Impact of a novel prognostic model on allogeneic hematopoietic stem cell transplantation outcomes in patients with CMML.

Chronic myelomonocytic leukemia (CMML) is a clonal hematopoietic stem cell malignancy, and allogeneic hematopoietic stem cell transplantation (allo-HSCT) is the only curable treatment. The outcomes after transplant are influenced by both disease characteristics and patient comorbidities. To develop a novel prognostic model to predict the post-transplant survival of CMML patients, we identified risk factors by applying univariable and multivariable Cox proportional hazards regression to a derivation cohort. In multivariable analysis, advanced age (hazard ratio [HR] 3.583), leukocyte count (HR 3.499), anemia (HR 3.439), bone marrow blast cell count (HR 2.095), and no chronic graft versus host disease (cGVHD; HR 4.799) were independently associated with worse survival. A novel prognostic model termed ABLAG (Age, Blast, Leukocyte, Anemia, cGVHD) was developed and the points were assigned according to the regression equation. The patients were categorized into low risk (0-1), intermediate risk (2, 3), and high risk (4-6) three groups and the 3-year overall survival (OS) were 93.3% (95%CI, 61%-99%), 78.9% (95%CI, 60%-90%), and 51.6% (95%CI, 32%-68%; p < .001), respectively. In internal and external validation cohort, the area under the receiver operating characteristic (ROC) curves of the ABLAG model were 0.829 (95% CI, 0.776-0.902) and 0.749 (95% CI, 0.684-0.854). Compared with existing models designed for the nontransplant setting, calibration plots, and decision curve analysis showed that the ABLAG model revealed a high consistency between predicted and observed outcomes and patients could benefit from this model. In conclusion, combining disease and patient characteristic, the ABLAG model provides better survival stratification for CMML patients receiving allo-HSCT.

[Retracted] In vitro and in vivo anticancer effects of marmesin in U937 human leukemia cells are mediated via mitochondrial­mediated apoptosis, cell cycle arrest, and inhibition of cancer cell migration.

Following the publication of the above paper, a concerned reader drew to the Editor's attention that a pair of tumors in Fig. 10 appeared to have been duplicated, although one of the tumors appeared at a larger size in the figure relative to the first one. Furthermore, the flow cytometric plots shown in Fig. 2B in the above paper appeared to be remarkably similar to data presented in a paper published in Phytomedicine [Sui C­G, Meng F­D and Jiang Y­H: Antiproliferative activity of rosamultic acid is associated with induction of apoptosis, cell cycle arrest, inhibition of cell migration and caspase activation in human gastric cancer (SGC­7901) cells. Phyomedicine 22: 796­806, 2015]. After having conducted an independent investigation in the Editorial Office, the Editor of Oncology Reports has determined that the above paper should be retracted from the Journal on account of a lack of confidence concerning the originality and the authenticity of the data. The authors were asked for an explanation to account for these concerns, but the Editorial Office never received any reply. The Editor regrets any inconvenience that has been caused to the readership of the Journal. [the original article was published in Oncology Reports 39: 597­602, 2018; DOI: 10.3892/or.2017.6147].

In vitro and in vivo anticancer effects of marmesin in U937 human leukemia cells are mediated via mitochondrial-mediated apoptosis, cell cycle arrest, and inhibition of cancer cell migration.

Leukemia is one of the highly lethal cancers among all pediatric cancers. With limited drug options and the severe side effects associated with the current chemotherapy, there is pressing need to look for new and novel anticancer agents. Against this backdrop, in the present study we evaluated the anticancer activity of a natural coumarin, marmesin against human leukemia cell line U937 and normal human monocytes It was observed that marmesin exhibited an IC50 value of 40 µM and exerted its cytotoxic effects in a dose-dependent manner. However, the cytotoxic effects of marmesin were comparatively lower for the normal human monocytes as evident from the IC50 of 125 µM. Our results indicated that marmesin inhibits colony formation and induces apoptosis dose-dependently. We also investigated the effect of marmesin on the expression of Bax and Bcl-2 proteins. It was observed that marmesin treatment triggered upregulation of Bax and downregulation of Bcl-2 causing significant increase in the Bax/Bcl-2 ratio, marmesin could also induce ROS mediated alterations in mitochondrial membrane potential. Additionally, marmesin induced G2/M cell cycle arrest and significantly inhibited cell migration potential of leukemia cells at the IC50. Remarkably, marmesin prevent tumor growth significantly in vivo at the dosage of 30 mg/kg in vivo. These results strongly indicate that marmesin may prove to be a novel anticancer lead for the management of leukemia.

A multicenter randomized open-label study of rituximab plus rhTPO vs rituximab in corticosteroid-resistant or relapsed ITP.

This study aimed to compare the efficacy and safety of rituximab (RTX) plus recombinant human thrombopoietin (rhTPO) with RTX alone in patients with immune thrombocytopenia (ITP) who had failed to respond to corticosteroids or relapsed. Recruited patients were randomized at a ratio of 2:1 into 2 groups: the combination group (RTX + rhTPO, n = 77) and the monotherapy group (RTX, n = 38). Overall response was achieved in 79.2% of patients in the combination group vs 71.1% in the monotherapy group (P = .36), and the complete response (CR) rate was 45.4% in the combination group compared with 23.7% in the monotherapy group (P = .026). The combination group had significantly shorter time to response (TTR; median and range, 7 and 4-28 days) compared with the monotherapy group (28 and 4-90 days) (P < .01). There was no difference between these 2 groups in terms of the long-term response (P = .12). Our findings demonstrated that the combination of RTX and rhTPO significantly increased the CR rate and shortened TTR compared with RTX monotherapy in the treatment of corticosteroid-resistant or relapsed ITP but failed to show a beneficial effect on the long-lasting response. This study is registered at www.clinicaltrials.gov as #NCT01525836.

[Study of WIF-1 promoter methylation with expressions of ß-catenin in acute leukemia].

OBJECTIVE: To explore the significance of WIF-1 gene promoter methylation and the expression of ß-catenin in acute leukemia (AL) patients. METHODS: The method of methylation specific polymerase chain reaction was employed to detect the status of WIF-1 gene methylation in 55 acute leukemia patients and normal controls from January 2009 to June 2010 in our hospital. The expression of ß-catenin was measured by flow cytometry. RESULTS: The methylation of WIF-1 gene promoter was found in 32.7% (18/55) AL patients. And the percentage was significantly higher than that of the controls (0). The patients with the methylation of WIF-1 gene had a lower complete remission rate (38.9%, 7/18) for the first chemotherapy than those without (81.1%, 30/37) (P < 0.05). The expressions of ß-catenin in methylation AL patients and those with non-methylation were 17.5% ± 3.3% and 15.4% ± 3.6% respectively. And they were significantly higher than the controls (10.5% ± 1.5%, P < 0.05). The expression of ß-catenin was higher in positive methylation patients than those negative ones (P < 0.05). CONCLUSION: The methylation of WIF-1 gene promoter and ß-catenin may be involved in the abnormal activation of Wnt/ß-catenin signal in acute leukemia.

[A preliminary study on the implication of Apaf-1 promoter methylation and the expression of apoptosis inhibitor protein Apollon in adult acute leukemia].

OBJECTIVE: To investigate the role of Apaf-1 gene promoter methylation and apoptosis inhibitor protein Apollon in pathogenesis of acute leukemia (AL) and their clinical significance. METHODS: Methylation specific PCR (MSP) was used to detect the methylation status of Apaf-1 gene promoter in 53 AL patients (28 AML, 10 ALL and 15 relapsed) and 10 healthy or nonmalignant blood diseases patients as control. RT-PCR was used to detect the expression levels of Apaf-1 mRNA and immunocytochemistry to detect the expression levels of Apollon protein. RESULTS: The abnromal methylation of Apaf-1 gene promotor in AL was 18/53(33.9%). No Apaf-1 mRNA was detected in methylation positive patients. Only one case in healthy and nonmalignant individuals was deletion of Apaf-1 mRNA expression without abnormal methylation. The positive methylation rate in AL bone marrow mononuclear cells was significantly higher than that in controls (P < 0.05). The expressin levels of Apollon protein in AL patients was higher than that in control (P < 0.05). The positive methylation ratio and Apollon protein level were higher in white blood cell count > 10 × 10(9)/L than in ≤ 10 × 10(9)/L (P < 0.05). There is a positive correlaiton between positive methylation ratio and Apollon protein expression in AL patients. CONCLUSION: Abnormal methylation of Apaf-1 gene promotor and high expression of Apollon might involved in leukemogenesis.

Relationship between cytokines and leukocytosis in patients with APL induced by all-trans retinoic acid or arsenic trioxide.

Leukocytosis or hyperleukocytosis occurs during ATRA or arsenic trioxide differentiation therapy, which is related to the RA syndrome. The number of WBC often increased by ten or more times as high as that of pretreatment, around 7 to 20 days after treatment with ATRA or arsenic trioxide. Usually, when number of WBC tended to peak, there was concomitance with down-regulation of promyelocytes, up-regulation of myelocytes and more mature neutrophils. The same trend of classification of BM was observed in most of the patients with APL to whom leukocytosis happened. Although the mechanism of leukocytosis has not been demonstrated clearly, so far the proliferation hypothesis by cytokines and rheological hypothesis by adhesion molecules were taken into consideration. Otherwise, hypothesis about more divisions of differentiated myelocytes induced by ATRA or arsenic trioxide remains unclear. Usually, this kind of leukocytosis or hyperleukocytosis itself requires no additional cytotoxic treatment.