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Biomedical subjects

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

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

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↗
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↗
PubMed2005

Marginal zone lymphoma of the lacrimal gland spreading to the lung and the bone marrow 11 years after first symptoms.

We report on the case of a 52-year-old male presenting with an extranodal marginal zone lymphoma of the mucosa-associated tissue (MALT lymphoma) in the lung 11 years after radiotherapy for a MALT lymphoma of the lacrimal gland, which was primarily diagnosed as dacryoadenitis. Both tumors were investigated by immunohistochemistry and molecular techniques demonstrating their clonal genetic relationship. Both harbored the t(14;18)(q32;q21) and a trisomy 3 and showed identical immunoglobulin heavy-chain gene rearrangements. At the time of pulmonary relapse, clonal CD20- and CD43-positive bone marrow B lymphocytes were detected as well. The elaboration of this case emphasizes the importance of the combined use of modern diagnostic methods for establishment of correct diagnosis of MALT lymphomas at late relapses, which is essential for proper patient management.

Adult↗
PubMed2005

Postmortem diagnostics using MSCT and MRI of a lethal streptococcus group A infection at infancy: a case report.

Postmortem cross-sectional imaging using multislice computed tomography (MSCT) and magnetic resonance imaging (MRI) was considered as a base for a minimal invasive postmortem investigation in forensic medicine such as within the Virtopsy approach. We present the case of a 3-year-old girl with a lethal streptococcus group A infection and the findings of postmortem imaging in this kind of natural death. Postmortem MSCT and MRI revealed an edematous occlusion of the larynx at the level of the vocal cords, severe pneumonia with atelectatic parts of both upper lobes and complete atelectasis of both lower lobes, purulent fluid-filled right main bronchus, enlargement of cervical lymph nodes and pharyngeal tonsils, and additionally, a remaining glossopharyngeal cyst as well as an ureter fissus of the right kidney. All relevant autopsy findings could be obtained and visualized by postmortem imaging and confirmed by histological and microbiological investigations supporting the idea of a minimal invasive autopsy technique.

Adenoids↗
PubMed2005

Proposal of a morphologic bone marrow response score for imatinib mesylate treatment in chronic myelogenous leukemia.

Cytogenetic and molecular analyses are essential disease-monitoring parameters in chronic myelogenous leukemia (CML) treated with imatinib. However, a bone marrow morphologic response has not been defined. We reviewed bone marrow histology and cytology of 39 imatinib-treated patients with CML over 49 weeks and introduced a morphologic response score. A significant positive correlation with a complete cytogenetic response was shown for absence of dry tap (P = .04) and abnormal megakaryocytes (P < 0.001), normalization of cellularity (P = .001) and reduction of fibrosis (P = .01), myelopoiesis:erythropoiesis index (P = .001), blast (P = .001) and basophil count (P < 0.001). The morphologic score integrating these parameters showed an early and late correlation with cytogenetic response. In conclusion, morphologic criteria for complete cytogenetic response in patients with CML treated with imatinib can be defined. Persistent high-level morphologic abnormalities herald early on a high likelihood to fail treatment and call for more intense or alternative therapy.

Adult↗
PubMed2005

Placental site trophoblastic tumor of the mediastinum.

Choriocarcinoma has been described as the most frequent subtype of mediastinal germ cell tumors showing trophoblastic differentiation. We report a unique case of a placental site trophoblastic tumor, which developed in the mediastinum of a 14-year-old boy 2 years after the resection of a mature teratoma. The recurrent tumor was composed of a grossly hemorrhagic and necrotic mass. Histologically, diffusely infiltrating large polygonal cells with focal nodular growth and a teratomatous part containing mature intestinal, respiratory, and squamous epithelium with adjacent cutaneous adnexal structures were found. The typical morphologic features included vessel wall infiltration by the neoplastic cells with fibrinoid deposits and geographic necroses within the tumor masses. Characteristic diffuse positivity for melanoma cell adhesion molecule and human leucocyte antigen G was found on immunohistochemical investigation, confirming the diagnosis of placental site trophoblastic tumor. The patient died 1 year later after polychemotherapy. The outcome of this rare tumor is similar to the reported poor clinical outcome in patients with mediastinal choriocarcinomas.

Adolescent↗
PubMed2005

Aberrant expression of cell cycle regulators in Hodgkin and Reed-Sternberg cells of classical Hodgkin's lymphoma.

The characteristic Hodgkin and Reed-Sternberg cells of classical Hodgkin's lymphoma, although highly positive for proliferation markers, do not accumulate to excessive cell numbers. These cells are characterized by abortive mitotic cycles, leading to multinucleation or cell death in mitosis. We have previously described high expression of G1-phase cyclins in classical Hodgkin's lymphoma, which could explain the high percentage of cells staining for proliferation markers. To further our understanding of proliferation control in classical Hodgkin's lymphoma, we extended our immunohistochemical analysis to the main S-phase cyclin, cyclin A, and its regulators p21CIP1 and p27KIP1. Expression of proliferating cell nuclear antigen (PCNA) was used as an additional marker for cells being in either S- or G2-phase. In 47% (112/239) of classical Hodgkin's lymphoma cases p21CIP1 was detected within a mean frequency of 15% positive Hodgkin's and Reed-Sternberg cells per case. Similarly, 47% (116/249) of the cases stained positively for p27KIP1 with a mean frequency of expression in Hodgkin's and Reed-Sternberg cells of 12%. In contrast, 90% of the cells in all 246 evaluable classical Hodgkin's lymphoma cases were positive for PCNA. In addition, 98% of Hodgkin's and Reed-Sternberg cells in 99% (250/253) of the cases stained strongly positive for cyclin A. These findings further corroborate the hypothesis that Hodgkin and Reed-Sternberg cells exhibit a disturbed cell cycle with an abnormally short or even absent G1-phase. In contrast to other tumors, expression of PCNA or cyclin A had no prognostic value for patient survival.

Adolescent↗
PubMed2005

Rare expression of T-cell markers in classical Hodgkin's lymphoma.

Hodgkin's and Reed-Sternberg cells of classical Hodgkin's lymphoma are primarily of B-cell origin, although there are instances of T-cell antigen expression suggesting T-cell origin. We comprehensively analyzed expression of various T-cell antigens in 259 classical Hodgkin's lymphoma cases using the tissue microarray technique. Expression of the T-cell antigens CD2, CD3, CD4, CD5, CD7 and CD8 was assessed by immunohistochemistry. Hodgkin's and Reed-Sternberg cells of T-cell marker-positive cases were microdissected and analyzed by a multiplex polymerase chain reaction for clonal immunoglobulin heavy chain- and T-cell receptor gamma gene rearrangements. In all, 12 cases (5%) expressed at least one T-cell marker in the following order: CD2 in 11 cases, CD4 in five, CD3 in two, and CD5 and CD8 in one case each; there were no CD7-positive cases, and five cases (2%) expressed more than one T-cell antigen. In positive cases, a mean fraction of 40% of the Hodgkin's and Reed-Sternberg cells (range 20-100%) expressed the analyzed T-cell markers. Two cases (<1%) evidenced clonal T-cell receptor gamma gene rearrangement. Phenotypic expression of T-cell antigens in Hodgkin's and Reed-Sternberg cells of classical Hodgkin's lymphoma is rare (5%), while genotypically, less than 1% of classical Hodgkin's lymphomas are of possible T-cell origin. Therefore, T-cell antigen expression on Hodgkin's and Reed-Sternberg cells is aberrant in the majority of cases and only infrequently classical Hodgkin's lymphomas are of T-cell origin.

Antigens, CD↗
PubMed2005

Expression of epithelial cell adhesion molecule (EpCam) in renal epithelial tumors.

EpCam is an epithelial adhesion molecule expressed in a broad range of carcinomas. Clinical trials with specific humanized anti-EpCam antibodies have shown promising results and have been inaugurated in renal cell carcinoma (RCC) therapy. To study the EpCam expression profile, primary renal cell neoplasms as well as corresponding metastases were evaluated by immunohistochemistry in tissue microarrays. EpCam expression in oncocytomas and chromophobe RCCs was determined on conventional large sections. Moderate or strong EpCam expression was found in eighteen percent of clear cell (n=147), 75% of chromophobe (n=12), and 55% of papillary RCCs (n=20), but not in oncocytomas (n=3). On large sections, 90% of chromophobe RCCs (n=20) showed a strong and homogeneous positivity, whereas oncocytomas (n=15) revealed EpCam positivity in single tumor cells or small clusters. Fourteen percent of RCC metastases (n=97) showed EpCam expression. Patients with EpCam expressing clear cell RCC showed a trend toward a better prognosis in a Cox regression analysis including stage, grade, and necrosis. The data suggest EpCam as a potential therapeutic target in a subset of patients with RCC. In addition, expression patterns of EpCam could become a helpful tool in the discrimination of chromophobe RCC and oncocytoma.

Adult↗
PubMed2005

High specificity of combined TRAP and DBA.44 expression for hairy cell leukemia.

Because of marrow fibrosis, bone marrow aspirations are often nonconclusive in patients with hairy cell leukemia (HCL). Therefore, histologic examination is important in HCL but often difficult in cases with low numbers of tumor cells. A combined immunohistochemical positivity for DBA.44 and tartrate-resistant phosphatase was previously found in 100% of HCL and suggested to be specific for this diagnosis. To further assess the diagnostic specificity and sensitivity of this immunohistochemical approach in a higher number of cases, we analyzed 56 HCLs and lymphoma tissue microarrays, including 840 cases of the most frequent non-Hodgkin lymphomas. All HCLs showed combined positivity for these two proteins (100% sensitivity). Both antibodies were often positive in other lymphoma types. DBA.44 reactivity was especially frequent in follicular lymphomas (46%), whereas tartrate-resistant acid phosphatase (TRAP) expression was often seen in mantle cell lymphomas (57%), primary mediastinal large B-cell lymphomas (54%), and chronic lymphocytic leukemia/small lymphocytic lymphoma (41%). A combined DBA.44/TRAP positivity was seen in only 3% of non-HCL non-Hodgkin lymphomas, including cases of diffuse large B-cell lymphomas, follicular lymphomas, chronic lymphatic leukemia/small lymphocytic leukemias, and mantle cell lymphomas. Overall, these data confirm the utility of combined immunohistochemical DBA.44/TRAP expression analysis in confirming the diagnosis of HCL. However, combined positivity for these markers is highly sensitive but not absolutely specific for HCL.

Acid Phosphatase↗
PubMed2005

Identification of outcome predictors in diffuse large B-cell lymphoma. Immunohistochemical profiling of homogeneously treated de novo tumors with nodal presentation on tissue micro-arrays.

BACKGROUND AND OBJECTIVES: Patients with diffuse large B-cell lymphoma (DLBCL) could benefit from integration of well-established bioclinical prognostic factors with new tools - such as micro-arrays - exploring aberrant gene and/or protein expression. DESIGN AND METHODS: Tissue micro-arrays (TMA) were constructed for the paraffin blocks of 68 patients with de novo DLBCL with nodal presentation, who underwent MACOP-B and were provided with complete clinical information. TMA were tested with specific antibodies against CD10, CD20, CD30, CD79a, CD138, Bcl-2, Bcl-6, IRF4, and IRTA1. RESULTS: The following phenotypic subclassification was made: a) CD10 +/Bcl-6 + or Bcl-6+/IRF4 +, but Bcl-2-/CD30-/CD138-- suggesting B-cells gathering/leaving the germinal center (group 1; n=36); b) Bcl-2+/CD10-/Bcl-6- and CD30+ or CD138+ corresponding to putative non-germinal center B-cells with features of activation or plasmablastic/plasmacellular differentiation (group 2; n=17); c) CD30-/CD138- with extensive Bcl-2 positivity and variable CD10, Bcl-6 and IRF4 combinations (group 3; n=15). Mean IPI scores were 0.6, 1.9 and 1.1 for groups 1, 2 and 3, respectively (p= 0.001). Complete remission (CR) rates were 89%, 53% and 73% (p= 0.015). The 3-year relapse-free survival (RFS) rates are 86%, 41% and 63% (p=0.001) and 42-month overall survival (OS) rates are 91%, 38% and 66% (p=0.0002). INTERPRETATION AND CONCLUSIONS: The present TMA-based study suggests an immunophenotypic profiling system for patients with de novo DLBCL that seems to provide additional prognostic information and contributes to the existing debate on the identification of suitable immunohistochemical surrogates of gene expression profiling results.

Adult↗
PubMed2005

Cyclin B1 expression is an independent prognostic marker for poor outcome in diffuse large B-cell lymphoma.

Diffuse large B-cell lymphoma (DLBCL) is the most frequent non-Hodgkin's lymphoma in the Western world; it is characterized by marked genetic, morphological and clinical heterogeneity. The identification of prognostic markers could help to develop risk-adapted treatment strategies. As proliferation of cells is essential for tumour growth, analysis of the cell cycle and its individual phases might give additional information on tumour progression and clinical behaviour. To investigate the prognostic value of proteins specifically related to the cell cycle phases S, G2 and M in DLBCL, the expression of cyclin A as a marker of S phase and cyclin B1 as a G2/M phase marker were analysed in combination with other clinicopathological parameters in a large cohort of patients. Expression of cyclin B1 and cyclin A were determined by immunohistochemistry using tissue microarray methodology. Immunoreactivity for cyclin B1 and cyclin A was correlated with clinical data using a two-sided Fisher's exact test. Impact on overall survival was analysed by the Kaplan-Meier method. A negative prognostic impact was found for expression of cyclin B1. Nuclear and/or cytoplasmic staining in > or = 1% of tumour cells was significantly associated with shorter overall survival in the multivariate analysis (p=0.008). Furthermore, the prognostic impact of cyclin B1 expression was independent of the tumour stage. No prognostic significance was found for expression of cyclin A. In conclusion, this study demonstrates the independent prognostic value of an expression of cyclin B1 in DLBCL and proposes its evaluation as a prognostic marker in the assessment of this entity which is easily applicable in daily routine practice.

Aged↗