[Florence Nightingale--"barracks" were a residence].
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Biomedical subjects
Publications and source records attributed to E Jakobsen.
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Bone marrow aspiration and biopsy was performed as part of routine staging in 425 patients with primary Hodgkin's disease. Only seven patients were found to have bone marrow disease by biopsy and only four by aspiration. All these patients had B symptoms and stage III or IV before bone marrow examination. Bone marrow infiltration did not influence treatment decision and there was no association between bone marrow findings and outcome of the disease.
An immunocytochemical method, involving four monoclonal antibodies (MAbs) previously selected for their specific binding to small cell lung cancer (SCLC) cells in human bone marrow, was used for detection of bone marrow metastases in 81 patients with diagnosed SCLC. This procedure was compared with two routine morphologic methods with regard to diagnostic efficiency and sensitivity. Bone marrow involvement was found in 26 patients (32%), one of which had limited disease according to conventional clinical criteria. Eight of the positive cases were exclusively diagnosed by immunocytochemistry, whereas the histologic and cytologic methods separately identified two patients each. Immunocytochemistry had a detection level of tumor cells in the mononuclear cell fraction of approximately 1-2%, whereas no patients with less than 10% immunocytologically detectable tumor cells were diagnosed by cytomorphologic examination of bone marrow aspirates. Evidence was obtained that the diagnostic efficiency of any method increased with the number of samples examined. Of the four MAbs used, the anti-NCAM antibody, MOC-1, labeled tumor cells in all immunologically positive patients, and in all but one of these patients all cytologically confirmed tumor cells were stained. The antibodies MOC-31, which recognize a cluster-2 antigen, and NrLu10 bound nearly all tumor cells in most cases, whereas MLuC1 only diagnosed tumor cells in a fraction of the patients. The results show that the immunocytochemical application of these antibodies is superior to morphologic techniques in detecting SCLC bone marrow metastases. Further use of the method might provide prognostically and therapeutically useful information.
An immunomagnetic method was developed to purge human bone marrow of malignant T cells, for use in conjunction with autologous bone marrow transplantation in patients with acute lymphoblastic leukemia and lymphoma. Three monoclonal antibodies anti CD2 (BH1), CD5 (BB8) and CD7 (BF12) were used. In model experiments employing MOLT4 cells it was found that with 50-fold excess of immunobeads relative to antigen-positive cells, the use of each antibody alone resulted in a 3.3-3.6 log tumor cell depletion, as assessed in a sensitive and reproducible clonogenic soft agar assay. When all three antibodies were used in a mixture, a purging efficacy of 5 logs was achieved. Two treatment cycles improved these figures to about 4 logs and more than 5 logs. When MOLT4 cells were mixed 1:10 with fresh bone marrow cells the antibody mixture yielded 3.1 and more than 5 log tumor cell depletion with one and two treatment cycles, respectively. This procedure resulted in only an insignificant reduction of the number of CFU-GM and CFU-GEMM progenitor cells. In two patients autotransplanted with purged marrow, the loss of CFU-GM was 37% and 48%, and no tumor cells could be detected by immunocytochemistry after purging. Rapid and sustained engraftment was achieved and both patients remain in complete remission after more than 20 months.
It has been widely assumed that anti-HLA-DR antibodies react with pluripotent stem cells and cannot be used in bone marrow purging. We report a case of non-Hodgkin's lymphoma in which an anti-HLA-DR antibody (AB4) was used for immunomagnetic purging and the subsequent autologous bone marrow transplantation resulted in rapid marrow engraftment with no serious complications. The results indicate that the AB4 antibody, which binds to an antigen encoded by the B3 gene of the DR region, can be safely used in the clinic in the purging of bone marrow from patients with AB4-positive tumors (non-T-cell acute lymphocytic leukemia, non-Hodgkin's lymphoma, and some cases of acute myelogenous leukemia.
Evaluation of oesophageal function was performed in 91 patients referred to a specialized department of cardiothoracic surgery for surgical treatment of benign oesophageal disease. Standard manometry was used in addition to radiology and endoscopy, and in some patients, an acid perfusion test, an acid clearing test, and a prolonged monitoring of pH in the distal oesophagus were additionally performed. The aim of this study was to evaluate whether assessment of oesophageal function is needed in such a patient group, and whether the results of these investigations were taken into account when making the final decision for therapy. Eleven percent of the patients referred with a diagnosis of hiatal hernia or reflux had achalasia or oesophageal spasm. Nine percent of the patients referred for motility disorders had reflux-related disease. The referral diagnosis was changed to a diagnosis with a different therapeutic approach in 16% of the patients. In 33%, a diagnosis of disordered oesophageal function was considered either at referral or during the routine assessment for oesophageal disease. Eighty-one percent of the patients with achalasia were treated in accordance with the manometric results. In all cases where an anatomical diagnosis was replaced by a diagnosis of disordered function, the treatment was in accordance with the findings of the motility studies. None of the patients with oesophageal spasm were suspected of having this disease. It is concluded, that not only anatomical features, but also functional considerations have to be taken into account when selecting treatment for benign oesophageal disease. Treatment failure and unnecessary surgical intervention can thus be avoided.
B-lymphoma cells were purged from human bone marrow by incubating the cell suspension with a cocktail of three different pan-B cell mouse IgG1 monoclonal antibodies, and then with immunobeads charged with sheep anti-mouse antibody, followed by magnetic separation. The primary antibodies used, HD37 (CD19), HD6 (CD22), and HH1 (CD37), bind to a very high percentage of the cells in non-Hodgkin's lymphomas of poor prognosis. The secondary antibody is directed against the Fc portion of the IgG antibodies. In model experiments Burkitt's lymphoma cells (Rael) were admixed to mononuclear bone marrow cells in the ratio 1/9. With a ratio of immunobeads/total antibody-binding B cells of 50/1 in a first treatment cycle and repeating the procedure with the same number of beads in a second cycle, a tumor cell depletion of more than 5 logs was achieved, as judged by a clonogenic assay. The concomitant reduction of CFU-GM and CFU-GEMM was about 20%. The purging procedure has been scaled up to clinical use. Equipment suitable for purging patients' marrow specimens, employing standard transfusion facilities, is described. With this equipment the efficacy of tumor cell removal was the same as in the model experiments, and the whole magnetic separation could be completed in 2 hours.
In an attempt to make well-defined cell culture systems, a method has been developed to produce clones of cells obtained from the synovial fluid of patients with rheumatoid arthritis and patients with HLA B-27 associated arthritis. A preliminary characterization of the cloned cells based on morphologic appearance, avidity for Sudan black B, phagocytosis of latex particles and E-rosette formation is here described.
The whole-body distribution of radioactivity after intraperitoneal instillation of 32P-labelled chromic hydroxide particles has been studied in patients operated for early-stage ovarian cancer. Gamma-camera imaging of the abdominal 32P-distribution revealed that the administration procedure was critical for obtaining a homogeneous plating of the radiocolloids on the serosal surface. Dose calculations based on a uniform distribution of 32P in a capillary layer covering the intraperitoneal surface gave an estimated tissue surface dose of about 30 Gy per 370 MBq of 32P administered. The amount of 32P in peripheral blood increased for seven days after instillation followed by a continuous decrease. Bone marrow concentration was from two to five times as high as that in blood, but the total amounts were too small to give significant radiation doses. Gel chromatography showed that 33% of the activity in blood consisted of high molecular weight material, probably colloids. The remainder of the activity (67%) was attached to material of very low molecular weight, appearing as a consequence of physiological degradation of the colloids.
The DNA content of rat bone marrow megakaryocytes (MK) was studied by Feulgen photometry following splenectomy and sham operation, respectively. The DNA measurements were preceded by acetylcholinesterase staining for identification of the 2N-8N MK. The number of 2N-8N MK decreased to minimum values, while the number of 16N-64N MK increased to maximum values about 4 days following both splenectomy and sham operation. However, the changes were somewhat more pronounced following splenectomy than sham operation. The total MK number did not change significantly. Platelet production, measured by 35S incorporation into platelets, increased during the first 2 days and remained high for 6-7 days, increasing the platelet counts. All values were about normal 30 days after surgery, except for a minor thrombocytosis following splenectomy. The early, highly significant thrombocytosis, following both splenectomy and general surgery, is caused by increased production of platelets due to the surgical trauma. This is caused by a direct action on bone marrow MK by transforming 2N-8N MK into higher ploidy classes. Lack of splenic platelet pooling may influence the grade and duration of the early thrombocytosis after splenectomy. The late, long-lasting, minor thrombocytosis, which occurs after splenectomy but not after sham operation, can be explained by the removal of the splenic platelet pool.
Serum ferritin has been analysed and bone marrow haemosiderin evaluated in 306 patients with malignancies, mostly lymphomas, and in 46 healthy controls. Also haemoglobin, serum iron, transferrin and liver enzymes were analysed simultaneously. 60% of the patients had serum ferritin above normal values and 20% had values above 1000 micrograms/l. There was a good correlation between serum ferritin and bone marrow iron both in the patients and in the controls, r = 0.67 and r = 0.77, respectively. There was a negative correlation between serum ferritin and haemoglobin concentration in the patients and a positive correlation in the controls. In patients with Hodgkin's disease serum ferritin was related to the stage of the disease.
Fourteen infants with birth weight appropriate for gestational age (AGA) and 16 small for gestational age (SGA) infants were investigated for haemoglobin concentration, haematocrit level and thrombocyte count on the first day of life. Cord serum was tested for erythropoietin (ESF) and thrombopoietin (TSF) activity. The same investigations were performed on venous blood and serum from 18 healthy adult individuals. SGA infants had higher haemoglobin concentration and haematocrit level (p less than 0.05), and lower platelet count (p less than 0.001) than AGA infants. Significant ESF activity was present in cord serum, but was not detectable in serum from adults. Significant TSF activity was present in cord serum as well as in serum from adults, with higher levels in the newborn infants (p less than 0.05). An inverse relationship was found between serum TSF activity and the number of platelets in adults, which was not demonstrable in newborn infants. Long-term intrauterine hypoxia because of placental dysfunction may be the reason for polycythemia and thrombocytopenia in SGA infants. Thrombocytopenia may be caused by competitive mechanisms on common stem cells for erythropoiesis and thrombopoiesis, shunting stem cells in direction of erythropoiesis during hypoxic exposure. Normal serum TSF activity in SGA infants indicates that lack of the humoral factor for platelet production is not the reason for the thrombocytopenia in these infants. A negative feed-back mechanism may exist between platelet number and TSF production.
In a prospective trial, 42 medical patients with a history of deep vein thrombosis of less than five days were allocated at random to treatment with streptokinase or heparin. Only patients with extensive thromboses were included. Streptokinase was given in a loading dose of 250 000 IU and a maintenance dose of 100 000 IU/hour for 4 days as a mean. Heparin was given in a loading dose of 15 000 IU and a maintenance dose of 20 000-50 000 IU/day. The therapeutic results were evaluated by phlebography. Significant thrombolysis occurred in 71.4% of 21 patients treated with streptokinase and in 23.8% of the 21 heparin-treated patients. Using the chi2-test for overall association, this difference was statistically highly significant (p = 0.002). Three patients in each treatment group experienced major bleeding, two in each group requiring blood transfusions. Minor bleeding and slight rise in temperature were encountered more often in the streptokinase than in the heparin group. It is concluded that patients with acute deep vein thrombosis with proximal extension of the thrombus beyond the calf veins should be offered a therapeutic trial with streptokinase.
The cells of human peripheral lymph collected from leg lymphatic of healthy volunteers have been studied by light- and electron microscopy. More than 80% of the cells were lymphocytes. The rest of the cells were neutrophils, monocytes, phagocytes, intermediate forms between lymphocytes and monocytes, erythrocytes and large cells. Ultrastructurally these large cells had many features in common with the Langerhans cells of normal epidermis and may represent this cell type or a closely related one.
The streptokinase titrated initial dose (TID) was estimated in 31 2 patients consecutively admitted to a medical department in Oslo. 93% had a TID below 250,000 IU, 97% below 425,000 IU and 98.5% below 650,000 IU. No differences were found between the two sexes. The highest values were found in patients 50--60 years old. Otherwise, no differences were found between different age groups from 10 to 90 years of age. Two patients with extremely high TID values were both anamnestically prone to streptococcal infections. It is concluded that our standard initial dose of 250,000 IU of streptokinase is sufcient for the great majority of our patients. Pre-treatment test for TID is recommended only when recent streptococcal infections are suspected.
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By infusion of large amounts of human fibrinogen into rabbits, the ethanol gelation test turned positive at various plasma concentrations of fibrinogen, depending on the fibrinogen preparation used, and on individual differences among the animals. After incubation of the fibrinogen preparation in the cold the precipitated material gave a positive ethanol gelation test at lower fibrinogen concentration whereas the ethanol gelation test remained negative in the supernatant at a higher fibrinogen level than that of the starting material. It is concluded that the finding of a positive ethanol gelation test is not due to the fibrinogen concentration per se. Most likely the test becomes positive due to the presence of soluble fibrin in the commercial preparations.
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