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51.
52.
Topotecan, a topoisomerase I inhibitor, is active in the treatment of myelodysplastic syndrome and chronic myelomonocytic leukemia 总被引:5,自引:2,他引:5
Beran M; Kantarjian H; O'Brien S; Koller C; al-Bitar M; Arbuck S; Pierce S; Moore M; Abbruzzese JL; Andreeff M; Keating M; Estey E 《Blood》1996,88(7):2473-2479
The aim of this study was to evaluate the activity of topotecan in patients with myelodysplastic syndrome (MDS) and chronic myelomonocytic leukemia (CMML). Forty-seven patients with a diagnosis of MDS (n = 22) or CMML (n = 25) were treated. The median age was 66 years. Chromosomal abnormalities were present in 70% and thrombocytopenia less than 50 x 10(3)/microL in 51%. Evaluation of outcome and of differences among subgroups was performed according to standard methods; the criteria for response were those used for acute leukemia. Topotecan was administered as 2 mg/ m2 by continuous infusion over 24 hours daily for 5 days (10 mg/m2 per course) every 3 to 4 weeks until remission, then once every month for a maximum of 12 courses. Thirteen patients (28%) achieved a complete response (CR) and six (13%) had hematologic improvement. A CR was achieved in six of 22 patients with MDS (27%) and in seven of 25 with CMML (28%). All eight patients who presented with cytogenetic abnormalities (five chromosome 5 or 7 abnormalities) who achieved CR were cytogenetically normal in CR. Characteristics for which there was evidence of association with a higher response rate were lack of prior chemotherapy, less than 10% marrow monocytes, and absence of RAS oncogene mutations. In contrast, CR rates were similar in patients with or without abnormal karyotypes. Mucositis occurred in 64% of patients (severe in 19%) and diarrhea in 32% (severe in 13%). Febrile episodes occurred in 85% of patients and documented infections in 47%. With a median follow-up duration of 8 months, the 12-month survival rate was 38%, median survival time 10.5 months, and median remission duration 7.5 months. We conclude that topotecan has significant activity in MDS and CMML, with acceptable side effects. Future studies will investigate topotecan combined with topoisomerase II reactive agents, cytarabine, or hypomethylating agents (azacytidine and decitabine). 相似文献
53.
Cardoso AA; Schultze JL; Boussiotis VA; Freeman GJ; Seamon MJ; Laszlo S; Billet A; Sallan SE; Gribben JG; Nadler LM 《Blood》1996,88(1):41-48
Even if neoplastic cells express tumor associated antigens they still may fail to function as antigen presenting cells (APC) if they lack expression of one or more molecules critical for the induction of productive immunity. These cellular defects can be repaired by physiologic activation, transfection, or fusion of tumor cells with professional APC. Although such defects can be repaired, antitumor specific T cells may still fail to respond in vivo if they may have been tolerized. Here, human pre-B cell acute lymphoblastic leukemia (pre-B ALL) was used as a model to determine if primary human tumor cells can function as alloantigen presenting cells (alloAPC) or alternatively whether they induce anergy. In the present report, we show that pre-B cell ALL express alloantigen and adhesion molecules but uniformly lack B7-1 (CD80) and only a subset express B7-2 (CD86). Pre-B ALL cells are inefficient or ineffective alloAPC and those cases that lack expression of B7-1 and B7-2 also induce alloantigen specific T- cell unresponsiveness. Under these circumstances, T-cell unresponsiveness could be prevented by physiologic activation of tumor cells via CD40, cross-linking CD28, or signaling through the common gamma chain of the interleukin-2 receptor on T cells. Taken together, these results suggest that pre-B ALL may be incapable of inducing clinically significant T-cell-mediated antileukemia responses. This defect may be not only due to their inability to function as APC, but also due to their potential to induce tolerance. Attempts to induce clinically significant antitumor immune responses may then require not only mechanisms to repair the antigen presenting capacity of the tumor cells, but also reversal of tolerance. 相似文献
54.
Platelet-melanoma cell interaction is mediated by the glycoprotein IIb- IIIa complex 总被引:3,自引:0,他引:3
A human malignant melanoma cell line (M3Dau) was observed by electron microscopy to interact directly with human platelets and induced platelet aggregation. Fab fragments of a monoclonal antibody MoAb (LYP18), directed against the platelet glycoprotein (GP) IIb-IIIa complex, inhibited platelet-melanoma interactions and platelet-platelet aggregation. M3Dau melanoma cells bind LYP 18 and synthesize IIb-IIIa- like GPs. When the melanoma cells were preincubated with LYP 18, tumor- platelet interaction did not occur, suggesting that the interaction may be mediated by the IIb-IIIa-like GPs present on the melanoma cell surface. Glanzmann's thrombasthenic platelets, lacking GPIIb and IIIa, did not interact with melanoma cells, indicating that the platelet GPIIb-IIIa complex is also necessary for the platelet-melanoma cell interaction. This work demonstrates the importance of the IIb-IIIa-like GPs, present on M3Dau melanoma cells, in mediating tumor-platelet interactions. 相似文献
55.
p16 gene homozygous deletions in acute lymphoblastic leukemia 总被引:15,自引:4,他引:15
Quesnel B; Preudhomme C; Philippe N; Vanrumbeke M; Dervite I; Lai JL; Bauters F; Wattel E; Fenaux P 《Blood》1995,85(3):657-663
The p16 protein is a cyclin inhibitor encoded by a gene located in 9p21, which may have antioncogenic properties, and is inactivated by homozygous p16 gene deletion or, less often, point mutation in several types of solid tumors often associated to cytogenetic evidence of 9p21 deletion. We looked for homozygous deletion and point mutation of the p16 gene in acute lymphoblastic leukemia (ALL), where 9p21 deletion or rearrangement are also nonrandom cytogenetic findings. Other hematologic malignancies including acute myeloid leukemia (AML), myelodysplastic syndromes (MDS), chronic lymphocytic leukemia (CLL), and myeloma were also studied. Homozygous deletion of the p16 gene was seen in 9 of the 63 (14%) ALL analyzed, including 6/39 precursor B-ALL, 3/12 T-ALL, and 0/12 Burkitt's ALL. Three of the 7 ALL with 9p rearrangement (including 3 of the 5 patients where this rearrangement was clearly associated to 9p21 monosomy) had homozygous deletion compared to 5 of the 55 patients with normal 9p (the last patient with homozygous deletion was not successfully karyotyped). Single stranded conformation polymorphism analysis of exons 1 and 2 of the p16 gene was performed in 88 cases of ALL, including the 63 patients analyzed by Southern blot. Twenty-six of the cases had 9p rearrangement, associated to 9p21 monosomy in at least 12 cases. A missense point mutation, at codon 49 (nucleotide 164), was seen in only 1 of the 88 patients. No homozygous deletion and no point mutation of the p16 gene was seen in AML, MDS, CLL, and myeloma. Homozygous deletion of interferon alpha genes (situated close to p16 gene in 9p21) was seen in only 3 of the 9 ALL patients with p16 gene homozygous deletion, and none of the ALL without p16 gene homozygous deletion. Our findings suggest that homozygous deletion of the p16 gene is seen in about 15% of ALL cases, is not restricted to cases with cytogenetically detectable 9p deletion, and could have a pathogenetic role in this malignancy. On the other hand, p16 point mutations are very rare in ALL, and we found no p16 homozygous deletions or mutations in the other hematologic malignancies studied. 相似文献
56.
Harrison J; Kappas A; Levere RD; Lutton JD; Chertkov JL; Jiang S; Abraham NG 《Blood》1993,82(12):3574-3579
The ability of combination treatment with erythropoietin (Epo) and heme to rescue hematopoietic activity in mice from the suppressive effect of azidothymidine (AZT) was determined. Exposure of mice to AZT for 5 weeks produced marked anemia, thrombocytopenia, neutropenia, and weight loss, whereas mice that received Epo and heme for 3 subsequent weeks showed significant alleviation of AZT cytotoxicity. Treatment with Epo (10 U for 5 times/week) stimulated hematopoietic recovery in the AZT- treated animals and reduced the severe anemia and thrombocytopenia by 3 weeks. Administration of a lower Epo dose (1 U Epo) resulted in only a modest retardation of AZT-induced anemia, although, when combined with heme, there was a great improvement in recovery of erythropoiesis. The combination of heme with Epo (10 U) produced the optimum response, resulting in almost normal recovery of bone marrow cellularity as well as recovery of burst-forming units-erythroid (BFU-E) and splenic hematopoietic progenitor content (colony-forming unit-spleen [CFU-S]) by the end of 3 weeks of post-AZT treatment. Treatment with heme alone markedly enhanced the recovery of BFU-E and CFU-S, as well as body weight post-AZT; however, this recovery was not to the extent seen in combination with Epo (10 U). Long-term bone marrow cultures (LTBMCs) established from mice exposed to AZT for 8 weeks showed a marked reduction in cellularity and this was completely alleviated when mice received heme and Epo (10 U) for 3 weeks after 5 weeks of AZT administration. The additive effect of heme and Epo was seen in BFU-E production, as well as in CFU-S production, in LTBMCs. Thus, heme exerts a significant protective effect on hematopoietic progenitors in vivo and may be of potential clinical use in combination with Epo to promote effective erythropoiesis in the setting of AZT therapy. 相似文献
57.
Guerci A; Merlin JL; Missoum N; Feldmann L; Marchal S; Witz F; Rose C; Guerci O 《Blood》1995,85(8):2147-2153
To evaluate the clinical relevance of multidrug resistance (MDR) phenotype, the intracellular daunorubicin accumulation (IDA) and P- glycoprotein (P-gp) expression were investigated in 87 adult patients with acute leukemia: 69 patients with de novo acute myeloid leukemia (AML), 10 with AML at relapse, and eight with secondary leukemia to myelodysplastic syndromes (MDS-AML). IDA and P-gp expression were determined by double-labeling flow cytometry analysis. Of 87 patients, 36 expressed P-gp (41%). P-gp expression was more frequently observed in AML at relapse and MDS-AML as compared with de novo AML (P = .0001). P-gp expression was significantly associated with CD34 expression (P = .0003) and chromosome 7 abnormalities (P = .027). A significantly reduced IDA was observed in P-gp+ as compared with P-gp- patients (P = .0007). Of the 87 patients, 51 achieved complete remission (CR). A reduced IDA was observed in patients in failure as compared with patients in CR (22% +/- 17% v 42% +/- 21%; P = 10(-4). Twelve of 36 P- gp+ patients as compared with 40 of 51 P-gp- patients achieved CR (33% v 78%; P = 10(-4). The prognostic value of IDA and P-gp expression was confirmed in multivariate analysis. These data suggest that the determination of IDA and P-gp expression may be useful in designing therapy for patients with AML. 相似文献
58.
Nayu Ikeda David Sapienza Ramiro Guerrero Wichai Aekplakorn Mohsen Naghavi Ali H Mokdad Rafael Lozano Christopher JL Murray Stephen S Lim 《Bulletin of the World Health Organization》2014,92(1):10-19C
Objective
To examine hypertension management across countries and over time using consistent and comparable methods.Methods
A systematic search identified nationally representative health examination surveys from 20 countries containing data from 1980 to 2011 on blood pressure measurements, the diagnosis and treatment of hypertension and its control with antihypertensive drugs. For each country, the prevalence of hypertension (i.e. systolic blood pressure ≥ 140 mmHg or antihypertensive use) and the proportion of hypertensive individuals whose condition was diagnosed, treated or controlled with medications (i.e. systolic pressure < 140 mmHg) were estimated.Findings
The age-standardized prevalence of hypertension varied between countries: for individuals aged 35 to 49 years, it ranged from around 12% in Bangladesh, Egypt and Thailand to around 30% in Armenia, Lesotho and Ukraine; for those aged 35 to 84 years, it ranged from 20% in Bangladesh to more than 40% in Germany, the Russian Federation and Turkey. The age-standardized percentage of hypertensive individuals whose condition was diagnosed, treated or controlled was highest in the United States of America: for those aged 35 to 49 years, it was 84%, 77% and 56%, respectively. Percentages were especially low in Albania, Armenia, the Islamic Republic of Iran and Turkey. Although recent trends in prevalence differed in England, Japan and the United States, treatment coverage and hypertension control improved over time, particularly in England.Conclusion
Globally the proportion of hypertensive individuals whose condition is treated or controlled with medication remains low. Greater efforts are needed to improve hypertension control, which would reduce the burden of noncommunicable diseases. 相似文献59.
Lorenza Magliano Melania Patalano Alessandra Sagliocchi Marianna Scutifero Antonella Zaccaro Maria Grazia D’Angelo Federica Civati Erika Brighina Giuseppe Vita Gian Luca Vita Sonia Messina Maria Sframeli Marika Pane Maria Elena Lombardo Roberta Scalise Adele D’Amico Giulia Colia Michela Catteruccia Umberto Balottin Angela Berardinelli Maria Chiara Motta Corrado Angelini Alessandra Gaiani Claudio Semplicini Luca Bello Roberta Battini Guja Astrea Giulia Ricci Luisa Politano 《Journal of neurology》2014,261(1):188-195
This paper focuses on the psychological benefits of caregiving in key relatives of patients with muscular dystrophies (MD), a group of rare diseases characterized by progressive weakness and restriction of the patient’s functional abilities. We describe whether relatives perceived caregiving to be a positive experience and test whether relatives’ perceptions vary in relation to their view of the patient as a valued person, the degree of involvement in care, and the level of support provided by social network and professionals. The study sample included 502 key relatives of patients aged 4–25 years, suffering from Duchenne, Becker, or limb-girdle MD, in treatment for at least 6 months to one of the eight participating centers, living with at least one relative aged 18–80 years. Of key relatives, 88 % stated that they had gotten something positive out of the situation, 96 % considered their patients to be sensitive, and 94 % viewed their patients as talented. Positive aspects of caregiving were more recognized by key relatives who were more convinced that the patient was sensitive and who perceived that they received higher level of professional help and psychological social support. These results suggest that most key relatives consider that their caregiving experience has had a positive impact on their lives, despite the practical difficulties of caring for patients with MD. Professionals should help relatives to identify the benefits of caregiving without denying its difficulties. Clinicians themselves should develop positive attitudes towards family involvement in the care of patients with long-term diseases. 相似文献
60.
B-cell growth factor receptor expression and B-cell growth factor response of leukemic B cell precursors and B lineage lymphoid progenitor cells 总被引:8,自引:1,他引:8
Uckun FM; Fauci AS; Heerema NA; Song CW; Mehta SR; Gajl-Peczalska K; Chandan M; Ambrus JL 《Blood》1987,70(4):1020-1034
The purpose of this study was to analyze the expression of B cell growth factor (BCGF) receptors and to elucidate the biologic effects of biochemically purified natural BCGF at the B cell precursor stage of human B lineage lymphoid differentiation. The specific binding of radioiodinated high-mol-wt BCGF (125I-HMW-BCGF) and low-molecular-wt BCGF (125I-LMW-BCGF) to fresh marrow blasts from B cell precursor acute lymphoblastic leukemia (ALL) patients was initially investigated. The estimated number of radioiodinated BCGF molecules bound per blast ranged from undetectable to 24.3 X 10(3) for HMW-BCGF, and from 11.5 X 10(3) to 457.8 X 10(3) for LMW-BCGF. In 3H-TdR incorporation assays, 75% of cases showed a significant response to LMW-BCGF with a median stimulation index of 9.3. By comparison, only 33% of cases showed a significant response to HMW-BCGF with a median stimulation index of 2.4. Subsequently, B cell precursor colony assays were performed to assess and compare the biologic effects of BCGF on leukemic B lineage lymphoid progenitor cells. Among 28 cases studied, 57% responded to both HMW-BCGF and LMW-BCGF, 21% responded only to LMW-BCGF, and the remaining cases showed no proliferative response to either growth factor. The response patterns of virtually pure populations of FACS- sorted leukemic B cell precursors were essentially identical to the proliferative responses of unsorted leukemic B-cell precursors. Synergistic effects between HMW-BCGF and LMW-BCGF were observed in 80% of the cases that responded to both. The numbers of cell-bound radioiodinated BCGF molecules, the stimulation indices, as well as the number of B cell precursor colonies in BCGF-stimulated cultures showed a marked interpatient variation. Patients with structural chromosomal abnormalities (SCAs) involving 12p11-13 or patients with a Philadelphia chromosome showed a greater HMW-BCGF response at the level of leukemic progenitor cells than did other patients (P = .02). The LMW-BCGF response was significantly greater for patients with SCA than for patients without SCA (P = .04). The response of leukemic progenitor cells to HMW-BCGF or LMW-BCGF did not correlate with sex, age, disease status, FAB morphology, WBC at diagnosis, or immunophenotype. To our knowledge, this study represents the first detailed analyses of BCGF receptor expression and BCGF effects in B cell precursor ALL. The data presented provide direct evidence for the expression of functional receptors for both HMW-BCGF and LMW-BCGF in B cell precursor ALL. 相似文献