Manuel Montesinos-Rongen

Bio: Manuel Montesinos-Rongen is an academic researcher from University of Cologne. The author has contributed to research in topics: Primary central nervous system lymphoma & Lymphoma. The author has an hindex of 30, co-authored 57 publications receiving 2376 citations. Previous affiliations of Manuel Montesinos-Rongen include University of Bonn.

Modern concepts in the biology, diagnosis, differential diagnosis and treatment of primary central nervous system lymphoma

Abstract: Recent studies addressing the molecular characteristics of PCNSL, which is defined as malignant B-cell lymphoma with morphological features of DLBCL, have significantly improved our understanding of the pathogenesis of this lymphoma entity, which is associated with an inferior prognosis as compared with DLBCL outside the CNS. This unfavorable prognosis stimulated intense efforts to improve therapy and induced recent series of clinical studies, which addressed the role of radiotherapy and various chemotherapeutic regimens. This review combines the discussion of diagnosis, differential diagnosis and recent progress in studies addressing the molecular pathogenesis as well as therapeutic options in PCNSL.

Primary Central Nervous System Lymphomas Are Derived from Germinal-Center B Cells and Show a Preferential Usage of the V4–34 Gene Segment

Abstract: Primary central nervous system lymphomas (PCNSLs) have recently received considerable clinical attention due to their increasing incidence. To clarify the histogenetic origin of these intriguing neoplasms, PCNSLs from 10 HIV-negative patients were analyzed for immunoglobulin (Ig) gene rearrangements. All tumors exhibited clonal IgH gene rearrangements. Of the 10 cases, 5 used the V4–34 gene segment, and all of these lymphomas shared an amino acid exchange from glycine to aspartate due to a mutation in the first codon of the complementarity-determining region 1. No preferential usage of D H , J H , V κ , J κ , V λ , or J λ gene segments was observed. All potentially functional rearrangements exhibited somatic mutations. The pattern of somatic mutations indicated selection of the tumor cells (or their precursors) for expression of a functional antibody. Mean mutation frequencies of 13.2% and 8.3% were detected for the heavy and light chains, respectively, thereby exceeding other lymphoma entities. Cloning experiments of three tumors showed ongoing mutation in at least one case. These data suggest that PCNSLs are derived from highly mutated germinal-center B cells. The frequent usage of the V4–34 gene and the presence of a shared replacement mutation may indicate that the tumor precursors recognized a shared (super) antigen.

Activating L265P mutations of the MYD88 gene are common in primary central nervous system lymphoma

Abstract: Primary central nervous system lymphoma (PCNSL) is a special lymphoma entity. Although being a rare disease, the incidence of PCNSL has significantly raised in the last decades [3, 4], however, a specific standard therapeutic regimen is still a matter of debate [2]. Despite the fact that PCNSL histopathologically resemble diffuse large B cell lymphoma (DLBCL) [3, 4], they are characterized by unique clinical and molecular features [6], including their exclusive manifestation in the unique microenvironment of the immunologically privileged CNS. Activation of the nuclear factor jB (NF-jB) pathway is a hallmark of PCNSL [1, 5]. Various mechanisms of NF-jB activation have been identified in PCNSL. These include gains in chromosome 18q21 being present in 37% of PCNSL and activating mutations of the CARD11 gene being present in 16% of PCNSL [5, 6]. Moreover, NF-jB activation might be triggered by stimulation of either the B cell receptor pathway, the tumor necrosis factor or the toll-like receptor (TLR) pathway. Here, we provide evidence for deregulation of the TLR pathway in the pathogenesis of PCNSL through mutation of the myeloid differentiation primary response gene 88 (MYD88). Analysis of the MYD88 gene, the central integrator of the TLR pathway, in a series of 14 PCNSL by a biphased PCR approach followed by sequencing of all the exons revealed mutations in seven (50%) of the tumors (for details see supplementary information). Interestingly, in five of these seven (71%) PCNSL, i.e. 36% of all tumors analyzed, mutations were identified as a leucine to proline exchange at position 265 (L265P), which is an oncogenically activating mutation and has recently been shown to be of somatic origin [7]. In the remaining two PCNSL, MYD88 mutations resided at positions 103 and 143, respectively. In one tumor a nucleotide exchange corresponded to a silent mutation (L103L). In the other PCNSL the mutation resulted in an amino acid exchange (Q143E), which has not been reported before and the functional impact of which remains to be elucidated. Till date, MYD88 mutations have been described only in 9% of gastric mucosa-associated lymphoid tissue lymphoma, in 3% of chronic lymphocytic leukemia, in 5% of Burkitt’s lymphoma, and in systemic DLBCL, affecting 39% of the activated B cell like (ABC)-DLBCL subtype and 6% of the germinal center B cell like subgroup, respectively [7, 8]. Interestingly, 29% of systemic ABCDLBCL harbored the MYD88 L265P mutation [7]. Two of the five PCNSL (40%) with the recurrent MYD88 L265P mutation concomitantly harbored a CARD11 mutation, which results in the constitutive activation of the CARD11 protein [5]. While either the MYD88 L265P or the CARD11 mutation activates the NF-jB pathway, the combined presence of these mutations may act synergistically; thus, further enhancing NFjB activation [1, 5]. In addition to a direct effect on the NF-jB pathway, MYD88 mutations may alter the Electronic supplementary material The online version of this article (doi:10.1007/s00401-011-0891-2) contains supplementary material, which is available to authorized users.

Gene expression profiling suggests primary central nervous system lymphomas to be derived from a late germinal center B cell

Abstract: To characterize the molecular origin of primary lymphomas of the central nervous system (PCNSL), 21 PCNSLs of immunocompetent patients were investigated by microarray-based gene expression profiling. Comparison of the transcriptional profile of PCNSL with various normal and neoplastic B-cell subsets demonstrated PCNSL (i) to display gene expression patterns most closely related to late germinal center B cells, (ii) to display a gene expression profile similar to systemic diffuse large B-cell lymphomas (DLBCLs) and (iii) to be in part assigned to the activated B-cell-like (ABC) or the germinal center B-cell-like (GCB) subtype of DLBCL.

I and i

Abstract: There is, I think, something ethereal about i —the square root of minus one. I remember first hearing about it at school. It seemed an odd beast at that time—an intruder hovering on the edge of reality. Usually familiarity dulls this sense of the bizarre, but in the case of i it was the reverse: over the years the sense of its surreal nature intensified. It seemed that it was impossible to write mathematics that described the real world in …

WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues

Abstract: WHO CLASSIFICATION OF TUMOURS OF HAEMATOPOIETIC AND LYMPHOID TISSUES , WHO CLASSIFICATION OF TUMOURS OF HAEMATOPOIETIC AND LYMPHOID TISSUES , کتابخانه مرکزی دانشگاه علوم پزشکی تهران

Integrative Genomics Viewer

Abstract: Rapid improvements in sequencing and array-based platforms are resulting in a flood of diverse genome-wide data, including data from exome and whole-genome sequencing, epigenetic surveys, expression profiling of coding and noncoding RNAs, single nucleotide polymorphism (SNP) and copy number profiling, and functional assays. Analysis of these large, diverse data sets holds the promise of a more comprehensive understanding of the genome and its relation to human disease. Experienced and knowledgeable human review is an essential component of this process, complementing computational approaches. This calls for efficient and intuitive visualization tools able to scale to very large data sets and to flexibly integrate multiple data types, including clinical data. However, the sheer volume and scope of data pose a significant challenge to the development of such tools.

Mechanisms of B-cell lymphoma pathogenesis

Abstract: Chromosomal translocations involving the immunoglobulin loci are a hallmark of many types of B-cell lymphoma. Other factors, however, also have important roles in the pathogenesis of B-cell malignancies. Most B-cell lymphomas depend on the expression of a B-cell receptor (BCR) for survival, and in several B-cell malignancies antigen activation of lymphoma cells through BCR signalling seems to be an important factor for lymphoma pathogenesis. Recent insights into the lymphomagenic role of factors supplied by the microenvironment also offer new therapeutic strategies.

Clonal Expansions of Cd8+ T Cells Dominate the T Cell Infiltrate in Active Multiple Sclerosis Lesions as Shown by Micromanipulation and Single Cell Polymerase Chain Reaction

Abstract: Clonal composition and T cell receptor (TCR) repertoire of CD4+ and CD8+ T cells infiltrating actively demyelinating multiple sclerosis (MS) lesions were determined with unprecedented resolution at the level of single cells. Individual CD4+ or CD8+ T cells were isolated from frozen sections of lesional tissue by micromanipulation and subjected to single target amplification of TCR-β gene rearrangements. This strategy allows the assignment of a TCR variable region (V region) sequence to the particular T cell from which it was amplified. Sequence analysis revealed that in both cases investigated, the majority of CD8+ T cells belonged to few clones. One of these clones accounted for 35% of CD8+ T cells in case 1. V region sequence comparison revealed signs of selection for common peptide specificities for some of the CD8+ T cells in case 1. In both cases, the CD4+ T cell population was more heterogeneous. Most CD4+ and CD8+ clones were represented in perivascular infiltrates as well as among parenchymal T cells. In case 2, two of the CD8+ clones identified in brain tissue were also detected in peripheral blood. Investigation of the antigenic specificities of expanded clones may help to elucidate their functional properties.