Biomedical subjects

H Griesser

Publications and source records attributed to H Griesser.

At least 19 recordsLinked to original sources

PubMed2001

Primary lymph node plasmacytomas (plasmacytic lymphomas).

To determine whether primary lymph node plasmacytoma (PLNP) is a distinct entity among other types of plasma cell neoplasia, we analyzed a large series of PLNPs from 2 large lymphoma registries to compare histologic, immunophenotypic, and clinical features of PLNPs, nonnodal extramedullary plasmacytomas, and multiple myeloma. Twenty-five PLNPs (clinical data on 15 cases) were compared with 10 non-lymph node plasmacytomas and 51 cases of multiple myeloma; 36 cases of reactive plasmacytoses were used as controls. The histologic features of PLNP and other extramedullary plasmacytomas were similar. The histologic features of PLNPs were more immature than those of reactive plasmacytoses and less immature than in multiple myeloma. The immunophenotype of PLNPs significantly differed from that of reactive plasmacytoses, other extramedullary plasmacytomas, and multiple myeloma. PLNPs did not progress to multiple myeloma, unlike other extramedullary plasmacytomas, even though survival in PLNPs and other extramedullary plasmacytomas was similar. Our findings suggest that PLNPs may be distinct from other plasma cell dyscrasias.

Adolescent↗

PubMed2001

[Cytopathology--current trends].

Modern imaging techniques help to detect minute tumours, even in remote locations of the body. This increases the demand to sample cellular material by minimal invasive procedures, such as fine needle aspiration (FNA). For optimal treatment, tumour cells should be characterized for prognostically relevant features. Primary and metastatic neoplasms, and individual disseminated cells of solid tumours are targets for FNA and exfoliative cytology. Recognition and typing of tumour cells is aided by immunochemistry and PCR based molecular studies. Especially immunostaining requires laboratory procedures adapted to cytology samples. Screening for precancerous lesions, highly successful in cervical cancer prevention, extends into areas such as bladder and lung cancer in selected patient groups. Cell image analysis, especially for DNA ploidy, and chromosomal FISH of interphase cells can have predictive value enhancing the information derived from the purely morphologic assessment. Prognostic tumour cell markers are studied using immunochemistry and PCR on cytological material. Cytology has to foster translational research and test the results from molecular cytogenetics, including comparative genomic hybridisation (CGH) and cDNA microarray techniques on dissociated solid tumour cells. Newly identified genetic abnormalities can be evaluated for their functional relevance and may correlate with distinct structural alterations of the tumour cells. Proper training, dedication to diagnostic cytologic work and molecular studies, and sufficient staffing will enable cytology to get the most for the patient out of limited cell material. This approach helps to distinguish genetically defined tumour subtypes by recognizing properties of the cell gestalt.

Biopsy, Needle↗

PubMed2000

Significantly different bcl-2 expression profiles in gastric and non-gastric primary extranodal high-grade B-cell lymphomas.

Fifty-five cases of primary extranodal high-grade B-cell non-Hodgkin's lymphoma were investigated for bcl-2 and p53 protein expression as well as for t(14;18) translocations and p53 mutations. Phenotypic and genotypic profiles were compared between tumours of gastric (27 cases) and non-gastric (28 cases) origin. bcl-2 protein expression was significantly lower in gastric (11/27) than in non-gastric (28/28) lymphomas (p<0.0001), while nuclear p53 protein expression did not differ significantly between these two groups. In the stomach, there were no significant differences in either bcl-2 or p53 expression profiles between high-grade lymphomas with (n=14) and without (n=13) evidence of a low-grade component of MALT type. However, secondary high-grade lymphomas showed a significant down-regulation of bcl-2 protein (p<0.0001) and, conversely, an up-regulation of p53 protein (p<0.0001) as compared with their low-grade tumour components. In extranodal high-grade B-cell lymphomas, bcl-2 protein expression was not associated with t(14;18) translocation. Only one gastric lymphoma had a p53 point mutation with potential alteration of the amino acid sequence. These findings indicate that primary gastric high-grade B-cell lymphomas are immunohistologically distinct from primary extranodal high-grade B-cell lymphomas of an origin other than in the stomach.

Biomarkers, Tumor↗

PubMed2000

Detection of c-kit mutation Asp 816 to Val in microdissected bone marrow infiltrates in a case of systemic mastocytosis associated with chronic myelomonocytic leukaemia.

BACKGROUND/AIMS: The occurrence of myeloid leukaemia in patients with systemic mastocytosis is a well recognised phenomenon. However, the pathophysiological basis of such a coevolution has not been clarified. Recent data have shown that the c-kit mutation Asp 816 to Val is detectable in neoplastic mast cells in most patients with systemic mastocytosis, including those who have associated haematological disorders. The aim of this study was to study clonal disease evolution by analysing bone marrow cells from a patient with systemic mastocytosis and associated chronic myelomonocytic leukaemia (CMML) for the presence of this mutation. METHODS: The DNA of microdissected bone marrow cells from a patient with systemic mastocytosis and associated CMML was analysed for the presence of the c-kit mutation Asp 816 to Val by means of HinfI digestion and direct sequencing of semi-nested polymerase chain reaction (PCR) products. RESULTS: The two neoplasms could easily be identified and discriminated in paraffin wax embedded bone marrow sections by tryptase and chloroacetate esterase staining. A total number of 10 tryptase positive systemic mastocytosis infiltrates and 10 tryptase negative CMML infiltrates were removed by microdissection. As assessed by HinfI digestion and direct sequencing of semi-nested PCR products, the c-kit mutation Asp 816 to Val was detected in five of seven systemic mastocytosis infiltrates and four of six CMML infiltrates. By contrast, no c-kit mutation Asp 816 to Val was found in bone marrow infiltrates in patients with CMML without associated systemic mastocytosis (n = 20). CONCLUSION: These data support a monoclonal evolution of systemic mastocytosis and concurrent CMML in the patient studied.

Aged↗

PubMed2000

Lymphomas in patients with connective tissue disease. Comparison of p53 protein expression and latent EBV infection in patients immunosuppressed and not immunosuppressed with methotrexate.

Cell cycle dysregulation as measured by p53 protein expression and latent Epstein-Barr (EBV) infection are important in the pathogenesis of lymphoma, particularly in immunosuppressed patients. Although latent EBV commonly is detected in lymphomas arising in patients with connective tissue disease who are immunosuppressed with methotrexate, p53 protein expression has not been reported. We compared the immunohistologic expression of p53 protein and the incidence of latent EBV infection in lymphomas arising in patients with connective tissue disease treated and not treated with methotrexate. Increased p53 staining was detected in 10 of 11 lymphomas arising in patients after methotrexate therapy vs 5 of 11 in patients not treated with methotrexate. Latent EBV was detected in 7 of 13 lymphomas arising in patients after methotrexate therapy vs 2 of 11 in patients not treated with methotrexate. Concordant p53 expression and latent EBV were detected in 5 of 7 lymphomas arising after treatment with methotrexate, including 1 that regressed after methotrexate therapy was withdrawn. These findings suggest that cell cycle dysregulation and EBV-related transformation are important in the pathogenesis of lymphomas arising in patients with connective tissue disease who are immunosuppressed with methotrexate.

Adolescent↗

PubMed1999

Synthesis and cytostatic activities of didemnin derivatives.

The highly cytostatic didemnins contain a 23-membered cyclopeptolide with a side chain attached to the backbone through the amine group of threonine. Thirty-six derivatives varying the side chain were prepared, but only compounds with D-MeLeu attached to threonine show remarkable biological activities. To protect the macrocycle from degradation by lipases the two ester bonds were replaced successively by amide bonds. Although these variations have a major effect on the conformation and rigidity of the ring, the compound which contains exclusively amide bonds is highly active, equivalent to acetyl-didemnin A.

Antineoplastic Agents↗

PubMed1999

Increased I-131 uptake in local recurrence and distant metastases after second treatment with retinoic acid.

We present a case of increased I-131 uptake in a patient with papillary thyroid carcinoma with local recurrence and distant metastases after a second treatment with retinoic acid as a sign of redifferentiation of the tumor cells. When fine-needle aspiration cytology before and after a second course of retinoic acid treatment were compared, signs of tumor cell redifferentiation were found. This was accompanied by biochemical reexpression of thyroid marker proteins.

Carcinoma, Papillary↗

PubMed1998

Leukemic predisposition of mice transplanted with gene-modified hematopoietic precursors expressing flt3 ligand.

flt3/flk-2 ligand (FL) is a cytokine that exhibits synergistic activities in combination with other early acting factors on subpopulations of hematopoietic stem/progenitor cells. In addition to normal hematopoietic precursors, expression of the FL receptor, flt3R, has been frequently demonstrated on the blast cells from patients with acute B-lineage lymphoblastic, myeloid, and biphenotypic (also known as hybrid or mixed) leukemias. Because many of these leukemic cell types express FL, the possibility has been raised that altered regulation of FL-mediated signaling might contribute to malignant transformation or expansion of the leukemic clone. In humans, FL is predominantly synthesized as a transmembrane protein that must undergo proteolytic cleavage to generate a soluble form. To investigate the consequences of constitutively expressing the analogous murine FL isoform in murine hematopoietic stem/progenitor cells, lethally irradiated syngeneic mice (18 total) were engrafted with post-5-fluorouracil-treated bone marrow cells transduced ex vivo with a recombinant retroviral vector (MSCV-FL) encoding murine transmembrane FL. Compared with control mice (8 total), MSCV-FL mice presented with a mild macrocytic anemia but were otherwise healthy for more than 5 months posttransplant (until 22 weeks). Subsequently, all primary MSCV-FL recipients observed for up to 1 year plus 83% (20 of 24) of secondary MSCV-FL animals that had received bone marrow from asymptomatic primary hosts reconstituted for 4 to 5 months developed transplantable hematologic malignancies (with mean latency periods of 30 and 23 weeks, respectively). Phenotypic and molecular analyses indicated that the tumor cells expressed flt3R and displayed B-cell and/or myeloid markers. These data, establishing that dysregulated expression of FL in primitive hematopoietic cells predisposes flt3R+ precursors to leukemic transformation, underscore a potential role of this cytokine/receptor combination in certain human leukemias.

Animals↗

PubMed1998

Immunophenotypic and genotypic characterisation of multiple myelomas with adverse prognosis characterised by immunohistological expression of the T cell related antigen CD45RO (UCHL-1).

AIMS: To investigate whether plasma cell expression of early B cell, late B cell/preplasma cell, T cell, and myelomonocytic antigens or myeloma associated lymphocytic infiltrates correlated with prognosis in bone marrow biopsy specimens of patients with multiple myeloma. METHODS: Bone marrow biopsy specimens of 23 patients with multiple myeloma were investigated for plasma cell expression and interstitial lymphocyte expression of T cell related antigen CD45RO (UCHL-1). RESULTS: Eight patients showed plasma cell expression of CD45RO and 16 showed increased tumour infiltrating CD45RO positive lymphocytes, which were correlated with poor survival by multivariate analyses (p = 0.005 and p = 0.04, respectively). B cell antigens (MB2, CD20) but no T cell specific antigens (CD3) or T cell receptor gene rearrangements were expressed by plasma cells in CD45RO positive myelomas. Of 16 patients with myeloma who had increased tumour infiltrating CD45RO positive lymphocytes, four had interstitial lymphocyte expression of B cell antigens and two had interstitial lymphocyte expression of the T cell specific antigen CD3. CONCLUSIONS: The recognition of plasma cell expression of CD45RO and increased interstitial CD45RO lymphocytes in bone marrow biopsy specimens of patients with multiple myeloma is an adverse prognostic finding not indicative of an aberrant T cell phenotype or genotype; it is consistent with B cell/pre-plasma cell antigen expression by myeloma cells and their lymphocytic precursors.

Adult↗

PubMed1997

Subclassification of diffuse large B-cell lymphomas according to the Kiel classification: distinction of centroblastic and immunoblastic lymphomas is a significant prognostic risk factor.

Among high-grade malignant non-Hodgkin's lymphomas the updated Kiel classification identifies three major B-cell entities: centroblastic (CB), B-immunoblastic (B-IB), and B-large cell anaplastic (Ki-1+) (now termed anaplastic large cell [CD30+], [B-ALC]). The clinical prognostic relevance of this distinction was evaluated in a randomized prospective treatment trial (COP-BLAM/IMVP-16 regimen randomly combined +/- radiotherapy in complete responders) conducted in adult (age 15 to 75) patients with Ann Arbor stage II-IV disease (n = 219) diagnosed by optimal histomorphology (Giemsa staining) and by immunohistochemistry. Overall survival was significantly better in CB lymphoma as compared to B-IB (P = .0002) or B-ALC (P = .046). Relapse-free survival was worse for B-IB (P = .0003) as compared to CB lymphomas. The prognostic differences between CB and B-IB were confirmed by multivariate analyses including the risk factors of the International Index. Overall survival was significantly determined by performance status (P = .0003), serum-LDH (P = .036), and B-IB histology subtype (P = .036). Relapse-free survival was influenced by age (P = .007) and histological subtype (P = .007). Thus, the diagnosis of the CB and B-IB lymphomas by the histological criteria of the Kiel classification was identified as an independent prognostic factor in diffuse large B-cell lymphomas.

Adolescent↗

PubMed1997

Mastocytosis: reactive or neoplastic?

Mast cells are now known to derive from CD34+ haemopoietic stem cells in the bone marrow. However, it has not yet been established whether the various types of mastocytosis, which involve tumour-like proliferation of mast cells, are true neoplastic disorders or reactive/hyperplastic conditions. In this study, tissue specimens (five bone marrow, two spleen, one skin) from female patients with histologically confirmed mastocytosis were investigated with a recently developed polymerase chain reaction assay for the determination of clonality of female cells using the human androgen receptor gene (HU-MARA). Mast cells purified to near homogeneity from hysterectomy specimens served as a control. The findings in bone marrow and skin either were not reproducible, or indicated polyclonality. However, both spleen specimens exhibited monoclonality. In addition, DNA analysis by flow cytometry was performed and revealed a diploid chromosome content with proliferation indices of under 8% in all the specimens. This is the first molecular biological study to indicate that mastocytosis is indeed neoplastic in nature.

Case-Control Studies↗

PubMed1996

Impaired negative selection of T cells in Hodgkin's disease antigen CD30-deficient mice.

CD30 is found on Reed-Sternberg cells of Hodgkin's disease and on a variety of non-Hodgkin's lymphoma cells and is up-regulated on cells after Epstein-Barr virus, human T cell leukemia virus, and HIV infections. We report here that the thymus in CD30-deficient mice contains elevated numbers of thymocytes. Activation-induced death of thymocytes after CD3 cross-linking is impaired both in vitro and in vivo. Breeding the CD30 mutation separately into alpha beta TCR-or gamma delta TCR-transgenic mice revealed a gross defect in negative but not positive selection. Thus, like TNF-receptors and Fas/Apo-1, the CD30 receptor is involved in cell death signaling. It is also an important coreceptor that participates in thymic deletion.

Animals↗

PubMed1996

Inflammatory pseudotumors of lymph node origin show macrophage- derived spindle cells and lymphocyte-derived cytokine transcripts without evidence of T-cell receptor gene rearrangements. Implications for pathogenesis and classification as an idiopathic retroperitoneal fibrosis-like sclerosing immune reaction.

Sclerosing pseudotumorous immune reactions of the retroperitoneum have been shown to consist of HLA-DR-positive spindle-shaped fibroblasts and macrophages that resemble fibroblasts, and in some instances they contain clonal populations of T lymphocytes not found in granulation tissue, keloids, nodular fasciitis, or fibromatoses. In patients who are iatrogenically immunosuppressed, circulating monocytes may be induced in vitro to transform into spindle-shaped macrophages, and secrete collagen after stimulation by conditioning medium from activated T lymphocytes. The authors investigated a series of five inflammatory pseudotumors (IPT) of lymph node origin for identification of spindle-shaped macrophages, T-cell receptor gene rearrangements, and lymphocyte-derived cytokine mRNA production. All cases of IPT demonstrated spindle-shaped macrophages resembling fibroblasts or myofibroblasts characterized by vimentin, CD45 (LCA), CD68 (KP1) or HAM-56, and HLA-DR(LN3) immunoreactivity and demonstrated production of procollagen-alpha1 (I) mRNA by in situ hybridization. Clonal T-cell receptor chain gene rearrangements were undetectable by polymerase chain reaction. Strong specific lymphocyte-derived interleukin-1beta and interleukin-6 mRNA cytokine transcripts were identified. Although all patients with IPT were managed with steroids and nonsteroidal anti-inflammatory medication, some had treatment-refractory disease. Because all-trans retinoic acid has been demonstrated to inhibit the in vitro transformation of monocytes into collagen-producing spindle-shaped macrophages ("neofibroblasts"), it may be of benefit for patients with IPT.

Antigens, CD↗

PubMed1995

Lymphoproliferative disorders with early lethality in mice deficient in Ctla-4.

The role of the cell-surface molecule CTLA-4 in the regulation of T cell activation has been controversial. Here, lymph nodes and spleens of CTLA-4-deficient mice accumulated T cell blasts with up-regulated activation markers. These blast cells also infiltrated liver, heart, lung, and pancreas tissue, and amounts of serum immunoglobulin were elevated. The mice invariably became moribund by 3 to 4 weeks of age. Although CTLA-4-deficient T cells proliferated spontaneously and strongly when stimulated through the T cell receptor, they were sensitive to cell death induced by cross-linking of the Fas receptor and by gamma irradiation. Thus, CTLA-4 acts as a negative regulator of T cell activation and is vital for the control of lymphocyte homeostasis.

Abatacept↗

PubMed1995

Deregulated T cell activation and autoimmunity in mice lacking interleukin-2 receptor beta.

In mice lacking the interleukin-2 receptor beta chain (IL-2R beta), T cells were shown to be spontaneously activated, resulting in exhaustive differentiation of B cells into plasma cells and the appearance of high serum concentrations of immunoglobulins G1 and E as well as autoantibodies that cause hemolytic anemia. Marked infiltrative granulocytopoiesis was also apparent, and the animals died after about 12 weeks. Depletion of CD4+ T cells in mutant mice rescued B cells without reversion of granulocyte abnormalities. T cells did not proliferate in response to polyclonal activators, nor could antigen-specific immune responses be elicited. Thus, IL-2R beta is required to keep the activation programs of T cells under control, to maintain homeostasis, and to prevent autoimmunity.

Animals↗

PubMed1995

SBH-1, a novel Reed-Sternberg-like cell line capable of inducing tumors in SCID mice: immunophenotypic, cytogenetic, and cytokine expression profiles.

A new cell line, SBH-1, with the morphologic, immunophenotypic, and karyotypic features consistent with those of Reed-Sternberg (RS) and Hodgkin (H) cells, has been established from the pleural effusion of a patient. The cytologic appearance of SBH-1 cells is characteristic of multinucleate RS and mononuclear H cells, all containing inclusion-like nucleoli. The SBH-1 cells express CD30, CD15, CD25, CD71, CD45, CD20, CD22, and bcl-2 protein and are negative for epithelial membrane antigen. Cytogenetic analysis showed multiple clonal abnormalities with breakpoints at 14q32, 6q21, and 11q23. The Ig heavy chain genes and both Ig light chain genes were rearranged in SBH-1 cells, whereas the bcl-2 gene was in germline configuration. Messages for the cytokines interleukin-1 beta (IL-1 beta), tumor necrosis factor-alpha, and transforming growth factor-beta and the cytokine receptors IL-2R, IL-4R, IL-6R, and IL-7R were detected by reverse transcription-polymerase chain reaction analysis. Xenotransplantation of SBH-1 cells into severe combined immunodeficient (SCID) mice led to local and disseminated tumor growth. The cytologic, histologic, and immunohistochemical features of SBH-1 cells in SCID mouse tumors were typical of RS and H cells. The SBH-1 cell line will be useful in the study of RS and H cell biology, inasmuch as it represents a cell line obtained from a previously untreated patient.

Aged↗

PubMed1995

Murine lupus in MRL/lpr mice lacking CD4 or CD8 T cells.

MRL/lpr mice develop a systemic autoimmune disease similar to systemic lupus erythematosus in humans. The mice show progressive lymphadenopathy due to the accumulation of an unusual population of CD4-8-(DN) B220+ alpha beta+ T cells. We bred MRL/lpr mice with mice lacking CD4+ or CD8+ T cells by gene targeting via homologous recombination in embryonal stem cells to determine the roles of these cells in the autoimmune disease. No difference in survival or autoantibody levels was noted between CD8-/-lpr and littermate controls. Interestingly, these CD8-/- lpr mice have a reduced level of B220+ DN T cells despite the fact that the degree of lymphadenopathy was unaltered. CD4-/- lpr mice had a diminished autoimmune disease with a reduction in autoantibody production and skin vasculitits, and increased survival compared to littermate controls. However, CD4-/- lpr mice had an enhanced splenomegaly that developed massively by 16-20 weeks of age (5 to 8 greater than lpr control mice) due to the accumulation of DN B220+ T cells. In addition, there were no differences in peripheral lymph node enlargement, although the proportion of DN B220+ T cells was about twofold higher in the CD4-/- lpr mice. These cells were phenotypically identical to the DN population in control lpr mice, indicating that the accumulating DN T cells can be dissociated from the autoimmune disease in these mice. Collectively, our results reveal that the autoimmune disease is dependent on CD4+, but not CD8+ T cells, and that many of the B220+ DN T cells traverse a CD8 developmental pathway.

Animals↗

PubMed1995

Gene rearrangements and chromosomal translocations in T cell lymphoma--diagnostic applications and their limits.

The diversity of the T cell receptor (TCR) repertoire is established for individual T lymphocytes by developmentally regulated gene rearrangements and shaped by predominantly intrathymic selection procedures. TCR gene probes in Southern blot experiments and TCR primers for the polymerase chain reaction (PCR) help to distinguish polyclonal from abnormal clonal T cell proliferations and to monitor clonal disease after treatment. Rearrangement studies can identify the lineage and developmental stage of a lymphocyte clone. Cross-lineage rearrangements, false positive or negative results are rarely misleading when morphology and immunophenotypical findings are considered. Rearrangement studies, however, have not contributed significantly to the comprehension of lymphomagenesis. Analyses of characteristic chromosomal translocations in T cell leukaemias and lymphomas may provide further insight into the mechanisms of malignant transformation. Transcription factors are often involved and sometimes abnormally transcribed, which may alter the physiological intracellular signalling in T cells. Interphase cytogenetic analysis by chromosomal fluorescence in situ hybridization (FISH) has become a new tool in the search for transformed T cells carrying specific translocations. Archival biopsy material is now accessible for PCR rearrangement studies and FISH cytogenetics. This adds another dimension to the diagnosis, disease monitoring and biological understanding of malignant T cell lymphomas and leukaemias.

Biomarkers↗