Expression of the c-myc, c-fos and c-rasHa protooncogenes during sex-differentiated rat liver carcinogenesis in the resistant hepatocyte model

The expression of the protooncogenes c-myc, c-fos and c-rasHa has been studied in rats treated according to the resistant hepatocyte model. Protooncogene expression was studied in male and female rat liver during the selection phase, when the outgrowth of putative preneoplastic foci/nodules is markedly faster in males, and compared with the expression in advanced nodules and hepatocellular carcinomas in males. During the first 16 h after partial hepatectomy the expression of c-fos and c-myc showed transient, 2- to 3-fold, increases in both sexes, both in initiated and in 'control' animals, receiving the selection/promotion regiment but no diethylnitrosamine, with a maximum at 0.5 and 2-4 h respectively. c-rasHa exhibited a moderate increase (1.5-fold) at 16-24 h in all groups. A second increase in c-myc expression (2-fold) started 24 h after partial hepatectomy and lasted over the entire selection period in initiated males, while it was unchanged in females and uninitiated males. The c-fos expression also showed a short-lived increase 24 h post partial hepatectomy in initiated males. The expression of c-myc and c-fos was increased 2- to 4-fold in both preneoplastic nodules and hepatocellular carcinomas, whereas c-rasHa expression was unchanged. In conclusion, sex differences were observed in the expression of c-myc and c-fos during the early outgrowth of preneoplastic lesions, possibly reflecting a connection between the expression of these genes and the sex differentiated response to promotion in the resistant hepatocyte model. Furthermore, an overexpression also in later stages of liver carcinogenesis might indicate that expression of the protooncogenes in question is related to the entire process of multistep carcinogenesis in this model.     

Prognostic features at diagnosis of chronic myelocytic leukemia

Clinical and laboratory findings at the time of diagnosis were correlated with the survival of 242 patients with chronic myelocytic leukemia. Twelve patients with the blastic stage of the disease (blasts greater than or equal to 29%) had a median survival of eight months. Of the nonblastic patients, 28 without the Philadelphia chromosome had a relatively constant mortality averaging 43% per year and a median survival of 13 months, markedly worse than the Ph1-positive group (mortality, 6% in the first year, 17% in the second year, and the 25% per year, with a median survival of 43 months; P less than 0.001). In the latter group of 202 patients, features reflecting the "quantity" of leukemia (leukocyte count, marrow cellularity, and M:E serum B12, different degrees of splenomegaly, presence or absence of symptoms) had weaker or short-term correlations with mortality, while "qualitative" abnormalities (e.g., increased percentage of circulating blast, extramedullary leukemic tumors, major abnormalities of erythropoiesis or platelet production, marked basophilia or eosinophilia) had strong and persistent correlations with mortality. Chromosome abnormalities in addition to the Ph appeared to have a delayed though significant effect on survival. Serum alkaline phosphatase and SGOT levels did not correlate significantly with survival, but major elevations of serum LDH were associated with increased mortality throughout the course of the disease.     

AML-6 study of the value of cyclic alternating chemotherapy during remission in acute myelocytic leukemia

Twenty-five institutions are participating in a randomized trial of the E.O.R.T.C. for improvement of remission incidence, disease-free interval and survival in adult acute non-lymphocytic leukemia. In order to delay the time of relapse, an intensive cyclic therapy is employed early after achievement of complete remission (C.R.) using either the same drugs of the induction regimen or rotating combinations of alternative drugs, e.g. mAMSA, 5-AZA and HD-Ara C. So far 266 patients entered the trial with a median age of 45 yrs. The overall C.R. rate is 71%; 52% of the responders reached C.R. after 1 cycle of induction treatment. 10% of the patients died within the first 7 days of induction or due to hypoplasia, 13% were absolute resistant to this regimen. Fifty-eight patients are randomized to 'maintenance' arm I, 54 to arm II, 79/112 patients are still under study. Treatment toxicity is tolerable. In 7% and 3% excessive toxicity was a reason for going off study during induction or 'maintenance'. As far as remission duration or survival within the two treatment arms is concerned, it is too early to draw any conclusions.     

AML-7 study of the value of intensive remission induction in aged patients with acute myelocytic leukemia

The intensity of modern protocols for remission induction of acute nonlymphocytic leukemia presents a major problem in elderly patients because of toxicity. Most studies concerning this question indicate that in higher age groups (greater than 60 yrs.) remission incidence worsens and the death rate increases. Therefore, the purpose of this multicenter study is to prospectively compare survival and quality of life of two different therapeutic strategies: immediate intensive remission induction using Daunomycin and Cytosine Arabinoside (branch I) versus supportive care, "wait and see" policy, and palliative cytoreduction (branch II) with Hydroxyurea and Ara C when necessary. During the first 8 months after activating this study, 27 patients entered, 13 were randomized to branch I and 14 to branch II. It is too early to report meaningful results.     

Thymidine kinase in human leukemia. Expression of the lymphoblastic isoenzyme in three patients with acute myelocytic leukemia

The dominating thymidine kinase activity in mononuclear white blood cells from three patients with untreated acute myelocytic leukemia (AML) was compared with TK 1 from phytohemagglutinin-stimulated and TK 2 from unstimulated, normal lymphocytes. The enzyme activity in the AML cells and the stimulated lymphocytes was found to be in the same range. Regarding the combined thymidine and dTTP kinetics, the enzymes from the three AML patients resembled TK 1, but the ATP kinetics were different and the molecular weights were lower, as previously found for thymidine kinases from other leukemic cells. Therefore, the designation TK-1-onc is suggested for the thymidine kinases from the AML cells.     

脑膜瘤中c-myc和c-fos mRNA的表达及作用

为探讨ｃ－ｍｙｃ和ｃ－ｆｏｓ ｍＲＮＡ在脑膜中的作用，作者采用原位杂交结合图像分析的方法对１４例脑膜瘤中ｃ－ｍｙｃ和ｃ－ｆｏｓ的ｍＲＮＡ表达进行了定位，定量研究，结果表明杂交阳性信号均位于肿瘤细胞核周胞质中，ｃ－ｍｙｃ和ｃ－ｆｏｓ ｍＲＮＡ在脑膜瘤中的表达率分别为６４．３％和３５．７％，说明这两种癌基因表达增高在脑膜瘤发生，发展中具有重要作用。     

Human histocompatibility antigens and survival in acute myelocytic leukemia

Several previous reports have suggested an association between human histocompatibility antigens (HLA) and survival in acute myelocytic leukemia (AML). The authors have retrospectively analyzed the records of 104 consecutive newly diagnosed patients with AML treated on the Leukemia Service of the Johns Hopkins Oncology Center from March 1978 through May 1982 who had HLA typing performed to further evaluate this point. The authors have been unable to demonstrate a statistically significant association of HLA phenotype with the ability to achieve a complete response (CR), length of CR, survival of the total group of treated patients, or survival of only those patients achieving a CR (P less than 0.05). The available evidence does not strongly support a significant influence of HLA on survival in AML.     

AML-6 and AML-7 studies on the treatment of acute myelocytic leukemia. Cyclic alternating chemotherapy during remission, and induction of remission and survival of elderly patients

Twenty-five institutions are participating in the AML-6-trial designed to improve remission incidence and to delay the time of relapse. Therefore, an intensive cyclic therapy is employed early after achievement of remission using either the same drugs of the induction regimen or rotating combinations of alternative drugs, e.g. AMSA, 5-AZA and HD-araC. So far, 266 patients entered the trial. The overall C.R. rate is 71%. 58 patients are randomized to 'maintenance' arm I, 54 to arm II, 79/112 patients are still being studied. Toxicity was in 7% and 3% respectively a reason to interrupt the study during induction or 'maintenance'. Since the intensity of modern protocols for remission induction of AML presents a major problem in elderly patients due to toxicity, and since most studies indicate low remission rates with an increasing death rate in this age group, the AML-7-study was initiated to prospectively compare survival and quality of life of two different therapeutic strategies: immediate intensive remission induction versus supportive care, 'wait and see' policy, and palliative cytoreduction with hydroxyurea and ara C when necessary. During the first 8 months after activating this study, 27 patients entered, 13 were randomized to branch I, and 14 to branch II.     

Diagnostic and prognostic relevance of the immunophenotype in acute myelocytic leukemia

The immunophenotype of 72 cases with acute myelocytic leukemia was investigated with a panel of monoclonal antibodies. When the morphologic criteria of the FAB classification was compared with the normal myeloid and erythroid pathway of differentiation identified by MoAbs, a relationship was found with FAB M5 and M6. Moreover, a constant negativity to HLA-DR and CD15 antigens in M3 and the contemporaneous expression of HLA-DR and CD11b antigens on the M4 and M5 leukemic cells were observed. We identified phenotypically distinct groups of patients with different responses to therapy. In fact, patients whose leukemic cells did not express the HLA-DR antigen showed, in a univariate analysis, a significantly higher percentage of complete remissions than did HLA-DR-positive patients. Multivariate discriminant analysis, in line with this result, showed that the parameters of discriminant capacity were, in order of statistical significance, young age, low WBC count and the lack of DR expression, respectively. A trend for a better response to therapy, without any statistical relevance, was also observed in CD11b-negative and CD33-positive cases. Similar results were detected in patients who expressed either DR or CD11b, or none of these markers. These findings indicate that immunophenotype may identify some FAB subtypes. Moreover, in some cases the phenotypic profile can provide useful information about the clinical outcome.     

慢性粒细胞性白血病患者多种细胞因子表达的对比研究

 目的　采用蛋白芯片对慢性粒细胞性白血病（CML）患者白细胞介素（IL）-2、IL-4、IL-12、IL-13、肿瘤坏死因子-α（TNF-α）、干扰素-γ（IFN-γ）、巨噬细胞炎性蛋白-1α（MIP-1α）7种免疫相关细胞因子进行测定,以评价其细胞因子的表达情况。方法　制作人类细胞因子蛋白质芯片;收集患者及健康人外周血,并提取血清（其中患者25例,对照25例）,用上述芯片及酶联免疫吸附试验（ELISA法）对样本进行测定。结果　CML患者IL-4表达水平为（102±12.33）pg／ml,IL-2表达水平为（78±14.08）pg／ml,均较对照组低（P＜0.05）; CML患者的MIP-1α表达水平与对照组差异无统计学意义。结论　CML患者的细胞免疫与体液免疫均受到一定程度的抑制;MIP-1α在CML发病过程中可能受到p210的抑制。     

Spontaneous remission in adult acute leukemia

A spontaneous complete remission of 34 months' duration was observed in an adult patient with acute myeloblastic leukemia. The remission occurred after a severe febrile pneumonia, which was treated with leukocyte transfusions. At relapse, chromosomal abnormalities reappeared slowly. Such spontaneous complete remissions, almost always associated with bacterial infections and blood transfusions, are extremely rare, and are usually of short duration. Previous cases are summarized, and the role of etiologic factors, including those related to the leukemic proliferation, are discussed.     

Prognostic factors affecting remission, remission duration, and survival in adult acute nonlymphocytic leukemia.

The medical records of 94 consecutive patients with acute nonlymphocytic leukemia (ANLL) were reviewed to identify significant prognostic factors. The data were analyzed using 1) Cox's linear hazard and linear logistic models, 2) chi-square comparison of the groups living longer than 2 years and those living less than 2 years, and 3) the Gehan-Breslow test of equal survival curves. The only statistically significant finding was that the presence of promyelocytic cell type and complete remission correlated with increased survival (p less than .05), but this was negated by the small number of patients with this cell type. There was a suggestive association between higher initial hemoglobin and survival (p = .09). The Gehan-Breslow test revealed a possible difference in survival between those patients more than 51 years of age and those less than 51 (p = .10). Thus none of the commonly accepted prognostic factors in acute nonlymphocytic leukemia was definitely shown to be useful. The findings of this study support an aggressive approach toward all patients with this disease.     

Deoxynucleoside anabolic enzyme levels in acute myelocytic leukemia and chronic lymphocytic leukemia cells

The deoxynucleoside kinase reaction is often rate-limiting in the anabolism of pharmacologically active anti-cancer nucleosides. The levels of thymidine kinase (TK), deoxycytidine kinase, deoxyguanosine kinase (dGK), and thymidylate kinase were determined in leukocyte extracts from patients with chronic lymphocytic leukemia (CLL) and acute myelocytic leukemia (AML). The extracts from AML patients showed significantly higher TK activity than the ones from CLL patients. There were no differences in the levels of the other three kinases. In the case of dGK, the determinations were carried out with both an immunoblotting assay and selective enzyme activity measurements.