Hong-hui Huang

SLC29A1 single nucleotide polymorphisms as independent prognostic predictors for survival of patients with acute myeloid leukemia: an in vitro study

BackgroundThe mechanism behind poor survival of acute myeloid leukemia (AML) patients with 1-barabinofuranosylcytosine (Ara-C) based treatment remains unclear. This study aimed to assess the pharmacogenomic effects of Ara-C metabolic pathway in patients with AML.MethodsThe genotypes of 19 single nucleotide polymorphisms (SNPs) of DCK, CDA and SLC29A1from 100 AML patients treated with Ara-C were examined. All the SNPs were screened with ligase detection reaction assay. The transcription analysis of genes was examined by quantitative real time polymerase chain reaction. The association between clinical outcome and gene variants was evaluated by Kaplan-Meier method.ResultsGenotypes of rs9394992 and rs324148 for SLC29A1 in remission patients were significantly different from those in relapsed ones. Post-induction overall survival (OS) significantly decreased in patients with the CC genotype of rs324148 compared with CT and TT genotypes (hazard ratio [HR] = 2.997 [95% confidence interval (CI): 1.71-5.27]). As compared with CT and TT genotype, patients with the CC genotype of rs9394992 had longer survival time (HR = 0.25 [95% CI: 0.075-0.81]; HR = 0.43 [95% CI: 0.24-0.78]) and longer disease-free survival (DFS) (HR = 0.52 [95% CI: 0.29-0.93]; HR = 0.15 [95% CI: 0.05-0.47]) as well As compared with CT and TT genotype, patients with the CC genotype of rs324148 had shorter DFS (HR = 3.18 [95% CI: 1.76-5.76]). Additionally, patients with adverse karyotypes had shorter DFS (HR = 0.17 [95% CI: 0.05-0.54]) and OS (HR = 0.18 [95% CI: 0.05-0.68]).ConclusionsAML patients with low activity of SLC29A1 genotype have shorter DFS and OS in Ara-C based therapy. Genotypes of rs9394992 and rs324148 may be independent prognostic predictors for the survival of AML patients.

Glycolytic inhibitor 2-deoxy-d-glucose suppresses cell proliferation and enhances methylprednisolone sensitivity in non-Hodgkin lymphoma cells through down-regulation of HIF-1α and c-MYC

Abstract Metabolic reprogramming is linked to tumorigenesis, disease progression, clinical outcome and resistance to chemotherapy. However, the significance of glycolytic metabolism in non-Hodgkin lymphoma (NHL) remains unclear. Here we report that both NHL patient-samples and cell lines exhibited significant up-regulation of glycolytic metabolism. The glycolytic inhibitor 2-deoxy-d-glucose (2-DG) inhibited glucose consumption, lactic acid generation and cell proliferation and induced cell cycle arrest in NHL cell lines under both normoxia and hypoxia, and hypoxia could even enhance the inhibitory effects of 2-DG. Furthermore, 2-DG combined with methylprednisolone synergistically inhibited cell proliferation, induced cell apoptosis and cell cycle arrest, and thus increased the sensitivity of NHL cells to methylprednisolone via down-regulation of HIF-1α and c-MYC. In conclusion, these results present a novel insight into critical roles of glycolytic pathway activation in NHL progression and glucocorticoid resistance. Inhibition of the glycolytic pathway may provide a new therapeutic strategy for the treatment of NHL.

Prognostic value of total lesion glycolysis of baseline 18 F-fluorodeoxyglucose positron emission tomography/computed tomography in diffuse large B-cell lymphoma

Purpose We evaluated the prognostic value of total lesion glycolysis (TLG) measured in baseline 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) in diffuse large B-cell lymphoma (DLBCL) treated with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP). Methods A total of 91 patients with newly diagnosed DLBCL underwent 18F-FDG PET/CT scans before R-CHOP therapy. Metabolic tumor volume (MTV) was measured with the marginal threshold of normal liver mean standard uptake value (SUVmean) plus 3 standard deviations (SD). TLG was the sum of the products of MTV and SUVmean in all measured lesions. The predictive value was estimated by Log-rank test and Cox-regression analysis. Results Median follow-up was 30 months (range, 5-124 months). The 5-year estimated progression-free survival (PFS) of the low and high TLG group were 83% and 34%, respectively (p<0.001). The 5-year overall survival (OS) of the same groups were 92% and 67%, respectively (p<0.001). Patients with high TLG level were more likely to relapse than those with low TLG level even though they had got complete or partial remission in R-CHOP therapy (40% versus 9%, p=0.012). Multivariate analysis revealed TLG was the only independent predictor for PFS (Hazard ratio=5.211, 95% confidence interval=2.210-12.288, p<0.001) and OS (Hazard ratio=9.136, 95% confidence interval=1.829-45.644, p=0.002). Other factors including MTV, National Comprehensive Cancer Network International Prognostic Index (NCCN-IPI) and Ann Arbor Stage were not independently predictive for survivals. Conclusion Baseline TLG is the only independent predictor for PFS and OS in DLBCL patients treated with R-CHOP therapy.

Co-Existent de novo Myelodysplastic Syndrome and T-cell Non-Hodgkin Lymphoma: a Common Origin or Not?

The co-existence of de novo myelodysplastic syndrome (MDS) and non-Hodgkin lymphoma (NHL) prior to therapy is an extremely unusual finding. We report here a case of co-existent de novo MDS-refractory cytopenia with multilineage dysplasia and T-cell NHL, including clinical features, histopathological findings, molecular assessment, treatment course and outcomes. Other cases from the literature showing co-existence of both disorders are also reviewed; to date 19 similar cases have been reported. Among all cases (including the present patient), eight cases were diagnosed with de novo MDS and NHL simultaneously, which were considered to be true coincidences. The mechanisms responsible for the appearance of co-existence have not yet been ascertained, however in the present case a common chromosomal abnormality (20q deletion) was found in bone marrow and lymph node preparations. We conclude, therefore, that the co-existent de novo MDS and T-cell NHL seen in the present case may have a common origin.

Modification of TGF-β1 signaling pathway during NB4 cells differentiation by all-trans retinoid acid induction

The aim of the study was to present the possible mechanisms of transforming growth factor beta 1(TGF-β1) signal pathway during cell differentiation by studying the expression levels of six components of TGF-β1 pathway (TGF-β1, two TGF-β1 receptors and three Smad proteins). The morphology change, the CD11 expression levels, and the mRNA and protein expression levels of TGF-β1, TGF-β ReceptorI (TβRI), TGF-β ReceptorII (TβRII), Smad2, Smad4 and Smad7 were assessed by exposing NB4 cells to all-trans retinoid acid (ATRA) using Wright’s stain, flow cytometry, real-time PCR assay and Western blot analysis. The mRNA and protein expression levels of all six components increased during NB4 cells differentiation induced by ATRA. They were most significantly increased after 24–72 h individually when cells were induced by ATRA (the mRNA and protein expression levels of TGF-β1, TβRI, TβRII and Smad2 reached their peaks at 48 and 48 h individually after the treatment, Smad4 at 48 and 72 h, and Smad7 at 72 and 72 h). The change in mRNA expression levels was earlier than the change in the same gene controlling protein. These results indicate that the upregulation of TGF-β1 pathway plays an important role in NB4 cells differentiation induced by ATRA.

Correlation of pretreatment 18F-FDG uptake with clinicopathological factors and prognosis in patients with newly diagnosed diffuse large B-cell lymphoma

ObjectivesThe aim of this study is to determine the correlation of pretreatment fluorine-18 fluorodeoxyglucose uptake with clinicopathological factors and its prognostic value in patients with newly diagnosed diffuse large B-cell lymphoma (DLBCL). Patients and methodsA cohort of 162 patients with newly diagnosed DLBCL who had undergone pretreatment PET/computed tomography was retrospectively reviewed. The relationship of pretreatment maximum standard uptake value (SUVmax) with clinical factors, molecular markers, and efficacy was evaluated. The value of SUVmax in predicting progression-free survival (PFS) and overall survival was analyzed. ResultsIn all, 72.9% of the patients received R-CHOP treatment; the rest received CHOP chemotherapy. The median follow-up duration was 30 months (range, 4–124 months). The median SUVmax was 12.2 (range, 1.7–42.7). SUVmax between groups differed significantly with respect to each of International Prognostic Index (IPI) factors, except for age and performance status. High SUVmax was associated with high Ki-67 and Glut-3 protein expression, but not with Glut-1. Complete remission rate differed significantly between the low (SUVmax⩽9.0) and the high SUVmax (SUVmax>9.0) groups (91.7 vs. 61.1%, P=0.000). Patients with low SUVmax showed favorable survival (3-year PFS: 92.2 vs. 63.6%, P=0.000; 3-year overall survival: 95.5 vs. 78.3%, P=0.003). On multivariate analyses, SUVmax predicted PFS independent of revised-IPI (SUVmax: P=0.011, hazard ratio 4.784; revised-IPI: P=0.004, hazard ratio 2.551). ConclusionPretreatment SUVmax was associated with clinicopathological factors, efficacy, and survival outcome. A novel prognostic model on the basis of IPI score/pretreatment SUVmax might be useful for risk stratification of patients with newly diagnosed DLBCL Video abstract: http://links.lww.com/NMC/A55.