Georges Mathé

TREATMENT OF ACUTE TOTAL-BODY IRRADIATION INJURY IN MAN

The treatment of total-body irradiation injury is essentially based on a very intensive symptomatic therapy (maintenance of patients in aseptic conditions, rational and not systematic use of antibiotics, platelet transfusions when the level of these cells is below 50,000); allogenic bonemarrow transfusion is indicated in case of failure of this symptomatic therapy, whether the dose of irradiation is 100% lethal or less. (auth)

Treatment of malignant gliomas and brain metastases in adults with a combination of adriamycin, VM 26, and CCNU. Results of a phase II trial

Forty‐three patients with inoperable or recurring malignant gliomas, and 30 patients with multiple recurring brain metastases were treated with a combination of Adriamycin (45 mg/m2) and 4‐dimethyl‐epipodophyllotoxin D‐thenylidene (VM 26) (60 mg/m2 for 2 days) with 1‐(2‐chloroethyl)‐3‐cyclohexyl‐1‐nitrosourea (CCNU) (60 mg/m2 for 2 days). These cycles of treatment were repeated as soon as the hematologic restoration was complete. The treatment was well tolerated and the clinical condition of 31 of 43 glioblastoma patients improved during the 2 months after the beginning of the treatment. Six of eight patients with breast cancer metastases, one of 13 with bronchial cancer metastases, and three of nine with other types of cancer metastases also benefitted from the treatment. Examination of the results obtained revealed the following characteristics: 1) This combination had a low degree of efficiency in the treatment of metastases to brain, except for breast cancer metastases; 2) there was no complete correlation between the clinical results observed and the cinegammagraphic developments; 3) the results obtained were similar, independent of the initial localization; and a 6‐month median survival period was established, with 10 patients now in a state of apparently complete remission, 180 to 506 days after beginning of the treatment.

A study of relapse and course of 153 cases of Hodgkin's disease (clinical stages I and II) treated at the institute gustave-roussy from 1963 to 1970 with radiotherapy alone or with adjuvant monochemotherapy

Seventy‐three relapses were observed among 153 patients with Hodgkins disease, clinical Stages I and II, who underwent treatment between 1963 and 1970. Treatment consisted of radiotherapy to the involved side of the diaphragm alone or followed by two years of weekly injections of Vinblastine® Half these patients had been included in the EORTC H1 trial, and the relapse‐free rate and survival rate of our study were similar to those observed in that investigation. The relapse‐free rate was higher for the group receiving combination therapy; the difference in survival, although smaller than the difference in relapse‐free rates, is significant. Among patients with poor prognostic factors, the survival rate was significantly higher for those who received monochemotherapy. The addition of chemotherapy did not significantly improve the survival rate for patients with good prognostic factors of the 73 patients who had relapses, 12 (16%) died during the first relapse, 23 (32%) are relapse‐free and the Hodgkins disease appears to be cured, and 38 (52%) experienced second relapses. The durations of the first and the second remissions were related. The survival rate was about 50% at five years after the first relapse; the rate was slightly lower for patients with relapses at extranodal sites. For the small group with marginal recurrence, the prognosis appeared to be better. The survival rate after relapse was not significantly influenced by the type of initial treatment. The incidence of transdiaphragmatic spread of the disease was 29% (40 of 137) for those with supradiaphragmatic disease and 63% (10/16) for those with subdiaphragmatic disease (clinical Stages I and II). It was as high as 75% for those with clinical Stage II subdiaphragmatic disease of the 32 splenectomies performed after relapse, 20 revealed splenic involvement. Histologic slides were initially classified and then reviewed blindly in 1975 by the same team of pathologists. The survival rate for those whose histologic type had changed between the first and second reading was significantly lower than that for those who remained in the same histologic group.

Treatment of malignant gliomas and brain metastases in adults using a combination of adriamycine, VM 26, and CCNU. Results of a type II trial.

Forty-three patients with inoperable and/or recurring malignant gliomas and 30 patients with multiple recurring brain metastases were treated with a combination of adriamycine (45 mg/m 2 and 4-dimethyl-epipodophyllotoxin D-thenylidene (VM 26) (60 mg/m 2 for 2 days) and 1-(2-chloroethyl)-3-cyclohexyl-1-nitroso-urea (CCNU) (60 mg/m 2 for 2 days). These cycles of treatment were repeated as soon as the hematologic restoration was complete. The treatment was well-tolerated and the clinical condition of 31 out of 43 glioblastoma patients improved during the 2 months after the beginning of the treatment. Six out of eight patients with breast cancer metastases, one out of 13 with bronchial cancer metastases, and three out of nine with other types of cancer metastases also benefitted from the treatment. Examination of the results reveals the following characteristics: 1. A low degree of efficiency of this combination in the treatment of brain metastases, except for breast cancer metastases. 2. Absence of complete correlation between the clinical results observed and the cinegammagraphic developments 3. Similarity of the results independent of the initial localization 4. Establishment of a 6-month median survival period, with ten patients at present in a state of apparently complete remission, 180-506 days after beginning of the treatment.

Adriamycin in the Treatment of Acute Leukemias

This paper describes the results of our clinical trial of adriamycin in the treatment of acute leukemias, done after the first results of Bonadonna et al. [1]. A trial of this drug in solid tumors is at present being made by the “clinical screening group” of the European Organisation for Research on the Treatment of cancer (E.O.R.T.C.).

RESTORATION OF HAEMOPOIETIC FUNCTION IN THE IRRADIATED MOUSE BY MEANS OF ALLOGENEIC BONE-MARROW GRAFTS FROM SEVERAL DONORS OF DIFFERENT STRAINS.

IN attempts to treat leukaemia in mice(Barnes and Loutit, 1957; devriesand Vos, 1958; Math6 and Bernard, 1958,1959; Matht, Amiel and Bernard, 1960; Math.6, Amiel and Niemetz, 1962) andin man(Math6et al., 1959a, 1960,1963) withwhole-bodyirradiation followed by injectionof allogeneic bone marrow, this injection must: (I) ensure the restoration of bone marrow in the irradiated leukaemic subject; (2) give rise to a non-fatal secondary syndrome; (3) bring about haemopoietic chimerism of a sufficiently long duration to obtain a maximal therapeutic effect. In order to fulfil these three conditions it is necessary in the first place to administer an optimal number of bone-marrow cells, as has been demonstrated in the mouse (Amiel, Tenenbaum, Mtry, Matsukura and Matht, 1962), and in the second place, to select an allogeneic donor suitable for the irradiated host. These two conditions can easily be fulfilled in the mouse, but in the human patient the former is technically difficult and the second constitutes an as yet unsolved problem. These two CGtficulties, owing to which therapeutic results as constant as in mice cannot yet be obtained in man, might be overcome if instead of a single donor several donors were to be used. In the mouse, this is possible, as has been demonstrated previously (Lengerovi, 1960; Matht, Amiel, Matsukura and Miry, 1962). The purpose of the present study was to compare in mice subjected to lethal whole-body irradiation, the result of bone-marrow grafting with a mixture from several genetically different donors, with that obtained with a graft from a single donor. We have judged the results on the basis of the three criteria mentioned above : restoration of bone marrow, occurrence of secondary syndromes, and production of haemopoietic chimerisms of sufficiently long duration.

REMISSION INDUCTION WITH POLY IC IN PATIENTS WITH ACUTE LYMPHOBLASTIC LEUKEMIA (PRELIMINARY RESULTS)

The oncostatic effect of polyinosinic-polycytidylic acid (poly IC) on several varieties of tumors has been reported previously (Levy et al., 1969) and we have observed its effect on Walker’s tumor. A number of clinical trials have been conducted (De Vita et al., 1970; Krakoff et al., 1970) but they merely confirmed tolerance to the product and did not yield therapeutical results. Although the mechanism of the oncostatic action exerted by polynucleotides on experimental tumors is not precisely defined, it is thought that it is probably multiple, for poly IC is cytotoxic (Braun, personal communication), is an inducer of interferon (Field et al., 1967), is an adjuvant of immunity, as reported by Braun et al. (1968), and as observed by us by studying its effect on the multiplication of cells capable of forming antibodies in mice immunized with sheep red blood cells (Hayat and Mathe, in preparation). From this last-mentioned type of study, we have deduced the hypothesis according to which poly IC could have an action on acute leukemia only when the number of tumor cells is not very high. In fact, we have shown (Mathe, 1968; Mathe et al., 1969) that the adjuvants of immunity in the animal exert a detectable oncostatic action only when the number of cancer cells is low.

Abnormal proliferation of T-colony-forming cells from peripheral blood of patients with T-cell acute lymphoblastic leukaemias and lymphomas in complete remission: potential prognostic value

Summary. Peripheral blood T‐colony‐forming cells (T‐CFC) from most patients with T‐cell acute lymphoblastic leukaemias (T‐ALL) and T‐cell non‐Hodgkins lymphomas (T‐NHL), can proliferate in vitro in methylcellulose in the absence of added growth factors or mitogens. We now report that spontaneous T‐cell colonies could also be obtained during complete remission of 13 out of 21 patients with T‐ALL and T‐NHL, but none of eight patients with common (pre‐B) ALL (cALL). Colony cells were mainly E+T3+, with a variable expression of other T cell markers. Spontaneous T‐CFC did not possess self‐renewal capacity in the absence of added growth factors. Moreover, incubation of spontaneous colonies with colchicine yielded mitoses in only two out of seven patients, with one normal and one abnormal karyotype. In five patients tested, recombinant interleukin 2 (IL2) could also induce the proliferation of some T‐CFC. Both spontaneous and IL2‐induced colonies were inhibited by an anti‐IL2 receptor monoclonal antibody, suggesting that interaction of IL2 with its receptor may be involved in the proliferation of some T‐CFC from these patients.

CLINICAL RESULTS WITH CISPLATIN ANALOGS

Publisher Summary Analogs represent an increasing proportion of new anticancer drugs brought into the clinic. The modifications of known active agents have dominated drug development in other areas of medical science. This approach has had its severe critics, but one needs only to recall the successful story of the oral diuretics and the classic antibiotics to remind them of its value. The cancer field has been no exception. Such an orientation toward analog development has been present since the birth of current cancer chemotherapy. A purposeful search for second-generation anticancer drugs has begun, and it has utilized the most up-to-date scientific concepts to accomplish the desirable goals of diminished toxicity and widened selectivity. Such a search is particularly germane to these groups of drugs because one cannot afford delaying the testing of promising compounds for the identification of the optimal one. Platinum analogs seem worthy of exploration for further clinical development. The derivatives of 1, 2 diaminocyclohexane seem most appropriate in this regard, particularly if solubility proves adequate for consistent formulation. In addition to more extensive phase II testing in cisplatin-resistant tumors, pharmacologic studies and studies in combination with radiation and other agents should follow in the future.

Treatment of Blastic Crisis in Chronic Myelocytic Leukemia

The development of an acute leukaemic syndrome can perhaps be considered to be the usual evolution of chronic myeloid leukaemia. Its occurrence is feared and its prognosis is still very poor, despite recent advances in treatment. Twenty-nine patients have been studied, 14 males and 15 females, their ages were 16–71 years (median 40 years). The acute leukaemic syndrome appeared 3 weeks to 7 years after the apparent onset of chronic myeloid leukaemia (median 26 months).