Biomedical subjects
Publications and source records attributed to M Ffrench.
Cell-cycle studies of bone marrow do not allow the detection of minimal residual disease in lymphoma or carcinoma. However, cell kinetics in acute myeloid leukemia may be a predictive test for relapse. Detection of minimal residual disease is all the more difficult that leukemic blast cells can differentiate to form mature cells.
Extracorporeal circulation (ECC) used in open heart surgery gives rise to several hemostatic defects. This work investigates the effect of ECC on patient platelets membrane glycoproteins IIb/IIIa. A monoclonal antibody (LYP 18) directed against the IIb/IIIa complex was used on patient platelets in binding and flow cytometry studies, before and at the end of ECC. An antithrombospondin (LYP 8) monoclonal antibody and a monoclonal antibody (LYP 7) directed against an alpha-granule glycoprotein of 136 kdaltons, present on the platelet surface after secretion, were used in binding studies together with electron microscopy to assess the release of alpha-granules. Results obtained in 7 patients show a significant reduction (p less than 0.02) in the number of LYP 18 monoclonal antibody binding to platelets having undergone ECC (n = 49,725 +/- 16,275) compared to platelets drawn before ECC (n = 72,671 +/- 13,302). Flow cytometry studies indicate a decrease (p less than 0.02) in the percentage of platelets bearing the LYP 18 determinant following ECC (75 +/- 12% vs 66 +/- 14%). Binding of monoclonal antibodies LYP 8 and LYP 7 and electron microscopy studies of patient platelets having undergone ECC do not show degranulation. These results suggest possible cleavage of the IIb/IIIa complex following ECC but no release of alpha-granules.
Flow cytometry with propidium iodide and fluorescein isothiocyanate was used to study 46 cases of adult acute lymphoid leukaemia (ALL) before any form of chemotherapy. Cell proliferation was related to the other clinical and biological characteristics and its prognostic significance was evaluated. The following cell-cycle variables were determined: S, G2 + M, and the Low Protein Content fraction of G1 (LPC fraction). The L3 group, corresponding to B-ALL, had significantly higher proliferation than L1 and L2 (P less than 0.01). The proliferation rate was not significantly higher for T-ALL than for the other phenotypes. Complete remission was successfully induced significantly more often in cases with the LPC fraction under 50% (P less than 0.05). Failure was mainly related to resistance to chemotherapy. Of the four patients who died during aplasia, three had an LPC fraction below 25%. Duration of complete remission and survival were significantly shorter for L3 which is the most proliferative ALL (P less than 0.01). Survival was also found to be longer (P less than 0.05) when G2 + M was between 3.8% and 5.1%. This finding and the negative correlation between S and G2 + M (P less than 0.01) are discussed.
We report the case of a 70-year-old woman in whom Philadelphia chromosome-positive acute leukaemia occurred 12 years after radiation therapy for a carcinoma of the cervix. Morphology of the blasts was undifferentiated and immunological studies were in favour of a CALLA-positive acute lymphoblastic leukaemia. A possible relationship between the onset of leukaemia and the former radiation therapy is suggested.
One hundred patients with aggressive malignant lymphomas treated with the LNH-80 regimen were evaluated for long-term survival and pretreatment characteristics predictive of response and survival. LNH-80 consists of three intensive courses of adriamycin cyclophosphamide vindesine bleomycin (ACVB) followed by sequential consolidation and final intensification. Eighty-four patients went into complete remission (CR), eight had a partial response (PR), three failed to respond, and five died during induction. Twenty-three patients (27%) relapsed, in two of whom a prolonged second remission was obtained. Sixty-three patients are currently alive, two of them with disease. Four patients died in CR. Median survival and median freedom from relapse survival were not reached with a median follow-up of 4 1/2 years. Characteristics negatively associated with response in multivariate analysis were: poor performance status, bone marrow involvement, and two or more extranodal sites of disease. Duration of CR was associated with splenic involvement. Three characteristics were negatively associated with survival in multivariate analysis: age, high grade subtypes, and bone marrow involvement.
Flow cytometry with simultaneous analysis of DNA and protein content allows a most exhaustive study of cell-cycle for the prognostic evaluation of acute myeloid leukemia (AML). Sixty-seven cases of AML were studied before any form of chemotherapy had been undertaken. We determined the following cell-cycle variables: S, S + G2 + M, low protein content fraction (LPC-fraction) and high protein content fraction of G1 (HPC-G1). Patients were stratified according to age: S and S + G2 + M phases were higher for patients over 50 who did not achieve a complete remission. LPC-fraction was significantly lower for patients older than 50 who did not achieve a complete remission not only compared to the complete remission group of patients over 50, but also compared to the younger non responder group. The duration of survival was significantly longer when LPC-fraction was higher than 26% and HPC-G1 lower than 70%. Length of survival was also better when S + G2 + M was longer than 5.75%. Analysis of the therapy failure showed that S + G2 + M and LPC-fraction were significantly different between the complete remission group and the group of patients dying in aplasia. Overall, patients older than 50 with a proliferative leukemia had a worse prognosis.
Ninety-seven patients with aggressive malignant lymphoma (ML) were treated with an intensive and sequential chemotherapy (protocol LNH-80). There were 42 patients with intermediate grade ML, 53 patients with high-grade ML, and two patients with true histiocytic ML. Most of the patients were in advanced stage: 21 stage III and 61 stage IV. The LNH-80 protocol schedule comprised three phases: (1) induction with three courses of an intensified CHOP-Bleo (cyclophosphamide, doxorubicin, vindesine, methylprednisolone, and bleomycin); (2) consolidation with cytarabine, followed by high-dose methotrexate and folinic acid rescue, then asparaginase; and (3) final intensification with two courses of CVAP-Bleo (cyclophosphamide, teniposide, cytarabine, methylprednisolone, and bleomycin). CNS prophylaxis included one injection of methotrexate during each induction course and the drugs of the consolidation phase. In cases of initial CNS localization, cranial radiotherapy was added. Eighty-four patients (87%) went into complete remission (CR), 18 (21%) of whom relapsed, usually during the phase of treatment or within 6 months of completing chemotherapy. Sixty-three patients are alive with an overall median follow-up of 24 months. The median survival time and the median disease-free survival have not been reached, and the survival curve seems to have plateaued at above 60%. There was no statistical difference between intermediate-grade ML (CR 90%, relapse 18%) and high-grade ML (CR 84%, relapse 24%). The toxicity of this treatment is mainly encountered during the induction phase: almost all patients had short-term neutropenia, less than 0.500 g/L in 57, with a documented infection in 25. Overall treatment-related mortality was 6%, with four patients dying during the induction phase.
Fourteen out of 283 patients with chronic lymphoid leukaemia, 2 out of 47 with Waldenström's disease and 16 out of 136 with low malignancy lymphoma (follicular with predominant small cleaved cells, mixed follicular with small and large cells, or diffuse lymphocytic) underwent histological transformation of their disease into a highly malignant lymphoma (immunoblastic in 14 of the 32 cases). There are no clinical or biological signs that predict these changes which seem to occur haphazardly in time. Seven patients died within one month of the diagnosis. The classical treatments failed. Complete remission was obtained in 5 cases with the intensive and sequential chemotherapy used for initially aggressive lymphomas.
Nineteen patients with severe aplastic anaemia were treated with 21 courses of horse antithymocyte globulins (ATG). Changes in haematological parameters were correlated with ATG dosage. One of the 11 patients who received less than 100 mg/kg is still alive after more than 12 months. One of the 10 patients who received more than 100 mg/kg died of infection; in the remaining 9 patients, treatment resulted in increase or even return to normal of haemoglobin, polymorphonuclear and platelet levels. None of these 9 patients relapsed during a median follow-up of 16 months (range: 7 to 35 months). Immediate drug tolerance and serum sickness were unrelated to ATG dosage. These results confirm the therapeutic effectiveness of antithymocytic globulins in severe aplastic anaemia; they also suggest that 150 mg/kg doses are required to obtain satisfactory and long-lasting results.
Simultaneous analysis of DNA and cellular proteins provides information on cell proliferation and metabolism. Cellular protein content coupled with nuclear geometric parameters can be used to evaluate cellular maturation and differentiation. In this study, leucoblasts from 50 cases of adult acute myeloid leukemia were analyzed by flow cytometry, and semiautomatic morphometry was performed on bone marrow smears. Ethanol-fixed bone marrow blast cells were stained for DNA with propidium iodide (PI) and for proteins with fluorescein isothiocyanate (FITC). On the resulting FITC versus PI histograms we defined the cells with low protein content which are associated with a nonproliferating subpopulation (LPC fraction). Low protein content fraction and S-phase are correlated (p less than 0.01). The LPC fraction values are more dispersed than S-phase values and thus should indicate more clearly eventual differences between cellular populations. This hypothesis has been tested with the prognostic significance of cell-cycle variables: The LPC fraction was significantly higher in the complete remission group than in the other (p less than 0.01), while S-phase did not show any difference. The peak value of the protein content histograms is significantly lower in the granulocytic leukemias (M1, M2, M3) than in the leukemias with a monoblastic component (M4, M5). Furthermore, we showed that the differentiation and the maturation of the myeloid blast cells modify the nuclear size. The combination of these two parameters provides useful information for cytological classification.
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DNA and proteins of ethanol fixed cells are simultaneously analysed by cytofluorimetry in 35 cases of adult acute leukemias. DNA is coloured by propidium iodide and proteins by FITC. These technics allow to know the GO/G1, S, G2 + M cell-cycle phases and the protein cell content for each phase. We also can evaluate the fraction of low protein content cells (LPC fraction) that seems to be the GO and early G1 fraction. A good correlation exists between the percentage of S phase cells and the LPC fraction. This parameter, because of its important dispersion, must have a better discriminating value than S phase, especially for the prognosis analysis. Furthermore acute myeloid leukemias have a protein content that varies with the cytological maturation. Therefore, P1 + FITC colorations would give quantitative criteria for the acute leukemias cytological analysis and their prognostic valuation.
Sixty-two patients with aggressive non-Hodgkin's lymphoma (diffuse mixed, diffuse large cells, non-cleaved small cells (Burkitt-like), immunoblastic, lymphoblastic and other non-epidermotropic T lymphomas) were treated by intensive sequential chemotherapy combining heavy induction treatment (modified CHOP-Bleo), sequential consolidation treatment (cytosine arabinoside and thioguanine, then high-dose methotrexate and L-asparaginase) and final reinforcement (CVAP-Bleo). Complete remission was achieved in 59 patients (95%); 11 patients (18%) relapsed. Two patients died during the induction phase and one failed to respond. Two patients died of an unrelated disease while in complete remission. Blood toxicity was tolerable and treatment could be conducted without problems in most cases. The median survival cannot be reached with a 14-months follow-up, but the survival rate seems to plateau at 70%. The only two prognostic factors identified were poor general condition and high serum lactate dehydrogenase levels.
Continuous infusion of amikacin, cotrimoxazole and carbenicillin was the second empirically established combination of antibiotics used when fever occurred during the induction phase of chemotherapy in sixty-five patients (58 acute myeloid leukemias, 5 acute lymphoid leukemias, 2 non Hodgkin lymphomas). Clinical evidence of infection was available in 25 cases and the infection was bacteriologically documented in 19 cases. Therapy was successful in 57 patients (89%). When infection was clinically or bacteriologically documented tha success rates were 92 and 82% respectively. The average length of treatment was ten days. In 25 patients receiving 2 g of amikacin in continuous infusion, the mean serum concentration was 15,9 micrograms/ml; in 17 patients receiving 3 g, the mean serum concentration was 19,4 micrograms/ml.
Morphometry was applied to quantitate characteristic microscopical features of the removed non invasive papillary bladder tumours in 60 patients and of the normal urothelium in 13 cases. The measurements of nuclear areas were made on routine HES section with a microscopic digitiser (ASM-Leitz). There was a significant difference, concerning the average nuclear area, between normal urothelium and bladder tumours and also a correlation between the number of relapses at two years and this parameter. A significant difference existed for the average nuclear area of tumour without any relapse and the tumours with one or several relapses (p less than 0,02). A difference existed also between the tumours that caused cystectomie or early death and other tumours (p less than 0,01). The anisocaryosis (evaluated by the mean of the coefficient of variation of the average nuclear area) was greater in cases of tumours with bad prognosis (death). These results confirm the prognostic value of morphometric parameters in the histological analysis of papillary bladder tumours.
BACKGROUND: The current study evaluated the construct validity of a physical activity intervention in primary care by testing whether the intervention changed hypothesized mediators and whether changes in the mediators were associated with behavior change. METHODS: Matched physician offices were nonrandomly assigned to intervention or control. Apparently healthy, sedentary, adult patients (N = 255) were recruited from physician offices. The intervention was brief, behaviorally based counseling by physicians, plus a telephone follow-up 2 weeks later. Assessments of physical activity and mediators were collected at baseline and at 4- to 6-week follow-up. Hypothesized mediators were processes of change, self-efficacy, and social support for exercise. RESULTS: Patients who were counseled improved significantly more than those in the control group on behavioral and cognitive processes of change. Other changes in mediators were nonsignificant. Behavioral processes of change and self-efficacy made significant contributions to the multiple regression model explaining self-report and objective measures of physical activity. CONCLUSIONS: The intervention affected some of the targeted mediators of physical activity change. Two of three mediator variables were associated with changes in physical activity regardless of experimental condition and other variables. The construct validity of the intervention was partially supported.