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Stephan Dirnhofer

Publications and source records attributed to Stephan Dirnhofer.

At least 19 recordsLinked to original sources
PubMed2007

Precursor B lymphoblastic leukemia 32 months after local therapy for a primary extramedullary myeloid cell tumor.

A primary extramedullary myeloid cell tumor (pEMT) of an inguinal lymph node was completely excised without subsequent anti-tumor therapy in a 6-year-old child. Clinical observation and monitoring of blood and bone marrow (BM) did not reveal any pathologic results before 32 months, when a precursor B lymphoblastic leukemia was diagnosed. Identical T-cell receptor gamma rearrangement in nodal pEMT and in precursor B lymphoblastic leukemia in BM indicates a clonal relationship of these two tumors.

Acute Disease↗
PubMed2006

Prognostic relevance of cytogenetics determined by fluorescent in situ hybridization in patients having myelofibrosis with myeloid metaplasia.

BACKGROUND: In chronic myelofibrosis (MF), distinct recurrent cytogenetic aberrations have been identified but their true prognostic relevance remains uncertain. In this disease, cytogenetic studies as assessed by conventional metaphase karyotyping are limited due to the inherent difficulties in obtaining adequate bone marrow aspirates and the low proliferative capacity of the clonal cells. Interphase fluorescent in situ hybridization (FISH) can partly overcome these limitations and increase the sensitivity of cytogenetic assessment in MF. METHODS: We retrospectively analyzed formalin-fixed, paraffin embedded bone marrow sections of 107 MF patients by FISH and correlated cytogenetic findings with clinical presentation and survival. RESULTS: Chromosomal aberrations were detected in 56% of patients, with 20q- (24.3%) and 13q- (16.8%) being the most frequent ones. Importantly, cytogenetic abnormalities were found in 8/17 patients displaying a normal karyotype as assessed by conventional cytogenetics. CONCLUSIONS: Cytogenetic abnormalities in patients with MF can be detected reliably using FISH. Rare abnormalities confer an adverse outcome, but the main recurrent chromosomal aberrations do not correlate with clinical features and prognosis.

Adult↗
PubMed2006

Cell cycle phase distribution analysis in chronic lymphocytic leukaemia: a significant number of cells reside in early G1-phase.

BACKGROUND AND AIMS: Chronic lymphocytic leukaemia (CLL) is a frequent non-Hodgkin lymphoma characterised by a heterogeneous clinical course. Assessment of cell cycle phase kinetics might be important for prediction of clinical behaviour and prognosis. METHODS: Distribution of neoplastic cells in CLL within the cell cycle was evaluated by determining the labelling indices (LI, i.e. percentage of positive cells) of markers specific for late G1-phase (cyclin E), S-phase (cyclin A), and G2/M-phase (cyclin B1), and Mcm2, a novel marker of proliferative potential, in a large cohort of patients (n = 79) using tissue microarray (TMA) technology. Utilising a combination of these markers, an algorithm was developed--subtracting the combined LIs of cyclin E, cyclin A and cyclin B1 from the LI of Mcm2--to determine the percentage of tumour cells residing in early G1-phase, which is probably a critical state for the malignant potential of CLL. RESULTS: 27.11% of cells had acquired proliferative potential as indicated by expression of Mcm2. Only a small number of cells were found to be in late G1-phase (7.16%), S-phase (3.31%) or G2/M-phase (0.98%), while 15.66% of cells were considered to be in early G1-phase. CONCLUSION: Cell cycle phase distribution can easily be assessed by immunohistochemistry in routinely processed paraffin-embedded specimens. A large number of neoplastic cells in CLL have proliferative potential, with a significant sub-population residing in early G1-phase. Estimates of these cells may identify cases likely to exhibit a more aggressive biological behaviour and adverse clinical course.

Adult↗
PubMed2006

Life with a single isoform of Akt: mice lacking Akt2 and Akt3 are viable but display impaired glucose homeostasis and growth deficiencies.

To address the issues of isoform redundancy and isoform specificity of the Akt family of protein kinases in vivo, we generated mice deficient in both Akt2 and Akt3. In these mice, only the Akt1 isoform remains to perform essential Akt functions, such as glucose homeostasis, proliferation, differentiation, and early development. Surprisingly, we found that Akt2(-/-) Akt3(-/-) and even Akt1(+/-) Akt2(-/-) Akt3(-/-) mice developed normally and survived with minimal dysfunctions, despite a dramatic reduction of total Akt levels in all tissues. A single functional allele of Akt1 appears to be sufficient for successful embryonic development and postnatal survival. This is in sharp contrast to the previously described lethal phenotypes of Akt1(-/-) Akt2(-/-) mice and Akt1(-/-) Akt3(-/-) mice. However, Akt2(-/-) Akt3(-/-) mice were glucose and insulin intolerant and exhibited an approximately 25% reduction in body weight compared to wild-type mice. In addition, we found substantial reductions in relative size and weight of the brain and testis in Akt2(-/-) Akt3(-/-) mice, demonstrating an in vivo role for both Akt2 and Akt3 in the determination of whole animal size and individual organ sizes.

Animals↗
PubMed2006

T-bet negatively regulates autoimmune myocarditis by suppressing local production of interleukin 17.

Experimental autoimmune myocarditis (EAM) appears after infectious heart disease, the most common cause of dilated cardiomyopathy in humans. Here we report that mice lacking T-bet, a T-box transcription factor required for T helper (Th)1 cell differentiation and interferon (IFN)-gamma production, develop severe autoimmune heart disease compared to T-bet+/+ control mice. Experiments in T-bet-/- IL-4-/- and T-bet-/- IL-4Ralpha-/- mice, as well as transfer of heart-specific Th1 and Th2 cell lines, showed that autoimmune heart disease develops independently of Th1 or Th2 polarization. Analysis of T-bet-/- IL-12Rbeta1-/- and T-bet-/- IL-12p35-/- mice then identified interleukin (IL)-23 as critical for EAM pathogenesis. In addition, T-bet-/- mice showed a marked increase in production of the IL-23-dependent cytokine IL-17 by heart-infiltrating lymphocytes, and in vivo IL-17 depletion markedly reduced EAM severity in T-bet-/- mice. Heart-infiltrating T-bet-/- CD8+ but not CD8- T cells secrete IFN-gamma, which inhibits IL-17 production and protects against severe EAM. In contrast, T-bet-/- CD8+ lymphocytes completely lost their capacity to release IFN-gamma within the heart. Collectively, these data show that severe IL-17-mediated EAM can develop in the absence of T-bet, and that T-bet can regulate autoimmunity via the control of nonspecific CD8+ T cell bystander functions in the inflamed target organ.

Animals↗
PubMed2006

Angiogenesis in nodal B cell lymphomas: a high throughput study.

AIM: To assess the biological significance of vascular endothelial growth factor (VEGF) A, VEGF receptor (Flk-1) and cyclooxygenase 2 (COX2) expression with respect to microvessel density (MVD), proliferative activity (Ki-67), expression of p53 and clinical presentation in a large cohort of nodal B cell lymphomas. METHODS: An immunohistochemical and morphometric study was performed on a validated tissue microarray containing 271 B cell lymphoma specimens, 197 of which included follow-up data. Statistical assessment was done by Pearson's chi(2) test, Spearman's rank correlation coefficient, analysis of variance and survival analysis. RESULTS: 266 (98%) cases were evaluable. Strong VEGF expression was observed in only 20 diffuse large B cell lymphomas (DLBCLs). Flk-1 and COX2 were expressed in 53 and 21 cases, respectively, mainly in DLBCLs, follicular lymphoma (FL) grade 3 and mantle cell lymphomas (MCLs), in a low proportion of cells. MVD decreased in the following order: DLBCLs, FLs, MCLs and small lymphocytic lymphomas/chronic lymphocytic leukaemia (SLL/CLLs). VEGF expression correlated with Ki-67, p53 and COX2 expression in the whole cohort and in DLBCLs. Flk-1 expression correlated with Ki-67 in the cohort and in SLL/CLL and FL grade 1 and 2. COX2 expression correlated with Ki-67 and p53. The analysed angiogenesis parameters did not correlate with clinical parameters or survival. CONCLUSIONS: Angiogenesis plays a differential role in various B cell lymphomas. Aggressive lymphomas express the potential molecular therapeutic targets VEGF and COX2, and have higher MVD. In a few low proliferation-fraction lymphomas, Flk-1 might have a role in proliferative advantage. Therapeutic strategies aimed at angiogenesis should take into account lymphoma heterogeneity.

Aged↗
PubMed2006

Cancer-associated carbohydrate identification in Hodgkin's lymphoma by carbohydrate array profiling.

Tumor-associated carbohydrates have potential not only as diagnostic tools but also as specific therapeutic targets. Their identification, however, has been hampered by the lack of suitable technologies. We used carbohydrate array technology to compare serum antibody (IgG and IgM) levels against 37 different carbohydrates between classical Hodgkin's lymphoma (cHL) patients and age/sex-matched healthy controls. Serum IgM levels measured by ELISA against 2 of the 5 carbohydrates identified using this technique, L-alpha-arabinose (L-Araf) and alpha-N-acetylgalactosamine (GalNAc(alpha)), were higher (F values of 11.30 and 18.27, respectively) in a cohort of cHL patients (n = 16) than either diffuse large B-cell lymphoma patients (n = 18) or control sera (n = 12). Higher anti-L-Araf IgM levels in cHL patients were associated with cytosine arabinoside treatment (p < 0.05). The GalNAc(alpha) glycotope, Tn, was found to be heterogeneously expressed in the Reed-Sternberg cells of 9/20 (45%) cHL cases, but not in malignant cells of 25 cases of lymphocyte-predominant HL or another 21 hematological disorders (291 cases) examined immunohistochemically. Tn was expressed in 41/238 (17%) classical HL cases present on a tissue microarray. Expression was associated with CD79a and LMP1 expression and negatively with p27(KIP1) expression (p < 0.05). Kaplan-Meier survival analysis revealed a trend towards improved relapse-free survival with Tn expression although this was not statistically significant (p = 0.271). We suggest that this technique could provide a powerful tool for identifying novel carbohydrates in other cancers.

Acetylgalactosamine↗
PubMed2006

Construction and validation of a bone marrow tissue microarray.

BACKGROUND: The use of tissue microarrays (TMAs) is now a generally accepted method for the investigation of solid tumours. However, little is known about the applicability of the TMA technique for analysis of patients with acute leukaemia. A bone marrow (BM)-TMA analysis with 15 different immunohistochemical markers was performed. The TMA was validated by comparison with the corresponding full tissue sections. MATERIALS AND METHODS: A BM-TMA comprising 148 cases of acute leukaemia, including 115 acute myeloid leukaemia (AML) and 33 acute lymphoblastic leukaemia (ALL) cases, was constructed. Expression of CD3, CD10, CD15, CD20, CD34, CD61, CD68, CD79a, CD99, CD117, CD138, myeloperoxidase, haemoglobin A1, glycophorin and terminal deoxynucleotidyl transferase was immunohistochemically analysed. 50 cases of the TMA were directly compared with the corresponding full tissue section to validate the results. RESULTS: Morphologically and immunohistochemically, 6 (4%) of 148 cases and 765 (11%) cores of 6912 individual analyses were not evaluable. A direct comparison of TMA cases with conventional full sections showed a concordance of the results of 100%. CONCLUSIONS: The small size of bone-marrow biopsies and the presence of bony trabeculae do not preclude construction and analysis of acute leukaemia TMAs. Acute leukaemia cases on TMA displayed the characteristic phenotypic profiles expected in different AML and ALL subtypes. Therefore, the TMA technique is also a promising method for high-throughput analysis of combined marker expression and clinicopathological correlations in patients with leukaemia.

Acute Disease↗
PubMed2006

Overexpression of epithelial cell adhesion molecule (Ep-CAM) is an independent prognostic marker for reduced survival of patients with epithelial ovarian cancer.

OBJECTIVE: Currently available clinical and molecular factors provide still an insufficient prognostic and predictive assessment for patients with epithelial ovarian cancer (EOC). To identify a potential molecular target and prognostic/predictive factor for EOC, we investigated in a retrospective study the prognostic value of Ep-CAM overexpression in EOC. METHODS: We assessed by immunohistochemistry the expression of the Ep-CAM antigen on tissue microarrays containing paraffin-embedded tissue samples of 199 patients with documented EOC. Patients were operated for ovarian cancer in the period between June 1980 and January 2000. RESULTS: We observed a rate of Ep-CAM overexpression of 68.8%. Ep-CAM overexpression was significantly related to a decreased overall survival (P = 0.036). The prognostic power of Ep-CAM overexpression was particularly strong in patients with stage III and IV disease. In fact, in this subgroup, median overall survival was twofold higher in patients without as compared to patients with Ep-CAM overexpression (46 vs. 23 months, P < 0.01). Univariate analysis revealed a correlation with histologic grade. We observed a significantly higher rate of Ep-CAM overexpression (83.5%) in grade 3 tumors. Histologic subtypes associated with a higher rate of Ep-CAM overexpression were serous carcinoma, squamous cell carcinoma, undifferentiated carcinoma, clear cell carcinoma, and endometrioid carcinoma. Cox regression analysis showed Ep-CAM overexpression to be an independent prognostic marker (P = 0.037, RR = 1.64). CONCLUSIONS: This retrospective analysis demonstrates for the first time an independent prognostic value of Ep-CAM overexpression in patients with EOC. Ovarian cancer patients with Ep-CAM overexpressing tumors are frequent and would qualify for treatment with Ep-CAM-specific immunotherapeutic approaches.

Adult↗
PubMed2006

Diffuse large B-cell lymphoma with overexpression of cyclin e substantiates poor standard treatment response and inferior outcome.

PURPOSE: Gold standard to predict survival and stratify patients for risk-adapted therapy in diffuse large B-cell lymphoma (DLBCL) is the international prognostic index, although it does not consider the molecular heterogeneity of DLBCL. Deregulation of cyclin E (CCNE) is a strong predictor of poor prognosis in some neoplastic diseases. In tumor cells, it induces chromosomal instability with an increased rate of aneuploidy/polyploidy. EXPERIMENTAL DESIGN: We analyzed in this retrospective study the prognostic value of immunohistochemical CCNE expression on a validated tissue microarray containing 101 de novo DLBCLs and, in 9 cases, the CCNE-induced chromosomal instability as assessed by cytometry. RESULTS: Forty-six of 98 evaluable DLBCLs expressed CCNE in a mean proportion of 20 +/- 29% of tumor cells; 38 cases expressed CCNE in >/=20% of tumor cells. CCNE-positive samples were aneuploid compared with near tetraploidy in CCNE-negative cases. Multivariate analysis showed CCNE expression in >/=20% of tumor cells to be an international prognostic index-independent, Adriamycin-based treatment-independent, and BCL2-independent prognostic factor for poor disease-specific survival. CCNE expression in >/=80% of tumor cells was associated with dismal short-term prognosis. CCNE expression in >/=50% of tumor cells emerged as an independent predictive factor for standard CHOP treatment resistance. CONCLUSIONS: CCNE expression assessment is easy on paraffin-embedded tissue. The high prognostic value of CCNE expression in DLBCL may be the basis for future prospective trials. In addition, a high CCNE expression hints at the presence of a possible target for individualized cancer therapy.

Aged↗
PubMed2006

Clinical and molecular studies of the effect of imatinib on advanced aggressive fibromatosis (desmoid tumor).

PURPOSE: To determine the clinical efficacy of imatinib in patients with advanced aggressive fibromatosis (AF) and to identify the molecular basis of response/nonresponse to this agent. PATIENTS AND METHODS: Nineteen patients with AF were treated with imatinib (800 mg/d) as part of a phase II clinical study. Tumor specimens were analyzed for mutations of KIT, PDGFRA, PDGFRB, and CTNNB1 (beta-catenin). Tumor expression of total and activated KIT, PDGFRA, and PDGFRB were assessed using immunohistochemistry and immunoblotting techniques. We also measured plasma levels of PDGF-AA and PDGF-BB in patients and normal patient controls. RESULTS: Three of 19 patients (15.7%) had a partial response to treatment, with four additional patients having stable disease that lasted more than 1 year (overall 1 year tumor control rate of 36.8%). No mutations of KIT, PDGFRA, or PDGFRB were found. Sixteen of 19 patients (84%) had mutations involving the WNT pathway (APC or CTNNB1). However, there was no correlation between WNT pathway mutations and clinical response to imatinib. AF tumors expressed minimal to null levels of KIT and PDGFRA but expressed levels of PDGFRB that are comparable with normal fibroblasts. However, PDGFRB phosphorylation was not detected, suggesting that PDGFRB is only weakly activated. AF patients had elevated levels of PDGF-AA and PDGF-BB compared with normal patient controls. Notably, the plasma level of PDGF-BB was inversely correlated with time to treatment failure. CONCLUSION: Imatinib is an active agent in the treatment of advanced AF. Imatinib response in AF patients may be mediated by inhibition of PDGFRB kinase activity.

Adolescent↗
PubMed2006

MyD88 signaling controls autoimmune myocarditis induction.

BACKGROUND: Experimental autoimmune myocarditis (EAM) is a CD4+ T-cell-mediated mouse model of postviral cardiomyopathy. Activation of interleukin-1 type 1 and Toll-like receptors that share the common downstream adaptor molecule MyD88 is required for disease induction. The specific role of MyD88 in myocarditis, however, is not known. METHODS AND RESULTS: In contrast to control littermates, MyD88(-/-) mice were protected from myocarditis after immunization with alpha-myosin heavy chain-derived peptide (MyHC-alpha) and complete Freund's adjuvant. Disease resistance of MyD88(-/-) mice resulted from impaired expansion of heart-specific CD4+ T cells after immunization. Intrinsic defects of MyD88(-/-) CD4+ T cells were excluded. In contrast, MyD88(-/-) but not MyD88(+/+) primary antigen presenting dendritic cells (DCs) were defective in their capacity to prime CD4+ T cells. This defect mainly resulted from the inability of MyD88(-/-) DCs to release tumor necrosis factor-alpha. The critical role of MyD88 signaling in DCs in the peripheral lymphatic compartments was finally proven by repetitive injection of activated, MyHC-alpha-loaded MyD88(+/+) DCs that fully restored T-cell expansion and myocarditis in MyD88(-/-) mice. CONCLUSIONS: Autoimmune myocarditis induction depends on MyD88 signaling in self-antigen presenting cells in the peripheral compartments. We conclude that MyD88 might become a target for prevention of heart-specific autoimmunity and cardiomyopathy.

Adaptor Proteins, Signal Transducing↗
PubMed2006

Age and hemoglobin level emerge as most important clinical prognostic parameters in patients with osteomyelofibrosis: introduction of a simplified prognostic score.

The course of disease in patients with myelofibrosis is highly variable, with survival ranging from few months to many years. Several prognostic models have been established, with the LILLE score now most commonly used. However, in recent series, the latter scoring system repeatedly failed to discriminate patients with intermediate and poor prognosis. In the present study, we re-evaluated previous prognostic models in a separate patient population. We have studied 107 patients with myelofibrosis and correlated clinical parameters at the time of diagnosis with survival. Previous scoring systems were applied to allocate patients to subgroups with distinct prognosis. Most previous scoring systems failed to clearly discriminate an intermediate and poor prognostic group. By contrast, age and hemoglobin level emerged as most significant parameters in multivariate analysis. By allocating one risk point each for hemoglobin < 10 g/dl and age >60 years, three subgroups of patients with distinct prognosis could be identified in our cohort. The overall model and the difference between each of the subgroups were statistically significant in a training group, a test group, the overall cohort of patients and the group of patients with chronic idiopathic myelofibrosis. In summary, we propose an alternative prognostic model for patients with myelofibrosis that reliably identifies three groups of patients with highly different outcome. This is in contrast to previous prognostic scores, in which the poor prognosis group was often very small and/or could not be consistently differentiated from patients with an intermediate prognosis.

Adult↗
PubMed2006

Thermal preconditioning protects the human internal mammary artery from hypoxia/re-oxygenation-induced damage.

1. Preconditioning has been demonstrated to ameliorate ischaemia/reperfusion injury in several cells and tissues. Therefore, in the present study we investigated whether preconditioning of human bypass grafts, internal mammary artery (IMA) and saphenous vein (SV) induces heat shock protein (Hsp) expression and reduces apoptosis in response to subsequent hypoxia/re-oxygenation damage in both vessels. 2. Internal mammary artery and SV rings, obtained from 30 patients (median age 66.5 years) undergoing coronary artery bypass grafting, were either incubated for 30 min at 42 degrees C (preconditioned) or kept in a standard incubator at 37 degrees C (not preconditioned). Six hours later, graft segments were exposed to 90 min hypoxia followed by a 30 min re-oxygenation period. Western blot, real-time quantative polymerase chain reaction analysis and apoptosis detection by the Terminal deoxyribonucleotidyl transferase-mediated dUTP-digoxigenin nick end-labelling method were performed. 3. Heat-preconditioned IMA showed significantly increased protein expression of Hsp72 after hypoxia/re-oxygenation treatment compared with controls (median 9.1 vs 5.0 microg/mg total protein; P = 0.048). Expression of Hsp73 was weak and Hsp60 was not detectable in the IMA. 4. In the SV, neither protein nor mRNA expression of Hsp were significantly different between preconditioned and not preconditioned veins. 5. There were significantly fewer apoptotic cells in the intima of the preconditioned compared with not preconditioned IMA (P = 0.041) after hypoxia/re-oxygenation injury, whereas in the SV apoptosis was not significantly prevented by preconditioning. 6. Mild heat preconditioning before hypoxia/re-oxygenation injury is a stimulus for Hsp72 protein expression and a reduction in apoptosis in the human IMA.

Aged↗
PubMed2006

Pathobiology of classical Hodgkin lymphoma.

The World Health Organization has acknowledged the malignant nature of classical Hodgkin lymphoma (cHL), which encompasses four histological subtypes. The diagnosis of cHL is based on the detection of malignant Hodgkin and Reed-Sternberg cells (HRSC) confirmed by immunophenotyping and the detection of growth patterns specific to each histological subtype. The pathologic HRSC arise from germinal center or immediate postgerminal cells that lack detectable immunoglobulin/B-cell antigen receptor expression, with a consequent loss of B-cell identity; very few cHL cases are of T-cell origin. To escape apoptosis, which normally occurs in B cells with nonfunctioning antigen receptor machinery, HRSC develop concurrent antiapoptotic mechanisms by activation of nuclear factor-kappaB or are rescued by Epstein-Barr virus infection. HRSC are characterized by a variable and inconstant immunophenotype, with a remarkable loss of lineage-specific cell antigens and expression of antigens of other cell lineages. The master plan of B-cell identity in HRSC is disturbed not only at the immunoglobulin expression level, but also at the transcriptional factor level. HRSC are further characterized by profound cell cycle deregulation with futile replication, multinucleation and poly- and aneuploidy. Here, we review pathobiological aspects of cHL with respect to lymphomagenesis and routine diagnostics.

Hodgkin Disease↗
PubMed2006

High rate of molecular alteration in histologically tumour-free bronchial epithelium of NSCLC patients detected by multicolour fluorescence in situ hybridisation.

Detection of molecular abnormalities could provide an essential tool for the diagnosis of non-small cell lung cancer (NSCLC) and defining patients at risk for early relapse. Fluorescence in situ hybridisation (FISH) targeting 17 gene loci was applied to determine the frequency of molecular alteration in NSCLC probes and adjacent tumour-free bronchial epithelium. FISH was performed on fresh frozen specimens from 76 patients with histologically confirmed NSCLC and 54 specimens of adjacent tumour-free tissue. Routine autopsy lung tissue probes from 7 cancer-free patients served as a control group. Locus-specific (3p14.2, 3p21.2, 3p21.3, 3p25.3, 5p15.2, 7p12, 8q24.12, 9p21, 13q14, and 17p13.1) as well as centromere probes (4, 6, 7, 9, 11 and 16) were used. Molecular alterations using FISH on interphase nuclei were detected in 100% of NSCLC tumour specimens and 89% of microscopically tumour-free tissues of NSCLC patients. In histologically 'normal' epithelium, the most frequent alterations were seen with locus-specific probes for 3p14.2, 3p.21, 3p21.3, 3p25.3 and 7p12 and centromere-specific probes 11 and 16 (12-93%). As expected, the majority of genetic alterations seen in 'premalignant' specimens were found in the correlating tumour probes. None of the tested parameters revealed prognostic significance in univariate Cox analysis. FISH analysis, performing multicolour strategies, demonstrated its power in detecting genetic abnormalities in NSCLC specimens and even in tumour-free sections of tumour patients.

Adult↗
PubMed2005

Expression of minichromosome maintenance protein 2 as a marker for proliferation and prognosis in diffuse large B-cell lymphoma: a tissue microarray and clinico-pathological analysis.

BACKGROUND: Minichromosome maintenance (MCM) proteins are essential for the initiation of DNA replication and have been found to be relevant markers for prognosis in a variety of tumours. The aim of this study was to assess the proliferative activity of diffuse large B-cell lymphoma (DLBCL) in tissue microarray (TMA) using one of the minichromosome maintenance proteins (Mcm2) and to explore its potential value to predict prognosis. METHODS: Immunohistochemistry for Mcm2 was performed on TMAs constructed from 302 cases of DLBCL. A monoclonal mouse antibody was used after heat induced antigen retrieval. Mcm2 expression was scored quantitatively. Positivity for Mcm2 was defined as presence of nuclear expression of Mcm2 in greater than or equal to 40 % of tumour cells. A statistical analysis was carried out of the association of Mcm2 and the clinico-pathological characteristics. RESULTS: Mcm2 expression was clearly evident in the nuclei of proliferating non-neoplastic cells and tumour cells. Positivity for Mcm2 was found in 46% (98/211) of analysable cases. A significant correlation existed between Mcm2 expression and presence of bulky disease (p = 0.003). Poor disease specific survival was observed in patients with DLBCL positive for Mcm2 expression in the univariate analysis (p = 0.0424). CONCLUSION: Mcm2 expression can be used to assess tumour proliferation and may be useful as an additional prognostic marker to refine the prediction of outcome in DLBCL.

Biomarkers, Tumor↗