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R Munker

Publications and source records attributed to R Munker.

At least 37 records · Page 2Linked to original sources
PubMed1998

Vitamin D analogs, leukemia and WAF1.

Vitamin D compounds induce differentiation of human leukemic cells and have potential for the treatment of leukemia. In this review we summarize some of the basic mechanisms underlying the action of vitamin D compounds. A variety of vitamin D analogues were synthesized until now, some of which have enhanced antileukemic activity and a decreased propensity to cause hypercalcemia. Most actions of vitamin D compounds are mediated by nuclear receptors. In vivo, vitamin D binding protein interacts with free vitamin D compounds. Both in normal and leukemic cells, vitamin D compounds cause a differentiation to monocytes and macrophages. A variety of genes are regulated by vitamin D compounds. Recently, the cell cycle inhibitory gene p21/WAF-1/CIP-1 was characterized. The expression de novo of WAF-1 in blasts of acute myelogenous leukemia is an independent factor of unfavorable prognosis. In HL-60 leukemic cells treated with vitamin D analogs, WAF-1 can be induced by nano- or picomolar concentrations of vitamin D analogs and correlates with the induction of a differentiated phenotype. When vitamin D analogs are combined in-vitro with retinoids, an irreversible differentiation is observed. Clinical trials of vitamin D analogs are indicated in the situation of minimal residual disease and in combination with standard chemotherapy.

Cell Differentiation↗
PubMed1998

Renal complications in acute leukemias.

BACKGROUND AND OBJECTIVE: Renal failure is a known complication of acute leukemias both at diagnosis and following cytostatic treatment. No recent studies give data on the incidence and risk factors of renal complications and their prognostic impact. DESIGN AND METHODS: Two hundred and twenty consecutive adult patients with newly diagnosed acute leukemia treated at a major university medical center were evaluated for renal complications before, during, and after treatment; 166 patients were treated by chemotherapy only and 54 patients were treated with chemotherapy and later transplanted with allogeneic or autologous bone marrow. Renal complications were subdivided into 3 entities: acute renal failure, major and minor complications, based on clinical and laboratory parameters. Renal failure occurring as a consequence of terminal multi-organ failure was excluded from the present study. RESULTS: Approximately 30% of patients in the chemotherapy group had a renal complication either before or after chemotherapy. Patients undergoing transplantation had a 50% risk of renal complications. Risk factors for complications were male sex, age, previous kidney disease, white cell count, and refractory leukemia (chemotherapy group) and allogeneic versus autologous transplant (transplant group). In the chemotherapy group, early but not delayed renal complications had a poor prognostic impact. In the transplant group renal complications had no impact on prognosis. In all patient groups, acute renal failure was prognostically unfavorable. INTERPRETATION AND CONCLUSIONS: We conclude from our study that renal complications are frequent in acute leukemias and that the treatment and prevention of renal complications is important for the management of acute leukemias.

Acute Disease↗
PubMed1998

Humanized M195 monoclonal antibody conjugated to recombinant gelonin: an anti-CD33 immunotoxin with antileukemic activity.

The recently characterized immunotoxin HuM195-gelonin consists of a humanized anti-CD33 monoclonal antibody conjugated to the single-chain plant toxin gelonin. Binding of the immunotoxin to hematopoietic cells that express the CD33 differentiation antigen has been demonstrated and results in cytotoxicity due to ribosomal inactivation by gelonin. Blast cells from most patients with acute myelogenous leukemia express CD33, whereas normal stem cells necessary for maintenance of hematopoiesis do not. We asked whether an immunoconjugate using recombinant gelonin rather than plant gelonin is toxic to acute myelogenous leukemia (AML) cell lines and primary AML blasts obtained from patients and exposed to the immunotoxin in vitro. The CD33pos cell lines HL60, OCI/AML2, and OCI/ AML5 showed decreased proliferation when exposed to immunotoxin for 24-72 h. The CD33neg cell line OCI/AML3 was relatively resistant to HuM195, and all cell lines were resistant to equimolar concentrations of unconjugated antibody and gelonin. Primary blast cultures from seven patients with AML had CD33 detectable on 75.7-99.8% of cells by flow cytometry, and all showed dose-dependent decreases in clonogenic cell survival during 24-h incubation with the immunotoxin. Cells selected for low CD33 expression by cell sorting or by prolonged incubation with immunotoxin could reexpress CD33 at baseline levels and remained sensitive to immunotoxin. We conclude that humanized M195 conjugated to recombinant gelonin has antileukemic activity and should be considered for clinical testing in Phase I trials.

Antibodies, Monoclonal↗
PubMed1997

HHV-8 (KSHV) does not establish latency in prostate cancer cell lines.

BACKGROUND: HHV-8 is a new herpesvirus found in lesions of Kaposi's sarcoma and some lymphoproliferative diseases. More recently, a report stated that normal prostate tissue also contains the virus. METHODS: The expression of HHV-8 was examined by a sensitive reverse-transcriptase PCR for the viral genes ORF 72, ORF 73, ORF 74, and ORF 75. In coculture experiments we attempted to infect 3 commonly studied prostate cancer cell lines using induced and uninduced lymphoid cell lines harboring HHV-8 (KS-1, BC-1, and BC-2). For induction of viral genes, butyrate and phorbol esters were used. RESULTS AND CONCLUSIONS: At baseline, prostate cancer cell lines LNCaP, DU-145, and PC-3 did not express viral gene products. Extensive coculture experiments were also negative. In no instance could latency for the virus be established. Our results argue against the involvement of HHV-8 in prostate cancer and for a limited tissue tropism of HHV-8.

B-Lymphocytes↗
PubMed1997

Expression of CD95(FAS) by gene transfer does not sensitize K562 to Fas-killing.

CD95(FAS/Apo-1) belongs to the family of TNF receptor related molecules and is expressed on many benign and malignant types of cells. CD95 triggering is involved in the apoptotic death of lymphoid cells and may also be important in myelopoiesis. Myeloid leukemia cells are in most cases resistant to CD95 triggering despite expressing the antigen. We reasoned that myeloid leukemic cells can become sensitized to the Fas pathway of cell death if CD95 expression is restored by gene transfer. As a model, we utilized the cell line K562 which does not express CD95 on their cell surface. The gene for CD95 was introduced into K562 cells (by electroporation). As a control, the gene coding for beta-galactosidase was used. The CD95 transfected K562 cells stably expressed CD95, and had a growth pattern comparable to untransfected cells, but still remained resistant to Fas-triggering (tested using recombinant Fas-ligand). Our experiment shows that antigen expression is not a critical determinant of Fas-mediated apoptosis, but further down-stream mechanisms determine the fate of the cells. The transfected cells also had a comparable susceptibility to NK-mediated lysis which shows that the expression of CD95 does not interfere with NK-mediated lysis of target cells.

Annexin A5↗
PubMed1997

Soluble CD95 in the serum of patients with low and intermediate grade malignant lymphomas: absence of prognostic correlations.

Several cytokines and the receptors for some cytokines are involved in the pathogenesis and progression of malignant lymphomas. CD95 (Fas/Apo-1) belongs to the TNF-receptor superfamily and may mediate apoptosis if triggered by Fas-ligand or specific antibodies. Recently soluble CD95 (a splice variant of the surface-bound molecule) was detected in the serum of patients with lymphoid leukemias and other disorders. In this study, we examined the levels of soluble CD95 (SCD95) in a series of patients with untreated malignant lymphomas and attempted to correlate this molecule with clinical, histological and laboratory parameters. The level of SCD95 was determined in the serum of 66 untreated patients with low and intermediate grade malignant lymphomas (NHLs) and in 20 normal controls using a solid phase ELISA. The total group of patients with NHLs had a trend towards increased values of SCD95 compared with normal controls (48.8+/-50.0 versus 75.0+/-136.3 U/ml, p < 0.1). However, among patients with NHL, elevated SCD95 did not correlate with the presence of B-symptoms, clinical stage, histologic subtype, LDH, beta-2 microglobulin, response to therapy or duration of response. We conclude that within the confines of this study, SCD95 has no prognostic value in patients with NHL.

Adolescent↗
PubMed1996

Flt3 ligand stimulates proliferation and inhibits apoptosis of acute myeloid leukemia cells: regulation of Bcl-2 and Bax.

Flt3/flk-2 ligand (flt3-L) is a potent costimulator of normal bone marrow (BM) myeloid progenitors. Flt3-L is produced by BM stromal cells and its receptor is expressed in the majority of acute myeloid leukemia (AML) cases. Therefore, flt3-L may play a role in the paracrine and/or autocrine loops sustaining leukemic cell growth. We evaluated the effects of recombinant human flt3-L on proliferation, apoptosis, and Bcl-2 and Bax expression in primary AML cells and compared them with those of stem cell factor (SCF). Mononuclear BM cells from patients with newly diagnosed AML were cultured in serum-free conditions with flt3-L, SCF, granulocyte colony-stimulating factor (G-CSF) and granulocyte macrophage-colony-stimulating factor (GM-CSF) alone and in combination. In 9 of 10 samples, flt3-L significantly increased [3H]thymidine uptake (geometric mean stimulation index, 7.5; range, 2.4 to 41.5). Flt3-L also increased the number of AML blast colonies by 126% (range, 61% to 181%). In these 9 samples, flt3-L significantly enhanced the proliferative response triggered by G-CSF or GM-CSF. Flt3-L prevented apoptosis in AML blasts. It reduced the number of apoptotic cells by 36% +/- 3.9% compared with control cultures. Combining flt3-L with G-CSF or GM-CSF doubled the antiapoptotic effect. Cellular Bcl-2 and Bax levels were determined separately for apoptotic and nonapoptotic cells by flow cytometry. Cells undergoing spontaneous apoptosis had low Bcl-2 and high Bax levels, whereas nonapoptotic cells had high Bcl-2 and low Bax levels. Flt3-L alone or in combination with G-CSF or GM-CSF did not upregulate Bcl-2. However, Bax expression decreased in viable cells in the presence of these cytokines and the lowest level was achieved when a combination of flt3 and GM-CSF was used. Proliferative and viability effects of flt3-L were similar to those of SCF. Our results demonstrate that flt3-L acts as a stimulatory factor for primary AML cells. The antiapoptotic effects of flt3-L or its combinations with G-CSF or GM-CSF correlate with their ability to prevent upregulation of Bax.

Acute Disease↗
PubMed1996

A new series of vitamin D analogs is highly active for clonal inhibition, differentiation, and induction of WAF1 in myeloid leukemia.

The active form of vitamin D3 [1 alpha, 25-dihydroxyvitamin-D3 (1 alpha, 25(OH)2D3)] modulates the proliferation and differentiation of hematopoietic cells. Analogs of 1 alpha, 25(OH)2D3 that have greater potency may have the potential as adjuvant therapy for high-risk patients in remission for acute myelogenous leukemia (AML) and myelodysplastic syndromes. A new generation of 11 analogs of 1 alpha, 25(OH)2D3 has been synthesized, and we examined their effects on the human leukemic cell line HL-60. This cell line provides a sensitive monitor of activity of the 1 alpha, 25(OH)2D3 analogs. All the compounds were potent, producing a 50% clonal inhibition (ED50) in the range of 10(-8) to 10(-11) mol/L; nine of the 11 analogs had ED50s at concentrations that were at least 10-fold lower than those for the parental 1,25(OH)2D3. The most active compound [cmpd LA, (22R)-1 alpha, 25-(OH)2-16,22,23-triene-D3] had an ED50 of 2 x 10(-11) mol/L; it was also tested on clonogenic cells from patients with AML, and it achieved an ED50 of approximately 6 x 10(-11) mol/L, while 1 alpha, 25(OH)2D3 produced an ED50 of approximately 10(-8) mol/L on the same population of cells. Five different cell surface markers were examined on HL-60 cells exposed to the 1 alpha, 25(OH)2D3 analogs: HLA-DR and CD11b were induced by all of the compounds; CD13 was induced by six of the 12 compounds, including 1,25(OH)2D3; CD14 was strongly induced by all compounds; and CD38 was induced rather weakly by nine of 12 analogs. WAF1/CIP1/p21, a cyclin-dependent kinase inhibitor (CDKI), which is important in blocking the cell cycle, was examined by Western blot and was found to be induced by all of the compounds, suggesting a possible mechanism by which these analogs inhibit leukemic growth. The induction of WAF1 occurred at concentrations of vitamin D analogs as low as 10(-10) mol/L. This structure-function study showed that a new series of 1 alpha, 25(OH)2D3 analogs was active in clonal inhibition, as well as induction of differentiation and WAF1 expression of HL-60 cells. The key structural motifs included C-16 double bond, double and/or triple bonds in the side chain, lengthening of the side chain, 20-epi-conformation of the side chain, replacement of six hydrogens at the end of the side chain with fluorines, and the removal of C-19. Consideration should be given to further in vivo testing of toxicity and efficacy to move toward a clinical trial, especially in a setting of minimal residual disease.

Animals↗
PubMed1996

Autoantibodies against p53 are not increased in human ascites and pleural effusions.

Mutated human p53 may give rise to the formation of autoantibodies and may be a marker for a worse prognosis. We speculated that ascites or pleural effusions may enhance the formation of such autoantibodies in cancer patients and, therefore, we measured the presence of autoantibodies in the ascites or pleural effusion of 40 patients with advanced malignancies. As controls, p53 autoantibodies were measured in 15 patients with effusions who did not have a malignancy. Using a specific enzyme-linked immunosorbent assay, p53 autoantibodies could only be detected in the effusions of 5/40 patients (12.5%) with known malignancies. The formation of autoantibodies did not correlate with the presence or absence of tumor cells in the effusion. The effusions of the patients without tumor were all negative for p53 autoantibodies. Our study shows that malignant or reactive effusions do not stimulate the local or systemic production of autoantibodies against p53.

Antibody Specificity↗
PubMed1996

Contrast enhancement and quantitative signal analysis in MR imaging of multiple myeloma: assessment of focal and diffuse growth patterns in marrow correlated with biopsies and survival rates.

OBJECTIVE: This study describes infiltration patterns of multiple myeloma in spinal MR imaging and correlates the findings with biopsies, survival rates, and signal intensity measurements in unenhanced and enhanced studies. MATERIALS AND METHODS: Fifty-three patients with multiple myeloma and 53 age-matched controls underwent MR imaging of the spine. Twenty-nine patients underwent sagittal T1-weighted spin-echo enhanced imaging and all patients underwent sagittal T1-weighted spin-echo unenhanced and opposed-phase gradient-recalled echo images, and signal intensity measurements were taken. MR imaging was correlated to marrow specimens (n = 40) and a clinical staging system. The probability of survival was also calculated. Finally, we performed qualitative visual evaluation (infiltration pattern, degree of tumor involvement) and a quantitative evaluation (marrow signal intensity ratios, contrast enhancement). RESULTS: Five infiltration patterns were found: normal-appearing marrow with low-grade interstitial infiltration (n = 5), focal (n = 18), diffuse (n = 12), focal and diffuse (n = 13), and salt-and-pepper (n = 5). Infiltration pattern correlated with clinical staging; all patients with normal-appearing and salt-and-pepper patterns were clinically stage I. Diffuse marrow infiltration was assessed by marrow ratios: low-grade infiltration, greater than 2.0; intermediate, 1.0-2.0; highgrade, less than 1.0. Contrast enhancement with a signal intensity increase greater than 40% indicated diffuse infiltration. In the control group, all of whom had no marrow disease, enhancement varied (mean +/- SD, 16% +/- 8.9%) but did not exceed 40%. Marrow involvement on MR images correlated significantly with clinical staging and survival (p < or = .001). CONCLUSION: MR imaging with opposed gradient-recalled echo sequences and contrast enhancement provided data that allowed us to classify infiltration patterns and to quantify diffuse marrow involvement in multiple myeloma, both of which correlated to clinical staging and biopsy. Also, the MR data was of prognostic value. Therefore, like laboratory parameters, biopsies, and radiographs, MR imaging can be a supporting pillar in staging and planning treatment of patients with multiple myeloma.

Adult↗
PubMed1996

Soluble FAS (CD95) is not elevated in the serum of patients with myeloid leukemias, myeloproliferative and myelodysplastic syndromes.

Soluble receptors have been identified for most members of the TNF-receptor/NGF receptor superfamily. CD95 (Fas/Apo-1) is of particular importance, since its triggering may induce apoptosis in sensitive cells. Recently, a soluble form of the CD95 molecule was described which interacts with the CD95-CD95 ligand death pathway. Increased concentrations of soluble CD95 (sCD95) were previously detected in some patients with T and B cell leukemias and lymphomas. In the present study we investigated sCD95 in the serum of patients with myeloid leukemias, myeloproliferative and myelodysplastic syndromes. A total of 72 patients was studied (29 AML, 17 MDS, 20 CML and six other myeloproliferative disorders). In AML with active disease, the levels of sCD95 tended to be elevated, but did not correlate with defined clinical or laboratory parameters. In the other disorders, the levels of sCD95 were not generally increased, although some patients had elevated levels. These data strongly suggest that sCD95 in AML patients is not derived from leukemic cells, but is possibly secreted or shed from reactive or stromal cells. This hypothesis is also supported by a group of eight patients with septicemia but not leukemia who had elevated sCD95 (P < 0.05). Furthermore, all three patients with elevated sCD95 who had undergone chemotherapy for AML had major infections. Taken together, this study shows that measuring soluble Fas-receptor in myeloid leukemia is not diagnostically useful, but increased sCD95 may be associated with clinical complications like septicemias.

Hepatitis B↗
PubMed1996

Induction of death (CD95/FAS), activation and adhesion (CD54) molecules on blast cells of acute myelogenous leukemias by TNF-alpha and IFN-gamma.

Leukemic growth is determined by the balance of cell proliferation, differentiation and cell death. In vitro, the blasts of acute myelogenous leukemia (AML) proliferate under the influence of certain positive and negative regulators (cytokines). We conducted this study to determine whether cytokines could induce markers of cell death (FAS/Apo-1/CD95), of cell activation (HLA-DR) and cell adhesion (ICAM-1, CD54) in AML cell lines and primary AML samples. As inducers, tumor necrosis factor (TNF)-alpha and interferon (IFN)-gamma were chosen. At baseline, CD95 and CD54 were weakly and HLA-DR was strongly expressed. CD95 was induced by TNF in 6/12 myeloid leukemia cell lines, and by IFN in 9/12 cell lines. Taken together, CD95 was upregulated by at least one cytokine in 11/12 cell lines. HLA-DR was inducible in 10/12 cell lines, with IFN being more potent than TNF. CD54 showed the strongest induction: TNF resulted in a more than 20-fold induction in positive cell lines, and IFN resulted in a more than 20-fold induction. In primary AML samples, CD95 was induced in 14/14 samples examined, with TNF being more potent than IFN. HLA-DR expression was increased by IFN in 12/15 samples and by TNF in 11/13 samples. The inducibility of HLA-DR by IFN was inversely correlated with baseline expression. As in the cell lines, CD54 was induced in most cases of AML. In addition to the induction of surface markers by cytokines, the culture of leukemia cells with fetal calf serum increased the expression of these markers, especially CD95 and CD54. Our results demonstrate that CD95 is not downregulated when TNF binds to its receptors, but is induced in cell lines and patient samples. Despite the induction of expression of CD95 (all cases of AML and most cell lines), 7/8 myelogenous leukemia lines and 6/7 patient samples remained resistant to CD95 triggering by antibody or by CD95 ligand, which suggests a lesion in normal cell signaling. As a positive control, a T-cell line (Jurkat) with 60% to > 90% apoptotic cells after a 22 h incubation was used. The number of CD95-binding sites was not correlated with the induction of apoptosis. The resistance of most cases of AML to CD95 triggering despite inducible expression may also be related to leukemia-specific antagonists of CD95 signal transduction, and requires further investigation. Altogether, our results indicate that surface markers related to apoptosis, activation and adhesion can be induced on AML blasts, and could be relevant to treatment strategies that exploit ligand binding to these surface epitopes.

Adult↗
PubMed1995

Diagnostic accuracy of ultrasound and computed tomography in the staging of Hodgkin's disease. Verification by laparotomy in 100 cases.

BACKGROUND: A staging laparotomy still is considered the gold standard to detect occult abdominal involvement in Hodgkin's disease. Computed tomography and ultrasound are routinely available for diagnostic imaging. To the authors' knowledge, the exact contribution of ultrasound for the staging of Hodgkin's disease has not been reported in a large series of patients before this study. METHODS: The diagnostic accuracy of abdominal ultrasound was compared with that of computed tomography and laparotomy in 100 patients with biopsy-proven Hodgkin's disease. Liver, spleen, paraaortic, and iliac lymph nodes were evaluated separately. RESULTS: Seventeen patients had a higher disease stage after surgery (17%). Considering only patients without known abdominal disease (supradiaphragmatic involvement), 14/79 (18%) had a positive staging laparotomy. Ultrasound had superior sensitivity for detecting splenic involvement with Hodgkin's disease (sensitivity, 63% compared with 37% for computed tomography). The specificity of both methods for detecting splenic disease was identical (99% vs. 96%). Inhomogeneities of structure or small nodular infiltrates were detected preferentially by ultrasound. Hepatic involvement also was visualized better by ultrasound than by computed tomography. Lymph nodes at the splenic hilus were recognized by both methods with identical sensitivity (64% vs. 62%). Paraaortic and iliac lymph nodes were recognized with greater sensitivity by computed tomography than by ultrasound (sensitivity, 93% and 100% vs. 77% and 67%, respectively). CONCLUSIONS: These results indicate that ultrasound and computed tomography each have their weaknesses and strengths and therefore should be combined, if possible. Ultrasound is the fastest and least invasive method and has particular accuracy for detecting splenic involvement, whereas computed tomography is more accurate in detecting involvement of paraaortic or iliac lymph node. If cost is important in the staging of Hodgkin's disease and if computed tomography is considered the standard, patients whose results are negative by computed tomography should be examined by ultrasound, focusing on splenic texture and size. Even in the era of combined modality treatment, surgical staging may be necessary to detect occult abdominal disease in a certain number of cases.

Abdominal Neoplasms↗
PubMed1995

[Second malignancy in patients with Hodgkin disease in full remission. Interim results].

Among 345 patients with Hodgkin's disease (HD) in full remission and followed for a mean of 7.2 years (11 months-26 years) since the initial diagnosis, 33 were found to have a second malignancy. The cumulative incidence after 10 years was 13.5%, after 15 years 21%. Non-Hodgkin lymphoma was the most frequent (n = 7), followed by bronchial carcinoma (n = 5) and acute myeloid leukaemia (n = 3). There was a definitely increased risk in elder patients (P < 0.001) and in those who had had a splenectomy. There was no demonstrable effect of type of therapy, primary stage and frequency of recurrence. It is concluded that patients with Hodgkin's disease should have life-long oncological follow-up. This preliminary study is being extended into a multicentre investigation of a larger number of patients.

Adult↗
PubMed1995

Expression of the Fas antigen on primary human leukemia cells.

The antigen defined by the monoclonal antibody anti-Fas can mediate apoptosis, is associated with the receptor for tumor necrosis factor, and is expressed on a limited number of human tissues. In this study we analyzed the expression of Fas on primary human leukemic cells and on mononuclear cells from other hematologic disorders. A total of 95 samples of blood or bone marrow were studied by indirect immunofluorescence. These samples included the normal controls, 47 cases of acute myelogenous leukemia (AML), 11 cases of acute lymphoblastic leukemia (ALL), 21 cases of leukemic lymphoma, seven cases of chronic myelogenous leukemia (CML), five cases of plasma cell leukemia or multiple myeloma, and five cases of myelodysplastic or myeloproliferative syndromes. Normal controls were negative without exception. Among AML, 13/47 cases (28%) were positive; among ALL, 1/11 cases (9%) was positive; among leukemic lymphomas, 3/21 cases (14%) were positive. In a case of plasma cell leukemia which strongly expressed the Fas antigen, we demonstrated that the antibody mediates cell lysis, which was synergistically enhanced by the addition of rabbit complement. In patients with AML, Fas positivity had no obvious clinical relevance. Taken together, our results show that approximately 30% of cases of AML and occasionally other leukemias express the Fas antigens, whereas normal controls are negative in our test system. These findings may be useful in the treatment of refractory leukemias or may permit the purging of autologous transplants.

Antigens, Surface↗
PubMed1995

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.

Adult↗