Biomedical subjects
Publications and source records attributed to G J Ossenkoppele.
Doxorubicin (Adriamycin) is an effective antitumour drug. Its major side-effect, cardiotoxicity, is markedly reduced by giving it as a continuous infusion, as illustrated by a case history and review of the literature.
A 30-yr-old woman is described with an intermediate-grade non-Hodgkin's lymphoma, localized in the mediastinum, diagnosed in the 22nd week of gestation. Combination chemotherapy with cyclophosphamide, doxorubicin, vincristine, prednisone, teniposide and bleomycin was instituted in the second and third trimesters, resulting in regression of the tumour. Foetal distress due to pre-eclampsia forced us to perform a Caesarean section at 31 weeks of pregnancy. A healthy boy was born without congenital abnormalities. Further chemotherapeutic treatment, combined with radiotherapy, led to a complete remission of the non-Hodgkin's lymphoma; the remission lasted for 6 months. A review of the literature on chemotherapeutic treatment in non-Hodgkin's lymphoma during gestation is provided. Despite the limited number of cases reported, it can be concluded that chemotherapy in non-Hodgkin's lymphoma during pregnancy is less harmful than might be thought.
A patient is described with chronic myelogenous leukemia (CML) and an unusual karyotype 46XY,t(Y;12) (q11;p12), whose clinical course was complicated by T-cell lymphoma 5 years later. At that time bone marrow cells showed an additional karyotypic abnormality 46XY,t(Y;12) (q11;p12) del(7) (pter-p21), which remained unchanged until blastic transformation of the CML 8 months later. The bone marrow biopsy specimen, which revealed the blastic transformation of the CML, also showed evidence for localization of T-cell lymphoma. This case, added to two previously reported cases of the concurrence of CML and T-cell lymphoma, suggests a relationship between the two diseases, which is discussed.
We present the case of a 56-year-old man who developed-at the age of 46-paraesthesia and numbness in the perianal region, the feet and lower legs accompanied by the presence of B-lymphocytes in the cerebrospinal fluid (CSF). Despite intensive work-up an explanation was not found until he developed hepato-splenomegaly ten years after the initial symptoms. Haematologic evaluation at that time disclosed a low-grade malignant B-cell lymphoma. Repeated CSF examination revealed 31 leukocytes/mm3, of which were mainly lymphocytes. These proved to be B-lymphocytes of monoclonal origin. These findings suggest that a leptomeningeal localisation of a low-grade malignant lymphoma had been present for ten years before systemic manifestation of the disease.
Bone marrow stromal cells are critical for the proliferation and differentiation of hemopoietic stem cells. The hemopoietic microenvironment is reproduced in long term bone marrow culture (LTBMC). Normal LTBMC versus leukemic LTBMC and their stroma conditioned medium were compared with respect to their proliferative and differentiation-inducing capacities. Myeloid leukemic cells (HL60) were layered onto LTBMCs derived from normal volunteers and patients with AML. Differentiation was measured with a comprehensive panel of maturation parameters, i.e. morphology, cytochemistry, quantitative enzyme determination, NBT test and immunophenotyping. Inhibition of proliferation occurred in all cocultures. Clear maturation in monocytic direction was obvious in one culture of HL60 cells layered onto a leukemic stroma. As stroma-derived conditioned medium has no effect, a cellular interaction seems involved. These observations support not only the concept that normal stroma influences leukemic cell growth but also that leukemic stroma can modulate cell growth and maturation.
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In order to study normal and abnormal human megakaryocytopoiesis we modified a glycoprotein Ib dependent megakaryocyte purification technique originally described in guinea pigs. After Percoll density centrifugation, 2 ml bone marrow aspirates were subjected to 3 steps of bovine plasma induced cell clumping, which should selectively agglutinate glycoprotein Ib positive cells. In 13 experiments the resulting samples contained 28-102 x 10(3) megakaryocytes (median 70) with a median purity of 79%. Megakaryocyte recovery ranged from 30-86% (median 51%). The DNA profile showed median values of 10% for 8 N, 44% for 16 N and 43% for 32 N megakaryocytes. The described method is relatively simple, inexpensive and gives results comparable with more elaborate techniques.
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In the human promyelocytic cell line HL60, we observed both a strong procoagulant activity (PCA) on the cell membrane and proteolytic activity in the lysate of these cells. Because these cell-line cells are susceptible to differentiation to either a more mature granulocytic or monocytic form, we were able to study the hypothesis that the combination of PCA and proteolytic activity is confined to the promyelocyte. This may explain the severe coagulopathy seen in patients with acute promyelocytic leukemia. Cell differentiation in a myeloid direction induced by retinoic acid or DMSO led to a diminished PCA, while not affecting the fibrinolytic activity. On the other hand, monocytic differentiation obtained by culturing the cells in the presence of 1; 25 dihydroxy vitamin D3 led to the complete disappearance of the proteolytic activity of the cell lysate, although the procoagulant activity was still present. Furthermore, we found that the elastase activity almost disappeared after monocytic differentiation. We also studied the PCA, proteolytic activity, and elastase activity of blast cells of patients with acute myeloid leukemia. Only in patients with acute promyelocytic leukemia did we observe both a strong PCA and fibrinolytic activity. This supports our hypothesis that the combination of these activities is unique to the promyelocyte and may explain the observed bleeding complications in patients with acute promyelocytic leukemia.
From ten consecutive patients with acute myeloid leukemia leukemic cells were isolated and cultured with and without 10(-6), 10(-7) and 10(-8) M 1.25(OH)2D3 (vit D3), retinoic acid (RA) cytosine-arabinoside (ARA-C) and 1.0, 1.25 and 1.5% dimethyl sulfoxide (DMSO). Maturation was measured with a comprehensive panel of qualitative and quantitative parameters of maturation. Six of those ten leukemias showed significant (p less than 0.01) changes in at least three parameters after exposure to either one of the differentiation inducers. Vit D3 induced maturation in four leukemias, in three of them clearly in monocytic direction. ARA-C showed changes in one leukemia in only three parameters not pointing to either granulocytic or monocytic direction. Maturation in granulocytic direction was observed after exposure to RA in one leukemia. Maturation induction was observed in six out of ten freshly isolated leukemic cells with vit D3 being the most potent inducer of maturation in monocytic direction. The data about inducibility of maturation in freshly isolated human leukemic cells are reviewed and discussed.
Cytosine-arabinoside (ARA-C) in low doses induces complete remissions in myelodysplastic syndromes and acute leukemia. Evidence is accumulating that these remissions are not reached by differentiation induction but through cytotoxicity. In HL60 cells differentiation was measured by a comprehensive panel of quantitative and qualitative markers of maturation. After exposure to ARA-C (10(-7) M) for 4 days HL60 cells did not mature morphologically. Cell volume increased. The increase in esterase activity was small and did not reach the amount measured in normal monocytes. There was no significant difference in latex phagocytosis and NBT reduction between cultures with and without ARA-C. HL60 cells were arrested in S-phase and clonogenic capacity persisted. The observed changes after exposure to ARA-C seem to be caused by impeded cell division while synthesis of protein continues. We conclude that ARA-C in low dose exerts its effect by halting proliferation through cytotoxic effects and not by differentiation induction.
In this retrospective study, 61 induction treatment periods in 57 patients with myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML) were evaluated. According to the WHO performance status, 6 patients received no chemotherapy, 20 had low dose cytosine arabinoside (LD ara-C) induction courses, and 35 received standard induction consisting of daunorubicin and cytosine arabinoside. Untreated patients had a poor survival. Of the 20 patients with LD ara-C induction courses, 4 (20%) achieved complete remission (CR). Three patients (15%) died during induction. Of 35 patients with standard induction, 21 patients (60%) achieved CR. Toxicity was considerable - 11 patients (31%) dying during treatment. We conclude that patients over 60 yr of age with RAEB, RAEB-t or AML had a CR rate and survival comparable to those of younger patients if treated with standard induction chemotherapy at the cost of serious therapy-related complications. In patients who were judged not to be able to tolerate standard induction and who were subsequently treated with LD ara-C, complications occurred less frequently, but the CR rate was low and survival short.
Eighteen patients with high-grade malignant lymphoma were treated with ifosfamide-VP16213 combinations after failing to respond completely or after relapsing on CHOP-like therapy. Responders to the salvage therapy were subsequently treated with ablative chemotherapy (BCNU, VP-16213, Ara-C and melfalan) and autografted. Of these 18 patients six were in relapse, six were partial responders and six failed CHOP-like therapy. There were two complete remissions and seven partial responses to the ifosfamide-VP-16213 combinations. Of them, eight patients were transplanted, together with one non-responder. Four of these nine patients were disease-free survivors 18-34 months after autografting. There were two early deaths: one before and one during the autografting procedure. Using one of the best salvage therapy combinations followed by high-dose chemotherapy and autografting is feasible. The results in this pilot study suggest that an appreciable number of patients may be cured by this procedure.
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From 1975 through 1985 88 patients with a primary manifestation of non-Hodgkin's lymphoma in the upper digestive and respiratory tract were referred to our hospital. Fifty-seven of them were in Stage I or II. The results of therapy in 48 evaluable patients are the subject of this retrospective study. Low, intermediate, and high grade malignant histologic features were encountered in 6, 27, and 15, respectively. The authors compared retrospectively the patients treated with radiotherapy (RT) with those who received additionally chemotherapy (RT + CT). Patients have been followed for a minimum of 1 year. Four of 29 patients with intermediate-grade or high-grade malignant lymphoma treated with CT and RT relapsed whereas eight of 13 patients treated with RT alone relapsed. Actuarial survival curves differed significantly in favour of the CT and RT group. These figures were also significant when the high-grade lymphomas plus centroblastic lymphomas were considered. It is recommended to add CT to RT in both Stage I and II NHL of high-grade and intermediate-grade malignancy.
In acute myeloid leukemia the leukemic cells are thought to be blocked in their normal differentiation. The stage of differentiation is the basis for the FAB classification. Induction of cell differentiation is a new and promising development in the treatment of some myeloproliferative diseases. The criteria for cell maturation and differentiation are almost all based on the morphology of the leukemic cells. In this study we tried to specify the maturation stage of the leukemic cells by quantitative enzyme analysis. In the HL60 (promyelocytic) cell line cells we determined the following enzymes: myeloperoxidase; alpha naphthyl acetate esterase; alpha naphthyl butyrate esterase and lactate dehydrogenase. The enzyme profiles obtained after culturing the cells in the presence of the differentiation inducing agents 1:25 dihydroxy vitamin D3 and DMSO were compared with several cytochemical and functional parameters. The results obtained in this study show that quantitative enzyme analysis is a useful tool in the study of myeloid or monocytic differentiation.
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