Doyeun Oh

Umbilical Cord Blood Therapy Potentiated with Erythropoietin for Children with Cerebral Palsy: A Double‐blind, Randomized, Placebo‐Controlled Trial

Allogeneic umbilical cord blood (UCB) has therapeutic potential for cerebral palsy (CP). Concomitant administration of recombinant human erythropoietin (rhEPO) may boost the efficacy of UCB, as it has neurotrophic effects. The objectives of this study were to assess the safety and efficacy of allogeneic UCB potentiated with rhEPO in children with CP. Children with CP were randomly assigned to one of three parallel groups: the pUCB group, which received allogeneic UCB potentiated with rhEPO; the EPO group, which received rhEPO and placebo UCB; and the Control group, which received placebo UCB and placebo rhEPO. All participants received rehabilitation therapy. The main outcomes were changes in scores on the following measures during the 6 months treatment period: the gross motor performance measure (GMPM), gross motor function measure, and Bayley scales of infant development‐II (BSID‐II) Mental and Motor scales (18). F‐fluorodeoxyglucose positron emission tomography (18F‐FDG‐PET/CT) and diffusion tensor images (DTI) were acquired at baseline and followed up to detect changes in the brain. In total, 96 subjects completed the study. Compared with the EPO (n = 33) and Control (n = 32) groups, the pUCB (n = 31) group had significantly higher scores on the GMPM and BSID‐II Mental and Motor scales at 6 months. DTI revealed significant correlations between the GMPM increment and changes in fractional anisotropy in the pUCB group. 18F‐FDG‐PET/CT showed differential activation and deactivation patterns between the three groups. The incidence of serious adverse events did not differ between groups. In conclusion, UCB treatment ameliorated motor and cognitive dysfunction in children with CP undergoing active rehabilitation, accompanied by structural and metabolic changes in the brain. STEM CELLS2013;31:581–591

Incidence of venous thromboembolism in Korea: from the Health Insurance Review and Assessment Service database

Summary.  Background: Venous thromboembolism (VTE), including deep vein thrombosis (DVT) and pulmonary embolism (PE), represents a major health concern in Caucasians. Although the incidence of VTE is generally known to be lower in Asians than in Caucasians, results of epidemiologic studies among Asians have been conflicting. In this study we performed a nationwide population‐based epidemiologic study to provide basic information regarding the incidence of VTE in the Korean population. Methods: Using the Korean Health Insurance Review and Assessment Service (HIRA) database, VTE patients from 2004 to 2008 were retrospectively identified by both diagnostic codes and medication codes for drugs used in initial treatment of VTE. Results: The respective age‐ and sex‐adjusted annual incidences of VTE, DVT and PE per 100 000 individuals increased significantly from 8.83, 3.91 and 3.74 in 2004 to 13.8, 5.31 and 7.01 in 2008 (P = 0.0001), with successive increments each year. All three annual incidences also increased steadily with age (P = 0.0001 for all), particularly among those over 60 years old. Conclusions: This represents the largest epidemiologic study that demonstrates a lower incidence of VTE in Asian compared with Western populations; however, it also demonstrates a yearly increasing incidence of VTE in the Korean population.

Association of the miR-146aC>G, 149C>T, 196a2C>T, and 499A>G polymorphisms with colorectal cancer in the Korean population.

MicroRNAs (miRNAs) are small, 18‐ to 22‐nucleotide non‐coding RNAs that regulate target gene expression. Although recent studies focused on various diseases that harbor the miR‐146aC>G (rs2910164), 149C>T (rs2292832), 196a2C>T (rs11614913), and 499A>G (rs3746444) polymorphisms, the role of miRNA genetic variants in colorectal cancer is still unknown. The present study aimed to evaluate the role of four miRNA polymorphisms in patients with colorectal cancer. We enrolled 446 colorectal cancer patients and 502 control subjects from the Korean population. We found a significantly increased colorectal cancer risk with the miR‐196a2CC genotype compared with the TT/CT genotype (AOR = 1.50; 95% CI = 1.11–2.04; P = 0.01; FDR‐P = 0.04). In the stratified analyses, we observed both weak and strong association data. We found stronger associations of the miR‐196a2 variants in the non‐diabetic and rectal cancer groups than other stratified groups. Our data suggest that the miRNA variants could affect the development of colorectal cancer in the Korean population.

Long-term Clinical Outcomes of Splanchnic Vein Thrombosis: Results of an International Registry

IMPORTANCE Little information is available on the long-term clinical outcome of patients with splanchnic vein thrombosis (SVT). OBJECTIVE To assess the incidence rates of bleeding, thrombotic events, and mortality in a large international cohort of patients with SVT. DESIGN, SETTING, AND PARTICIPANTS A prospective cohort study was conducted beginning May 2, 2008, and completed January 30, 2014, at hospital-based centers specialized in the management of thromboembolic disorders; a 2-year follow-up period was completed January 30, 2014, and data analysis was conducted from July 1, 2014, to February 28, 2015. Participants included 604 consecutive patients with objectively diagnosed SVT; there were no exclusion critieria. Information was gathered on baseline characteristics, risk factors, and antithrombotic treatment. Clinical outcomes during the follow-up period were documented and reviewed by a central adjudication committee. MAIN OUTCOMES AND MEASURES Major bleeding, defined according to the International Society on Thrombosis and Hemostasis; bleeding requiring hospitalization; thrombotic events, including venous and arterial thrombosis; and all-cause mortality. RESULTS Of the 604 patients (median age, 54 years; 62.6% males), 21 (3.5%) did not complete follow-up. The most common risk factors for SVT were liver cirrhosis (167 of 600 patients [27.8%]) and solid cancer (136 of 600 [22.7%]); the most common sites of thrombosis were the portal vein (465 of 604 [77.0%]) and the mesenteric veins (266 of 604 [44.0%]). Anticoagulation was administered to 465 patients in the entire cohort (77.0%) with a mean duration of 13.9 months; 175 of the anticoagulant group (37.6%) received parenteral treatment only, and 290 patients (62.4%) were receiving vitamin K antagonists. The incidence rates (reported with 95% CIs) were 3.8 per 100 patient-years (2.7-5.2) for major bleeding, 7.3 per 100 patient-years (5.8-9.3) for thrombotic events, and 10.3 per 100 patient-years (8.5-12.5) for all-cause mortality. During anticoagulant treatment, these rates were 3.9 per 100 patient-years (2.6-6.0) for major bleeding and 5.6 per 100 patient-years (3.9-8.0) for thrombotic events. After treatment discontinuation, rates were 1.0 per 100 patient-years (0.3-4.2) and 10.5 per 100 patient-years (6.8-16.3), respectively. The highest rates of major bleeding and thrombotic events during the whole study period were observed in patients with cirrhosis (10.0 per 100 patient-years [6.6-15.1] and 11.3 per 100 patient-years [7.7-16.8], respectively); the lowest rates were in patients with SVT secondary to transient risk factors (0.5 per 100 patient-years [0.1-3.7] and 3.2 per 100 patient-years [1.4-7.0], respectively). CONCLUSIONS AND RELEVANCE Most patients with SVT have a substantial long-term risk of thrombotic events. In patients with cirrhosis, this risk must be balanced against a similarly high risk of major bleeding. Anticoagulant treatment appears to be safe and effective in most patients with SVT.

The incidence, risk factors and prognostic implications of venous thromboembolism in patients with gastric cancer

Summary.  Background: Data on venous thromboembolism (VTE) in gastric cancer (GC) are very scarce. Objective: To investigate the incidence, risk factors and prognostic implications of VTE in Asian GC patients. Methods: Prospective databases containing clinical information on GC patients (n = 2,085) were used. Results: The 2‐year cumulative incidences of all VTE events were 0.5%, 3.5% and 24.4% in stages I, II–IV(M0) and IV(M1), respectively. Advanced stage, older age and no major surgery were independent risk factors for developing VTE. When the VTE cases were classified into extremity venous thrombosis (EVT), pulmonary thromboembolism (PTE) or intra‐abdominal venous thrombosis (IVT), IVTs (62%) were more common than EVTs (21%) or PTEs (17%). Although peri‐operative pharmacologic thromboprophylaxis was not routinely administered, the VTE incidence after major surgery was only 0.2%. During chemotherapy, EVT/PTE developed more frequently than IVT (54% vs. 19%); however, during untreated or treatment‐refractory periods, IVT developed more frequently than EVT/PTE (69% vs. 36%). In multivariate models, the development of EVT/PTE was a significant predictor of early death when compared with no occurrence of VTE (P < 0.05). However, IVT did not affect survival. Conclusion: This is the largest study that specially focused on VTE in GC and the VTE incidence in Asian GC patients was first demonstrated. Considering the low incidence of post‐operative VTE development, the necessity of peri‐operative pharmacologic thromboprophylaxis should be evaluated separately in Asian patients. The clinical situation of the development of EVT/PTE and IVT differed. Only EVT/PTE had an adverse effect on survival and IVT had no prognostic significance.

Association study of vascular endothelial growth factor polymorphisms with the risk of recurrent spontaneous abortion.

OBJECTIVE To investigate the association of vascular endothelial growth factor (VEGF) polymorphisms (-2578C>A, -1154G>A, -634G>C, 936C>T) with idiopathic recurrent spontaneous abortion (RSA) in Koreans. DESIGN Prospective case-control study. SETTING University-based hospital. PATIENT(S) Two hundred and fifteen patients with a history of two or more unexplained consecutive pregnancy losses and 113 healthy controls with at least one live birth and no history of pregnancy loss. INTERVENTION(S) None. MAIN OUTCOME MEASURE(S) Polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP) analyses were performed for the -2578C>A and 936C>T genotypes. Real-time PCR was also used to analyze the -1154G>A and -634G>C genotypes. RESULT(S) The GA (adjusted odds ratio [AOR] 2.774; 95% confidence interval [CI] 1.512-5.092) genotype of the VEGF -1154G>A polymorphism was significantly different between women with idiopathic RSA and controls. The difference in overall (GA + AA) frequency was also marginally significant between the controls and patients with idiopathic RSA (AOR, 2.006; 95% CI, 1.158-3.473). The differences in frequencies of the A-A-G-T and C-A-G-T haplotypes of the VEGF polymorphisms (-2578C>A, -1154G>A, -634G>C, 936C>T) were marginally significant between the patient and control groups. CONCLUSION(S) This study suggests that VEGF polymorphisms and haplotypes are a genetic determinant for the risk of idiopathic RSA in Korean women.

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.

Association Between VEGF Polymorphisms and Homocysteine Levels in Patients With Ischemic Stroke and Silent Brain Infarction

Background and Purpose— Vascular endothelial growth factor (VEGF) plays a role in atherosclerosis-related diseases such as cerebrovascular or cardiovascular diseases. However, the effect of VEGF -2578C>A, -1154G>A, -634G>C, and 936C>T polymorphisms on the susceptibility to stroke and silent brain infarction has not been reported. Methods— Using polymerase chain reaction-amplified DNA, VEGF polymorphisms were analyzed in 615 patients with ischemic stroke, 376 patients with silent brain infarction, and 494 control subjects. Results— The AA and CC+CA (C allele bearing) genotype frequencies of the -2578C>A polymorphism and the CT+TT (T allele-bearing) genotype frequency of the 936C>T polymorphism were significantly different between the stroke and control groups (false discovery rate-adjusted probability values of 0.016, 0.044, and 0.044, respectively). When stratified by the size of the occluded vessel, the VEGF polymorphisms were associated with patients with multiple small-artery occlusions. Several haplotypes of the VEGF polymorphisms were significantly different between the control and stroke groups. With respect to silent brain infarction, the difference in the frequency of the -634G>C polymorphism between the GC+CC (C allele-bearing) genotype and the controls was marginally significant (false discovery rate-adjusted probability value of 0.056). On the other hand, the -634G>C and 936C>T polymorphisms were associated with plasma homocysteine levels of patients with multiple or single small-artery occlusions, respectively. Conclusions— This study suggests that VEGF polymorphisms and haplotypes are possible genetic determinants for the risk of ischemic stroke, particularly in patients with multiple small-artery occlusions. However, VEGF polymorphisms had only a weak association with plasma homocysteine levels in the Korean population.

Placenta-derived mesenchymal stem cells have an immunomodulatory effect that can control acute graft-versus-host disease in mice.

Background and Aims: Immunomodulatory properties of mesenchymal stem cells (MSCs) have been applied to reduce the incidence of graft-versus-host disease (GVHD) after hematopoietic stem cell transplantation (HSCT). Among the various sources of MSCs that have immunomodulatory effects in vitro, only placenta-derived MSCs (PD-MSCs) have not been evaluated in an in vivo model of GVHD. In this study, we investigated the immunomodulatory properties of PD-MSCs in vitro and evaluated their clinical potential for controlling GVHD in an animal model. Methods: A GVHD animal model was established by transplanting C57BL/6 donor bone marrow cells and spleen cells into lethally irradiated BALB/c recipient mice. To control GVHD, human PD-MSCs were transplanted into recipient mice (5 × 105 or 1 × 106 cells). Results: PD-MSCs suppressed mitogen-stimulated T cell proliferation in vitro in a dose-dependent manner. Moreover, PD-MSCs inhibited cytokine secretion (interleukin-12, tumor necrosis factor-α and interferon-γ) of activated T cells. In vivo, the survival rate in the PD-MSC group (transplanted with 1 × 106 cells) was higher than that in the control group and histological scores were low in the PD-MSC group. Conclusion: We present the first evidence that human PD-MSCs can efficiently control GVHD in an HSCT in vivo model.

Venous thromboembolism in patients with pancreatic adenocarcinoma : Lower incidence in Asian ethnicity

BACKGROUND Pancreatic adenocarcinoma is one of the cancers most frequently associated with venous thromboembolism (VTE), with the varying incidences of 10%-20% reported in Western countries. Asians are known to have a lower risk for VTE than Caucasians, but few studies have been conducted regarding the incidence of VTE in Asian cancer patients. MATERIALS AND METHODS Incidence of radiologically confirmed VTE was assessed by review of medical records of all patients histologically diagnosed with advanced pancreatic adenocarcinoma, with follow-up conducted at a regional teaching hospital from Jun 2003 to Dec 2005. RESULTS Seventy five patients with advanced pancreatic adenocarcinoma were identified for evaluation (M:F=44:31, locally advanced:metastatic=25:50, median age:67 years). Four patients (5.3%) developed VTE during median follow-up period of 124 days. Three of four patients had metastatic disease and were receiving chemotherapy when VTE developed. The mean time from cancer diagnosis to the detection of VTE was 160 days. No episodes of peripheral arterial thrombosis were detected, but three multiple cerebral infarctions occurred, which proved fatal in all three. Median survival time was shorter in patients with VTE than those without, but the difference was not statistically significant (4.3 vs 6.6 months). CONCLUSION The incidence of VTE complications in Korean patients with advanced pancreatic cancer was 5.3%, which is lower than that observed in other ethnic groups. Our study warrants further prospective investigations on the incidence and mechanism of VTE and cerebral infarctions in cancer patients of different ethnic groups.