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Only one treatise devoted to medical history taking (anamnesis) has come down to us from antiquity: Medical questions by Rufus Ephesius (from about 80 to about 150 AD). The work was rediscovered, published and translated from Greek into French by Daremberg and Ruelle in the 19th century. The word 'anamnesis' for history taking only came into use halfway through the 19th century in German-speaking countries and in the Netherlands. The term was not used in this sense by physicians in antiquity. In contrast to several authors of the Corpus Hippocraticum (5th to 1st century BC), Rufus attached great importance to the interview with the patient and in particular to questions concerning the patient's lifestyle prior to the illness. In this respect, his opinions are remarkably close to modern views.

The proband is an elderly woman (79 years of age) of Surinamese-Hindustani origin, suspected of being a carrier of a nondeletional alpha-thalassemia (thal) because of a moderate microcytic hypochromic anemia at normal ferritin levels and in the absence of any other alpha-thal deletions. Sequence analysis revealed a silent mutation (GGC-->GGT) at codon 22 of the alpha2-globin gene. This mutation generates a splice donor site consensus sequence (GGTGAG) between codons 22 and 23. The abnormally spliced mRNA leads to a premature termination between codons 48 and 49. The presence of a downstream intron may induce the intracellular degradation of the affected mRNA, a pathway known as nonsense mediated decay (NMD), and this explains the alpha(+)-thal phenotype observed in the patient. The codon 22 (GGC-->GGT) transition described in this report is the first mutation creating a splice donor site in one of the alpha-globin genes.

The standard entitled 'Anaemia in the midwife practice' issued by the Royal Dutch Organisation of Midwives presumes that the only reason for iron therapy in pregnancy is the prevention of adverse pregnancy outcome due to a low haemoglobin level. Pregnant women are screened for iron deficiency anaemia by means of sequential testing of haemoglobin and mean corpuscular volume (MCV). As a result only 10% of pregnant women will receive iron supplements. This practice will lead to a deterioration in the already low iron status of Dutch premenopausal women. As the haemoglobin reference values are lower than hitherto used, only severely anaemic women will be detected. Due to the low diagnostic accuracy of the MCV test the subsequent selection will be an arbitrary one. The standard sets the cut-off values for haemoglobin in black women at an even lower level, which will reduce the number of haemoglobinopathies detected in the immigrant population. The non-carriers in this group will run an increased risk of adverse pregnancy outcome if these cut-off values are used. We are strongly in favour of the measurement of haemoglobin, erythrocyte indices and ferritin in early pregnancy. In this way, iron deficiency, iron deficiency anaemia, anaemia due to other causes and haemoglobinopathies, the latter highly underestimated in the standard, can be detected.

Background: A person exposed to foreign blood group antigens may produce antibodies. The persistence of antibodies varies among people and among antibodies. A study was performed to investigate the persistence of clinically significant RBC alloantibodies over a period of 20 years., Study Design and Methods: A retrospective examination was performed of all records of RBC antibodies in the transfusion laboratory computer database from 1978 through 1997. Records of patients who underwent at least one antibody investigation after an antibody had been detected were studied. The study included all antibodies against the Rh, K, Fy, Jk, and MNs blood group systems. An antibody was regarded as not persistent if, after previous detection, the screening or panel studies became negative for the antibody under study. Anti-D due to RhIg administration was excluded., Results: An analysis was performed of 480 records consisting of 593 antibodies that fulfilled the criteria. Median antibody follow-up was 10 months (range, 1-240). In 137 patients, 153 (26%) antibodies became undetectable over the course of time. After initial negative screening investigations, 310 antibodies were formed. The antibodies that were still detectable had a median follow-up of 7 months (range, 1-193). A patient's age, sex, and antibody specificity were of no influence on the length of time that antibodies were detectable. Antibodies detected with a more sensitive screening technique were less persistent (p = 0.0002). For 28 patients, detection of antibodies was highly irregular., Conclusions: About 25 percent of all antibodies became undetectable over the course of time. The antibody screening technique used, rather than the antibody specificity, affected these results. To prevent delayed hemolytic transfusion reactions, precise antibody documentation is of great importance.

Background: Because of intensive marrow depression and improved survival, patients with hematologic and oncologic malignancies are dependent on transfusion for a longer period. It has been advocated that these patients should receive blood that is matched for blood group antigens other than ABO and D. A retrospective study was performed on the rate of alloimmunization against red cell antigens in 564 patients with malignant hematologic diseases over a period of 10 years., Study Design and Methods: Records of transfusion and immunohematologic studies of all patients (n = 1066) with malignant myeloproliferative and lymphoproliferative diseases diagnosed between 1987 and 1996 at one hospital were collected from the hospital computer blood bank files. Transfusions were correlated with antibody formation. Factors affecting this correlation were analyzed., Results: Seventy-one antibodies were found in 51 patients. The overall immunization rate was 9.0 percent. Fifty percent of antibodies were formed after 13 units had been transfused. Once a patient had formed an antibody, the probability of additional antibodies increased 3.3-fold. Anti-c, anti-E, and anti-K composed the majority of antibodies found. Four patients formed Rh system antibodies after incompatible platelet transfusions. Patients who underwent intensive chemotherapy formed antibodies at a much lower rate than other patients. More than 40 percent of antibodies became undetectable after the first detection. No difficulty was encountered in finding compatible blood for these patients., Conclusions: Antibody formation in hematologic malignancies is comparable to that in other diseases requiring multiple blood transfusions. Extensive antigen matching before transfusion of patients with hematologic and oncologic malignancies is not necessary and leads to increased costs.

We describe a family with beta thalassaemia, apparently not linked to the beta-globin gene cluster, in combination with alpha thalassaemia. The propositus, an adult Dutch Caucasian male, and his son presented with microcytic hypochromic parameters. Their lysates displayed the normal adult pattern on electrophoresis. The HbA2 concentration, which is usually increased in beta thalassaemia, was normal. The in vitro biosynthetic rate of the globin chains was strongly unbalanced even in the presence of a coexisting alpha-thalassaemia defect. Routine analysis of the beta genes, including the promoter region, was performed repeatedly by polymerase chain reaction (PCR), denaturing gradient gel electrophoresis (DGCE) and direct sequencing. No molecular abnormalities were detected. Large beta deletions were excluded by haplotype determination, using seven polymorphic markers distributed over an area of 50 kb, from 1 kb 5' of the epsilon gene to 4 kb 3' of the beta gene. The haplotype analysis of the beta-gene cluster revealed that the unaffected daughter had received the same beta haplotype as her beta-thalassaemic brother from their beta-thalassaemic father. These data suggest that the beta-gene cluster shared by father and son was not directly associated with a reduced beta-globin chain expression. In order to exclude the remote possibility of a beta-locus-control region (LCR) rearrangement in the paternal haplotype of the daughter, the sequence of the HS2 element was examined in the nuclear family. We compared the haematological and clinical data of this family with the data reported in the limited number of similar cases. We discuss the possibility that the mutation of a trans-acting erythroid factor(s), not linked to the beta-genes cluster, may impair the beta-gene expression of both alleles.

Hyperhomocysteinemia is a risk factor for atherosclerosis and thrombosis and is inversely related to plasma folate and vitamin B12 levels. We assessed the effects of vitamin supplementation on plasma homocysteine levels in 89 patients with a history of recurrent venous thrombosis and 227 healthy volunteers. Patients and hyperhomocysteinemic (homocysteine level >16 micromol/L) volunteers were randomized to placebo or high-dose multivitamin supplements containing 5 mg folic acid, 0.4 mg hydroxycobalamin, and 50 mg pyridoxine. A subgroup of volunteers without hyperhomocysteinemia was also randomized into three additional regimens of 5 mg folic acid, 0.5 mg folic acid, or 0.4 mg hydroxycobalamin. Before and after the intervention period, blood samples were taken for measurements of homocysteine, folate, cobalamin, and pyridoxal-5'-phosphate levels. Supplementation with high-dose multivitamin preparations normalized plasma homocysteine levels (< or = 16 micromol/L) in 26 of 30 individuals compared with 7 of 30 in the placebo group. Also in normohomocysteinemic subjects, multivitamin supplementation strongly reduced homocysteine levels (median reduction, 30%; range, -22% to 55%). In this subgroup the effect of folic acid alone was similar to that of multivitamin: median reduction, 26%; range, -2% to 52% for 5 mg folic acid and 25%; range, -54% to 40% for 0.5 mg folic acid. Cobalamin supplementation had only a slight effect on homocysteine lowering (median reduction, 10%; range, -21% to 41%). Our study shows that combined vitamin supplementation reduces homocysteine levels effectively in patients with venous thrombosis and in healthy volunteers, either with or without hyperhomocysteinemia. Even supplementation with 0.5 mg of folic acid led to a substantial reduction of blood homocysteine levels.

Purpose: To investigate the value of intensive consolidation chemotherapy not followed by maintenance therapy in adult acute lymphoblastic leukemia (ALL)., Materials and Methods: A multicenter phase II trial was conducted in 130 adult patients with ALL between 16 and 60 years of age. After standard induction therapy, postinduction chemotherapy was given: three courses of high-dose cytarabine (2,000 mg/m2 every 12 hours for four doses) in combination with amsacrine (course one), mitoxantrone (course two), and etoposide (course three). CNS prophylaxis consisted of 10 injections of intrathecal methotrexate (IT MTX). Patients younger than 50 years with an HLA-identical sibling were eligible to receive allogeneic bone marrow transplantation (BMT)., Results: Ninety-five patients (73%) achieved complete remission (CR); 82% were younger than 50 years and 41% were older than 50 years. Seventeen patients (13%) were resistant to chemotherapy, and 18 (14%) died during induction treatment. Only age and performance status were significantly associated with response (P<.001 and .03, respectively). Death during consolidation occurred in four patients. The estimated 5-year overall survival (OS) was 22% for the entire group and 26% for patients younger than 35 years. Disease-free survival (DFS) at 5 years was 28% +/- 6 for patients younger than 35 years, 25% +/- 9 for patients between 35 and 50 years, and 0% for patients older than 50 years. Increasing age (P<.01) and expression of CD34 (P<.01) were adverse factors. Only three patients (3%) developed an isolated CNS relapse., Conclusion: Intensive consolidation including high-dose cytarabine not followed by maintenance therapy provides an outcome for adult patients with ALL that may be worse or even inferior compared with studies using long-term maintenance therapy. High-dose cytarabine in combination with IT MTX was effective for CNS prophylaxis.

Purpose: To evaluate the impact of granulocyte-macrophage colony-stimulating factor (GM-CSF) or placebo on the durations of intravenous (IV) antibiotic use, hospitalization, neutropenia, and fever, as well as remission rates, after high-dose melphalan (HDM) without stem-cell transplantation (SCT) in patients with multiple myeloma (MM)., Patients and Methods: One hundred two patients with high-risk MM were randomized 2:1 in a prospective multicenter trial to receive 5 microg/kg/d GM-CSF (69 patients) or placebo (33 patients) starting the day after 140 mg/m2 IV melphalan for up to 21 days., Results: GM-CSF significantly reduced neutropenia after HDM (median, 23.5 v 29 days; P = .0468), with a trend to reduce the duration of hospitalization (median, 32 v 38 days; P = .0841). Nevertheless, GM-CSF did not significantly reduce infectious toxicity as regards the number of days with fever (median, 5 v 3; P = .359), the number of days with IV antibiotics (median, 22 v 27; P = .14), or early deaths, with an 11.5% treatment-related mortality rate in the GM-CSF group (eight of 69 v two of 32 patients in the placebo group; P = .686). There was no difference in response rates between the two groups of patients., Conclusion: GM-CSF after HDM without SCT is feasible and significantly shortens neutropenia with a trend toward reduction of hospitalization duration, but does not significantly reduce the morbidity and mortality of such therapy. Thus, when intensive therapy is indicated, given that the mortality of HDM followed by SCT reported in the literature is less than 5% and patients are discharged at approximately day 15, despite the risk of contamination by clonogenic malignant cells, SCT appears to be preferable to GM-CSF after HDM.

We report the characterization of an alpha +(-)thalassaemia determinant due to a transition A-->G of the acceptor splice consensus site sequence (IVS1-116) of the first intron of the alpha 2-globin gene. The mutation, found in two apparently unrelated Dutch Caucasian families, was detected by DGGE analysis followed by direct sequencing. Haplotype analysis suggests a common origin of the mutation in both families. The disruption of the acceptor splice site consensus sequence interferes with the correct splicing and leads to the retention of the first intron in the abnormally spliced mRNA. The alpha +(-)thalassaemia phenotype observed in the carriers is caused by the absence of functional mRNA which cannot be replaced by the abnormally spliced mRNA. The low amounts of abnormal mRNA found in reticulocytes is, most probably, due to the post-transcriptional instability which follows the presence of a termination codon in the retained intronic sequence. This situation is often associated with a decreased mRNA stability as observed for several nonsense mutations of the beta-globin gene.

Objective: To determine if there is a place for radiophosphorus (32P) in the treatment of polycythaemia vera (PV) and essential thrombocytosis (ET)., Design: Retrospective., Setting: Leyenburg Hospital, The Hague, the Netherlands., Method: Data on 144 patients with the diagnoses 'PV' or 'ET' from 1965 to 1994 were collected. Available data were insufficient in 19 of these. Regarding 125 patients, 80 with PV and 45 with ET, the survival and the frequency of acute leukaemia with various forms of treatment (32P, busulfan or combination of several treatment modalities) were studied. Moreover, in the PV group the duration of survival was compared with the expected duration of survival in a comparable group of the population., Results: Of the 80 PV patients, five developed acute leukaemia: two in the 32P group (5%), two in the busulfan group (12%) and one in the group given combination therapy (4%). Of the 26 patients of the ET group treated with busulfan, one developed acute leukaemia (4%). The survival in the PV group was 4 years shorter than the expected duration of survival in a comparable group of the population., Conclusion: Since 32P is efficacious and causes little inconvenience, it should be the drug of first choice in the treatment of PV in the elderly.

We report a 27-year-old male patient with acute myeloid leukaemia who was successfully treated with an unrelated bone marrow graft within 7 days following the loss of his autologous bone marrow graft. Several factors were found to be essential in order to locate an HLA-ABDR (DRB1)DQ(DQB1) identical, sex-matched, CMV-negative and ABO compatible donor within a week. These included a common HLA phenotype of the patient, the presence of an experienced donor registry in close proximity to a blood bank associated with an HLA laboratory, a large donor file with fully HLA-ABDR typed donors and the almost exclusive use of blood bank donors as potential bone marrow donors. The possibility of further streamlining the logistics of finding a suitable unrelated bone marrow donor is discussed.

Purpose: We studied the prognostic significance of bcl2 and p53 protein expression in relation to clinical and pathologic characteristics in patients with diffuse large B-cell lymphoma (LCL)., Patients and Methods: Three hundred seventy-two patients with LCL were retrieved from a population-based registry for non-Hodgkin's lymphoma (NHL). bcl2 and p53 protein expression was studied on paraffin-embedded tumor tissue by immunohistochemistry in relation to clinical factors. Response to therapy and survival were analyzed in 165 patients who were uniformly staged and treated and for whom all prognostic data were available according to the International Prognostic Index (IPI)., Results: Forty-five percent of tumors showed strong expression of the bcl2 protein (bcl2++), with a higher frequency in patients with primary nodal involvement. Disease-free survival (DFS) was significantly better in bcl2-negative/intermediate (bcl2-/+) cases as compared with bcl2++ cases (P = .0011). At 5 years, bcl2-/+ patients showed a DFS rate of 74%, in contrast to bcl2++ patients with a DFS rate of 41% (P = .002). Bcl2 was the strongest independent prognostic value in a multivariate analysis, with a relative risk (RR) of 3.0 in comparison to p53 expression and the clinical factors of the IPI. Overall survival (OS) was not significantly influenced by bcl2 protein expression. p53 protein expression was found in 13% of cases, with a higher frequency in patients with extensive disease. p53 expression did not influence the chance to achieve complete remission (CR) and survival., Conclusion: bcl2 protein is frequently expressed in LCL and is a strong independent prognostic factor for DFS. p53 expression is related with high tumor burden, but is not an independent risk factor for CR and survival.

In four patients, a woman aged 85 and three men aged 33, 42 and 70 years, clozapine-induced agranulocytosis was diagnosed. In three patients the white cell counts were not performed as they should have been. Two patients were treated for their agranulocytosis with granulocyte colony-stimulating factor (G-CSF; filgrastim). Two patients were not treated. The literature concerning clozapine-induced agranulocytosis and its treatment with growth factors consists of only a few case reports. Therefore a definite conclusion about the efficacy of the treatment for this particular indication is not yet possible.

Background: High-dose chemoradiotherapy combined with autologous bone marrow transplantation can cure patients with disseminated, aggressive non-Hodgkin's lymphoma in whom first-line chemotherapy has failed. In contrast, cure is rare with second-line chemotherapy. It has been suggested that patients with slow responses to the initial phase of first-line chemotherapy are at high risk for relapse. Therefore, such patients are potential candidates for early bone marrow transplantation., Methods: To investigate whether patients with slow responses, defined as only a partial response after three courses of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP), would benefit from early transplantation, we conducted a prospective, randomized trial. The early application of high-dose chemoradiotherapy and autologous bone marrow transplantation was compared with the continuation of CHOP therapy for another five courses. Patients with complete responses after three courses of CHOP (fast responses) and patients who responded partially but still had tumor-positive marrow continued with another five courses of CHOP. The study end points were the response rate, overall survival, disease-free survival, and event-free survival., Results: Of 286 patients who could be evaluated for the rapidity of their response after three courses of CHOP, 38 percent had fast responses, 47 percent had slow responses, and 15 percent had no response. Among 106 patients with slow responses who had lymphoma-negative marrow, 69 patients (65 percent) were randomized. Seventy-four percent of the CHOP group and 68 percent of the transplantation group had complete remissions (P = 0.54). At four years the rates of overall, disease-free, and event-free survival were 85, 72, and 53 percent, respectively, in the CHOP group and 56, 60, and 41 percent in the transplantation group (P > 0.10). The disease-free survival in both groups did not differ significantly from that of nonrandomized patients with fast responses (54 percent at four years)., Conclusions: The early application of high-dose, marrow-ablative chemoradiotherapy with autologous bone marrow transplantation does not improve the outcome in patients with aggressive non-Hodgkin's lymphoma that responds slowly to first-line CHOP chemotherapy.

Several studies have shown a relation between hyperhomocysteinaemia and arterial vascular disease. We looked at the association between hyperhomocysteinaemia and venous thrombosis which could be clinically important as hyperhomocysteinaemia is easily corrected by vitamin supplementation. We studied 185 patients with a history of recurrent venous thrombosis and 220 controls from the general population. Homocysteine concentrations were measured before and 6 h after oral methionine loading. We defined hyperhomocysteinaemia as the homocysteine concentration above the fasting or the postmethionine value found for the 90th percentile of the controls. Of the 185 patients with recurrent thrombosis, 46 (25%) had fasting homocysteine concentrations above the 90th percentile or the controls (odds ratio is 3.1 [1.8-5.5]). After adjustment for age, sex, and menopausal status the odds ratio was 2.0 (1.5-2.7). Similar results were found for the post-methionine value (unadjusted odds ratio 3.1 [1.7-5.5], adjusted 2.6 [1.9-3.5]). Hyperhomocysteinaemia is a common risk factor for recurrent venous thrombosis and can lead to a two-fold or three-fold increase in risk.

Fludarabine monophosphate (FAMP) has been shown to be highly effective against low-grade malignant B-cell lymphoproliferative diseases. Because some opportunistic infections were observed in patients treated with FAMP, we investigated the influence of this drug on several parameters of immunocompetence. For 17 consecutive patients treated with FAMP for CLL or low-grade malignant lymphoma we studied T-cell subpopulations during and after therapy by flow cytometry and our findings were correlated with the clinical course of their disease. A pronounced decrease in the various T-cell subpopulations was seen in all cases, that for CD4+ cells was still present 11-13 months after the end of the therapy. In 7 patients a severe opportunistic infection developed; the outcome was fatal in 2 cases. Only 5 patients did not experience any serious infection. These results show that FAMP therapy in a dose of 25 mg/m2/day for 5 d every 4 weeks might be too toxic for patients with very advanced disease. However, in view of the efficacy of FAMP, the possibility of less intensive schedules for these advanced cases should be explored.

Fifty-seven patients with relapsed non-Hodgkin's lymphoma (NHL) of low, intermediate and high-grade malignancy were treated with mitoxantrone, teniposide (Vm26), chlorambucil (Leukeran) and prednisone (MVLP). The median age was 71 years; none of the patients was excluded due to poor performance status (PS). Out of 44 patients with PS (according to WHO) < or = 2, 38 responded with a median progression free survival (PFS) of 21.5 months. Of 13 patients with PS > 2, 6 responded with a median PFS of 8.2 months. Haematopoietic toxicity was related to PS rather than to dose intensity or bone marrow involvement. Three patients died within a short time due to toxicity; another two died later as a result of cardiac failure probably due to accumulated toxicity of adriamycin and mitoxantrone. MVLP chemotherapy is effective and feasible and has only moderate toxicity in patients with relapsed NHL and PS < or = 2, despite advanced age.

Bone marrow cells of four patients with t(1;7) and myelodysplasia or acute myeloid leukemia were analyzed using nonradioactive in situ hydridisation. As probes, centromeric alphoid DNA sequences of chromosomes 1 and 7, a satellite DNA probe for 1q12, and chromosome-specific libraries of chromosomes 1 and 7 were used. The breakpoints of the t(1;7)(p11;p11) as determined by banding analysis could be studied more accurately, and the recently proposed designation t(1;7)(cen;cen) was confirmed in all four cases. Colocalization of alphoid DNA sequences of chromosomes 1 and 7 by double target in situ hybridisation was demonstrated in metaphase cells and also in interphase nuclei. The in situ hybridisation method described is applicable for the screening of peripheral blood cells or archival material.

This case report describes a patient with localized hyaline-vascular (H-V) type Castleman's disease with concomitant malignant B-cell lymphoma. Malignant lymphoma has been described in association with multicentric type Castleman's disease, but not in association with the localized H-V type. Evidence for a relation between the two lesions in this patient by means of histologic, flow-cytometric, cytogenetic and gene rearrangement studies was not found.

In this study we measured platelet size in blood smears using the Kontron Mop Videoplan (Kontron Electronic Group, Weesp, Holland). The blood smears were prepared at different times after phlebotomy; samples were collected in three different anticoagulants and 100 consecutive platelets were measured in each smear. A number of platelet parameters were determined, some of which were based on the log normal distribution of the platelet area. We found that the size of platelets in blood smears is also dependent on the time after phlebotomy and the anticoagulant used. This may be important for the comparison of platelet areas, a characteristic of various disorders. Our data indicate that the optimal interval after phlebotomy for preparation of blood smears is 2-5 min.

A follow-up study of 10 patients suffering from acquired aplastic anaemia, comprising methocrylate-embedded bone marrow biopsies and CFU cultures, is presented. The haematopoietic recovery patterns and changes in the inflammatory infiltration after permanent engraftment could be distinguished from those in non-transplanted patients. After anti-thymocyte globulin treatment followed by allogeneic bone marrow infusion, the recovery pattern resembled that in non-transplanted patients. The persistently low colony-forming capacity in some patients could be explained by the existence of lymphoid inhibitory cells, which suggests an immunologic auto-destructive mechanism.

Forty-one patients, suffering from severe aplastic anaemia were treated either with ALG alone (27 patients) or ALG followed by infusion of allogeneic bone marrow (14 patients). Eighteen patients (67 per cent) are presently alive after ALG alone at over 100 to over 550 days. Fourteen (52 per cent) showed sustained improvement of haematopoiesis, two are alive without change, one recovered autologous haematopoiesis after cyclophosphamide conditioning and transfusion of HLA identical marrow and one is lost to follow-up. Eight patients (57 per cent) are currently alive after ALG and transfusion of haplotype identical marrow with self-sustaining autologous haematopoiesis at over 200 days to over four and a half years. No lethal complications occurred and none of the bone marrow infusions led to permanent engraftment or graft-versus-host disease. The mechanism of action is not known, but our results support the hypothesis that unspecified autoimmune reactions block the normal outgrowth of haematopoietic precursor cells in a substantial number of patients with aplastic anaemia. This therapeutic approach seems to offer good chances of survival, especially for those patients who do not have an HLA identical sibling. Its value should be further investigated.

Peripheral blood cells from untransfused rabbits that were treated with a moderate dose of benzene during 2 months were cocultivated with autologous and normal bone marrow. In a significant number of experiments, CFUE and BFUE growth of both autologous and normal bone marrow was suppressed. Further experiments showed that this inhibition was associated with adherent mononuclear peripheral blood cells. It is concluded that benzene, an established myelotoxic agent, also induces CFUE and BFUE inhibiting activity in adherent peripheral blood cells.

We describe a patient with hemophilia A and primary malignant teratoma of the lung. Hemothorax and pseudotumor in hemophilia are rare disorders and can raise many differential diagnostic problems.

Three patients with megakaryoblastic leukaemia are described. All three presented with pancytopenia, a few blast cells in the peripheral blood and absence of overt hepatosplenomegaly. In two of them bone marrow aspiration yielded a dry tap. Histological investigation of the bone marrow indicated that the megakaryocytic cell line was the dominant proliferating lineage. Cytochemical and EM investigation supported these findings. The isomorphic isoenzyme pattern of the elevated serum lactic dehydrogenase might be of diagnostic importance. Despite chemotherapy, there was a rapidly fatal terminal leukaemic phase with high blast cell counts. The differentiation from other haematological malignancies, especially acute (aleukaemic) leukaemias and the accelerated phase of primary (chronic) myelofibrosis, is discussed. The picture appears to be identical with acute (malignant) myelofibrosis.

Of the 14 patients with aplastic anaemia treated in our hospital with anti-thymocyte globulin (ATG), four were refractory to random platelets before therapy due to the presence of leucocyte antibodies. In contrast to the ten nonrefractory patients in whom no success was obtained, three of the four refractory patients showed haematological improvement after ATG. Additionally, two patients could be substituted again with random platelets. The other two hardly needed platelet-transfusions after ATG, and they were given HLA-compatible platelets. To determine the degree of immunosuppression, these four patients were tested for the presence of antibodies against leucocytes and two endemic viruses, i.e., mumps and rubella virus. Before ATG, all sera reacted with almost the whole leucocyte testpanel. After treatment, the leucocyte antibodies disappeared completely in three patients. In one patient there was no dramatic change. In all patients, however, the antibody-titre against the mumps and rubella viruses remained constant and there was only a slight decrease in total IgG content in the three "suppressed" patients. We conclude that it might be worthwhile to study systematically the selective immuno-suppressive effect of ATG.

Bone marrow scintigraphy, using 111Indium-chloride, was performed in 24 patients with acquired aplastic anaemia to investigate: (1) a possible relationship between bone marrow scintigraphy and peripheral blood cell values, (2) a possible relationship between scintigraphy and histology of the bone marrow and (3) the ability to distinguish various aplastic anaemia subtypes with bone marrow scintigraphy. For this purpose a semi-quantitative scoring of scintigraphic results was used. Only a weak correlation was found between the radionuclide studies and blood counts. It appeared that an abnormal 111In-scintigraphic activity in the pelvis was related to an abnormal quality and quantity of haematopoietic tissue. To study a correlation with histological subtype grading, the patients were grouped in 4 categories based on clinical-histological results. Thus it could be demonstrated that the presence of 111In-activity in long bones ('scintigraphic extension') is an important parameter in distinguishing patients who are believed to suffer from a primary stem-cell defect, from patients who may suffer from an auto-aggressive disorder.

In 53 patients with aplastic anemia (AA) a number of parameters concerning immune responsiveness were analyzed. Severe monocytopenia and B-lymphocytopenia was detected in most patients, especially in those with diffuse lymphocyte infiltration in the bone marrow. T-inducer (OKT4)/T-suppressor (OKT8) ratios were normal. The mean IgG level was significantly decreased. The frequency of specific antibodies to common viruses was comparable to that of healthy donors except for cytomegalovirus to which antibodies were less frequently found. The responding capacity in MLC was normal but patients' lymphocytes were often less stimulating than control lymphocytes. Radioresistant suppressor cells were found in 1 patient. In vitro lymphocyte reactivity to mitogens and antigens was severely impaired, related to the numbers of monocytes present. When allogeneic monocytes were added, mitogen responses could be restored.

In 25 patients and 11 follow-up studies the clinical usefulness of bone marrow scanning with 111In-chloride in aplastic anaemia is evaluated. Semi-quantitative scanning of bone marrow scan results and the presence of bone marrow extension have proven to be helpful in monitoring the disease and determining aetiological factors. This study shows that 111In-chloride is able to demonstrate regional difference in the bone marrow status of the patient suffering from aplastic anaemia, thereby offering a useful alternative for iron radionuclides.

Bone marrow histology plays a crucial role in the clinical diagnosis of aplastic anaemia. The nature of the disease means that few studies are available on the histological changes which occur in the early stages of the development of aplasia. We describe here an animal model which may have some relevance in this respect. Rabbits were chronically exposed to busulphan (BU) to induce aplasia. Sequential histological monitoring of the bone marrow was performed to obtain information about the events preceding full-blown aplasia. There was an early decrease and ultimate disappearance of granulo- and megakaryopoiesis with relative sparing of erythropoiesis which showed severe displasia. Increasing lymphoplasmacytoid infiltrate resembling that seen in human aplasia could be observed in the majority of the animals, together with a decrease of the peripheral lymphocyte number. Lymph nodes and spleen did not show lymphocyte depletion and serum gamma-globulin remained stable. Fibrosis was observed in 50% which is in contrast with human aplasia at diagnosis. In half of the animals there was a rise in MCV, which was not correlated with reticulocytosis or degree of dyserythropoiesis. BU-induced aplasia in rabbits, which resembles long-standing grade II human aplasia in many respects, might be a suitable model for the study of aplastic anaemia due to stem cell defects.