Low heart and skin toxicity of a tetrahydropyranyl derivative of adriamycin (THP-ADM) as observed by electron and light microscopy.
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Biomedical subjects
Publications and source records attributed to G Mathé.
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Intravenous injection (i.v.) of heat-killed Pseudomonas aeruginosa in mice produced histologic changes in the thymic cortex, some of which resembled, while others differed from, those produced by i.v. injection of living BCG. The changes that were similar consisted of pyroninophilia of cortical lymphocytes and hyperplasia of epithelial cells in the medulla and at the corticomedullary junction with increased PAS positive cells and secretions. Major differences, however, in the sequence and nature of the histologic events were observed. Pseudomonas injections produced thymic epithelial cell hyperplasia with increased PAS positive cells and secretions and pyroninophilia of thymic cortical lymphocytes earlier than did i.v. BCG (day 1 versus day 7). Corticomedullary inversion of thymic structure and early transient hyperplasia of the thymus dependent areas in the lymph nodes and spleen occurred after Pseudomonas but not after BCG injections. Hyperplasia in the B cell areas and germinal centers started to appear at day 10 after injection of Pseudomonas and persisted up to day 21 (compared to day 7 and day 14, respectively, for BCG). In contrast to i.v. BCG, Pseudomonas injections did not produce granulomas or macrophage proliferations.
An attempt to correct the state of immunodeficiency in old age was made by repeatedly injecting a chemically defined immunostimulating agent, bestatin, to 16 month old (C57Bl/6 x BALB/c) F1 mice. Aged mice were found to have depressed T-cell and B-cell responses but increased ADCC activity. Weekly injections of bestatin over a period of 6 months resulted in varying effects depending on the dose administered. Small doses (10 microgram per injection) were more effective in restoring humoral responses to SRBC rather than delayed-type hypersensitivity reactions, whereas large doses (100 microgram per injection) acted in the opposite way. Macrophage activation was only obtained after the administration of the high doses of bestatin. Continuous treatment with bestatin did not prevent the appearance of suppressor cells induced by ageing. It led to a significant reduction of ADCC activity in aged animals near to the base line value of young animals. Animals were examined for the presence of spontaneous tumours from the end of the treatment until the age of 28 months. A significant reduction of spontaneous tumour incidence was observed in mice given repeated injections of 100 microgram bestatin when compared to untreated aged mice and to mice given the low doses of bestatin.
The sequence of histologic events in graft-versus-host reaction (GVHR) caused by major and/or minor histoincompatibilities was studied. It was discovered that GVHR may manifest itself in the form of two distinct multiphasic disease entities, depending on whether the donor cells are incompatible with the host for both major and minor histocompatibility antigens ("major GVHR") or for minor histocompatibility antigens alone ("minor GVHR"). The acute or major GVHR has four phases: 1) a transient phase of aplasia, 2) a repopulation phase, 3) a proliferative phase involving lymphoid, presumably immunocompetent, cells, and 4) a phase of acute organ rejection (terminal). The chronic or minor GVHR is characterized by six phases, namely: 1) a transient phase of aplasia, 2) a repopulation phase, 3) a phase of proliferation and tissue infiltration by lymphoid, presumably immunocompetent cells, 4) a phase of major immunologic injuries, 5) a phase of repair, and 6)a terminal phase with advanced sclerosis and proliferative glomerulonephritis. In acute or major GVHR the disease was manifested by the tissue reactions characteristic of acute organ rejection. Lesions were seen in the kidney, liver, bone marrow, lymph nodes, spleen, thymus, intestine, and skin. In the chronic or minor GVHR, tissue injuries were more widespread, affecting the collagen, vessel walls, adipose tissue, renal glomeruli, heart muscle, fascias of skeletal muscles, lymph nodes, spleen, thymus, bone marrow, intestine, skin, esophageal mucosa, and urinary tract. A pronounced plasma cell proliferation was a striking feature in the minor GVHR. Its evolution coincided with advanced thymic epithelial atrophy. It is suggested that the destruction of thymic epithelium resulted in depletion of suppressor T cells and, consequently, in an unopposed proliferation of plasma cells.
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Golden hamsters received Adriamycin (ADR), detorubicin (DTR), AD-32, or aclacinomycin (ACM) three times weekly at doses extrapolated from optimal doses in L1210 leukemia. Minimal early lesions of the myocardium were detected by electron microscopy in ACM-treated animals. These lesions were aggravated after several weeks of treatment but remained reversible. Lesions in AD-32-treated hamsters were slightly more marked than those seen in ACM-treated animals but were much less severe than those observed in ADR- or DTR-treated animals. Similarly, light microscopy revealed pathologic changes in the skin following ADR or DTR administration. These changes were not seen in animals receiving AD-32 or ACM.
Cytotoxic autoreactive lymphoid cells have been demonstrated to be a normal immunologic component in both normal and tumor-bearing organisms. The cells have a high antineoplastic potential. They are cytotoxic in vitro to non-immunogenic tumor cells, and a high in vivo activity of such cells may be positively correlated to in vivo regression of tumors. It is suggested that the cytotoxic activity of cytotoxic autoreactive cells reflects a natural mechanism to removal of all types of aberrant cells of which malignant cells are only a subset. It is further deduced that such mechanisms must be independent of cell surface neoantigens, and that cytotoxic autoreactive mechanisms with high probability therefore also are efficient against spontaneous malignant tumors.
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Sixty-six patients with bronchus non resectable squamous cell carcinoma (stage III and 14) entered into a protocol of chemotherapy depending upon their initial immunological status. These patients with (+) skin tests to recall antigens were allocated to a chemotherapy programme; patients with initially (-) skin tests were submitted to a protocol of immunorestauration with B.C.G. After three weeks of B.C.G. applications on scarifications 17 patients out of 31 presented with (+) skin tests and were considered as immunocompetent patients. All the patients then were submitted to chemotherapy protocol. The comparison of different median of survival have demonstrated that immune status appears as the more fundamental prognosis factor; the B.C.G. is able to transitory restore the immunity of the patients without any modification of the tumour progress. The median of survival of patients with initially (+) skin tests was ten months, and only two months for patients with (-) skin tests. The median of survival of patients whom immunity was restored with B.C.G. was nine months. The results of this trial let us to propose new strategy for treatment of these patients.
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The categorization of lymphosarcomas with immune markers has enriched the prognosis value of the WHO classification. The prolymphocytic (centrofollicular) B-type and the null lymphoblastic subtype have a good prognosis, while the (T- or B-) immunoblastic type and the T-lymphoblastic subtype have a poor prognosis.
We have studied 24 cases of secondarily leukemic (stage V) lymphosarcoma (LS), 31 cases of "d'emblée" leukemic LS, and ten cases of lymphoid leukemic neoplasias transitional between "d'emblée" leukemic LS and chronic lymphocytic leukemia (CLL). These cases only concern the common types of the WHO classification of LS, i.e., the prolymphocytic, the lymhoblastic, and the immunoblastic. Some cases have also been classified by cell surface markers. The secondarily leukemic conversion occurred in 40% of the lymphoblastic types, in 14% of the prolymphocytic types, and in 17% of the immunoblastic types. It never occurred at stage I but could occur after any other stage. The mediastinal involvement was observed in three types, but most often in the lymphoblastic type. The prognosis after an acute lymphoid leukemia (ALL) treatment comprising active immunotherapy following chemo(radio)therapy is better for the leukemic prolymphocytic and lymphoblastic LS than for the immunoblastic type. Two patients (one of the lymphoblastic type) are in complete remission after 8 and 5 years, respectively. We have described ten cases of "d'emblée" leukemic LS with either large lymphoid or extra-lymphoid masses, bone marrow leukemic cell involvement, and LS aspects of neoplastic cells. Mediastinal abdominal, or other tumor masses are frequent. The prognosis for "d'emblée" leukemic LS following an ALL treatment is less favorable than ALL prognosis for patients of all ages including children. However, the first remission curve breaks at the 18th month and may form a plateau for about 30% of the patients of all ages. One patient has been in remission for more than 8 years after immunotherapy. We have also described ten cases of lymphoid neoplasia, whose cells cytologically and by the intensity of Ig secretion resemble leukemic prolymphocytic LS cells. However, the disease is more sensitive to CLL treatment than to LS or ALL treatment. Hence, there may be transitional conditions between leukemic LS and CLL. Finally, we have discussed the different possible frontiers between nonleukemic and leukemic LS and proposed two tests to detect the leukemic stage early: the systematic search for LS cells in the peripheral blood after concentration of nucleated cells by centrifugation and for cells carrying immune markers in the isolated mononuclear cell population of peripheral blood and the bone marrow.
One hundred and one patients with advanced (stage III and IV) LS and RS at the first presentation of the disease or on relapse were treated with a regimen combining initial chemotherapy, complementary radiotherapy on "icebergs," supplementary chemotherapy, and finally, active immunotherapy. The overall complete remission rate was about 79% for LS and 73% for RS. About 50% of the patients were still in remission for both diseases after 2 years; 60% with LS were still alive after 2 years and 44% with Rs. This study shows the useful prognostic value of the WHO classification for LS and RS: the prognosis of prolymphocytic (centrofollicular) LS is far better than that of the lymphoblastic type, which is itself better than that of the very poor prognostic immunoblastic type. The prognosis of RS is intermediate between that of the best prognostic type and that of the poorest prognostic type of LS.
1. A type 2 therapeutic trial consisting of the administration of monthly cycles of chemohormonotherapy, each cycle combining weekly sequences of mephalan, prednisone, cyclophosphamide, and prednisone, has been achieved in 20 stage II or III myeloma patients. Tolerance of this regimen in treated out-patients was found to be excellent. Preliminary data indicate that the better survival rate in patients treated by this regimen is still not reached at a 30-month follow-up examination by three other nonrandomized control groups of patients receiving continuous therapy with prednisone alone, prednisone + cyclophosphamide, or prednisone + melphalan. 2. Analysis of the main prognostic factors of the four trials indicates that a) IgG-type myelomas are associated with a better prognosis than IgA type; nonexcreting myelomas are associated with the best prognosis, while Bence Jones myelomas are associated with a prognosis as poor as that of the IgA type; b) tumor volume as well as renal insufficiency, at the time of diagnosis, are also prognosis factors; this study confirms the prognostic value of the recently proposed clinical staging system based on these parameters but outlines that 10% of the patients died from a cause not directly related to myeloma plasmocyte proliferation. 3. In conclusion, these results point out: a) the possible advantage of using two alkylating agents instead of one at the beginning of the disease; b) the need to classify multiple myeloma according to prognosis before attempting therapeutic trials.
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