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Biomedical subjects

K Havemann

Publications and source records attributed to K Havemann.

At least 19 recordsLinked to original sources
PubMed1998

Contiguous pattern spreading in patients with Hodgkin's disease.

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.

Adult↗
PubMed1998

Frequent detection of ras and p53 mutations in brush cytology samples from lung cancer patients by a restriction fragment length polymorphism-based "enriched PCR" technique.

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.

Aged↗
PubMed1997

Differential expression and biological activity of the heparin-binding growth-associated molecule (HB-GAM) in lung cancer cell lines.

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.

Blotting, Western↗
PubMed1997

Control of proteinase expression by phorbol-ester- and Fos-dependent pathways in human non-small-cell lung-cancer cells.

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.

Carcinoma, Non-Small-Cell Lung↗
PubMed1997

[Value of radiotherapy in disseminated high-grade non-Hodgkin's lymphoma].

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.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1997

Soluble intercellular adhesion molecule-1 in patients with lung cancer and benign lung diseases.

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.

Adolescent↗
PubMed1997

Preferential histiotypic expression of CD44-isoforms in human lung cancer.

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.

Adenocarcinoma↗
PubMed1997

Chronic eosinophilic leukaemia (CEL): a distinct myeloproliferative disease.

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.

Blast Crisis↗
PubMed1997

Nuclear localization of insulin-like growth factor binding protein 3 in a lung cancer cell line.

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.

Blotting, Western↗
PubMed1997

Phenotypic analysis of receptor-ligand pairs on B-cells in B-chronic lymphocytic leukemia.

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.

Aged↗
PubMed1996

Steroid-hormone receptors in cell lines and tumor biopsies of human lung cancer.

Female gender is a significant independent favorable prognostic factor in lung cancer. To study the possible role of sex hormones in lung cancer, the expression of sex-steroid receptors and the glucocorticoid receptor was investigated in 29 lung-cancer cell lines stemming from small-cell lung cancer (SCLC) and non-small-cell lung cancer (NSCLC) by means of immunocytochemistry, ligand-binding assays and RNA expression via polymerase chain reaction. In at least 2 methods of investigation, NSCLC cell lines showed a low expression of estrogen receptor in 6, progesterone receptor in 13 and androgen receptor in 12 out of 17 cases examined; sex-steroid-receptor expression was virtually absent in SCLC cell lines. The glucocorticoid receptor was expressed in all 29 cell lines studied. Additionally, 52 tumor samples from primary lung cancer were investigated for their receptor expression by means of immunohistochemistry. Among patients with primary lung-cancer sex-steroid-receptor expression in tumor biopsies was detected most frequently in female patients (in 69% of 16 cases, vs. 42% of 36 tumors from men) and in patients with adenocarcinoma. Further research will focus on these subgroups. Immunohistology is a feasible method of studying steroid-receptor expression in lung cancer.

Base Sequence↗
PubMed1996

[Integrative concept on the treatment of highly malignant non-Hodgkin lymphomas].

With CHOP, the standard protocol for the treatment of high-grade non-Hodgkin's lymphomas, about 40% of long term survival has been reported. A recent randomized comparison of CHOP vs. ProMACE-Cyta-BOM vs. m-BACOD vs. MACOP-B showed no advantage of these third generation protocols. The analysis of prognostic factors in several controlled trials and the results of the International Non-Hodgkin's Lymphoma Prognostic Factors Project identified stage, LDH, performance status and number of extranodal sites as the most important pretreatment factors. Already the pretreatment LDH-level (normal vs. enhanced) defines accurately cohorts of patients with low or high risk. Based on these results two cooperative trials were initiated: In trial A we are currently evaluating in a randomised fashion the concept of high dose chemotherapy (BEAM) with autologous stemcell rescue vs. a standard treatment for high risk patients < 60 years. In trial B low risk patients or high risk patients > 60 years are randomised to receive either CHOP or CHOEP at two or three weeks intervals.

Adult↗
PubMed1996

Expression of vitamin D receptor in lung cancer.

The active metabolite of vitamin D 1,25-dihydroxycholecalciferol is a hormone-like agent that regulates cell differentiation and proliferation. Various vitamin D derivatives have been shown to induce differentiation in neoplastic cells. The prerequisite for any hormone action is the presence of its receptor. We studied the expression of vitamin D receptor in human lung cancer cell lines and in primary lung cancer tissue. Employing the polymerase chain reaction, 10 out of 11 cell lines stemming from small-cell lung cancer and 15 out of 15 cell lines stemming from non-small-cell lung cancer demonstrated vitamin D receptor expression. An immunohistochemical analysis, using a specific monoclonal antibody, demonstrated vitamin D receptor protein expression in 31 out of 117 (26%) primary small-cell lung cancer cases tested. Positive cells exhibited a nuclear reaction pattern. Twenty-one out of 37 primary non-small-cell lung cancer cases, particularly adenocarcinomas (9/14) and squamous-cell carcinomas (10/15), exhibited vitamin D receptor. Results indicate that a subset of lung cancer cases may be susceptible to the differentiating effects of vitamin D analogues.

Base Sequence↗
PubMed1996

Storage of noncryopreserved periphered blood stem cells for transplantation.

Mobilized peripheral blood stem cells (PBSC) were collected in autologous plasma and acid-citrate-dextrose formula A (ACD-A) by leukaphereses using the CS3000 cell separator (Baxter) and stored at 4 degrees C in a refrigerator for 8 days. We have looked at the viability of the nucleated cells with the trypan blue test and the proliferation and differentiation capacity using a standardized progenitor cell cloning assay. The changes in viability, granulocyte-macrophage colony-forming units (CFU-GM), erythroid burst-forming units (BFU-E), and mixed-lineage colony-forming units (CFU-GEMM) were determined daily during the storage period. Viability was 90.8% (SD 8%) at day 0 and declined to a mean of 69.5% (SD 15.5%) at day 8. CFU-GM decreased to 47% (SD 28.7%), CFU-GEMM to 48% (SD 42.2%), and BFU-E to 40.1% (SD 18.4%) after 6 days. After 5 days of storage the mean viability was 79.7% (SD 17.8%), whereas the mean CFU-GM were 65.3% (SD 28.4%) the mean CFU-GEMM were 61.8% (SD 30.4%) and the mean BFU-E were 55.1% (SD 18.2%). At day 4 viability was still 82.5% (SD 17.0%), recovery of CFU-GM was 78.5% (SD 28.8%), recovery of CFU-GEMM was 70.7% (SD 40.4%) and recovery of BFU-E was 65.0% (SD 17.5%). These data show, that PBSC can be stored safely over at least 5 days at 4 degrees C while the patient receives high-dose chemotherapy.

Blood Component Removal↗
PubMed1996

Soluble CD56 (NCAM): a new differential-diagnostic and prognostic marker in multiple myeloma.

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.

Biomarkers, Tumor↗