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  1. Article ; Online: Genetic Factors in Familial Manifestation of Primary Mediastinal Large B-Cell Lymphoma over Two Generations.

    Juskevicius, Darius / Lundberg, Pontus / Tzankov, Alexandar / Dirnhofer, Stefan / Stenner, Frank

    Pathobiology : journal of immunopathology, molecular and cellular biology

    2023  Volume 90, Issue 6, Page(s) 422–428

    Abstract: Introduction: Primary mediastinal large B-cell lymphoma (PMBL) is a rarely occurring lymphoid malignancy which typically affects young adults and presents itself as an anterior mediastinal mass. Gene expression profiling as well as somatic genetic ... ...

    Abstract Introduction: Primary mediastinal large B-cell lymphoma (PMBL) is a rarely occurring lymphoid malignancy which typically affects young adults and presents itself as an anterior mediastinal mass. Gene expression profiling as well as somatic genetic analysis revealed that it is closely related to classical Hodgkin lymphoma, whereas morphologically, it tends to resemble diffuse large B-cell lymphoma. Familial clustering of PMBL is rare - only two reports have been published to date. While it is generally accepted that positive family history is associated with increased risk of developing a lymphoma, genetic risk factors which might predispose to PMBL are largely unknown.
    Case presentation: We performed germline and tumor genetic analyses by whole-exome sequencing and array-CGH of a family, in which the father and the son both developed a PMBL. Germline investigations of both affected patients and of their two unaffected family members have not been able to provide a single risk factor associated with lymphoma predisposition. In addition, genes that were previously implicated in increased risk for PMBL, namely MLL (KMT2A) and TIRAP, were found to be intact in all investigated family members. Somatic genetic investigations identified known as well as novel genetic aberrations in tumors of the affected subjects.
    Conclusion: We conclude that predisposition to a PMBL might be inherited through a combination of low- or moderate-risk factors and provide a shortlist of the most likely selected candidates, which can be used in future studies.
    MeSH term(s) Young Adult ; Humans ; Lymphoma, Large B-Cell, Diffuse/genetics ; Gene Expression Profiling
    Language English
    Publishing date 2023-07-25
    Publishing country Switzerland
    Document type Case Reports
    ZDB-ID 1022703-9
    ISSN 1423-0291 ; 1015-2008
    ISSN (online) 1423-0291
    ISSN 1015-2008
    DOI 10.1159/000532053
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: Mutational landscape of marginal zone B-cell lymphomas of various origin: organotypic alterations and diagnostic potential for assignment of organ origin.

    Vela, Visar / Juskevicius, Darius / Dirnhofer, Stefan / Menter, Thomas / Tzankov, Alexandar

    Virchows Archiv : an international journal of pathology

    2021  Volume 480, Issue 2, Page(s) 403–413

    Abstract: This meta-analysis aims to concisely summarize the genetic landscape of splenic, nodal and extranodal marginal zone lymphomas (MZL) in the dura mater, salivary glands, thyroid, ocular adnexa, lung, stomach and skin with respect to somatic variants. A ... ...

    Abstract This meta-analysis aims to concisely summarize the genetic landscape of splenic, nodal and extranodal marginal zone lymphomas (MZL) in the dura mater, salivary glands, thyroid, ocular adnexa, lung, stomach and skin with respect to somatic variants. A systematic PubMed search for sequencing studies of MZL was executed. All somatic mutations of the organs mentioned above were combined, uniformly annotated, and a dataset containing 25 publications comprising 6016 variants from 1663 patients was created. In splenic MZL, KLF2 (18%, 103/567) and NOTCH2 (16%, 118/725) were the most frequently mutated genes. Pulmonary and nodal MZL displayed recurrent mutations in chromatin-modifier-encoding genes, especially KMT2D (25%, 13/51, and 20%, 20/98, respectively). In contrast, ocular adnexal, gastric, and dura mater MZL had mutations in genes encoding for NF-κB pathway compounds, in particular TNFAIP3, with 39% (113/293), 15% (8/55), and 45% (5/11), respectively. Cutaneous MZL frequently had FAS mutations (63%, 24/38), while MZL of the thyroid had a higher prevalence for TET2 variants (61%, 11/18). Finally, TBL1XR1 (24%, 14/58) was the most commonly mutated gene in MZL of the salivary glands. Mutations of distinct genes show origin-preferential distribution among nodal and splenic MZL as well as extranodal MZL at/from different anatomic locations. Recognition of such mutational distribution patterns may help assigning MZL origin in difficult cases and possibly pave the way for novel more tailored treatment concepts.
    MeSH term(s) Humans ; Lymphoma, B-Cell, Marginal Zone/diagnosis ; Lymphoma, B-Cell, Marginal Zone/genetics ; Lymphoma, B-Cell, Marginal Zone/pathology ; Mutation/genetics ; NF-kappa B
    Chemical Substances NF-kappa B
    Language English
    Publishing date 2021-09-08
    Publishing country Germany
    Document type Journal Article ; Meta-Analysis
    ZDB-ID 1184867-4
    ISSN 1432-2307 ; 0945-6317
    ISSN (online) 1432-2307
    ISSN 0945-6317
    DOI 10.1007/s00428-021-03186-3
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  3. Article ; Online: Cluster Analysis According to Immunohistochemistry is a Robust Tool for Non-Small Cell Lung Cancer and Reveals a Distinct, Immune Signature-defined Subgroup.

    Sterlacci, William / Fiegl, Michael / Juskevicius, Darius / Tzankov, Alexandar

    Applied immunohistochemistry & molecular morphology : AIMM

    2019  Volume 28, Issue 4, Page(s) 274–283

    Abstract: Clustering in medicine is the subgrouping of a cohort according to specific phenotypical or genotypical traits. For breast cancer and lymphomas, clustering by gene expression profiles has already resulted in important prognostic and predictive subgroups. ...

    Abstract Clustering in medicine is the subgrouping of a cohort according to specific phenotypical or genotypical traits. For breast cancer and lymphomas, clustering by gene expression profiles has already resulted in important prognostic and predictive subgroups. For non-small cell lung cancer (NSCLC), however, little is known. We performed a cluster analysis on a cohort of 365 surgically resected, well-documented NSCLC patients, which was followed-up for a median of 62 months, incorporating 70 expressed proteins and several genes. Our data reveal that tumor grading by architecture is significant, that large cell carcinoma is likely not a separate entity, and that an immune signature cluster exists. For squamous cell carcinomas, a prognostically relevant cluster with poorer outcome was found, defined by a high CD4/CD8 ratio and lower presence of granzyme B+ tumor-infiltrating lymphocytes (TIL). This study shows that clustering analysis is a useful tool for verifying established characteristics and generating new insights for NSCLC. Importantly, for one "immune signature" cluster, the signature of the TIL (especially the amount of CD8+ TIL) was more crucial than the histologic or any other phenotypical aspect. This may be an important finding toward explaining why only a fraction of eligible patients respond to immunomodulating anticancer therapies.
    MeSH term(s) Aged ; CD4-Positive T-Lymphocytes/metabolism ; CD4-Positive T-Lymphocytes/pathology ; CD8-Positive T-Lymphocytes/metabolism ; CD8-Positive T-Lymphocytes/pathology ; Carcinoma, Non-Small-Cell Lung/metabolism ; Carcinoma, Non-Small-Cell Lung/pathology ; Female ; Gene Expression Regulation, Neoplastic ; Humans ; Immunohistochemistry ; Lung Neoplasms/metabolism ; Lung Neoplasms/pathology ; Lymphocytes, Tumor-Infiltrating/metabolism ; Male ; Middle Aged ; Retrospective Studies
    Language English
    Publishing date 2019-04-24
    Publishing country United States
    Document type Journal Article
    ZDB-ID 1473273-7
    ISSN 1533-4058 ; 1062-3345 ; 1541-2016
    ISSN (online) 1533-4058
    ISSN 1062-3345 ; 1541-2016
    DOI 10.1097/PAI.0000000000000751
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  4. Article: Genomic Landscape of Hodgkin Lymphoma.

    Brune, Magdalena M / Juskevicius, Darius / Haslbauer, Jasmin / Dirnhofer, Stefan / Tzankov, Alexandar

    Cancers

    2021  Volume 13, Issue 4

    Abstract: Background: Hodgkin lymphoma (HL) is predominantly composed of reactive, non-neoplastic cells surrounding scarcely distributed tumor cells, that is, so-called Hodgkin and Reed-Sternberg (HRS) or lymphocyte predominant (LP) cells. This scarcity impeded ... ...

    Abstract Background: Hodgkin lymphoma (HL) is predominantly composed of reactive, non-neoplastic cells surrounding scarcely distributed tumor cells, that is, so-called Hodgkin and Reed-Sternberg (HRS) or lymphocyte predominant (LP) cells. This scarcity impeded the analysis of the tumor cell genomes for a long time, but recently developed methods (especially laser capture microdissection, flow cytometry/fluorescence-activated cell sorting) facilitated molecular investigation, elucidating the pathophysiological principles of "Hodgkin lymphomagenesis".
    Methods: We reviewed the relevant literature of the last three decades focusing on the genomic landscape of classic and nodular lymphocyte predominant HL (NLPHL) and summarized molecular cornerstones.
    Results: Firstly, the malignant cells of HL evade the immune system by altered expression of
    Conclusion: The blueprint of HL genomics has been laid, paving the way for future investigations into its complex pathophysiology.
    Language English
    Publishing date 2021-02-08
    Publishing country Switzerland
    Document type Journal Article ; Review
    ZDB-ID 2527080-1
    ISSN 2072-6694
    ISSN 2072-6694
    DOI 10.3390/cancers13040682
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  5. Article ; Online: Testicular Rosai-Dorfman disease clonally related to CMML - Case report and literature review.

    Fiegl, August / Dirnhofer, Stefan / Juskevicius, Darius / Zagrapan, Branislav / Dertinger, Susanne / Bösl, Andreas / Milos, Stella / Brunner, Jürgen / Bertolini, Franz / Offner, Felix A

    Pathology, research and practice

    2023  Volume 247, Page(s) 154548

    Abstract: Background: Rosai-Dorfman disease (RDD), a rare form of non-Langerhans cell histiocytosis with heterogenous clinical features, arises from precursor cells that give rise to cells of the histiocytic and monocytic lineages. An association with ... ...

    Abstract Background: Rosai-Dorfman disease (RDD), a rare form of non-Langerhans cell histiocytosis with heterogenous clinical features, arises from precursor cells that give rise to cells of the histiocytic and monocytic lineages. An association with hematological neoplasms has been reported. Testicular RDD is rarely described, with only 9 reported cases in the literature. Genetic data to assess clonal relationships between RDD and other hematological neoplasms remain scarce. We describe an instance of testicular RDD against a background of chronic myelomonocytic leukemia (CMML), with genetic studies in both neoplasms.
    Case presentation: A 72-year-old patient with a history of CMML sought evaluation of growing bilateral testicular nodules. Solitary testicular lymphoma was suspected; orchidectomy was performed. The diagnosis of testicular RDD was established morphologically and confirmed immunohistochemically. Molecular analysis of testicular lesions and of archived patient bone marrow revealed the KRAS variant c 0.35 G>A / p.G12D in both, suggesting a clonal relationship.
    Conclusion: These observations support classifying RDD as a neoplasm that can be clonally related to myeloid neoplasms.
    MeSH term(s) Male ; Humans ; Adult ; Aged ; Histiocytosis, Sinus/genetics ; Histiocytosis, Sinus/complications ; Histiocytosis, Sinus/diagnosis ; Leukemia, Myelomonocytic, Chronic/genetics ; Histiocytes/pathology ; Lymphoma, Non-Hodgkin ; Bone Marrow/pathology
    Language English
    Publishing date 2023-05-19
    Publishing country Germany
    Document type Review ; Case Reports
    ZDB-ID 391889-0
    ISSN 1618-0631 ; 0344-0338
    ISSN (online) 1618-0631
    ISSN 0344-0338
    DOI 10.1016/j.prp.2023.154548
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  6. Article ; Online: Genetic background and evolution of relapses in aggressive B-cell lymphomas.

    Juskevicius, Darius / Dirnhofer, Stephan / Tzankov, Alexandar

    Haematologica

    2017  Volume 102, Issue 7, Page(s) 1139–1149

    Abstract: Relapses of aggressive B-cell lymphomas pose a higher risk to affected patients because of potential treatment resistance and usually rapid tumor growth. Recent advances, such as targeting Bruton tyrosine kinase, have provided promising results in small ... ...

    Abstract Relapses of aggressive B-cell lymphomas pose a higher risk to affected patients because of potential treatment resistance and usually rapid tumor growth. Recent advances, such as targeting Bruton tyrosine kinase, have provided promising results in small numbers of cases, but treatment for the majority of patients remains challenging and outcomes are generally poor. A number of recent studies have utilized state-of-the-art genomic technologies in an attempt to better understand tumor genome evolution during relapse and to identify relapse-specific genetic alterations. It has been found that in some settings (e.g. diffuse large B-cell lymphomas in immunocompromised patients, secondary diffuse large B-cell lymphomas as Richter transformations) a significant part of the recurrences are
    MeSH term(s) Animals ; Clonal Evolution ; Disease Progression ; Genetic Association Studies ; Genetic Background ; Genetic Predisposition to Disease ; Genetic Variation ; Humans ; Immunomodulation/genetics ; Immunomodulation/immunology ; Lymphoma, B-Cell/genetics ; Lymphoma, B-Cell/immunology ; Lymphoma, B-Cell/pathology ; Recurrence
    Language English
    Publishing date 2017-05-29
    Publishing country Italy
    Document type Journal Article ; Review
    ZDB-ID 2333-4
    ISSN 1592-8721 ; 0017-6567 ; 0390-6078
    ISSN (online) 1592-8721
    ISSN 0017-6567 ; 0390-6078
    DOI 10.3324/haematol.2016.151647
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  7. Article ; Online: Bone Marrow Infiltration of Angioimmunoblastic T-Cell Lymphoma: Identification and Prognostic Impact of Histologic Patterns and Diagnostic Application of Ancillary Phenotypic and Molecular Analyses.

    Gerlach, Magdalena M / Juskevicius, Darius / Vela, Visar / Dirnhofer, Stefan / Tzankov, Alexandar

    Archives of pathology & laboratory medicine

    2019  Volume 144, Issue 5, Page(s) 602–611

    Abstract: Context.—: Angioimmunoblastic T-cell lymphomas originate from T follicular helper cells and express respective markers (BCL6, CD10, CXCL13, ICOS, and PD-1). Although commonly present, bone marrow involvement by angioimmunoblastic T-cell lymphoma can be ... ...

    Abstract Context.—: Angioimmunoblastic T-cell lymphomas originate from T follicular helper cells and express respective markers (BCL6, CD10, CXCL13, ICOS, and PD-1). Although commonly present, bone marrow involvement by angioimmunoblastic T-cell lymphoma can be diagnostically challenging. Additionally, only little is known about the distribution of T follicular helper cells in healthy and reactively changed bone marrows or in samples affected by other lymphomas.
    Objective.—: To establish a diagnostic approach to reliably identify bone marrow infiltration of angioimmunoblastic T-cell lymphoma.
    Design.—: We analyzed the morphologic infiltration pattern and the expression of T follicular helper-cell markers in 42 matched paired lymph node and bone marrow samples and applied comparative clonality testing. Furthermore, we studied the expression of BCL6 and PD-1 in a control cohort of healthy, reactively changed, and otherwise affected bone marrows.
    Results.—: We identified 3 different bone marrow infiltration patterns correlating with overall survival (interstitial/micronodular infiltration with or without eosinophilia and diffuse infiltration with eosinophilia). The matched pairs showed a consistent (co)expression of PD-1 and BCL6 with a generally weaker expression in the bone marrow than in the lymph nodes. Comparative clonality testing was helpful in only a minority of cases. Infiltrates of the most important differential diagnoses contained either PD-1- or BCL6-positive tumor-infiltrating cells, but no coexpressing cells.
    Conclusions.—: Bone marrow infiltration by angioimmunoblastic T-cell lymphoma displays 3 different patterns that correlate with prognosis. BCL6 and PD-1 can be reliably used to identify lymphoma infiltrates and to help rule out several differential diagnoses. Comparative clonality testing rarely provides additional value and cannot replace morphologic and phenotypic analyses.
    MeSH term(s) Aged ; Aged, 80 and over ; Biomarkers, Tumor/metabolism ; Bone Marrow/pathology ; Chemokine CXCL13/metabolism ; Female ; Humans ; Immunoblastic Lymphadenopathy/diagnosis ; Immunoblastic Lymphadenopathy/metabolism ; Immunoblastic Lymphadenopathy/pathology ; Lymph Nodes/pathology ; Lymphoma, Follicular/diagnosis ; Lymphoma, Follicular/metabolism ; Lymphoma, Follicular/pathology ; Lymphoma, T-Cell/diagnosis ; Lymphoma, T-Cell/metabolism ; Lymphoma, T-Cell/pathology ; Male ; Middle Aged ; Neprilysin/metabolism ; Phenotype ; Prognosis ; Programmed Cell Death 1 Receptor/metabolism ; Proto-Oncogene Proteins c-bcl-6/metabolism ; Switzerland ; T-Lymphocytes, Helper-Inducer/pathology
    Chemical Substances BCL6 protein, human ; Biomarkers, Tumor ; CXCL13 protein, human ; Chemokine CXCL13 ; PDCD1 protein, human ; Programmed Cell Death 1 Receptor ; Proto-Oncogene Proteins c-bcl-6 ; Neprilysin (EC 3.4.24.11)
    Language English
    Publishing date 2019-09-26
    Publishing country United States
    Document type Journal Article
    ZDB-ID 194119-7
    ISSN 1543-2165 ; 0363-0153 ; 0096-8528 ; 0003-9985
    ISSN (online) 1543-2165
    ISSN 0363-0153 ; 0096-8528 ; 0003-9985
    DOI 10.5858/arpa.2019-0007-OA
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  8. Article ; Online: How to resolve a clinical and molecular puzzle: concomitant monoclonal gammopathy of undetermined significance (MGUS) with neutrophilia and clonal hematopoiesis of indeterminate potential (CHIP).

    Haefliger, Simon / Juskevicius, Darius / Höller, Sylvia / Buser, Ulrich / Dirnhofer, Stefan / Tzankov, Alexandar

    Annals of hematology

    2019  Volume 98, Issue 10, Page(s) 2431–2432

    MeSH term(s) Hematopoiesis ; Humans ; Leukocytosis/complications ; Leukocytosis/diagnosis ; Leukocytosis/metabolism ; Leukocytosis/pathology ; Male ; Middle Aged ; Monoclonal Gammopathy of Undetermined Significance/complications ; Monoclonal Gammopathy of Undetermined Significance/diagnosis ; Monoclonal Gammopathy of Undetermined Significance/metabolism ; Monoclonal Gammopathy of Undetermined Significance/pathology
    Language English
    Publishing date 2019-08-20
    Publishing country Germany
    Document type Case Reports ; Letter
    ZDB-ID 1064950-5
    ISSN 1432-0584 ; 0939-5555 ; 0945-8077
    ISSN (online) 1432-0584
    ISSN 0939-5555 ; 0945-8077
    DOI 10.1007/s00277-019-03786-9
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  9. Article ; Online: Is Rosai-Dorfman disease a reactve process? Detection of a MAP2K1 L115V mutation in a case of Rosai-Dorfman disease.

    Matter, Matthias S / Bihl, Michel / Juskevicius, Darius / Tzankov, Alexandar

    Virchows Archiv : an international journal of pathology

    2017  Volume 471, Issue 4, Page(s) 545–547

    Language English
    Publishing date 2017-10
    Publishing country Germany
    Document type Journal Article
    ZDB-ID 1184867-4
    ISSN 1432-2307 ; 0945-6317
    ISSN (online) 1432-2307
    ISSN 0945-6317
    DOI 10.1007/s00428-017-2173-4
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  10. Article ; Online: Array CGH-based analysis of post-transplant plasmacytic hyperplasia reveals 'intact genomes' arguing against categorizing it as part of the post-transplant lymphoproliferative disease spectrum.

    Menter, Thomas / Juskevicius, Darius / Tzankov, Alexandar

    Transplant international : official journal of the European Society for Organ Transplantation

    2015  Volume 28, Issue 1, Page(s) 120–122

    MeSH term(s) Adolescent ; Adult ; Algorithms ; Child ; Child, Preschool ; Chromosome Aberrations ; Comparative Genomic Hybridization ; Epstein-Barr Virus Infections ; Formaldehyde/chemistry ; Genome ; Heart Transplantation/adverse effects ; Humans ; Hyperplasia ; Interferon Regulatory Factors/metabolism ; Kidney Transplantation/adverse effects ; Lymphoproliferative Disorders/immunology ; Middle Aged ; Oligonucleotide Array Sequence Analysis ; Plasma Cells/cytology ; Postoperative Complications ; Software
    Chemical Substances Interferon Regulatory Factors ; interferon regulatory factor-4 ; Formaldehyde (1HG84L3525)
    Language English
    Publishing date 2015-01
    Publishing country England
    Document type Case Reports ; Letter ; Research Support, Non-U.S. Gov't
    ZDB-ID 639435-8
    ISSN 1432-2277 ; 0934-0874
    ISSN (online) 1432-2277
    ISSN 0934-0874
    DOI 10.1111/tri.12400
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