Reperfusion treatment delays amongst patients with painless ST segment elevation myocardial infarction.

OBJECTIVE: Early reperfusion therapy in the treatment of ST segment elevation myocardial infarction (STEMI) patients can improve outcomes. Silent myocardial infarction is associated with poor prognosis, but little is known about its effect on treatment delays. We aimed to characterize STEMI patients presenting without complaints of pain to the emergency departments (EDs) in Singapore. METHODS: Retrospective data were requested from the Singapore Myocardial Infarction Registry (SMIR), a national level registry in Singapore. Painless STEMI was defined as the absence of pain (chest, back, shoulder, jaw, and epigastric pain) during ED presentation. The primary outcome was door-to-balloon (D2B) time, defined as the earliest time a patient arrived in the ED to balloon inflation. Secondary outcomes were 1-month and 1-year mortality and occurrence of adverse events. RESULTS: From January 2010 to December 2012, the SMIR collected 6412 cases; 10.9% of patients presented without any pain. These patients were older (median age =75 v. 58 years old), more likely to be females (39.9% v. 16.1%), Chinese (74.9% v. 62.7%), obese (median body mass index [BMI] =24.5 v. 22.1), and with history of hypertension (71.1% v. 54.6%), diabetes mellitus (48.6% v. 37.0%), and acute myocardial infarction (20.0% v. 12.3%). They had a longer median D2B (80.5 v. 63 minutes, p<0.001) and a higher occurrence of 30-day (38.4% v. 5.7%) and 1-year mortality rates (47.3% v. 8.5%). CONCLUSION: A small proportion of STEMI patients presented without any pain to the ED. They tended to have a higher D2B and risks of mortality. Targeted effort is required to improve diagnostic and treatment efficiency in this group.

Symptom-to-door delay among patients with ST-segment elevation myocardial infarction in Singapore.

OBJECTIVES: Symptom-to-door time (S2D) is one of the important components of ischaemic time, which might affect the infarct size and outcomes of acute myocardial infarction. The aim of the present study was to identify patients' characteristics associated with delayed symptom-onset-to-arrival at EDs in ST-segment elevation myocardial infarction (STEMI) patients in Singapore. METHODS: Retrospective data of STEMI patients presenting to the ED of all public hospitals with onsite primary percutaneous coronary intervention facilities between 2010 and 2012 were obtained from the Singapore Myocardial Infarction Registry. Based on the S2D of 120 min, characteristics of patients were compared between short S2D (≤120 min) and long S2D (>120 min). Multivariate logistic and linear regression analyses were performed. RESULTS: Out of 3848 patients, 1682 patients had an S2D of ≤120 min, and 2166 had an S2D >120 min. In the multivariate analyses, older age, Malay ethnicity, diabetes mellitus, presenting symptoms of back and epigastric pain were independently associated with long S2D. Patients who utilised the emergency medical services, presented after office hours and with symptoms of chest pain, breathlessness, diaphoresis and past history of percutaneous transluminal coronary angioplasty/primary percutaneous coronary intervention, were independently associated with short S2D. Patients with long S2D had lower probability of receiving reperfusion treatment with delayed symptom-to-balloon and door-to-balloon time and higher probabilities of complications and mortality. CONCLUSION: The present study shows that longer S2D was associated with older age, ethnicity, diabetes mellitus, delay in receiving early reperfusion treatment and poorer prognosis.

EGFR kinase inhibitors and gastric acid suppressants in EGFR-mutant NSCLC: a retrospective database analysis of potential drug interaction.

BACKGROUND: Erlotinib and gefitinib are weak base drugs whose absorption and clinical efficacy may be impaired by concomitant gastric acid suppressive (AS) therapy, yet proton pump inhibitors (PPIs) and histamine-2 receptor antagonists (H2As) are widely indicated in non-small cell lung cancer (NSCLC) patients for the prevention and treatment of erlotinib-induced gastrointestinal injury and corticosteroid-associated gastric irritation. We assessed the clinical relevance of this potential drug-drug interaction (DDI) in a retrospective cohort of EGFR-mutant NSCLC patients. RESULTS: The AS usage rate was 35%. In the overall cohort, AS users did not experience poorer OS (HR: 1.47, 95% CI: 0.92 - 2.35, P = 0.10; median, 11.4 versus 17.5 months) or PFS (HR = 1.37, 95% CI: 0.89 - 2.12, P = 0.16; median, 7.6 versus 8.7 months) compared with non-users in multivariate Cox regression analysis. However, subgroup analyses indicated that AS usage was associated with significantly poorer OS and PFS in patients who had fewer or milder comorbidities (Charlson comorbidity index ≤ 2), those with Karnofsky performance status < 90, and never-smokers. MATERIALS AND METHODS: A retrospective database analysis of 157 patients given erlotinib or gefitinib for EGFR-mutant advanced NSCLC from two institutions was conducted. Patients were classified as AS-users if the periods of AS and anti-EGFR therapy overlapped by ≥ 30%. Overall survival (OS) and progression-free survival (PFS) were assessed according to AS usage. CONCLUSIONS: Concomitant AS therapy did not have an adverse impact on OS and/or PFS in the overall cohort. Our subgroup findings should be regarded exploratory and require replication in a large prospective cohort.

Emergency Medical Services Utilization among Patients with ST-Segment Elevation Myocardial Infarction: Observations from the Singapore Myocardial Infarction Registry.

OBJECTIVE: Early activation of emergency medical services (EMS), rapid transport, and treatment of patients experiencing ST-segment elevation myocardial infarction (STEMI) can improve outcomes. The Singapore Myocardial Infarction Registry (SMIR) is a nation-wide registry that collects data on STEMI. We aimed to determine the prevalence, predictors, and outcomes of EMS utilization among STEMI patients presenting to Emergency Departments (ED) in Singapore. METHODS: We analyzed STEMI patients enrolled by SMIR from January 2010 to December 2012. We excluded patients who were transferred, developed STEMI in-hospital or suffered cardiac arrest out-of-hospital or in the ED. Primary outcome was process-of-care timings. Secondary outcomes included the occurrence of cardiac complications. Multivariate analysis was used to examine independent factors associated with EMS transport. RESULTS: 6412 patients were enrolled into the study; 4667 patients were eligible for analysis. 49.8% of patients utilized EMS transport. EMS transport was associated with higher rate of reperfusion therapy (74.3% vs. 65.1%, p < 0.01), shorter median symptom-to-door time (119 vs. 182 minutes, p < 0.01), door-to-balloon time (59 vs. 70 minutes, p < 0.01), and symptom-to-balloon time (185 vs. 233 minutes, p < 0.01). EMS transport had more patients with Killip Class 4 (7.5% vs 4.0%, p < 0.01) and was associated with greater presentation of heart failure, arrhythmias, and complete heart block. Independent predictors of EMS transport were age, syncope and Killip score; after-office-hour presentation was a negative predictor. CONCLUSION: Less than half of STEMI patients utilized EMS and EMS patients had faster receipt of initial reperfusion therapies. Targeted public education to reduce time to treatment may improve the care of STEMI patients.

National Breast Cancer Screening Programme, Singapore: evaluation of participation and performance indicators.

OBJECTIVE: To evaluate participation rates and performance indicators in the National Breast Cancer Screening Programme, BreastScreen Singapore (BSS). METHODS: Data on women aged 40-69 screened in the period 2002-2009 was obtained from BSS and from the Singapore Cancer Registry. Participation rates and performance indicators (including screen detection rates, small tumour detection rates, recall rates, accuracy and interval cancer rates) were examined. RESULTS: BSS participation rate has remained above 10% since 2005. Based on health surveys, national mammography rates have increased from 29.7% before BSS to 39.6% in 2010 after BSS. Performance indicators, with the exception of recall rates, specificity, and interval cancer rate (for first screen), generally improved from 2002-2006 to 2007-2009 and are comparable with organized breast screening programmes in other developed countries. CONCLUSION: BSS breast cancer screening coverage and rescreen rates in Singapore could be improved. Mechanisms to monitor recall rates are in place, and training opportunities are provided to aid the professional development of radiologists.

Gender and ethnic differences in incidence and survival of lymphoid neoplasm subtypes in an Asian population: Secular trends of a population-based cancer registry from 1998 to 2012.

Descriptive epidemiology on incidence and survival by lymphoid neoplasm (LN) subtypes using the 2008 World Health Organisation (WHO) classification remained limited in Asia. The aim of this study was to evaluate whether gender and ethnic differences in incidence and survival of LN subtypes existed using the Singapore Cancer Registry (SCR) from 1998 to 2012. We derived age standardised incidence rates (ASIRs) by the direct standardisation method and 5-year relative survival (RSR) by the Ederer II method and period approach. Five-year observed survival (OS) was obtained for each ethnicity. Malays had the highest ASIR of total LNs among the three ethnicities for each time period. The largest increase in 5-year RSR subtypes was follicular lymphoma from 43.8% in 1998-2002 to 82.3% in 2008-2012; followed by chronic lymphocytic leukaemia (CLL)/small lymphocytic lymphoma (SLL) from 48.1% in 1998-2002 to 77.9% in 2008-2012. Although males had higher incidence than females in each time period, females had greater 5-year RSR for follicular lymphoma (89.8% in 2008-2012 for females vs. 76.6% in 2008-2012 for males) and CLL/SLL (78.7% in 2008-2012 for females vs. 76.7% in 2008-2012 for males). All three ethnicities experienced an overall increase in 5-year OS for mature B-cell lymphoma, with Indians experiencing the greatest increase (37.1% in 1998-2002 to 61.1% in 2008-2012), followed by Malays (30.8% in 1998-2002 to 48.7% in 2008-2012) and then Chinese (36.4% in 1998-2002 to 51.3% in 2008-2012). Our study demonstrated that improved mature B-cell lymphoma survival was not only observed in the West, but also in Singapore.

Clinical outcome of palliative radiotherapy for locally advanced symptomatic gastric cancer in the modern era.

The purpose of this study was to report the outcomes of patients with symptomatic locally advanced/recurrent gastric cancer treated with radiotherapy (RT) using modern 3-dimensional conformal techniques.We retrospectively reviewed patients who had palliative RT for index symptoms of gastric bleeding, pain, and obstruction. Study endpoints included symptom response, median survival, and treatment toxicity.Of 115 patients with median age of 77 years, 78 (67.8%) patients had metastatic disease at the time of treatment. Index symptoms were gastric bleeding, pain, and obstruction in 89.6%, 9.2%, and 14.3% of patients, respectively. Dose fractionation regimen ranged from 8-Gy single fraction to 40 Gy in 16 fractions. One hundred eleven patients (93.3%) were computed tomography (CT) planned. Median follow-up was 85 days. Response rates for bleeding, pain, and obstruction were 80.6% (83/103), 45.5% (5/11), and 52.9% (9/17), respectively, and median duration of response was 99 days, 233 days, and 97 days, respectively. Median survival was 85 days. Actuarial 12-month survival was 15.3%. There was no difference in response rates between low (≤39 Gy) and high (>39 Gy) biologically effective dose (BED) regimens (α/ß ratio = 10). Median survival was significantly longer in patients who responded to RT compared with patients who did not (113.5 vs 47 days, P < 0.001). Three patients (2.6%) had grade 3 Common Toxicity Criteria equivalent toxicity (nausea/vomiting/anorexia).External beam RT delivered using 3-dimensional conformal techniques is highly effective and well tolerated in the local palliation of gastric cancer, with palliation lasting the majority of patient's lives. Short (≤39 Gy BED) RT schedules are adequate for effective symptom palliation. A phase II study of palliative gastric RT is ongoing.

Lung cancer incidence in Singapore: ethnic and gender differences.

OBJECTIVES: Lung cancer is the leading cause of cancer death in Singapore. We examine trends of lung cancer from 1968 to 2007, explore ethnic and gender-specific incidence rates, and examine period and cohort effects in Chinese and Malays using Age-Period-Cohort (APC) analysis. METHODS: Aggregated data for cancer incidences and estimated person-years for the period 1968-2007 were obtained from the Singapore Cancer Registry. An APC analysis was performed using a Poisson regression model. RESULTS: Lung cancer incidence rates were more than two times higher in males compared to females, and also higher in Chinese compared to Malays and Indians. While rates in Chinese men, and, to a lesser extent, Chinese women, had been declining since the early 1980s, rates in Malay men continued to increase. The full APC model described the cancer trend in Chinese males, Chinese females and Malay males, while an age-drift model described the cancer trend in Malay females. Among Chinese males, Chinese females and Malay males, there was no clear pattern to the period curvature effects, although similar cohort curvatures were seen, with positive curvature effects in older cohorts that declined towards zero and negative effects in younger cohorts. CONCLUSION: There are strong gender and ethnic differences in lung cancer incidence in Singapore. Differences in smoking rates and differential ethnic effects of smoking may explain some but not all of these differences. The similar cohort curvatures suggest that environmental factors in Singapore occurring in the past but no longer present at similar intensity or frequency may explain the positive deviation from a linear trend. Apart from smoking, other environmental factors such as changes in diet, improved sanitation and ventilation, and declines in infectious diseases like tuberculosis may play a role.

Cancer among end-stage renal disease patients on dialysis.

INTRODUCTION: The aim of this study is to investigate the risk of cancer among end-stage renal disease (ESRD) patients on dialysis in Singapore. MATERIALS AND METHODS: The study looks at a retrospective cohort of 5505 ESRD patients who had received dialysis between 1998 and 2007. The cancer risk of these patients would be compared against the risk of the general population. RESULTS: During a median follow-up time of 3.9 years, 267 (4.9%) dialysis patients developed cancer. The risk of cancer (excluding non-melanoma skin cancer) is 1.66 times higher in dialysis patients than the general population, and is highest at age less than 35 years old and at first year after dialysis. Cancer risk was found to be significantly higher among Chinese dialysis patients, followed by Malays, compared to the general population. The 3 sites with highest elevated cancer risks among dialysis patients compared to the general population are kidney, tongue and multiple myeloma. CONCLUSION: The finding of elevated cancer risk among younger dialysis patients is similar to other international studies. High cancer risks among specific cancer sites were also consistent with other studies. In view of the lack of screening procedures for these cancers and shortened expected survival of ESRD patients, cancer screening of ESRD patients should be individualised and based on a reasonable life expectancy and transplant candidacy, keeping in mind the competing risk of cardiovascular mortality.

A comparative population-based study of prostate cancer incidence and mortality rates in Singapore, Sweden and Geneva, Switzerland from 1973 to 2006.

BACKGROUND: Prostate cancer is the most commonly diagnosed malignancy in men in Sweden and Geneva, and the third most common in men in Singapore. This population-based study describes trends in the incidence and mortality rates of prostate cancer in Singapore, Sweden and Geneva (Switzerland) from 1973 to 2006 and explores possible explanations for these different trends. METHODS: Data from patients diagnosed with prostate cancer were extracted from national cancer registries in Singapore (n = 5,172), Sweden (n = 188,783) and Geneva (n = 5,755) from 1973 to 2006. Trends of incidence and mortality were reported using the Poisson and negative binomial regression models. The age, period and birth-cohort were tested as predictors of incidence and mortality rates of prostate cancer. RESULTS: Incidence rates of prostate cancer increased over all time periods for all three populations. Based on the age-period-cohort analysis, older age and later period of diagnosis were associated with a higher incidence of prostate cancer, whereas older age and earlier period were associated with higher mortality rates for prostate cancer in all three countries. CONCLUSIONS: This study demonstrated an overall increase in incidence rates and decrease in mortality rates in Singapore, Sweden and Geneva. Both incidence and mortality rates were much lower in Singapore. The period effect is a stronger predictor of incidence and mortality of prostate cancer than the birth-cohort effect.

The discovery of human genetic variations and their use as disease markers: past, present and future.

The field of human genetic variations has progressed rapidly over the past few years. It has added much information and deepened our knowledge and understanding of the diversity of genetic variations in the human genome. This significant progress has been driven mainly by the developments of microarray and next generation sequencing technologies. The array-based methods have been widely used for large-scale copy number variation (CNV) detection in the human genome. The arrival of next generation sequencing technologies, which enabled the completion of several whole genome resequencing studies, has also resulted in a massive discovery of genetic variations. These studies have identified several hundred thousand short indels and a total of thousands of CNVs and other structural variations in the human genome. The discovery of these 'newer' types of genetic variations, indels, CNVs and copy neutral variations (inversions and translocations) has also widened the scope of genetic markers in human genetic and disease gene mapping studies. The aim of this review article is to summarize the latest developments in the discovery of human genetic variations and address the issue of inadequate coverage of genetic variations in the current genome-wide association studies, which mainly focuses on common SNPs. Finally, we also discuss the future directions in the field and their impacts on next generation genome-wide association studies.

Molecular epidemiology and its current clinical use in cancer management.

The revelation of the entire human DNA sequence in 2001, and the launching of the international haplotype map (HapMap) project, made the identification of common markers of disease possible, dramatically transforming molecular epidemiology. In recent years, the development of, and discoveries within, human genome research have been rapid, highlighted by the current explosion of genome-wide association studies (GWAS). GWAS aim at finding germline changes that increase cancer risk. An equally important and rapid development had been seen in cancer genomics, with great strides being made in our understanding of somatic mutations that allow and accompany cancer development. In this review we discuss whether it is currently possible to use these new discoveries to aid the reduction of cancer mortality by reducing risk of disease, improving prognosis, and keeping complications due to treatment to a minimum. Findings from GWAS have mostly been used to predict risk, but there is the potential to use them for prognostication and even treatment prediction. Expression arrays have identified prognostic patterns for breast cancer, but few reliable patterns are available for treatment prediction. More importantly, virtually no genetic signatures are available to predict morbidity from treatment. Thus, there is a need to bring different biological techniques together and integrate them with existing clinical oncological care for a simultaneous risk and outcome assessment.

The pursuit of genome-wide association studies: where are we now?

It is now 5 years since the first genome-wide association studies (GWAS), published in 2005, identified a common risk allele with large effect size for age-related macular degeneration in a small sample set. Following this exciting finding, researchers have become optimistic about the prospect of the genome-wide association approach. However, most of the risk alleles identified in the subsequent GWAS for various complex diseases are common with small effect sizes (odds ratio <1.5). So far, more than 450 GWAS have been published and the associations of greater than 2000 single nucleotide polymorphisms (SNPs) or genetic loci were reported. The aim of this review paper is to give an overview of the evolving field of GWAS, discuss the progress that has been made by GWAS and some of the interesting findings, and summarize what we have learned over the past 5 years about the genetic basis of human complex diseases. This review will focus on GWAS of SNPs association for complex diseases but not studies of copy number variations.

Researching genetic versus nongenetic determinants of disease: a comparison and proposed unification.

Research standards deviate in genetic versus nongenetic epidemiology. Besides some immutable differences, such as the correlation pattern between variables, these divergent research standards can converge considerably. Current research designs that dissociate genetic and nongenetic measurements are reaching their limits. Studies are needed that massively measure genotypes, nongenetic exposures, and outcomes concurrently.