Immunosuppressive treatment of aplastic anemia with antilymphocyte globulin, methylprednisolone, and cyclosporine appears to be more effective than a regimen of antilymphocyte globulin and methylprednisolone without cyclosporine and may thus represent a treatment of choice for patients who are not eligible for bone marrow transplantation.

Median overall survival of patients with advanced nonblastoid MCL almost doubled during the past 30 years. Potential reasons for this apparent improvement in overall survival include the application of anthracycline-containing regimens and new approaches, such as antilymphoma antibodies or stem cell transplantation. Advances in general supportive care, new diagnostic tools, and general improvement of life span might have also reinforced this effect. However, our results are questioning the validity of historical comparisons which had been frequently applied in previous trials.

Clinical and prognostic relevance of the Kiel classification of non-Hodgkin lymphomas (NHL) was investigated in 1127 patients entering a prospective multicenter observation study. Survival of the 782 (69.4 per cent) patients with low-grade malignant NHL (lymphocytic lymphomas, predominantly B-CLL, LP immunocytoma, centrocytic lymphoma, centroblastic-centrocytic lymphoma) exceeded that of the 341 patients (30.2 per cent) with high-grade malignant NHL (centroblastic, immunoblastic, lymphoblastic lymphomas). Prognosis was best in centroblastic-centrocytic lymphoma and in B-CLL and least favorable in immunoblastic and lymphoblastic lymphomas. Survival of LP immunocytoma and centrocytic lymphoma patients was intermediate after 2 to 2.5 years of follow-up. Corresponding to histopathology, pattern of survival curves of low-grade malignant NHL (slow decline, no plateauing) differed from that of high-grade malignant NHL (rapid decline, subsequent plateauing). Prognosis of B-CLL was superior to that of LP immunocytoma. Stages I and II were more frequent in centroblastic-centrocytic lymphoma (21 per cent) than in LP immunocytoma (2.5 per cent) and centrocytic lymphoma (11 per cent). Ability of radiotherapy to induce stable complete remissions in stage III of centroblastic-centrocytic lymphoma indicates prolonged restriction of lymphoma to the lymphatic system. In immunoblastic and centroblastic lymphomas, stages I and II were diagnosed in 34 and 38 per cent of cases, respectively, but only in stage I/IE of centroblastic lymphoma prolonged remissions were achieved by radiotherapy. In advanced high-grade malignant NHL marked improvement of prognosis was solely possible by induction of complete remissions whereas in corresponding low-grade malignant lymphomas also partial remissions were prognostically relevant.

Within a multicentre observation study on non-Hodgkin lymphomas (NHL) diagnosed according to the Kiel classification advanced stages III and IV of centrocytic (CC) lymphoma exhibited the worst prognosis among lymphomas of low-grade malignancy with a 5-year survival probability of less than 10 per cent. Treatment had been solely expectative and palliative with treatment results showing a prognostic superiority of patients achieving partial and complete remissions over non-responders. Therefore, a randomized multicentre study was initiated to compare the remission-inducing potential of the COP regimen (Bagley et al., 1972) with that of the more intensive adriamycin-containing CHOP regimen (McKelvey et al., 1976). From 91 newly diagnosed CC lymphomas 63 fulfilled randomization criteria with 37 patients assigned to the COP regimen and 26 patients to the CHOP regimen. Between the COP- and CHOP-treated patients no significant differences could be demonstrated with respect to initial clinical parameters, rate of complete (41 per cent versus 58 per cent) or partial remissions (43 per cent versus 31 per cent), median overall survival probability (32 versus 37 months), relapse-free survival (10 versus 7 months) and rates of relapse (73 per cent versus 67 per cent) and death (57 per cent versus 50 per cent). It can be concluded that CC lymphoma is a typical lymphoma of low-grade malignancy with its inability to reach stable remissions while the demonstration of identical survival probabilities for patients with complete and partial remissions constitutes a unique feature of this lymphoma entity. These observations prove advanced CC lymphoma to represent an incurable neoplastic disease under conventional therapeutic approaches.

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 IIa 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 IIa 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)(1976)(1977)(1978)(1979)(1980)(1981)(1982)(1983)(1984)(1985) were investigated immunohistochemically with monoclonal antibodies against topo IIa (Ki-S4) and Ki-67 (Ki-S5). Patients with low (0-10%) topo IIa expression had a median overall survival time of 49.0 months, compared to 17.0 months for patients with high (more than 10%) topo IIa expression. The Kaplan-Meier analysis showed a significant difference in the overall survival time related to the percentage of topo IIa (Po0.001) and Ki-67 (Po0.001) positive tumor cells. Multivariate Cox regression analysis revealed the expression of topo IIa as the most important prognostic factor (Po0.001) in MCL superior to the international prognostic index (IPI), the Ki-67 index and other clinical characteristics.

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.

Minichromosome maintenance protein 6 (MCM6) is one of six proteins of the MCM family which are involved in the initiation of DNA replication and thus represent a marker of proliferating cells. Since the level of cell proliferation is the most valuable predictor of survival in mantle cell lymphoma (MCL), we investigated lymph node biopsy specimens from 70 patients immunohistochemically with a monoclonal antibody against MCM6. The percentage of MCM6 expressing lymphoma cells ranged from 12.0 to 95.6%, with a mean of 61.0%, and was significantly higher than the percentage of Ki-67-positive cells (Po0.0001). Surprisingly, the ratio of MCM6-positive cells to Ki-67-positive cells was higher than in normal stimulated peripheral blood mononuclear cells, indicating a cell early G1-phase arrest in MCL. A high MCM6 expression level of more than 75% positive cells was associated with a significantly shorter overall survival time (16 months) compared to MCL with a low MCM6 expression level of less than 25% (no median reached, Po0.0001). Multivariate analysis revealed MCM6 to be an independent predictor of survival that is superior to the international prognostic factor and the Ki-67 index. Therefore, aside from gene expression profiling, immunohistochemical detection of MCM6 seems to be the most promising marker for predicting the outcome in MCL.

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