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Die chronische lymphatische Leukamie (CLL) ist die haufigste Leukamie der westlichen Welt. In den letzten 10 Jahren haben sich die Konzepte zur Therapie der CLL erheblich geandert. Neue Therapieverfahren wie Purinanaloga, Hochdosistherapie und monoklonale Antikorper trugen wesentlich zu diesem Fortschritt bei. Die Behandlung der CLL ist heute wesentlich differenzierter als vor wenigen Jahren und erfordert eine alters- und risikoangepasste Vorgehensweise. Dabei ist zu betonen, dass noch viele wesentliche Fragen zur Therapie der CLL offen sind. Nur durch Einbringen der Patienten in multizentrische Protokolle, wie sie die Deutsche CLL-Studiengruppe im deutschsprachigen Raum durchfuhrt, werden diese Fragen in den nachsten Jahren zu beantworten sein.

The authors analysed the effect of protein kinase A (PKA) activation on the protein synthesis and secretion in the T-helper 2 cell line D10.G4.1 (D10) using an assay that allows the detection of almost all secreted proteins of a cell. IL-4 and IL-10 were quantified. Three groups of secretory products could be defined. The T-cell receptor (TCR)-induced production of the first group (A) of proteins including IL-4 was enhanced by low concentrations of PKA activators. At higher concentrations the enhancement was less marked. The synthesis and secretion of a second group (B) of proteins including IL-10 remained unaffected. The production of a third group (C) of proteins was inhibited in a concentration-dependent manner. Biochemical analysis revealed a block of phospholipase C gamma (PLC gamma) activity by PKA activators. When D10 cells were stimulated by a phorbol ester plus calcium ionophore the production of group A proteins was enhanced almost fourfold, whereas production of group B proteins was unaffected by PKA activation. This effect was observed at all concentrations of various PKA activators tested. The secretion of group C proteins was no longer inhibited. The same results were obtained when analysing IL-4 and IL-10 m-RNA by Northern blotting. The data demonstrate a lymphokine specific mode of action on a single cell basis. Furthermore, it suggests that the inhibitory action of PKA in D10 cells is due partly to blocking of PLC gamma activity.

Background: Galactosyltransferases (Gal-T) are intracellular and cell surface enzymes involved in the biosynthesis of glycoconjugates. Gal-T were suggested to be implicated in oncogenesis, since their levels are elevated in various body fluids of patients with different types of malignoma; the invasiveness of certain neoplastic cell lines is correlated with their cell surface Gal-T activities, and cancer-associated Gal-T-isoforms were identified. Material and Methods: Gal-T activities in the cerebrospinal fluid (CSF) of patients with meningeal involvement in acute leukaemia or high-grade lymphoma (n = 8), normal controls (n = 54), patients with acute viral meningitis/encephalitis (n = 8) and multiple sclerosis (n = 10) were compared. CSF Gal-T activities were measured with uridine diphosphate-14C-galactose as substrate after isolation of the enzymatically transferred 14C-galactose by high-voltage electrophoresis. Simultaneously, the permeability of the blood-CSF barrier was analysed by the Q-albumin method. Results: In case of an intact blood-CSF barrier, Gal-T activities were elevated exclusively in patients with meningeal involvement in malignancies, but declined rapidly during intrathecal polychemotherapy. Conclusions: CSF Gal-T activities might prove to be a marker for early or residual involvement of the central nervous system in acute leukaemia or high-grade lymphoma.

The increasing information available about molecular biological and cytogenetic determinants has greatly substantiated the catalogue of characteristic features of non-Hodgkin’s lymphoma (NHL) entities

Background: In high-grade malignant non-Hodgkin lymphomas (NHL), prognostic risk is assessable by a series of initial parameters but adequate treatment approaches to high-risk patients remain to be established. The aim of the present study was therefore to evaluate the feasibility and efficiency of the intensified induction chemotherapy regimen ACOMED for poor prognosis patients. Patients and Methods: Unpretreated patients with high-grade malignant NHL (Kiel classification) presenting with Ann Arbor stage Il-IV disease and at least one prognostic risk factor (stage III/IV, serum LDH > normal, performance status ECOG > 2, bulky disease > 10 cm) were treated with the ACOMED regimen consisting of four courses of adriamycin 25 mg/m2 i.v. days 4-5, cyclophosphamide 250 mg/m2 i.v. days 1-5, vincristine 2 mg i.v. absolute day 1, methotrexate 500 mg/m2 i.v. day 1 with leucovorin-rescue, etoposide 100 mg/m2 i.v. days 1-5, dexamethasone 10 mg/m2 p.o. days 1-5, supported by G-CSF and repeated on day 21. Results: Of 44 patients recruited to the study, 31 have already completed treatment and are thus fully evaluable. Complete remissions were obtained in 25/31 (81%) of the patients; 4/25 (16%) relapsed, median observation time for all is 12 (3-18) months. The major side effect was mucositis occurring as WHO grade 4 in 30% of the patients in cycle 1, gradually decreasing in incidence and severity in further cycles but leading to an early discontinuation of the protocol and a switch to COP-BLAM or CHOP in 8/31 patients after 2 (1-3) cycles. Infections were rarely severe and myelotoxicity of WHO grade 4, though observed in one-third of the cycles, was only of short duration. Conclusions: ACOMED thus presents a highly effective regimen for remission induction in NHL poor-risk patients with longer observation periods required for the final judgement on remission stability. However, modifications of supportive care to ameliorate mucositis do seem to be desirable.

We evaluated recombinant human granulocyte-macrophage colony- stimulating factor (rhGM-CSF; Sandoz Pharma [Basel, Switzerland]/Schering-Plough [Kenilworth, NJ]) as an adjunct to a modified (mainly cyclophosphamide and doxorubicin increased 1.5-fold) COP-BLAM regimen in the primary treatment of high-grade malignant non- Hodgkin's lymphomas (NHL). Patients (n = 182; stage II-IV; age, 15 to 73 years) were randomized to rhGM-CSF (400 micrograms) or placebo for 7 days subcutaneously after chemotherapy. Efficacy was analyzed for patients receiving at least 70% of study medication (n = 125). The frequency of clinically relevant infection was reduced by rhGM-CSF (28 v 69 infections, 16 v 30 patients, P = .02) with a cumulative probability of remaining infection free in 70% versus 48% (P = .05 log rank test at 190 days). Periods of neutropenia (P = .01 in 5 of 6 courses), days with fever (2.1 v 4.0, P = .04) and days of hospitalization for infection (3.5 v 8.0 days, P = .01) were significantly reduced. Complete response (CR) rates, assessed by prognostic risk, were 15 of 19 (79%) in treated versus 20 of 21 (95%) in controls in the low-risk group (P = .12). In the high-risk group, 31 of 45 (69%) treated patients achieved CR versus 25 of 52 (48%) of controls (P = .04). No difference in survival has been seen after 1 year. Only injection site reactions (45% treated v 7% controls) and rash (26% v 2%) occurred more frequently in treated patients (n = 176). These data show that rhGM-CSF is well tolerated in most patients with NHL, significantly reduces infection, and improves response.

Using metabolic radiolabelling of proteins, which are newly synthesized during TCR-triggered T cell activation we were able to visualize distinct patterns of secreted polypeptides (with molecular weights ranging from 6 to 44 kDa) in supernatants of different T helper-1, T helper-2 and cytotoxic T cell clones. Most of these detected proteins are secreted in response to TCR-crosslinking (or to combined action of PMA and A231287), in an extracellular Ca 2+ -dependent manner and their appearance in supernatants was completely blocked by the addition of RNA synthesis or protein synthesis inhibitors or EGTA. Cyclosporin A (CsA) blocks secretion of several detected polypeptides, but does not affect TCR-triggered synthesis and secretion of others reflecting the existence of TCR-triggered, CsA-insensitive protein synthesis and secretion pathway. The insensitivity of secretion of several easily detectable polypeptides to inhibition by CsA offers a promising approach to further define the CsA-resistant and calcineurin-independent molecular pathways of TCR-triggered T cell activation. Several lymphokines (e.g., interferon-γ, tumor necrosis factor, interleukin-4 and interleukin-10) are identified among the visualized set of secreted polypeptides. Since other, yet unidentified, secreted polypeptides in the same set of secreted proteins share important properties with known lymphokines it seems promising to use described approach in search for new lymphokines.

Die Stadieneinteilung erfolgt nach der Ann-Arbor-Klassifikation der Hodg-kin-Lymphome (Carbone et al. 1989) gegebenenfalls in der Modifikation von Musshoff u. Schmidt-Vollmer (1975).

Mantle cell lymphoma (MCL) is a malignant lymphoma associated with a relatively aggressive clinical course and a median overall survival time of 3-4 years. Treatment usually consists of combination chemotherapy, often including topoisomerase (topo) inhibitors such as doxorubicin, etoposide and mitoxantrone. Topo IIalpha is an enzyme that is needed whenever uncoiling of DNA is necessary during the cell cycle. The enzyme is a marker of cell proliferation. We analyzed the expression of topo IIalpha in relation to Ki-67 and the clinical outcome in patients with MCL. Biopsy specimens from 95 untreated patients enrolled in two multicenter trials (1975-1985) were investigated immunohistochemically with monoclonal antibodies against topo IIalpha (Ki-S4) and Ki-67 (Ki-S5). Patients with low (0-10%) topo IIalpha expression had a median overall survival time of 49.0 months, compared to 17.0 months for patients with high (more than 10%) topo IIalpha expression. The Kaplan-Meier analysis showed a significant difference in the overall survival time related to the percentage of topo IIalpha (P0.001) and Ki-67 (P0.001) positive tumor cells. Multivariate Cox regression analysis revealed the expression of topo IIalpha as the most important prognostic factor (P0.001) in MCL superior to the international prognostic index (IPI), the Ki-67 index and other clinical characteristics.

The translocation t(8;21)(q22;q22), AMLl /ETO, one of the most frequent genetic aberrations in acute myelogenous leukemia is detectable in 40% of AML FAB M2. This entity is characterized by myeloblasts with a tendency towards differentiation and a comparably good prognosis (Mitelmann and Heim, 1998).

The transcription factor AML1 (CBFA2) is indispensable for early fetal hematopoiesis, but also transactivates target genes which are important for further downstream hematopoiesis. However, little is known about the impact of AML1 on lineage-committed stages. We investigated the transcription of AML1 in subfractions of four normal adult bone marrow aspirates isolated by fluorescence-activated cell sorting. AML1 is transcribed in early (CD34+/CD38–) and late (CD34+/CD38+) hematopoietic progenitors, B-cell precursors (CD10+/CD19+) as well as in immature monocytes (CD14–/CD11c+), myeloid (CD15+/CD33+ and CD15+/CD33–) and erythroid (GPA+/CD3–/CD45–) cells, but not in T lymphocytes (GPA–/CD3+/CD45+). These data suggest that in adult hematopoiesis AML1 may be critically involved in differentiation of early hematopoietic progenitors, erythroid cells, and lymphoid precursors. These subfractions are interesting targets to study the importance of AML1 in definitive hematopoiesis.

In peripheral blood of at least 50% of healthy individuals, the translocations t(9;22) BCR/ABL, t(14;18) IgH/BCL-2, t(2;5) NPM-ALK and MLL duplications, which characterize chronic myelogenous leukemia and acute lymphoblastic leukemia, follicular lymphoma, anaplastic large cell lymphoma, and acute myelogenous leukemia, respectively, are detectable by sensitive polymerase chain reaction (PCR). No structural differences between these aberrations in normal or disturbed hematopoiesis are apparent. While the total count of t(9;22)- and t(14;18)-positive cells does not exceed 10(4), those with MLL duplications are more frequent and account for approximately 10(7) cells in the total blood pool. t(14;18)-positive cells seem to be immortalized, but the biological consequences of the other aberrations in positive healthy persons have not been studied in detail. Due to the high frequency of positive individuals, most of them will not suffer from the correspondent leukemia or lymphoma, and criteria for subgroups that may be at a higher risk remain to be determined. Most likely, the number of genetic aberrations in healthy individuals, which so far are only associated with hematopoietic disorders, will increase in the near future.

The efficacy and toxicity of a combination of fludarabine and cyclophosphamide (FC) was evaluated in patients with B-cell chronic lymphocytic leukaemia (CLL). Between April 1997 and July 1998, 36 patients with CLL (median age 59 years) received a regimen that consisted of fludarabine 30 mg/m(2) in a 30-min IV infusion, d 1-3, and cyclophosphamide 250 mg/m(2) in a 30-min IV infusion on d 1-3. Cycles were repeated every 28 d. Twenty-one patients had received between one and three different treatment regimens prior to the study, while 15 patients had received no prior therapy. The median Eastern Cooperative Oncology Group performance score was 1. One patient was at Binet stage A, 18 were stage B and 17 patients were stage C. Objective responses, assessed according to the revised guidelines of the National Cancer Institute-sponsored Working Group, were recorded in 29 out of 32 assessable patients (90.6%). Twenty-four partial remissions and five complete remissions were observed. Two patients showed no change and one patient showed disease progression. At February 2000, three of the responders had relapsed. Severe neutropenia, anaemia and thrombocytopenia (Common Toxicity Criteria grade 3 and 4) were observed in 25, six and six patients (69.4%, 16.7% and 16.7%) respectively. Other side-effects were uncommon. No treatment-related deaths and no grade 3 or 4 infections occurred. We conclude that the combination of fludarabine and cyclophosphamide showed significant activity in patients with CLL. Myelosuppression was the major side-effect. These results warrant further study on the FC combination in randomized trials.

We treated 153 patients with de novo acute myeloid leukemia (AML) with two induction courses of conventional-dose cytosine arabinoside (ara-C) and idarubicin (AIDA) followed by either a third course of AIDA, high-dose ara-C or bone-marrow transplantation. The complete remission (CR) rate for all patients was 63.4%, with a higher CR rate for patients with a normal (versus unfavorable) karyotype (73.2% vs 52.5%; P=0.038). The probability of overall survival (OS) was 30.7% after 5 years (26.3% after 7 years). Improved OS at 5 years could be observed for patients up to 50 years old versus patients older than 50 years of age (37.6% vs 19.9%; P=0.001) and patients with a normal (versus unfavorable) karyotype (42.9% vs 14.1%; P=0.0016). Disease-free survival (DFS) after 5 years was 33.2% for all 97 CR patients and was significantly better for patients with a normal (versus unfavorable) karyotype (44.3% vs 12.3%; P= 0.003). Multivariate analysis revealed that the age for OS (P < 0.02) and the karyotype for both OS (P

A rare multi-organ involvement in plasma-cell dyscrasias has been named POEMS-syndrome: it is a synopsis of monoclonal gammopathy (M-gradient), osteosclerotic bone lesions, peripheral polyneuropathy, organomegaly, endocrinopathy and skin lesions.A patient is presented who had a classical manifestation of this disease known mainly in Japan. A monoclonal IgA-lambda-gammopathy was determined as cause of a gradually progressive polyneuropathy. The patient had a hypergonadotropic hypogonadism, hyperprolactinaemia, and sclerotic bone lesions. In addition, he showed a changing organomegaly, and hyperpigmentation of the skin.As yet, aetiology and pathophysiology are not fully understood. Irradiation or surgical resection of one or several osteosclerotic bone lesions may improve the polyneuropathy or may even lead to a complete remission of all symptoms. Thus, monoclonal immunoglobulins should be searched for in any unclear polyneuropathy, as should be for other symptoms of the POEMS-syndrome.

To identify prognostic factors alternative or additional to P-glycoprotein (Pgp), we studied the impact of the multidrug resistance-related protein (MRP), bcl-2 (flow cytometry), mutant p53 (single-strand conformation polymorphism), and heat-shock protein 27 (HSP27, Western blotting) in myeloid blasts obtained at the time of diagnosis in patients with de novo acute myeloid leukemia (AML). We collected bone marrow samples from untreated AML patients, prepared the cells as well as the cellular protein, and froze all the material. We then analyzed 20 patients who responded with complete remission (CR) and 20 patients who had blast persistence (BP). The purpose of the study was to determine whether leukemic blasts from patients with BP were more resistant to chemotherapy than those from patients with CR. There was no significant correlation between the expression of any of these proteins alone and treatment outcome in both groups studied. In contrast, there was a significant correlation between the coexpression of at least two of these proteins and response (p = 0.0298), which turned out to be a significant independent prognostic factor for treatment failure (p = 0.0329, relative risk = 1.5) according to multivariate analysis. We conclude that drug resistance in AML is multifactorial. Thus, coexpression of different resistance mechanisms may be responsible for the primary drug resistance in de novo AML.

In 1994 the International Lymphoma Study Group (ILSG) published the "Revised European-American Classification of Lymphoid Neoplasms" (R.E.A.L. Classification). Lymphomas were classified according to their presumed normal counterparts, to the extent possible. Within both T- and B-cell categories differentiation between lymphomas and/or leukemias of "precursor" or "peripheral" neoplasms are defined arising from antigen independend or antigen reactive cell proliferation. Lymphomas undoubtedly characterized by currently available morphologic, immunologic, and genetic technics represent "real" disease entities. Provisional categories include lymphomas that have been described in some detail, but without consensus within the ILSG. Proposed names are based predominantly on established usage. With respect to similar treatment approaches and difficulties of the ILSG members in subclassifying large cell lymphomas, centroblastic, immunoblastic and large cell anaplastic lymphomas of B-cell type were "lumped" together as large B-cell lymphomas. Within a prospective treatment trial overall survival was significantly better in centroblastic as compared to B-cell immunoblastic lymphoma diagnosed by optimal histomorphology according the criteria of the Kiel Classification. Thus the R.E.A.L. Classification fails to identify patients who may require other than standard treatment. Future studies will demonstrate whether subclassifying the proposed "peripheral" T-cell lymphomas, unspecified into T-zone lymphoma, lymphoepitheloid (Lennert's) lymphoma and pleomorphic, small, medium, and large cell lymphomas according the Kiel Classification is of clinicopathologic relevance. On the contrary the subtypes of chronic lymphocytic leukemia of T-cell type form two distinct entities within the R.E.A.L. Classification separating T-CLL/prolymphocytic leukemia from large granular lymphocyte leukemia of T- and NK-cell type. Within the R.E.A.L. Classification the lymphoplasmacytoid immunocytoma of the Kiel Classification will be subsumed together with the prognostically significantly better B-cell chronic lymphocytic leukemia. Opposite to the original intention of the ILSG two proposals are developed on clinical grouping of entities. Clinical indolent lymphoid neoplasms usually have "low grade" histologic appearances, with a predominance of small cells subsuming with the exception of the mantle cell lymphoma all of the low grade lymphomas of the Kiel classification. Aggressive lymphomas (intermediate risk) are defined as tumors whose survival if untreated is measured in months, highly or very aggressive lymphomas and/or leukemias will kill untreated patients within weeks. Unlike the Kiel Classification proposed categories subsume lymphomas irrespective of cytomorphology, thus grouping together potentially curable and uncurable diseases. Undoubtedly the R.E.A.L. Classification forms at present the best compilation of existing knowledge upon neoplasms of the immune system, enabling cooperation between clinicians and scientists all over the world. According to the ILSG this proposal should be considered a starting point for future periodic reevaluations.

Purpose Determination of the potential resistance markers P-glycoprotein (Pgp), the multidrug resistance-related protein (MRP), bd-2, mutant p53 and the heat shock protein 27 (HSP27) in myeloid blasts for patients with de novo acute myeloid leukemia (AML) at the time of diagnosis. Evaluation whether these proteins alone or in combination are predictive for the response to induction chemotherapy with cytosine arabinoside (ara-C) idarubicin (AIDA).

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.

In 1992, after a history of more than two decades a subgroup within the diffuse low-grade B cell lymphomas designated centrocytic lymphoma, lymphocytic lymphoma of intermediate differentiation or mantle zone lymphoma gained general acceptance, now referred to as mantle cell lymphoma. Similarities between these entities were emphasized by identification of rearrangement and overexpression of CCND1 (bcl1/PRAD1) gene in the majority of cases. Unlike in all other non-Hodgkin's lymphomas sex distribution demonstrates a striking preponderance of males over females with a ratio of 3:1. Initial parameters in all published series are advanced disease with generalized lymphadenopathy in 90%, bone marrow infiltration in 60-75%, splenomegaly in 55%, hepatomegaly in 35%, gastrointestinal involvement in about 25% and peripheral blood lymphocytosis in 20-30% of patients. In generalized disease, clinical course is characterized by continuous progression with a median survival probability of 3-4 years within most series. Overall response rates of 56-88% with complete remissions in the range of 9-58% are attainable but relapse occurs predominantly within 20 months. At present there is no evidence that any conventional regimen is curative. Prospective multicenter studies are mandatory to overcome this therapeutic dilemma. Patients suitable for some form of maintenance or consolidation therapy should initially be treated intensively by anthracycline-containing regimens. Whether maintenance with interferon or intermittent chemotherapy including new agents, like purine analogues or (un)conjugated monoclonal antibodies are able to influence overall survival is a matter of (ongoing) investigations. Further experimental approaches arise from antisense oligonucleotides or ribozymes blocking the overexpression of bcl-1 especially in this lymphoma entity. At present high-dose myeloablative consolidation radiochemotherapy followed by stem cell rescue in first remission seems to be the most attractive option in younger patients.

Morphologische und immunhistochemische Kriterien fuhren innerhalb der Kiel-Klassifikation zur Differenzierung zwischen der chronischen lymphatischen Leukamie (B-CLL) und dem Immunozytom (Lennert u. Feller 1992). Fur die klinische und prognostische Bedeutung dieser Unterteilung sprechen die Ergebnisse einer prospektiven, multizentrischen Beobachtungsstudie (Brittinger et al. 1984, 1985; Engelhard et al. 1991). Das Immunozytom subsumiert die fruher als nosologische Einheit betrachtete Makroglobulinamie Waldenstrom sowie Erkrankungsformen, die vor der Erarbeitung der Kiel-Klassifikation klinisch-prognostisch als „atypische“ chronische lymphatische Leukamie imponierten.

Haufigkeit: Als zentrozytisches Lymphom wurden 5,4% der Non-Hodgkin-Lymphome (NHL) im Kieler Lymphknotenregister diagnostiziert.

Erst nach mehr als 2 Jahrzehnten wurde das zentrozytische Lymphom unter seiner heutigen Bezeichnung Mantelzell-Lymphom als eigenstandige Entitat akzeptiert und in die Revised-European-American Classification of Lymphoid Neoplasms (R.E.A.L.-Klassifikation) integriert (Harris et al. 1994). Die histo-pathologischen Charakteristika wurden bereits Anfang der 70er Jahre von Lennert et al. unter dem Begriff Germinozytom herausgearbeitet und in der 1974 publizierten Kiel-Klassifikation als zentrozytisches Lymphom unter den Non-Hodgkin-Lymphomen (NHL) von niedrigem Malignitatsgrad eingeordnet (Gerard-Marchant et al. 1974; Lennert et al. 1975 a, b). Bereits 1978 hatte das American Pathology Panel for Lymphoma Clinical Studies dieses Lymphom als eigenstandige NHL-Entitat unter der Bezeichnung „lymphocytic lymphoma of intermediate grade differentiation“ (Kim et al. 1982) akzeptiert. Jaffe et al. (1987) war 1987 die Ahnlichkeit zwischen dem zentrozytischem Lymphom und dem von Berard u. Dorfman (1974) beschriebenen malignant lymphoma, lymphocytic type of intermediate grade differentiation aufgefallen. Weisenburger et al. grenzten 1982 eine follikulare Variante vom intermediate lymphocytic lymphoma ab, die sie als Mantelzonen-Lymphom bezeichneten (Weisenburger et al. 1982).

Alcaligenes xylosoxidans subsp. xylosoxidans (A. x. xylosoxidans) is a nonfermenting gram-negative peritrichous rod and opportunistic pathogen. The organism is frequently found in an aqueous environment. In the past few years, nosocomial infections caused by A. x. xylosoxidans have become more evident. The literature suggests that systemic infections are severe and often lethal and an optimal antibiotic therapy is not well established. This report describes nosocomial infections in 11 patients of a hematology ward over a 2-month period. Primary infection occurred during the neutropenic phase after cytotoxic chemotherapy. Reinfection spread from central venous catheters that had been implanted before the first infection. The bacteremia was successfully treated by imipenem. None of the 11 patients died from the bacteremia, but 3 died of their underlying diseases. Despite an intensive search for the source, the route of infection remained uncertain. Nosocomial infections by A. x. xylosoxidans are of growing importance in high-risk patients. Although the source of infection often remains unknown, infection seems to originate from contaminated solutions. Treatment with imipenem and the removal of central venous catheter systems successfully eliminated A. x. xylosoxidans, which adheres to plastic material.

The standardized fluorescence intensity as expressed in molecules of equivalent soluble fluorescence (MESF) of lymphocytes from normal individuals and patients suffering from low-grade non-Hodgkin's-lymphomas was obtained comparing different staining patterns of CD45(FITC) and CD20(PerCP). After standardization of the flow cytometer using standardized fluorescent particles ('beads') significant differences could be obtained for hairy cell leukemia, chronic lymphocytic leukemia and immunocytomas in the peripheral blood. In contrast, centroblastic-centrocytic as well as centrocytic lymphomas showed no significant variations as compared to normal peripheral blood lymphocytes. According to these results, a new lymphocyte gating procedure was established by adding CD14(PE) and three-color measurement by CD45/CD14/CD20 staining of peripheral blood using erythrocyte lysis. The established gating procedure leads to a crucial discrimination and quantification of abnormal and normal lymphocytes per one measurement, whereas the 'leucogate' as defined by CD45/CD14 staining alone was insufficient for correct lymphocyte gate setting. In conclusion, the different staining of CD45 and CD20 in leukemic peripheral blood should be considered when fluorescence intensity or atypical peaks occurred in flow cytometric histograms suggesting for abnormal cell populations. In addition, it is possible to use this information to classify low-grade lymphomas.

In order to establish the clinico-pathological properties of angioimmunoblastic lymphadenopathy (AILD)-type T-cell lymphoma, we evaluated the type, incidence and prognostic significance of clinical and laboratory symptoms.Sixty-two consecutive patients diagnosed at the Kiel lymph node registry participated in the study. The median patient age was 64 years (range 21-87 years) and the female to male ratio was 1:1.4. Ninety percent of the patients were in stage III and IV and B-symptoms were observed in 68%. At diagnosis patients presented with skin rash (49%), pruritus (32%), edema (38%), pleural effusion (37%), arthritis (18%) and ascites (23%). Furthermore, they exhibited autoimmune phenomena such as cold agglutinines, circulating immune complexes, a positive Coombs test, smooth muscle antibodies, rheumatoid factors, immune hemolysis, a paraprotein, antinuclear antibodies and cryoglobulins.In univariate analysis, survival was significantly related to age (p=0.032), stage (p=0.037), B symptoms (p=0.007), rash/pruritus (p=0.038), edema (p=0.030), ascites (p=0.013), number of clinical symptoms including B symptoms (p=0.004) and excluding B symptoms (p=0.017), lactate dehydrogenase (p=0.007) and hemoglobin (p=0.020).AILD type T-cell lymphoma characteristically differs from other non-Hodgkin's lymphomas in its clinical signs and laboratory symptoms.

To analyse incidence, risk factors, causes and prognostic significance of venous thromboembolism (VTE) in high-grade non-Hodgkin's lymphoma (HG-NHL) a prospective clinical trial (N = 593), also undertaken to analyse other aspects of HG-NHL, a study of haemostasis (N = 25) and a post-mortem analysis (N = 70) were performed. Clinical analysis documented a 6.6% incidence of VTE, and 77% of all cases occurred before or within the first 3 months of chemotherapy. Ann Arbor stage IV and B-mediastinal clear cell histology were risk factors for VTE, while rapid changes in tumour load or application of consolidation chemotherapy were not. Vessel compression by HG-NHL was the leading cause of VTE, whereas a significant (paraneoplastic or chemotherapy-induced) thrombophilic state was not disclosed by haemostatic tests. While VTE-related fatality was found to be low in the clinical trial (1.7%) and at necropsy (8.5%), the occurrence of VTE was associated with an unsatisfactory response of HG-NHL to chemotherapy and a high incidence of treatment-related mortality due to diffuse alveolitis. Thus, fatal VTE in HG-NHL is rare, but VTE is associated with an unfavourable clinical course of HG-NHL.

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.

This study focuses on possible functional defects of circulating mature neutrophils in chronic phase chronic myelogenous leukemia (CML) and their modulation by interferon-alpha (IFN-alpha). Polymorphonuclear cells (PMN) of seven untreated and nine IFN-alpha-treated patients were evaluated for the following parameters by the following methods: generation of oxygen species, by luminol-dependent chemiluminescence; leukotriene B4 (LTB4) generation, by high-performance liquid chromatography (HPLC); expression of LTB4 and formylmethionyl-leucyl phenylalanine (FMLP) receptor sites, by 3H-binding assay; and GTPase activity, by 32P-gamma-GTP. Compared to normal controls, reduced values were obtained in treated and untreated CML for most parameters studied. Therapy with IFN-alpha resulted in significantly diminished values for oxygen species (NaF stimulation) and LTB4 (FMLP stimulation) generation, as well as FMLP receptor expression as compared to untreated CML. We conclude that alterations at the level of oxygen species production, mediator generation, receptor expression, and transmembrane signaling are involved in functional defects of circulating mature neutrophils from CML patients. IFN-alpha seems to enhance some of these functional defects, but the clinical relevance of these findings has be elucidated.

We evaluated recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF; Sandoz Pharma [Basel, Switzerland]/Schering-Plough [Kenilworth, NJ]) as an adjunct to a modified (mainly cyclophosphamide and doxorubicin increased 1.5-fold) COP-BLAM regimen in the primary treatment of high-grade malignant non-Hodgkin's lymphomas (NHL). Patients (n = 182; stage II-IV; age, 15 to 73 years) were randomized to rhGM-CSF (400 micrograms) or placebo for 7 days subcutaneously after chemotherapy. Efficacy was analyzed for patients receiving at least 70% of study medication (n = 125). The frequency of clinically relevant infection was reduced by rhGM-CSF (28 v 69 infections, 16 v 30 patients, P = .02) with a cumulative probability of remaining infection free in 70% versus 48% (P = .05 log rank test at 190 days). Periods of neutropenia (P = .01 in 5 of 6 courses), days with fever (2.1 v 4.0, P = .04) and days of hospitalization for infection (3.5 v 8.0 days, P = .01) were significantly reduced. Complete response (CR) rates, assessed by prognostic risk, were 15 of 19 (79%) in treated versus 20 of 21 (95%) in controls in the low-risk group (P = .12). In the high-risk group, 31 of 45 (69%) treated patients achieved CR versus 25 of 52 (48%) of controls (P = .04). No difference in survival has been seen after 1 year. Only injection site reactions (45% treated v 7% controls) and rash (26% v 2%) occurred more frequently in treated patients (n = 176). These data show that rhGM-CSF is well tolerated in most patients with NHL, significantly reduces infection, and improves response.

We analyzed the transcriptional events involved in the T cell receptor (TcR)-alpha mRNA expression in a human lymphoblastic T-cell line CEM. CD3-negative and CD3-positive CEM subclones that either lack mature TcR-alpha mRNA or express TcR-alpha mRNA were used. Exposure of the TcR-alpha mRNA negative subclones to phorbol 12-myristate 13-acetate (PMA) was followed by 2- to 3-fold increase of transcription, indicating that PMA acts on a transcriptional level. No increase of transcription was observed after blocking protein synthesis with cycloheximide (CHX) or after sequential stimulation with CHX followed by PMA. On the posttranscriptional level, CHX as well as PMA induced a progressive stabilization of TcR-alpha mRNA in the nuclear compartment, which was independent of ongoing transcription. The half-life of the TcR-alpha mRNA upon stimulation was about 6 hours. The accumulation of mature TcR-alpha mRNA seemed to be controlled by nuclear events on a transcriptional as well as posttranscriptional level. The data imply that alterations of TcR-alpha gene transcription are dependent on protein synthesis. DNA-binding proteins enhance transcription and labile nuclear proteins target TcR-alpha mRNA for rapid turnover.

Bei 60 Pt. mit Chemotherapie-induzierter Neutropenie wurde GM-CSF (oder Placebo) als Interventionsbehandlung uber 5 Tage gegeben. GM-CSF beschleunigte die Neutrophilenerholung signifikant. Am besten wirksam waren Dosen im mittleren Bereich (3,7 bis 11,0 µg/kg K.G.). In einer multizentrischen Placebo-kontrol-lierten Phase III Studie wurde GM-CSF prophylaktisch bei der Chemotherapie hochmaligner Lymphome eingesetzt. 125 Pt. erhielten die Substanz uber 5–6 Chemotherapiekurse. Infektionen des Schweregrades 2–4 traten 69mal bei Kontrollpatienten und 28mal bei GM-CSF behandelten Patienten auf. Die kumulative Wahrscheinlichkeit einer Infektion betrug 50% vs. 27% (P = 0,04). Diese Daten belegen, das GM-CSF sowohl in der Prophylaxe als auch in der Therapie neutropenischer Infektionen erfolgreich eingesetzt werden ka

To describe the clinical course of patients with angioimmunoblastic lymphadenopathy (AILD)-type lymphoma with a sequential treatment with prednisone and COPBLAM/IMVP-16.A multicenter, prospective, nonrandomized trial.University medical centers and community hospitals.Sixty-seven patients were registered, 28 were excluded, and 39 patients were evaluable for response (median age, 59 years; range, 25 to 82 years) (stages I and II, 10%; stages III and IV, 90%; B symptoms, 74%).Response, survival, and relapse.Patients initially received prednisone and no further treatment if a complete remission was achieved. Relapsing or refractory patients were treated with COPBLAM/IMVP-16. Patients with life-threatening tumor progression or extension received COPBLAM/IMVP-16 initially. Treatments were chosen in accordance with tumor extension and response to prednisone. Treatment modalities were not compared.Twenty-eight patients received primary prednisone, 18 received secondary prednisone, and 11 received primary chemotherapy. The complete response rates (with 95% CIs) were 29% (CI, 12% to 46%), 56% (CI, 33% to 79%), and 64% (CI, 36% to 92%), respectively. The median observation time of surviving patients was 28 months (range, 7 to 53). The median overall survival time was 15 months. The probabilities (with 95% CIs) of overall survival, event-free survival, and relapse at 36 months were 40.5% (CI, 24% to 56%), 32.3% (CI, 17% to 47%), and 34.6% (CI, 14% to 56%), respectively. At the time of evaluation, 22 of 39 patients had died, 7 of noninfectious complications and 14 of infections.Prednisone with or without COPBLAM/IMVP-16 treatment in AILD-type lymphoma leads to complete remissions in about half of the patients and in long-term, disease-free survival for one third.

To characterize the requirements for the induction of an anergic state in immunocompetent cells we examined the effect of an increase in intracellular calcium concentration on the subsequent responsiveness of cytolytic T cells to antigenic stimulation in vitro. Pretreatment of a murine cytolytic T cell clone with the calcium-ionophore A23187 resulted in the induction of an anergic state characterized by a decrease in cytolytic activity and granule exocytosis upon Ag-specific stimulation. Furthermore, IFN-gamma synthesis declined whereas de novo synthesis of a yet unidentified protein with a molecular mass of 33 kDa as well as proliferative response of cells in response to exogenous IL-2 were unaffected. This state of partial unresponsiveness 1) could be prevented by concomitant pretreatment of cells with cyclosporin A or protein synthesis inhibitors and 2) was reversible within 48 h. Biochemical analysis of TCR-induced intracellular activation revealed a block in signal transduction before the activation of protein kinase C because cellular unresponsiveness could be bypassed by the phorbol ester PMA plus the calcium-ionophore A23187. However, phosphatidylinositol turnover was markedly inhibited in unresponsive cells that also did not show a calcium influx on stimulation with concanavalin A. We conclude that a rise in intracellular calcium in cytolytic T cells might not only be necessary for cellular activation but may also trigger the induction of a partial unresponsiveness to antigenic stimulation due to an inhibition in the early phase of signal transduction.