East Asian Subgroup Research Articles

Dual Anti-Thrombotic Therapy With Dabigatran After Percutaneous Coronary Intervention in Atrial Fibrillation - Japanese and East-Asian Subgroup Analysis of the RE-DUAL PCI Trial.

In the RE-DUAL PCI trial, dual anti-thrombotic therapy with dabigatran and a P2Y12inhibitor had a lower risk of bleeding and similar risk reduction of thromboembolic events, compared with warfarin triple therapy, in patients with NVAF undergoing PCI. This subanalysis investigated whether the efficacy and safety of dabigatran dual therapy in Japanese and East-Asian patients enrolled in the RE-DUAL PCI trial were similar to those of the overall patient population of the trial. Methods and Results: RE-DUAL PCI was a multicenter, randomized trial. The primary endpoint was the time to first International Society on Thrombosis and Hemostasis major or clinically relevant non-major bleeding events. Of the East-Asian patients (n=240) enrolled in the RE-DUAL PCI trial, 111 were Japanese and received dabigatran 110 mg (n=50) or 150 mg (n=13) dual therapy, or warfarin triple therapy (n=48). The incidence of the primary endpoint in Japanese patients was 26.0% and 29.2% with dabigatran 110-mg dual therapy and the corresponding warfarin triple therapy, and 23.1% and 30.8% with dabigatran 150-mg dual therapy and the corresponding warfarin triple therapy, respectively. Similar results were observed in the East-Asian population. This subanalysis of the RE-DUAL PCI trial demonstrated that, like in the overall patient population, dabigatran dual therapy may offer physicians additional options for managing Japanese and East-Asian patients with NVAF receiving PCI.

A randomized placebo-controlled trial of delayed-release dimethyl fumarate in patients with relapsing-remitting multiple sclerosis from East Asia and other countries

BackgroundDelayed-release dimethyl fumarate (DMF) has demonstrated efficacy and a favorable benefit-risk profile in phase 2 and 3 studies that enrolled predominantly white patients with relapsing-remitting multiple sclerosis (RRMS). In this study (APEX, Part I), we evaluated the efficacy/safety outcomes of DMF in a predominantly East Asian population of patients with RRMS.MethodsIn this 24-week, randomized, double-blind, placebo-controlled phase 3 study, 225 patients, 142 of which were East Asian (63.4%), were enrolled: Japan (n = 114), South Korea (n = 20), Taiwan (n = 8), the Czech Republic (n = 42), and Poland (n = 40). Key exclusion criteria included diagnosis of neuromyelitis optica spectrum disorder. Stratified by country, patients were randomized 1:1 to receive DMF 240 mg twice daily or placebo. Clinical assessments, including neurological examination and EDSS scoring, were conducted at baseline and at weeks 12 and 24.ResultsA total of 213 patients (95.1%) completed the study. From weeks 12 – 24, the total number of new gadolinium-enhancing (Gd+) lesions was reduced by 84% (p < 0.0001) in DMF compared with placebo. For the secondary endpoint, from baseline to week 24, the total number of new Gd+ lesions was reduced by 75% and the mean number of new/newly enlarging T2 hyperintense lesions was reduced by 63% (both p < 0.0001). Flushing and flushing-related symptoms, and gastrointestinal events were adverse events related to DMF treatment. Efficacy and safety results in the Japanese subgroup and the East Asian subgroup (which included patients from Japan, Taiwan, and South Korea) were consistent with the overall study population.ConclusionThe strong efficacy and favorable benefit-risk profile of DMF extends to Japanese, and more broadly, East Asian patients with RRMS.Trial registrationThis trial is registered on ClinicalTrials.gov (identifier: NCT01838668), April 20, 2013 (retrospectively registered). The registration can be found at the following URL: https://clinicaltrials.gov/ct2/show/NCT01838668

M235T polymorphism in the angiotensinogen gene and cardiovascular disease: An updated meta-analysis of 39 case-control comparisons.

Objective:M235T polymorphism of the angiotensinogen (AGT) gene has been linked with cardiovascular disease (CVD). The aim of this meta-analysis was to investigate whether combined evidence supports this association.Methods:A systematic search was conducted for studies published up to October 2018 that evaluate the association between AGT M235T polymorphism and risk of CVD. Case–control studies were identified, and the association between AGT M235T polymorphism and CVD risk was assessed using genetic models.Results:Thirty-nine comparisons from 38 studies were collected, and a meta-analysis and subgroup analysis was performed based on ethnicity. In the overall population (9225 cases and 8406 controls), the occurrence of CVD was found to be associated with AGT M235T polymorphism in both allelic [T vs. M: odds ratio (OR)=1.16] and recessive (TT vs. MT+MM: OR=1.14) models. In subgroup analyses, a significant association was identified between AGT M235T polymorphism and CVD risk in East Asian subgroups in allelic (T vs. M: OR=1.46), homozygous (TT vs. MM: OR=1.78), dominant (MT+TT vs. MM: OR=1.47), and recessive (TT vs. MT+ MM: OR=1.68) models, but there was no significant association in Caucasian populations.Conclusion:Among East Asians, the AGT variant M235T is associated with CVD risk. However, current evidence suggests that there is no such association in the Caucasian population.

Fear and Anxiety Pathways Associated with Root Canal Treatments Amongst a Population of East Asian Origin.

Objective:This study aimed to identify and compare the pathways of endodontic fear and anxiety amongst East Asian origin patients attending Griffith University’s Dental Clinics, Gold Coast, Australia.Methods:East Asian patients who attended the Griffith University dental clinics were included in this study. The “My Endodontic Fear” survey was used. The pathways involved in self-perception of dental fear and anxiety were assessed through 5 different questions. Chi-square test was for statistical analysis and the level of significance was set at P<0.05.Results:One hundred and forty six participants (n=146) (ages 18-62 years) of East Asian descent met the criteria to participate. 58.2% were females, and 41.8% males. The ethnicities were split into Chinese origin and non-Chinese origin (Korean, Phillipino, Japanese, Vietnamese). Results indicate multiple pathways affect the origin of fear, regardless of ethnicity. The Cognitive Conditioning pathway was the primary pathway selected by the Chinese and non-Chinese sub groups (51.4%, 43.6%) followed by the Informative (38.3%, 38.5%), then Vicarious (27.1%, 33.3%) and Parental (18.7%, 33.3%) pathways respectively.The Verbal Threat pathway was the least selected pathway for both groups, however the non- Chinese group selected this pathway significantly more often than the Chinese group (P<0.001).Conclusion:This study demonstrates that the Cognitive Conditioning pathway was the primary fear and anxiety pathway utilized by both East Asian sub-groups. Understanding how patients develop fear and anxiety can help treating dentists discuss triggering factors for patients and alleviate undue anxiety prior to treatment.

Health Economic Analysis of Antiplatelet Therapy for Acute Coronary Syndromes in the Context ofFive Eastern Asian Countries.

The economic outcomes of dual antiplatelet therapy in East Asian patients are still unclear. We aimed to evaluate the economic outcomes of ticagrelor versus clopidogrel for patients with acute coronary syndrome (ACS) in China, Japan, Korea, Taiwan and Hong Kong. A two-phase model consisting of a 1-year decision tree and a lifetime Markov model was used to estimate the economic outcomes. The data from the East Asian subgroup of Platelet Inhibition and Patient Outcomes (PLATO) and PHILO studies were used for the calculation of the events rate for ticagrelor and clopidogrel in the first 12months, whereas the costs were obtained from East Asian sources and utility from the published literature. Sensitivity analyses were conducted to test model robustness. Ticagrelor showed the marginal lifetime quality-adjusted life-year (QALY) of 0.0050, 0.0091, 0.0107, 0.0050, and 0.0050 in China, Japan, Korea, Taiwan, and Hong Kong compared with clopidogrel, with marginal healthcare costs of (all values in US dollars) $562, $595, $975, $611, and $672, respectively. The marginal cost per QALY gained with ticagrelor was $112,051, $65,692, $91,207, $121,838, and $133,953 from a public healthcare system perspective of China, Japan, Korea, Taiwan, and Hong Kong, respectively. The sensitivity analysis showed consistent results. Treatment of ACS for 12months with ticagrelor is not a cost-effective option for the prevention of thrombotic events in East Asia.

Efficacy and safety of paliperidone palmitate three-monthly formulation in East Asian patients with schizophrenia: subgroup analysis of a global, randomized, double-blind, Phase III, noninferiority study.

ObjectiveTo demonstrate the efficacy and safety of paliperidone palmitate three-monthly (PP3M) formulation in an East Asian population with schizophrenia by subgroup analysis of a double-blind (DB), multicenter, noninferiority study.Patients and methodsOf 1,429 patients who entered the open-label (OL) phase, 510 were East Asian (China: 296 [58%], Japan: 175 [34%], South Korea: 19 [4%] and Taiwan: 20 [4%]). In the 17-week OL phase, patients received paliperidone palmitate once-monthly (PP1M) formulation on day 1 (150 mg eq.), day 8 (100 mg eq.) and once-monthly thereafter (50–150 mg eq., flexible). Following the OL phase, patients (n=344 East Asian) entered DB phase and were randomized (1:1) to PP1M (n=174) or PP3M (n=170). Primary efficacy endpoint was the percentage of patients who remained relapse free at the end of the 48-week DB phase, using Kaplan–Meier cumulative survival estimate. Secondary efficacy endpoints included change from DB baseline to endpoint in Positive and Negative Syndrome Scale, Clinical Global Impression Severity, Personal and Social Performance scores and symptomatic remission. Additional assessments included caregiver burden and safety.ResultsA total of 285/344 (83%) randomized East Asian patients completed the DB phase. The percentage of patients who had a relapse event was similar on comparing PP3M (17 [10.2%]) to PP1M (20 [11.8%]), and also for Japan (PP3M: 9 [17.6%], PP1M: 13 [23.2%]) and China (PP3M: 6 [5.9%], PP1M: 7 [6.9%]). Mean change from baseline in secondary efficacy parameters was similar to the global population, regardless of treatment. Symptomatic remission was attained by 50% of the treated patients. Caregiver burden was significantly reduced (P<0.001) following treatment with PP3M/PP1M. Frequency of treatment-emergent adverse events in PP3M group during DB phase was greater in the East Asian subgroup (81%) than the global population (68%) and was higher in Japan (92%) than China (75%).ConclusionResults suggest that PP3M is efficacious in the East Asian subgroup. Although treatment-emergent adverse events were slightly higher in the East Asian subgroup versus the global population, no new safety signals were identified.

MTHFR Gene Polymorphism-Mutations and Air Pollution as Risk Factors for Breast Cancer: A Metaprediction Study.

BackgroundThe methylenetetrahydrofolate reductase gene (MTHFR) is one of the most investigated genes associated with breast cancer for its role in epigenetic pathways.ObjectivesThe objectives of this metaprediction study were to examine the polymorphism-mutation risk subtypes of MTHFR and air pollution as contributing factors for breast cancer.MethodsFor triangulation purposes in metapredictive analyses, we used a recursive partition tree, nonlinear association curve fit, and heat maps for data visualization, in addition to the conventional comparison procedure and pooled analyses.ResultsWe included 36,683 breast cancer cases and 40,689 controls across 82 studies for MTHFR 677 and 23,252 cases and 27,094 controls across 50 studies for MTHFR 1298. MTHFR 677 TT was a risk genotype for breast cancer (p = .0004) and in the East Asian subgroup (p = .005). On global maps, the most polymorphism-mutations on MTHFR 677 TT were found in the Middle East, Europe, Asia, and the Americas, whereas the most mutations on MTHFR 1298 CC were located in Europe and the Middle East for the control group. The geographic information system maps further revealed that MTHFR 677 TT mutations yielded a higher risk of breast cancer for Australia, East Asia, the Middle East, South Europe, Morocco, and the Americas and that MTHFR 1298 CC mutations yielded a higher risk in Asia, the Middle East, South Europe, and South America. Metapredictive analysis revealed that air pollution level was significantly associated with MTHFR 677 TT polymorphism-mutation genotype.DiscussionWe present the most comprehensive analyses to date of MTHFR polymorphism-mutations and breast cancer risk. Future nursing studies are needed to investigate the health impact on breast cancer of epigenetics and air pollution across populations.

Second-line ramucirumab therapy for advanced hepatocellular carcinoma (REACH): an East Asian and non-East Asian subgroup analysis

PurposeREACH investigated second-line ramucirumab therapy for advanced hepatocellular carcinoma.ResultsMedian overall survival was 8.2 months for ramucirumab and 6.9 months for placebo (HR, 0.835; 95% CI, 0.634–1.100; p = 0.2046) for East Asians, and 10.1 months for ramucirumab and 8.0 months for placebo (HR, 0.895; 95% CI, 0.690–1.161; p = 0.4023) for non-East Asians. Median overall survival in patients with baseline alpha-fetoprotein ≥ 400 ng/mL was 7.8 months for ramucirumab and 4.2 months for placebo (HR, 0.749; 95% CI, 0.519–1.082; p = 0.1213) for East Asians (n = 139), and 8.2 months for ramucirumab and 4.5 months for placebo (HR, 0.579; 95% CI, 0.371–0.904; p = 0.0149) for non-East Asians (n = 111). The most common grade ≥ 3 treatment-emergent adverse events in East Asians and non-East Asians included hypertension and malignant neoplasm progression.Materials and methodsA post-hoc analysis of East Asians (N = 252) and non-East Asians (N = 313) in the intent-to-treat population was performed.ConclusionsIn East Asians and non-East Asians, ramucirumab did not significantly prolong overall survival. In patients with baseline alpha-fetoprotein ≥ 400 ng/mL, a potentially larger survival benefit was observed in both subgroups. Safety for East Asians was similar to non-East Asians.

An East Asian subgroup analysis of PROCLAIM, a phase III trial of pemetrexed and cisplatin or etoposide and cisplatin plus thoracic radiation therapy followed by consolidation chemotherapy in locally advanced nonsquamous non–small cell lung cancer

PROCLAIM, a phase III trial of patients with nonsquamous non-small cell lung cancer comparing concurrent pemetrexed-cisplatin and thoracic radiation therapy followed by consolidation pemetrexed, did not meet its primary endpoint of superior overall survival versus etoposide-cisplatin and thoracic radiation therapy followed by a consolidation platinum doublet of choice. The results from an East Asian subgroup analysis are presented here. A subgroup analysis was performed for all patients randomized from China (n = 61), Taiwan (n = 25), and Korea (n = 11). Baseline characteristics were balanced between treatment arms for East Asian patients. In the 97 randomized East Asian patients, median overall survival was 26.8 months for the pemetrexed-cisplatin arm and 36.3 months for the etoposide-cisplatin arm (hazard ratio: 1.23; 95% confidence interval: 0.70-2.14; P = 0.469). Median progression-free survival was 10.0 months for the pemetrexed-cisplatin arm and 7.6 months for the etoposide-cisplatin arm (hazard ratio: 0.97; 95% confidence interval: 0.61-1.54; P = 0.890). The objective response rate was 47.7% in the pemetrexed-cisplatin arm and 34.0% in the etoposide-cisplatin arm (P = 0.167). In the 90 treated East Asian patients, the overall incidence of drug-related grade 3-4 treatment-emergent adverse events was significantly lower in the pemetrexed-cisplatin arm versus the etoposide-cisplatin arm (61.4% vs 91.3%; P = 0.001). For East Asian patients, pemetrexed-cisplatin combined with thoracic radiation therapy, followed by consolidation pemetrexed, did not improve overall survival but did have a good safety profile with a trend for improved progression-free survival and objective response rate compared to standard chemoradiotherapy for stage III unresectable nonsquamous non-small cell lung cancer.

Efficacy and safety of pemetrexed/cisplatin versus gemcitabine/cisplatin as first-line treatment in Chinese patients with advanced nonsquamous non-small cell lung cancer

ObjectivesRetrospective subgroup analysis in JMDB study indicates that the between-arm differences in overall survival (OS) in the East Asian subgroup were consistent with those observed in the entire JMDB study population. This bridging study (JMIL) further evaluated the efficacy and safety of first-line pemetrexed/cisplatin (PC) versus gemcitabine/cisplatin (GC) in Chinese patients with nonsquamous non-small cell lung cancer (NSCLC). The primary endpoint of this local registration trial was designed to compare OS in the combined dataset, consisting of Chinese patients in JMIL and 1252 nonsquamous patients in JMDB. Materials and methodsChinese patients with stage IIIB/IV nonsquamous NSCLC were randomly assigned (1:1) to 6 cycles maximum (21 days/cycle) of pemetrexed 500mg/m2+cisplatin 75mg/m2 (day 1), or gemcitabine 1250mg/m2 (days 1 and 8)+cisplatin 75mg/m2 (day 1). ResultsIn JMIL, 256 Chinese patients were randomized (PC, n=126; GC, n=130). Patient baseline characteristics were balanced between treatment arms. In the combined dataset, PC was superior to GC in prolonging OS, with adjusted hazard ratio (HR) of 0.87 (95% CI: 0.77–0.98, p=0.023) and median OS of 11.76 versus 10.94 months. In the JMIL-only population, no significant OS difference observed between treatment arms (adjusted HR=1.03 [95% CI: 0.77–1.39, p=0.822]; unadjusted HR=0.996 [95% CI: 0.74–1.33, p=0.980]), nor for other secondary efficacy endpoints. Significantly fewer patients in the PC arm experienced drug-related grade 3/4 toxicities, 54 (43.2%) versus 71 (55.9%) for GC (p=0.045), with significantly lower rates of leukocytopenia, thrombocytopenia, and fatigue. ConclusionThis study showed that in the combined population, OS of PC was superior to GC, while in the Chinese-only population, no significant difference was observed; a better safety and risk/benefit profile was found in the PC arm. A PC regimen should be considered as a standard of care in Chinese nonsquamous NSCLC patients in a first-line setting.

Association of glutathione peroxidase-1 (GPx-1) rs1050450 Pro198Leu and Pro197Leu polymorphisms with cardiovascular risk: a meta-analysis of observational studies.

ObjectiveTo clarify the association between rs1050450 polymorphism in Glutathione peroxidase-1 (GPx-1) and the risk of cardiovascular diseases (CVD) by performing a meta-analysis of published studies. There is growing evidence from different study types for an association of the GPx-1 polymorphism and cardiovascular outcomes, but observational studies have so far shown inconsistent results.MethodsRelevant publications were searched through PubMed, Embase database databases and the Cochrane Library. We used odds ratios (ORs) with 95% confidence intervals (CIs) to assess the strength of association under the best genetic model. Both Q statistic and the I2 were used to check heterogeneity. Meta-regression analysis was performed to explore heterogeneity source. Sensitivity analysis, cumulative meta-analysis analysis and publication bias were used to test the reliability of the results.ResultsData were available from two cohort studies and 8 case-control studies involving 1,430 cases and 3,767 controls. The pooled ORs for overall CVD risk was 1.36 with 95% CI: 1.08–1.70 under a co-dominant model, and that for East Asian subgroup was 1.84 (95% CI: 1.39–2.43). Substantial heterogeneity for ORs were detected among all the included studies, mainly caused by ethnic differences between East Asian and non-East Asian populations. Although Egger's regression test suggested no statistical significant publication bias, Begg's funnel plot exhibited obvious asymmetry. The statistical significance disappeared after adjusting for potential publication bias in the overall studies. However, no substantial publication bias was found in the East Asian subgroup.ConclusionsGPx-1 gene Pro198Leu and Pro197Leu polymorphisms considerably increased the risk of CVD in the East Asian population. Large-scale investigations are needed to confirm the results in different ethnicities.

Qualitative research on suicide in East Asia: A scoping review

BackgroundSuicide is a serious problem in East Asia. Yet, there is a significant lack of research on the topic, particularly using qualitative methodology.ObjectivesThis scoping review reports on findings drawn from 11 qualitative studies, providing up-to-date knowledge and understandings about suicide in East Asian populations.MethodsA web-based literature search was performed to identify empirical qualitative research articles addressing suicide in East Asia, published from January 2002 to December 2011.ResultsThree themes were identified within the reviewed studies; (1) influence of cultural beliefs; (2) the role of caregivers; and (3) specific sociological contexts. These themes are interrelated rather than mutually exclusive.ConclusionThe findings drawn from this scoping review reveal specific as well as broad contexts where suicidal ideation and behaviours occur among East Asians. To advance understandings, future studies should focus on comparative and longitudinal research to distil prevailing trends as well as the specificities that reside among particular East Asian subgroups (i.e. gender, sexual identity and generational) as a means to developing culturally sensitive and targeted suicide prevention programs.

The Association of ACT -17 A/T Polymorphism with Alzheimer’s Disease: A Meta-Analysis

Association studies between Alpha-1-antichymotrypsin (ACT)-17(A > T) polymorphisms and Alzheimer's disease (AD) susceptibility have shown conflicting results. In this investigation, we performed a meta-analysis to assess the purported associations. Subgroup analyses based on ethnicity (Caucasians, East-Asian and American mixed) were also performed including a total of 5,676 AD patients and 5,460 controls for ACT-17. Overall, allele contrast (A vs. T) of ACT -17 polymorphism produced significant results in the worldwide population [P(heterogeneity)=0.01, random-effects (RE) odds ratio (OR) 1.12; 95% CI 1.04-1.21, P=0.003] and in the Caucasian population [P(heterogeneity)=0.03, RE OR1.11 95% CI 1.01-1.24, P=0.04]. Meta-analyses of other genetic contrasts suggested that the A allele carriers are associated with increased susceptibility to AD in variant populations. No significant association was observed in the East-Asian subgroup analysis. In conclusion, ACT-17 variation presents a risk factor for AD in the worldwide population, especially in the Caucasian population.

Association study between methylenetetrahydrofolate reductase polymorphisms and unexplained recurrent pregnancy loss: A meta-analysis

BackgroundRecurrent pregnancy loss is an important clinical problem. Recently, high-level homocysteine in blood has been considered as a possible cause. Genetic polymorphisms in methylenetetrahydrofolate reductase (MTHFR) have been proved to be the common hereditary factors of high-level homocysteine. The association between MTHFR polymorphisms and unexplained recurrent pregnancy loss (URPL) has been reported but with controversial results. The purpose of present study is to collect and analyze published available data, and evaluate the association between MTHFR polymorphisms and URPL. MethodsA meta-analysis was performed to examine the association between MTHFR polymorphisms (C677T and A1298C) and URPL. Odds ratio (OR) and its 95% confidence interval (CI) were used in each study of genotype and allele contrast. Result(s)MTHFR C677T: The analysis included 3559 URPL cases and 5097 healthy controls. Overall random-effects odds ratios (ORs) were 1.68 (95% CI, 1.32–2.13; P<0.0001) for TT versus total genotypes, 1.35 (95% CI, 1.04–1.76; P=0.0224) for TT and CT genotype combined versus total genotypes and 1.34 (95%CI, 1.13–1.58; P<0.0001) for T versus total alleles. Although significant heterogeneity was found in C677T, it became weaker in the East Asian subgroup and the mixed subgroup when separated by ethnic subgroups. The results showed significant association between MTHFR C677T and URPL in the East Asian subgroup (ORs 2.11 for TT versus total genotype (P=0.0004) and 1.53 for T versus total alleles (P<0.0001)) and in the mixed subgroup (ORs 3.47 for TT versus total genotypes (P<0.0001) and 1.80 for T versus total alleles (P<0.027)), but not in Caucasian subgroup. MTHFR A1298CThe study involved 1163 URPL cases and 1061 healthy controls. Overall random-effects odds ratios (ORs) were 1.37 (95% CI, 0.71–2.67; P=0.3456) for CC versus total genotypes, 1.16 (95%CI, 0.98–1.38; P=0.0833) for CC+AC versus total genotypes and 1.04 (95%CI, 0.84–1.29; P=0.7112) for C versus total alleles. No significant association between MTHFR A1298C polymorphism and URPL was found. ConclusionsThese results indicate a significant association between MTHFR C677T mutation and URPL in the East Asian subgroup and mixed subgroup, but no significance in MTHFR A1298C mutation.

Is interleukin-6 circulating levels associated with coronary artery disease?

I read with great interest the meta-analysis by Niu et al. [1] who reported that interleukin 6 (IL-6) gene G-174C polymorphism might increase the risk of coronary artery disease (CAD) among allelic model (odds ratio (OR)=1.04, 95% confidence interval (CI) 0.97–1.10) and dominant model (OR=1.08, 95%CI 0.96–1.22). Interestingly, the associations among European populations (OR=1.04, 95%CI 0.97–1.12) and East Asians (OR=0.54, 95%CI0.26–1.12)were somewhat conflicting.However, the all associations abovewere not statistically significant. In addition, the authors found statistically significant associations between G-174C polymorphism and circulating IL-6 levels (P=0.047), and between IL-6 levels and CAD (OR=1.60, 95%CI 1.44–1.72) among Europeanpopulation. Even though, several issues should be considered in this meta-analysis. First, I am skeptical of the reality of the significant association between G-174C polymorphism and circulating IL-6 levels since the authors did not perform the sensitivity analysis. From Fig. 4, I noted that the study by Bennet [2] who reported very strong associationweighted 34.60% of all included studies, and I believed that the marginal association (P=0.047) found by the authors would disappear if this study is excluded by sensitivity analysis. In addition, the authors reported statistically significant association between IL-6 levels and CAD, but there is no table or figure demonstrating the related result. In myopinion, it is themainfindingof this paper and it should be described in details. Second, in my opinion, it might not be appropriate to include the study byMaitra et al. [3] in the East Asian subgroup since the ethnicity of the population in this study is Indian. As is known, Asian Indians are mainly of Indo-European and Dravidian ancestries. Therefore, I suggest the population in this study be categorized to other population subgroup. Third, several errors existed in the paper. For example, the genetic models which were described in the main text and Fig. 2 were not in agreement (they mentioned “dominant model” in the main text, but “recessive model” in the right pane of Fig. 2). In addition, regarding to the legend of the Supplementary Fig. S2, the authors described “Risk estimates of IL-6 gene G-174C polymorphism for CHD risk upon stratification by ethnicity in the allelic (left pane) and dominant (right pane) models”, but the right pane of the figure was the results by types of CAD rather than those by ethnicity. In conclusion, as the authors argued, this is the first study demonstrating the significant association between circulating IL-6 levels and CAD by implementing Mendelian randomization approach. However, the result should be interpreted with caution since it was based on limited sample size and also sensitivity analysis was not performed to confirm the robust of the association.

Efficacy and Safety of Pemetrexed Maintenance Therapy versus Best Supportive Care in Patients from East Asia with Advanced, Nonsquamous Non-small Cell Lung Cancer: An Exploratory Subgroup Analysis of a Global, Randomized, Phase 3 Clinical Trial

In a recent global phase 3 trial, patients with advanced non-small cell lung cancer (NSCLC), who had not progressed after four cycles of platinum-based induction chemotherapy, were randomized to maintenance therapy with pemetrexed or placebo. The objective of this retrospective, exploratory, post hoc subgroup analysis was to compare outcomes of East Asian patients with non-East Asian patients treated with pemetrexed or placebo. Only patients with nonsquamous histology were analyzed. Patients were grouped by enrollment location (East Asian = China, Korea, or Taiwan; non-East Asian = all other countries). The Kaplan-Meier method was used to calculate median progression-free survival (PFS) and overall survival (OS) times. Hazard ratios (HRs) were calculated using unadjusted Cox proportional hazard models. Of the 663 patients enrolled in the study, 481 patients had nonsquamous NSCLC: East Asian = 27% and non-East Asian = 73%. In the East Asian subgroup, there were more women, never smokers, and patients with adenocarcinoma. PFS was similar between the subgroups and significantly prolonged in patients treated with pemetrexed than placebo (median PFS: East Asian, 4.4 versus 1.6 months, HR = 0.42, p < 0.001; non-East Asian, 4.5 versus 2.8 months, HR = 0.45, p < 0.001). OS was numerically prolonged in East Asians (median OS: pemetrexed, 19.7 months; placebo, 16.4 months) compared with non-East Asians (pemetrexed, 13.2 months; placebo, 8.5 months). Pemetrexed was reasonably well tolerated with few severe adverse events reported. The results of this subgroup analysis support pemetrexed as maintenance therapy for East Asian patients with advanced, nonsquamous NSCLC.

Meta-Analysis of the Association of the C677T Polymorphism of the Methylenetetrahydrofolate Reductase Gene with Hyperuricemia

Background: The association between the MTHFR C677T polymorphism and hyperuricemia has been investigated in several studies. Although these epidemiological studies have shown that genetic factors are determinants of serum uric acid levels, the power of the association is weak due to the small sample size. Methods: To study whether the MTHFR C677T polymorphism has an effect on hyperuricemia, we carried out a meta-analysis of case-control studies from PubMed, EMBASE and CNKI (China National Knowledge Infrastructure) databases mainly in English and Chinese. We used the odds ratio (OR) as main effect size; explored potential sources of heterogeneity; performed subgroup analyses by race and performed sensitivity analyses of studies meeting the Hardy-Weinberg equilibrium (HWE). Results: Six studies with 1,470 subjects were included in the meta-analysis. Tests for heterogeneity showed the difference in OR among studies was not statistically significant (p = 0.63, I² = 0). When excluding the study of Caucasians not in HWE, the association remained robust (OR = 1.82, 95% CI 1.52-2.17) in the East Asian subgroup and sensitivity analyses. Conclusions: Although the mechanism of the relationship between the C677T polymorphism and uric acid still remains unclear, these original articles showed that the MTHFR C677T polymorphism may be an independent risk factor for hyperuri-cemia.

Efficacy and Safety of Cisplatin/Pemetrexed Versus Cisplatin/Gemcitabine as First-Line Treatment in East Asian Patients with Advanced Non-small Cell Lung Cancer: Results of an Exploratory Subgroup Analysis of a Phase III Trial

We conducted an exploratory, post hoc, subgroup analysis of the East Asian (EA) patients in a multinational phase III trial to determine whether the efficacy results for this subgroup were consistent with those observed for the entire study population. Thousand seven hundred twenty-five patients with advanced non-small cell lung cancer (NSCLC), including 126 EA patients (7.3%) from Taiwan and Korea, were enrolled in the trial and randomly assigned first-line chemotherapy with cisplatin and pemetrexed (CP; n = 862) or cisplatin and gemcitabine (CG; n = 863). Adjusted Cox proportional hazards models were used to compare overall survival and progression-free survival between the treatment arms in the EA subgroup. Median time-to-event data were estimated with the Kaplan-Meier method. Consistent with the results for the entire study population, survival in the EA subgroup trended in favor of CP over CG in patients with non-squamous histology, despite the more frequent use of post discontinuation targeted therapy in the CG arm. The opposite trend was noted for patients with squamous tumors. A higher proportion of patients in the EA subgroup were never smokers compared with the entire study population. A trend toward improved survival with CP compared with CG was seen regardless of smoking status, particularly in non-squamous patients. The key finding of this subgroup analysis was that the NSCLC histology effect on treatment outcomes for pemetrexed-treated patients seen in the entire study population was also apparent in the EA subgroup. The potential prognostic influence of race, histology subtype, and smoking status should be assessed in future NSCLC studies.

Efficacy of pemetrexed-cisplatin (PC) in East Asian patients (pts): Subgroup analysis of a phase III study comparing PC versus gemcitabine-cisplatin (GC) in first-line treatment of advanced non-small cell lung cancer (NSCLC)

8045 Background: East Asian ethnicity is a recognized favorable prognostic factor in the treatment of NSCLC in trials with either chemotherapy or EGFR tyrosine-kinase inhibitors (TKIs). In a global phase III study (Scagliotti JCO 2008), superior efficacy of PC was shown for pts with nonsquamous NSCLC, while Asian ethnicity was prognostic in the overall population. The purpose of this analysis is to describe the patient and disease characteristics of the East Asian pts enrolled in this study and assess efficacy according to histology and smoking history. Methods: This retrospective analysis of a large phase III study included only patients enrolled from Korea and Taiwan. For survival and progression-free survival (PFS), Cox-adjusted analyses were used to estimate the hazard ratio and 95% CI, while medians were estimated using Kaplan-Meier method. Results: Results for PFS and response rate showed trends similar to overall survival in East Asian pts, favoring PC therapy in nonsquamous pts. The use of post-discontinuation targeted therapies such as EGFR-TKIs was similar between treatment arms in the overall population and in nonsquamous pts. In East Asian pts, EGFR-TKI use was slightly higher in the GC arm, in both the overall population and in nonsquamous pts. In a further subgroup analysis defined by smoking status, East Asian nonsquamous pts treated with PC had longer survival (not statistically significant). Conclusions: Pt and disease characteristics between the East Asian subgroup and the overall population were similar, with notable differences in the percentage of pts with no smoking history and the greater use of EGFR-TKIs as post-discontinuation therapy. This analysis shows the improved efficacy outcomes for East Asian nonsquamous pts treated with PC is consistent with the previously observed treatment effect of PC on nonsquamous NSCLC. [Table: see text] [Table: see text]

Polymorphisms of tumor necrosis factor-alpha are associated with increased susceptibility to gastric cancer: a meta-analysis

We conducted a meta-analysis to assess the association between tumor necrosis factor-alpha (TNF-alpha) gene TNFA-308 (G > A) and TNFA-857 (C > T) polymorphisms and gastric cancer (GC) susceptibility. We also performed subgroup analyses based on ethnicity (Caucasian, east Asian, and other populations) and tumor location [noncardia gastric cancer (NCGC)]. There were 3,335 GC patients and 5,286 controls for TNFA-308, and 1,118 GC patients and 1,591 controls for TNFA-857 in our analysis. Overall, allele contrast (A vs. G) of TNFA-308 polymorphism produced significant results in worldwide populations [Pheterogeneity = 0.05, random-effects (RE) odds ratio (OR) 1.19; 95% confidence interval (CI) 1.03-1.37, P = 0.02] and Caucasian populations (Pheterogeneity = 0.15, fixed-effects (FE), OR 1.27; 95% CI 1.11-1.45, P = 0.0005). Similar results were also obtained in recessive models and homozygote contrasts. No significant association was observed in NCGC and east Asian subgroup analysis. T variant of TNFA-857 produced significant results only in allele contrast (Pheterogeneity = 0.38, FE OR 1.17; 95% CI 1.01-1.35, P = 0.04). In conclusion, TNFA-308 locus of TNF-alpha would be a risk factor for GC, especially in Caucasian populations. Besides, TNFA-857 locus may be related to GC risk, which demonstrated changeability of results in different contrasts.