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2.
Leuk Res ; 25(10): 839-45, 2001 Oct.
Article in English | MEDLINE | ID: mdl-11532515

ABSTRACT

An unusually high incidence of acute myeloid leukemia (AML) and chronic myeloid leukemia (CML) concentrated in a specific locality of a region in Germany motivated a descriptive incidence study in that region which showed a near 10-fold increased risk of CML among males but not among females (Kolb G, Becker N, Scheller S, Zugmaier G, Pralle H, Wahrendorf J, Havemann K. Increased risk of acute myelogenous leukemia (AML) and chronic myelogenous leukemia (CML) in a County of Hesse, Germany, Soc Prev Med 1993;38:190-195). Since a serious environmental contamination of areas in this locality with armament wastes containing toluene-derivatives has been known for a long time, the hypothesis arose that TNT production and the related severe contamination of soil and water might be responsible for the observed higher risk. We carried out a case-control study within the cluster to test this hypothesis. Overall, the results do not confirm the hypothesis. There is an indication of a relationship of an increased odds ratio with the exposure for a small group of persons who lived at a particular site in one of the two communities involved during the peak phase of TNT production during the 1940s. However, this finding is spurious and cannot explain the large majority of cases which occurred in that area in the 1980s. At the moment, no other explanation can be given for the increased risk of leukemias in that area.


Subject(s)
Chemical Warfare Agents/adverse effects , Environmental Exposure/adverse effects , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/epidemiology , Leukemia, Myeloid, Acute/epidemiology , Trinitrotoluene/adverse effects , Adult , Case-Control Studies , Cause of Death , Female , Germany/epidemiology , Humans , Incidence , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/etiology , Leukemia, Myeloid, Acute/etiology , Male , Odds Ratio , Risk Factors , Soil Pollutants/adverse effects
3.
Eur J Cell Biol ; 80(1): 99-110, 2001 Jan.
Article in English | MEDLINE | ID: mdl-11211940

ABSTRACT

CD14-positive monocytes obtained from human peripheral blood were cultured with GM-CSF and IL-4. During the early culture phase immature dendritic cells (DCs) developed which not only expressed CD1a, HLA-DR and CD86, but also expressed the endothelial cell markers von Willebrand factor (vWF), VE-cadherin and VEGF receptors Flt-1 and Flt-4. Further maturation of DCs was achieved by prolonged cultivation with TNFalpha. These cells showed typical DC morphology and like professional antigen-presenting cells (APCs) expressed CD83 and high levels of HLA-DR and CD86. However, if immature DCs were grown with VEGF, bFGF and IGF-1 on fibronectin/vitronectin-coated culture dishes, a marked change in morphology into caudated or oval cells occurred. In the presence of these angiogenic growth factors the cultured cells developed into endothelial-like cells (ELCs), characterized by increased expression of vWF, KDR and Flt-4 and a disappearance of CD1a and CD83. Addition of IL-4 and Oncostatin M also increased VE-cadherin expression, and the loosely adherent cells formed clusters, cobblestones and network-like structures. vWF- expressing ELCs mainly originated from CD1a-positive cells, and VEGF was responsible for the decrease in the expression of the DC markers CD1a and CD83. In mixed leukocyte cultures, mature DCs were more potent APCs than ELCs. Moreover, Ac-LDL uptake, and the formation of tubular structures on a plasma matrix was restricted to ELCs. These results suggest that in the presence of specific cytokines immature DCs have the potential to differentiate along different lineages, i.e. into a cell type resembling ELCs.


Subject(s)
Cadherins/biosynthesis , Dendritic Cells/metabolism , Extracellular Matrix Proteins/biosynthesis , Monocytes/metabolism , Receptor Protein-Tyrosine Kinases/biosynthesis , Receptors, Growth Factor/biosynthesis , von Willebrand Factor/biosynthesis , Antigens, CD , Antigens, CD1/metabolism , Biomarkers , Blood Coagulation , Cell Differentiation , Cell Division/drug effects , Cells, Cultured , Coculture Techniques , Dendritic Cells/cytology , Dendritic Cells/drug effects , Endothelial Growth Factors/pharmacology , Endothelium , Fibroblast Growth Factor 2/pharmacology , Granulocyte-Macrophage Colony-Stimulating Factor/pharmacology , Insulin-Like Growth Factor I/pharmacology , Interleukin-4/pharmacology , Lipopolysaccharide Receptors/metabolism , Lymphokines/pharmacology , Monocytes/cytology , Monocytes/drug effects , Oncostatin M , Peptides/pharmacology , Vascular Endothelial Growth Factor A , Vascular Endothelial Growth Factor Receptor-1 , Vascular Endothelial Growth Factor Receptor-3 , Vascular Endothelial Growth Factors
4.
Differentiation ; 65(5): 287-300, 2000 May.
Article in English | MEDLINE | ID: mdl-10929208

ABSTRACT

In the present study, we show that endothelial-like cells (ELCs) can develop from human CD14-positive mononuclear cells (CD14 cells) in the presence of angiogenic growth factors. The CD14 cells became loosely adherent within 24 h of culture and subsequently underwent a distinct process of morphological transformation to caudated or oval cells with eccentric nuclei. After 1 week in culture the cells showed a clear expression of endothelial cell markers, including von Willebrand factor (vWF), CD144 (VE-cadherin), CD105 (endoglin), acetylated low-density lipoprotein (AC-LDL)-receptor, CD36 (thrombospondin receptor), FLT-1, which is vascular endothelial cell growth factor (VEGF) receptor-1, and, to a weaker extent, KDR (VEGF receptor-2). Furthermore, in these cells structures resembling Weibel-Palade bodies at different storage stages were identified by electron microscopy, and upon culturing on three-dimensional fibrin gels the cells build network-like structures. In addition, cell proliferation and vWF expression was stimulated by VEGF, and the endothelial cell adhesion molecules CD54 (ICAM-1), and CD106 (VCAM-1) became transiently inducible by tumor necrosis factor-alpha (TNF-alpha). In contrast, the dendritic markers CD1a, and CD83 were not expressed to any significant extent. The expression of CD68, CD80 (B7-1), CD86 (B7-2), HLA-DR and CD36 may also suggest that ELCs might be related to macrophages, sinus lining or microvascular endothelial cells. Taken together, our observations indicate that ELCs can differentiate from cells of the monocytic lineage, suggesting a closer relationship between the monocyte/macrophage- and the endothelial cell systems than previously supposed.


Subject(s)
Endothelium/cytology , Lipopolysaccharide Receptors/metabolism , Monocytes/cytology , Antigens, Differentiation/metabolism , Biomarkers/analysis , Cell Differentiation , Cell Line, Transformed , Cells, Cultured , DNA Primers/chemistry , Endothelial Growth Factors/pharmacology , Endothelium/drug effects , Endothelium/metabolism , Flow Cytometry , Fluorescent Antibody Technique , Humans , Immunohistochemistry , Lymphokines/pharmacology , Microscopy, Electron , Monocytes/drug effects , Monocytes/metabolism , Neovascularization, Physiologic , Reverse Transcriptase Polymerase Chain Reaction , Tumor Necrosis Factor-alpha/metabolism , Vascular Endothelial Growth Factor A , Vascular Endothelial Growth Factors
5.
Leuk Lymphoma ; 36(1-2): 101-8, 1999 Dec.
Article in English | MEDLINE | ID: mdl-10613454

ABSTRACT

Lymphoblastic lymphoma (LBL) and Burkitt's lymphoma belong to the very aggressive lymphomas requiring intensive therapy. We retrospectively analyzed 29 patients with Burkitt's lymphoma and 29 patients with LBL who received induction therapy with a CHOP-like lymphoma protocol. Patients with Burkitt's lymphoma (with a median age of 54.5 years) have a CR rate of 72% and a lymphoma free long-time survival of 55%. The International Prognostic Index was the most valuable prognostic factor for survival. Patients with LBL with a median age of 45 years had a CR rate of 55% and a lymphoma-free survival of 38%. Stage was the most predictive prognostic factor. Our data suggest that for older patients (>50) treatment with lymphoma protocols may yield response rates that are comparable to the results of patients with disseminated diffuse large cell lymphoma. Younger patients with risk factors should be treated with more intensive therapy like ALL-protocols. The role of auto-transplantation after high dose therapy (HDT) however as part of primary treatment still needs to be evaluated in clinical trials. One of four patients with LBL who received HDT and one of four patients with Burkitt's lymphoma who received HDT achieved long-term remission.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Burkitt Lymphoma/therapy , Precursor Cell Lymphoblastic Leukemia-Lymphoma/therapy , Adolescent , Adult , Aged , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Burkitt Lymphoma/mortality , Cyclophosphamide/administration & dosage , Doxorubicin/administration & dosage , Female , Hematopoietic Stem Cell Transplantation , Humans , Male , Middle Aged , Precursor Cell Lymphoblastic Leukemia-Lymphoma/mortality , Prednisone/administration & dosage , Prognosis , Retrospective Studies , Vincristine/administration & dosage
6.
Radiother Oncol ; 47(1): 7-16, 1998 Apr.
Article in English | MEDLINE | ID: mdl-9632287

ABSTRACT

BACKGROUND: In 1966, Rosenberg and Kaplan hypothesized that Hodgkin's disease (HD) arises at a discrete primary site and subsequently spreads in a predictable manner via functionally contiguous lymph nodes. However, their results were not statistically evident. It was our aim to describe the spreading in the lymphatic system more precisely and to confirm their postulate. METHODS: Between 1971 and 1992, 297 patients underwent pathological staging for HD. Our subsequent evaluation was restricted to the 236 cases with cervical involvement (65 bilateral, 80 dextral and 91 sinistral), those with lymph nodes on the right side (65 + 80 = 145) being analyzed separately from those with tumours on the left (65 + 91 = 156). Spreading via the lymphatic system was assessed by scoring of the number of involved and uninvolved nodes in six regions, which are functionally contiguous in the lymph system but not necessarily anatomically neighboured. The number of 'gaps' (i.e. missed nodes) observed according to a systematic spreading model was compared with that expected (probability model) if a random course had been followed. RESULTS: Of the 156 patients with left cervical HD, 117 (75%) had para-aortic or spleen involvement, 90 (58%) had mediastinal involvement, 65 (42%) had right cervical involvement, 50 (32%) had axillary involvement and 23 (15%) had inguinal involvement. Of the 145 patients with right cervical HD, 112 (77%) had mediastinal involvement, 89 (61%) had para-aortic or spleen involvement, 65 (44%) had left cervical involvement, 44 (30%) had axillary involvement and 16 (11%) had inguinal involvement. In patients with left or right cervical lymph nodes, the proportions observed with gaps in the spreading were 37 and 27% (SE 7%), respectively, whereas the corresponding values of gaps expected in a probability model if a random course of spreading had been followed would have been 84 and 73% (P = 0.0001 and 0.0001, respectively). CONCLUSION: Our data support the concept that HD spreads in a predictable manner via functionally contiguous lymph nodes. In patients with right cervical lymph nodes, HD spreads via the upper mediastinum and pulmonary hila to the upper abdominal nodes and the spleen. In those with left cervical tumours, HD spreads directly to the abdomen (bypassing the mediastinum), then upward again via the pulmonary hila and upper mediastinum to the neck region (bilateral involvement) and from here it proceeds to the axillary nodes. Finally the inguinal nodes are involved.


Subject(s)
Hodgkin Disease/pathology , Lymph Nodes/pathology , Adult , Female , Hodgkin Disease/therapy , Humans , Lymphatic Metastasis/pathology , Male , Neoplasm Staging , Probability , Prognosis , Retrospective Studies
7.
Clin Cancer Res ; 4(2): 361-71, 1998 Feb.
Article in English | MEDLINE | ID: mdl-9516924

ABSTRACT

RFLP-mediated PCR has been successfully applied as a reliable tool in the detection of ras mutations in many cancers and provides a basis for "mutant-enriched PCR" protocols. We have, therefore, modified this technique to the sensitive detection of K-ras codon 12 and also p53 "hot spot" mutations, which, frequently in lung cancer, affect codons at the positions 157, 175, 245, 248, 249, and 273. With a high sensitivity of 1 mutant allele in 10(4) normal alleles, our enrichment assay allows the detection of oncogene alleles when only a few tumor cells are present within a normal cell population. Brush cytology material obtained from the tumor site of 20 patients with endoscopically apparent bronchial carcinoma was compared to macroscopically normal mucosa taken from the contralateral bronchus ("control" cytology). We found K-ras codon 12 mutations in 5 cases (25%) and p53 mutations in 13 cases (65%) in the tumor-derived cell material but, with the exception of two cases, not in cell material taken from the control cytology. Seventy-five % of the samples analyzed showed that at least one of the two oncogenes was affected. In several cases, two p53 lesions were detected concomitantly. The majority of the mutations could be reconfirmed by an alternative approach exploiting changes in the genomic RFLP pattern induced by these mutations and were also demonstrated in separate diagnostic biopsies taken. Thus, we conclude that the established enriched PCR protocol ensures a high sensitivity and preserved specificity for the diagnosis of oncogene lesions associated with lung cancer. Because conventional techniques normally yield a lower incidence of corresponding ras and p53 mutations, we think that both the high rate and the heterogeneity of p53 mutations found in some cases are, indeed, related to the increased sensitivity of this new enriched PCR technique.


Subject(s)
Genes, p53 , Genes, ras , Lung Neoplasms/genetics , Lung Neoplasms/pathology , Mutation , Polymerase Chain Reaction/methods , Aged , Aged, 80 and over , Alleles , Biopsy , Codon , Cytological Techniques , DNA Primers , Exons , Female , Humans , Male , Middle Aged , Polymorphism, Restriction Fragment Length , Sensitivity and Specificity , Tumor Cells, Cultured
8.
Int J Cancer ; 73(4): 537-43, 1997 Nov 14.
Article in English | MEDLINE | ID: mdl-9389569

ABSTRACT

The growth of human lung cancer cells is regulated positively and negatively by a variety of growth factors through autocrine as well as paracrine mechanisms. In the present report, we studied the differential role and expression of a neuropolypeptide growth factor in 26 lung cancer cell lines. Expression of the heparin-binding growth-associated molecule (HB-GAM) in 12 small cell lung cancer (SCLC) cell lines was compared to that in 14 non-small cell lung cancer (NSCLC) cell lines. HB-GAM mRNA was expressed in 9 of 12 SCLC and 3 of 14 NSCLC cell lines as determined by RT-PCR analyses. Normal human bronchial epithelial cells were used as negative controls. All cell lines which expressed HB-GAM mRNA produced HB-GAM protein as well. Western blot analysis showed that the tumor cells secreted HB-GAM into the media. HB-GAM, purified from lung cancer cell lines, exerted biological activity on fibroblasts, endothelial cells and SW13 cells as determined by thymidine incorporation and soft agar cloning assays. In addition, the biological activity of HB-GAM was blocked by a specific antibody in a dose-dependent way. Our findings suggest that HB-GAM may serve as a marker for SCLC cell lines and that it may function as a paracrine growth factor in human lung cancer. HB-GAM may be a further member of the network of growth factors involved in proliferation, angiogenesis and metastasis of lung tumors.


Subject(s)
Carcinoma, Small Cell/metabolism , Carrier Proteins/metabolism , Cytokines/metabolism , Growth Substances/metabolism , Lung Neoplasms/metabolism , Neoplasm Proteins/metabolism , Blotting, Western , Carcinoma, Small Cell/pathology , Carrier Proteins/genetics , Carrier Proteins/isolation & purification , Cytokines/genetics , Cytokines/isolation & purification , Growth Substances/genetics , Growth Substances/isolation & purification , Humans , Lung Neoplasms/pathology , Neoplasm Proteins/genetics , Neoplasm Proteins/isolation & purification , RNA, Messenger/metabolism , Tumor Cells, Cultured , Tumor Stem Cell Assay
9.
Leuk Lymphoma ; 25(3-4): 301-11, 1997 Apr.
Article in English | MEDLINE | ID: mdl-9168440

ABSTRACT

Whole-blood three-color immunofluorescence analysis was used to investigate the role of CD5/CD72 and CD21/CD23 receptor-ligand pair formation on B-chronic lymphocytic leukemia (B-CLL) cells as well as sCD23 and bcl-2 oncoprotein expression in disease progression and activity and total tumor mass in B-cell chronic leukemia (B-CLL) patients. Thirty-four patients with B-CLL and 19 controls were included in the study. The majority of B-cells in B-CLL patients coexpressed CD5 and CD72 as well as the CD23 antigen. Unlike B-cells in B-CLL patients, B-cells in all healthy controls tested had high expression of CD21 antigen. We identified two groups of B-CLL patients according to high (n = 20) or low levels (n = 14) of CD21 expression on CD19+CD23+ B-cells. Only in the patients with high CD21 expression, were sCD23 levels positively correlated with factors known to have prognostic significance in B-CLL (Rai stage and TTM) and could, therefore, be used as a prognostic parameter for these B-CLL patients. Bcl-2 oncoprotein expression did not differ between these patient groups. We presumed that in patients with a lower expression of CD21 antigen, the contribution of the CD21 molecule to homotypic adhesion was lacking. Further studies are necessary to determine the possible association of higher expression of the CD21 antigen with disease progression and the aggressive character of the B-CLL.


Subject(s)
Antigens, CD/metabolism , B-Lymphocytes/metabolism , Leukemia, Lymphocytic, Chronic, B-Cell/immunology , Leukemia, Lymphocytic, Chronic, B-Cell/metabolism , Proto-Oncogene Proteins c-bcl-2/metabolism , Aged , Antigens, Differentiation, B-Lymphocyte/metabolism , B-Lymphocytes/immunology , CD5 Antigens/metabolism , Case-Control Studies , Female , Flow Cytometry , Fluorescent Antibody Technique, Direct/methods , Humans , Leukemia, Lymphocytic, Chronic, B-Cell/pathology , Male , Middle Aged , Neoplasm Staging , Phenotype , Receptors, Complement 3d/metabolism , Receptors, IgE/blood , Receptors, IgE/metabolism
10.
Int J Cancer ; 71(2): 275-83, 1997 Apr 10.
Article in English | MEDLINE | ID: mdl-9139854

ABSTRACT

Activation of protein kinase C- (PKC) and Fos/Jun-dependent signal transduction pathways are thought to be major effects of oncogene action in different tumor systems including human non-small-cell lung carcinoma (NSCLC). We have previously shown that the phorbol ester analogue phorbol-myristate-acetate (PMA), which is a potent activator of PKC, can induce squamous-type cellular differentiation and the expression of proteinases, such as plasminogen activators and pro-cathepsin L, in several NSCLC cell lines. To investigate the PMA-dependent effect on proteinase secretion in more detail, we have now analysed the role of a downstream transmitter of PKC activity in this process, namely Fos, which is part of the AP-1 transcription factor in the nucleus. We transfected a cell line derived from an undifferentiated squamous-cell lung carcinoma with different chimeric fos-estrogen receptor constructs (fos-ER) which makes selective activation of this transcription factor possible. The resulting clones were treated either with PMA as activator of PKC, or with diethylstilbestrol (DES), an estrogen analogue binding to and thereby activating preformed Fos-ER molecules. We show that cells treated with either substance undergo similar phenotypic changes (change from cuboidal to spindle-cell type) and decrease their doubling rates and cloning efficiencies. This is paralleled by the induction of several proteinase genes such as t-PA, urokinase, and pro-cathepsins B and L. Contrary to activated PKC, Fos in this system seems to be unable to initiate terminal squamous-cell differentiation, as assessed by the production of cornified envelopes. It is, however, efficient in the stimulation of neutral or lysosomal proteinase secretion as determined by Western-blot analysis and zymography. This Fos-ER expressing system thus seems to be a valuable tool in the molecular dissection of pathways that lead to the activation and secretion of proteinases in NSCLC cells.


Subject(s)
Carcinoma, Non-Small-Cell Lung/metabolism , Endopeptidases/metabolism , Gene Expression Regulation, Enzymologic , Lung Neoplasms/metabolism , Proto-Oncogene Proteins c-fos/metabolism , Tetradecanoylphorbol Acetate/pharmacology , Carcinoma, Non-Small-Cell Lung/enzymology , Carcinoma, Non-Small-Cell Lung/pathology , Cell Differentiation/drug effects , Cell Division/drug effects , Cell Size/drug effects , DNA Primers/chemistry , Diethylstilbestrol/pharmacology , Estrogens, Non-Steroidal/pharmacology , Gene Expression Regulation, Enzymologic/drug effects , Humans , Immunoblotting , Lung Neoplasms/enzymology , Lung Neoplasms/pathology , Protein Kinase C/pharmacology , Proto-Oncogene Proteins c-fos/genetics , Signal Transduction , Transfection , Tumor Cells, Cultured
11.
Endocrinology ; 138(4): 1767-70, 1997 Apr.
Article in English | MEDLINE | ID: mdl-9075742

ABSTRACT

Considerable evidence exists that lung cancer cell lines produce large amounts of insulin-like growth factor-binding proteins (IGFBPs). In addition, these cells are subject to an autocrine or paracrine growth control by insulin-like growth factors (IGFs). We now demonstrate by immunocytochemistry with IGFBP-3 antibodies that nuclei of a lung cancer cell line distinctly immunostain for IGFBP-3. This finding led us to investigate in more detail the localization of this protein that, to date, had only been known to occur extracellularly. Ligand blotting revealed that purified nuclear extracts contain a 43,000-Da IGFBP which can bind [I125]IGF-I. By Western blot this protein was identified as IGFBP-3. Thus, our data are consistent with the results of a previous structural study predicting a nuclear localization for IGFBP-3. Moreover, our findings raise the possibility that nuclear IGFBP-3 is functional and involved in the pathogenesis of lung cancer.


Subject(s)
Cell Nucleus/chemistry , Insulin-Like Growth Factor Binding Protein 3/analysis , Lung Neoplasms/chemistry , Blotting, Western , Culture Media, Conditioned , Humans , Tumor Cells, Cultured
12.
Strahlenther Onkol ; 173(3): 136-40, 1997 Mar.
Article in German | MEDLINE | ID: mdl-9122853

ABSTRACT

BACKGROUND: Radiotherapy is part of the treatment protocols in localized low-grade lymphomas as well as localized high-grade lymphomas adjunct to polychemotherapy. Integration of radiotherapy into the treatment of disseminated high-grade lymphomas is controversial. PATIENTS AND METHOD: The current literature and our own experience with radiotherapy as part of the treatment of disseminated high-grade lymphomas will be discussed. RESULTS: Retrospective analysis of large clinical trials suggest the value of radiotherapy in the treatment of disseminated high-grade lymphomas. Relapse occurs more frequently in non-irradiated regions than in fields of prior radiotherapy. Integration of radiotherapy into treatment protocols seems to be beneficial in patients with bulky disease. A dose/response relationship has been described. The few randomized trials, however, could not clearly demonstrate an advantage of radiotherapy adjuvant to chemotherapy in disseminated lymphomas. A possible advantage can be seen in patients who did not receive more than 4 cycles of polychemotherapy. CONCLUSION: Although the value of radiotherapy adjunct to polychemotherapy in disseminated high-grade lymphomas has not been proven in randomized studies retrospective analysis suggest an advantage. A large randomized study should clarify the role of radiotherapy.


Subject(s)
Lymphoma, Non-Hodgkin/radiotherapy , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Clinical Trials, Phase II as Topic , Clinical Trials, Phase III as Topic , Combined Modality Therapy , Cyclophosphamide/therapeutic use , Dose-Response Relationship, Radiation , Doxorubicin/therapeutic use , Etoposide/therapeutic use , Follow-Up Studies , Humans , Lymphoma, Non-Hodgkin/drug therapy , Prednisolone/therapeutic use , Prospective Studies , Radiotherapy Dosage , Radiotherapy, Adjuvant , Randomized Controlled Trials as Topic , Retrospective Studies , Time Factors , Vincristine/therapeutic use
13.
Lung Cancer ; 16(2-3): 151-72, 1997 Mar.
Article in English | MEDLINE | ID: mdl-9152947

ABSTRACT

The CD44 transmembrane glycoprotein is expressed in most adult tissues and in the majority of neoplasias. Due to alternative splicing, this cell adhesion molecule exists in multiple isoforms some of which have been associated with specific types of tumours as well as with increased tumour metastasis. In this study, we have looked at the level and type of CD44 expression in lung cancer which represents a histologically heterogenous form of cancer composed of small cell lung carcinoma (SCLC) and non-small cell lung carcinoma (NSCLC), the latter subgroup comprising adenocarcinoma (ADC), bronchio-alveolar carcinoma (BAC), large cell carcinoma (LCC), and squamous cell carcinoma (SCC). We analysed 20 lung cancer cell lines and 64 primary tumours by RT-PCR and immunohistochemical detection of the CD44 standard and variant protein isoforms. Our results suggest that (i) CD44 is expressed in all histologically distinct subsets of lung cancer with a tendency SCC > BAC > ADC > LCC > SCLC, (ii) expression of the CD44 isoforms v5, v7, v8, and, most notably that of CD44 exon v6, strongly correlates with tumours of squamous cell and bronchio-alveolar carcinoma origin, tumours which commonly exhibit a comparatively low metastasizing potential, and (iii) the expression of CD44 isoforms is independent from the tumour size and lymph node status at surgery, the proliferative status of the tumour cell population (Ki67 antigen expression) and the histopathological grading (G1 to G3). Only non-differentiated tumours (G4), which were restricted to SCLC and LCC samples revealed markedly reduced CD44 standard and isoform antigen. In conclusion, our data point to a clear histiotype-related pattern of CD44 variant expression preferentially that of CD44v6 in SCC and BAC.


Subject(s)
Antigens, CD/biosynthesis , Hyaluronan Receptors/biosynthesis , Lung Neoplasms/immunology , Lung Neoplasms/pathology , Adenocarcinoma/immunology , Adenocarcinoma/pathology , Adenocarcinoma, Bronchiolo-Alveolar/immunology , Adenocarcinoma, Bronchiolo-Alveolar/pathology , Adult , Alternative Splicing , Antigens, CD/analysis , Carcinoma, Large Cell/immunology , Carcinoma, Large Cell/pathology , Carcinoma, Non-Small-Cell Lung/classification , Carcinoma, Non-Small-Cell Lung/immunology , Carcinoma, Non-Small-Cell Lung/pathology , Carcinoma, Small Cell/immunology , Carcinoma, Small Cell/pathology , Carcinoma, Squamous Cell/immunology , Carcinoma, Squamous Cell/pathology , Cell Division , Cell Line , DNA Primers , Exons , Humans , Hyaluronan Receptors/analysis , Immunohistochemistry , Ki-67 Antigen/analysis , Lung Neoplasms/classification , Neoplasm Staging , Polymerase Chain Reaction , RNA, Messenger/biosynthesis , Transcription, Genetic , Tumor Cells, Cultured
16.
Br J Haematol ; 96(1): 117-23, 1997 Jan.
Article in English | MEDLINE | ID: mdl-9012697

ABSTRACT

Chronic eosinophilic leukaemia has not yet been clearly defined, mainly due to the fact that it has not been conclusively shown as a monoclonal disease which should be separated from chronic myelogenous leukaemia, acute myelogenous leukaemia with eosinophilia (AML, FAB M4Eo), and the idiopathic hypereosinophilic syndrome. We report a patient with a white blood cell count of 17.6 x 10(9)/l with 74% eosinophils, normal platelet count and haemoglobin. No blasts were seen in the peripheral blood and the percentage of blasts in the bone marrow was < 3%. A diagnosis of chronic eosinophilic leukaemia was made. Chromosome analysis of a bone marrow aspirate disclosed a trisomy 15 together with loss of the Y chromosome. Moreover, FISH analysis on May-Grünwald-Giemsa-stained peripheral blood smears demonstrated trisomy 15 in the eosinophils. 3 months after initial diagnosis the patient went into blast crisis and died. The blast cells exhibited trisomy 15 and loss of the Y chromosome in a complex, aberrant karyotype. In conclusion, the case shows that chronic eosinophilic leukaemia is a monoclonal, myeloproliferative disease with eosinophils as part of the malignant clone. Clinically, chronic eosinophilic leukaemia can be separated into a chronic phase and a blast crisis.


Subject(s)
Chromosomes, Human, Pair 15 , Hypereosinophilic Syndrome/diagnosis , Trisomy , Blast Crisis , Chronic Disease , Fatal Outcome , Humans , Hypereosinophilic Syndrome/blood , Hypereosinophilic Syndrome/genetics , In Situ Hybridization, Fluorescence , Karyotyping , Leukocyte Count , Male , Middle Aged , Platelet Count
17.
J Cancer Res Clin Oncol ; 123(11-12): 632-8, 1997.
Article in English | MEDLINE | ID: mdl-9620222

ABSTRACT

Intercellular adhesion molecule-1 (ICAM-1) expression correlates with tumour progression in patients with malignant melanoma or renal cell carcinoma. To assess the value of soluble ICAM-1 (sICAM-1) for lung cancer patients, sICAM-1 was determined by means of an enzyme-linked immunosorbent assay. Sera from 147 patients with lung cancer, from 75 patients with benign lung diseases and from 108 healthy adults were investigated for sICAM-1 expression. Significant differences in sICAM-1 levels were detected in lung cancer patients (387 +/- 176 ng/ml) and patients with benign lung diseases (365 +/- 110 ng/ml) compared to the group of healthy adults (310 +/- 90 ng/ml). There was no difference in sICAM-1 level among the subtypes of lung cancer. Advanced tumour stages and patients with progressive disease tended to be associated with higher sICAM-1 levels, the site of metastasis being relevant for the level attained. Patients with liver metastasis had the highest sICAM-1 levels (547 +/- 295 ng/ml) compared to patients with cerebral metastasis (317.8 +/- 92.2 ng/ml). An increase of sICAM-1 expression during the progression of the disease coincided with a poorer survival prognosis for the patients compared to patients with stable or falling sICAM-1 levels.


Subject(s)
Intercellular Adhesion Molecule-1/blood , Lung Diseases/blood , Lung Neoplasms/blood , Adolescent , Adult , Aged , Biomarkers, Tumor/blood , Disease Progression , Female , Humans , Lung Neoplasms/mortality , Male , Middle Aged , Survival Rate
19.
Semin Oncol ; 23(6 Suppl 16): 108-12, 1996 Dec.
Article in English | MEDLINE | ID: mdl-9007135

ABSTRACT

In a clinical phase II trial, escalating doses of paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) were given with concurrent radiation to patients with stage IIIA/B non-small cell lung cancer. Radiotherapy was given in daily doses of 2 Gy, 5 days a week, in weeks 1 through 3 and 6 through 8. Paclitaxel was given on day 1 of weeks 1 through 3 and 6 through 8, at a starting dose level of 50 mg/m2. Subsequent paclitaxel dose levels were 60, 72, 86, and 103 mg/m2. Three to six patients were included at each dose level until intolerable toxicity (World Health Organization grade 3 or 4 leukopenia) occurred in three of six patients. To date, 27 patients have entered the protocol. Hematologic toxicity was mild with no severe myelosuppression up to the 86-mg/m2 dose level. At paclitaxel 103 mg/m2, four of six patients developed grade 3 or 4 leukopenia, and dose escalation was stopped. The maximum tolerated dose was thus determined to be 86 mg/m2. The main clinical toxicity was the occurrence of pulmonary infections (seven patients), one of whom had Pneumocystis carinii infection; the six others had interstitial infections with no pathogen isolated. Mild to moderate esophagitis was seen in five patients. Thus far, of 24 patients evaluable for response, 18 showed decreased tumor size. Four patients achieved major responses (near-complete disappearance of radiologic tumor signs), 11 patients achieved partial remission, and three patients had a minor response. The overall response rate was 75%. In summary, the maximum tolerated dose of paclitaxel in this study has been determined to be 86 mg/m2 weekly. Pulmonary infections represent the major clinical toxicity, and the high response rate merits further clinical evaluation of this regimen.


Subject(s)
Antineoplastic Agents, Phytogenic/administration & dosage , Carcinoma, Non-Small-Cell Lung/therapy , Lung Neoplasms/therapy , Paclitaxel/administration & dosage , Adult , Aged , Antineoplastic Agents, Phytogenic/toxicity , Carcinoma, Non-Small-Cell Lung/radiotherapy , Combined Modality Therapy , Drug Administration Schedule , Drug Tolerance , Esophagitis/chemically induced , Female , Humans , Leukopenia/chemically induced , Lung Diseases/etiology , Lung Neoplasms/radiotherapy , Male , Middle Aged , Paclitaxel/toxicity , Pneumocystis Infections/etiology , Radiotherapy Dosage , Treatment Outcome
20.
Ann Hematol ; 73(3): 121-6, 1996 Sep.
Article in English | MEDLINE | ID: mdl-8841099

ABSTRACT

A retrospective study was carried out to determine the diagnostic and prognostic value of the soluble form of the embryonal neural cell adhesion molecule NCAM (CD56) in paraproteinemia. NCAM, beta 2-microglobulin, and interleukin-6 levels were measured in the sera of 170 patients with paraproteinemia. Of these, 125 had multiple myeloma, 20 Waldenström's disease, and 25 monoclonal gammopathy of unknown significance. Serum NCAM proved superior to beta 2-microglobulin and interleukin-6 in distinguishing multiple myeloma from paraproteinemias of various causes, with a high specificity of 95.5% in detecting multiple myeloma, although with a low sensitivity of 40%. In multiple myeloma NCAM is significantly correlated with beta 2-microglobulin, paraproteinemia, and low albumin levels. For the determination of tumor load beta 2-microglobulin levels accord best with the Salmon and Durie classification scheme. When patients are grouped according to their clinical course, the disease development is reflected better by NCAM than by beta 2-microglobulin or interleukin-6. Survival data indicate that all three markers have prognostic potential. Prognostic accuracy with respect to overall survival is best with beta 2-microglobulin.


Subject(s)
CD56 Antigen/analysis , Multiple Myeloma/diagnosis , Multiple Myeloma/immunology , Biomarkers, Tumor , Diagnosis, Differential , Female , Humans , Interleukin-6/blood , Male , Middle Aged , Multiple Myeloma/blood , Paraproteinemias/blood , Paraproteinemias/diagnosis , Paraproteinemias/immunology , Prognosis , Retrospective Studies , Solubility , beta 2-Microglobulin/analysis
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