Challenges and insights of early oncology drug development in the Asia-Pacific region: introduction of phase I oncology clinical trial center and experience sharing for early clinical trials in Seoul National University Hospital, Korea.

Korea has become the hub of clinical trials in the world. Korea Good Clinical Practice was legislated in 1995, with an amendment in 2001 to adopt International Council of Harmonization (ICH)-Good Clinical Practive (GCP). New Clinical Trial Authorization (CTA) process, which was introduced in 2002 to streamline the regulatory process along with faster study start up, facilitated clinical trials registration in Korea. Following 2002, the number of multinational trials conducted in Korea began to increase rapidly. It was initially centered on late-phase trials, but subsequently moved on to early phase research incorporating translational research and pharmacokinetic (PK) and pharmacodynamic (PD) studies including ethnic difference research. Globally, Seoul National University Hospital Clinical Trials Center (SNUH CTC) is one of the most experienced clinical research facilities. In 2018, 33 phase III studies, 43 phase II studies, and 44 phase I studies were initiated at SNUH CTC oncology team. Oncology phase I clinical trials contributed 42.7% of newly started phase I clinical trials in SNUH CTC in 2018. One of the most important strengths of our oncology team is that SNUH and Seoul National University Bundang Hospital Clinical Trials Center (SNUBH CTC) are working together in one team for all solid tumor types. This collaborative work was very efficient to recruit patients for multi-cohort in early phase trials including basket trial, umbrella trial, and platform trials. One of the main focus of SNUH oncology team is to perform first in human phase I study. We believe target identification and enrichment through translational research is an important process in drug development. SNUH/SNUBH CTC will continue top-notch clinical trials for the global drug development.

Unprocessed Meat Consumption and Incident Cardiovascular Diseases in Korean Adults: The Korean Genome and Epidemiology Study (KoGES).

Meat consumption has been shown to be associated with cardiovascular disease (CVD) risk in Western societies; however, epidemiological data are limited on the Korean population. Therefore, we examined the associations between unprocessed meat consumption and CVD incidence in Korea. Data were derived from the Ansung-Ansan cohort (2001-2012), including 9370 adults (40-69 years) without CVD or cancer at baseline. Total unprocessed meat consumption was estimated as the sum of unprocessed red meat (beef, pork, and organ meat) and poultry consumption. In the fully adjusted Cox regression model, the relative risks of CVD across increasing quintiles of total unprocessed meat intake were 1.0 (reference), 0.72 (95% confidence interval (CI): 0.55, 0.95), 0.57 (95% CI: 0.42, 0.78), 0.69 (95% CI: 0.51, 0.95), and 0.69 (95% CI: 0.48, 0.97), but no significant linear trend was detected (p for trend = 0.14). Frequent poultry consumption was significantly associated with a decreased CVD risk; this association showed a dose-response relationship (p for trend = 0.04). This study showed that a moderate intake of total unprocessed meat was inversely associated with CVD risk. A significant inverse association between poultry consumption and incident CVD was observed in Korean adults, requiring further confirmation in other populations.

Association between Genetic Variations Affecting Mean Telomere Length and the Prevalence of Hypertension and Coronary Heart Disease in Koreans.

In this study, we investigated whether the single nucleotide polymorphisms (SNPs) associated with telomere length (TL) were associated with the incidence of hypertension (HTN)/coronary heart disease (CHD) and cardiovascular risk factors in the Korean population. Data from 5,705 (ages 39-70) participants in the Korean Genome Epidemiology Study (rural Ansung and urban Ansan cohorts) were studied. Twelve SNPs known to be associated with telomere biology were tested for an association with HTN/CHD. As results, no significant associations were found between the selected TL-related SNPs and prevalence of HTN and CHD. Among non-alcohol users, subjects with minor alleles in rs1269304 and rs10936601 (TERC and LRRC34, respectively) exhibited a higher rate of CHD occurrence (odds ratio [OR], 1.862; 95% confidence intervals [CIs], 1.137, 3.049; OR, 1.855; 95% CIs, 1.111, 2.985; respectively). However, alcohol users with minor alleles in rs398652 (PELI2) were significantly associated with higher HTN prevalence (OR, 1.179; 95% CIs, 1.040, 1.336). Of the 3 SNPs related to disease outcomes, rs1296304 was significantly associated with increased levels of diastolic blood pressure (ß estimate, 0.470; 95% CIs, 0.013, 0.926). The minor allele in rs398652 was significantly associated with higher levels of body mass index (OR, 0.128; 95% CIs, 0.010, 0.246) and γ-glutamyl transpeptidase (OR, 0.013; 95% CIs, 0.001, 0.024). In conclusion, there were no significant associations between the selected TL-related SNPs and the occurrence of HTN/CHD in Koreans. However, the results suggest the presence of a possible interaction between related SNPs and alcohol behavior associated with HTN/CHD occurrence.

Consumption of whole grains and legumes modulates the genetic effect of the APOA5 -1131C variant on changes in triglyceride and apolipoprotein A-V concentrations in patients with impaired fasting glucose or newly diagnosed type 2 diabetes.

BACKGROUND: The apolipoprotein A5 gene (APOA5) -1131 T > C polymorphism is associated with mild hypertriglyceridemia in type 2 diabetic subjects, and interacts with dietary fat in the determination of triglyceride concentrations. We examined whether a substitution of whole grains and legumes for refined rice in a high carbohydrate diet (about 65% of energy derived from carbohydrate) may modify the effect of this variant on changes in apolipoprotein A-V (apoA-V) and triglyceride concentrations. METHODS: We genotyped the APOA5 -1131 T > C in individuals with impaired fasting glucose (IFG) or newly diagnosed type 2 diabetes, who were randomly assigned to either a group ingesting whole grain and legume meals daily or a control group for 12 weeks. RESULTS: After dietary intervention, we observed significant interactions between the APOA5 -1131 T > C polymorphism and carbohydrate sources (whole grains and legumes versus refined rice) in the determination of mean percent changes in triglyceride and apoA-V (P interactions <0.001 and =0.038, respectively). In the refined rice group (n = 93), the carriers of the risk C allele (n = 50) showed a greater increase in the mean percent changes of triglyceride and apoA-V than noncarriers after adjusting for HOMA-IR (P = 0.004 and 0.021, respectively). The whole grain and legume group (n = 92), however, showed a decrease in fasting glucose, HOMA-IR, and triglyceride, and an increase in apoA-V, irrespective of genotype. CONCLUSIONS: The data showed that the magnitude of the genetic effect of the APOA5 -1131C variant on triglyceride and apoA-V levels was modulated when substituting consumption of whole grains and legumes for refined rice as a carbohydrate source in IFG or diabetic subjects. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01784952.

Mild weight loss reduces inflammatory cytokines, leukocyte count, and oxidative stress in overweight and moderately obese participants treated for 3 years with dietary modification.

Obesity-induced oxidative stress and inflammation are involved in the pathogenesis of cardiovascular disease. We investigated whether diet-induced, long-term, mild weight loss improved proinflammatory cytokine levels, leukocyte count, and oxidative stress. Overweight/obese participants (25 ≤ body mass index < 34 kg/m(2), N = 122, 30-59 years) joined a 3-year-long clinical intervention involving daily 100-kcal calorie deficits. Successful weight loss was defined as a reduction in initial body weight equal to 2 kg after the clinical intervention period. Body weight in the successful mild weight loss group (SWL, n = 50) changed 5.4% (-4.16 ± 0.31 kg) compared to 0.05 ± 0.14 kg in the unsuccessful weight loss group (n = 49). After 3 years, SWL participants exhibited significantly reduced insulin, triglycerides, total and low-density lipoprotein cholesterol, free fatty acids, and leukocyte count (P = .030). Furthermore, in the SWL group, serum interleukin (IL)-1ß, IL-6, and urinary 8-epi-prostaglandin (PG)F2α were significantly reduced (45%, 30%, and 14%, respectively). In contrast, the unsuccessful weight loss group exhibited significant increases in percentage of body fat, waist circumference, oxidized low-density lipoprotein, and tumor necrosis factor-α, as well as a significant decrease in high-density lipoprotein cholesterol. After adjusting for baseline values, the 2 groups demonstrated significantly different percentage of body fat, waist circumference, leukocyte count (P = .018), insulin, IL-6 (P = .031), IL-1ß (P < .001), and tumor necrosis factor-α (P < .001), as well as urinary 8-epi-PGF2α (P = .036). A positive correlation existed between IL-1ß and urinary 8-epi-PGF2α (r = 0.435, P < .001) and between changes in IL-6 and urinary 8-epi-PGF2α (r = 0.393, P < .001). Long-term mild weight loss reduces inflammatory cytokine levels, leukocyte counts, and oxidative stress and may reverse the elevated oxidative stress induced by inflammatory mediators in the overweight and obese.

Increased oxidative stress in normal-weight postmenopausal women with metabolic syndrome compared with metabolically healthy overweight/obese individuals.

OBJECTIVE: The purpose of this study was to assess whether the metabolically healthy overweight/obese phenotype is associated with decreased oxidative stress compared with normal-weight individuals with metabolic syndrome (MetS). MATERIALS/METHODS: Plasma oxidized LDL (ox-LDL) and urinary 8-epi-prostaglandin F2α (8-epi-PGF2α) were analyzed in a cross-sectional study of 1846 healthy postmenopausal women. Participants were classified by presence (n=569) or absence (n=1277) of MetS and by BMI (18.5-24.9kg/m(2)=normal weight, n=1254; ≥25kg/m(2)=overweight/obese, n=592). MetS was diagnosed with the modified National Cholesterol Education Program Adult Treatment Panel III criteria. RESULTS: Compared to normal weight women with MetS (n=296), metabolically healthy overweight/obese women (n=319) showed lower blood pressure, triglyceride, and glucose and higher HDL cholesterol, adiponectin, and LDL particle size. Ox-LDL was higher in overweight/obese women without MetS than in normal weight women without MetS (n=958) but was lower than in women with MetS. Urinary 8-epi-PGF2α level was about 11% lower in women without MetS than in women with MetS. Normal weight women with MetS had greater odds of having ox-LDL (multivariate odds ratio [OR] 2.42, 95% CI: 1.65-3.55) and 8-epi-PGF2α (OR 1.49; CI: 1.03-2.14) levels in the top quartile compared to normal weight women without MetS after adjusting for age, drinking, smoking, total- and LDL-cholesterol, and high sensitivity C-reactive protein. Additionally, there was no significant correlation between ox-LDL and 8-epi-PGF2α. CONCLUSIONS: The metabolically healthy overweight/obese phenotype was associated with a better overall metabolic profile and less oxidative stress than that observed in normal weight individuals with MetS. Furthermore, there was a lack of association between ox-LDL and 8-epi-PGF2α.

Supervised exercise program, BMI, and risk of type 2 diabetes in subjects with normal or impaired fasting glucose.

OBJECTIVE: To determine the association of regular exercise, BMI, and fasting glucose with the risk of type 2 diabetes and to predict the risk. RESEARCH DESIGN AND METHODS: Korean subjects (n = 7,233; 40-79 years old) who were not diagnosed with diabetes at baseline were enrolled through the National Health Insurance Corporation. All participants underwent biennial examinations, and 1,947 of 7,233 subjects also underwent a 6-month program of moderate-intensity exercise (300 min/week) without dietary advice. RESULTS: During follow-up (mean = 2 years), there were 303 incidents of type 2 diabetes in the nonexercise program group (n = 5,286) and 83 in the exercise program group (n = 1,947). After adjusting for confounders, the risk of type 2 diabetes was positively associated with BMI and inversely with regular exercise, especially among overweight/obese subjects. After further adjustment for BMI, the odds ratios for risk of diabetes associated without and with regular exercise were 1.00 and 0.77, respectively. Among subjects with normal fasting glucose, exercise reduced the diabetes risk; however, among those with impaired fasting glucose (IFG), the protective effect of exercise was found only among overweight/obese subjects. The overweight/obese subjects in the exercise program group exhibited improved fasting glucose compared with the nonexercise program group and showed 1.5 kg of weight loss and a 3-cm decrease in waist circumference. Among overweight/obese subjects with unchanged fasting glucose, weight loss was greater in the exercise program group. CONCLUSIONS: Regular exercise reduces the risk of type 2 diabetes in overweight/obese individuals. Particularly, regular exercise and weight or waist circumference control are critical factors for preventing diabetes in overweight/obese individuals with IFG.

Association of Lp-PLA(2) activity and LDL size with interleukin-6, an inflammatory cytokine and oxidized LDL, a marker of oxidative stress, in women with metabolic syndrome.

OBJECTIVE: We investigated an association between lipoprotein-associated phospholipase A(2) (Lp-PLA(2)) activity, inflammation, and oxidative stress in women with metabolic syndrome (MS). METHODS: We performed a case-control study in MS women (n=368) and non-MS women (n=854). Lp-PLA(2) activity LDL particle size; leukocyte number; ox-LDL, LDL-cholesterol, TNF-α, IL-6, and CRP levels were measured. RESULTS: MS women had smaller LDL particle size; higher plasma ox-LDL levels and Lp-PLA(2) activity; and higher serum TNF-α, IL-6, and CRP, than non-MS women. In controls, Lp-PLA(2) activity weakly but significantly correlated with LDL-cholesterol; in MS women, Lp-PLA(2) activity positively correlated with LDL-cholesterol, ox-LDL, TNF-α, and IL-6 after adjusting for age and BMI. The relationship between Lp-PLA(2) activity and ox-LDL still maintained after further adjustment for LDL-cholesterol. Additionally, Lp-PLA(2) activity together with LDL particle size were significant independent predictors of MS (multivariate analysis), and ox-LDL was a major contributor to the increase in Lp-PLA(2) activity in MS women (multiple stepwise regression). In a subgroup analysis, Lp-PLA(2) activity was negatively associated with IL-6 levels in non-MS postmenopausal women, but positively with IL-6 in both postmenopausal and premenopausal women with MS. Postmenopausal women with MS had significantly higher Lp-PLA(2) activity, ox-LDL and IL-6 than those without MS, and premenopausal women with or without MS, after the adjustment. CONCLUSIONS: Elevated plasma Lp-PLA(2) activity was associated with an increase in inflammatory cytokines, particularly IL-6 and ox-LDL in MS women. This association was also affected by menopause status, suggesting that Lp-PLA(2) may represent a novel marker for oxidation and inflammation in MS.