ABSTRACT
A total of 153 diagnostic bone marrow biopsies from patients with advanced stages of multiple myeloma corresponding to stages II and III according to the Durie/Salmon classification were evaluated prior to any treatment in a prospective therapy trial of the German Myeloma Treatment Group. Histologic sections were analyzed according to a pre-defined system of criteria microscopically by 2 observers, determining three criteria: 1) grading by histopathology, regarding the cytologic differentiation of neoplastic cells and quantifying the percentage of plasmacytic, pleomorphic, and plasmablastic myeloma cells distributed within the sections; 2) the volume of infiltration; and 3) the pattern of neoplastic growth. Furthermore, four other criteria, namely hematopoiesis, fiber increase, osteomalacia, and micro-osteo-lesions, were evaluated. A cluster analysis using the three histological criteria revealed three groups of patients with significantly different survival times based on histological criteria only; the three criteria were mentioned above. It is concluded from these results that bone marrow biopsies, when evaluated histologically by grading and staging according to the three criteria, provide most valuable prognostic parameters in myeloma patients.
Subject(s)
Bone Marrow/pathology , Multiple Myeloma/pathology , Bone Marrow Examination/classification , Cluster Analysis , Humans , Multiple Myeloma/mortality , Neoplasm Staging , Prognosis , Survival RateABSTRACT
406 untreated multiple myeloma patients of stage I (n = 54), II (n = 148) and III (n = 204) were enrolled in the trial. 51/54 stage I and 60/148 stage II patients were asymptomatic and followed without treatment until disease progression (progression free survival: 60% after 4 years for stage I versus 50% after 1 year for stage II). Symptomatic patients of stage I (n = 3/54) and II (n = 88/148) presenting with tumour progression, received melphalan 15 mg/m2 intravenously (i.v.) and prednisone 60 mg/m2 oral days 1-4 (MP). Stage II disease remission rate was 59%, and 50% tumour related survival (TRS) was 59 months. Stage III patients were randomised to receive MP or VBAMDex (vincristine/BCNU/doxorubicin/melphalan/dexamethasone) treatment. 43% of MP treated patients responded compared with 64% of the VBAMDex group. 50% TRS was 36 months in both groups without a detectable difference. 117 responders of stage II and III with stable disease were randomised to receive either IFN-alpha (5 x 10(6) IU, subcutaneous (S.C.) 3 times per week) or no maintenance treatment. The relapse rate in both groups was 50% after 13 months. No survival benefit for IFN alpha treated patients was observed (50% TRS: 45 months).
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Multiple Myeloma/therapy , Aged , Carmustine/administration & dosage , Dexamethasone/administration & dosage , Doxorubicin/administration & dosage , Female , Humans , Interferon-alpha/therapeutic use , Male , Melphalan/administration & dosage , Middle Aged , Multiple Myeloma/mortality , Prednisone/administration & dosage , Prospective Studies , Remission Induction , Survival Rate , Vincristine/administration & dosageABSTRACT
The role of platelet-associated immunoglobulins (PAIg) of four different immunoglobulin classes--IgM, IgG, IgA, and IgE--and their relation to platelet count and platelet kinetics was studied in 33 patients with idiopathic thrombocytopenic purpura (ITP). During the course of 1 year, repeated determinations of PAIg were made. The results indicate that PAIgG, PAIgM, and PAIgA are present in all ITP patients, and that autoantibodies of all three Ig classes show highly significant correlations to the platelet counts (p < 0.0001). Double logarithmic negative correlations have been found between PAIgG and platelet count (r = -0.71), PAIgM and platelet count (r = -0.84), and PAIgA and platelet count (r = -0.79). Statistical analyses using partial correlation and multiple regression methods showed that PAIgM is predominantly related to the platelet count, whereas PAIgG and PAIgA are only of secondary importance. Accordingly, a relation of PAIgM (and PAIgA) to increased liver destruction of platelets was found in kinetic studies using 111indium-labeled platelets. Taken together, these results suggest a predominant role of PAIgM in the pathogenesis of ITP.
Subject(s)
Blood Platelets/immunology , Immunoglobulin A/blood , Immunoglobulin E/blood , Immunoglobulin G/blood , Immunoglobulin M/blood , Purpura, Thrombocytopenic, Idiopathic/immunology , Autoantibodies/blood , Female , Humans , Kinetics , Male , Platelet Count , Regression AnalysisABSTRACT
In order to investigate, if complement levels can be used as an indicator of clinical activity in systemic lupus erythematosus (SLE), levels of C3, C4, CH50, and C3d were measured in 79 patients, 41 with inactive, 31 with moderately active and 7 with severely active disease. Our study shows that C3d, and particularly the C3d/C3 ratio, provide sensitive markers for disease activity in SLE. Since C3d is a direct measurement of complement turnover, it reflects complement activation better than C3, C4 and CH50.
Subject(s)
Complement C3d/analysis , Lupus Erythematosus, Systemic/immunology , Severity of Illness Index , Adolescent , Adult , Aged , Antibodies, Antinuclear/analysis , Child , Complement C3/analysis , Complement C4/analysis , Complement Hemolytic Activity Assay , Female , Humans , Lupus Erythematosus, Systemic/physiopathology , Male , Middle AgedABSTRACT
Follow-up data of 320 multiple myeloma (MM) patients entering the German Myeloma Treatment Group (GMTG) trial MM01 were analysed for factors predicting overall (OAS) and tumour related survival (TRS). Response to primary induction chemotherapy was relevant for prognosis if a limit of 25% tumour cell mass (TCM) reduction was used to separate responders from non-responders. Furthermore, TCM, histological grading of myeloma cells, degree of bone marrow infiltration, haemoglobin, platelet counts, calcium, creatinine, albumin, beta 2M, and Bence Jones proteinuria correlated to both OAS and TRS. Age was relevant for OAS only. The multivariate analysis revealed histological grading, TCM and platelets as the most reliable prognostic factors. Based on these data the Durie/Salmon classification could be improved by defining poor prognosis patients (50% TRS: 16 months) characterised by pretreatment platelets of < or = 150,000 and/or poorly differentiated myeloma cell morphology. Patients lacking both risk factors displayed 50% survival times of 46 months in stage III and 88 months in stage II.
Subject(s)
Multiple Myeloma/mortality , Bone Marrow/pathology , Calcium/blood , Hemoglobins/analysis , Humans , Multiple Myeloma/blood , Multiple Myeloma/drug therapy , Multiple Myeloma/pathology , Multivariate Analysis , Platelet Count , Predictive Value of Tests , Prognosis , Risk Factors , Time FactorsABSTRACT
In a multicenter study more than 300 central European systemic lupus erythematosus (SLE) patients were examined for HLA-B, HLA-DR, and complement C4 phenotypes. For 174 SLE patients MHC haplotypes were determined by family segregation analysis, and for 155 patients C4 gene deletions were determined by TaqI restriction fragment length polymorphism. Two haplotypes, B8-C4AQ0-C4B1-DR3 and B7-C4A3-C4B1-DR2, were identified as risk factors for SLE. These findings were confirmed by applying the haplotype frequency difference (HFD) method, which uses nontransmitted haplotypes from the family study as internal controls. Furthermore, only HLA-DR2, but not DR3, B7, or B8, was significantly increased in SLE patients independently of the two risk haplotypes. C4A gene deletions, but not silent C4AQ0 alleles, were increased in SLE patients and neither C4BQ0 alleles nor C4B gene deletions were increased. The observed frequencies of homozygosity and heterozygosity for the two haplotypes and the frequencies of homozygotes for C4AQ0 and C4A deletions did not differ from the expected values, indicating that the risk for SLE is conveyed by single allele effects. In conclusion, there are two MHC-linked susceptibility factors for Caucasian SLE patients carried by the haplotypes B7-DR2 and B8-DR3. The results argue against C4Q0 alleles being the decisive factors increasing susceptibility to SLE.
Subject(s)
Alleles , Complement C4/genetics , Haplotypes , Lupus Erythematosus, Systemic/genetics , Major Histocompatibility Complex , HLA-B Antigens/genetics , HLA-DR Antigens/genetics , HumansABSTRACT
Anticardiolipin antibodies (aCL) and HLA-DR antigens were determined in 314 central European patients with systemic lupus erythematosus (SLE). Both HLA-DR4 and DR7 were increased in aCL-positive patients, and aCL were significantly associated with DRw53. The association between DRw53 and aCL was also apparent in those 17 patients with SLE and the anticardiolipin syndrome. There was no association between aCL and HLA-DQ or C4 alleles in SLE.
Subject(s)
Antibodies, Anticardiolipin/blood , Antiphospholipid Syndrome/immunology , Autoimmune Diseases/immunology , HLA Antigens/analysis , Lupus Erythematosus, Systemic/immunology , Major Histocompatibility Complex , Antiphospholipid Syndrome/complications , Antiphospholipid Syndrome/genetics , Autoimmune Diseases/genetics , Disease Susceptibility/immunology , Europe , Genetic Predisposition to Disease , HLA Antigens/genetics , Humans , Immunoglobulin G/immunology , Immunoglobulin M/immunology , Lupus Erythematosus, Systemic/complications , Lupus Erythematosus, Systemic/genetics , White People/geneticsABSTRACT
Antibodies against recombinant 52 kD-Ro, recombinant 60 kD-Ro and recombinant La protein were determined by ELISA in over 300 central European patients with systemic lupus erythematosus (SLE). A strong association with HLA-DR3 was found for antibodies against 52 kD-Ro and La, but not for recombinant 60 kD-Ro antibodies in the absence of antibodies against 52 kD-Ro or La. Ro/La negative SLE patients still showed an increased frequency of HLA-DR3 as compared to healthy controls. These results indicated that the preferential formation of Ro and La antibodies was not due to an unspecific stimulatory effect of HLA-DR3 but that the antibody response to certain defined proteins (52 kD-Ro and La) was influenced by MHC genes in SLE. Furthermore, the association of SLE with HLA-DR3 was independent of the effects of DR3 on the formation of 52 kD-Ro and La antibodies.
Subject(s)
Autoantibodies/immunology , Autoantigens/immunology , HLA Antigens/immunology , Lupus Erythematosus, Systemic/immunology , RNA, Small Cytoplasmic , Ribonucleoproteins/immunology , Antibody Specificity , Counterimmunoelectrophoresis , Enzyme-Linked Immunosorbent Assay , Humans , Odds Ratio , Recombinant Proteins , SS-B AntigenABSTRACT
Antibodies against Ro and La, including recombinant La and recombinant 60 kD-Ro, were determined by counter immunoelectrophoresis and ELISA in over 300 central European systemic lupus erythematosus (SLE) patients. The presence of both Ro and La antibodies was strongly associated with the MHC haplotype B8-C4AQ0-DR3-DQ2, the association being strongest for DR3. After exclusion of all B8-DR3 positive patients only DR3 positive patients still showed an increased incidence of Ro and La antibodies, suggesting DR3 as the primary association factor. High titers of La antibody, but not of 60 kD-Ro antibody, were also significantly associated with the presence of DR3. Other DR and DQ antigens or heterozygous DQ combinations were not significantly associated with Ro and La antibodies.
Subject(s)
Antibodies, Antinuclear/immunology , Antibodies, Antinuclear/analysis , Antibody Formation , Counterimmunoelectrophoresis , Enzyme-Linked Immunosorbent Assay , HLA Antigens/immunology , HLA-DR Antigens/immunology , Humans , Immunogenetics , Lupus Erythematosus, Systemic/immunologyABSTRACT
An analysis of HLA class II antigens in 356 white patients with systemic lupus erythematosus (SLE) showed that all HLA-DR and -DQ homozygous and heterozygous combinations appear with frequencies expected from the observed gene frequencies. HLA-DR2 and HLA-DR3 gene frequencies were both increased in SLE, as were the odds ratios of all DR2 and DR3 hetero- and homozygous combinations. HLA-DR2/C4AQ0 heterozygotes were also not increased over expected values. Therefore, gene complementation at MHC loci does not contribute to susceptibility to SLE, but rather one or two MHC allele(s) in linkage with HLA-DR2 and HLA-DR3.
Subject(s)
Autoimmune Diseases/genetics , Genes, MHC Class II , HLA-D Antigens/genetics , Lupus Erythematosus, Systemic/genetics , Alleles , Autoimmune Diseases/immunology , Disease Susceptibility/immunology , Gene Frequency , Genetic Predisposition to Disease , Genotype , HLA-D Antigens/immunology , HLA-DQ Antigens/genetics , HLA-DR Antigens/genetics , Haplotypes , Humans , Linkage Disequilibrium , Lupus Erythematosus, Systemic/immunology , Models, Genetic , White People/geneticsABSTRACT
OBJECTIVE: To evaluate the effectiveness of a polyclonal immunoglobulin (Ig) preparation containing IgG, IgM, and IgA as an adjunctive therapy for septic shock. DESIGN: Prospective, randomized clinical trial. SETTING: A clinical immunology ward at the center for internal medicine in a university hospital. PATIENTS: Fifty-five patients with septic shock were randomly allocated to two groups according to criteria of septic shock. INTERVENTION: One group of patients (n = 27) received a commercially available immunoglobulin preparation (containing high titers of antibodies specific for determinants to bacterial endotoxin) during the first 3 days after inclusion in the study. The other randomized group (n = 28) did not receive any immunoglobulin preparation. MEASUREMENTS AND MAIN RESULTS: During the period of less than or equal to 6 wks after the beginning of clinically apparent septic shock, death related to the septic process occurred in one (4%) of 27 patients who received immunoglobulin. By comparison, nine (32%) of 28 control group patients died during this period (p less than .01). Within the first 48 hrs after onset of the clinically apparent septic process, significantly increased activity of circulating endotoxin and simultaneously decreased specific IgG serum titers to lipid A were detected in the group of nonsurvivors. CONCLUSION: Administration of a polyclonal immunoglobulin preparation in the early phase of septic shock was associated with significantly improved survival.
Subject(s)
Bacterial Infections/therapy , Gram-Negative Bacteria , Immunization, Passive , Shock, Septic/therapy , Antibodies, Bacterial/blood , Bacterial Infections/immunology , Bacterial Infections/mortality , Endotoxins/blood , Female , Gram-Negative Bacteria/immunology , Humans , Immunization, Passive/methods , Immunoglobulin G/analysis , Immunoglobulin M/analysis , Lipopolysaccharides/immunology , Male , Prospective Studies , Shock, Septic/immunology , Shock, Septic/mortalityABSTRACT
STUDY OBJECTIVE: To determine forms of malnutrition and basal metabolism at different stages of immunological impairment in clinically stable patients infected with Human Immunodeficiency Virus (HIV). DESIGN: Cross sectional study. SETTING: 53 outpatients with HIV-infection classified according to the Walter Reed staging system (WR1 to WR6). MEASUREMENTS AND MAIN RESULTS: 87% of the patients showed some evidence of malnutrition. Reduced body weight was found in 53%, 68% and 25% had decreases in fat and body cell mass, 17% had visceral protein deficiency, whereas extracellular mass and serum triglyceride concentrations were increased in 58% and 30%, respectively. Reduced serum albumin and transferrin closely paralleled immunological depression, whereas alterations in body composition were manifest early during HIV-infection (WR3) and remained unchanged during the transition to the Acquired Immune Deficiency Syndrome itself. Resting metabolic rate increased from WR1 to WR3; it remained within the expected range during later stages (WR4-WR6), but was not appropriately reduced in response to the loss in body cell mass. CONCLUSIONS: HIV-infected patients display both, calorie and protein malnutrition. Immunological depression was independent of loss of body mass, but was closely associated to decreases in serum albumin values. Nutritional assessment and intervention should therefore be performed at an early stage of HIV-infection.
Subject(s)
Energy Metabolism/physiology , HIV Infections/immunology , Protein-Energy Malnutrition/immunology , Adult , Cross-Sectional Studies , Female , Humans , Immune Tolerance/immunology , Immunoglobulins/metabolism , Leukocyte Count , Male , Middle Aged , Nutrition Assessment , Opportunistic Infections/immunology , T-Lymphocyte Subsets/immunologySubject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Multiple Myeloma/mortality , Cisplatin/administration & dosage , Cyclophosphamide/administration & dosage , Humans , Melphalan/administration & dosage , Methotrexate/administration & dosage , Prednisone/administration & dosage , Vincristine/administration & dosageABSTRACT
Systemic lupus erythematosus (SLE) is a complex disease which is partly determined by genetic factors which influence susceptibility to the disease phenotype. In this association study we try to define the high risk haplotypes which are responsible for this disease, together with other environmental factors. In many other association studies a set of SLE patients is compared to a set of controls. The basic assumption about the underlying population is that the disease and control sample should originate from the same genetic population, which is not always completely satisfied in many studies. Therefore, we analyse our family data by applying the Haplotype Frequency Difference (HFD) Method, which constructs its internal control group from those haplotypes not transmitted to the affected individual. Results partially conform with other studies, showing that the haplotypes B8 DR3 as well as B7 DR2 have a high positive association with SLE. When the DR locus was analyzed alone, we found besides the alleles DR2 and DR3 a negative association for DR1, DR5, and DR6.
Subject(s)
Lupus Erythematosus, Systemic/genetics , Adult , Epidemiologic Methods , Female , Germany/epidemiology , HLA-DR Antigens/genetics , Haplotypes , Humans , Lupus Erythematosus, Systemic/epidemiology , Male , Models, Genetic , Risk FactorsABSTRACT
Immunoglobulin heavy chains (G1m, G2m, G3m, A2m) and kappa light chain (Km) allotype and phenotype frequencies were examined in 323 central European Caucasian patients with systemic lupus erythematosus (SLE). No significant differences were found between the different allotype or phenotype frequencies of the SLE patients and a control group of healthy individuals. Our results indicate that Gm, A2m and Km allotypes do not represent susceptibility factors for SLE in Caucasians.
Subject(s)
Immunoglobulin Allotypes/genetics , Lupus Erythematosus, Systemic/immunology , Gene Frequency , Humans , Immunoglobulin A/genetics , Immunoglobulin Gm Allotypes/genetics , Immunoglobulin Km Allotypes/genetics , Lupus Erythematosus, Systemic/genetics , Phenotype , White PeopleABSTRACT
Immunoglobulin heavy chain (G1m, G2m, G3m, A2m) and kappa light chain (Km) allotype and phenotype frequencies of 323 central European Caucasian patients with systemic lupus erythematosus (SLE) were examined and correlated with various genetic, serologic and clinical markers of SLE. No significant associations were found between immunoglobulin allotypes or phenotypes and all 20 parameters tested (nephritis, vasculitis, arthralgias, photosensitivity, discoid lesions, central nervous system disease, Raynaud's phenomenon, sex, anti-Ro, anti-La, anti-nRNP, HLA-DR1-DR7, HLA phenotypes B8-DR3, B7-DR2). It could therefore be assumed that Gm, A2m and Km allotypes were not associated with HLA-antigens and had no influence on the serologic and clinical expression of SLE.
Subject(s)
Autoantibodies/immunology , HLA Antigens/immunology , Immunoglobulin Allotypes/immunology , Lupus Erythematosus, Systemic/immunology , Europe , Genetic Markers , Humans , Immunoglobulin Allotypes/genetics , Immunoglobulin Heavy Chains/immunology , Immunoglobulin kappa-Chains/immunology , Lupus Erythematosus, Systemic/epidemiology , Lupus Erythematosus, Systemic/genetics , Phenotype , White People/geneticsABSTRACT
277 untreated multiple myeloma patients of stage 1 (n = 33), II (n = 106) and III (n = 138) entered the study. Patients of stage II presenting a progressive tumor (n = 64) initially or during observation (n = 14) were treated with MivP (remissions: 61%). 138 patients of stage III were randomized to receive MivP or VBAMDex treatment. 51% of MivP treated patients responded versus 70% of the VBAMDex group. 71 responders of stage II and III with stable disease were randomized on Ifn-alpha maintenance versus no maintenance treatment. The relapse rate in both groups was 50% after 7 months. 75% survival was greater than 36 months in stage II and 11 months in stage III patients.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Interferon Type I/administration & dosage , Multiple Myeloma/therapy , Carmustine/administration & dosage , Combined Modality Therapy , Dexamethasone/administration & dosage , Doxorubicin/administration & dosage , Female , Humans , Male , Melphalan/administration & dosage , Multiple Myeloma/drug therapy , Multiple Myeloma/pathology , Neoplasm Staging , Prednisone/administration & dosage , Recombinant Proteins , Vincristine/administration & dosageABSTRACT
136 untreated multiple myeloma patients of stage II and III were collected in the study. 37/51 stage II patients had progressive disease and were treated with melphalan and prednisone (MP). 85 patients were of stage III and randomized into MP and vincristine, BCNU, adriamycin, melphalan and dexamethasone (VBAMDex) treatment groups. 55% of MP treated patients responded versus 75% of the VBAMDex group. Since the study has been activated only 16 months ago, no difference in survival could be observed.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Multiple Myeloma/drug therapy , Carmustine/administration & dosage , Dexamethasone/administration & dosage , Doxorubicin/administration & dosage , Female , Follow-Up Studies , Humans , Male , Melphalan/administration & dosage , Multicenter Studies as Topic , Multiple Myeloma/pathology , Neoplasm Staging , Prednisone/administration & dosage , Vincristine/administration & dosageABSTRACT
In a prospective multicenter trial, 320 untreated myeloma patients of stage II and III were randomized for remission induction into two groups receiving six monthly courses of either MP or VCMP treatment. Response rates were equal in both groups: 72% remission, 21% no change, 7% progress for patients evaluable by TCM changes and 56% remission, 11% no change, 33% progress for BJ- and non-secretory myelomas. The overall survival rate was 60% after 4 years. An unexpected finding was the significantly longer survival of MP treated patients compared to the VCMP group. After successful remission induction, patients were randomized into one group receiving maintenance treatment using the induction scheme q 8 weeks, and another group without further chemotherapy. Although patients in the latter group relapsed significantly earlier, differences between both groups concerning acquired resistance to first line therapy or survival have not been noticed to date.