revealed other non-synonymous variants of NBL-related genes (TP53, DMD, ROS, LMO3, PRUNE2, ERBB3, and PHOX2B) and of genes cardinal for other cancers (KRAS, PIK3CA, and FLT3). Beyond, GOSeq analysis determined genes involved in biological adhesion, neurological cell-cell adhesion, JNK cascade, and immune response of cell surface signaling pathways. We were able to identify novel coding variants present in more than one patient in nine biologically relevant genes for NBL, including TMEM14B, TTN, FLG, RHBG, SHROOM3, UTRN, HLA-DRB1, OR6C68, and XIRP2. Our results may provide novel information about genes and signaling pathways relevant for the pathogenesis and clinical course in high-risk NBL.
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- 2022
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4. The DLBCL90 gene‐expression assay identifies double‐hit lymphomas with high sensitivity in patients from two phase II clinical trials with high‐risk diffuse large B‐cell lymphoma
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David W. Scott, Kathrine T. Isaksen, Judit Jørgensen, Sirpa Leppä, Marja-Liisa Karjalainen-Lindsberg, June Helen Myklebust, Harald Holte, Marianne Brodtkorb, Yngvild Nuvin Blaker, Erlend B. Smeland, Klaus Beiske, Leo Meriranta, Mats Jerkeman, Faculty of Medicine, Helsinki University Hospital Area, HUS Comprehensive Cancer Center, Department of Oncology, Digital Precision Cancer Medicine (iCAN), HUSLAB, Department of Pathology, Medicum, Clinicum, and Research Programs Unit
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0303 health sciences ,Double hit ,business.industry ,education ,3122 Cancers ,Phases of clinical research ,medicine.disease ,3. Good health ,03 medical and health sciences ,0302 clinical medicine ,030220 oncology & carcinogenesis ,Gene expression ,Cancer research ,medicine ,In patient ,Sensitivity (control systems) ,business ,Diffuse large B-cell lymphoma ,030304 developmental biology - Published
- 2020
5. Immune cell constitution in the tumor microenvironment predicts the outcome in diffuse large B-cell lymphoma
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Klaus Beiske, Satu Mustjoki, Sirpa Leppä, Judit Jørgensen, Harald Holte, Marja-Liisa Karjalainen-Lindsberg, Oscar Brück, Suvi-Katri Leivonen, Matias Autio, Teijo Pellinen, Faculty of Medicine, ATG - Applied Tumor Genomics, Research Programs Unit, University of Helsinki, Department of Oncology, HUS Comprehensive Cancer Center, Digital Precision Cancer Medicine (iCAN), Department of Clinical Chemistry and Hematology, TRIMM - Translational Immunology Research Program, Hematologian yksikkö, Department of Pathology, Medicum, Institute for Molecular Medicine Finland, Doctoral Programme in Biomedicine, and Precision Systems Medicine
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0301 basic medicine ,LAG3 ,BLOCKADE ,3122 Cancers ,Biology ,UP-REGULATION ,LYMPHOCYTES ,Article ,03 medical and health sciences ,Lymphocytes, Tumor-Infiltrating ,0302 clinical medicine ,Immune system ,Tumor Microenvironment ,medicine ,PD-1 EXPRESSION ,Humans ,Cytotoxic T cell ,REGULATORY T-CELLS ,CHEMOTHERAPY PLUS RITUXIMAB ,Tumor microenvironment ,HIGH NUMBERS ,FOXP3 ,Hematology ,medicine.disease ,GENE ,Immunohistochemistry ,Immune checkpoint ,3. Good health ,030104 developmental biology ,030220 oncology & carcinogenesis ,SURVIVAL ,Cancer research ,Lymphoma, Large B-Cell, Diffuse ,Diffuse large B-cell lymphoma ,CHOP ,CD8 ,T-Lymphocytes, Cytotoxic - Abstract
The tumor microenvironment (TME) and limited immune surveillance play important roles in lymphoma pathogenesis. Here we aimed to characterize immunological profiles of diffuse large B-cell lymphoma (DLBCL) and predict the outcome in response to immunochemotherapy. We profiled the expression of 730 immune-related genes in tumor tissues of 81 patients with DLBCL utilizing the Nanostring platform, and used multiplex immunohistochemistry to characterize T-cell phenotypes, including cytotoxic T cells (CD8, Granzyme B, OX40, Ki67), T-cell immune checkpoint (CD3, CD4, CD8, PD1, TIM3, LAG3), as well as regulatory T-cells and Th1 effector cells (CD3, CD4, FOXP3, TBET) in 188 patients. We observed a high degree of heterogeneity at the transcriptome level. Correlation matrix analysis identified gene expression signatures with highly correlating genes, the main cluster containing genes for cytolytic factors, immune checkpoint molecules, T cells and macrophages, together named a TME immune cell signature. Immunophenotyping of the distinct cell subsets revealed that a high proportion of immune checkpoint positive T cells translated to unfavorable survival. Together, our results demonstrate that the immunological profile of DLBCL TME is heterogeneous and clinically meaningful. This highlights the potential impact of T-cell immune checkpoint in regulating survival and resistance to immunochemotherapy. (Registered at clinicaltrials.gov identifiers: NCT01502982 and NCT01325194.)
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- 2020
6. Chromosome Translocation t(14;21)(q11;q22) Activates Both OLIG1 and OLIG2 in Pediatric T-cell Lymphoblastic Malignancies and May Signify Adverse Prognosis
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Ludmila Gorunova, Kristin Andersen, Inga Maria Johannsdottir, Sverre Heim, Ioannis Panagopoulos, Klaus Beiske, and Arild Holth
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congenital, hereditary, and neonatal diseases and abnormalities ,Cancer Research ,OLIG2 Gene ,medicine.diagnostic_test ,T cell ,Lymphoblastic lymphoma ,Immunocytochemistry ,Chromosomal translocation ,Biology ,medicine.disease ,Biochemistry ,OLIG2 ,03 medical and health sciences ,0302 clinical medicine ,medicine.anatomical_structure ,hemic and lymphatic diseases ,030220 oncology & carcinogenesis ,Genetics ,medicine ,Cancer research ,Molecular Biology ,Gene ,Fluorescence in situ hybridization - Abstract
Background/aim The chromosome translocation t(14;21)(q11;q22) was reported in four pediatric T-cell lymphoblastic leukemias and was shown to activate the OLIG2 gene. Materials and methods A pediatric T-cell lymphoblastic lymphoma was investigated using G-banding chromosome analysis, fluorescence in situ hybridization (FISH), and immunocytochemistry. Results The malignant cells carried a t(14;21)(q11;q22) aberration. The translocation moves the enhancer elements of TRA/TRD from band 14q11 to 21q22, a few thousands kbp downstream of OLIG1 and OLIG2, resulting in the production of both OLIG1 and OLIG2 proteins. Conclusion The translocation t(14;21)(q11;q22) occurs in some pediatric T-cell lymphoblastic malignancies. Activation of both OLIG1 and OLIG2 by t(14;21)(q11;q22) in T-lymphoblasts and the ensuing deregulation of thousands of genes could explain the highly malignant disease and resistance to treatment that has characterized this small group of patients.
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- 2019
7. Novel ZEB2-BCL11B Fusion Gene Identified by RNA-Sequencing in Acute Myeloid Leukemia with t(2;14)(q22;q32).
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Synne Torkildsen, Ludmila Gorunova, Klaus Beiske, Geir E Tjønnfjord, Sverre Heim, and Ioannis Panagopoulos
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Medicine ,Science - Abstract
RNA-sequencing of a case of acute myeloid leukemia with the bone marrow karyotype 46,XY,t(2;14)(q22;q32)[5]/47,XY,idem,+?4,del(6)(q13q21)[cp6]/46,XY[4] showed that the t(2;14) generated a ZEB2-BCL11B chimera in which exon 2 of ZEB2 (nucleotide 595 in the sequence with accession number NM_014795.3) was fused to exon 2 of BCL11B (nucleotide 554 in the sequence with accession number NM_022898.2). RT-PCR together with Sanger sequencing verified the presence of the above-mentioned fusion transcript. All functional domains of BCL11B are retained in the chimeric protein. Abnormal expression of BCL11B coding regions subjected to control by the ZEB2 promoter seems to be the leukemogenic mechanism behind the translocation.
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- 2015
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8. BIOMARKER‐DRIVEN TREATMENT STRATEGY IN HIGH RISK DIFFUSE LARGE B‐CELL LYMPHOMA: RESULTS OF A NORDIC PHASE 2 STUDY
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Marianne Brodtkorb, M‐L Karjalainen‐Lindsberg, Sirpa Leppä, Annika Pasanen, K Drott, S. Mannisto, Thomas Stauffer Larsen, Sirkku Jyrkkiö, Harald Holte, Peter Nørgaard, Peter D. Brown, Kristiina Karihtala, Judit Jørgensen, Øystein Fluge, Klaus Beiske, B Wold, Unn‐M Fagerli, and Lars Munksgaard
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Cancer Research ,business.industry ,Aggressive B-cell non-Hodgkin lymphoma Combination Therapies ,Phases of clinical research ,Hematology ,General Medicine ,medicine.disease ,Oncology ,medicine ,Cancer research ,Biomarker (medicine) ,Treatment strategy ,business ,Diffuse large B-cell lymphoma - Published
- 2021
9. Preclinical development of CD37CAR T-cell therapy for treatment of B-cell lymphoma
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June Helen Myklebust, Sébastien Wälchli, Are Kolstad, Yngvild Nuvin Blaker, Solrun Melkorka Maggadottir, Sarah Elisabet Josefsson, Kanutte Huse, Pierre Dillard, Gunnar Kvalheim, Hakan Köksal, Else Marit Inderberg, Anne Fåne, Harald Holte, Sylvie Pollmann, Erlend B. Smeland, and Klaus Beiske
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0301 basic medicine ,Adoptive cell transfer ,Lymphoma, B-Cell ,Immunobiology and Immunotherapy ,Tetraspanins ,T cell ,Antigens, CD19 ,Mice, SCID ,Jurkat cells ,CD19 ,Jurkat Cells ,Mice ,03 medical and health sciences ,0302 clinical medicine ,Antigen ,Antigens, Neoplasm ,Mice, Inbred NOD ,immune system diseases ,Precursor B-Cell Lymphoblastic Leukemia-Lymphoma ,hemic and lymphatic diseases ,medicine ,Animals ,Humans ,B-cell lymphoma ,Receptors, Chimeric Antigen ,biology ,business.industry ,Hematology ,medicine.disease ,Adoptive Transfer ,Xenograft Model Antitumor Assays ,Chimeric antigen receptor ,Lymphoma ,030104 developmental biology ,medicine.anatomical_structure ,030220 oncology & carcinogenesis ,biology.protein ,Cancer research ,K562 Cells ,business - Abstract
T cells modified to express chimeric antigen receptor (CAR) targeting CD19 (CD19CAR) have produced remarkable clinical responses in patients with relapsed/refractory B-cell acute lymphoblastic leukemia. CD19CAR T-cell therapy has also demonstrated prominent effects in B-cell non-Hodgkin lymphoma (B-NHL) patients. However, a subset of patients who relapse after CD19CAR T-cell therapy have outgrowth of CD19− tumor cells. Hence, development of alternative CARs targeting other B-cell markers represents an unmet medical need for B-cell acute lymphoblastic leukemia and B-NHL. Here, we confirmed previous data by showing that, overall, B-NHL has high expression of CD37. A second-generation CD37CAR was designed, and its efficacy in T cells was compared with that of CD19CAR. In vitro assessment of cytotoxicity and T-cell function upon coculture of the CAR T cells with different target B-cell lymphoma cell lines demonstrated comparable efficacy between the 2 CARs. In an aggressive B-cell lymphoma xenograft model, CD37CAR T cells were as potent as CD19CAR T cells in controlling tumor growth. In a second xenograft model, using U2932 lymphoma cells containing a CD19− subpopulation, CD37CAR T cells efficiently controlled tumor growth and prolonged survival, whereas CD19CAR T cells had limited effect. We further show that, unlike CD19CAR, CD37CAR was not sensitive to antigen masking. Finally, CD37CAR reactivity was restricted to B-lineage cells. Collectively, our results demonstrated that CD37CAR T cells also can effectively eradicate B-cell lymphoma tumors when CD19 antigen expression is lost and support further clinical testing for patients with relapsed/refractory B-NHL.
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- 2019
10. TIGIT and PD-1 Mark Intratumoral T Cells with Reduced Effector Function in B-cell Non-Hodgkin Lymphoma
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Arne Kolstad, Sarah Elisabet Josefsson, Sébastien Wälchli, Erlend B. Smeland, Yngvild Nuvin Blaker, Harald Holte, June Helen Myklebust, Eva Kimby, Bjørn Østenstad, Ronald Levy, Klaus Beiske, Mette Førsund, Kanutte Huse, Baoyan Bai, and Hakan Köksal
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Adult ,0301 basic medicine ,Cancer Research ,medicine.medical_treatment ,Receptor expression ,Programmed Cell Death 1 Receptor ,Immunology ,Biology ,Ligands ,Article ,03 medical and health sciences ,0302 clinical medicine ,TIGIT ,T-Lymphocyte Subsets ,immune system diseases ,Cell Line, Tumor ,hemic and lymphatic diseases ,Tumor Microenvironment ,medicine ,Humans ,Receptors, Immunologic ,Aged ,Aged, 80 and over ,Follicular dendritic cells ,Lymphoma, Non-Hodgkin ,Middle Aged ,medicine.disease ,Lymphoma ,030104 developmental biology ,Cytokine ,030220 oncology & carcinogenesis ,B-Cell Non-Hodgkin Lymphoma ,Cancer research ,Cytokines ,Female ,Mantle cell lymphoma ,Immunologic Memory ,CD8 - Abstract
Checkpoint blockade can reverse T-cell exhaustion and promote antitumor responses. Although blocking the PD-1 pathway has been successful in Hodgkin lymphoma, response rates have been modest in B-cell non-Hodgkin lymphoma (NHL). Coblockade of checkpoint receptors may therefore be necessary to optimize antitumor T-cell responses. Here, characterization of coinhibitory receptor expression in intratumoral T cells from different NHL types identified TIGIT and PD-1 as frequently expressed coinhibitory receptors. Tumors from NHL patients were enriched in CD8+ and CD4+ T effector memory cells that displayed high coexpression of TIGIT and PD-1, and coexpression of these checkpoint receptors identified T cells with reduced production of IFNγ, TNFα, and IL2. The suppressed cytokine production could be improved upon in vitro culture in the absence of ligands. Whereas PD-L1 was expressed by macrophages, the TIGIT ligands CD155 and CD112 were expressed by lymphoma cells in 39% and 50% of DLBCL cases and in some mantle cell lymphoma cases, as well as by endothelium and follicular dendritic cells in all NHLs investigated. Collectively, our results show that TIGIT and PD-1 mark dysfunctional T cells and suggest that TIGIT and PD-1 coblockade should be further explored to elicit potent antitumor responses in patients with NHL.
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- 2019
11. Efficacy of the Nordic and the MSKCC chemotherapy protocols on the overall and progression-free survival in intracranial PCNSL
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Klaus Beiske, Torstein R. Meling, Guro Jahr, Harald Holte, and Michele Da Broi
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Adult ,Male ,Oncology ,medicine.medical_specialty ,Multivariate analysis ,Databases, Factual ,Lymphoma ,medicine.medical_treatment ,Central Nervous System Neoplasms ,03 medical and health sciences ,0302 clinical medicine ,Statistical significance ,Internal medicine ,Antineoplastic Combined Chemotherapy Protocols ,medicine ,Humans ,Progression-free survival ,Molecular Biology ,Aged ,Chemotherapy ,Univariate analysis ,Brain Neoplasms ,business.industry ,Cancer ,Cell Biology ,Hematology ,Middle Aged ,medicine.disease ,Progression-Free Survival ,Survival Rate ,030220 oncology & carcinogenesis ,Molecular Medicine ,Female ,Rituximab ,business ,030217 neurology & neurosurgery ,medicine.drug - Abstract
Background: To compare the Nordic and the Memorial Sloan-Kettering Cancer Center (MSKCC) chemotherapy protocols for Overall Survival (OS) and Progression-Free Survival (PFS) for intracranial primary CNS lymphoma (PCNSL). Methods: A prospective database at Oslo University Hospital of PCNSL was reviewed over a 12-year period (2003–2014). Results: Overall, 79 patients with PCNSL were identified, of whom 57 received chemotherapy. MSKCC with Rituximab (RTX) was used in 18 patients (32%) who had median OS of 46.3 months [9.8–131.9] and median PFS of 34.6 months [6.4–131.9]. The Nordic protocol was used in 14 patients (25%) who had median OS of 30.9 months [2.7–106.3] and PFS of 14.3 months [0.0–106.3]. The MSKCC was used without RTX in 25 patients (44%) who had OS of 15.2 months [0.7–136.5] and PFS of 12.0 months [0.0–117.0]. MSKCC with RTX had a significantly longer median OS (p
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- 2018
12. Frequency and prognostic impact of ALK amplifications and mutations in the European Neuroblastoma Study Group (SIOPEN) high-risk neuroblastoma trial (HR-NBL1)
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Ulrike Pötschger, Gudrun Schleiermacher, Sally L George, Nick Bown, Jaydutt Bhalshankar, Sylvain Baulande, Peter F. Ambros, Josef Malis, Gaëlle Pierron, Eve Lapouble, Katia Mazzocco, Virginie Bernard, Jaime Font de Mora, Katleen De Preter, Annick Mühlethaler-Mottet, Nadine Van Roy, Martina Morini, Genevieve Laureys, Bárbara Marques, Dominique Valteau-Couanet, Olivier Delattre, Marta Jeison, Victoria Castel, Shifra Ash, Valérie Combaret, Nathalie Auger, Ruth Ladenstein, Sabine Taschner-Mandl, Louis Chesler, Maria Rossing, David R. Betts, Ales Vicha, Rosa Noguera, Klaus Beiske, Angela Bellini, Walentyna Balwierz, Deborah A. Tweddle, Maja Popovic-Beck, Marie Bernkopf, Nathalie Clément, Per Kogner, Tommy Martinsson, Roberto Luksch, Martin Elliott, and Irene Jiménez
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0301 basic medicine ,Cancer Research ,Prognostic Impact ,Anaplastic Lymphoma Kinase/genetics ,Child, Preschool ,Clinical Trials, Phase III as Topic ,Europe ,Female ,Follow-Up Studies ,Gene Amplification ,Humans ,Infant ,Male ,Mutation Rate ,N-Myc Proto-Oncogene Protein/genetics ,Neuroblastoma/genetics ,Prognosis ,Randomized Controlled Trials as Topic ,Risk Factors ,Survival Rate ,European Neuroblastoma Study Group ,SIOPEN ,RELAPSE ,03 medical and health sciences ,Neuroblastoma ,0302 clinical medicine ,Text mining ,hemic and lymphatic diseases ,REVEALS ,Medicine and Health Sciences ,KINASE ,Medicine ,High risk neuroblastoma ,HETEROGENEITY ,CRIZOTINIB ,SEGMENTAL CHROMOSOMAL ALTERATIONS ,ACTIVATING MUTATIONS ,PEDIATRIC-PATIENTS ,business.industry ,ALK receptor tyrosine kinase ,Point mutation ,REARRANGEMENTS ,CHEMOTHERAPY ,medicine.disease ,Doenças Genéticas ,030104 developmental biology ,ALK ,Oncology ,030220 oncology & carcinogenesis ,Cancer research ,business - Abstract
Purpose: In neuroblastoma (NB), the ALK receptor tyrosine kinase can be constitutively activated through activating point mutations or genomic amplification. We studied ALK genetic alterations in high-risk (HR) patients on the HR-NBL1/SIOPEN trial to determine their frequency, correlation with clinical parameters, and prognostic impact. Materials and methods: Diagnostic tumor samples were available from 1,092 HR-NBL1/SIOPEN patients to determine ALK amplification status (n = 330), ALK mutational profile (n = 191), or both (n = 571). Results: Genomic ALK amplification (ALKa) was detected in 4.5% of cases (41 out of 901), all except one with MYCN amplification (MNA). ALKa was associated with a significantly poorer overall survival (OS) (5-year OS: ALKa [n = 41] 28% [95% CI, 15 to 42]; no-ALKa [n = 860] 51% [95% CI, 47 to 54], [P < .001]), particularly in cases with metastatic disease. ALK mutations (ALKm) were detected at a clonal level (> 20% mutated allele fraction) in 10% of cases (76 out of 762) and at a subclonal level (mutated allele fraction 0.1%-20%) in 3.9% of patients (30 out of 762), with a strong correlation between the presence of ALKm and MNA (P < .001). Among 571 cases with known ALKa and ALKm status, a statistically significant difference in OS was observed between cases with ALKa or clonal ALKm versus subclonal ALKm or no ALK alterations (5-year OS: ALKa [n = 19], 26% [95% CI, 10 to 47], clonal ALKm [n = 65] 33% [95% CI, 21 to 44], subclonal ALKm (n = 22) 48% [95% CI, 26 to 67], and no alteration [n = 465], 51% [95% CI, 46 to 55], respectively; P = .001). Importantly, in a multivariate model, involvement of more than one metastatic compartment (hazard ratio [HR], 2.87; P < .001), ALKa (HR, 2.38; P = .004), and clonal ALKm (HR, 1.77; P = .001) were independent predictors of poor outcome. Conclusion: Genetic alterations of ALK (clonal mutations and amplifications) in HR-NB are independent predictors of poorer survival. These data provide a rationale for integration of ALK inhibitors in upfront treatment of HR-NB with ALK alterations. Key Objective: High risk neuroblastoma (HR-NB) is one of the most difficult childhood cancers to cure. This study examined whether the presence of an ALK alteration (amplification or mutation) was associated with a poor prognosis in a large patient series treated on the prospective European high-risk neuroblastoma trial (HR-NBL1). Knowledge Generated: We found that ALK amplification or clonal mutation was associated with inferior prognosis in patients with HR-NB and both are independent prognostic variables on multivariate analysis. To our knowledge, this is the first study to report the highly prognostic significance of ALK amplification in HR-NB. Relevance: As ALK can be targeted therapeutically, this study convincingly argues for the introduction of ALK inhibitors for upfront management of patients with HR-NB with ALK aberrations. Importantly, the prognostic significance of ALK alterations included a subgroup of trial patients treated with the current standard of care for HR-NB including anti-GD2 immunotherapy. info:eu-repo/semantics/publishedVersion
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- 2021
13. Age Inherently Links to Histology to Define Histoprognostic Classification of Peripheral Neuroblastic Tumors
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Hiroyuki Shimada, Naohiko Ikegaki, and Klaus Beiske
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Cancer Research ,Pathology ,medicine.medical_specialty ,business.industry ,MEDLINE ,Mitosis ,Histology ,Prognosis ,Neuroblastic Tumor ,Peripheral ,Neuroblastoma ,Text mining ,Oncology ,medicine ,Biomarkers, Tumor ,Humans ,business - Published
- 2020
14. Patients with high-risk DLBCL benefit from dose-dense immunochemotherapy combined with early systemic CNS prophylaxis
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Elisabeth Ralfkiaer, Sirpa Leppä, Klaus Beiske, Harald Holte, Thomas Stauffer Larsen, Mats Jerkeman, Judit Jørgensen, Unn-Merete Fagerli, Martin Maisenhölder, Marja-Liisa Karjalainen-Lindsberg, Signe Spetalen, Magnus Björkholm, Leo Meriranta, Lars Munksgaard, Øystein Fluge, Ingunn Østlie, Peter de Nully Brown, Knut Liestøl, Anne Tierens, Susanna Mannisto, Kaija Vasala, Sirkku Jyrkkiö, Peter Meyer, Department of Oncology, HUS Comprehensive Cancer Center, Research Programs Unit, Helsinki University Hospital Area, ATG - Applied Tumor Genomics, Faculty of Medicine, University of Helsinki, Medicum, and Department of Pathology
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Adult ,Oncology ,Vincristine ,medicine.medical_specialty ,Adolescent ,Clinical Trials and Observations ,3122 Cancers ,Aggressive lymphoma ,Young Adult ,03 medical and health sciences ,0302 clinical medicine ,International Prognostic Index ,Prednisone ,Internal medicine ,Antineoplastic Combined Chemotherapy Protocols ,LEPTOMENINGEAL DISEASE ,Journal Article ,medicine ,Humans ,RITUXIMAB ,ELDERLY-PATIENTS ,AGGRESSIVE LYMPHOMA ,business.industry ,Research Support, Non-U.S. Gov't ,Hazard ratio ,B-CELL LYMPHOMA ,DOUBLE-HIT LYMPHOMA ,Hematology ,Middle Aged ,medicine.disease ,METHOTREXATE ,3. Good health ,030220 oncology & carcinogenesis ,PHASE-II ,YOUNG-PATIENTS ,Cytarabine ,Rituximab ,Lymphoma, Large B-Cell, Diffuse ,Neoplasm Recurrence, Local ,NON-HODGKIN-LYMPHOMA ,business ,Diffuse large B-cell lymphoma ,030215 immunology ,medicine.drug - Abstract
Survival of patients with high-risk diffuse large B-cell lymphoma (DLBCL) is suboptimal, and the risk of central nervous system (CNS) progression is relatively high. We conducted a phase 2 trial in 139 patients aged 18 to 64 years who had primary DLBCL with an age-adjusted International Prognostic Index (aaIPI) score of 2 to 3 or site-specific risk factors for CNS recurrence. The goal was to assess whether a dose-dense immunochemotherapy with early systemic CNS prophylaxis improves the outcome and reduces the incidence of CNS events. Treatment consisted of 2 courses of high-dose methotrexate in combination with biweekly rituximab (R), cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP-14), followed by 4 courses of R-CHOP-14 with etoposide (R-CHOEP) and 1 course of high-dose cytarabine with R. In addition, liposomal cytarabine was administered intrathecally at courses 1, 3, and 5. Coprimary endpoints were failure-free survival and CNS progression rates. Thirty-six (26%) patients experienced treatment failure. Progression occurred in 23 (16%) patients, including three (2.2%) CNS events. At 5 years of median follow-up, failure-free survival, overall survival, and CNS progression rates were 74%, 83%, and 2.3%, respectively. Treatment reduced the risk of progression compared with our previous trial, in which systemic CNS prophylaxis was given after 6 courses of biweekly R-CHOEP (hazard ratio, 0.49; 95% CI, 0.31-0.77; P = .002) and overcame the adverse impact of an aaIPI score of 3 on survival. In addition, outcome of the patients with BCL2/MYC double-hit lymphomas was comparable to the patients without the rearrangements. The results are encouraging, with a low toxic death rate, low number of CNS events, and favorable survival rates. This trial was registered at www.clinicaltrials.gov as #NCT01325194.
- Published
- 2020
15. Molecularly matched therapy in the context of sensitivity, resistance, and safety; patient outcomes in end-stage cancer - the MetAction study
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Vessela N. Kristensen, Gry A. Geitvik, Christin Johansen, Kjetil Boye, Eivind Hovig, Sigve Nakken, Anne Hansen Ree, Gunhild Mari Mælandsmo, Daniel Heinrich, Vigdis Nygaard, Ole Christian Lingjærde, Svein Dueland, Vivi Ann Flørenes, Anne Negård, Anne Lise Børresen-Dale, Lars Julsrud, Claudius H Reisse, Vegard Nygaard, Salah Nasser, Hege G. Russnes, Klaus Beiske, Kjersti Flatmark, Inger Riise Bergheim, Marius Lund-Iversen, and Espen A. Ruud
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Oncology ,Male ,Colorectal cancer ,030218 nuclear medicine & medical imaging ,0302 clinical medicine ,Neoplasms ,Antineoplastic Combined Chemotherapy Protocols ,Clinical endpoint ,Precision Medicine ,Immune Checkpoint Inhibitors ,Panitumumab ,Sarcoma ,Hematology ,General Medicine ,DNA, Neoplasm ,Middle Aged ,Progression-Free Survival ,Survival Rate ,Tolerability ,Response Evaluation Criteria in Solid Tumors ,030220 oncology & carcinogenesis ,Female ,Signal Transduction ,Adult ,medicine.medical_specialty ,Antineoplastic Agents ,Irinotecan ,03 medical and health sciences ,Young Adult ,Crizotinib ,Internal medicine ,medicine ,Humans ,Radiology, Nuclear Medicine and imaging ,VDP::Medisinske Fag: 700 ,Progression-free survival ,Survival rate ,Aged ,business.industry ,Carcinoma ,Cancer ,Sequence Analysis, DNA ,medicine.disease ,Precision medicine ,VDP::Medical disciplines: 700 ,Vemurafenib ,Drug Resistance, Neoplasm ,Mutation ,business - Abstract
Background: In precision cancer medicine, the challenge is to prioritize DNA driver events, account for resistance markers, and procure sufficient information for treatment that maintains patient safety. The MetAction project, exploring how tumor molecular vulnerabilities predict therapy response, first established the required workflow for DNA sequencing and data interpretation (2014–2015). Here, we employed it to identify molecularly matched therapy and recorded outcome in end-stage cancer (2016–2019). Material and methods: Metastatic tissue from 26 patients (16 colorectal cancer cases) was sequenced by the Oncomine assay. The study tumor boards interpreted called variants with respect to sensitivity or resistance to matched therapy and recommended single-agent or combination treatment if considered tolerable. The primary endpoint was the rate of progression-free survival 1.3-fold longer than for the most recent systemic therapy. The objective response rate and overall survival were secondary endpoints. Results: Both common and rare actionable alterations were identified. Thirteen patients were found eligible for therapy following review of tumor sensitivity and resistance variants and patient tolerability. The interventions were inhibitors of ALK/ROS1-, BRAF-, EGFR-, FGFR-, mTOR-, PARP-, or PD-1-mediated signaling for 2–3 cases each. Among 10 patients who received treatment until radiologic evaluation, 6 (46% of the eligible cases) met the primary endpoint. Four colorectal cancer patients (15% of the total study cohort) had objective response. The only serious adverse event was a transient colitis, which appeared in 1 of the 2 patients given PD-1 inhibitor with complete response. Apart from those two, overall survival was similar for patients who did and did not receive study treatment. Conclusions: The systematic MetAction approach may point forward to a refined framework for how to interpret the complexity of sensitivity versus resistance and patient safety that resides in tumor sequence data, for the possibly improved outcome of precision cancer medicine in future studies.
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- 2020
16. 11q Deletion or ALK Activity Curbs DLG2 Expression to Maintain an Undifferentiated State in Neuroblastoma
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Joachim T. Siaw, Wei-Yun Lai, Ana P. Berbegall, Per Kogner, Tommy Martinsson, Gunhild Trøen, Malin Östensson, Angela Martinez-Monleon, Rose-Marie Sjöberg, Jimmy Van den Eynden, Dan E. Lind, Ruth H. Palmer, Helena Carén, Anna Djos, Klaus Beiske, Niloufar Javanmardi, Rosa Noguera, Susanne Fransson, and Bengt Hallberg
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0301 basic medicine ,Transcription, Genetic ,Carcinogenesis ,Chromaffin Cells ,Retinoic acid ,law.invention ,Neuroblastoma ,chemistry.chemical_compound ,0302 clinical medicine ,law ,Nerve Growth Factor ,Medicine and Health Sciences ,retinoic acid ,Anaplastic Lymphoma Kinase ,lcsh:QH301-705.5 ,Neurons ,Mice, Inbred BALB C ,Neural crest ,Cell Differentiation ,Prognosis ,Candidate Tumor Suppressor Gene ,DLG2 ,Up-Regulation ,Cell biology ,Gene Expression Regulation, Neoplastic ,ERK ,Phenotype ,Treatment Outcome ,medicine.anatomical_structure ,Female ,Chromosome Deletion ,tumor suppressor ,MAP Kinase Signaling System ,Sp1 Transcription Factor ,Schwann cell ,Genetics and Molecular Biology ,Tretinoin ,Biology ,General Biochemistry, Genetics and Molecular Biology ,03 medical and health sciences ,Adrenergic Agents ,Cell Line, Tumor ,medicine ,Animals ,Humans ,Progenitor cell ,Gene ,Psychological repression ,Cell Proliferation ,Chromosomes, Human, Pair 11 ,Tumor Suppressor Proteins ,medicine.disease ,030104 developmental biology ,ALK ,lcsh:Biology (General) ,chemistry ,Trk receptor ,General Biochemistry ,Suppressor ,Schwann Cells ,Guanylate Kinases ,030217 neurology & neurosurgery - Abstract
High-risk 11q deleted neuroblastomas typically display undifferentiated/poorly differentiated morphology. Neuroblastoma is thought to develop from Schwann cell precursors and undifferentiated neural crest (NC) derived cells. It is therefore vital to understand mechanisms involved in the block of differentiation. We identify an important role for oncogenic ALK-ERK1/2-SP1 signaling in maintenance of undifferentiated NC-derived progenitors via repression of DLG2, a tumor suppressor in neuroblastoma. DLG2 is expressed in the ‘bridge signature’ that represents the transcriptional transition state when neural crest cells or Schwann Cell Precursors become chromaffin cells of the adrenal gland. We show that restoration of DLG2 expression spontaneously drives neuroblastoma differentiation highlighting the importance of DLG2 in this process. Further, genetic analysis of high-risk 11q-deletion neuroblastomas identified genetic lesions in the DLG2 gene. Our data also suggest that further exploration of other ‘bridge genes’ may help elucidate the mechanisms underlying the differentiation of NC-derived progenitors and their contribution to neuroblastoma.
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- 2020
17. N-cadherin in neuroblastoma disease: expression and clinical significance.
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Tim Lammens, Katrien Swerts, Lara Derycke, Annemie De Craemer, Sara De Brouwer, Katleen De Preter, Nadine Van Roy, Jo Vandesompele, Frank Speleman, Jan Philippé, Yves Benoit, Klaus Beiske, Marc Bracke, and Geneviève Laureys
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Medicine ,Science - Abstract
One of the first and most important steps in the metastatic cascade is the loss of cell-cell and cell-matrix interactions. N-cadherin, a crucial mediator of homotypic and heterotypic cell-cell interactions, might play a central role in the metastasis of neuroblastoma (NB), a solid tumor of neuroectodermal origin. Using Reverse Transcription Quantitative PCR (RT-qPCR), Western blot, immunocytochemistry and Tissue MicroArrays (TMA) we demonstrate the expression of N-cadherin in neuroblastoma tumors and cell lines. All neuroblastic tumors (n = 356) and cell lines (n = 10) expressed various levels of the adhesion protein. The N-cadherin mRNA expression was significantly lower in tumor samples from patients suffering metastatic disease. Treatment of NB cell lines with the N-cadherin blocking peptide ADH-1 (Exherin, Adherex Technologies Inc.), strongly inhibited tumor cell proliferation in vitro by inducing apoptosis. Our results suggest that N-cadherin signaling may play a role in neuroblastoma disease, marking involvement of metastasis and determining neuroblastoma cell viability.
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- 2012
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18. Mutational dynamics and immune evasion in diffuse large B-cell lymphoma explored in a relapse-enriched patient series
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Erlend B. Smeland, Eivind Hovig, Lars Birger Aasheim, Ragnhild A. Lothe, Daniel Vodak, Ole Christian Lingjærde, Jillian F. Wise, Yngvild Nuvin Blaker, Sirpa Leppä, Gunhild Trøen, Annika Pasanen, Bjarne Johannessen, Michael S. Lawrence, Harald Holte, Leonardo A. Meza-Zepeda, Susanne Lorenz, June Helen Myklebust, Vera Hilden, Sigve Nakken, Chloé B. Steen, Baoyan Bai, Ola Myklebost, Anita Sveen, Klaus Beiske, Department of Oncology, and HUS Comprehensive Cancer Center
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0301 basic medicine ,EXPRESSION ,education ,Biology ,03 medical and health sciences ,0302 clinical medicine ,Immune system ,immune system diseases ,CLASS-I ,hemic and lymphatic diseases ,REVEALS ,medicine ,Humans ,HETEROGENEITY ,Immune Evasion ,Cancer ,Hematology ,SOMATIC MUTATIONS ,medicine.disease ,Evasion (ethics) ,CANCER ,GENE ,Stimulus Report ,GENOME ,030104 developmental biology ,030220 oncology & carcinogenesis ,DISCOVERY ,DLBCL ,3121 General medicine, internal medicine and other clinical medicine ,Mutation ,Cancer research ,Lymphoma, Large B-Cell, Diffuse ,Neoplasm Recurrence, Local ,Diffuse large B-cell lymphoma - Abstract
Key Points Diagnostic and relapse diffuse large B-cell lymphoma (DLBCL) biopsies reveal increased mutational burden/loss of heterozygosity in HLA-A. Serially sampled tumor biopsies provide insight into therapeutic targets and evolutionary divergence in relapsed/refractory DLBCL.
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- 2019
19. The MCL35 gene expression proliferation assay predicts high-risk MCL patients in a Norwegian cohort of younger patients given intensive first line therapy
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Merrill Boyle, Arne Kolstad, Ole Christian Lingjærde, Lisa M. Rimsza, Gunhild Trøen, Klaus Beiske, Erlend B. Smeland, Andreas Rosenwald, Sunniva Kvaløy, David W. Scott, Harald Holte, Yngvild Nuvin Blaker, and June Helen Myklebust
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Adult ,Male ,Oncology ,medicine.medical_specialty ,Proliferation index ,Biopsy ,Kaplan-Meier Estimate ,Lymphoma, Mantle-Cell ,Cell morphology ,Article ,03 medical and health sciences ,0302 clinical medicine ,International Prognostic Index ,Risk Factors ,Internal medicine ,Antineoplastic Combined Chemotherapy Protocols ,Gene expression ,medicine ,Humans ,RNA, Neoplasm ,Aged ,Cell Proliferation ,business.industry ,Gene Expression Profiling ,Hematopoietic Stem Cell Transplantation ,Hematology ,Middle Aged ,Prognosis ,medicine.disease ,030220 oncology & carcinogenesis ,Cohort ,Female ,Mantle cell lymphoma ,Rituximab ,Stem cell ,business ,030215 immunology ,medicine.drug - Abstract
Patients with mantle cell lymphoma (MCL) generally have a dismal prognosis. Intensified induction treatment with rituximab and high dose cytarabine (R_HDAC), and consolidation with high-dose therapy with autologous stem cell support has resulted in 10-year overall survival (OS) higher than 60%. However, the clinical course varies. Diagnostic tools capable of stratifying patients include the MCL International Prognostic Index (MIPI), gene expression-based proliferation signature, Ki-67 proliferation index or tumour cell morphology. Here, we tested the performance of a newly developed Nanostring-based RNA expression-based proliferation assay (MCL35) on formalin-fixed paraffin-embedded tumour tissue from younger patients recruited in or treated according to Nordic MCL protocols compared to the prognosticators listed above. Seventy-four patients were included and the assay performed well in all cases except four, which had inadequate RNA quality. The patients were evenly distributed in the MCL35 low-, intermediate- and high-risk categories. MCL35 low- and intermediate- risk groups had overlapping progression-free survival (PFS), while patients in the high-risk category had significantly inferior PFS. Combining MCL35 with MIPI or the MIPI-C (MIPI with the addition of binary Ki67 score +/-30%) showed a better discrimination than either assessment alone. In conclusion, the MCL35 assay alone or combined with MIPI or MIPI-C scores can identify patients who still have a dismal outcome despite intensified treatment.
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- 2018
20. Is deep brain involvement in intracranial primary central nervous system lymphoma of importance for penetration of chemotherapeutic agents?
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Anna Latysheva, Torstein R. Meling, Guro Jahr, Klaus Beiske, Michele Da Broi, Harald Holte, and Kyrre E. Emblem
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Adult ,Male ,Oncology ,medicine.medical_specialty ,Neurology ,Adolescent ,Lymphoma ,medicine.medical_treatment ,Contrast Media ,Central Nervous System Neoplasms ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,medicine ,Humans ,Radiology, Nuclear Medicine and imaging ,Prospective Studies ,Aged ,Neuroradiology ,Aged, 80 and over ,Chemotherapy ,Norway ,business.industry ,Primary central nervous system lymphoma ,Middle Aged ,Prognosis ,medicine.disease ,Magnetic Resonance Imaging ,Chemotherapy regimen ,Survival Rate ,030220 oncology & carcinogenesis ,Female ,Neurology (clinical) ,Neurosurgery ,Cardiology and Cardiovascular Medicine ,business ,Perfusion ,030217 neurology & neurosurgery - Abstract
The purposes of this study are to study the impact of deep brain involvement on overall survival (OS) and progression-free survival (PFS) in intracranial primary CNS lymphoma (PCNSL), and to explore possible mechanisms for this impact using advanced MRI techniques. Seventy-nine patients with histologically verified PCNSL were identified from a prospective clinical database of patients treated at Oslo University Hospital between 2003 and 2014. Patients were treated per standard chemotherapeutic regimens (N = 57) or no chemotherapy (N = 22). Anatomical MRIs were available in all patients to assess tumor load and location based on contrast agent enhancement visible on T1-weighted images. Diffusion MRIs were available in 33 (42%) patients and perfusion MRI in 13 (16%) patients that received active treatment. Across all patients, OS and PFS were 16.4 and 9.8 months, respectively. In multivariate analysis, MRI-based deep brain involvement (80%) was the only negative significant factor of OS (OR = 14.2; P
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- 2018
21. Protein Profiling Identify Distinct Tumor-Tissue Protein Expression Pattern Specific for Relapsing Diffuse Large B-Cell Lymphoma
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Marja-Liisa Karjalainen-Lindsberg, Bent Honoré, Judit Jørgensen, Francesco d'Amore, Lars Pedersen, Diani Wilken, Sirpa Leppä, Harald Holte, Jan Delabie, Klaus Beiske, and Maja Ludvigsen
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0303 health sciences ,Chemistry ,Immunology ,Cell Biology ,Hematology ,medicine.disease ,Biochemistry ,Tumor tissue ,Protein expression ,3. Good health ,Protein profiling ,03 medical and health sciences ,0302 clinical medicine ,Cancer research ,medicine ,Diffuse large B-cell lymphoma ,030304 developmental biology ,030215 immunology - Abstract
Diffuse large B-cell lymphoma (DLBCL) is a heterogeneous disease. Several genetic drivers have been suggested based on gene-expression and RNA sequencing. However, clinical trials based on these molecular subclassifications have failed to improve treatment results and standard of care in DLBCL is still R-CHOP (rituximab, cyclophosphamide, doxorubicin, prednisone) based therapy, which results in approximately an 70% 5-year overall survival rate. Nordic Lymphoma Group (NLG) has conducted two large phase II trials (NLG-LBC-04; NCT 01502982 and NLG-LBC-05; NCT 01325194) during the last decade with the aim of improving the treatment outcome for young ( The aim of our study was to search for prognostic markers and possible therapeutic targets at the protein level in a uniformly treated patient cohort from the two Nordic trials (n=64) with available tumor-tissue. Thus, in this study, we investigated the protein expression pattern in the pre-therapeutic formalin-fixed paraffin embedded tumor samples by nano liquid-chromatography coupled to a mass spectrometer (Orbitrap Fusion) through an EASY-Spray nano-electrospray ion source (nLC-MS/MS). We identified 4,622 proteins with at least two unique peptides across all samples. In the combined cohort, we were able to, based on differential protein expression of 190 proteins between patients (p Disclosures Holte: Gilead: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; Nordic: Membership on an entity's Board of Directors or advisory committees; Nanovector: Membership on an entity's Board of Directors or advisory committees, Other: lectures honorarias; Novartis: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees. Jørgensen: Gilead/Kite: Consultancy; Novartis: Consultancy; Celgene/BMS: Consultancy; Roche: Consultancy.
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- 2021
22. The Genomic Landscape of Plasmablastic Lymphoma (PBL) - an L.L.M.P.P. Project
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Giorgio Inghirami, Joo Y. Song, Timothy C. Greiner, German Ott, Kerry J. Savage, Philipp W. Raess, Catalina Amador, Pedro Farinha, Itziar Salaverria, David W. Scott, Brett Collinge, Ryan D. Morin, Andrew J. Mungall, Andrew L. Feldman, Kai Fu, Dennis D. Weisenburger, James R. Cook, Lisa M. Rimsza, Graham W. Slack, Klaus Beiske, Jasper Wong, Jan Delabie, Susana Ben-Neriah, Laura K Hilton, Stefania Pittaluga, Elias Campo, Harald Holte, Andreas Rosenwald, Wing C. Chan, Elaine S. Jaffe, and Christian Steidl
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Immunology ,medicine ,Cell Biology ,Hematology ,Biology ,medicine.disease ,Biochemistry ,Molecular biology ,Plasmablastic lymphoma - Abstract
Introduction: Plasmablastic lymphoma (PBL) is an aggressive B-cell lymphoma that predominantly occurs in patients with HIV or other causes of immunodeficiency. Frequent infection by the Epstein-Barr virus (EBV) and MYC translocations have been described as major features contributing to the pathogenesis of PBL. Prior studies examining the genetic landscape of PBL have largely relied on targeted capture-based sequencing approaches. As such, the molecular features of PBL remain to be fully explored. Here, we provide a comprehensive description of the genomic landscape of PBL using whole-genome and whole-exome sequencing to identify commonly perturbed pathways. Method: Archival diagnostic fresh frozen and formalin fixed paraffin embedded tissue biopsies from 58 PBL tumours were accrued from Lymphoma/Leukemia Molecular Profiling Project (LLMPP) sites, including 15 tumours from Ramis-Zaldivar et al., Haematolgica 2021. MYC rearrangements were identified by break-apart fluorescent in situ hybridization (FISH) and rearrangement partner was determined in a subset of tumours from capture or genome sequencing data using structural variant callers Manta, GRIDSS, and Delly. High confidence somatic mutations (SNVs/Indels) were identified in data from whole-genome (n=5) or whole-exome (n=53) sequencing through an ensemble voting approach utilizing four variant callers (Strelka2, Lofreq, Mutect2, SAGE). Mutation frequencies in known lymphoma-related genes were compared to activated B-cell (ABC)-DLBCL (Schmitz et al., NEJM 2018), as the closest tumour entity in terms of putative cell-of-origin differentiation stage, to identify differences in genetic aberrations. Candidate somatic copy number alterations (CNAs) were identified from exome and genome sequencing data, using CopywriteR and ControlFREEC, respectively, and high-confidence CNAs were determined using GISTIC2.0. Results: Within the study cohort, 81% of patients were male with a median age of 59 years (range 11-88). HIV and EBV statuses were available for 47% of patients and 95% of tumours, respectively, with 49% (13/27) of the patients being HIV+ and 69% (38/55) of tumours being EBV+. MYC rearrangement was observed in 60% (35/58) of PBLs, with IGH as the partner gene in 88% (21/24) of tumours. The most frequently mutated genes were STAT3 (38%), TP53 (22%), NRAS (21%), and TET2 (16%), consistent with previous studies, however novel mutations were seen in DUSP2 (21%), KLHL6 (16%), and BHLHE41 (16%). Recurrent CNAs included amplifications in 1q, whole gains of 7, 8q24, 11p12 and deletions affecting 4p16, 5p15, 10q11.22. While the mutational landscapes were similar between samples with and without a MYC translocation, the MYC-translocated PBLs showed more frequent amplification of 1q32.1. When stratifying by EBV status, STAT3 and SOCS1 mutations were more frequent in EBV-positive tumours, whereas TP53, TET2, KRAS, and MMRN2 mutations were associated with EBV-negativity. In comparison to ABC-DLBCL, PBLs were significantly enriched in STAT3 and NRAS mutations, and lacked common mutations affecting the NF-κB pathway (eg. MYD88, CD79B, and NFKBIZ 3' UTR mutations). Mutations in genes that are frequently mutated in ABC-DLBCLs, such as those associated with plasma cell differentiation (eg. PRDM1) or a memory B-cell fate (eg. TBL1XR1), were also not mutated in PBLs. Finally, genetic alterations associated with immune evasion, such as deletion of MHC I and II and mutations in B2M, CIITA, and CD58, were rarely observed. Conclusion: These data present a comprehensive overview of the genomic landscape of PBLs in a large cohort. We show frequent mutations involving the JAK-STAT and MAPK pathways, wherein the genetic landscape can be differentially characterized by EBV status and MYC rearrangement status. We show that PBLs are genetically distinct from ABC-DLBCLs, with absence of mutations in genes affecting the NF-κB pathway, immune evasion, and driving a memory B-cell fate. Disclosures Slack: Seagen: Consultancy, Honoraria. Raess: Scopio Labs: Research Funding. Holte: Gilead: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; Nordic: Membership on an entity's Board of Directors or advisory committees; Nanovector: Membership on an entity's Board of Directors or advisory committees, Other: lectures honorarias; Novartis: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees. Savage: Servier: Consultancy, Honoraria; Roche: Research Funding; BMS: Consultancy, Honoraria, Other: Institutional clinical trial funding; Astra-Zeneca: Consultancy, Honoraria; Merck: Consultancy, Honoraria, Other: Institutional clinical trial funding; AbbVie: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria; Takeda: Other: Institutional clinical trial funding; Beigene: Other: Institutional clinical trial funding; Genentech: Research Funding. Steidl: Seattle Genetics: Consultancy; Curis Inc.: Consultancy; Bayer: Consultancy; Epizyme: Research Funding; Trillium Therapeutics: Research Funding; AbbVie: Consultancy; Bristol-Myers Squibb: Research Funding. Rimsza: NanoString Technologies: Other: Fee-for-service contract. Morin: Foundation for Burkitt Lymphoma Research: Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy; Epizyme: Patents & Royalties. Scott: Abbvie: Consultancy; AstraZeneca: Consultancy; Rich/Genentech: Research Funding; BC Cancer: Patents & Royalties: Patent describing assigning DLBCL COO by gene expression profiling--licensed to NanoString Technologies. Patent describing measuring the proliferation signature in MCL using gene expression profiling. ; Incyte: Consultancy; Janssen: Consultancy, Research Funding; Celgene: Consultancy; NanoString Technologies: Patents & Royalties: Patent describing measuring the proliferation signature in MCL using gene expression profiling..
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- 2021
23. Heterogeneity of Regulatory T Cells in B-Cell Non-Hodgkin Lymphoma
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Kjetil Taskén, June Helen Myklebust, Johanna Olweus, Kanutte Huse, Ivana Spasevska, Chloé B. Steen, Klaus Beiske, Erlend B. Smeland, Sarah Elisabet Josefsson, Suzanne Lorenz, Ankush Sharma, Saskia Meyer, Eva Kimby, Harald Holte, Ash A. Alizadeh, Kushi Kushekhar, Yngvild Nuvin Blaker, Arne Kolstad, and Bjørn Østenstad
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LAG3 ,Immunology ,Follicular lymphoma ,FOXP3 ,hemic and immune systems ,chemical and pharmacologic phenomena ,Cell Biology ,Hematology ,Biology ,medicine.disease ,Biochemistry ,Immune checkpoint ,TIGIT ,Cancer research ,medicine ,Cytotoxic T cell ,Mantle cell lymphoma ,IL-2 receptor - Abstract
Introduction: Regulatory T cells (Tregs), a highly immunosuppressive subset of CD4 T cells, are enriched in B-cell non-Hodgkin lymphoma (NHL) and constitute a barrier to potent antitumor immune responses. Despite extensive studies, the significance of tumor-infiltrating Tregs on disease outcome is unclear and while Tregs may express co-inhibitory and co-stimulatory receptors, the role of intratumoral Tregs in the context of immune checkpoint therapy remains elusive. Emerging evidence suggests heterogeneity among Tregs and their suppressive capacities in cancer, emphasizing the need for additional markers to identify highly suppressive Tregs. Therefore, an in-depth characterization of Treg heterogeneity in NHL could provide important insight into the disease pathogenesis and have implications for rational drug design. Methods: Expression of checkpoint receptors in Tregs was characterized by fluorescence flow cytometry and mass cytometry analysis of single-cell suspensions from diffuse large B-cell lymphoma (DLBCL; n = 16), follicular lymphoma (FL; n = 8), mantle cell lymphoma (MCL; n = 10), marginal zone lymphoma (MZL; n = 2), chronic lymphocytic lymphoma (CLL; n = 7), as well as tonsils (n = 8) and peripheral blood (n = 4) from healthy donors. Functional characterization of intratumoral Tregs was performed by a proliferation assay using FACS-sorted Tregs as suppressor cells and autologous CellTrace Violet-labelled T effector cells as responder cells. Single-cell RNA sequencing (scRNA-seq) was performed on FACS-sorted CD4 T cells from 3 DLBCL, 3 FL and 3 healthy donor tonsils using the 10X Genomics single cell 5' based library construction and VDJ libraries for TCR-sequencing. Additionally, for simultaneous profiling of phenotypic features with the mRNA expression in single cells, Cellular Indexing of Transcriptomes and Epitopes by Sequencing (CITEseq) was applied. The Treg compartment was characterized by clustering into distinct transcriptional Treg states and differential expression of marker genes. Results: TIGIT and CTLA-4 were identified as common markers of intratumoral Tregs, in addition to FOXP3 and CD25. Unsupervised computational analysis revealed two distinct Treg subsets, based on contrasting expression of PD-1, OX40, CD226 and ICOS (Figure 1A). One subset displayed a checkpoint receptorlow phenotype that corresponded to peripheral blood Tregs. The second subset had a checkpoint receptorhigh phenotype with elevated levels of PD-1, OX40, ICOS, TIGIT, CTLA-4 and increased levels of activation markers CD28, CD69 and CD95/Fas. The frequency of checkpoint receptorhigh Tregs was significantly increased in NHL tumors, compared to PBMCs and tonsils from healthy donors. FL tumors had the highest frequency of Tregs with receptorhigh phenotype among the NHL entities (median frequency of 86%, range 71-92%) and DLBCL had the highest donor-to-donor variation (median frequency of 77%, range 35-98%) (Figure 1B). This phenotypic heterogeneity of the Treg compartment reflected different suppressive capacities of the two subsets. Checkpoint receptorhigh Tregs were more potent mediators of immunosuppression in terms of suppressing the proliferation of autologous effector CD4 and CD8 T cells (Figure 1C). Furthermore, transcriptomic analysis of CD4 T cells by scRNA-seq and CITEseq revealed distinct transcriptomic signatures of the checkpoint receptorhigh and -receptorlow subsets. In addition, a third subset of Tregs, characterized by increased expression of LAG3 and immunosuppression-associated genes (CTLA-4, IL10, CD38, KLRB1) but lack of FOXP3, was identified (Figure 1D-E). Analysis of scTCR-sequences to compare TCR repertoires and to identify developmental trajectories will further add to our knowledge of intratumoral Tregs. Conclusions: These results reveal heterogeneity within the Treg compartment in NHL based on expression of checkpoint receptors, transcriptional profiles and suppressive capacities. As intratumoral Treg phenotypes differ from peripheral blood Tregs, this presents new therapeutic opportunities. Specific targeting of intratumoral Tregs would lead to stronger antitumor effects while limiting immune-related adverse events. A deeper understanding of Treg heterogeneity within the tumor microenvironment could therefore open new paths for rational design of immune checkpoint therapy. Disclosures Kolstad: Merck: Research Funding; Nordic Nanovector: Membership on an entity's Board of Directors or advisory committees, Research Funding. Alizadeh:Janssen: Consultancy; Genentech: Consultancy; Pharmacyclics: Consultancy; Chugai: Consultancy; Celgene: Consultancy; Gilead: Consultancy; Roche: Consultancy; Pfizer: Research Funding.
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- 2020
24. Fusion of the genes ataxin 2 like, ATXN2L, and Janus kinase 2, JAK2, in cutaneous CD4 positive T-cell lymphoma
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Klaus Beiske, Signe Spetalen, Ludmila Gorunova, Assia Bassarova, Francesca Micci, Sverre Heim, and Ioannis Panagopoulos
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0301 basic medicine ,Janus kinase 2 ,biology ,food and beverages ,Chromosomal translocation ,medicine.disease ,Molecular biology ,Fusion protein ,Fusion gene ,03 medical and health sciences ,030104 developmental biology ,Oncology ,Fusion transcript ,hemic and lymphatic diseases ,Ataxin ,Immunology ,biology.protein ,medicine ,T-cell lymphoma ,Gene ,hormones, hormone substitutes, and hormone antagonists - Abstract
Acquired mutations were recently described in cutaneous T-cell lymphomas for the JAK1, JAK3, STAT3, and STAT5B genes of the JAK-STAT pathway. In the present study, RNA-sequencing of a primary cutaneous CD4 positive T-cell lymphoma carrying a three-way t(9;13;16)(p24;q34;p11) chromosome translocation showed that JAK2 from chromosome band 9p24 was rearranged and fused to a novel partner gene, ATXN2L, from 16p11. RT-PCR together with Sanger sequencing verified the presence of the ATXN2L-JAK2 fusion transcript. The ATXN2L-JAK2 fusion gene would code for a chimeric protein containing all domains of ATXN2L and the catalytic domain of the JAK2 tyrosine kinase. The ATXN2L-JAK2 chimeric protein could lead to constitutive activation of the downstream JAK-STAT signaling pathway in a manner similar to that seen for other JAK2 fusion proteins.
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- 2017
25. Folliculotropic Mycosis Fungoides with Skewed T-cell Receptor CDR3 Motif: Suggestive of Lipid-antigen Selection?
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Klaus Beiske, Agnieszka Malecka, Gunhild Trøen, Panagiota Mantaka, Jan Delabie, Per Helsing, and Petter Gjersvik
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Skin Neoplasms ,T-cellreceptorβ ,T cell ,folliculotropicmycosisfungoides ,CD1 ,Dermatology ,030226 pharmacology & pharmacy ,Antigens, CD1 ,03 medical and health sciences ,Mycosis Fungoides ,0302 clinical medicine ,Antigen ,medicine ,Humans ,gene ,Glycoproteins ,Mycosis fungoides ,business.industry ,T-cell receptor ,cutaneousT-celllymphoma ,complementarity-determiningregion3 ,Dendritic Cells ,General Medicine ,Dendritic cell ,mycosisfungoides ,Folliculotropic Mycosis Fungoides ,Hair follicle ,medicine.disease ,Complementarity Determining Regions ,Immunohistochemistry ,Molecular biology ,Lymphoma, T-Cell, Cutaneous ,medicine.anatomical_structure ,RL1-803 ,Case-Control Studies ,030220 oncology & carcinogenesis ,Genes, T-Cell Receptor beta ,Immunology ,business ,Hair Follicle - Abstract
Folliculotropic mycosis fungoides (FMF), a variant of mycosis fungoides (MF) with distinct clinical features, is characterized by infiltration of malignant T cells in hair follicles. This raises the hypothesis that antigens in the hair follicle may contribute to the pathogenesis of FMF. T-cell receptor β gene (TRB) sequences as well as dendritic cell subsets in patients with FMF (n = 21) and control patients with MF (n = 20) were studied to explore this hypothesis. A recurrent usage of the TRB junctional genes TRBJ2-1 and TRBJ2-7 was found in patients with FMF compared with those with MF. These genes contribute to an amino acid motif in the complementarity-determining region 3 (CDR3) of the T-cell receptor. This motif was previously found in T cells stimulated by lipids bound to CD1 on antigen-presenting cells. Additional immunohistochemical analysis revealed abundant CD1c- and CD1a- expressing dendritic cells in FMF. The combined findings support a role for lipid-antigen stimulation in FMF.
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- 2017
26. Recommendations for the standardization of bone marrow disease assessment and reporting in children with neuroblastoma on behalf of the International Neuroblastoma Response Criteria Bone Marrow Working Group
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Peter F. Ambros, Michelle Haber, Frank Berthold, Hiroyuki Shimada, Julie R. Park, Susan A. Burchill, Robert C. Seeger, Godelieve A.M. Tytgat, Penelope Brock, and Klaus Beiske
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0301 basic medicine ,Oncology ,Cancer Research ,medicine.medical_specialty ,Standardization ,business.industry ,Cancer ,Disease ,medicine.disease ,Bone marrow disease ,Surgery ,Neuroblastoma cell ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,medicine.anatomical_structure ,030220 oncology & carcinogenesis ,Internal medicine ,Neuroblastoma ,medicine ,Bone marrow ,Response criteria ,business - Abstract
BACKGROUND: The current study was conducted to expedite international standardized reporting of bone marrow disease in children with neuroblastoma and to improve equivalence of care. METHODS: A multidisciplinary International Neuroblastoma Response Criteria Bone Marrow Working Group was convened by the US National Cancer Institute in January 2012 with representation from Europe, North America, and Australia. Practical transferable recommendations to standardize the reporting of bone marrow disease were developed. RESULTS: To the authors' knowledge, the current study is the first to comprehensively present consensus criteria for the collection, analysis, and reporting of the percentage area of bone marrow parenchyma occupied by tumor cells in trephine-biopsies. The quantitative analysis of neuroblastoma content in bone marrow aspirates by immunocytology and reverse transcriptase-quantitative polymerase chain reaction are revised. The inclusion of paired-like homeobox 2b (PHOX2B) for immunohistochemistry and reverse transcriptase-quantitative polymerase chain reaction is recommended. Recommendations for recording bone marrow response are provided. The authors endorse the quantitative assessment of neuroblastoma cell content in bilateral core needle biopsies-trephines and aspirates in all children with neuroblastoma, with the exception of infants, in whom the evaluation of aspirates alone is advised. It is interesting to note that 5% disease is accepted as an internationally achievable level for disease assessment. CONCLUSIONS: The quantitative assessment of neuroblastoma cells is recommended to provide data from which evidence-based numerical criteria for the reporting of bone marrow response can be realized. This is particularly important in the minimal disease setting and when neuroblastoma detection in bone marrow is intermittent, where clinical impact has yet to be validated. The wide adoption of these harmonized criteria will enhance the ability to compare outcomes from different trials and facilitate collaborative trial design.
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- 2016
27. Prognostic implications of the microenvironment for follicular lymphoma under immunomodulation therapy
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Thomas Menter, Yara Banz, Luca Mazzucchelli, Birgitta Sander, Christer Sundström, Marja-Liisa Karjalainen-Lindsberg, Sergio Cogliatti, Magnus Hultdin, Hanne Hawle, Klaus Beiske, Alexandar Tzankov, Stefanie Hayoz, Eva Kimby, Rainer Grobholz, Stefan Dirnhofer, Emanuele Zucca, and Gieri Cathomas
- Subjects
Oncology ,Adult ,Male ,medicine.medical_specialty ,Follicular lymphoma ,Immunomodulation ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,medicine ,Tumor Microenvironment ,Humans ,Lymphoma, Follicular ,Lenalidomide ,Aged ,Aged, 80 and over ,Tumor microenvironment ,Hematology ,business.industry ,GATA3 ,Middle Aged ,medicine.disease ,Prognosis ,Progression-Free Survival ,3. Good health ,Lymphoma ,030220 oncology & carcinogenesis ,Rituximab ,Female ,business ,CD8 ,030215 immunology ,medicine.drug - Abstract
Follicular lymphoma (FL) constitutes a significant proportion of lymphomas and shows frequent relapses. Beyond conventional chemotherapy, new therapeutic approaches have emerged, focussing on the interplay between lymphoma cells and the microenvironment. Here we report the immunophenotypic investigation of the microenvironment of a clinically well-characterized prospective cohort (study SAKK35/10, NCT01307605) of 154 treatment-naive FL patients in need of therapy, who have been treated with rituximab only or a combination of rituximab and the immunomodulatory drug lenalidomide/Revlimid® A high ratio of CD4- to CD8-positive T cells (P = 0·009) and increased amounts of PD1+ tumour-infiltrating T cells (P = 0·007) were associated with inferior progression-free survival in the whole cohort. Interestingly, the prognostic impact of PD1+ T cells and the CD4/CD8 ratio lost its significance in the subgroup treated with R2 . In the latter group, high amounts of GATA3+ T helper (Th2) equivalents were associated with better progression-free survival (P < 0·001). We identified tumour microenvironmental features that allow prognostic stratification with respect to immuno- and combined immuno- and immunomodulatory therapy. Our analysis indicates that lenalidomide may compensate the adverse prognostic implication of higher amounts of CD4+ and, particularly, PD1+ T cells and that it has favourable effects mainly in cases with higher amounts of Th2 equivalents. [Correction added on 11 February 2020, after online publication: The NCT-trial number was previously incorrect and has been updated in this version].
- Published
- 2019
28. Responsiveness to PD-1 Blockade in End-Stage Colon Cancer with Gene Locus 9p24.1 Copy-Number Gain
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Anne Hansen Ree, Inger Riise Bergheim, Eivind Hovig, Anne Negård, Hege G. Russnes, Gunhild Mari Mælandsmo, Daniel Heinrich, Kjersti Flatmark, Anne Lise Børresen-Dale, Christin Johansen, Vegard Nygaard, Vigdis Nygaard, and Klaus Beiske
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0301 basic medicine ,Cancer Research ,DNA Copy Number Variations ,Colorectal cancer ,Immunology ,Programmed Cell Death 1 Receptor ,Pembrolizumab ,Gene mutation ,Antibodies, Monoclonal, Humanized ,Metastasis ,03 medical and health sciences ,0302 clinical medicine ,Antineoplastic Agents, Immunological ,Biopsy ,Medicine ,Humans ,VDP::Medisinske Fag: 700 ,medicine.diagnostic_test ,biology ,business.industry ,Liver Neoplasms ,Middle Aged ,medicine.disease ,Immune checkpoint ,Blockade ,VDP::Medical disciplines: 700 ,030104 developmental biology ,Treatment Outcome ,Genetic Loci ,030220 oncology & carcinogenesis ,Colonic Neoplasms ,Mutation ,Cancer research ,biology.protein ,Female ,Antibody ,business ,Chromosomes, Human, Pair 9 - Abstract
Most patients whose large bowel cancer has spread to other organs do not respond to immune therapy. We detected a rare gene mutation, termed 9p24.1 copy-number gain (CNG), in an otherwise incurable colorectal cancer that provoked an immune therapy response. We identified this gene mutation by gene-panel sequencing of DNA from a liver metastasis biopsy from a patient who had disease refractory to standard therapies. Following immune checkpoint blockade (ICB) with pembrolizumab (anti–PD-1), the patient experienced conversion of the tumor phenotype from one with epithelial features to that of an inflamed microenvironment, detected by high-resolution RNA sequencing. Circulating tumor DNA disappeared over the first weeks of therapy. As assessed by standard radiographic measurement, the patient had a partial response that was durable. This patient's response may support the use of histology-agnostic ICB in solid tumors that carry the rare 9p24.1 CNG.
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- 2018
29. Mutational Dynamics and Evolutionary Divergence in DLBCL: A Call for Relapse Sampling
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Sirpa Leppä, Harald Holte, Michael S. Lawrence, Lars Birger Aasheim, June Helen Myklebust, Vera Hilden, Klaus Beiske, Baoyan Bai, Bjarne Johannessen, Yngvild Nuvin Blaker, Sigve Nakken, Leonardo A. Meza-Zepeda, Jillian F. Wise, Erlend B. Smeland, Annika Pasanen, Chloé B. Steen, Eivind Hovig, Ragnhild A. Lothe, Anita Sveen, Ola Myklebost, Ole Christian Lingjærde, Daniel Vodák, Gunhild Trøen, and Suzanne Lorenz
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Oncology ,medicine.medical_specialty ,business.industry ,Immunology ,Salvage therapy ,Cell Biology ,Hematology ,Human leukocyte antigen ,medicine.disease ,Biochemistry ,Somatic evolution in cancer ,3. Good health ,Lymphoma ,Loss of heterozygosity ,Internal medicine ,medicine ,Personalized medicine ,business ,Diffuse large B-cell lymphoma ,Exome sequencing - Abstract
Introduction Relapses of diffuse large B-cell lymphoma typically occur within 2-3 years and only 10% of these patients reach a 3-year progression-free survival compared to 65% at diagnosis. Our ability to distinguish patients at risk for relapse remains based on clinical staging. We hypothesized that identifying genetic alterations in serial tumour biopsies at diagnosis and relapse would improve our ability to identify high-risk patients, make therapeutic selections and reveal molecular markers for chemo-immunotherapy resistant tumours. However, relatively few relapsed/refractory biopsies have been sequenced. A unique, clinically annotated, Nordic DLBCL cohort was used to identify significantly mutated genes, assess potential driver genes, comprehensively examine clonal evolution, and gauge the importance of clinical relapsed sampling. Methods To address the lack of information on the molecular foundations of relapsed/refractory DLBCL, we performed whole exome sequencing (WES) on 42 DLBCL cases, with 34% representing relapsed/refractory biopsies and 13 serially sample cases. Enriched with relapsed/refractory diffuse large B-cell lymphoma cases, we performed multiple computational analyses to identify significantly mutated genes (MutSig2CV), mutational signatures (NMF and DeConstructsSig), driver genes (IntOgen and CADD), clonal evolution architecture (SciClone and ClonEvol), druggable gene analysis (DGIdb), and HLA-inference and mutation calling (Polysolver). Results Clonal evolution analysis of 13 paired diagnostic and relapsed biopsies revealed that relapsed/refractory biopsies have remarkable similarities to diagnostic biopsies and often present with late divergent clonal evolution of the tumor. Mutational analysis of 18 serially sampled tumors determined that in the majority of cases druggable oncogenic variants do arise at relapse. In addition, time to relapse correlated with divergence of mutations from the diagnostic biopsy. In addition to being identified as a significantly mutated gene, mutations in HLA-A had an increased incidence in cases that ultimately relapsed. This result led to an in-depth investigation into the mutational prevalence, timing, impact on prognosis, and loss of heterozygosity in the human leukocyte antigen (HLA) haplotypes of relapsed/refractory DLBCL. HLA-A mutagenesis and loss of heterozygosity was discovered as mechanisms of immune evasion in cases that go on to relapse from R-CHOP like therapies (Figure 1). Conclusions Our results yield insight into the development of chemo-immunotherapy resistant diffuse large B-cell lymphoma, and highlight the clinical importance of sampling relapsed biopsies. Analysis of immune evasion through MHC Class I/II, specifically HLA-A, may provide better characterization of patients for relapse prediction. In the age of personalized medicine it will be instrumental to determine if relapsed biopsies offer additional insight for salvage therapy treatment. Divergence of biopsies, as characterized by shared genomic mutations, increase with time and the majority of cases present with new alterations in druggable genes post-therapy. Disclosures Leppa: Roche: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Celgene: Consultancy; Bayer: Research Funding. Holte:Novartis: Honoraria, Other: Advisory board.
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- 2019
30. The DLBCL90 Double-Hit Gene Expression Signature Is Not Associated with Inferior Survival in Young High-Risk Patients with Diffuse Large B-Cell Lymphoma Treated with Dose-Intensive Immunochemotherapy
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Erlend B. Smeland, Leo Meriranta, June Helen Myklebust, Judit Jørgensen, David Scott, Kathrine T. Isaksen, Marianne Brodtkorb, Klaus Beiske, Mats Jerkeman, Marja-Liisa Karjalainen-Lindsberg, Sirpa Leppä, Harald Holte, and Yngvild Nuvin Blaker
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Oncology ,Double hit ,medicine.medical_specialty ,Immunology ,Chromosomal translocation ,Biochemistry ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,Biopsy ,Gene expression ,Medicine ,030304 developmental biology ,0303 health sciences ,medicine.diagnostic_test ,business.industry ,Mediastinum ,Cell Biology ,Hematology ,medicine.disease ,3. Good health ,Lymphoma ,medicine.anatomical_structure ,Cytarabine ,business ,Diffuse large B-cell lymphoma ,030215 immunology ,medicine.drug - Abstract
Background: High-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements (HGBL-DH/TH) occurs in approximately 8% of de novo diffuse large B-cell lymphoma (DLBCL) cases, with BCL2 translocations (HGBL-DH/TH-BCL2) being a germinal center B-cell like (GCB) phenomenon (Scott et al. Blood 2018). HGBL-DH/TH is associated with poor outcome when treated with standard R-CHOP-therapy, but retrospective studies suggest that more aggressive treatment may improve outcome (Petrich et al. Blood 2014; Oki et al. BJH 2014). To overcome limitations with identification of HGBL-DH/TH by fluorescence in situ hybridization (FISH), Ennishi et al. developed a gene expression signature (DHITsig) that identified tumors with a HGBL-DH/TH-BCL2 gene expression phenotype. This DHITsig was translated into a new assay (DLBCL90) for application on formalin-fixed paraffin-embedded (FFPE) biopsies (Ennishi et al. J Clin Oncol 2019), and included identification of cell-of-origin (COO) and primary mediastinal B-cell lymphoma (Scott et al. Blood 2014; Mottok et al. Blood 2018). The DHITsig roughly doubled the number of cases in the HGBL-DH/TH-group compared with FISH, and was associated with a poor prognosis in patients treated with R-CHOP. In our study we aimed to validate the DLBCL90 assay in an independent cohort of young high-risk patients treated with dose-intensive immunochemotherapy within two Nordic trials. Patients and methods: RNA was extracted from pretreatment FFPE biopsies from 88 high-risk de novo DLBCL patients treated with dose-dense immunochemotherapy with systemic CNS prophylaxis in two Nordic trials (Holte et al. Ann. Oncol. 2013; Leppä et al. 15-ICML 2019). In the first trial patients received 6 courses of R-CHOEP-14 followed by 1 course of HD-Mtx and HD-Ara-C. In the second trial 2 courses of HD-Mtx were given in combination with R-CHOP-14 at the start of treatment, followed by 4 courses of R-CHOEP-14 and 1 course of R-HD-Ara-C at the end. Liposomal Ara-C was also administered intrathecally at courses 1, 3 and 5. Digital gene expression was performed, applying the DLBCL90 assay on the NanoString platform (NanoString Technologies, Seattle, WA) and FISH break-apart probes for MYC, BCL2 and BCL6 were used for identification of HGBL-DH/TH. Results: The COO assay assigned 54%, 31% and 15% of the tumors to the GCB, activated B-cell like (ABC) and unclassified group, respectively. The ABC- and unclassified DLBCLs showed a trend towards inferior outcome when compared to the GCB-group (OS: 59%, 66%, 91%, p=0.076, PFS: 74%, 59%, 85%, p=0.122, FFS: 63%, 51%, 83%, p=0.052, respectively). The DHITsig was only seen in the GCB subtype. Of the patients with the GCB subtype, 5 (10%) and 11 patients (23%) were assigned to the DHITsig-positive and DHITsig-indeterminate group, respectively. FISH results were available for 71 samples, and 6 were identified as HGBL-DH/TH-BCL2. Four of them were assigned to the DHITsig-positive group, while 1 case was assigned to the DHITsig-indeterminate group with a 79% probability of belonging to the DHITsig-positive group (cut-off 80%). The last case was a triple-hit tumor that was assigned to the DHITsig-negative group. This patient had a favorable outcome with a complete remission after first line therapy, and was still in remission at the last follow-up 45 months after diagnosis. Overall, after a median follow-up of 64 months, 17 patients (19%) experienced relapse and 13 patients (15%) had died. Within the GCB subgroup, there were no significant differences in clinical outcome (OS, PFS, FFS) between the DHITsig positive, negative and indeterminate groups when analyzed as separate groups, or when the positive/indeterminate groups were merged (figure). Conclusion: We confirm that the DLBCL90 gene expression assay identifies HGBL-DH/TH-BCL2 in FFPE biopsies. This, together with a rapid turnaround time, makes it an attractive alternative to FISH for double-hit assignment in the clinical setting. In our cohort of young-high risk patients treated with dose-dense immunochemotherapy, the DHITsig was not associated with inferior survival. Of note, neither was the HGBL-DH/TH defined by FISH. This may be due to the intensified treatment, overcoming the poor prognostic impact of the double-hit biology. Disclosures Jørgensen: Gilead: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees. Jerkeman:Roche: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Gilead: Honoraria, Research Funding; Acerta: Honoraria, Research Funding; Celgene: Honoraria, Research Funding. Scott:Roche/Genentech: Research Funding; Celgene: Consultancy; Janssen: Consultancy, Research Funding; NanoString: Patents & Royalties: Named inventor on a patent licensed to NanoSting [Institution], Research Funding. Holte:Novartis: Honoraria, Other: Advisory board.
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- 2019
31. Heterogeneous MYCN amplification in neuroblastoma: a SIOP Europe Neuroblastoma Study
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Rosa Noguera, Peter F. Ambros, Carole Coze, Dominik Bogen, Katia Mazzocco, Raffaella Defferrari, Klaus Beiske, Vassilios Papadakis, Gabriele Amann, Ellen Ruud, Angela Rita Sementa, Inge M. Ambros, Luigi Varesio, Valérie Combaret, Samuel Navarro, Victoria Castel, Ana P. Berbegall, Marta Jeison, Ruth Ladenstein, Nick Bown, Cormac Owens, Ulrike Pötschger, Ales Vicha, and Shifra Ash
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0301 basic medicine ,Oncology ,Male ,Cancer Research ,medicine.medical_specialty ,Clone (cell biology) ,Article ,03 medical and health sciences ,Genetic Heterogeneity ,Neuroblastoma ,0302 clinical medicine ,Internal medicine ,Gene duplication ,medicine ,Humans ,Stage (cooking) ,neoplasms ,Survival analysis ,N-Myc Proto-Oncogene Protein ,business.industry ,Genetic heterogeneity ,Age Factors ,Gene Amplification ,Infant, Newborn ,Infant ,medicine.disease ,Prognosis ,Survival Analysis ,3. Good health ,Europe ,030104 developmental biology ,Homogeneous ,030220 oncology & carcinogenesis ,Mycn amplification ,Female ,business - Abstract
Background In neuroblastoma (NB), the most powerful prognostic marker, the MYCN amplification (MNA), occasionally shows intratumoural heterogeneity (ITH), i.e. coexistence of MYCN-amplified and non-MYCN-amplified tumour cell clones, called heterogeneous MNA (hetMNA). Prognostication and therapy allocation are still unsolved issues. Methods The SIOPEN Biology group analysed 99 hetMNA NBs focussing on the prognostic significance of MYCN ITH. Results Patients 18 m: 0.67 ± 0.14, p = 0.011; metastatic: 18 m: 0.28 ± 0.09, p = 0.084). The genomic 'background’, but not MNA clone sizes, correlated significantly with relapse frequency and OS. No relapses occurred in cases of only numerical chromosomal aberrations. Infiltrated bone marrows and relapse tumour cells mostly displayed no MNA. However, one stage 4s tumour with segmental chromosomal aberrations showed a homogeneous MNA in the relapse. Conclusions This study provides a rationale for the necessary distinction between heterogeneous and homogeneous MNA. HetMNA tumours have to be evaluated individually, taking age, stage and, most importantly, genomic background into account to avoid unnecessary upgrading of risk/overtreatment, especially in infants, as well as in order to identify tumours prone to developing homogeneous MNA.
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- 2018
32. CLINICAL SIGNIFICANCE OF T-CELL EXHAUSTION IN PATIENTS WITH DIFFUSE LARGE B-CELL LYMPHOMA
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Teijo Pellinen, Klaus Beiske, Judit Jørgensen, Oscar Brück, Suvi-Katri Leivonen, Sirpa Leppä, Satu Mustjoki, Marja-Liisa Karjalainen-Lindsberg, Harald Holte, and Matias Autio
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Cancer Research ,Pathology ,medicine.medical_specialty ,business.industry ,T cell ,Hematology ,General Medicine ,medicine.disease ,medicine.anatomical_structure ,Oncology ,medicine ,Clinical significance ,In patient ,business ,Diffuse large B-cell lymphoma - Published
- 2019
33. Bilateral uveal melanomas with different gene expression detected with 7 years interval
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Øystein Fodstad, Øystein Garred, Klaus Beiske, and Nils Eide
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Male ,Pathology ,medicine.medical_specialty ,Monosomy ,genetic structures ,Enucleation ,Biology ,Melanosis ,03 medical and health sciences ,0302 clinical medicine ,medicine ,Humans ,Fluorescein Angiography ,In Situ Hybridization, Fluorescence ,Aged ,Neoplasm Staging ,Ultrasonography ,Nevus, Pigmented ,BAP1 ,medicine.diagnostic_test ,Choroid Neoplasms ,Tumor Suppressor Proteins ,Melanoma ,Micrometastasis ,Retinal detachment ,Melanoma, Amelanotic ,General Medicine ,medicine.disease ,Fluorescein angiography ,eye diseases ,Ocular melanocytosis ,Ophthalmology ,030220 oncology & carcinogenesis ,030221 ophthalmology & optometry ,Chromosomes, Human, Pair 3 ,sense organs ,Ubiquitin Thiolesterase - Abstract
Purpose To report a bilateral uveal melanoma detected in a micrometastasis study. Method Case report. Results At enucleation of a circumpapillary amelanotic mixed melanoma in a patient with ocular melanocytosis, a pigmented lesion in the other eye was detected, thought to be a naevus. BAP1 was positive showing nuclear staining of the tumour cells. Seven years later the naevus showed growth and development of a retinal detachment. FNAB disclosed monosomy 3 in the spindle tumour cells. Conclusion A case of bilateral melanoma with long-term survival without metastatic diseases is reported. Different gene expressions in the two eyes were revealed. The case is a reminder that follow-up over years is essential in patients with a uveal melanoma, especially with ocular melanocytosis.
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- 2015
34. Influence of segmental chromosome abnormalities on survival in children over the age of 12 months with unresectable localised peripheral neuroblastic tumours without MYCN amplification
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Valérie Combaret, A. Valent, Bárbara Marques, Ales Vicha, Tommy Martinsson, N. Van Roy, Riccardo Haupt, Gian Paolo Tonini, Gudrun Schleiermacher, Alberto Garaventa, M. Jeison, Stefano Parodi, Peter F. Ambros, Claudio Gambini, Giovanni Erminio, J.A. Kohler, I.M. Ambros, Nicole Gross, John Lunec, Raffaella Defferrari, Rosa Noguera, Ana P. Berbegall, Jérôme Couturier, Clare Bedwell, Deborah A. Tweddle, Klaus Beiske, Jean Bénard, Eva Villamón, Katia Mazzocco, and Nick Bown
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Cancer Research ,medicine.medical_specialty ,Pathology ,MYCN Amplification ,Kaplan-Meier Estimate ,unresectable ,Gastroenterology ,Disease-Free Survival ,segmental chromosome alterations ,Neuroblastoma ,neuroblastoma ,DDX1 ,FISH ,aCGH ,Older patients ,Peripheral Nervous System Neoplasms ,Internal medicine ,MYCN ,medicine ,Humans ,Multiplex ligation-dependent probe amplification ,Gain ,Chromosome Aberrations ,Oncogene Proteins ,Comparative Genomic Hybridization ,N-Myc Proto-Oncogene Protein ,business.industry ,Significant difference ,Gene Amplification ,Segmental Chromosome abnormalities ,Infant ,Nuclear Proteins ,Chromosome ,Prognosis ,localised ,medicine.disease ,Doenças Genéticas ,MLPA ,3. Good health ,Peripheral ,Oncology ,Mycn amplification ,Clinical Study ,Histopathology ,business - Abstract
Background: The prognostic impact of segmental chromosome alterations (SCAs) in children older than 1 year, diagnosed with localised unresectable neuroblastoma (NB) without MYCN amplification enrolled in the European Unresectable Neuroblastoma (EUNB) protocol is still to be clarified, while, for other group of patients, the presence of SCAs is associated with poor prognosis. Methods: To understand the role of SCAs we performed multilocus/pangenomic analysis of 98 tumour samples from patients enrolled in the EUNB protocol. Results: Age at diagnosis was categorised into two groups using 18 months as the age cutoff. Significant difference in the presence of SCAs was seen in tumours of patients between 12 and 18 months and over 18 months of age at diagnosis, respectively (P = 0.04). A significant correlation (P = 0.03) was observed between number of SCAs per tumour and age. Event-free (EFS) and overall survival (OS) were calculated in both age groups, according to both the presence and number of SCAs. In older patients, a poorer survival was associated with the presence of SCAs (EFS = 46% vs 75%, P = 0.023; OS = 66.8% vs 100%, P = 0.003). Moreover, OS of older patients inversely correlated with number of SCAs (P = 0.002). Finally, SCAs provided additional prognostic information beyond histoprognosis, as their presence was associated with poorer OS in patients over 18 months with unfavourable International Neuroblastoma Pathology Classification (INPC) histopathology (P = 0.018). Conclusions: The presence of SCAs is a negative prognostic marker that impairs outcome of patients over the age of 18 months with localised unresectable NB without MYCN amplification, especially when more than one SCA is present. Moreover, in older patients with unfavourable INPC tumour histoprognosis, the presence of SCAs significantly affects OS.
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- 2014
35. Abstract 1422: Preclinical development of CD37CAR T-cell therapy for treatment of B-cell lymphoma
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Erlend B. Smeland, Harald Holte, Anne Fåne, Yngvild Nuvin Blaker, Sylvie Pollmann, June Helen Myklebust, Klaus Beiske, Sébastien Wälchli, Solrun Melkorka Maggadottir, Else Marit Inderberg, Ane Kolstad, Pierre Dillard, Kanutte Huse, Hakan Köksal, Gunnar Kvalheim, and Sarah Josefsson
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Cancer Research ,biology ,business.industry ,T cell ,Cancer ,medicine.disease ,Chimeric antigen receptor ,CD19 ,Lymphoma ,medicine.anatomical_structure ,Oncology ,Antigen ,Cell culture ,hemic and lymphatic diseases ,medicine ,Cancer research ,biology.protein ,business ,B-cell lymphoma - Abstract
T cells modified to express chimeric antigen receptor (CAR) targeting CD19 have produced remarkable clinical responses in patients with relapsed/refractory B-cell acute lymphoblastic leukemia (B-ALL). CD19CAR T-cell therapy has also demonstrated prominent effects in B-cell non-Hodgkin lymphoma (B-NHL) patients. However, a subset of patients who relapse after CD19CAR T-cell therapy have outgrowth of CD19-negative tumor cells. Hence, development of alternative CARs targeting other B-cell markers represents an unmet medical need for B-ALL and B-NHL. Here, we confirmed previous data by showing that B-NHL overall have high expression of CD37. A second generation CD37CAR was designed and its efficacy in T cells was compared to that of CD19CAR. In vitro assessment of cytotoxicity and T-cell function upon co-culture of the CAR T cells with different target B-cell lymphoma cell lines demonstrated comparable efficacy between the two CARs. In an aggressive B-cell lymphoma xenograft model, CD37CAR T cells were as potent as CD19CAR T cells in controlling tumor growth. In a second xenograft model, using U2932 lymphoma cells containing a CD19-negative subpopulation, CD37CAR T cells efficiently controlled tumors and cured the mice while CD19CAR T cells had limited effect. We further show that, unlike CD19CAR, CD37CAR was not sensitive to antigen masking. Finally, CD37CAR reactivity was restricted to B-lineage cells. Collectively, our results demonstrated that CD37CAR T cells effectively can eradicate B-cell lymphoma tumors also when CD19 antigen expression is lost, and support further clinical testing for patients with relapsed/refractory B-NHL. Citation Format: Pierre Dillard, Hakan Köksal, Sarah Josefsson, Solrun Melkorka Maggadottir, Sylvie Pollmann, Anne Fåne, Yngvild Nuvin Blaker, Klaus Beiske, Kanutte Huse, Ane Kolstad, Harald Holte, Gunnar Kvalheim, Erlend Bremertun Smeland, June Myklebust, Else Marit Inderberg, Sebastien Wälchli. Preclinical development of CD37CAR T-cell therapy for treatment of B-cell lymphoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1422.
- Published
- 2019
36. Young High Risk Patients with MYC/BCL2 Double Hit Lymphoma, BCL2+ and/or Germinal Centre B-Cell like Diffuse Large B-Cell Lymphoma Benefit from Dose-Dense Chemoimmunotherapy Including Early CNS Prophylaxis: Analysis of Data from the Nordic Lymphoma Group CRY-04 and Chic Trials
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Signe Spetalen, Marja-Liisa Karjalainen-Lindsberg, Elisabeth Ralfkiaer, Leo Meriranta, Judit Jørgensen, Jan Delabie, Klaus Beiske, Sirpa Leppä, and Harald Holte
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High risk patients ,business.industry ,Immunology ,Double-Hit Lymphoma ,Cell Biology ,Hematology ,CNS Prophylaxis ,medicine.disease ,Biochemistry ,3. Good health ,Lymphoma ,03 medical and health sciences ,0302 clinical medicine ,medicine.anatomical_structure ,Chemoimmunotherapy ,030220 oncology & carcinogenesis ,Cancer research ,Medicine ,business ,Diffuse large B-cell lymphoma ,Neprilysin ,B cell ,030215 immunology - Abstract
Background. Survival of patients with high-risk diffuse large B-cell lymphoma (DLBCL) is suboptimal, and the risk of central nervous system (CNS) progression is relatively high. We investigated the efficacy of dose-dense chemoimmunotherapy and systemic CNS prophylaxis in two Nordic trials including patients less than 65 years with high-risk DLBCL. We combined individual patient data from these trials to compare clinical outcome and biological prognostic factors in patients treated with CNS prophylaxis given in the beginning (CHIC) versus at the end (CRY-04) of therapy. Patients and methods. In CRY-04 study, patients were treated with six courses of R-CHOEP14 followed by HD-Mtx and HD-Ara-C. In CHIC trial, treatment started with two courses of HD-Mtx in combination with R-CHOP14, followed by four courses of R-CHOEP-14 and one course of R-HD-AraC. In addition, liposomal AraC was administered intrathecally at courses 1, 3 and 5. For the correlative studies, formalin fixed paraffin embedded pretreatment tumor samples were analyzed by fluorescent in situ hybridization for BCL2 and c-MYC breakpoints and by immunochemistry for CD10, BCL6, MUM1, MYC and BCL2 expression. Germinal center B-cell-like (GCB)/non-GCB) subclassification was performed according to Hans algorithm. Results. Among 303 patients enrolled in the trials (CRY-04, n=160 and CHIC, n=143), 295 (CRY-04, n=154 and CHIC, n=139) were evaluable for baseline characteristics and outcome. Median age (54 and 56 years, p=0.222), male/female ratio, stage, and aaIPI scores were comparable in the two cohorts. CHIC regimen improved outcome over CRY-04; the findings included 4-year estimates of PFS (81% vs 66%, p=0.003), OS (83% and 79%, p=ns) and cumulative incidence rates of CNS progression (2.4% and 5.0%, p=ns). Treatment with the CHIC regimen reduced the risk of systemic progression (aaIPI adjusted RR=0.489, 95%CI 0.308-0.777, p=0.002). PFS benefit with CHIC over CRY-04 was observed across pre-specified subgroups, and particularly in patients less than 60 years old (p=0.008). In the entire study population, dual protein expression (DPE) of BCL2 and MYC was the only parameter to be significantly correlated with a worse PFS (4-y PFS 77% vs 50%, p=0.024; RR=2.300, 95% CI 1.088-4.860, p=0.029). Neither any single immunohistochemical marker nor the GCB/non-GCB subtype or MYC/BCL2-translocations significantly affected outcome. However, when treatment interaction was tested, MYC/BCL2 double hit status (DHL; 13%) predicted poor outcome among patients treated with CRY-04 regimen compared with patients who received CHIC regimen (4-y PFS; 38% vs 78%, p=0.086). GCB subtype and BCL2 positivity were also associated with better outcome in the CHIC cohort (4 y PFS; 63% vs 84%, p=0.011 and 61% vs 80%, p=0.007, respectively), whereas there were no significant survival differences between these regimens among the patients with non-GCB subtype, BCL2 negative DLBCL or DPE lymphomas. Conclusions. Our results derived from trial data with homogenous treatment support the use of HD-Mtx in the beginning rather than at the end of therapy. The survival benefit related to CHIC regimen over CRY-04 is due to better systemic control of the disease, and at least partly linked to improved survival among patients with GCB subtype, BCL2 positivity and DHL. Disclosures Leppa: Takeda: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Bayer: Research Funding; Roche: Consultancy, Honoraria, Research Funding; Celgene: Consultancy. Holte:Novartis Pharmaceuticals Corporation: Membership on an entity's Board of Directors or advisory committees; Roche, Norway: Research Funding.
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- 2018
37. Extra-adrenal composite phaeochromocytoma/neuroblastoma in a 15-month-old child
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Tom Monclair, Ingegerd Aagenæs, Henrik Holmstrøm, Marius Asplin, Ellen Ruud, and Klaus Beiske
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medicine.medical_specialty ,Pathology ,endocrine system diseases ,lcsh:Surgery ,Composite paraganglioma ,Differentiating Neuroblastoma ,chemistry.chemical_compound ,Paraganglioma ,Internal medicine ,Neuroblastoma ,Extra-adrenal phaeochromocytoma/neuroblastoma ,medicine ,Vanillylmandelic acid ,Youngest child ,business.industry ,Extra-Adrenal ,Homovanillic acid ,lcsh:RJ1-570 ,lcsh:Pediatrics ,lcsh:RD1-811 ,medicine.disease ,Endocrinology ,chemistry ,Pediatrics, Perinatology and Child Health ,Hypertension ,Catecholamine ,Surgery ,business ,medicine.drug - Abstract
A 15-month-old boy was diagnosed with malignant hypertension caused by a catecholamine excreting retroperitoneal paraganglioma consisting of a composite phaeochromocytoma/differentiating neuroblastoma. After alpha-blockade the tumor was excised. No adjuvant treatment was given, and he is doing well eight years after the diagnosis. The patient is the first child known to have an extra-adrenal retroperitoneal composite tumor, and also the youngest child with a composite phaeochromocytoma/neuroblastoma reported in the English literature.
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- 2015
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38. The tumour microenvironment influences survival and time to transformation in follicular lymphoma in the rituximab era
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Yngvild Nuvin Blaker, Ole Christian Lingjærde, Signe Spetalen, Klaus Beiske, Christopher Michael Melen, Bjørn Østenstad, Björn E. Wahlin, Birgitta Sander, June Helen Myklebust, Marianne Brodtkorb, Harald Holte, Jan Delabie, and Erlend B. Smeland
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Oncology ,Adult ,Male ,medicine.medical_specialty ,Pathology ,Time Factors ,Biopsy ,Follicular lymphoma ,Antineoplastic Agents ,03 medical and health sciences ,Young Adult ,0302 clinical medicine ,Lymphocytes, Tumor-Infiltrating ,Internal medicine ,medicine ,Tumor Microenvironment ,Humans ,Lymphoma, Follicular ,Aged ,Proportional Hazards Models ,Tumor microenvironment ,medicine.diagnostic_test ,Follicular dendritic cells ,business.industry ,CD68 ,FOXP3 ,Hematology ,Middle Aged ,medicine.disease ,Prognosis ,Cell Transformation, Neoplastic ,030220 oncology & carcinogenesis ,Rituximab ,Female ,Neoplasm Grading ,business ,CD8 ,Biomarkers ,030215 immunology ,medicine.drug ,Follow-Up Studies - Abstract
The tumour microenvironment influences outcome in patients with follicular lymphoma (FL), but its impact on transformation is less studied. We investigated the prognostic significance of the tumour microenvironment on transformation and survival in FL patients treated in the rituximab era. We examined diagnostic and transformed biopsies from 52 FL patients using antibodies against CD3, CD4, CD8, CD21 (CR2), CD57 (B3GAT1), CD68, FOXP3, TIA1, PD-1 (PDCD1), PD-L1 (CD274) and PAX5. Results were compared with a second cohort of 40 FL patients without signs of transformation during a minimum of five years observation time. Cell numbers and localization were semi-quantitatively assessed. Better developed CD21+ follicular dendritic cell (FDC) meshworks at diagnosis was a negative prognostic factor for overall survival (OS), progression-free survival (PFS) and time to transformation (TTT) in patients with subsequently transformed FL. Remnants of FDC meshworks at transformation were associated with shorter OS and PFS from transformation. High degrees of intrafollicular CD68+ and PD-L1+ macrophage infiltration, high total area scores and an extrafollicular/diffuse pattern of FOXP3+ T cells and high intrafollicular scores of CD4+ T cells at diagnosis were associated with shorter TTT. Scores of several T-cell subset markers from the combined patient cohorts were predictive for transformation, especially CD4 and CD57.
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- 2016
39. Peripheral neuroblastic tumors with genotype-phenotype discordance: A report from the Children's Oncology Group and the International Neuroblastoma Pathology Committee
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Wendy B. London, Michael D. Hogarty, Rie Suganuma, A. Thomas Look, Claudio Gambini, Arlene Naranjo, Hideki Sano, Catherine Cullinane, Larry Wang, Hiroyuki Shimada, Gabriele Amann, Emanuele S.G. d'Amore, Jason A. Jarzembowski, John M. Maris, Robert C. Seeger, Klaus Beiske, Susan L. Cohn, Samuel Navarro, Michel Peuchmaur, Julie M. Gastier-Foster, Vijay V. Joshi, and Julie R. Park
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Oncology ,Pathology ,medicine.medical_specialty ,business.industry ,Cancer ,Hematology ,medicine.disease ,Neuroblastic Tumor ,N-Myc Proto-Oncogene Protein ,Genotype phenotype ,Peripheral ,Neuroblastoma ,Internal medicine ,Pediatrics, Perinatology and Child Health ,Mycn amplification ,Medicine ,Immunohistochemistry ,business ,neoplasms - Abstract
Background Of 4,706 peripheral neuroblastic tumors (pNTs) registered on the Children’s Cancer Group and Children’s Oncology Group Neuroblastoma Study between 1989 and 2010, 51 cases (1.1%) had genotype-phenotype discordance characterized by MYCN amplification (indicating poor prognosis) and Favorable Histology (indicating better prognosis).
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- 2012
40. Kronisk lymfatisk leukemi i Norge - insidens og prognose ved diagnosetidspunktet
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Sverre Heim, Klaus Beiske, Viggo Jønsson, Tom Børge Johannesen, Bernt Ly, Anne Tierens, and Geir E. Tjønnfjord
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Poor prognosis ,medicine.medical_specialty ,education.field_of_study ,Lymphocytic leukaemia ,business.industry ,Population ,General Medicine ,Disease ,medicine.disease ,Gastroenterology ,Cytogenetic Aberrations ,Asymptomatic ,Internal medicine ,medicine ,Stage (cooking) ,medicine.symptom ,education ,business ,Trisomy - Abstract
BACKGROUND The clinical courses of chronic lymphocytic leukaemia (CLL) are very heterogeneous. Biological markers that provide good prognostic information at the time of diagnosis are available. The aim of the study was to determine the prevalence of these markers in a population-based material. MATERIAL AND METHOD Biological markers were examined using standard laboratory methods after obtaining an informed consent statement from patients diagnosed with chronic lymphocytic leukaemia in the period 1.10.2007-31.12.2009. RESULTS There were 388 new cases of chronic lymphocytic leukaemia during the study period, and 236 patients (61%) were included in the study. Of 222 patients, 178 (80%) were in Binet's stage A, 26 (12%) in stage B and 18 (8%) in stage C. The V(H) gene was mutated in 69% and unmutated in 31% of cases. Cytogenetic aberrations were found in 68%: del(13q14) in 48%, trisomy 12 in 13%, del(11q22) in 10% and del(17p13) in 7%. CD38-positive disease was found in 28% of the patients. The V(H) gene was mutated in 67% of the patients in Binet's stage A, and in the majority of these a mutated V(H) gene was associated with non-expression of CD38 and del(13q14). INTERPRETATION At the time of diagnosis, most patients are asymptomatic and do not need treatment. The biological markers that indicate a favourable prognosis occur most frequently in this group. Markers that indicate a poor prognosis occur more frequently in the group that has symptoms at the time of diagnosis.
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- 2012
41. Segmental chromosomal alterations lead to a higher risk of relapse in infants with MYCN-non-amplified localised unresectable/disseminated neuroblastoma (a SIOPEN collaborative study)
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Gaëlle Pierron, Andrew D.J. Pearson, B. De Bernardi, Ruth Ladenstein, Nathalie Auger, Gian Paolo Tonini, Mary Gerrard, Combaret, Bárbara Marques, K Wheeler, Klaus Beiske, A F de Lacerda, Jérôme Couturier, Olivier Delattre, Jean Bénard, Deborah A. Tweddle, Gudrun Schleiermacher, Bénédicte Brichard, Agnès Ribeiro, Hervé Rubie, Rosa Noguera, I.M. Ambros, Castel, Mosseri, Katia Mazzocco, Nick Bown, Adela Cañete, R. Defferrari, Caroline Munzer, Peter F. Ambros, Jean Michon, Isabelle Janoueix-Lerosey, A. Di Cataldo, Eva Villamón, and N. Van Roy
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Oncology ,Cancer Research ,medicine.medical_specialty ,Pathology ,Chromosomal Alterations ,N-Myc Proto-Oncogene Protein ,segmental chromosome alterations ,neuroblastoma ,Neuroblastoma ,Recurrence ,Internal medicine ,medicine ,Humans ,Prospective Studies ,Stage (cooking) ,Relapse risk ,Prospective cohort study ,genomic profile ,Survival analysis ,Chromosome Aberrations ,Oncogene Proteins ,infants ,business.industry ,Infant ,Nuclear Proteins ,Genetics and Genomics ,Prognosis ,medicine.disease ,Survival Analysis ,Doenças Genéticas ,Segmental Chromosome Alterations ,High Risk ,Genomic Profile ,business - Abstract
BACKGROUND: In neuroblastoma (NB), the presence of segmental chromosome alterations (SCAs) is associated with a higher risk of relapse. METHODS: In order to analyse the role of SCAs in infants with localised unresectable/disseminated NB without MYCN amplification, we have performed an array CGH analysis of tumours from infants enrolled in the prospective European INES trials. RESULTS: Tumour samples from 218 out of 300 enroled patients could be analysed. Segmental chromosome alterations were observed in 11%, 20% and 59% of infants enroled in trials INES99.1 (localised unresectable NB), INES99.2 (stage 4s) and INES99.3 (stage 4) (P
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- 2011
42. Mantle cell lymphoma with features of marginal-zone lymphoma
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Anne Tierens, Jan Delabie, Klaus Beiske, Sverre Heim, Ulla Randen, and Olav Erich Yri
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medicine.medical_specialty ,Pathology ,Histology ,Chemistry(all) ,Energy Engineering and Power Technology ,Somatic hypermutation ,Physics and Astronomy(all) ,Biology ,Marginal-zone lymphoma ,Pathology and Forensic Medicine ,Cyclin D1 ,immune system diseases ,hemic and lymphatic diseases ,Internal medicine ,medicine ,GI tract ,Gastrointestinal tract ,Mantle cell lymphoma ,Hematology ,medicine.disease ,Pollution ,BCL10 ,Lymphoma ,Fuel Technology ,Chromosome 3 ,Chemical Engineering(all) ,Original Article - Abstract
We present seven cases of mantle cell lymphoma with morphological features of marginal-zone lymphoma. Of particular interest, four of the patients had predominant involvement of the gastrointestinal tract. All cases displayed the translocation t(11;14)(q13;q32) and expressed cyclin D1. Cytogenetic analysis revealed trisomy 3 in one case and somatic hypermutation of immunoglobulin heavy genes could be demonstrated in two out of four cases. The latter features are reminiscent of marginal-zone lymphoma. The localization of these lymphomas mainly in the gastrointestinal tract and the higher exposure to antigens in this area may explain why this variant of mantle cell lymphoma harbours features of marginal-zone lymphoma.
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- 2011
43. BRAF-mutations in non-small cell lung cancer
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Asma Malik Khattak, Åslaug Helland, Odd Terje Brustugun, Anette Kjoshagen Trømborg, Marius Lund-Iversen, Marzieh Beigi, and Klaus Beiske
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Adult ,Male ,Proto-Oncogene Proteins B-raf ,Pulmonary and Respiratory Medicine ,Cancer Research ,Lung Neoplasms ,endocrine system diseases ,medicine.drug_class ,Translocation, Genetic ,Tyrosine-kinase inhibitor ,Young Adult ,Risk Factors ,Carcinoma, Non-Small-Cell Lung ,medicine ,Humans ,Anaplastic Lymphoma Kinase ,Epidermal growth factor receptor ,skin and connective tissue diseases ,Lung cancer ,neoplasms ,Aged ,Neoplasm Staging ,Aged, 80 and over ,biology ,business.industry ,Respiratory disease ,Receptor Protein-Tyrosine Kinases ,Cancer ,Middle Aged ,medicine.disease ,digestive system diseases ,Subtyping ,respiratory tract diseases ,ErbB Receptors ,Oncology ,Mutation ,Cohort ,Cancer research ,biology.protein ,Female ,business ,V600E - Abstract
Objectives Targeted therapies in non-small cell lung cancer (NSCLC) now also include inhibitors against mutated BRAF. We present clinicopathological characteristics of nearly one thousand unselected NSCLC patients tested for the targetable V600E/K BRAF-mutation. Material and methods NSCLC routinely tested for EGFR-mutations at Oslo University Hospital in the period February 2011–July 2013 were tested for V600E/K BRAF-mutations using a PCR-based method. Results We found a BRAF-mutation frequency of 1.7% in the total cohort of 979 patients, and 2.3% among 646 adenocarcinomas. One of the BRAF-positive samples was also KRAS-mutated, and one had an ALK-translocation. None of 231 squamous cell carcinomas were BRAF-mutated. The proportion of never-smokers among BRAF-positives was high (29%). Conclusion BRAF-mutation analysis should be part of the subtyping of non-squamous NSCLC.
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- 2014
44. Abstract A101: The MetAction trial: long-lasting responses to molecularly matched therapy in end-stage cancer
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Gunhild Mari Mælandsmo, Daniel Heinrich, Gry A. Geitvik, Christin Johansen, Klaus Beiske, Vegard Nygaard, Vigdis Nygaard, Anne Hansen Ree, Marius Lund-Iversen, Eivind Hovig, Sigve Nakken, Menaka Sathermugathevan, Ole Christian Lingjærde, Inger Riise Bergheim, Anne Lise Børresen-Dale, Hege G. Russnes, Vivi Ann Flørenes, Svein Dueland, Kjersti Flatmark, and Kjetil Boye
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Oncology ,Cancer Research ,medicine.medical_specialty ,Crizotinib ,business.industry ,Cancer ,Common Terminology Criteria for Adverse Events ,Pembrolizumab ,medicine.disease ,Response Evaluation Criteria in Solid Tumors ,Internal medicine ,medicine ,Clinical endpoint ,Panitumumab ,Sarcoma ,business ,medicine.drug - Abstract
Background: The first phase of the MetAction trial established the required diagnostic infrastructure, implemented security-approved systems for handling of sensitive information, educated the Trial Team within the context of tumor boards, and estimated costs of the initiative within public health services. The endeavor enabled expedited and safe mutation profiling of metastatic tumors in order to offer molecularly matched medication for end-stage cancer (Ree et al., ESMO Open 2017;2:e000158). The aim of the second trial phase was to investigate the utility of the MetAction pipeline in clinical practice. Procedures: An eligible patient with end-stage metastatic disease from any origin had been on the previous line of systemic therapy for 6 or more weeks with radiologic evaluation intervals of 6-12 weeks and disease progression according to the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Biopsy-sampled metastatic tissue was analyzed by DNA sequencing (Ion Oncomine™ Comprehensive Panel), where called variants were filtered prior to assessment and prioritization, supplemented with fluorescence in situ hybridization to cover relevant biomarkers. The Molecular Tumor Board interpreted the findings within the likelihood of signaling pathway activity, for the sequential Clinical Tumor Board to conclude on potential systemic tumor-directed medication. On study therapy, radiologic work-up was performed every 8 weeks. The primary objective was to compare progression-free survival (PFS) on study treatment, termed Period-B, with PFS for the most recent therapy, termed Period-A. If Period-B/Period-A was ≥1.3, the study therapy was deemed to be of benefit. The incidence of diagnostic adverse events and treatment-related grade 3-5 Common Terminology Criteria for Adverse Events (CTCAE) toxicities was secondary end points. Results: 26 patients were enrolled. Biopsy procedures were undertaken at lung or pleural sites (6 cases), liver or peritoneal sites (19 cases), and an inguinal lymph node (1 case), and did not cause adverse events. Histologic entities were 18 adenocarcinomas (AC), 2 undifferentiated carcinomas, 1 case each of cholangiocarcinoma and squamous cell carcinoma, and 4 different sarcoma entities. 13 patients were found eligible for off-label use of molecularly matched therapy (inhibitor of ALK-, BRAF-, EGFR-, FGFR-, mTOR-, PARP-, ROS1-, or PD-1-mediated signaling). Among the 10 individuals who received study treatment until radiologic evaluation, 5 met the primary end point. The patient with cholangiocarcinoma and a patient with rectal AC primaries, both given crizotinib, obtained Period-B/Period-A outcome slightly better than 1.3. Notably, 3 patients with colon AC primaries, receiving either a combination of panitumumab with vemurafenib or chemotherapy or single-agent pembrolizumab, obtained long-lasting responses. In addition, 1 colon AC patient receiving pembrolizumab with RECIST progression (i.e., primary end point failure) before a long-lasting response to off-protocol continuation, reported CTCAE grade 3 toxicity (a colitis event that immediately resolved on high-dose prednisolone). Conclusion: MetAction procedures and treatments were safe. 15% (4/26) of patients with progressing end-stage cancer had the disease course substantially reversed by this biomarker-directed therapy approach. Citation Format: Anne Hansen Ree, Kjersti Flatmark, Vigdis Nygaard, Daniel Heinrich, Kjetil Boye, Svein Dueland, Vegard Nygaard, Eivind Hovig, Klaus Beiske, Marius Lund-Iversen, Vivi A. Flørenes, Christin Johansen, Inger Riise Bergheim, Menaka Sathermugathevan, Sigve Nakken, Gry A. Geitvik, Ole C. Lingjærde, Anne-Lise Børresen-Dale, Hege G. Russnes, Gunhild M. Mælandsmo. The MetAction trial: long-lasting responses to molecularly matched therapy in end-stage cancer [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr A101.
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- 2018
45. Chemokines and common variable immunodeficiency; possible contribution of CCL19, CCL21 and CCR7 to immune dysregulation
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Stig S. Frøland, Børre Fevang, Arne Yndestad, Klaus Beiske, P. Aukrust, Jan Kristian Damås, Bente Halvorsen, and Are Martin Holm
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Adult ,Male ,Receptors, CCR7 ,endocrine system ,Chemokine ,Translational Studies ,T cell ,Immunology ,Gene Expression ,chemical and pharmacologic phenomena ,Inflammation ,medicine.disease_cause ,Peripheral blood mononuclear cell ,Monocytes ,Autoimmunity ,Immune system ,T-Lymphocyte Subsets ,Humans ,Immunology and Allergy ,Medicine ,RNA, Messenger ,Cells, Cultured ,Chemokine CCL21 ,biology ,Reverse Transcriptase Polymerase Chain Reaction ,business.industry ,Common variable immunodeficiency ,hemic and immune systems ,Middle Aged ,Immune dysregulation ,medicine.disease ,Common Variable Immunodeficiency ,medicine.anatomical_structure ,biology.protein ,Chemokine CCL19 ,Cytokines ,Female ,Chemokines ,medicine.symptom ,business ,Spleen - Abstract
Summary Common variable immunodeficiency (CVID) is a heterogeneous syndrome characterized by defective immunoglobulin production and high frequency of bacterial infections, autoimmunity and manifestations of chronic inflammation. The homeostatic chemokines CCL19 and CCL21 and their receptor CCR7 are associated with modulation of inflammatory responses. CVID patients have decreased proportions of CCR7+ T cells in peripheral blood and we hypothesized a further dysregulation of CCL19/CCL21/CCR7 in CVID. Serum levels of CCL19 and CCL21 were compared in CVID patients and controls. T cell expression of CCR7 was related to clinical characteristics in CVID patients. Spleens extirpated from CVID patients were analysed for expression of CCL19, CCL21 and CCR7. Peripheral blood mononuclear cells (PBMC) from CVID patients and controls were analysed for cytokine response on stimulation with CCL19 and CCL21. The main findings were: (i) CVID patients have raised serum levels of CCL19 and CCL21 independently of features of chronic inflammation; (ii) CCL19 and CCR7 have similar expression in spleens from CVID patients and controls, while CCL21 is variably down-regulated in spleens from patients; (iii) T cell expression of CCR7 is particularly low in patients characterized by chronic inflammation in vivo; and (iv) PBMC from CVID patients had attenuated cytokine response to stimulation with CCL19 and CCL21. CVID patients have raised circulatory levels of CCL19 and CCL21, and an attenuated cytokine response to stimulation with these chemokines. Because CCR7, CCL19 and CCL21 are key mediators balancing immunity and tolerance in the immune system, the abnormalities of these mediators might contribute to the profound immune dysregulation seen in CVID.
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- 2009
46. Predicting outcomes for children with neuroblastoma using a multigene-expression signature: a retrospective SIOPEN/COG/GPOH study
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Gian Paolo Tonini, Jo Vandesompele, Wendy B. London, Genevieve Laureys, André Oberthuer, Matthias Fischer, Rosa Noguera, Adela Cañete, Jean Bénard, Peter F. Ambros, Bárbara Marques, Klaus Beiske, Patrick McGrady, Marta Piqueras, Arlene Naranjo, Liesbeth Vercruysse, Victoria Castel, Bruno De Bernardi, Sophie Bravo, J.A. Kohler, Jan Hellemans, Joëlle Vermeulen, Valreie Combaret, Paolo Scaruffi, Nadine Van Roy, Jean Michon, Hervé Rubie, Michael D. Hogarty, Olivier Delattre, Katrien Swerts, Katleen De Preter, Franki Speleman, Ruth Ladenstein, Isobelle Janoueix-Lerosey, Gudrun Schleiermacher, and Ulrike Pötschger
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Oncology ,Pediatrics ,medicine.medical_specialty ,Multivariate analysis ,business.industry ,Case-control study ,Odds ratio ,medicine.disease ,Breast cancer ,Neuroblastoma ,Internal medicine ,medicine ,Stage (cooking) ,business ,Prospective cohort study ,Survival analysis - Abstract
Summary Background More accurate prognostic assessment of patients with neuroblastoma is required to better inform the choice of risk-related therapy. The aim of this study is to develop and validate a gene-expression signature to improve outcome prediction. Methods 59 genes were selected using an innovative data-mining strategy, and were profiled in the largest neuroblastoma patient series (n=579) to date using real-time quantitative PCR starting from only 20 ng of RNA. A multigene-expression signature was built using 30 training samples, tested on 313 test samples, and subsequently validated in a blind study on an independent set of 236 tumours. Findings The signature has a performance, sensitivity, and specificity of 85·4% (95% CI 77·7–93·2), 84·4% (66·5–94·1), and 86·5% (81·1–90·6), respectively, to predict patient outcome. Multivariate analysis indicates that the signature is a significant independent predictor of overall survival and progression-free survival after controlling for currently used risk factors: patients with high molecular risk have a higher risk of death from disease and higher risk of relapse or progression than patients with low molecular risk (odds ratio 19·32 [95% CI 6·50–57·43] and 3·96 [1·97–7·97] for overall survival and progression-free survival, respectively, both p MYCN status, age, International Neuroblastoma Staging System stage, ploidy, International Neuroblastoma Pathology Classification grade of differentiation, and mitosis karyorrhexis index (odds ratios between 4·81 and 10·53 depending on the model for overall survival and 3·68 [95% CI 2·01–6·71] for progression-free survival). Interpretation The 59-gene expression signature is an accurate predictor of outcome in patients with neuroblastoma. The signature is an independent risk predictor, identifying patients with an increased risk of poor outcome in the current clinical-risk groups. The method and signature is suitable for routine laboratory testing, and should be evaluated in prospective studies. Funding The Belgian Foundation Against Cancer, the Children Cancer Fund Ghent, the Belgian Society of Paediatric Haematology and Oncology, the Belgian Kid's Fund and the Fondation Nuovo-Soldati (JV), the Fund for Scientific Research Flanders (KDP, JH), the Fund for Scientific Research Flanders, the Institute for the Promotion of Innovation by Science and Technology in Flanders, Strategisch basisonderzoek, the Fondation Fournier Majoie pour l'Innovation, the Instituto Carlos III, the Italian Neuroblastoma Foundation, the European Community under the FP6, and the Belgian programme of Interuniversity Poles of Attraction.
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- 2009
47. t(3;21)(q22;q22) leading to truncation of the RYK gene in atypical chronic myeloid leukemia
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Klaus Beiske, Francesca Micci, Hege Kilen Andersen, Geir E. Tjønnfjord, Lisbeth Haugom, Sverre Heim, and Ioannis Panagopoulos
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Male ,Cancer Research ,Chromosomes, Human, Pair 21 ,PDGFRB ,PDGFRA ,Biology ,Leukemia, Myeloid, Chronic, Atypical, BCR-ABL Negative ,Translocation, Genetic ,Gene product ,Fusion gene ,medicine ,Humans ,Oncogene Fusion ,Aged ,Adenosine Triphosphatases ,ABL ,Membrane Proteins ,Receptor Protein-Tyrosine Kinases ,Mitochondrial Proton-Translocating ATPases ,medicine.disease ,Fusion protein ,Molecular biology ,Oncology ,Atypical chronic myeloid leukemia ,Cancer research ,Carrier Proteins ,Tyrosine kinase - Abstract
The analysis of a small number of patients with atypical chronic myeloid leukemia showing balanced chromosomal translocations has revealed diverse tyrosine kinase fusion genes, most commonly involving FGFR1, PDGFRA, PDGFRB, JAK2, and ABL. We present a case of aCML with a 3q22;21q22-translocation that led to truncation of the receptor-like tyrosine kinase (RYK) gene and its juxtaposition with sequences from chromosome 21 including the ATP5O gene coding for a mitochondrial ATP synthase. The resulting fusion was not in frame, however, which is why we speculate that an abrogated RYK gene product rather than a chimeric protein might be the leukemogenic result.
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- 2009
48. Transformation of B cell lymphoma to histiocytic sarcoma: somatic mutations of PAX-5 gene with loss of expression cannot explain transdifferentiation
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Ida Münster Ikonomou, Jahn M. Nesland, Jan Delabie, Gunhild Trøen, Assia Bassarova, Alexander Fosså, and Klaus Beiske
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Histology ,Chemistry(all) ,Lymphoma ,Somatic cell ,Somatic hypermutation ,Energy Engineering and Power Technology ,B-cell ,Histiocytic sarcoma ,Biology ,Physics and Astronomy(all) ,Pathology and Forensic Medicine ,medicine ,B-cell lymphoma ,B cell ,Transdifferentiation ,Germinal center ,Hematology ,medicine.disease ,Pollution ,medicine.anatomical_structure ,Fuel Technology ,PAX-5 ,Cancer research ,Chemical Engineering(all) ,Original Article - Abstract
Transdifferentiation of B cell lymphoma of germinal center cell origin to histiocytic sarcoma has recently been described but is a rare occurrence. The cause for loss of B cell differentiation in these lymphomas is unknown. We investigated whether somatic hypermutation of the PAX-5 gene, a transcription factor that is important for maintaining B cell identity and is frequently mutated in B cell lymphomas of germinal center cell origin, might be a cause for loss of PAX-5 expression and thus B cell phenotype. However, no somatic hypermutation of the PAX-5 gene was detected in the two cases we studied. The molecular basis for transdifferentiation of B cell lymphoma to histiocytic sarcoma remains therefore unresolved.
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- 2009
49. Storcellet granulær lymfocytt-leukemi
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Anne Tierens, Klaus Beiske, Elisabeth Schrumpf, Silje Michalsen, Geir E. Tjønnfjord, and Vigdis Stenberg
- Subjects
Cytopenia ,Pediatrics ,medicine.medical_specialty ,medicine.diagnostic_test ,business.industry ,Incidence (epidemiology) ,chemical and pharmacologic phenomena ,Retrospective cohort study ,General Medicine ,Disease ,Neutropenia ,medicine.disease ,Asymptomatic ,Bone marrow examination ,hemic and lymphatic diseases ,medicine ,medicine.symptom ,business ,Rare disease - Abstract
BACKGROUND: Large granular lymphocytic leukaemia (LGL-leukaemia) is considered a rare disease. LGL-leukaemia is usually of the T-cell type, but a minority displays an NK-cell phenotype. Incidence and prevalence are unknown. MATERIAL AND METHODS: We identified patients with LGL-leukaemia (with well-defined diagnostic criteria) diagnosed at Rikshospitalet University Hospital between 01.10.2001 and 31.12.2007. Their medical records were assessed retrospectively. RESULTS: LGL-leukaemia was diagnosed in 52 patients, 26 women and 26 men, median age of 59 (26 - 86) years, during the study period. The leukaemia displayed NK-cell phenotype in one patient and T-cell phenotype in the remaining 51 patients. Slightly more than one third of the patients were asymptomatic. Cytopenia, mostly neutropenia, was usually the cause of the clinical phenotype in symptomatic patients. Co-morbidity with autoimmune disease was common, and we also found a high prevalence of clonal B-cell disease (17 %). INTERPRETATION: Our data support the notion that LGL-leukaemia is under-diagnosed. Unexplained cytopenias should suggest the possibility of LGL-leukaemia, and appropriate diagnostic measures should be undertaken. An early diagnosis may save patients an extensive and unnecessary diagnostic work-up and ensure that a simple and effective treatment is offered.
- Published
- 2009
50. Can morphology predict 1p/19q loss in oligodendroglial tumours?
- Author
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Klaus Beiske, Milada Cvancarova, I Benestad, Kari Skullerud, Eirik Helseth, Per Arne Andresen, Torstein R. Meling, Sverre Mørk, and David Scheie
- Subjects
Oncology ,medicine.medical_specialty ,Pathology ,Histology ,Anatomical pathology ,General Medicine ,Odds ratio ,Biology ,medicine.disease ,Confidence interval ,Pathology and Forensic Medicine ,Central nervous system disease ,Loss of heterozygosity ,Internal medicine ,Genotype ,Cohort ,medicine ,Oligodendroglioma - Abstract
Aims: To investigate the relationship between phenotype and genotype in oligodendroglial tumours and evaluate whether 1p/19q status can be reliably predicted from histological findings. Methods and results: Three neuropathologists reviewed the association between 10 histological variables, location and genetic losses at 1p, 19q and 17p13 in 63 oligodendroglial tumours (cohort 1). Based on these findings, a multiple logistic regression model for prediction of 1p/19q status was constructed. The ability of this model to predict 1p/19q status was tested on cohort 2, comprising 20 oligodendroglial tumours. Loss of heterozygosity at 1p, 19q and 17p13 was analysed using polymerase chain reaction. Combined 1p/19q loss and losses at 17p13 were mutually exclusive (P
- Published
- 2008
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