Advancing the use of new approach methodologies for assessing teratogenicity: Building a tiered approach.

Many New Approach Methodologies (NAMs) have been developed for the safety assessment of new ingredients. Research into reproductive toxicity and teratogenicity is a particularly high priority, especially given their mechanistic complexity. Forty-six non-teratogenic and 39 teratogenic chemicals were screened for teratogenic potential using the in silico DART model from the OECD QSAR Toolbox; the devTox quickPredict™ (devTox assay) test and the Zebrafish Embryotoxicity Test (ZET). The sensitivity and specificity were 94.7% and 84.1%, respectively, for the DART tree (83 chemicals), 86.1% and 35.6% for the devTox (81 chemicals) and 77.8% and 76.7% for the ZET (57 chemicals). Fifty-three chemicals were tested in all three assays and when results were combined and based on a "2 out of 3 rule", the sensitivity and specificity were 96.0% and 71.4%, respectively. The specificity of the devTox assay for a sub-set of 43 chemicals was increased from 26.1% to 82.6% by incorporating human plasma concentrations into the assay interpretation. When all 85 chemicals were assessed in a decision tree approach, there was an excellent predictivity and assay robustness of 90%. In conclusion, all three models exhibited a good sensitivity and specificity, especially when outcomes from all three were combined or used in "2 out of 3" or a tiered decision tree approach. The latter is an interesting predictive approach for evaluating the teratogenic potential of new chemicals. Future investigations will extend the number of chemicals tested, as well as explore ways to refine the results and obtain a robust Integrated Testing Strategy to evaluate teratogenic potential.

[Use of local cobalt therapy in peripheral neuropathies associated with chronic lymphopathies (lymphoses). 2 cases with histo-immunologic and ultrastructural records]. / Intérêt de la cobaltothérapie locale dans les neuropathies périphériques des lymphopathies chroniques (lymphoses). Deux observations avec documents histo-immunologiques et ultrastructuraux.

In two cases of peripheral neuropathy, associated with a chronic lymphopathy, cobalt therapy to the lower limbs provided considerable relief of pain, with partial motor recovery. The disappearance after cobalt therapy of the lymphoid infiltrate of the peripheral nerve leads to discussion of the pathogeni role of this infiltrate. Immunofluorescent and electron microscopic studies form the basis of a discussion of the mechanism of involvement of the peripheral nerve non-secreting lymphopathies (chronic lymphoid leukaemia) and in secreting lymphopathies (Waldenström's disease).

[Study of neurological manifestations of chronic lymphatic leukemia (lymphosis). Role of associated globulin anomalies (apropos of 8 cases)]. / Contribution à l'étude des manifestations neurologiques des leucémies lymphoïdes chroniques (lymphoses). Role des anomalies globuliniques associées (a propos de huit observations)

The authors emphasize the relative frequency of neurological symptoms in lymphatic leukaemia. Clinically, these cause more or less diffuse encephalitic or multineuritic syndromes, generally a combination of the two. Their pathogenesis is usually connected with lymphoid tissue infiltration into either the meninges or the vascular sheaths of the central nervous system or the sheaths of the roots or of the peripheral nerves. The authors stress the possible function of immunoglobulin abnormalities of the C.S.F. indicative of the presence of the leukaemic process within the nervous system. This pathogenesis prompts the use of therapeutic methods directly attacking leukaemic infiltration of the nervous system (focal cobalt therapy, intrathecal chemotherapy) and the authors have found that these give favourable results.

[Endolymphatic curietherapy by lymphography with labelled lipiodol in Hodgkin's disease. A report on 408 cases (author's transl)]. / La curiethérapie endolymphatique par lymphographie au lipiodol marqué dans la maladie de Hodgkin. 408 observations.

The results of 373 lymphography examinations with radioactive lipiodol, conducted in 408 patients with Hodgkin's disease for diagnostic and prophylactic therapeutic purposes, during investigations carried out from 1966 to 1973 are analyzed. Tolerance was always excellent, especially from the hematological point of view. The efficacy of the procedure can be assessed by the fact that there were only 6% of failures (21/373) in glandular regions irradiated in this way for prophylactic purposes. Relapses occur more frequently in the inguino-iliac and lumbo-aortic regions than in the pelvic chains which were perfectly protected. This technique also enables both pelvic irradiation and ovarian protection in young women without any risk of failure. The procedure is particularly indicated in the following cases: supradiaphragmatic stages I and II, whatever the sex, and stage III especially in women. In sub-diaphragmatic stages I and II, it allows, in favourable cases, the ovarian function in women to remain intact by limiting external irradiation to invaded regions only.

Polymorphonuclear function in acute myeloblastic leukemia.

A study of granulocyte functions in acute myeloblastic leukemia is reported. Functions were assessed by the ability of polymorphonuclear to migrate in Boyden's chamber, to ingest and kill staphylococcus aureus. Chemotaxis was grossly impaired. Cellular imparirment of phagocytosis and bactericidal capacity was observed in 5 and 9 patients. An inhibitor of phagocytosis and bactericidal capacity was observed in 9 and 4 patients. Results improved in complete remission.

Specific anti-hairy cell and anti-B cell antisera: characterization of surface antigens and origin of hairy cells.

Hairy cells obtained from nine patients with hairy cell leukaemia were found to be sensitive to a heterologous anti-human B lymphocyte serum using a cytotoxicity assay and the ultrastructural characterization after immunoperoxydase labelling. This antiserum raised in the rabbit and rendered specific by extensive absorptions with human immunoglobulins, erythrocytes, thymocytes and monocytes, reacted with normal and pathological B lymphocytes but not with monocytes, as demonstrated by ultrastructural studies. In addition, a heterologous anti-hairy cell serum was prepared and absorbed with erythrocytes, thymocytes and monocytes. The in vitro properties of this antiserum were identical to those of the anti-human B cell serum in the various assays: cytotoxicity, rosette inhibition and ultrastructural characterization. These results demonstrate that hairy cells of the studied patients express surface antigenic specificities of the B cell population, not shared by monocytes. Further absorption of the anti-hairy cell serum with CLL cells suggested that hairy cells express other characteristic antigens in addition to the B lymphocyte antigens. HLA-DR alloantigens were also shown to be present at the surface of hairy cells. This type of immunological analysis may prove to be of help in the understanding of the differentiation abnormalities in the hairy cell leukaemia as well as in other lymphoproliferative disorders.

Short induction treatment in acute granulocytic leukemia.

Short treatment with four cytostatics in acute granulocytic leukemia induced aplasia and reduction of total leukemic cells in 50 over 59 patients. Complete remission occured in 30 and 20 died with infectious complications during induction. Short induction treatment allowed a reduction of induction period and so a reduction of high risk period of induction before completion of complete remission.

Chemo-immunotherapy versus chemotherapy in acute myeloid leukemia. Preliminary results.

Since November 1974, 44 patients with acute myeloid leukemia, in first remission were randomized between chemotherapy alone and chemotherapy plus BCG. There were 8 relapses and 7 deaths with chemotherapy, 7 relapses and 3 deaths with chemotherapy plus BCG. The survival of both groups is not, at the time, significantly different.

[The Waardenburg-Klein syndrome]. / Le syndrome de waardenburg-klein

A case of Waardenburg-Klein syndrome associated with a Hodgkin's disease is reported in a 29 year old female. Such an association seems to be fortuitous. The authors discuss the dermatological aspects of this rare disease, particularly the disturbances of cutaneous pigmentation. Ultrastructural study of depigmented skin indicates the melanocytes are absent and precise the place of this depigmentation in the group of genetic abnormalities of skin pigmentation.

[Prognostic value of delayed-hypersensitivity skin tests and rosette studies in acute non-lymphoid leukemias]. / Valeur pronostique des réactions cutanées d'hypersensibilité retardée et de l'étude des rosettes dans les leucémies aiguës non lymphoïdes.

Delayed hypersensitivity skin reactions to Tuberculin and Candidin were studied in 28 patients with non lymphoid acute leukemias. The reactions were found negative in most patients during blastic crises, whereas delayed skin reactions to Candidin were positive during remissions. The possible prognostic significance of the depressed delayed hypersensitivity response in such patients deserves further studies. Alterations of circulating T lymphocytes were observed, including low percentages of E and active E rosette-forming cells during blastic crises, and persisting low E and E active rosettes in some patients in remission; such abnormalities were less frequent in patients with remission of long duration. The percentages of EA and EAC rosettes-forming cells were found normal during blastic crises and remissions. In some patients in remission, lymphocytes were found to bind sheep erythrocytes either uncoated or coated with IgM antibodies, this penomenon which is not observed with normal lymphocytes may reveal persisting abnormalities of a yet undefined nature.

Delayed hypersensitivity skin reactions in the induction phase of remission in acute non lymphoid leukemias.

Delayed skin reactions to Tuberculin (10 units, intradermal) and Candidin (1:1000, intra dermal) were studies in a homogenous group of 41 patients with acute non lymphoid leukemias in their initial phase. Remission-rate is higher in non-anergic patients (63%) than in anergic patients (32%), (p less than 0.05). Death-rate (within 30 days after chemotherapy) is higher in anergic patients (50%) than in non-anergic patients (16%), (p less than 0.05). There is no correlation between delayed skin reactions and age, initial absolute counts of neutrophil-lymphocyte-monocyte-blast cells, and results of humoral immunity. Delayed skin reactions are interesting in defining a high-risk group in the induction phase of remission of acute non lymphoid leukemias.

[Encephalic pseudotumoral toxoplasmosis in the course of blood diseases]. / Toxoplasmose encéphalique pseudo-tumorale au cours d'une hémopathie. Deux observations

The authors report two cases, the first pathological and the second clinical of pseudo-tumoural cerebral toxoplasmosis, occurring during the course of blood diseases. They refer to the conditions of appearance of this rare complication, with only twenty cases recorded in the literature, during malignant blood diseases. They stress the primordial role of immunological deficiency related either to the underlying disease (especially Hodgkin's disease) or to immuno-suppressive therapy. The clinical picture, with little in the way of typical features, is thus that of a diffuse méningo-encéphalitis. Pseudo-tumoural forms are rare. The authors also stress the minimum conditions required for the validity of the dye test and the value of the diagnosis of cerebral toxoplasmosis. An association of sulphadiazine-purimethamine, active and effective, cured the second patient.

[Prolonged survival in 16 cases of acute myeloid leukemia [author's transl)]. / Leucémies myéloïdes aiguës. Survie supérieure à 3 ans chez 16 malades.

16 our of 370 acute myeloid leukemias treated between 1964 and 1973 have been in long survival for more than three years. In the first period 1964-1971 the overall remission rate was 20% and 6 patients has a long survival. In the last two years of study, 10 out of 96 patients have more than three years of survival, the remission rate was over 50%. All the cases were slightly proliferative the first group did not recieve intensive chemotherapy and appear as spontaneous long remission, but in thelast patients intensive chemotherapy seems responsible for the good results.

BCG therapy in acute non lymphoid leukaemias.

The survival of patients with acute non-lymphoid leukaemias (ANLL) receiving chemotherapy (32 patients) or chemotherapy plus BCG (31 patients) has been compared in a randomized trial which started in Nov 1974. Fresh BCG (Institut Pasteur, Paris) was administered by Heaf gun in the interval of chemotherapy cycles. The overall survival was better in the chemo-immunotherapy group (median duration of survival of 25 months compared to 16 months in the chemotherapy group). However, the first remission duration did not differ (median duration of the 15 and 12 months, respectively). Plateau survival curves were not obtained in either group. A second complete remission was obtained in 7 out of 12 patients with bone marrow relapses in the chemo-immunotherapy group, and only in 2 out of 15 in the chemotherapy group (P less than 0.05). BCG seemed more efficient in patients older than 40 years; no difference was observed according to sex.

[Treatment of 100 acute myeloid leukemias (author's transl)]. / Traitement de cent leucémies myéloides aigues.

Between november 1974 and august 1976, 100 acute myeloïd leukemias were treated by the same protocol L. 275. Induction treatment was daunorubicine, vincristine, cytosine arabinoside, in one intensive course for patients under 65 and cyclophosphamide (CPM), VCR and CAR in a less intensive and repetitive courses for patients over 65. In remission, there were three phases: consolidation, prevention of central nervous system leukemia, maintenance. All patients in remission received an androgenotherapy and two groups were randomised: chemotherapy and chemotherapy plus BCG. 68 patients were in complet remission (CR) 61 out of 80 patients under 65 and 7 out of 20 over 65. Median duration of first remission was 12 months. Median duration of survival was 13 months for all patients, 15 months for patients under 65, 3 months for patients over 65, and 22 months for 68 patients in CR. Survival of patients receiving BCG was slightly better than patients without BCG.