Jong Gwang Kim

Vascular Endothelial Growth Factor Gene Polymorphisms Associated with Prognosis for Patients with Colorectal Cancer

Purpose: Vascular endothelial growth factor (VEGF) or its family may be considered to play an important role in lymphangiogenesis and lymphatic tumor spread, thereby affecting prognosis of colorectal cancer. Accordingly, the present study analyzed VEGF gene polymorphisms and their effect on the prognosis for patients with colorectal cancer. Experimental Design: Four hundred and forty-five consecutive patients with surgically treated colorectal adenocarcinoma were enrolled in the present study. The genomic DNA was extracted from fresh colorectal tissue and three VEGF (−2578C>A, −634G>C, and +936C>T) gene polymorphisms were determined using a PCR/denaturing high-performance liquid chromatography assay. Results: Multivariate survival analysis showed that the survival for the patients with the −634 G/C genotype [overall survival (OS): hazard ratio (HR), 0.158; P < 0.001] or C/C genotype (OS: HR, 0.188; P < 0.001) were better than for the patients with the −634G/G genotype, whereas the +936 C/T genotype (OS: HR, 12.809; P < 0.001) or T/T genotype (OS: HR, 37.260; P < 0.001) was associated with a worse survival compared with the +936 C/C genotype. In haplotype analysis, the −2578A/−634G/+936T haplotype exhibited a significantly worse survival when compared with the wild −2578C/−634G/+936C haplotype (OS: HR, 3.866; P < 0.001). Conclusions:VEGF gene polymorphisms were found to be an independent prognostic marker for patients with colorectal cancer. Accordingly, the analysis of VEGF gene polymorphisms can help identify patient subgroups at high risk of a poor disease outcome.

Clinical impact of early absolute lymphocyte count after allogeneic stem cell transplantation

The role of repopulating lymphocytes after allogeneic stem cell transplantation (SCT) includes the prevention of serious infections and attacking residual tumour cells in the early post‐transplant phase. Therefore, the current study analysed the role of the absolute lymphocyte count (ALC) on day 21 after SCT in predicting transplant outcomes of 82 patients in terms of the risk of opportunistic infections and recurrence of original disease. The median dose of CD34+, CD3+ and mononuclear cells (MNC) infused was 6·41 × 106/kg, 1·96 × 108/kg and 6·81 × 108/kg respectively. The high ALC group (high ALC on day 21; ≥0·35 × 109/l) was associated with the use of peripheral blood stem cells, matched sibling donors and higher cell doses of MNC, CD3+ and CD4+ cells. The high ALC group also exhibited a better overall survival (56·3% vs. 17·7%) and disease‐free survival (50·1% vs. 15·9%) after 3 years and lower incidences of relapse (33·6% vs. 67·1%) and fungal infections (3·0% vs. 19·5%) after 1 year. The incidence of cytomegalovirus antigenaemia was lower in the high ALC group (47·7% vs. 73·7%). Accordingly, identifying the ALC on day 21 would appear to be a useful and simple measurement to predict those patients with a high risk of opportunistic infections and relapse after allogeneic SCT.

Multidrug resistance‐1 gene polymorphisms associated with treatment outcomes in de novo acute myeloid leukemia

Multidrug resistance‐1 (MDR‐1) gene single nucleotide polymorphisms (SNPs) have been identified as associated with the treatment outcomes of acute myeloid leukemia (AML) in Caucasians; yet, similar evidence is lacking for Asian populations. A total of 101 AML patients were enrolled in the current study. Two MDR1 SNPs (C3435T and G2677T/A) were analyzed with PCR/RFLP assay. As regards C3435T polymorphism, C/C genotype was significantly correlated with lower functional P‐glycoprotein (P‐gp) activity in leukemic blasts (7.5%) compared with C/T (10.7%) or T/T genotype (19.9%, p = 0.029). In genotypic analyses, C/C at −3435 (p = 0.05) and G/G at −2677 (p = 0.04) were strongly associated with a higher probability of complete remission (CR). In addition, the 3‐year event‐free survival (EFS) was higher in G/G genotype at −2677 (60.6%) than nonG/G (21.9%; p = 0.0241), in C/C at −3435 was higher than nonC/C genotype (p = 0.0139), and was higher in GC haplotype homozygote (58.2%) than nonGC homozygote (22.6%; p = 0.0427). In a multivariate analysis, the group without GC haplotype showed worse EFS (p = 0.030), with unfavorable cytogenetic risk (p = 0.008). However, no differences were noted in overall survival according to the MDR1 SNPs (p = 0.491 for C3435T and p = 0.955 for G2677T/A).

Different efficacy of mycophenolate mofetil as salvage treatment for acute and chronic GVHD after allogeneic stem cell transplant.

Abstract:  Objective:  The therapeutic options currently available for treating refractory graft‐vs.‐host disease (GVHD) are limited. Therefore, the present study evaluated the efficacy of mycophenolate mofetil (MMF) as a salvage treatment for acute and chronic GVHD in allograft patients.

Clinical implications of angiogenic factors in patients with acute or chronic leukemia: Hepatocyte growth factor levels have prognostic impact, especially in patients with acute myeloid leukemia

The present study evaluated the serum levels of known angiogenic factors and analysed their prognostic significance in patients with acute or chronic leukemia. Enzyme-linked immunosorbent assays (ELISAs) were performed to quantify the basic fibroblast growth factor (bFGF), vascular endothelial growth factor (VEGF), hepatocyte growth factor (HGF), tumor necrosis factor-alpha (TNF-alpha), angiogenin, and matrix metalloproteinase-9 (MMP-9) in stored samples obtained before treatment from patients with acute myeloid leukemia (AML; 30 patients), acute lymphoblastic leukemia (ALL; 10 patients), and chronic myelogenous leukemia (CML; 14 patients). The levels of VEGF, HGF, angiogenin, and MMP-9 were all significantly higher in patients with CML than in healthy individuals. The HGF levels were also higher in patients with AML than in healthy individuals, plus there was a significant correlation between the HGF level and the white blood cell count, monocyte count, and serum level of lactate dehydrogenase (LDH) in patients with AML. In a univariate analysis, age and HGF level were both found to be significant parameters predictive for an achievement of complete remission (CR) in patients with AML. Meanwhile, in a multivariate analysis using a logistic regression model, the HGF level was the only parameter strongly predictive for CR (P=0.047). The leukemia-free survival (LFS) rate for AML patients with a lower HGF concentration was better than that for AML patients with a higher HGF concentration (1 year LFS rates=75.0% vs. 37.5%, P=0.065). The HGF concentration was an independent prognostic factor for an achievement of CR, plus higher HGF concentrations were associated with a lower survival in patients with AML.

Investigation of Vascular Endothelial Growth Factor Gene Polymorphisms and Its Association with Clinicopathologic Characteristics in Gastric Cancer

Objective: Vascular endothelial growth factor (VEGF) is known to be a potent proangiogenic factor. This study evaluates the potential association of three VEGF gene polymorphisms (–460T > C, +405G > C, and 936C > T) with the susceptibility to and clinicopathologic characteristics of gastric cancer. Methods: The VEGF genotypes were determined using paraffin-embedded tissue from 413 patients who underwent a surgical resection and peripheral blood lymphocytes from 413 healthy controls by PCR-RFLP assay. Results: There was no difference in the allele frequency of –460T > C polymorphism. However, for the +405G > C polymorphism, the +405C allele was associated with a significantly decreased susceptibility to gastric cancer [odds ratio (OR) 0.686; 95% confidence interval (CI) 0.564–0.834]. Although there was no significant difference in the distribution of the 936C > T polymorphism between the two groups, the 936T allele was associated with a decreased susceptibility to gastric cancer (OR 0.757; 95% CI 0.591–0.970). In the haplotype analyses, the haplotype TCT (OR 0.405; 95% CI 0.263–0.624) was most closely associated with a decreased susceptibility to gastric cancer. However, no significant association was observed between the frequency of the genotypes or alleles and the clinicopathologic characteristics of gastric cancer. Conclusion: These observations imply that the VEGF gene polymorphisms may be associated with the susceptibility to gastric cancer. However, further studies of other VEGF sequence variants and their biological functions are needed to understand the role of the VEGF polymorphisms in determining the susceptibility to gastric cancer.

Transplantation with higher dose of natural killer cells associated with better outcomes in terms of non-relapse mortality and infectious events after allogeneic peripheral blood stem cell transplantation from HLA-matched sibling donors.

Abstract:  Background: Little is known about the role of the CD56+ natural killer (NK) cell dose on the outcome of allogeneic peripheral blood stem cell transplantation (PBSCT). Recently, higher dose of NK cells has been associated with a lower incidence of severe graft‐versus‐host disease (GVHD). The current study attempted to evaluate the effect of the NK cell dose on transplant outcomes in allogeneic PBSCT setting. Methods and materials: Sixty‐one cytokine mobilized PBSC recipients were analyzed according to the infused dose of CD34+ cells and NK cells in relation to overall survival (OS), non‐relapse mortality (NRM), GVHD, and infectious events. Results: The group received a higher dose of NK cells (≥5 × 107/kg) showed a lower incidence of NRM (P = 0.0186) and infectious events (P = 0.0107). In a multivariate analysis, a higher dose of NK cells was correlated to better transplant outcomes for NRM (P = 0.042) with CD34+ cell dose (P = 0.018), and for infectious events (P = 0.013) with CD34+ cell dose (P = 0.016). Higher NK cell infusion group also showed a faster immune recovery in serial measurements at days +90, +180, and +365. Conclusions: High dose of NK cells may play an important role in improving transplant outcomes, in terms of reducing NRM and infectious events together with CD34+ cells.

Phase II study of docetaxel and capecitabine in patients with metastatic or recurrent gastric cancer

Objectives: A phase II study was conducted to evaluate the response rate and safety of a combination regimen of docetaxel plus capecitabine in patients with advanced gastric cancer. Patients and Methods: Patients with previously untreated metastatic or recurrent measurable gastric cancer received i.v. docetaxel 75 mg/m2 on day 1 and oral capecitabine 1,000 mg/m2 twice daily from day 1 to 14 every 3-week cycle. Results: Thirty-two patients were enrolled in the current study. Of these, 30 patients were assessable for efficacy and 31 assessable for toxicity. One complete response and 13 partial responses were confirmed, giving an overall response rate of 43.8% (95% CI; 25.6–61.9%). The median time to progression and median overall survival for all patients was 5.07 months and 8.4 months, respectively. Grade 3/4 neutropenia occurred in 3 patients (9.7%) and febrile neutropenia was observed in 2 patients (6.3%). Grade 1/2 nausea was observed in 45.2% of patients. Grade 2–3 hand-foot syndrome occurred in 4 patients (12.9%). Conclusions: The combination of docetaxel and capectabine was found to be well tolerated and effective in patients with advanced gastric cancer. Accordingly, this regimen can be regarded as an important first-line treatment option for advanced gastric cancer.

Interleukin-10 gene polymorphism influences the prognosis of T-cell non-Hodgkin lymphomas.

Interleukin‐10 (IL‐10) is one of the cytokines implicated in the pathogenesis of diffuse large B‐cell lymphoma (DLBCL) in which it acts as auto/paracrine growth factor for lymphoma growth. T‐cell non‐Hodgkin lymphoma (NHL) is a heterogeneous disease, the biological basis of which is not fully understood. Some evidence suggests that IL‐10 might be associated with the progression of T‐cell NHLs and that IL‐10 may be involved in a rescue effect, protecting T cells from apoptotic cell death associated with upregulated bcl‐2 expression. The current study evaluated the impact of IL‐10 gene (IL10) polymorphism on the response to chemotherapy and survival in T‐cell NHL. IL10 polymorphisms were determined in 108 patients with T‐cell NHL. The response to chemotherapy was not dependent on IL10 polymorphism, while survival differed significantly according to IL10 polymorphism. The group with ATA haplotype showed superior overall survival (61·2 ± 5·9% vs. 21·2 ± 11·7%, P = 0·001) and failure‐free survival (35·0 ± 5·7% vs. 13·2 ± 8·7%, P = 0·001) compared to those without ATA haplotype. The ATA haplotype was identified as a favourable prognostic factor compared to non‐ATA haplotype (P = 0·037, hazard ratio 2·1), together with international prognostic index (IPI) in a multivariate model for overall survival. In conclusion, IL10 polymorphism may affect the survival of T‐cell NHL patients.

No Association of Vascular Endothelial Growth Factor-A (VEGF-A) and VEGF-C Expression with Survival in Patients with Gastric Cancer

PURPOSE Although the vascular endothelial growth factor (VEGF) superfamily has been identified to critically influence tumor-related angiogenesis, the prognostic significance of a VEGF expression in gastric cancer is still controversial. Accordingly, the present study analyzed the VEGF-A and VEGF-C expressions and their impact on the prognosis of patients with gastric cancer. MATERIALS AND METHODS Three hundred seventy-five consecutive patients who underwent surgical resection for gastric adenocarcinoma with a curative intent were enrolled in the present study. Immunohistochemical staining for VEGF-A and VEGF-C was performed using the formalin fixed, paraffin embedded tumor tissues. RESULTS Positive VEGF-A and VEGF-C expressions were observed in 337 (90.1%) and 278 (74.9%) cases, respectively. The survival analysis showed that the expression of VEGF-A and VEGF-C had no effect on the OS and DFS. On the multivariate analysis that included age, gender and the TNM stage, no significant association between the grade of the VEGF-A or VEGF-C expression and survival was observed. CONCLUSION The current study suggests that the tissue expression of VEGF-A or VEGF-C alone is not an independent prognostic marker for patients with surgically resected gastric adenocarcinoma.