Interleukin-17 in acute myeloid leukemia

There are several reports that angiogenesis plays important roles in hematological malignancies including acute myeloid leukemia (AML). Human interleukin-17 (IL-17) is a proinflammatory cytokine produced by activated CD4 T cells. IL-17 plays a potential role in T cell mediated angiogenesis. The role of IL-17 in pathologic angiogenesis has not been evaluated yet. The aim of the study was to determine plasma level of IL-17 in patients with AML. IL-17 levels were measured by ELISA in plasma samples taken from 68 adult patients with AML before chemotherapy was administered. In addition 20 out of 68 patients were reanalysed after achieving complete remission (CR). Ten samples from healthy volunteers were evaluated as the control. In this study we have demonstrated that serum level of IL-17 is not elevated in AML patients. These results suggest that angiogenesis in AML is not mediated by CD4 T cells. To our knowledge this is the first report about IL-17 serum level in acute leukemias. We are currently evaluating IL-17 levels in others haematological malignancies.     

Regression of syndesmophyte after bone marrow transplantation for acute myeloid leukemia in a patient with ankylosing spondylitis: a case report

ABSTRACT: INTRODUCTION: Disease progression of ankylosing spondylitis has been considered irreversible. However, wereport a case of spontaneous regression of syndesmophyte development following allogeneicperipheral blood stem cell transplantation in a patient with acute myeloid leukemia, who wasalso diagnosed as having ankylosing spondylitis. To the best of our knowledge, this is thefirst case report presenting the partial radiologic regression of syndesmophytes. CASE PRESENTATION: A 39-year-old man with active ankylosing spondylitis achieved clinical remission and partialradiological regression of cervical spine syndesmophytes following a peripheral blood stemcell transplantation for acute myeloid leukemia. Our patient received an allogeneic peripheralblood stem cell transplantation following a pre-transplantation conditioning regimen of totalbody irradiation and cyclophosphamide. The donor was a human leukocyte antigen-matched29-year-old man. Our patient has remained asymptomatic and has received no medication forankylosing spondylitis for nearly three years. CONCLUSIONS: Several explanations are proposed for the regression of syndesmophytes and clinicalimprovement in active ankylosing spondylitis observed in our patient, including changes inbone remodeling and immune reconstitution following stem cell transplantation, the effect ofimmunosuppressive agents, or fluctuation in the natural course of ankylosing spondylitisalthough further studies are required. The regression of syndesmophytes in ankylosingspondylitis in this case raises the possibility that stem cell transplantation might contribute tothe development of a novel therapeutic strategy for treatment of the disease.     

Systemic mastocytosis associated with t(8;21)(q22;q22) acute myeloid leukemia

Although KIT mutations are present in 20–25% of cases of t(8;21)(q22;q22) acute myeloid leukemia (AML), concurrent development of systemic mastocytosis (SM) is exceedingly rare. We examined the clinicopathologic features of SM associated with t(8;21)(q22;q22) AML in ten patients (six from our institutions and four from published literature) with t(8;21) AML and SM. In the majority of these cases, a definitive diagnosis of SM was made after chemotherapy, when the mast cell infiltrates were prominent. Deletion 9q was an additional cytogenetic abnormality in four cases. Four of the ten patients failed to achieve remission after standard chemotherapy and seven of the ten patients have died of AML. In the two patients who achieved durable remission after allogeneic hematopoietic stem cell transplant, recipient-derived neoplastic bone marrow mast cells persisted despite leukemic remission. SM associated with t(8;21) AML carries a dismal prognosis; therefore, detection of concurrent SM at diagnosis of t(8;21) AML has important prognostic implications.     

Characterization of in vitro and in vivo hypomethylating effects of decitabine in acute myeloid leukemia by a rapid, specific and sensitive LC-MS/MS method

DNA hypermethylation is a common finding in malignant cells and has been explored as a therapeutic target for hypomethylating agents (e.g., decitabine). Detection of changes in DNA methylation might serve as a pharmacodynamic endpoint to establish the biological activity of these agents and predict clinical response. We developed and validated a rapid, sensitive and specific LC-MS/MS method for determination of global DNA methylation (GDM) in vitro and in vivo. Ratios of 5-methyl-2′-deoxycytidine (5mdC) to the internal standard 2-deoxyguanosine (2dG) in mass signal were used to quantify GDM levels. The assay was validated in a linear range from 40 fmol to 200 pmol 5mdC. The intra-day precision values ranged from 2.8 to 9.9% and the inter-day values from 1.1 to 15.0%. The accuracy of the assay varied between 96.7 and 109.5%. This method was initially applied for characterization of decitabine-induced GDM changes in in-vitro-treated leukemia cells. Following exposure to 2.5μM decitabine, GDM decreased to ~50% of the baseline value. The clinical applicability of this method was then demonstrated in bone marrow samples from patients with acute myeloid leukemia treated with decitabine. Our data support the use of our LC-MS/MS method for clinical pharmacodynamic determination of changes in GDM in vivo.     

Experience with using aclarubicin in the treatment of acute leukemia and blast crisis of chronic myeloid leukemia]

The clinical efficacy of aclarubicin, an anthracycline antibiotic, was studied in 48 patients with leukemia. The antibiotic was used in the following combinations with cytarabine: "7 + 7", "5 + 5" and "7 & 3". A complete remission was stated in 14 (42.4 per cent) out of 33 patients with acute nonlymphoid leukemia, 6 (43 per cent) out of the 14 patients having relapses. The combined therapy was effective in 4 out of 5 pre-resistant patients. The "7 + 3" scheme was the most beneficial. The most common adverse reactions were nausea and vomiting.     

Therapy for acute myeloid leukemia in 119 adults: a comparison of two treatment protocols

Of 119 patients with acute myeloid leukemia, 69 were treated with Adriamycin, Vincristine and Cytosine Arabinoside (Therapy 1) and 50 with Daunorubicin, Cytosine Arabinoside and 6-Thioguanine (Therapy 2) as well as a consolidation therapy. The maintenance therapy with Cytosine Arabinoside and 6-Thioguanine was the same for both groups. The complete remission rate was 44% for Therapy 1 and 68% for Therapy 2 (p less than 0.05). - The median values for remission duration were 7 and 13 months respectively (p = 0.10); for survival time the median values were 18 and 19 months. These figures show in retrospect that high remission rates can be attained through intensive induction therapy and that longer remission duration is correlated with more aggressive induction therapy. A mild form of maintenance therapy seems to have little effect on the duration of complete remission.     

Cytoenzymochemical changes in acute leukemia cells under cytostatic treatment

Cytomorphologic and cytoenzymochemical changes occurring in leukemic blastic cells of bone marrow and peripheral blood were studied concomitantly in 180 cases of acute leukemia treated with one or more cytostatics, in various association related to the main cytologic type. Cellular effects due to monochemotherapy in various types of acute leukemia varied depending on the cytostatic dose, duration of treatment, and sensitivity of blastic cells to the cytostat. The expression of cellular sensitivity was marked by megaloblastosis of myeloid elements, cell gigantism and intranuclear and cytoplasmic vacuolization. Resistance to cytostatics was demonstrated both by the morphologic aspect of blastic cells which remained unchanged and by their overloading with glycogen, lipids and peroxidases. The relationships between posttherapeutic cellular changes and clinical parameters are discussed.     

Complex cytogenetic abnormalities in a patient with chronic myeloid leukemia: a case report

A case of multiple chromosome aberrations in a patient with CML (chronic myeloid leukemia) in the accelerated phase was described. Cytogenetic and molecular genetic studies revealed the presence of a t(9; 22)(q34; q11) translocation and some additional abnormalities such as t(1; 2)(p36; p21), del(6)(q21), +del(8)(q22), del(18)(q21), and +der(22), part of which is not typical for this kind of pathology. The correlation between the obtained data and the data presented in different publications is considered. A probable connection of the detected changes with previously received treatment and a possible effect of these changes on CML progression are discussed.     

阿萨希毛孢子菌致白血病患者血流感染1例

患者,男,41岁,急性白血病化疗后骨髓抑制期出现高热,广谱抗生素覆盖,患者体温好转后再次高热。第1次发热血培养缓症链球菌/葡萄球菌。第2次发热血培养阿萨希毛孢子菌。血清隐球菌抗原(免疫胶体金法)阳性,胸部CT提示肺部感染。加用国产伏立康唑后体温曾下降,再次上升,换用进口伏立康唑患者未再发热,持续口服伏立康唑,2个月后复查胸部CT肺部病灶好转。     

Hyper-radiosensitivity affects low-dose acute myeloid leukemia incidence in a mathematical model

In vitro experiments show that the cells possibly responsible for radiation-induced acute myeloid leukemia (rAML) exhibit low-dose hyper-radiosensitivity (HRS). In these cells, HRS is responsible for excess cell killing at low doses. Besides the endpoint of cell killing, HRS has also been shown to stimulate the low-dose formation of chromosomal aberrations such as deletions. Although HRS has been investigated extensively, little is known about the possible effect of HRS on low-dose cancer risk. In CBA mice, rAML can largely be explained in terms of a radiation-induced Sfpi1 deletion and a point mutation in the remaining Sfpi1 gene copy. The aim of this paper is to present and quantify possible mechanisms through which HRS may influence low-dose rAML incidence in CBA mice. To accomplish this, a mechanistic rAML CBA mouse model was developed to study HRS-dependent AML onset after low-dose photon irradiation. The rAML incidence was computed under the assumptions that target cells: (1) do not exhibit HRS; (2) HRS only stimulates cell killing; or (3) HRS stimulates cell killing and the formation of the Sfpi1 deletion. In absence of HRS (control), the rAML dose-response curve can be approximated with a linear-quadratic function of the absorbed dose. Compared to the control, the assumption that HRS stimulates cell killing lowered the rAML incidence, whereas increased incidence was observed at low doses if HRS additionally stimulates the induction of the Sfpi1 deletion. In conclusion, cellular HRS affects the number of surviving pre-leukemic cells with an Sfpi1 deletion which, depending on the HRS assumption, directly translates to a lower/higher probability of developing rAML. Low-dose HRS may affect cancer risk in general by altering the probability that certain mutations occur/persist.

     

Phosphodiesterase 5 inhibitor acts as a potent agent sensitizing acute myeloid leukemia cells to 67-kDa laminin receptor-dependent apoptosis

(−)-Epigallocatechin-3-O-gallate (EGCG), a polyphenol in green tea, induces apoptosis in acute myeloid leukemia (AML) cells without affecting normal cells. In this study, we observed that cGMP acts as a cell death mediator of the EGCG-induced anti-AML effect through acid sphingomyelinase activation. EGCG activated the Akt/eNOS axis, a well-known mechanism in vascular cGMP upregulation. We also observed that a major cGMP negative regulator, phosphodiesterase 5, was overexpressed in AML cells, and PDE5 inhibitor, an anti-erectile dysfunction drug, synergistically enhanced the anti-AML effect of EGCG. This combination regimen killed AML cells via overexpressed 67-kDa laminin receptors.