A family of secreted pathogenesis-related proteins in Candida albicans.

Analysing culture supernatants of yeast and hyphal cells of Candida albicans, we found two close homologues of pathogenesis-related (PR-) 1 proteins, Rbe1p and Rbt4p, in the secretome. Due to sequence homology, three additional, yet not characterized open reading frames, ORF19.6200, ORF19.2787 and ORF19.2336, together with RBE1 and RBT4 were assigned to a novel family of CaPRY proteins. In a Δrbe1/Δrbt4 deletion strain, genome-wide transcriptional analysis revealed differential transcription of only a limited set of genes implicated in virulence and oxidative stress response. Single deletion of RBE1 or RBT4 in a clinical C. albicans isolate resulted in a moderate but significant attenuation in virulence in a mouse model for disseminated candidiasis. However, a synergistic effect was observed in a Δrbe1/Δrbt4 double deletion strain, where virulence was strongly affected. Remarkably, transcription of RBT4 and RBE1 was each upregulated in blastospores of Δrbe1 or hyphae of Δrbt4 deletion strains respectively, indicating functional complementation thereby compensating a potential virulence defect in the single deletion strains. Furthermore, the double deletion strain showed increased sensitivity to attack by polymorphonuclear leucocytes. Therefore, the crucial contribution of both C. albicans pathogenesis-related proteins to virulence might be vested in protection against phagocyte attack.

The potential impact of geological environment on health status of residents of the Slovak Republic.

In order to assess the potential impact of the geological environment on the health of the population of the Slovak Republic, the geological environment was divided into eight major units: Paleozoic, Crystalline, Carbonatic Mesozoic and basal Paleogene, Carbonatic-silicate Mesozoic and Paleogene, Paleogene Flysch, Neovolcanics, Neogene and Quaternary sediments. Based on these geological units, the databases of environmental indicators (chemical elements/parameters in groundwater and soils) and health indicators (concerning health status and demographic development of the population) were compiled. The geological environment of the Neogene volcanics (andesites and basalts) has been clearly documented as having the least favourable impact on the health of Slovak population, while Paleogene Flysch geological environment (sandstones, shales, claystones) has the most favourable impact. The most significant differences between these two geological environments were observed, especially for the following health indicators: SMRI6364 (cerebral infarction and strokes) more than 70 %, SMRK (digestive system) 55 %, REI (circulatory system) and REE (endocrine and metabolic system) almost 40 % and REC (malignant neoplasms) more than 30 %. These results can likely be associated with deficit contents of Ca and Mg in groundwater from the Neogene volcanics that are only about half the level of Ca and Mg in groundwater of the Paleogene sediments.

Bone marrow involvement in Hodgkin's disease: an analysis of 135 consecutive cases. German Hodgkin's Lymphoma Study Group.

PURPOSE: To describe the incidence of primary bone marrow involvement (BMI) in Hodgkin's disease (HD) and its correlation with clinical and laboratory features present at diagnosis, and to evaluate the prognostic relevance of BMI. PATIENTS AND METHODS: Between 1983 and 1991, 2,307 patients with HD were treated according to two trial generations (HD1-3 and HD4-6) of the German Hodgkin's Lymphoma Study Group (GHSG). RESULTS: One hundred thirty-five cases of primary BMI were observed. The incidence of BMI was 4.8% in the HD4-6 study generation, which included all stages. Among stage IV patients, 32% had BMI. Among those with BMI, other organs were also involved in 33%. Among all patients, the presence of BMI was significantly associated with B symptoms, lymph nodes on both sides of the diaphragm, mixed cellularity histologic subtype, leukocytopenia, anemia, thrombocytopenia, lactate dehydrogenase (LDH) level more than 400 U/L, and erythrocyte sedimentation rate (ESR) more than 40 mm/h. BMI was negatively correlated with a large mediastinal tumor (3.7% v 20.0% in non-BMI cases). Eighty-seven of 108 (81%) assessable patients with BMI achieved a complete remission (CR). This compares favorably with the overall CR rate in all stage IIIB/IV patients. Among stage IV patients, BMI has no prognostic relevance with regard to freedom from treatment failure and overall survival. Twenty-one patients with BMI relapsed after having achieved a CR. Only five of these (24%) again had a positive bone marrow biopsy. CONCLUSION: The prognosis of patients with BMI is not worse than the prognosis of other advanced-stage HD patients. BMI alone does not define a special high-risk group in which a different treatment approach is indicated.

Dose-response relationship of complementary radiotherapy following four cycles of combination chemotherapy in intermediate-stage Hodgkin's disease.

PURPOSE: To determine the appropriate irradiation dose after four cycles of modern combination chemotherapy in nonbulky involved field (IF/BF) and noninvolved extended-field (EF/IF) sites in patients with intermediate-stage Hodgkin's disease (HD). MATERIALS AND METHODS: HD patients in stage I to IIIA with a large mediastinal mass, E stage, or massive spleen involvement were treated with two double cycles of alternating cyclophosphamide, vincristine, procarbazine, and prednisone (COPP) plus doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) followed by EF irradiation in two successive trials (HD1 and HD5). In the HD1 trial (1983 to 1988), 146 patients who responded to chemotherapy were randomized to receive 20 Gy (70 patients) or 40 Gy (76 patients) of EF irradiation in all fields outside bulky disease sites. A cohort of 111 patients who fulfilled the same inclusion criteria in the subsequent trial HD5 (1988 to 1993) were treated with 30 Gy. Bulky disease always received 40 Gy. RESULTS: Freedom-from-treatment-failure (FFTF) and survival (SV) curves showed no differences between the 20-, 30-, and 40-Gy groups. However, acute toxicities were more frequent in the 40-Gy arm. Analysis of relapse patterns showed that 18 of 26 relapsing patients either failed to respond in initial bulky sites (n = 5) or had an extranodal relapse (n = 9) or both (n = 4). After 5 years, the cumulative risk for relapse in bulky sites is 10%, despite 40 Gy of radiation. CONCLUSION: Our results strongly suggest that there is no relevant radiotherapy dose effect in the range between 20 Gy and 40 Gy in IF/BF and EF/IF after 4 months of modern polychemotherapy in patients with intermediate-stage HD. Relapse patterns indicate that patients destined to relapse need more systemic, rather than local, treatment. Based on our data, we conclude that 20 Gy is sufficient in EF/IF of intermediate-stage HD following four cycles of modern polychemotherapy.

C-reactive protein measured in dried blood spots from patients with cystic fibrosis.

There was no significant difference in C-reactive protein concentration determined in paired serum and eluates from dried blood spots collected on Guthrie cards; mean difference 0.6 microgram/ml (95% CI -3.3-2.2 micrograms/ml; n = 101). Dried blood spot samples were stable for up to 21 days and were unaffected by posting to the laboratory. In eight patients with cystic fibrosis undergoing specific antibiotic treatment for Pseudomonas aeruginosa pulmonary infection the fall in C-reactive protein concentration was not significantly different between serum and dried whole blood spot specimens. This method could be used to monitor infection and the response to antibiotic treatment.

Prevention of chemotherapy-induced nausea and emesis in patients responding poorly to previous antiemetic therapy. Comparing tropisetron with optimised standard antiemetic therapy.

In a multicentre trial, 78 patients with a variety of malignancies, who had experienced insufficient control of emesis (greater than or equal to 3 episodes within 24 hours) while receiving standard antiemetics during previous chemotherapy, were randomly assigned to receive tropisetron 5mg once daily for 5 days or conventional antiemetic drugs. No attempt was made to standardise the conventional antiemetic treatment, which was given according to the usual practice of the participating institutions. Emesis was evaluated by counting emetic episodes and nausea by asking the patients to record on a diary chart the duration and severity of the nausea. Emesis was much better controlled with tropisetron than with standard drugs, complete control during the first 24 hours being achieved in 42% and 8% of patients, respectively, (p less than 0.001). Nausea was of significantly shorter duration (6.9 vs 10.3 hours; p less than 0.01) and was less severe (p less than 0.005) in the tropisetron group. The patients' overall assessment of treatment outcome was markedly better for tropisetron than for the standard antiemetic therapy. The superior efficacy of tropisetron was especially marked during the first 24 hours. For delayed nausea, no significant difference between treatments was seen. No serious adverse effects were observed.

Prognostic significance of glucocorticoid receptor determination in patients with chronic lymphocytic leukemia and immunocytoma--lack of a positive correlation between receptor levels and clinical responsiveness.

Glucocorticoid receptors (GR) have been suggested to have prognostic significance in patients with CLL treated with chemotherapy containing glucocorticoid. In this study, the GR levels in 65 patients with advanced CLL and immunocytoma (clinical stages III and IV according to Rai) were determined by means of a whole cell assay. The median GR-level was 1,920 bs/c with a range from 0 to 9591. The patients were subsequently treated according to a prospective, randomized trial with either a combination of chlorambucil and prednisolone, or with prednimustine. No significant difference in receptor levels was found between responders (median = 1940 bs/c; n = 47) and nonresponders (median = 1950 bs/c; n = 14). To assess the influence of receptor content on prognosis we have analyzed the relationship between GR content and survival time and duration of response. There was no significant difference in duration of response and in survival between those patients with high (greater than 1920 bs/c) and those with low GR levels (less than 1920 bs/c) (log-rank test). Our data suggest that determination of GR provides no reliable indicator for clinical response to regimens with glucocorticoid as a component in patients with CLL and immunocytoma.

Second malignancies.

The secondary development of malignant tumors after the treatment of Hodgkin's disease has been termed the price of success, but is relevant also to other types of cancer and gives an opportunity to study mechanisms of carcinogenesis and tumor induction. The authors review here their experience with second malignant neoplasms (SMN) as well as the result of an extensive search of the recent literature. The primary malignancies discussed in this article include Hodgkin's disease, pediatric cancer, breast cancer, lung cancer and other types of tumors. The international literature was searched (Medline 1989-1995) for reports of SMN with special emphasis on risk factors and the molecular mechanisms of tumor induction. In Hodgkin's disease, a 3 to 5-fold elevated risk for SMN was recognized, with a 15-year cumulative incidence in the range of 11-18%. All types of malignancies have a statistically increased risk (leukemias, non-Hodgkin's lymphomas, solid tumors). The risk for leukemia is related to the intensity of treatment with alkylating agents. Some solid tumors like lung cancer or breast cancer are related to radiation therapy. Present-day treatments may carry a lower risk of inducing secondary malignancies than treatments in the past. For non-Hodgkin's lymphoma as primary malignancy, fewer data exist on SMN. In pediatric cancer, no general risk estimate can be given and the genetic influence is greater as a cause of SMN. The improved prognosis for acute lymphoblastic leukemia has led to a changing pattern of pediatric SMN. In head and neck- and in lung cancer, the same etiologic factors which cause the primary tumor may also cause SMN. SMN occur as part of familial cancer syndromes. Two types of treatment related leukemias (mostly AMLs) exist and can be recognized by cytogenetic and molecular analysis. A complete follow-up is necessary to fully appreciate the risk of second malignancy. The goal to prevent SMN must be reached without decreasing the cure rates of the primary tumor. New treatment approaches need to be carefully monitored for SMN. Improved tests of mutagenesis and molecular screening may help to recognize patients prone to develop SMN and permit to estimate certain types of risk. Screening and prevention strategies are useful in high-risk situations.

Hemostatic parameters in sepsis patients treated with anti-TNF alpha-monoclonal antibodies.

Tumor necrosis factor-alpha (TNF alpha) is a central mediator in the pathogenesis of sepsis. It also interferes with the hemostatic system and exerts and a net procoagulant effect. Since TNF alpha may contribute to thrombotic complications in sepsis patients, we determined markers of thrombin activation, parameters of the fibrinolytic system (D-dimer, tissue plasminogen activator antigen (tPA) urinary type plasminogen activator antigen (uPA), plasminogen activator inhibitor antigen (PAI-1) and von Willebrand factor antigen (vWF) in 30 patients with sepsis or septic shock. All patients were treated with standard therapy, but 14 patients were treated additionally with an anti-TNF alpha monoclonal antibody (MAK 195F); 16 patients served as historical controls. No significant effect of the antibody on the parameters of the hemostatic system could be determined. Our data speak against a modulation of coagulation or the fibrinolytic system by the monoclonal anti-TNF alpha antibody MAK 195F in this cohort of sepsis patients.

Endothelial cell markers in bone marrow transplant recipients with and without acute graft-versus-host disease.

To investigate endothelial cell alterations in BMT recipients developing acute graft-versus-host disease (aGVHD) we determined levels of the endothelial cell markers von Willebrand factor (VWF) and thrombomodulin (TM) in 57 patients undergoing BMT. Before conditioning VWF and TM levels did not differ significantly between transplant recipients who later developed no or mild (grade I) aGVHD (group A, allogeneic n = 22, autologous n = 7; VWF 136.0 +/- 44.1%; TM 29.5 +/- 18.0 ng/ml), and those with moderate or severe (grade II or III) aGVHD (group B, n = 28; VWF 142.2 +/- 37.6%; TM 35.2 +/- 20.1 ng/ml). A first significant rise of both VWF and TM level was noted after conditioning (day 0) both in group A (VWF 197.0 +/- 113.3%; P < 0.001; TM 39.3 +/- 23.3 ng/ml; P < 0.01) as well as in group B (VWF 201.7 +/- 53.3%; P < 0.0001; TM 43.5 +/- 23.5 ng/ml; P < 0.05). Subgroup analysis of autografted patients revealed no significant increase after conditioning in these patients. At the time of engraftment and onset of aGVHD (day 21), when VWF and TM levels within the groups were significantly elevated as compared with baseline (day -8) levels, group B patients (62.7 +/- 38.5 ng/ml) had significantly higher (P < 0.01) TM levels than patients of group A (37.4 +/- 19.6 ng/ml). This significant elevation also persisted at the end of the investigational period (day 28; group B: 56.0 +/- 37.6 ng/ml; group A: 38.2 +/- 23.7 ng/ml; P < 0.01). An elevation of endothelial cell markers is found in the course of BMT, particularly after conditioning and at the time of engraftment. This increase is pronounced in patients with aGVHD suggesting not only epithelial cell but also endothelial cell injury during aGVHD.

Flow cytometric findings in platelets of patients following allogeneic hematopoietic stem cell transplantation.

Following allogeneic hematopoietic stem cell transplantation (HSCT) patients may have an increased bleeding tendency in spite of a normal platelet count. Moreover, an association between chronic graft-versus-host disease (cGVHD) and a thrombophilic state has been observed. Platelet receptors and granules from 27 patients following HSCT (13 without cGVHD, 14 with cGVHD) were evaluated by flow cytometric analysis and compared to 62 healthy controls. Platelets from HSCT patients stained weakly with mepacrine indicating a reduced content of dense bodies, whereas no significant degranulation reaction of alpha granules and lysosomes was detectable. In addition, a lower surface expression of GP Ia/IIa was observed, indicating an acquired thrombocytopathy. The surface receptors are activated in HSCT patients, which could be seen by the lower surface expression of GP Ib internalized during the activation process and elevated levels of LIBS-1 and PAC-1 antibody binding. Patients with cGVHD had a seven-fold increased ratio of microparticles. This study demonstrates platelet receptor and granule defects in patients following HSCT. The key role of platelets in HSCT-associated hemostatic disorders is underscored by the high levels of circulating microparticles in cGvHD patients which might explain the thrombophilic state in these patients.

Laboratory markers of veno-occlusive disease in the course of bone marrow and subsequent liver transplantation.

Plasminogen activator inhibitor 1 (PAI-1) and amino-propeptide of type III procollagen (PIIINP) have been described as markers of hepatic veno-occlusive disease (VOD) after bone marrow transplantation (BMT). We determined these parameters in two patients undergoing BMT and subsequent liver transplantation due to VOD. Previously normal PAI-1 levels (maximum 30.0 ng/ml in patient 1, 23.7 ng/ml in patient 2) were elevated for the first time in both patients at the time of clinically diagnosed VOD on days 40 and 20, respectively (patient 1: 317.5 ng/ml; patient 2: 317.2 ng/ml). Levels remained elevated until liver transplantation was performed on days 79 and 41, respectively. Baseline levels (day -8) of aminopropeptide of type III collagen (patient 1: 4.44 microg/l; patient 2: 8.1 microg/l) peaked at the time of BMT in both patients (155.0 microg/l and 108.3 microg/l). After an intermittent decrease at the time of discharge on day 32, a second elevation was observed in patient 1 when she was readmitted and presented with typical signs of VOD on day 40. In patient 2, PIIINP levels remained high until VOD was diagnosed (day 20) and liver transplantation was performed. After liver transplantation, PAI-1 levels normalized in both patients and PIIINP levels declined. Both patients died due to infectious complications and multiorgan failure on days 141 and 101, respectively. Whereas the early rise of PIIINP did not correlate with the clinical onset of VOD, the results emphasise the relevance of PAI-1 for diagnosing VOD.

Treatment of aGVHD with OKT3: clinical outcome and side-effects associated with release of TNF alpha.

Monoclonal antibodies are increasingly used for treatment of acute graft-versus-host disease (aGVHD) in bone marrow transplantation. We treated seven patients with steroid resistant aGVHD with the monoclonal anti-T cell antibody OKT3. Though five patients showed improvement of aGVHD, only two became long-term survivors. OKT3 treatment was accompanied by deterioration of microangiopathy and prolonged increase of tumor-necrosis-factor alpha serum levels indicating activation of monocytes/macrophages in vivo, as this was not observed in a control group of patients receiving anti-T cell globulin. These findings may be related to immunostimulatory activity reported for OKT3 in vitro. Strategies interfering with cytokine release should improve clinical results of OKT3 treatment.

Parameters of the fibrinolytic system in patients undergoing BMT: elevation of PAI-1 in veno-occlusive disease.

Veno-occlusive disease (VOD) represents one of the more frequent and most severe complications after BMT. The pathophysiology of VOD is poorly understood. To investigate a possible link between endothelial cell damage and VOD, tissue plasminogen activator (tPA) and its inhibitor (PAI-1) were measured in 32 patients as endothelial cell-derived parameters of the fibrinolytic system. A nearly fivefold increase (mean 103.9 ng/ml, range 22.6-582.4 ng/ml, p < 0.05) in PAI-1 levels was found in the four patients who developed VOD compared with patients without this complication (mean 22.2 ng/ml, range 1.4-131.6 ng/ml). No significant difference was found in tPA levels between patient groups with or without VOD or other complications following BMT, indicating a shift of the fibrinolytic balance towards hypofibrinolysis particularly in patients with VOD. We conclude that alterations of the fibrinolytic system occur in patients undergoing BMT. Hypofibrinolysis seems to be at least one factor in the pathogenesis of VOD and the determination of PAI-1 might be helpful for diagnosing the disease. Our data also may explain the reported successful treatment of VOD by recombinant tPA.

The impact of antithymocyte globulin on short-term toxicity after allogeneic stem cell transplantation.

Antithymocyte globulin (ATG) is commonly used in allogeneic haematopoietic stem cell transplantation (HSCT). Little information is available, however, as to the optimal protocol for use and the side-effects occurring if ATG is administered in high daily doses (10-30 mg/kg). We report our experience with ATG Fresenius (ATG-F) in conditioning for allogeneic HSCT. During a period of 3 days, 47 patients received doses between 10 and 30 mg/kg either over 4 h preceded by 1-1.5 mg/kg prednisolone 30 min before the start of ATG-F (protocol A) or alternatively, over 12 h with 3-4 mg/kg prednisolone being administered before and 6 h after start of ATG (protocol B). During treatment with ATG-F, the side-effects observed included inflammation, disseminated intravascular coagulation, hyperdynamic circulation and renal dysfunction. Although these complications caused substantial morbidity, they were reversible within a few days. Side-effects were significantly more severe in patients treated according to protocol A than in those treated according to protocol B. As prolonged infusion of ATG-F does not reduce T cell clearance due to the long half-life of ATG-F, and since less cytokine release during conditioning might have beneficial long-term effects, we recommend administering ATG-F over 12 h preceded by high-dose steroid treatment.

Critical evaluation of platelet aggregation in whole human blood.

Platelet aggregation studies generally are performed in platelet-rich plasma (PRP) by the turbidometric method. The authors compared this technic with the recently introduced impedance aggregometry in PRP and whole blood (WB). In healthy controls there was a good correlation between the two technics when aggregation was induced by ADP or collagen. As compared with PRP, platelets in WB were more sensitive to the aggregating effect of thrombin, ristocetin, and arachidonic acid. Platelet sensitivity to prostacyclin was increased in WB. The anti-platelet effect of a single oral dose of aspirin could be detected for a longer period in WB than in PRP. Platelet aggregation tests in WB from patients with platelet dysfunctions showed the same response pattern to different aggregating agents as in PRP. In contrast to turbidometry, the impedance method in PRP and WB enabled registration of platelet aggregation in a dose-dependent fashion in a sample from a patient with severe hyperlipoproteinemia. It is concluded that platelet aggregation can be studied conveniently with the impedance method in the more physiologic medium of WB. Providing the same information as the well-established turbidometry, the time-sparing impedance method needs less citrated blood. Moreover, our results show an increased sensitivity of the WB system to some aggregating and anti-platelet agents.

Prognosis of high dose chemotherapy/autologous bone marrow transplantation candidates not receiving this treatment after failure of primary therapy of Hodgkin's disease.

In a multicenter study on the therapy of Hodgkin's disease, in 88 out of 297 patients with primary advanced stages IIIB/IV, a failure to the treatment with the alternating chemotherapy COPP/ABVD +/- radiation was recorded. The cause of failure was as follows: tumor progression under current therapy (PD) 23/88, partial response at the end of therapy (PR) 28/88, early nodal relapses 13/88, late nodal relapses 16/88, extranodal relapses 7/88, undetermined localization 1/88.36 months after manifestation of the failure to treatment, 45% of all patients were still alive. In cases of primary PD the prognosis was the worst of all. Only 1/23 of these patients received a long-term continuous complete remission (cCR) with the salvage therapy. 11 patients with only a nodal relapse received a cCR with irradiation alone. These cases could be regarded as low risk relapses. For the high risk relapse group (n = 57) an indication for high dose chemotherapy with subsequent autologous bone marrow transplantation (HDC/ABMT) would have been imperative, following the present-day definition. The probability of survival of these patients who, however, only received a conventional salvage therapy was up to 38% (95% confidence interval 22-54%). Comparing these data with the literature our results seem not to be substantially worse than those for patients who underwent HDC/ABMT. Only in a randomized comparison can the decision be made on whether HDC/ABMT would be superior to high dose conventional chemotherapy supported by hematopoietic growth factors. It is suggested that such a therapy study be performed as soon as possible.

The relevance of plasminogen activator inhibitor 1 (PAI-1) as a marker for the diagnosis of hepatic veno-occlusive disease in patients after bone marrow transplantation.

Hepatic veno-occlusive disease (VOD) is the third most important fatal complication in allogeneic bone marrow transplantation (BMT), the second most significant one in the autologous setting and the most severe of all the regimen related toxicities. A growing number of VOD cases has to be expected due to the increasing number of high dose chemotherapies given with consecutive stem cell transplantation in patients with solid tumors. Confirmation of the diagnosis of VOD by biopsy is associated with a high risk of severe bleeding complications and, unfortunately, until now reliable laboratory markers have not as yet been established. Recently, plasminogen activator inhibitor 1 (PAI-1), the main inhibitor of the fibrinolytic system, has been found to be significantly elevated in VOD patients probably reflecting hypofibrinolysis in these patients. Furthermore, PAI-1 was able to distinguish between patients with VOD and those with hyperbilirubinemia after BMT caused by graft-versus-host-disease (GVHD) or toxic effects, in which cases the PAI-1 levels were mostly within the normal range. In this overview we summarize the data strongly indicating that PAI-1 is a useful marker for the diagnosis of VOD and helps in the differential diagnosis of hyperbilirubinemia after BMT.

Risk factor adapted treatment of Hodgkin's lymphoma: strategies and perspectives.

In a national multicenter trial in the Federal Republic of Germany, patients with Hodgkin's lymphoma in stages I, II and IIIA presenting with large mediastinal tumor (MT), extranodal (E), or massive spleen (S) involvement received a combined modality treatment with 2x (COPP + ABVD) followed by 20 or 40 Gy EF radiation (HD1 protocol). By October 1987, 89 patients aged 15-60 years had finished therapy and were evaluable for response. Of these 74 (83%) achieved complete remission (CR). After 3 years freedom from treatment failure (FFTF) is 80% (+/- 8%, 95% confidence interval) and survival (SV) 92% (+/- 6%, 95% confidence interval). In a univariate and multivariate analysis using FFTF as endpoint we could not identify any particularly prominent prognostic risk factor among the following examined: stage, constitutional symptoms, MT, E stage, S involvement, age, sex, histology, laparotomy, erythrocyte sedimentation rate (ESR), leukocytes, lymphocytes, and alkaline phosphatase (AP). These data suggest that the inclusion criteria have selected a fairly homogeneous group of patients with respect to prognosis. In a separate trial (HD3 protocol) patients in stages IIIB/IV received induction chemotherapy with 3x (COPP + ABVD). Patients in complete remission (CR) received consolidation therapy by either radiotherapy (20 Gy IF) or further chemotherapy (COPP + ABVD). Patients not in CR received salvage therapy (40Gy in the case of persisting nodal disease, or else 4x CEVD chemotherapy). By October 1987, 137 patients had finished therapy and were evaluable for response. Of these 86 (63%) achieved CR after induction chemotherapy. Including salvage therapy a total of 104 patients (76%) achieved CR. After 3 years FFTF is 56% (+/- 10%, 95% confidence interval) and SV 84% (+/- 8%, 95% confidence interval). Univariate and multivariate prognostic risk factor analyses were performed using FFTF as endpoint. Sex, age, stage, splenectomy, bone marrow, and liver and bone involvement had no prognostic impact. In contrast, a pretreatment erythrocyte sedimentation rate (ESR) above 80 mm/h and a serum alkaline phosphatase (AP) above 230 IU/ml each appeared as significant prognostic factors (P less than 0.01; relative risk, 2.3). The two parameters can be combined to separate two groups (A: ESR and AP both low; B: ESR and/or AP high) which differ significantly for FFTF (P less than 0.001) and survival (P less than 0.04). The decision for risk-adapted treatment requires identification of groups of patients in the frame of specified diagnostic and therapeutic strategies.(ABSTRACT TRUNCATED AT 400 WORDS)