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ABSTRACT: Differentiation of chronic gastritis from marginal zone B-cell lymphoma (MZoL) of MALT type is often difficult for the pathologist. Diagnostic tools include CD20 stain to highlight lymphoepithelial lesions, Wotherspoon grading of the infiltrate, and clonality analysis of the B-cells. MZoL may partially transform into a diffuse, large B-cell lymphoma, which the authors have named blastic MZoL. Blastic MZoL may be present with or without small cell MZoL. Without this component, blastic MzoL, while being CD10-negative, is presently difficult to positively diagnose since specific immune markers are still lacking. Blastic MZoL has a very favourable outcome compared to conventional diffuse large B-cell lymphomas (DLBCL). Moreover, there are conventional DLBCL in the stomach, mostly in a setting of a secondary organ involvement. The biology of these gastric DLBCL is identical to their extragastric counterparts. This is also true for primary gastric Burkitt lymphoma and mucosal involvement in B-CLL or mantle cell lymphoma. Unfavourable outcomes are always observed for EBV-triggered lymphoproliferations in immunodeficiency and peripheral T-cell lymphomas which might also arise or be initially diagnosed in the stomach.
Der Pathologe 04/2013; · 0.67 Impact Factor
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ABSTRACT: Tumor necrosis factor α (TNFα) and other members of the TNF family affect adipose tissue metabolism and contribute to the obesity-related inflammation of adipose tissue. Here, we sought to identify the effects of TRAIL (TNF-related apoptosis-inducing ligand) on fat cell biology. TRAIL-receptor 2 (TRAIL-R2) and its mouse homolog DR5 were regulated upon acute and chronic energy imbalance in murine and human adipose tissue. TRAIL inhibited insulin-stimulated glucose uptake and de novo lipogenesis in human adipocytes. Interestingly, TRAIL did not interfere with the phosphorylation of insulin-stimulated kinases such as Akt or Erk and did not activate the NF-κB pathway. Instead, TRAIL activated cleavage of caspase-8 and caspase-3. The subsequent cleavage of PPARγ led to its inactivation and resulted in reduced expression of lipogenic genes, such as Glut-4, FASN, and ACC. Taken together, we discovered a so far unknown function of the death ligand TRAIL in regulating adipocyte metabolism. Our results imply that TRAIL/TRAIL-R system might provide a new target for the prevention and treatment of obesity and its co-morbidities.
Cell Death & Disease 01/2013; 4:e474. · 5.33 Impact Factor
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T F E Barth,
L Floßbach,
H-W Bernd,
R Bob,
M Buck,
S B Cogliatti,
A C Feller,
M L Hansmann,
S Hartmann,
H Horn,
W Klapper,
D Kradolfer,
T Mattfeldt, P Möller,
A Rosenwald,
H Stein,
C Thorns,
G Ott
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ABSTRACT: BACKGROUND: The detection of characteristic genomic aberrations by fluorescence in situ hybridization (FISH) has a high diagnostic impact on lymphomas according to the World Health Organization (WHO). To investigate the reproducibility of non-isotopic ISH results a multicenter trial was carried out involving eight institutes for hematopathology. MATERIAL AND METHODS: Analyses were performed on two diffuse large B-cell lymphomas (DLBCL) without known aberrations, on one follicular lymphoma with a IGH/BCL2 translocation and BCL6 split and on two B-cell lymphomas intermediate between DLBCL and Burkitt's lymphoma with c-MYC and BCL2 rearrangements, one with an additional BCL6 split. Break-apart probes for BCL6 and c-MYC, as well as fusion probes for the c-MYC/IGH and the IGH/BCL2 translocations were used. RESULTS: All aberrations were correctly detected by all centres and no false positive or false negative results were obtained. The numbers of positive cells varied from 25% to 94%. Pearson's correlation coefficient between the centres was always > 0.8. CONCLUSIONS: The ISH analysis of recurrent genomic aberrations in formalin-fixed paraffin-embedded (FFPE) tissue is a highly reproducible technique which yields substantial additive help for lymphoma diagnostics.
Der Pathologe 11/2012; · 0.67 Impact Factor
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ABSTRACT: Das Skelettsystem ist häufig der Metastasierungsort urologischer Karzinome. Ossäre Metastasen werden in osteoneutral, osteolytisch,
osteoblastisch und gemischtförmig unterschieden. Osteolytisch wirkende Metastasen führen über Aktivierung der Osteoklasten
zur Knochenresorption, wohingegen osteoblastische Metastasen durch parakrine Sekretion Osteoblasten aktivieren und so die
Osteoneogenese fördern. Neben dem lokalen osteoblastischen Effekt kommt es zu einem sekundären systemischen Knochenabbau.
Als supportive Therapie hat sich der Einsatz von Bisphosphonaten etabliert. Neue, z.T. noch experimentelle Ansätze bestehen
in der gezielten Intervention in die Pathophysiologie der Knochenmetastasierung und der Radioimmuntherapie.
The skeletal system is the most frequent metastatic site of hematogenous spread of urologic carcinomas. Osseus metastases
are classified as osteoneutral, osteolytic, osteoblastic and combinations thereof. Osteolytic metastases lead to bone resorption
by activating osteoclasts, while osteoblastic metastases stimulate osteoblasts by paracrine mechanisms. The local osteoblastic
effect is associated with secondary systemic bone resorption. The use of bisphosphonates is now an established supportive
therapy and newer treatment strategies including targeted intervention in the pathophysiology of bone metastases and radioimmunotherapy
are being applied or will be coming soon.
Der Urologe 04/2012; 46(8):888-890. · 0.50 Impact Factor
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ABSTRACT: Mature donor-derived T cells in allogeneic bone marrow (BM) transplants mediate the graft-versus-tumor (GVT) effect by recognizing alloantigens on leukemic cells. However, alloantigen reactivity towards non-malignant tissues also induces graft-versus-host disease (GVHD). Defining T-cell subpopulations that mediate the GVT effect in the absence of GVHD induction remains a major challenge in allogeneic BM transplantation. In this study, we show that in vitro-generated alloantigen-specific CD8(+) cytotoxic T cells (CTLs) established by weekly stimulation with alloantigen-expressing antigen-presenting cells did not induce GVHD in two major histocompatibility complex-mismatched BM transplantation models, where induction of lethal GVHD is dependent on the presence of either CD4(+) or CD8(+) T cells. Despite their strong alloantigen specificity, transplantation of CTLs did not induce the expression of GVHD-associated cytokines IFN-γ and TNF-α or clinical or histological signs of GVHD, and lead to a survival rate of above 90%. However, transplantation of unstimulated CD8(+) T cells, which were not primed by the alloantigen in vitro, induced GVHD in both the transplantation models. Although CTLs were impaired in GVHD induction, they efficiently eradicated Bcr-Abl-transformed B-cell leukemias or mastocytomas. Thus, in vitro-derived CTLs might be useful for optimizing anti-tumor therapy in the absence of GVHD induction.
Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, U.K 02/2011; 25(5):848-55. · 8.30 Impact Factor
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N Bhattacharya,
S Diener,
I S Idler,
T F Barth,
J Rauen,
A Habermann,
T Zenz, P Möller,
H Döhner,
S Stilgenbauer,
D Mertens
Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, U.K 01/2011; 25(4):722-6. · 8.30 Impact Factor
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ABSTRACT: The marginal zone B-cell lymphoma, MALT-type (MZBL, MT) is a low-grade B-cell lymphoma which is predominantly localised in the stomach with a typical morphology and cytogenetic pattern. The coexistence of a diffuse large B-cell lymphoma (DLBCL) with an MZBL, MT in the gastrointestinal tract is defined as a composite lymphoma (ComL) and represents a fascinating model of lymphoma progression. In this review we focus on current aspects regarding the molecular characterisation of MZBL, MT and gastrointestinal DLBCL and their mutual relationships.
Zeitschrift für Gastroenterologie 08/2010; 48(8):833-8. · 0.90 Impact Factor
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K Giannopoulos,
D Mertens,
A Bühler,
T F E Barth,
I Idler, P Möller,
A Kröber,
J Greiner,
S Chocholska,
A Dmoszyñska,
J Roliñski,
H Döhner,
S Stilgenbauer,
M Schmitt
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ABSTRACT: Differential expression of molecules in chronic lymphocytic leukemia (CLL) may define prognostic markers and suitable targets for immunotherapy. Expression of the tumor-associated antigen (TAA) RHAMM (receptor for hyaluronic acid-mediated motility) as well as RHAMM splicing variants was assessed in series of 72 CLL patients. Quantitative reverse transcriptase PCR showed higher RHAMM expression in high-risk CLL patients, as well as in the advanced stages of the disease. CLL cases with a higher RHAMM expression showed a significantly shorter median treatment-free survival. Among patients with mutated immunoglobulin heavy chain genes, an analysis of RHAMM expression enabled to distinguish subgroup of patients with favorable prognosis. In lymph nodes, RHAMM staining correlated with a higher Ki-67 index and CD40L expression. Functionally, stimulation with CD40L enhanced RHAMM expression in CLL. We further characterized RHAMM-specific CD8(+) T cells in patients with CLL, as the expression of TAAs might influence the clinical outcome by the means of immune reactions. The cytotoxic potential of RHAMM-specific T cells was shown against target cells bearing RHAMM-derived epitope as well as against CLL cells expressing RHAMM. In conclusion, RHAMM expression appears to be of prognostic value, as well as may reflect the proliferative capacity of CLL cells, and might therefore represent interesting target for immunotherapy.
Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, U.K 01/2009; 23(3):519-27. · 8.30 Impact Factor
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ABSTRACT: Die Hodgkin-Zelllinie U-HO1 wurde isoliert aus dem malignen Pleuraerguss eines 23-jährigen männlichen Patienten, der am Endstadium
eines therapierefraktären klassischen Hodgkin-Lymphoms (cHL) vom nodulär-sklerosierenden Typ litt. Seit ihrer Etablierung
im Jahr 2005 weist die Zelllinie in vitro stabile Charakteristika auf. Unter standardisierten Zellkulturbedingungen beträgt die Verdopplungszeit etwa 4 Tage. In Suspension
bildet U-HO1 typische Sternberg-Reed-Zellen, ist EBV- wie HLA-ABC-negativ und HLA-D- wie CD74-positiv. Auf der Oberfläche
wird CD15 zusammen mit CD30 exprimiert, CD19 und CD20 fehlen. Die Karyotypisierung zeigte einen hyperdiploiden Karyotyp mit
multiplen klonalen Aberrationen. Am auffälligsten ist ein verlängertes Chromosom2, der(2)t(2;10)(q35;q16.1)add(2)(p13). Die
CGH-Analyse ergab Imbalancen: ish cgh dim(1)(p13p31)(p12q21), enh(2)(p13p23), dim(4)(q31.3qter), enh(6)(q22q27), enh(12),
enh(18),enh(20)(q13.1pter). Die FISH-Analyse zeigte eine 6-fache Amplifikation von REL und BCL-11A, d.h., U-HO1 ist in jeder bisher untersuchten Hinsicht prototypisch für das cHL. Zytogenetisch hat sich U-HO1 im Vergleich
mit anderen HL-Zelllinien als wesentlich stabiler erwiesen, sodass wahrscheinlich ist, dass sich der ausgeprägte Phänotyp
eines primär therapierefraktären cHL allein aufgrund der U-HO1-Imbalancen entwickelt.
The Hodgkin cell line U-HO1 was established from a malignant pleural effusion of a 23-yr-old male patient during the end stage
of refractory nodular sclerosing classical Hodgkin lymphoma (cHL). Since its establishment in 2005, U-HO1 has maintained stable
characteristics in vitro and has a doubling time of about 4 days under standard culture conditions. U-HO1 forms typical Reed/Sternberg cells in suspension,
is EBV negative, lacks HLA-ABC- but expresses HLA-D- proteins/CD74 and surface exposes CD15 together with CD30 in the absence
of CD19 and CD20. Karyotype analysis of U-HO1 revealed a hyperdiploid karyotype with multiple clonal aberrations. Most significant
is an elongated chromosome 2, der(2)t(2;10)(q35;q16.1)add(2)(p13). CGH analysis revealed the following imbalances: ish cgh
dim(1)(p13p31)(p12q21), enh(2)(p13p23), dim(4)(q31.3qter), enh(6)(q22q27), enh(12), enh(18),enh(20)(q13.1pter). FISH analysis
showed about six-fold amplification of REL and BCL-11A, thus, U-HO1 is prototypical for cHL in every aspect tested so far. Compared to other HL cell lines, U-HO1 proved far less
genetically aberrant suggesting that U-HO1’s imbalances suffice to cause the full-blown phenotype of primary refractory cHL.
Der Pathologe 10/2008; 29:317-318. · 0.67 Impact Factor
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ABSTRACT: The Hodgkin cell line U-HO1 was established from a malignant pleural effusion of a 23-yr-old male patient during the end stage of refractory nodular sclerosing classical Hodgkin lymphoma (cHL). Since its establishment in 2005, U-HO1 has maintained stable characteristics in vitro and has a doubling time of about 4 days under standard culture conditions. U-HO1 forms typical Reed/Sternberg cells in suspension, is EBV negative, lacks HLA-ABC- but expresses HLA-D- proteins/CD74 and surface exposes CD15 together with CD30 in the absence of CD19 and CD20. Karyotype analysis of U-HO1 revealed a hyperdiploid karyotype with multiple clonal aberrations. Most significant is an elongated chromosome 2, der(2)t(2;10)(q35;q16.1)add(2)(p13). CGH analysis revealed the following imbalances: ish cgh dim(1)(p13p31)(p12q21), enh(2)(p13p23), dim(4)(q31.3qter), enh(6)(q22q27), enh(12), enh(18),enh(20)(q13.1pter). FISH analysis showed about six-fold amplification of REL and BCL-11A, thus, U-HO1 is prototypical for cHL in every aspect tested so far. Compared to other HL cell lines, U-HO1 proved far less genetically aberrant suggesting that U-HO1's imbalances suffice to cause the full-blown phenotype of primary refractory cHL.
Der Pathologe 10/2008; 29 Suppl 2:317-8. · 0.67 Impact Factor
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S Bentink,
S Wessendorf,
C Schwaenen,
M Rosolowski,
W Klapper,
A Rosenwald,
G Ott,
A H Banham,
H Berger,
A C Feller, [......],
D Hasenclever,
M Hummel,
D Lenze, P Möller,
B Stuerzenhofecker,
M Loeffler,
L Truemper,
H Stein,
R Siebert,
R Spang
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ABSTRACT: Deregulation of cell signaling pathways controlling cell growth and cell survival is a common feature of all cancers. Although a core repertoire of oncogenic mechanisms is widely conserved between various malignancies, the constellation of pathway activities can vary even in patients with the same malignant disease. Modern molecularly targeted cancer drugs intervene in cell signaling compensating for pathway deregulation. Hence characterizing tumors with respect to pathway activation will become crucial for treatment decisions. Here we have used semi-supervised machine learning methodology to generate signatures of eight oncogene-inducible pathways, which are conserved across epithelial and lymphoid tissues. We combined them to patterns of pathway activity called PAPs for pathway activation patterns and searched for them in 220 morphologically, immunohistochemically and genetically well-characterized mature aggressive B-cell lymphomas including 134 cases with clinical data available. Besides Burkitt lymphoma, which was characterized by a unique pattern, the PAPs identified four distinct groups of mature aggressive B-cell lymphomas across independent gene expression studies with distinct biological characteristics, genetic aberrations and prognosis. We confirmed our findings through cross-platform analysis in an independent data set of 303 mature aggressive B-cell lymphomas.
Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, U.K 07/2008; 22(9):1746-54. · 8.30 Impact Factor
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Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, U.K 05/2008; 22(11):2106-10. · 8.30 Impact Factor
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Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, U.K 04/2008; 22(10):1942-4. · 8.30 Impact Factor
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ABSTRACT: Ductal concretions in chronic pancreatitis (CP) are one of the causes of ductal obstruction, resulting in pancreatic ductal hypertension (PDH) and duct ectasia. Ductal epithelium subjected to chronic stress by PDH may undergo molecular alterations, thereby not only initiating and sustaining the inflammatory process but also activating molecules that have transforming potential. Acino-ductal metaplasia and pancreatic intraepithelial neoplasia (PanIN) are frequently seen in CP. Using laser capture microdissection, cDNA microarrays and Ingenuity Pathways Analysis, we found an altered Notch pathway in the ectatic ducts of CP. The microarray data was further validated by real-time PCR. We also found elevated transcripts of Notch receptors, Notch1 and Notch3 in microdissected ectatic ducts of CP. The Notch pathway ligands, Jagged/Delta-like and a Notch target, HES-related repressor protein (HERP), were up-regulated in ectatic compared to normal pancreatic ducts, while another target of Notch, hairy/enhancer of split (HES), was down-regulated. The transcripts of Delta-like1 and Jagged1 were increased 3.7-fold and 1.3-fold, respectively, while those of HERP1 were elevated 2.4-fold in the ectatic ducts of CP, compared to normal ducts. Immunohistochemistry showed that Jagged1 was not expressed in normal pancreatic ducts, while it was highly expressed in ectatic ducts. This pattern of Notch component alteration in ectatic ducts was mimicked to some extent in vitro in a human pancreatic duct epithelial (HPDE) cell line, when subjected to a pressure of 200 mmHg for 24 h. Therefore, we conclude that in the ectatic ducts of CP, PDH activates signalling pathways such as Notch, which have transforming potential.
The Journal of Pathology 03/2008; 214(3):312-9. · 6.32 Impact Factor
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Histopathology 03/2008; 52(3):399-402. · 3.08 Impact Factor
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S Wessendorf,
T F E Barth,
A Viardot,
A Mueller,
H A Kestler,
H Kohlhammer,
P Lichter,
M Bentz,
H Döhner, P Möller,
C Schwaenen
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[hide abstract]
ABSTRACT: Primary mediastinal B-cell lymphoma (PMBL) is an aggressive extranodal B-cell non-Hodgkin's lymphoma with specific clinical, histopathological and genomic features. To characterize further the genotype of PMBL, we analyzed 37 tumor samples and PMBL cell lines Med-B1 and Karpas1106P using array-based comparative genomic hybridization (matrix- or array-CGH) to a 2.8k genomic microarray. Due to a higher genomic resolution, we identified altered chromosomal regions in much higher frequencies compared with standard CGH: for example, +9p24 (68%), +2p15 (51%), +7q22 (32%), +9q34 (32%), +11q23 (18%), +12q (30%) and +18q21 (24%). Moreover, previously unknown small interstitial chromosomal low copy number alterations (for example, -6p21, -11q13.3) and a total of 19 DNA amplifications were identified by array-CGH. For 17 chromosomal localizations (10 gains and 7 losses), which were altered in more than 10% of the analyzed cases, we delineated minimal consensus regions based on genomic base pair positions. These regions and selected immunohistochemistries point to candidate genes that are discussed in the context of NF-kappaB transcription activation, human leukocyte antigen class I/II defects, impaired apoptosis and Janus kinase/signal transducer and activator of transcription (JAK/STAT) activation. Our data confirm the genomic uniqueness of this tumor and provide physically mapped genomic regions of interest for focused candidate gene analysis.
Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, U.K 01/2008; 21(12):2463-9. · 8.30 Impact Factor
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[show abstract]
[hide abstract]
ABSTRACT: The skeletal system is the most frequent metastatic site of hematogenous spread of urologic carcinomas. Osseus metastases are classified as osteoneutral, osteolytic, osteoblastic and combinations thereof. Osteolytic metastases lead to bone resorption by activating osteoclasts, while osteoblastic metastases stimulate osteoblasts by paracrine mechanisms. The local osteoblastic effect is associated with secondary systemic bone resorption. The use of bisphosphonates is now an established supportive therapy and newer treatment strategies including targeted intervention in the pathophysiology of bone metastases and radioimmunotherapy are being applied or will be coming soon.
Der Urologe 09/2007; 46(8):888-90. · 0.50 Impact Factor
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C Renné,
K Willenbrock,
J I Martin-Subero,
N Hinsch,
C Döring,
E Tiacci,
W Klapper, P Möller,
R Küppers,
M-L Hansmann,
R Siebert,
A Bräuninger
[show abstract]
[hide abstract]
ABSTRACT: Mediastinal large B-cell (MBL) and classical Hodgkin lymphoma (HL) have several pathogenic mechanisms in common. As we recently observed aberrant tyrosine kinase (TK) activities in HL, we now analysed also MBL for such activities. Indeed, MBL and HL were the only B-cell lymphomas where elevated cellular phospho-tyrosine contents were typical features. Three TKs, JAK2, RON and TIE1, not expressed in normal B cells, were each expressed in about 30% of MBL cases, and 75% of cases expressed at least one of the TKs. Among the intracellular pathways frequently triggered by TKs, the PI3K/AKT pathway was activated in about 40% of MBLs and essential for survival of MBL cell lines, whereas the RAF/mitogen-activated protein kinase pathway seemed to be inhibited. No activating mutations were detected in the three TKs in MBL cell lines and primary cases. RON and TIE1 were each also expressed in about 35% and JAK2 in about 53% of HL cases. JAK2 genomic gains are frequent in MBL and HL but we observed no strict correlation of JAK2 genomic status with JAK2 protein expression. In conclusion, aberrant TK activities are a further shared pathogenic mechanism of MBL and HL and may be interesting targets for therapeutic intervention.
Leukemia 05/2007; 21(4):780-7. · 9.56 Impact Factor
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ABSTRACT: Mediastinal B-cell lymphoma is a locally highly aggressive tumour which was first described in the early 1980s. The incidence is about 2-3% of all non-Hodgkin's lymphomas. The conceptional evolution of this lymphoma entity was hampered by its low incidence and the broad spectrum of morphological variants present. However, since mediastinal B-cell lymphoma has distinct morphological, immunological, genetic, and clinical features, it has been listed in the revised European-American Classification of Lymphoid Neoplasms (REAL-Classification) since 1994 as a variant of diffuse large B-cell lymphoma. In the World Health Organization classification of malignant lymphomas, mediastinal B-cell lymphoma is now listed with an own disease code (ICD-9679/3).
Der Pathologe 03/2007; 28(1):36-40. · 0.67 Impact Factor
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ABSTRACT: The pathogenetic relationship of marginal zone B-cell lymphoma (MALT lymphoma) of the gastrointestinal (GI) tract and eventually co-existing aggressive B-cell lymphoma and primary aggressive B-cell lymphoma remains to be elucidated. The RNA of laser-microdissected cells was isolated and amplified from small and/or large cell compartments of eight MALT lymphomas (small cell lymphoma, SCL), 14 GI diffuse large B-cell lymphomas (large cell lymphoma, LCL), and ten GI B-cell lymphomas with composite small and large cell compartments (ComL) and expression analyses were performed using cDNA arrays. Hierarchical cluster analysis clearly separated SCL and LCL and the small and large cell compartments of ComL. Likewise, cluster analysis with all samples of SCL, LCL, and ComL yielded two main 'small cell' and 'large cell' branches. Furthermore, 60 genes were differentially expressed between SCL and LCL, and 82 genes between the small and large cell components of ComL; 26 genes were discriminators in both settings. Use of the profiles of ComL as training sets for class prediction resulted in 95% accuracy for the classification of SCL and LCL. Collectively, the data strongly suggest that both secondary and primary aggressive B-cell lymphomas of the GI tract are blastic marginal zone lymphomas.
The Journal of Pathology 03/2007; 211(3):305-13. · 6.32 Impact Factor
