Yong Park

Comparative analysis between azacitidine and decitabine for the treatment of myelodysplastic syndromes

The present study aimed to directly compare the efficacy and safety of azacitidine and decitabine in patients with myelodysplastic syndromes (MDS). We compared the overall response rate (ORR) (complete responses, partial responses, marrow complete responses, and haematological improvements), overall survival (OS), event‐free survival (EFS), time to leukaemic transformation, and adverse outcomes between azacitidine and decitabine. To minimize the effects of treatment selection bias in this observational study, adjustments were made using the propensity‐score matching method. Among 300 patients, 203 were treated with azacitidine and 97 with decitabine. Propensity‐score matching yielded 97 patient pairs. In the propensity‐matched cohort, there were no significant differences between the azacitidine and decitabine groups regarding ORR (44% vs. 52%), OS (26 vs. 22·9 months), EFS (7·7 vs. 7·0 months), and rate of leukaemic transformation (16% vs. 22% at 1 year). In patients ≥65 years of age, survival was significantly better in the azacitidine group (P = 0·017). Patients who received decitabine experienced more frequent episodes of grade 3 or 4 cytopenia and infectious episodes. We found that azacitidine and decitabine showed comparable efficacy. Among patients ≥65 years of age, survival was significantly better in the azacitidine group (ClinicalTrials.gov Identifier: NCT01409070).

A prognostic index for natural killer cell lymphoma after non-anthracycline-based treatment: a multicentre, retrospective analysis

BACKGROUND The clinical outcome of extranodal natural killer T-cell lymphoma (ENKTL) has improved substantially as a result of new treatment strategies with non-anthracycline-based chemotherapies and upfront use of concurrent chemoradiotherapy or radiotherapy. A new prognostic model based on the outcomes obtained with these contemporary treatments was warranted. METHODS We did a retrospective study of patients with newly diagnosed ENKTL without any previous treatment history for the disease who were given non-anthracycline-based chemotherapies with or without upfront concurrent chemoradiotherapy or radiotherapy with curative intent. A prognostic model to predict overall survival and progression-free survival on the basis of pretreatment clinical and laboratory characteristics was developed by filling a multivariable model on the basis of the dataset with complete data for the selected risk factors for an unbiased prediction model. The final model was applied to the patients who had complete data for the selected risk factors. We did a validation analysis of the prognostic model in an independent cohort. FINDINGS We did multivariate analyses of 527 patients who were included from 38 hospitals in 11 countries in the training cohort. Analyses showed that age greater than 60 years, stage III or IV disease, distant lymph-node involvement, and non-nasal type disease were significantly associated with overall survival and progression-free survival. We used these data as the basis for the prognostic index of natural killer lymphoma (PINK), in which patients are stratified into low-risk (no risk factors), intermediate-risk (one risk factor), or high-risk (two or more risk factors) groups, which were associated with 3-year overall survival of 81% (95% CI 75-86), 62% (55-70), and 25% (20-34), respectively. In the 328 patients with data for Epstein-Barr virus DNA, a detectable viral DNA titre was an independent prognostic factor for overall survival. When these data were added to PINK as the basis for another prognostic index (PINK-E)-which had similar low-risk (zero or one risk factor), intermediate-risk (two risk factors), and high-risk (three or more risk factors) categories-significant associations with overall survival were noted (81% [95% CI 75-87%], 55% (44-66), and 28% (18-40%), respectively). These results were validated and confirmed in an independent cohort, although the PINK-E model was only significantly associated with the high-risk group compared with the low-risk group. INTERPRETATION PINK and PINK-E are new prognostic models that can be used to develop risk-adapted treatment approaches for patients with ENKTL being treated in the contemporary era of non-anthracycline-based therapy. FUNDING Samsung Biomedical Research Institute.

The Bone Morphogenesis Protein-2 (BMP-2) is Associated with Progression to Metastatic Disease in Gastric Cancer

PURPOSE Bone Morphogenetic Proteins (BMPs) are members of the TGF-beta superfamily and it has been demonstrated that BMPs enhance migration, invasion and metastasis. The purpose of this study was to identify the association between the serum BMP-2 level and the progression status of gastric cancer. MATERIALS AND METHODS Fifty-five patients with metastatic gastric cancer (metastatic disease group), six patients with early gastric cancer without lymph node metastasis (the EGC group), and ten healthy control subjects were enrolled in this study. The serum BMP-2 level was quantified by use of a commercially available ELISA kit. In EGC group patients and patients with metastatic disease, whole blood was obtained before endoscopic mucosal resection and before the commencement of a scheduled cycle of systemic chemotherapy, respectively. RESULTS No significant difference in the mean serum BMP-2 levels was observed between the control subjects and the EGC group patients (87.95 pg/ml for the control subjects and 84.50 pg/ml for the EGC group, p=1.0). However, the metastatic disease group patients had a significantly higher level of serum BMP (179.61 pg/ml) than the control subjects and EGC group patients (87.95 pg/ml for the control subjects and 84.50 pg/ml for the EGC group, p<0.0001). Moreover, the mean serum BMP-2 level from patients with a bone metastasis was significantly higher than the mean serum BMP-2 level from patients without a bone metastasis (204.73 pg/ml versus 173.33 pg/ml, p=0.021). CONCLUSIONS BMP-2 seems to have a role in progression to metastatic disease in gastric cancer, especially in the late stage of tumorigenesis, including invasion and metastasis. BMP-2 may facilitate bone metastasis in gastric cancer. To confirm these findings, further studies are required with tissue specimens and the use of a cancer cell line.

Prognostic factors in primary diffuse large B-cell lymphoma of adrenal gland treated with rituximab-CHOP chemotherapy from the Consortium for Improving Survival of Lymphoma (CISL).

BackgroundThe objective of this study was to identify prognostic factors for survival in patients with primary diffuse large B-cell lymphoma (DLBCL) of the adrenal gland.MethodsThirty one patients diagnosed with primary adrenal DLBCL from 14 Korean institutions and treated with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone) were analyzed.ResultsComplete remission (CR) and overall response rate after R-CHOP chemotherapy were 54.8% and 87.0%. The 2-year estimates of overall survival (OS) and progression-free survival (PFS) were 68.3% and 51.1%. In patients achieving CR, significant prolongations of OS (P = 0.029) and PFS (P = 0.005) were observed. Ann Arbor stage had no influence on OS. There was no significant difference in OS between patients with unilateral involvement of adrenal gland and those with bilateral involvement. When staging was modified to include bilateral adrenal involvement as one extranodal site, early stage (I or II) significantly correlated with longer OS (P = 0.021) and PFS (P < 0.001).ConclusionsContrary to prior reports, our data suggests that outcomes of primary adrenal DLBCL are encouraging using a regimen of R-CHOP, and that achieving CR after R-CHOP is predictive of survival. Likewise, our modified staging system may have prognostic value.

Human feeder cells can support the undifferentiated growth of human and mouse embryonic stem cells using their own basic fibroblast growth factors.

In the culture system using human feeder cells, the mechanism through which these cells support undifferentiated growth of embryonic stem cells (ESCs) has not been well investigated. Here, we explored the mechanisms of 3 kinds of human feeder cells, including human placental cells from the chorionic plate, human bone marrow stromal cells, and human foreskin fibroblasts. First, we determined that undifferentiated growth of 2 kinds each of human (H1 and HSF6) and mouse (D3 and CE3) ESCs was possible in all human feeder cell types tested (human placental cells, human bone marrow stromal cells, and human foreskin fibroblasts), without the need for exogenous cytokine supplementation including basic fibroblast growth factor (bFGF) and leukemia inhibitory factor. We then prepared their corresponding endogenous bFGF-knockout feeders using siRNA and tried to maintain human and mouse ESCs in their undifferentiated state; however, neither human nor mouse ESCs could be maintained in bFGF-knockout human feeder cells. The expressions of stemness markers such as Oct-4 and Nanog were significantly decreased in the bFGF-knockout group compared with those in the controls, and differentiation had already occurred, despite the undifferentiated morphologic appearance of the ESCs. In conclusion, human feeder cells are able to support the undifferentiated growth of human and mouse ESCs via bFGF synthesis. Further, a bFGF-dependent pathway might be crucial for maintaining the undifferentiated characteristics of mouse and human ESCs.

Clinical Outcomes and Prognostic Factors of Up-Front Autologous Stem Cell Transplantation in Patients with Extranodal Natural Killer/T Cell Lymphoma

Limited data exist on up-front autologous stem cell transplantation (ASCT) in extranodal natural killer/T cell lymphoma (ENKTL). Sixty-two patients (43 men and 19 women) with newly diagnosed ENKTL who underwent up-front ASCT after primary therapy were identified. Poor-risk characteristics included advanced stage (50%), high-intermediate to high-risk International Prognostic Index (25.8%), and group 3 to 4 of NK/T Cell Lymphoma Prognostic Index (NKPI, 67.7%). Pretransplant responses included complete remission in 61.3% and partial remission in 38.7% of patients, and final post-transplantation response included complete remission in 78.3%. Early progression occurred in 12.9%. At a median follow-up of 43.3 months (range, 3.7 to 114.6), 3-year progression-free survival (PFS) was 52.4% and 3-year overall survival (OS) was 60.0%. Patients with limited disease had significantly better 3-year PFS (64.5% versus 40.1%, P = .017) and OS (67.6% versus 52.3%, P = .048) than those with advanced disease. Multivariate analysis showed NKPI and pretransplant response were independent prognostic factors influencing survival, particularly NKPI in limited disease and pretransplant response in advanced disease. Radiotherapy was an independent factor for reduced progression and survival in patients with limited disease, but anthracycline-based chemotherapy was a poor prognostic factor for progression in patients with advanced disease. Up-front ASCT is an active treatment in ENKTL patients responding to primary therapy.

Undifferentiated Propagation of the Human Embryonic Stem Cell Lines, H1 and HSF6, on Human Placenta-Derived Feeder Cells Without Basic Fibroblast Growth Factor Supplementation

In order for human embryonic stem cells (hESCs) to be cultured on mouse embryonic fibroblast (MEFs) feeder cells, continuous basic fibroblast growth factor (bFGF) supplementation is required. However, the role of bFGF in a culture system using human-derived feeder cells has not been evaluated until now. In this study, we propagated the widely used hESC lines, H1 and HSF6, on human placenta-derived feeder cells (HPCs) without exogenous bFGF supplementation, and were able to propagate hESCs on HPC feeders up to 50 passages. The absence of bFGF in culture media did not interrupt the undifferentiated propagation and the expression of pluripotent stem cell markers ALP, SSEA-4, TRA-60, Oct-4, Nanog, and Rex-1, as well as the formation of embryoid bodies (EBs) and their differentiation potential. In contrast, hESCs cocultured with MEF feeders could not propagate and form EBs without exogenous bFGF supplementation. Expression of bFGF and the activation of the ERK1/2-c-Fos/c-Jun pathway, which is known as the signaling pathway of bFGF, were identifiable not only in hESCs cultured in bFGF-containing media regardless of feeder cell type, but also in hESCs cocultured with HPC feeder cells in media without bFGF. These findings may support the hypothesis that HPC feeder cells enhance endogenous bFGF production and activation of the ERK1/2-c-Fos/c-Jun pathway, which suggests that HPCs have an additional advantage in their hESC propagation compared with MEF.

Hepatitis B virus reactivation in a surface antigen-negative and antibody-positive patient after rituximab plus CHOP chemotherapy.

Rituximab is a monoclonal antibody that targets B-lymphocytes, and it is widely used to treat non-Hodgkins lymphoma. However, its use has been implicated in HBV reactivation thats related with the immunosuppressive effects of rituximab. Although the majority of reactivations occur in hepatitis B carriers, a few cases of reactivation have been reported in HBsAg negative patients. However, reactivation in an HBsAg negative/HBsAb positive patient after rituximab treatment has never been reported in Korea. We present here an HBsAg-negative/HBsAb-positive 66-year-old female who displayed reactivation following rituximab plus CHOP chemotherapy for diffuse large B-cell lymphoma. While she was negative for HBsAg at diagnosis, her viral status was changed at the time of relapse as follows: HBsAg positive, HBsAb negative, HBeAg positive, HBeAb negative and an HBV DNA level of 1165 pg/ml. Our observation suggests that we should monitor for HBV reactivation during rituximab treatment when prior HBV infection or occult infection is suspected, and even in the HBsAg negative/HBsAb positive cases.

The suggestion of a risk stratification system for febrile neutropenia in patients with hematologic disease

We analyzed the prognostic factors from 259 cases of febrile neutropenia occurring in 137 patients with hematologic disease. Based on multivariate analysis, significant prognostic factors are recovery of neutropenia, respiratory infection, baseline serum albumin, baseline bicarbonate, baseline CRP, and CRP on the fifth day after antibiotic treatment. From these variables, we derived a predictive model for the prognosis of febrile neutropenia using baseline serum albumin, bicarbonate, and CRP, which could be easily checked before chemotherapy. Further studies in prospective setting are needed for the validation of this model.

Glucose Transporter-1 Expression in Squamous Cell Carcinoma of the Tongue

PURPOSE Tumor cells are known to express hypoxia-related proteins such as glucose transporter-1 (Glut-1). These hypoxia-induced changes may allow tumor cells to survive under sustained hypoxic microenvironments, and the surviving tumor cell under hypoxia may develop a more aggressive phenotype and so result in a poor prognosis. MATERIALS AND METHODS The Glut-1 expression was analyzed by immunohistochemistry, and its association with the prognosis was assessed in 60 patients with squamous cell carcinoma of the tongue. RESULTS The Glut-1 expression was diffuse with a membranous pattern, and the median percentage of Glut-1 positive tumor cells was 60% (range: 0.0 approximately 90.0%). A high Glut-1 expression (the percentage of positive tumor cells >or= the median value, 60%) was associated with the location of primary lesion, lymph node metastasis status and disease stage (p<0.05). The expression of Glut-1 was correlated with the Ki-67 expression (r=0.406, p=0.001). Microvessel density, as represented by CD31 staining, was also correlated with the Glut-1 expression although its significance is weak (r=0.267, p=0.039). On the univariate analysis, the group with a high Glut-1 expression showed poorer overall survival than the group with a low Glut-1 expression (p<0.05). However, the Glut-1 expression failed to show any independent prognostic significance on the multivariate analysis. CONCLUSION The expression of Glut-1 may be useful for predicting the prognosis and determining the treatment strategy for the management of squamous cell carcinoma of the tongue.