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Häftad, Engelska, 2014
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G.MATHE Institut de Cancerologie et d''Immunogenetique (INSERM et Association Claude-Bernad), H6pital Paul-Brousse and Institute Gustave-Roussy, Villejuif 20 years ago, the main, if not only object of the cancer therapist was to effect complete surgical exeresis or radiotherapeutic destruction of a local tumor, or to obtain, by means of chemotherapy, an "apparently complete regression" of a local or disseminated neoplasia. Today it is realized that (a) at the time of the operation or radiotherapy, two patients in every three carrying an apparently localized tumor have a few cancer cells outside the area where the tumor seems localized; (b) when "apparently complete regression" or even an "apparently complete remission" is induced by chemotherapy, not all the neoplastic cells have been eradicated. In both cases an imperceptible residual neoplasm persists, the growth of which will in due course make it perceptible again, giving rise to metastasis or to a systemic or localized relapse. There is thus an urgent need for a new technique capable of killing the last cell or cells. Our experiments in mice on the effectiveness of active immunotherapy, which involves the manipulation of the immune machinery, have shown that this treatment is able to kill all the cells, down to the very last cell of a given leukemia, provided that the total number of cells does not exceed a few thousand [1, 2].
Häftad, Engelska, 2012
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G.MATHE Institut de Cancerologie et d'Immunogenetique (INSERM et Association Claude-Bernad), H6pital Paul-Brousse and Institute Gustave-Roussy, Villejuif 20 years ago, the main, if not only object of the cancer therapist was to effect complete surgical exeresis or radiotherapeutic destruction of a local tumor, or to obtain, by means of chemotherapy, an "apparently complete regression" of a local or disseminated neoplasia. Today it is realized that (a) at the time of the operation or radiotherapy, two patients in every three carrying an apparently localized tumor have a few cancer cells outside the area where the tumor seems localized; (b) when "apparently complete regression" or even an "apparently complete remission" is induced by chemotherapy, not all the neoplastic cells have been eradicated. In both cases an imperceptible residual neoplasm persists, the growth of which will in due course make it perceptible again, giving rise to metastasis or to a systemic or localized relapse. There is thus an urgent need for a new technique capable of killing the last cell or cells. Our experiments in mice on the effectiveness of active immunotherapy, which involves the manipulation of the immune machinery, have shown that this treatment is able to kill all the cells, down to the very last cell of a given leukemia, provided that the total number of cells does not exceed a few thousand [1, 2].
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Scientific and Ethical Discipline in Clinical Trials on Acute Leukemia G. MATHE Institut de Cancerologie ct d''Immunogenetique "'', Hi''ipital Paul-Brousse "."", Villejuif/France Clinical research is still in an evolutionary stage. Although scientific technology was readily accepted and applied, scientific methodology has been accepted much more slowly and is very rarely properly applied. There are three reasons why this is so. First, medical ethics frequently limits the applicability of clinical research, for doctors have to be more than scientists. They must also remain moral philosophers, as they were before medicine became a science. Second, the heterogeneity of the material on which clinical researchers work in studying human diseases makes the application of scientific methodology difficult. Third, researchers must publish. This means that they must obtain publishable results, and too often this means results in accordance with established concepts, easily accepted by the editors of established journals, which are read by the establishment. It is the privilege of too many people to be able to accept "truth" and recipes from other people and confirm their truth and results. It is the mission of a very few others to accept nothing as "truth" and to consider no recipe ideal, either in concept or detail.
Häftad, Engelska, 2012
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Scientific and Ethical Discipline in Clinical Trials on Acute Leukemia G. MATHE Institut de Cancerologie ct d'Immunogenetique "', Hi'ipital Paul-Brousse "."", Villejuif/France Clinical research is still in an evolutionary stage. Although scientific technology was readily accepted and applied, scientific methodology has been accepted much more slowly and is very rarely properly applied. There are three reasons why this is so. First, medical ethics frequently limits the applicability of clinical research, for doctors have to be more than scientists. They must also remain moral philosophers, as they were before medicine became a science. Second, the heterogeneity of the material on which clinical researchers work in studying human diseases makes the application of scientific methodology difficult. Third, researchers must publish. This means that they must obtain publishable results, and too often this means results in accordance with established concepts, easily accepted by the editors of established journals, which are read by the establishment. It is the privilege of too many people to be able to accept "truth" and recipes from other people and confirm their truth and results. It is the mission of a very few others to accept nothing as "truth" and to consider no recipe ideal, either in concept or detail.
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G. MATHE and R. K. OLDHAM''~ Institut de Cancerologie et d''Immunogem!tique, Hopital Paul Brousse, Villejuif Since the last war, cancer chemotherapy has been the object of very intensive and expensive research. Nevertheless, its development has been very slow, and its ultimate potential is today somewhat in doubt. In doubt because it does not cure any cancer patients except a) females carrying placental choriocarcinoma, a semi-allogenic tumor, in which case, cure may be in fluenced by immune rejection, and b) children suffering from Burkitt''s tumor, where the probable reason for the cure is that all the neoplastic cells are in the cycle, which is a unique condition among all the human tumor varieties. Whether the long term survivors in acute leukemia, lymphomas, certain sarcomas and certain testicular tumors are "cures" will require longer follow-up. The idea that chemotherapy does not cure most cancer patients because all their neoplastic cells are not in cycle has led to the use of drug combinations. Whatever they are, "cocktail combinations" which are made up of drugs given according to any timing, or scientific combinations, based on pharmacodynamics, pharmaco kinetics or cell kinetics data, are more toxic than single drugs, and are all the more toxic as the number of drugs in the combination is increased.
Häftad, Engelska, 2012
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G. MATHE and R. K. OLDHAM'~ Institut de Cancerologie et d'Immunogem!tique, Hopital Paul Brousse, Villejuif Since the last war, cancer chemotherapy has been the object of very intensive and expensive research. Nevertheless, its development has been very slow, and its ultimate potential is today somewhat in doubt. In doubt because it does not cure any cancer patients except a) females carrying placental choriocarcinoma, a semi-allogenic tumor, in which case, cure may be in fluenced by immune rejection, and b) children suffering from Burkitt's tumor, where the probable reason for the cure is that all the neoplastic cells are in the cycle, which is a unique condition among all the human tumor varieties. Whether the long term survivors in acute leukemia, lymphomas, certain sarcomas and certain testicular tumors are "cures" will require longer follow-up. The idea that chemotherapy does not cure most cancer patients because all their neoplastic cells are not in cycle has led to the use of drug combinations. Whatever they are, "cocktail combinations" which are made up of drugs given according to any timing, or scientific combinations, based on pharmacodynamics, pharmaco kinetics or cell kinetics data, are more toxic than single drugs, and are all the more toxic as the number of drugs in the combination is increased.
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I would like to thank all my co-workers who have collaborated with me, from 1963 until now, in biological and clinical research in the field of cancer active immunotherapy, of its immuno prevention and immunorestoration. They will often be quoted in this book. I am particularly grateful to those who have helped me to write it by reviewing some chapters: D. BELPOMME, J. F. DOR~, IRENE FLORENTIN, A. GOUTNER, I. J. Hm, R. HUCHET and MARIE-CHRISTINE SIMMLER. I also thank NICOLE VRIZ, MARIE-CLAUDE SCHNEIDER, FENELLARIsELEY and M. JUVET for their willing and efficient co-operation in the preperation of the manuscript. I am finally grateful to all authors of books or articles who authorized me to reproduce their figures or tables. Paris, April 1976 G. MAT~ Contents Chapter 1. Introduction and Definitions 1 Chapter 2. Biological Basis: Tumour Associated Antigens, the Immune Machinery and Its Behaviour Concerning Cancer Cells 5 2. 1. Tumour-Associated Antigens 5 2. 2. The Immune Machinery 19 2. 2. 1. Humoral Mediated Immunity and Cell Mediated Immunity 19 2. 2. 2. T- and B-Lymphocyte and Monocyte Differen tiation 22 2. 2. 3. T-Lymphocyte Functions 25 2. 2. 4. B-Lymphocyte Functions 30 2. 2. 5. Macrophage Functions 31 2. 2. 6. K-Cell Function 32 2. 3. The Immune Machinery and Cancer Cells 33 2. 3. 1. Mechanisms Involved in Tumour Cell Rejec tion 33 2. 3. 1. 1. In vivo Evidence for Tumour Immunity 33 2. 3. 1. 2.
Häftad, Engelska, 2012
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I would like to thank all my co-workers who have collaborated with me, from 1963 until now, in biological and clinical research in the field of cancer active immunotherapy, of its immuno prevention and immunorestoration. They will often be quoted in this book. I am particularly grateful to those who have helped me to write it by reviewing some chapters: D. BELPOMME, J. F. DOR~, IRENE FLORENTIN, A. GOUTNER, I. J. Hm, R. HUCHET and MARIE-CHRISTINE SIMMLER. I also thank NICOLE VRIZ, MARIE-CLAUDE SCHNEIDER, FENELLARIsELEY and M. JUVET for their willing and efficient co-operation in the preperation of the manuscript. I am finally grateful to all authors of books or articles who authorized me to reproduce their figures or tables. Paris, April 1976 G. MAT~ Contents Chapter 1. Introduction and Definitions 1 Chapter 2. Biological Basis: Tumour Associated Antigens, the Immune Machinery and Its Behaviour Concerning Cancer Cells 5 2. 1. Tumour-Associated Antigens 5 2. 2. The Immune Machinery 19 2. 2. 1. Humoral Mediated Immunity and Cell Mediated Immunity 19 2. 2. 2. T- and B-Lymphocyte and Monocyte Differen tiation 22 2. 2. 3. T-Lymphocyte Functions 25 2. 2. 4. B-Lymphocyte Functions 30 2. 2. 5. Macrophage Functions 31 2. 2. 6. K-Cell Function 32 2. 3. The Immune Machinery and Cancer Cells 33 2. 3. 1. Mechanisms Involved in Tumour Cell Rejec tion 33 2. 3. 1. 1. In vivo Evidence for Tumour Immunity 33 2. 3. 1. 2.
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Fresh living Bacillus Calmette-Guerin (BeG), injected i.v. into (C57BI/ 6xDBA/2)FI mice, activated peritoneal macrophages rendering them highly cytotoxic for tumor cells in vitro. This cytotoxic activity w~s already maximal 14 days after injection of 1 mg of BCG and remained stable when 3 or 5 mg of BCG were given. At the same time spleen cells of the BCG-treat~d mice showed strongly depressed responses to the T-cell mitogens,PHA and Con A, irrespective of the dose of BCG injected. The inhibitory effect was shown to be mediated by suppressor cells which had characteristics of macrophages since they could be removed by carbonyl iron and magnet treatment and were adherent to plastic. In contrast to it was observed after injec tion of 1 mg of BCG, these suppressor cells alone did not account for the depression of T-cell re.sponses induced by higher doses of BCG. Nylon-nonadherent cell populations obtained from spleen cells treated with 3 or 5 mg BCG partially retained the inhibitory activity suggesting that suppressor T cells were also induced after injection of high doses of BCG. In contrast, the responses to the B-cell mitogen LPS of unfractionated and macrophage-depleted spleen cells were not affected or significantly enhanced depending on the dose of BCG injected.
Häftad, Engelska, 2011
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Fresh living Bacillus Calmette-Guerin (BeG), injected i.v. into (C57BI/ 6xDBA/2)FI mice, activated peritoneal macrophages rendering them highly cytotoxic for tumor cells in vitro. This cytotoxic activity w~s already maximal 14 days after injection of 1 mg of BCG and remained stable when 3 or 5 mg of BCG were given. At the same time spleen cells of the BCG-treat~d mice showed strongly depressed responses to the T-cell mitogens,PHA and Con A, irrespective of the dose of BCG injected. The inhibitory effect was shown to be mediated by suppressor cells which had characteristics of macrophages since they could be removed by carbonyl iron and magnet treatment and were adherent to plastic. In contrast to it was observed after injec tion of 1 mg of BCG, these suppressor cells alone did not account for the depression of T-cell re.sponses induced by higher doses of BCG. Nylon-nonadherent cell populations obtained from spleen cells treated with 3 or 5 mg BCG partially retained the inhibitory activity suggesting that suppressor T cells were also induced after injection of high doses of BCG. In contrast, the responses to the B-cell mitogen LPS of unfractionated and macrophage-depleted spleen cells were not affected or significantly enhanced depending on the dose of BCG injected.
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CNRS International Colloquium, Held in Paris on June 22-24, 1977
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We have studied 24 cases of secondarily leukemic (stage V) lymphosarcoma (LS), 31 cases of "d''emblee" leukemic LS, and ten cases of lymphoid leukemic neoplasias transitional between "d''emblee" leukemic LS and chronic lymphocytic leukemia (eLL). These cases only concern the common types ofthe WHO classification ofLS, i.e., the prolymphocytic, the lymphoblastic, 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''emblee" 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.
Häftad, Engelska, 2012
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We have studied 24 cases of secondarily leukemic (stage V) lymphosarcoma (LS), 31 cases of "d'emblee" leukemic LS, and ten cases of lymphoid leukemic neoplasias transitional between "d'emblee" leukemic LS and chronic lymphocytic leukemia (eLL). These cases only concern the common types ofthe WHO classification ofLS, i.e., the prolymphocytic, the lymphoblastic, 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'emblee" 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.
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P. Denoix and G. Mathe Approximately 70% of cancer patients relapse after surgery before the 5th year and, in most cases, for example in breast carcinoma, they relapse still later up to the 20th year. For some considerable time, the strategy of cancer treatment has been limited to the sophistication of surgery-radiotherapy combinations that maximally decreased the incidence of local and regional relapses in sites that were within their reach. Today, the practice of clinical oncology is unthinkable without the active participation of the medical oncologist. He is the "third man" of the clinical oncology team, and he has recently focused attention on the fact that most relapses arise from distant metastases due to the proliferation of cells seeded there after having left the primary tumor site at the time of operation and, hence, are inaccessible to any form oflocal and/or regional treatment. On this evidence, medical oncologists have proposed the application of medical treatments for disseminated minimal residual disease (MRD). They have two available means: chemother apy and immunotherapy. Medical oncologists in general can be divided into three groups: chemotherapists, immunotherapists, and chemoimmunotherapists. The pure chemotherapists, who had already cured some malignant neoplasias such as Hodgkin''s disease, acute lymphoid leukemia, placental choriocarcinoma, and Wilms'' tumor, thought they might have the means of attacking the residual disease of common cancers.
Häftad, Engelska, 2011
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P. Denoix and G. Mathe Approximately 70% of cancer patients relapse after surgery before the 5th year and, in most cases, for example in breast carcinoma, they relapse still later up to the 20th year. For some considerable time, the strategy of cancer treatment has been limited to the sophistication of surgery-radiotherapy combinations that maximally decreased the incidence of local and regional relapses in sites that were within their reach. Today, the practice of clinical oncology is unthinkable without the active participation of the medical oncologist. He is the "third man" of the clinical oncology team, and he has recently focused attention on the fact that most relapses arise from distant metastases due to the proliferation of cells seeded there after having left the primary tumor site at the time of operation and, hence, are inaccessible to any form oflocal and/or regional treatment. On this evidence, medical oncologists have proposed the application of medical treatments for disseminated minimal residual disease (MRD). They have two available means: chemother apy and immunotherapy. Medical oncologists in general can be divided into three groups: chemotherapists, immunotherapists, and chemoimmunotherapists. The pure chemotherapists, who had already cured some malignant neoplasias such as Hodgkin's disease, acute lymphoid leukemia, placental choriocarcinoma, and Wilms' tumor, thought they might have the means of attacking the residual disease of common cancers.
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A prospective randomized clinical trial of treatment with vincristine, cyclophosphamide, methotrexate and 5-fluorouracil after conventional curative treatment for stage II breast cancer is described. The results at 2 years are recorded together with details of toxicity. Future plans are discussed briefly. Acknowledgement We wish to acknowledge the participation of all the collaborators in this study, the co-ordinator Dr. ERICA MANSBACHER and the support of Action Cancer in Belfast. References 1. Ahmann, D. L. , O'Connell, M. J. , Hahn, R. G. , Bisel, H. F. , Lee, R. A. , Edmonson, J. H. : An evaluation of early or delayed adjuvant chemotherapy in premenopause1 patients with advanced breast cancer undergoing oophorectomy. New Engl. J. Med. 297, 356-360 (1977) 2. Ahmann, D. L. , Scanlon, P. W. , Bisel, H. F. , Edmonson, J. H. , Frytak, S. , Payne, W. S. , O'Fallon, J. R. , Hahn, R. J. , Ingle, J. N. , O'Connell, M. J. , Rubin, J. : Repeated adjuvant chemotherapy with Phenyl-alanine mustard, or 5-Fluorouracil, Cyclophosphamide and Prednisone with or without radiation after mastectomy for breast cancer. Lancet 1978//, 893-896 3. Bonadonna, G. , Rossi, A. , Valagussa, P. , Banfi, A., Veronesi, U. : The CMF program for operable breast cancer with positive axillary nodes. Cancer 39, 2904-2915 (1977) 4. Edelstyn, G. A. , Bates, T. S. , Brinkley, D. , Macrae, K. D. , Spittle, M. , Wheeler, T. : Comparison of 5-day, I-day and 2-day cyclical combination chemotherapy in advanced breast cancer.
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Local treatment cures about 30 to 40% of cancers, this proportion depending on the follow-up required to establish it. This means that 60 to 70% of the malignant neoplasias are disseminated either perceptibly (leukemias, visible metas- tases) or imperceptibly, forming a 'minimal imperceptible disease', which local treatment leaves, whether it consists of surgery, radiotherapy, or surgery plus radiotherapy. When the neoplastic tissue is voluminous enough to be per- ceptible, cures can be obtained with chemotherapy or chemo- immunotherapy. When the neoplastic disease is imperceptible, made up of micrometastases, it apparently can be cured by systemic postsurgical chemotherapy, immunotherapy, or chemoimmunotherapy. Hence there is the need for intensive development of these medical therapies which are applied by the medical oncol- ogist and, at present, consist of chemotherapy, immuno- therapy, or chemoimmunotherapy. These medical thera- peutics can only grow with scientific development, the main weapon of which is experimental and clinical pharmacology. These volumes report the communications presented at the 1979 EORTC Annual Plenary Session on Cancer Chemo- and Immunopharmacology.
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Häftad, Engelska, 2011
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The impressive advances in all branches of medical science during the first half of this century with the discovery of many chemotherapeutic or immunogenic agents gave rise to brilliant achievements in the struggle against some infectious diseases and aroused in many scientists the wishful thought that drugs for cancer therapy would, soon lead to additional great success. Notwithstanding ever-increasing worldwide endeavors, the major problems in prevention or treatment of neoplastic diseases are still unsolved. The approach to the resolution of these problems follows many different pathways. Basic research tries to cast light on the genetic and biochemical processes underly ing cell division and differentiation as well as the interactions occurring between the cell and the oncogenic stimulus, or between the neoplastic cells and the different body systems endowed with immunological reactivity. Another line of approach, coherent with the classic basis of chemotherapy, relies upon the search for new compounds selectively blocking the multiplication of the neoplastic cells. The remarkable progress made in treating human cancer, as a result of these efforts, has been until now ascribable chiefly to the accomplishment of the chemo therapeutic approach. Studies on the cytostatic activity of the anthracycline antibiotics carried out over many years eventually led the investigators of Farmitalia (Milan, Italy) to discover and characterize some new compounds endowed with interesting chemotherapeutic properties against malignant neoplastic diseases.
Häftad, Engelska, 2012
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The impressive advances in all branches of medical science during the first half of this century with the discovery of many chemotherapeutic or immunogenic agents gave rise to brilliant achievements in the struggle against some infectious diseases and aroused in many scientists the wishful thought that drugs for cancer therapy would, soon lead to additional great success. Notwithstanding ever-increasing worldwide endeavors, the major problems in prevention or treatment of neoplastic diseases are still unsolved. The approach to the resolution of these problems follows many different pathways. Basic research tries to cast light on the genetic and biochemical processes underly ing cell division and differentiation as well as the interactions occurring between the cell and the oncogenic stimulus, or between the neoplastic cells and the different body systems endowed with immunological reactivity. Another line of approach, coherent with the classic basis of chemotherapy, relies upon the search for new compounds selectively blocking the multiplication of the neoplastic cells. The remarkable progress made in treating human cancer, as a result of these efforts, has been until now ascribable chiefly to the accomplishment of the chemo therapeutic approach. Studies on the cytostatic activity of the anthracycline antibiotics carried out over many years eventually led the investigators of Farmitalia (Milan, Italy) to discover and characterize some new compounds endowed with interesting chemotherapeutic properties against malignant neoplastic diseases.