Yeo-Kyeoung Kim

Association between folate-metabolizing pathway polymorphism and non-Hodgkin lymphoma

Polymorphisms in the genes coding folate‐metabolizing enzymes affect the risk of some forms of cancer. We investigated the association between these polymorphisms and non‐Hodgkin lymphoma (NHL) risk in a population‐based study (583 cases and 1700 controls). The MTHFR 677TT and CT genotypes were associated with reduced risk for NHL [odds ratios (OR) = 0·79; 95% confidence intervals (CI) = 0·65–0·98 for 677CT and 0·61; 0·45–0·82 for 677TT] and diffuse large B‐cell lymphoma (DLBCL) (OR = 0·68; 0·51–0·88 for 677CT; OR = 0·56; 0·38–0·83 for 677TT). The MTHFR 1298CC genotype was associated with increased risk for NHL (OR = 1·71; 1·07–2·75) and T‐cell lymphoma (OR = 3·05; 1·53‐6·11). The MTRR 66GG genotype was associated with increased risk for DLBCL (OR = 1·56; 1·03‐2·38) and the TYMS 2R2R genotype was associated with increased risk for T‐cell lymphoma (OR = 2·83; 1·33–6·01). Using subjects with 3RG3RG as a reference group, TYMS 2R2R was associated with increased risk for T‐cell lymphoma (OR = 2·46; 1·04–5·79). Interestingly, we observed a reduced association between the TYMS 2R3RG genotype and DLBCL (OR = 0·61; 0·38–0·99). These results suggest that MTHFR, MTRR and TYMS polymorphisms may play a significant role in the risk for NHL.

Association between polymorphisms of folate-metabolizing enzymes and hematological malignancies

Several genetic polymorphisms in the genes coding folate-metabolizing enzymes have been associated with susceptibility to hematology malignancies. We conducted a Korean population-based case-control study to examine the relationship between the polymorphisms of folate-metabolizing enzymes and the risk of AML (acute myelogenous leukemia), CML (chronic myelogenous leukemia), MDS (myelodyspastic syndrome), and ALL (acute lymphoblastc leukemia). The MTHFR 677TT genotype was associated with an increased risk for ALL (odds ratios (OR)=1.77; 95% confidence intervals (CI)=1.02-3.09, p=.044). The MTRR 66 AG genotype was associated with an increased risk for MDS (OR=1.59; 1.06-2.38, p=.026) and the MTRR 66 GG genotype was associated with increased risk for AML (OR=1.51; 1.03-2.23, p=.037). The TYMS 2R3R genotype was associated with a decreased risk for AML (OR=0.76; 0.60-0.96, p=.022). The TYMS hap3 (2R-6bp) and hap4 (2R-0bp) were associated with decreased risk (OR=0.69; 0.53-0.90, p=.006) and increased risk (OR=1.65; 1.20-2.27, p=.002), respectively for AML. Hap C (677T-1298A) was associated with an increased risk (OR=1.40; 1.02-1.92, p=.04) for ALL. The risk for ALL appears to be associated with the MTHFR 677 polymorphism. The results are supportive of a risk modification by folate polymorphisms in several hematologic malignancies in Korea. The pattern of results suggests that MDS was associated with the DNA methylation status and the risk for AML was associated with both the DNA synthesis and DNA methylation status.

Prognostic significance of interim 18F-FDG PET/CT after three or four cycles of R-CHOP chemotherapy in the treatment of diffuse large B-cell lymphoma

PURPOSE (18)F-fluoro-2-dexoy-D-glucose-positron emission tomography (FDG-PET)/computerised tomography (CT) has been used for staging and monitoring responses to treatment in patients with diffuse large B cell lymphoma (DLBCL). The sequential interim PET/CT was prospectively investigated to determine whether it provided additional prognostic information and could be a positive predictable value within patients with the same international prognostic index (IPI) after the use of rituximab in DLBCL. METHODS One hundred and sixty-one patients with newly diagnosed DLBCL were enroled; the assessment of the PET/CT was performed at the time of diagnosis and mid-treatment of rituxibmab, cyclophosphamide, doxorubicin, vincristine and prednisolone (R-CHOP). RESULTS Sixty-seven patients (41.6%) presented with advanced stage disease and 27 (16.8%) had bulky lesions. Forty-three patients (26.7%) continued to have positive metabolic uptakes with a significantly high relapse rate (62.8%) compared to the patients with a negative interim PET/CT (12.1%) (P<0.01). After a median follow-up of 30.8months, the positivity of interim PET/CT was found to be a prognostic factor for both overall survival (OS) and progression-free survival (PFS), with a hazard ratio of 4.07 (2.62-6.32) and 5.46 (3.49-8.52), respectively. In the low-risk IPI group, the 3-year OS and PFS rates were significantly different in the patients with positive (53.3% and 52.5%) and negative (93.8% and 88.3%) interim PET/CT, respectively (P<0.01). These significant prognostic differences of interim PET/CT responses were consistent with the results of the patients with high-risk IPI group (P<0.01). CONCLUSIONS Interim PET/CT scanning had a significant predictive value for disease progression and survival of DLBCL in post-rituximab treatment; it might be the single most important determinant of clinical outcome in patients with the same IPI risk.

The dysfunction and abnormal signaling pathway of dendritic cells loaded by tumor antigen can be overcome by neutralizing VEGF in multiple myeloma

We investigated whether dendritic cells (DCs) from multiple myeloma (MM) patients were affected by loading tumor antigens and whether the defective DC function associated with MM could be overcome by the neutralization of VEGF. MM-specific DCs were generated by loading tumor lysates from myeloma cells at diagnosis or relapsed/progressive state, respectively. DCs loaded with tumor lysates showed lower phenotypic maturation, less T cell stimulatory capacity, less cytotoxic T lymphocyte activities, and highly abnormal cytokine secretions of IL-6 and IL-12, compared to myeloma lysate-unloaded DCs. The levels of VEGF, phospho-STAT3 and phospho-ERK1/2 in DCs were significantly higher with loading myeloma lysates. After the neutralization of VEGF activity, the DC function, signal transduction and cytokine production returned to normal. The defective function of DC in patients with MM is significantly affected by loading tumor antigens, correlating with abnormal STAT3 and the NF-kappaB signaling pathway, and neutralization of VEGF can overcome this DC dysfunction through the elimination of abnormal signal transduction.

Metabolic Syndrome Is Associated With Venous Thromboembolism in the Korean Population

Background—The metabolic syndrome (MS) is a known risk factor for arterial thromboembolism. Preliminary reports have also suggested the association between MS and venous thromboembolism (VTE). Methods and Results—In this case–control study, we investigated the association between MS and VTE in Korean patients. Patients with objectively diagnosed VTE and healthy control subjects underwent clinical assessment for the presence of MS according to the National Cholesterol Education Adult Treatment Panel III criteria modified with body mass index (WHO Asian Pacific Perspective, 2000). The presence of known risk factors for VTE was ascertained. Patients with VTE secondary to cancer were excluded. The prevalence of MS was compared between VTE group and controls. Two hundred eight VTE patients and 300 controls were assessed. VTE was idiopathic in 91 patients and secondary to a known risk factor in 117. The prevalence of MS was significantly higher in VTE patients (47.6%) than in controls (37.7%) (OR: 1.50; 95% CI: 1.05 to 2.15, P=0.026). After adjusting for age, sex, and smoking status, metabolic MS remained independently associated with VTE (OR: 1.56; 95% CI: 1.07 to 2.27, P=0.020). In the subgroup analysis, MS was also independently associated with idiopathic VTE (OR: 1.71; 95% CI: 1.04 to 2.81, P=0.033), but not with secondary VTE (OR: 1.43; 95% CI: 0.91 to 2.99, P=0.121). Multivariate analysis demonstrated that high BMI (OR: 1.70, 95% CI: 1.01 to 2.87), decreased HDL cholesterol (OR: 1.99, 95% CI: 1.17 to 3.39), and elevated fasting glucose levels (OR: 2.31; 95% CI: 1.35 to 3.94) were associated with idiopathic VTE. Conclusion—MS is associated with VTE and in particular with idiopathic VTE in the Korean population.

Induction of multiple myeloma-specific cytotoxic T lymphocyte stimulation by dendritic cell pulsing with purified and optimized myeloma cell lysates

We investigated the possibility of immunotherapy for multiple myeloma (MM) using myeloma-specific cytotoxic T lymphocytes (CTLs) that were stimulated in vitro by dendritic cells (DCs) pulsing with purified and optimized myeloma lysates. CD14+ cells were cultured in the presence of GM-CSF and IL-4. On day 6, the immature DCs were pulsed with the purified myeloma cell lysates, and then maturation of the DCs was induced by the addition of a cytokine cocktail. There were no differences in the phenotypic expressions of mature DCs that were generated by pulsing with CD138+ cell lysates or total cell lysates. In optimization of the concentration of myeloma lysates, DCs pulsed with 10 µg/mL of myeloma lysate had greater allogeneic T-cell stimulatory capacities than those pulsed with higher concentrations of myeloma lysates. The CTL lines generated by DCs pulsed with myeloma lysates demonstrated potent cytotoxic activities against autologous target cells, but not against HLA-A2− cell lines or K562 cell lines. The DCs pulsed with myeloma lysates demonstrated a higher stimulatory capacity for autologous CTL compared with mature nonpulsed DCs. These results suggested that the DCs pulsed with purified and optimized myeloma cell lysates could generate potent myeloma-specific CTLs for approaches in MM.

The clinical and histological effect of home‐use, combination blue–red LED phototherapy for mild‐to‐moderate acne vulgaris in Korean patients: a double‐blind, randomized controlled trial

Background  Blue and red light have been reported to have beneficial effects on acne. However, there has been no double‐blind, randomized study of acne treatment for combined blue and red light‐emitting diode (LED) devices, and the associated molecular mechanisms have rarely been investigated.

Type I and II interferons enhance dendritic cell maturation and migration capacity by regulating CD38 and CD74 that have synergistic effects with TLR agonists

The major limitation for the maturation of dendritic cells (DCs) using Toll-like receptor (TLR) agonists is their decreased ability to migrate into lymph nodes compared with conventional DCs. CD38 can be used as a multifunctional marker to modulate migration, survival and Th1 responses of DCs. CD74 has been shown to negatively regulate DC migration. The goal of this study was to investigate the combinations of TLR agonists and interferons (IFNs) that most effectively regulate CD38 and CD74 expression on DCs. Synergistic TLR agonist stimulation in combination with IFN-α and IFN-γ was the best method for regulating CD38 and CD74 expression and inducing the highest secretion of IL-12p70. An in vitro migration assay showed that DCs treated with this combination had significantly enhanced migratory ability, similar to that observed in cells expressing CD38, CD74 and CCR7. The results of this study suggest that an alternative maturation protocol in which two TLR ligands are combined with type I and II IFNs generates potent DCs that have both a high migratory capacity and high IL-12p70 production.

Predictive factors for successful imatinib cessation in chronic myeloid leukemia patients treated with imatinib

Although recent studies have suggested that cessation of imatinib (IM) in chronic myeloid leukemia patients can be associated with sustained response, further validation is needed to explore predictive factors. In a prospective, multicenter study, chronic phase patients were eligible for cessation of IM therapy after more than 3 years if they had no detectable BCR‐ABL1 transcript for at least 2 years. A total of 48 patients with a median age of 47 years (19–74 years) were enrolled. Twenty patients received IM for post‐transplant relapse. After a median follow‐up of 15.8 months (1.4–28.2 months) after IM discontinuation, nine of the non‐transplant group lost undetectable molecular residual disease (UMRD) and major molecular response (MMR), whereas none of the 20 patients in the transplant group experienced UMRD loss. Probabilities for sustained MMR and UMRD were 64.4% and 66.3% in the non‐transplant group, respectively. Of nine patients re‐treated with IM, eight patients re‐achieved MMR at a median of 1.7 months (0.9–2.8 months). Seven of these patients re‐achieved UMRD at a median of 5.6 months (2.8–12.1 months). Previous transplantation, IM duration, and UMRD duration were significantly associated with sustained molecular responses. Our data strongly suggest that immunological control contributes to sustained suppression of residual leukemia cell expansion and that IM can be safely discontinued in patients with post‐transplant relapse. Am. J. Hematol. 88:449–454, 2013.

A genome-wide association study identifies novel loci associated with susceptibility to chronic myeloid leukemia.

In the current study, we identified 2 genetic markers for susceptibility to chronic myeloid leukemia (CML) using a genome-wide analysis. A total of 2744 subjects (671 cases and 2073 controls) were included, with 202 Korean CML patients and 497 control subjects enrolled as a discovery set. Significant findings in the discovery set were validated in a second Korean set of 237 patients and 1000 control subjects and in an additional Canadian cohort of European descent, including 232 patients and 576 control subjects. Analysis revealed significant associations of 2 candidate loci, 6q25.1 and 17p11.1, with CML susceptibility, with the lowest combined P values of 2.4 × 10⁻⁶ and 1.3 × 10⁻¹², respectively. Candidate genes in those regions include RMND1, AKAP12, ZBTB2, and WSB1. The locus 6q25.1 was validated in both Korean and European cohorts, whereas 17p11.1 was validated only in the Korean cohort. These findings suggest that genetic variants of 6q25.1 and 17p11.1 may predispose one to the development of CML.