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Biomedical subjects

R Parwaresch

Publications and source records attributed to R Parwaresch.

At least 109 records · Page 6Linked to original sources
PubMed1996

Prednimustine, mitoxantrone (PmM) vs cyclophosphamide, vincristine, prednisone (COP) for the treatment of advanced low-grade non-Hodgkin's lymphoma. German Low-Grade Lymphoma Study Group.

The current study was initiated to compare the anti-lymphoma activity and side-effects of prednimustine/mitoxantrone (PmM) vs cyclophosphamide, vincristine, prednisone (COP) in patients with advanced low-grade non-Hodgkin's lymphomas in way of a prospective randomized multicenter trial. Two hundred and forty-six patients with stage III or IV centroblastic-centrocytic (CB-CC (Kiel-classification)) or follicle center lymphoma (FCL (REAL classification)) and centrocytic (CC) or mantle-cell-lymphoma (MCL) were randomized for therapy with either PmM or COP and are fully evaluable for response and toxicity. PmM consisted of prednimustine 100 mg/m2/day on days 1-5 and mitoxantrone 8 mg/m2 /day days 1 and 2, while COP comprised cyclophosphamide 400 mg/m2/day on days 1-5, vincristine 1.4 mg/m2/day on day 1 and prednisone 100 mg/m2/day on days 1-5. Both regimens were repeated for a total of six cycles followed by an additional two courses for consolidation in responding cases and a subsequent second randomization for interferon alpha maintenance vs observation only. Overall response rates were comparable with 83% complete and partial remissions after COP and 84% remissions after PmM. PmM revealed a significantly higher rate of complete remissions (36 vs 18%, P < 0.006), the majority being achieved after four courses. The more rapid and possibly also more effective reduction of the lymphoma cell mass by PmM resulted in a tendency to a longer event-free interval for patients achieving remissions after PmM as compared to COP with estimated median event-free intervals of 31 vs 14 months, respectively (P=0.04). Separate analysis of lymphoma subtypes showed a tendency to a lower rate of complete remission in CC or MCL as compared to CB-CC or FCL (16 vs 30%, P=0.12, NS) while overall response rates were in a similar range (81 vs 85%). In both subtypes, PmM induced a higher rate of complete remission while overall response rates were comparable after PmM or COP. Treatment associated side-effects comprised predominantly myelosuppression and granulocytopenia in particular which was more frequently observed after PmM than COP (43 vs 31 %, P < 0.0001). This difference was clinically irrelevant, however, since serious infectious complications were encountered in less than 3% of cycles after both regimens. COP therapy was associated with a significantly higher incidence and degree of hair loss and complete alopecia (31 vs 2%) as well as of peripheral neurotoxicity (23 vs 2%). These data show that both PmM and COP reveal a high anti-lymphoma activity in patients with advanced stage non-Hodgkin's lymphoma. PmM appears advantageous with a higher rate of complete remissions and a better tolerability with regard to secondary side-effects. A longer follow-up is needed to assess the long-term effects of initial treatment on disease-free and overall survival and the impact on additional maintenance therapy with interferon alpha.

Adult↗
PubMed1995

Temperature gradient gel electrophoresis for analysis of clonal evolution in non-Hodgkin's lymphoma of the thyroid.

To analyze the transition of an autoimmune disease into a mucosa-associated lymphoid tissue-non-Hodgkin's lymphoma (MALT-NHL), we investigated a total of 27 cases of clinically diagnosed autoimmune thyroiditis with lymphoid hyperplasia. Three cases of thyroid hyperplasia served as controls. Monoclonal B cells were detected by studying rearrangement patterns of the hypervariable CDR III regions within the immunoglobulin heavy chain gene locus and the T-cell receptor gamma chain gene (TCRG). We used a seminested polymerase chain reaction (PCR) to demonstrate immunoglobulin rearrangements and a multiplex PCR for TCRG rearrangements. The PCR products were analyzed by temperature gradient gel electrophoresis to expand mixtures of homo- and hetero-duplices within heterogeneous populations of B cells. With this approach we found monoclonality in 14 of the 27 cases of Hashimoto's disease. In a reinvestigation we discovered additional histological and immunohistochemical features of MALT-NHL in 17 cases. The 14 cases of thyroiditis with clonally expanded B cells clearly demonstrate the transition from autoimmune disease to non-Hodgkin's lymphoma.

B-Lymphocytes↗
PubMed1995

Temperature gradient gel electrophoresis for analysis of a polymerase chain reaction-based diagnostic clonality assay in the early stages of cutaneous T-cell lymphomas.

By means of a multiplex polymerase chain reaction (PCR) we amplified rearranged T-cell receptor gamma chain genes to detect monoclonality in 370 formalin-fixed skin biopsy specimens, showing histological features of parapsoriasis or mycosis fungoides. PCr products were analyzed by temperature gradient gel electrophoresis (TGGE). We selected 20 positive cases for use in a comparison of this technique with conventional agarose and polyacrylamide gel electrophoresis (PAGE). With TGGE the T-cells had shown monoclonality in 272 of the 370 cases; with agarose electrophoresis they did so in only 5 of the 20 selected cases and with PAGE in 16. Where multiple biopsy specimens from the same patient were analyzed, PCR products showed identical rearrangement patterns in TGGE. TGGE is an efficient technique that works on routine material and can help to verify a histological diagnosis of cutaneous T-cell lymphoma.

Base Sequence↗
PubMed1995

Primary non-Hodgkin's lymphoma of the vagina. Case report and review of the literature.

The genital tract as primary site of malignant non-Hodgkin's lymphoma in women is extremely rare, whereas secondary involvement in advanced disease is found in about 40% of cases. In this report a patient is presented who had a primary vaginal non-Hodgkin's lymphoma of the centroblastic type according to the Kiel classification, with an excellent response to cytotoxic chemotherapy (CHOP) and event-free disease for 3 years. A review of the literature shows that favorable prognosis of localized disease seems to be a common experience. Primary involvement of the vagina can be successfully treated by pelvic irradiation, but in young women cytotoxic chemotherapy should be considered to preserve fertility.

Adult↗
PubMed1995

Non-Hodgkin's lymphomas of childhood and adolescence: results of a treatment stratified for biologic subtypes and stage--a report of the Berlin-Frankfurt-Münster Group.

PURPOSE: To prove the efficacy of a treatment stratified according to histology for children with non-Hodgkin's lymphoma (NHL), including acute B-cell leukemia (B-ALL). PATIENTS AND METHODS: From October 1986 to March 1990, 302 assessable patients, 0.6 to 17.8 years of age, with newly diagnosed NHL were enrolled onto study ALL/NHL-BFM 86. Fifty percent of patients had Burkitt-type lymphomas, including B-ALL; 24% had lymphoblastic lymphoma; 18% had diffuse large-cell lymphoma; and 8% had an NHL not further classified. Therapy group B included Burkitt's-type lymphomas, B-ALL, and most large-cell lymphomas including Ki-1 anaplastic large-cell lymphoma. Patients with stage I and II disease resected received three, while all others received six, 5-day therapy courses (dexamethasone, methotrexate [MTX] 0.5 g/m2 [5 g/m2 for stage IV and B-ALL], and intrathecal [IT] therapy in each course, plus ifosfamide, cytarabine, and etoposide alternating with cyclophosphamide and doxorubicin). Therapy for group non-B patients (lymphoblastic lymphoma and pleomorphic T-cell lymphoma [PTCL]) consisted of a Berlin-Frankfurt-Münster (BFM) acute lymphoblastic leukemia protocol, including cranial irradiation for advanced stage. Local therapy was restricted to patients with incomplete tumor regression. RESULTS: The probabilities of event-free survival (pEFS) at 7 years were 80% +/- 2% for the whole group, 81% +/- 3% for group B (n = 225), and 78% +/- 5% for group non-B (n = 77) with a follow-up duration of 3.6 to 7 years (median 5 years). Treatment results were comparable between NHL subtypes, except for PTCL, in which three of four patients suffered from relapse. Local disease manifestations were the most frequent site of failure. CONCLUSION: This therapy strategy provided patients of all NHL subtypes with an equally high chance to survive event-free, except patients with PTCL. With reduced systemic failure, local tumor control may become more important.

Adolescent↗
PubMed1995

Identification and structural analysis of rearranged immunoglobulin heavy chain genes in lymphomas and leukemias.

The third complementarity determining region (CDR3) of the hypervariable domain of immunoglobulin heavy chain (IgH) genes represents a highly variable and clone-specific IgH-CDR3 sequences in 10 non-Hodgkin's lymphomas (NHL), five chronic lymphocytic leukemias (CLL) and five acute lymphoblastic leukemias (ALL) of B cell lineage. The IgH-CDR3 sequences were amplified using DNA extracted from clinical specimens (bone marrow, peripheral blood and fresh-frozen or paraffin-embedded lymph nodes) by a semi-nested PCR with consensus primers directed to conserved regions within the variable (VH) and the joining (JH) gene segments. In 17/20 samples (85%), a distinct IgH-CDR3 PCR product was obtained. Individual PCR products were sequenced after cloning. The nucleotide sequences of 134 randomly chosen recombinant vectors were determined demonstrating in 17/20 cases (85%) monoclonal VH-N-DH-N-JH junctions. Analysis of PCR products by temperature-gradient gel electrophoresis (TGGE) confirmed the specificity of the IgH-CDR3 PCR/sequencing results. Moreover, the combination of PCR/TGGE technology allowed the rapid and specific characterization of clonal IgH-CDR3 junctions in B cell proliferations by direct sequencing even in the presence of admixed polyclonal B cells.

Base Sequence↗
PubMed1994

Blood monocytes and spleen macrophages differentiate into microglia-like cells on monolayers of astrocytes: morphology.

Several morphological and functional properties of microglial cells, the resident immunoeffector cells of the central nervous system (CNS), differ from those of monocytes/macrophages in other tissues. Microglia are assumed to derive from myelonocytic lineage, possibly as a distinct subpopulation that diverges from a common cell line early in ontogeny, invades the CNS, proliferates, and differentiates into ameboid and then ramified microglia. We tested the hypothesis that some morphological and functional properties of microglia are induced in myelomonocytic cells by nervous tissue, specifically astrocytes. In the present in vitro studies we compared the differentiation of microglia, blood monocytes, and spleen macrophages on acellular substrates and on monolayers of astrocytes and fibroblasts. On acellular substrates, microglial cells at first acquire an ameboid morphology; later they show a few short, unbranched processes. On monolayers of pure astrocytes, microglial cells at first also differentiate into ameboid cells, but after 5 to 7 days they start to develop processes with large lamellopodial tips. These lengthen and branch continuously during the next 2 weeks in vitro, demarcating a round to oval territory around the small ellipsoid cell body. By contrast, on monolayers of fibroblasts the microglial cells develop an ameboid morphology, but do not grow the typical long branched processes of the ramified form. Blood monocytes and spleen macrophages behave indistinguishably from microglia both on acellular and cellular substrates, i.e., on astroglia they develop the ramified form, while on fibroblasts they retain the ameboid shape. When microglia, macrophages, or monocytes are cultured on coverslips on top of astrocytic monolayers, i.e., physically separated from the astroglia, but exposed to the medium conditioned by astrocytes, a significant proportion of them also develop the ramified shape. These findings indicate that the ramified shape of microglia is induced by astrocytes. Since this morphology can also be induced in blood monocytes and macrophages, we take this to be further evidence for the proposition that microglial cells are derived from the myelomonocytic lineage, and, moreover, that properties of resident macrophages are largely determined by tissue components of their host organ.

Animals↗
PubMed1994

The impact of EBV, proliferation rate, and Bcl-2 expression in Hodgkin's disease in childhood.

The role of Epstein-Barr virus (EBV) in the pathogenesis of Hodgkin's disease (HD) has not yet been clarified. Using RNA in situ hybridization (ISH) and immunohistochemistry (IHC), the occurrence of small Epstein-Barr virus encoded RNA (EBER) and latent membrane protein-1 (LMP-1) was studied in 22 tissue samples from 21 patients between 4 and 17 years of age with Hodgkin's disease. EBER was detected in eight of 21 patients (38%) in Hodgkin and Reed-Sternberg cells and reactive lymphocytes irrespective of initial clinical stage and histological subtype, whereas LMP-1, positive in ten of 21 patients (48%), was restricted to neoplastic cells. All cases positive for EBER expressed LMP-1 as well. Additionally, oncoprotein Bcl-2 was identified in nine of 21 patients (43%), indicating, besides immortalization of HD cells by EBV, a further growth advantage due to apoptosis prevention by overexpression of this protein. Proliferation-associated antigens Ki-S1 and Ki-S5 were highly expressed in Hodgkin and Reed-Sternberg cells. CD 30 antigen was found in most cases, using two different antibodies (90% and 80%). The presence of this protein, which belongs to the family of nerve growth factor receptor (NGFR), is related to high expression of Ki-67 protein, detected by Ki-S5. CD 20 antigen was detectable in only three of 21 patients (14%). If we compare results of ISH and IHC with clinical data, the occurrence of EBV genome in children with HD seems to have no adverse effect on the final outcome of these patients.

Adolescent↗
PubMed1994

Blood monocytes and spleen macrophages differentiate into microglia-like cells when cultured on astrocytes.

Microglial cells are resident immunoeffector cells of the central nervous system. They differ from most other resident macrophages by their ramified shape, their capacity to proliferate, and by a distinct pattern of ion channels. They have therefore been proposed to be a subpopulation of macrophages that arise from a distinct pool of myelomonocytes by early determination of their lineage within the bone marrow. Here we present data which show that distinct properties of the microglial cells are not intrinsic to this subpopulation of macrophages, but are acquired subsequent to their interaction with astroglial cells, since similar properties can be induced in both blood monocytes and spleen macrophages, when these are cultured on astrocytes. These findings add further evidence to the proposition that microglial cells are derived from the myelomonocytic lineage, and also indicate that the properties of resident macrophages are largely determined by tissue components of the host organ.

Animals↗
PubMed1994

Peripheral T-cell non-Hodgkin's lymphomas of low malignancy: prospective study of 25 patients with pleomorphic small cell lymphoma, lymphoepitheloid cell (Lennert's) lymphoma and T-zone lymphoma. The Kiel Lymphoma Study Group.

Peripheral T-cell lymphomas comprise a heterogenous group of low- and high-grade malignancies differing in their histopathological appearance and also in clinical and prognostic aspects. We prospectively studied 25 patients with low-grade peripheral T-cell lymphomas: pleomorphic, small cell lymphoma (PSC) (n = 9), lymphoepitheloid (Lennert's) lymphoma (LEL) (n = 12) and T-zone lymphoma (TZL) (n = 4). The median patient age was 55 years (range 19-75 years); the male to female ratio was 1.5. 13 patients (52%) had limited stages (I+II), 12 patients (48%) had advanced disease (stage III+IV). 21 patients received the COPBLAM/IMVP-16 regimen. Two patients received more intensive treatments; two received less intensive therapy. Complete remissions were achieved in 16/25 patients (64%). The median observation time of surviving patients was 30 months (range 5-72 months). The actuarial overall survival and event-free survival at 2 years of 21 patients receiving COPBLAM/IMVP-16 were 69% and 35%, respectively. Intensive chemotherapy led to complete remissions in about 60% of the patients and to long-term disease-free survival for one-third. The observed clinical courses illustrate the aggressive nature of PSC, LEL and TZL.

Adult↗
PubMed1994

Successful treatment strategy for Ki-1 anaplastic large-cell lymphoma of childhood: a prospective analysis of 62 patients enrolled in three consecutive Berlin-Frankfurt-Munster group studies.

PURPOSE: To prove prospectively the efficacy of a short-pulse chemotherapy for treatment of Ki-1 anaplastic large-cell lymphoma (ALCL) of childhood. PATIENTS AND METHODS: From October 1983 to December 1992, 62 patients (median age, 9.7 years) with newly diagnosed Ki-1 ALCL were enrolled onto Non-Hodgkin's Lymphoma-Berlin-Frankfurt-Munster (NHL-BFM) studies 83, 86, and 90. The most frequent immunophenotype was T cell. Ki-1 ALCL differed from other subsets of NHL of childhood by the more frequent involvement of bone, soft tissue, and skin, and by the lack of bone marrow (BM) disease. A 5-day prephase course (prednisone/cyclophosphamide) was followed by two different 5-day courses of chemotherapy: course A consisted of dexamethasone, methotrexate (MTX) 0.5 g/m2 (24-hour infusion), intrathecal chemotherapy, ifosfamide, cytarabine (Ara-C), and etoposide (VP-16); course B consisted of cyclophosphamide and doxorubicin instead of ifosfamide, and Ara-C/VP-16, respectively. Treatment was stratified into three branches. Branch 1 (stage I and stage II resected) received three courses; branch 2 (stage II not resected, stage III), six courses; and branch 3 (stage IV), six intensified courses containing MTX 5 g/m2, and Ara-C 2 g/m2. Local radiotherapy was not performed. RESULTS: Four patients failed to enter remission, and one died of infection. Seven patients relapsed within 9 months after diagnosis; two patients had isolated local relapses, but BM and CNS were never involved. Fifty patients have been in first continuous complete remission (CR) for 0.6 to 9.7 years (median, 2.5), and 56 are alive. The probabilities for survival and event-free survival (EFS) at 9 years are 83% +/- 7% (SE) and 81% +/- 5%. Skin involvement was the only negative prognostic parameter. CONCLUSION: Short-pulse chemotherapy over 2 to 5 months without local therapy modalities is effective in the treatment of Ki-1 ALCL.

Adolescent↗
PubMed1993

Amplification of c-myc but not of c-erbB-2 is associated with high proliferative capacity in breast cancer.

Proliferative capacity provides an independent prognostic marker of progression in breast cancer. Little is known about the molecular mechanisms influencing the cell division rate in mammary carcinomas. In order to address this issue, the copy numbers of c-erbB-2 (HER/neu) and c-myc protooncogenes that have been shown to be amplified in aggressive types of cancers were determined in 60 mammary carcinomas and related to the proliferation rate. The proliferative activity was determined by labeling of the proliferation-associated nuclear antigen which is defined by the recently described monoclonal antibody Ki-S1. Approximately one-third of samples under investigation displayed a Ki-S1 labeling index exceeding 30%. In this subgroup, amplification of c-myc was found in 52.6%, whereas in the remaining cases, 26.1% exhibited an enhanced copy number of c-myc (P < 0.025). By contrast, c-erbB-2 amplification was not found to be associated with a higher proliferation index. Except for one case of invasive lobular carcinoma, both protooncogenes exhibited regular copy numbers in the low proliferation subgroup (< 20%; P < 0.03). We conclude from our findings that c-myc amplification may be one of the molecular causes underlying the highly proliferating phenotype of mammary carcinoma, known to be associated with an unfavorable clinical course.

Base Sequence↗
PubMed1993

Determination of the growth fraction in non-Hodgkin's lymphomas by monoclonal antibody Ki-S5 directed against a formalin-resistant epitope of the Ki-67 antigen.

Relevant prognostic information can be added to the histological classification of non-Hodgkin's lymphoma (NHL) by the determination of the growth fraction. In unfixed fresh tissue samples the Ki-67 antigen has proven its utility as an operational marker of proliferative activity in NHL. We have generated a monoclonal antibody directed against a formalin-resistant epitope of the Ki-67 antigen, designated Ki-S5. The immunoreactivity of Ki-S5 is confined to the nuclei of proliferating cells and, unlike Ki-67, no cross-reactivity with cytoplasmic antigens of epithelial cells occurs. In 100 cases of different NHL types, parallel staining of Ki-67 and Ki-S5 antigen yielded almost identical results in fresh tissues and fixed tissues, respectively (P < 0.00001; r = 0.95). In some cases, the Ki-S5 labeling index exceeded that of Ki-67, most probably due to a partial degradation of the epitope recognized by Ki-67 in frozen stored tissue samples. Significant differences in the median Ki-S5 labeling index could be demonstrated between high grade (> 50%) and low grade malignant NHL (< or = 30%), although the proliferative activity varied to a considerable range within identical histological categories (P < 0.001). We conclude that Ki-S5 provides a reliable means to assess proliferation in paraffin-embedded NHL specimens. Retrospective studies relating the proliferative activity to clinical outcome are thus rendered possible using archival routinely processed tissue samples.

Aged↗
PubMed1993

A new proliferation-associated nuclear antigen detectable in paraffin-embedded tissues by the monoclonal antibody Ki-S1.

A monoclonal antibody (Ki-S1) has been raised that reacts with the nuclei of proliferating cells. The antigen recognized is resistant to formalin fixation and can be detected in frozen tissues as well as in routinely processed specimens. In immunohistochemistry, nuclear staining can be seen in those tissues and cellular compartments known to be actively proliferating. Peripheral blood lymphocytes are negative but show a strong increase in antigen expression after mitogen stimulation. Flow cytometric determination of DNA content and antigen expression revealed negativity of G0 cells and positivity of G1 to G2/M cells. A cytoplasmic co-reactivity, not associated with proliferation, was confined to Langerhans islands of the pancreas. The nuclear localized antigen has a molecular mass of 160 kd and therefore seems to be different from all other known immunohistochemical markers of proliferating cells. We conclude that the monoclonal antibody Ki-S1 might provide a useful tool for studying cell proliferation in situ under normal and pathological circumstances.

Animals↗
PubMed1993

Prognostic significance of a formalin-resistant nuclear proliferation antigen in mammary carcinomas as determined by the monoclonal antibody Ki-S1.

Proliferative activity is a potential prognostic indicator of neoplastic cell growth. Usually the assessment of the tumor growth fraction requires specially processed or frozen tissue. We have raised a monoclonal antibody, Ki-S1, suitable for the detection of proliferating cells in routinely processed and paraffin-embedded tissue specimens. A retrospective study was conducted on 83 mammary carcinoma patients with a median follow-up of 45.6 months. Ki-S1 positivity was significantly (P < 0.0001) correlated with the S-phase fraction. A high proliferative activity of more than 30% of tumor cells being Ki-S1-positive was significantly correlated with recurrence (P < 0.001). Cumulative survival was significantly reduced in the high Ki-S1 expressing subgroup. In a multivariate model including Ki-S1, lymph node metastases, tumor size, and progesterone receptor positivity, independent significant information was provided by Ki-S1. We conclude that in mammary carcinomas, Ki-S1-determined growth fraction represents a significant and independent prognostic predictor.

Adult↗
PubMed1992

KiS1--a novel monoclonal antibody which recognizes proliferating cells: evaluation of its relationship to prognosis in mammary carcinoma.

Immunohistochemical staining with a novel monoclonal antibody, KiS1, which recognizes a cell cycle-associated antigen, was investigated in 142 cases of stage I and II invasive breast carcinoma. KiS1 staining indices were compared with disease-free interval, overall survival, and post-relapse survival. Using a semi-quantitative method of assessment, we found that tumours with a high level of staining (34/142, 24 per cent) had a significantly worse prognosis than those with a low level of staining (108/142, 76 per cent). Significant correlations were found between KiS1 staining and disease-free interval (P < 0.001), overall survival (P < 0.001), and post-relapse survival (P = 0.008). A more time-consuming, quantitative method of assessment gave similar results. Cox multivariate analysis showed these results to be independent of nodal status, histological type, and grade of tumour (P = 0.01). We conclude that KiS1 is a valuable new antibody which affords useful prognostic information in breast carcinoma. As it can be used in formalin-fixed, paraffin-embedded material, it may be of particular use in the study of small lesions such as those identified in the Breast Cancer Screening Programme.

Adult↗
PubMed1992

DNA analysis to aid in the diagnosis of chronic myeloproliferative disorders.

Diagnosing chronic myeloproliferative disorders (CMPD) can be difficult because of overlap and possible transitions between the different conditions and their similarity to reactive myeloproliferations. DNA analysis was applied to improve differentiation of CMPDs. All subtypes of CMPD analyzed, including chronic myeloid leukemia, agnogenic myeloid metaplasia, polycythemia vera, and essential thrombocythemia, had in common that granulocytes and bone marrow cells were clonal in origin, as shown by X chromosome-linked DNA polymorphism in conjunction with methylation patterns (n = 32). Reactive myeloproliferations, by contrast, showed polyclonal inactivation patterns. Clonality could not distinguish CMPD from cases of myelodysplastic syndrome because the latter (n = 7) also exhibited clonal hematopoiesis. Because of their clonal origin, peripheral granulocytes were used in all cases (n = 201) to detect bcr gene rearrangement. Despite possible morphologic overlap between different types of CMPD, bcr gene rearrangement was specific for chronic myeloid leukemia and could be applied to differentiate chronic myeloid leukemia from other CMPDs in cases of equivocal morphologic diagnosis. Chronic myeloproliferative disorders represent clonal hemopoietic diseases that probably have specific underlying genetic defects. Thus DNA analysis can aid substantially in the differential diagnosis of CMPD.

Adolescent↗