Emily Y. Y. Chan

Effect of oxaliplatin, fluorouracil, and leucovorin with or without cetuximab on survival among patients with resected stage III colon cancer: a randomized trial.

CONTEXT Leucovorin, fluorouracil, and oxaliplatin (FOLFOX) is the standard adjuvant therapy for resected stage III colon cancer. Adding cetuximab to FOLFOX benefits patients with metastatic wild-type KRAS but not mutated KRAS colon cancer. OBJECTIVE To assess the potential benefit of cetuximab added to the modified sixth version of the FOLFOX regimen (mFOLFOX6) in patients with resected stage III wild-type KRAS colon cancer. DESIGN, SETTING, AND PARTICIPANTS A randomized trial of 2686 patients aged 18 years or older at multiple institutions across North America enrolled following resection and informed consent between February 10, 2004, and November 25, 2009. The primary randomized comparison was 12 biweekly cycles of mFOLFOX6 with and without cetuximab. KRAS mutation status was centrally determined. The trial was halted after a planned interim analysis of 48% of predicted events (246/515) occurring in 1863 (of 2070 planned) patients with tumors having wild-type KRAS. A total of 717 patients with mutated KRAS and 106 with indeterminate KRAS were accrued. The 2070 patients with wild-type KRAS provided 90% power to detect a hazard ratio (HR) of 1.33 (2-sided α = .05), with planned interim efficacy analyses after 25%, 50%, and 75% of expected relapses. MAIN OUTCOME MEASURES Disease-free survival in patients with wild-type KRAS mutations. Secondary end points included overall survival and toxicity. RESULTS Median (range) follow-up was 28 (0-68) months. The trial demonstrated no benefit when adding cetuximab. Three-year disease-free survival for mFOLFOX6 alone was 74.6% vs 71.5% with the addition of cetuximab (HR, 1.21; 95% CI, 0.98-1.49; P = .08) in patients with wild-type KRAS, and 67.1% vs 65.0% (HR, 1.12; 95% CI, 0.86-1.46; P = .38) in patients with mutated KRAS, with no significant benefit in any subgroups assessed. Among all patients, grade 3 or higher adverse events (72.5% vs 52.3%; odds ratio [OR], 2.4; 95% CI, 2.1-2.8; P < .001) and failure to complete 12 cycles (33% vs 23%; OR, 1.6; 95% CI, 1.4-1.9; P < .001) were significantly higher with cetuximab. Increased toxicity and greater detrimental differences in all outcomes were observed in patients aged 70 years or older. CONCLUSION Among patients with stage III resected colon cancer, the use of cetuximab with adjuvant mFOLFOX6 compared with mFOLFOX6 alone did not result in improved disease-free survival. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00079274.

Public-health risks of melamine in milk products

News stories about the contamination of milk with melamine in China fi rst emerged on Sept 11, 2008, and the situation has since become an international health scare. Melamine (also known as tripolycyanamide) is an industrial chemical in the production of melamine resins, which are used in laminates, glues, adhesives, and plastics. When added to milk, melamine increases the nitrogen concentration, which suggests a false increase in protein concentration. Melamine has low oral acute toxicity but excessive exposure in animals causes renal stones. When consumed by human beings, babies and children are aff ected the most because of their dependence for nutrition, compounded by immaturity of their organs, which renders them vulnerable to chemical damage. The practice of mixing preservatives and chemicals, including antibiotics, with milk to make it last longer, taste better, and record higher protein values refl ects an inadequately regulated and managed supply-chain and an agricultural industry in need of reform. Chinese people have only recently started to appreciate milk products and many producers are small farmers, under pressure to maximise milk yield in the face of rising grain prices. Middlemen between milk producers and some of the big dairy companies have been selling substandard milk at discount prices. Although China has a monitoring system for nutritional contents, there is no regular reporting system for the concentration of common chemicals (illegal preservatives), veterinary antibiotic use, and carcinogenic components in dairy products. The Government has now recognised the need for support, training, and investment in the industry to safeguard potential risk to public health. Meanwhile, by Sept 22, the Chinese authorities had reported that 52 857 children had been treated for renal complications. At least four children have died as a direct result. By Sept 28, in Hong Kong where 95% of food is imported, much of it from the mainland, 15 017 children had attended designated clinics. Five of these children were found to have kidney stones, and four of these fi ve had a history of living in the mainland. Because infant formula has been supplied to a large number of countries as far afi eld as Burundi, Yemen, and Tanzania, the UN has issued a worldwide alert and the European Union banned China-made baby-food. In the UK, all products from China containing more than 15% milk as an ingredient will be subject to documentary, identity, and physical checks and those products containing more than 2·5 mg melamine per kg will be destroyed. The USA has advised those travelling to China with small children to take their own baby-food and formula. The Chinese Government’s response has been to curb the risks, punish the perpetrators, and help the victims. The Government has enacted the Emergency Public Health Response Regulations drawn up in 2003 in response to the outbreak of severe acute respiratory syndrome (SARS). This plan formulates a contingency response for major emergencies. However, the plan was drafted for infectious diseases such as SARS, and there are no clear guidelines or regulations which govern responsibilities and liabilities in a case such as that of melamine contamination. The Minister of Health has promised care will be provided free to aff ected children and the Government is providing screening to reassure anxious parents. However, for those with permanent clinical problems and aff ected children beyond China’s borders, fi nancial compensation and long-term follow-up is less certain and questions of liability are as yet unresolved. Public concern was raised after New-Zealand-based food-giant Fonterra learnt from its Chinese partner Sanlu Group that infant formula was contaminated. Re ut er s

A study of intracity variation of temperature-related mortality and socioeconomic status among the Chinese population in Hong Kong

Background Hong Kong, a major city in China, has one of the worlds highest income inequalities and one of the worlds highest average increases in urban ambient temperatures. Heat-related mortality in urban areas may vary with acclimatisation and population characteristics. This study examines how the effect of temperature on mortality is associated with sociodemographic characteristics at an intracity level in Hong Kong, China, during the warm season. Methods Data from the Hong Kong Observatory, Census and Statistics Department, Environmental Protection Department and government general outpatient clinics during 1998–2006 were used to construct generalised additive (Poisson) models to examine the temperature mortality relationship in Hong Kong. Adjusted for seasonality, long-term trends, pollutants and other potential confounders, effect modification of the warm season temperature–mortality association by demographic, socioeconomic factors and urban design were examined. Results An average 1°C increase in daily mean temperature above 28.2°C was associated with an estimated 1.8% increase in mortality. Heat-related mortality varied with sociodemographic characteristics: women, men less than 75 years old, people living in low socioeconomic districts, those with unknown residence and married people were more vulnerable. Non-cancer-related causes such as cardiovascular and respiratory infection-related deaths were more sensitive to high temperature effects. Conclusion Public health protection strategies that target vulnerable population subgroups during periods of elevated temperature should be considered.

Meta-analysis on night shift work and risk of metabolic syndrome

This study aims to quantitatively summarize the association between night shift work and the risk of metabolic syndrome (MetS), with special reference to the dose–response relationship with years of night shift work. We systematically searched all observational studies published in English on PubMed and Embase from 1971 to 2013. We extracted effect measures (relative risk, RR; or odd ratio, OR) with 95% confidence interval (CI) from individual studies to generate pooled results using meta‐analysis approach. Pooled RR was calculated using random‐ or fixed‐effect model. Downs and Black scale was applied to assess the methodological quality of included studies. A total of 13 studies were included. The pooled RR for the association between ‘ever exposed to night shift work’ and MetS risk was 1.57 (95% CI = 1.24–1.98, pheterogeneity = 0.001), while a higher risk was indicated in workers with longer exposure to night shifts (RR = 1.77, 95% CI = 1.32–2.36, pheterogeneity = 0.936). Further stratification analysis demonstrated a higher pooled effect of 1.84 (95% CI = 1.45–2.34) for studies using the NCEP‐ATPIII criteria, among female workers (RR = 1.61, 95% CI = 1.10–2.34) and the countries other than Asia (RR = 1.65, 95% CI = 1.39–1.95). Sensitivity analysis confirmed the robustness of the results. No evidence of publication bias was detected. The present meta‐analysis suggested that night shift work is significantly associated with the risk of MetS, and a positive dose–response relationship with duration of exposure was indicated.

Effect modification of the association between short-term meteorological factors and mortality by urban heat islands in Hong Kong.

Background Prior studies from around the world have indicated that very high temperatures tend to increase summertime mortality. However possible effect modification by urban micro heat islands has only been examined by a few studies in North America and Europe. This study examined whether daily mortality in micro heat island areas of Hong Kong was more sensitive to short term changes in meteorological conditions than in other areas. Method An urban heat island index (UHII) was calculated for each of Hong Kong’s 248 geographical tertiary planning units (TPU). Daily counts of all natural deaths among Hong Kong residents were stratified according to whether the place of residence of the decedent was in a TPU with high (above the median) or low UHII. Poisson Generalized Additive Models (GAMs) were used to estimate the association between meteorological variables and mortality while adjusting for trend, seasonality, pollutants and flu epidemics. Analyses were restricted to the hot season (June-September). Results Mean temperatures (lags 0–4) above 29°C and low mean wind speeds (lags 0–4) were significantly associated with higher daily mortality and these associations were stronger in areas with high UHII. A 1°C rise above 29°C was associated with a 4.1% (95% confidence interval (CI): 0.7%, 7.6%) increase in natural mortality in areas with high UHII but only a 0.7% (95% CI: −2.4%, 3.9%) increase in low UHII areas. Lower mean wind speeds (5th percentile vs. 95th percentile) were associated with a 5.7% (95% CI: 2.7, 8.9) mortality increase in high UHII areas vs. a −0.3% (95% CI: −3.2%, 2.6%) change in low UHII areas. Conclusion The results suggest that urban micro heat islands exacerbate the negative health consequences of high temperatures and low wind speeds. Urban planning measures designed to mitigate heat island effects may lessen the health effects of unfavorable summertime meteorological conditions.

Thymidylate synthase genotype-directed chemotherapy for patients with gastric and gastroesophageal junction cancers

Background Retrospective studies indicate associations between TSER (thymidylate synthase enhancer region) genotypes and clinical outcomes in patients receiving 5-FU based chemotherapy, but well-controlled prospective validation has been lacking. Methods In this phase II study (NCT00515216 registered through ClinicalTrials.gov, http://clinicaltrials.gov/show/NCT00515216), patients with “good risk” TSER genotypes (at least one TSER*2 allele) were treated with FOLFOX chemotherapy to determine whether prospective patient selection can improve overall response rates (ORR) in patients with gastric and gastroesophageal junction (GEJ) cancers, compared with historical outcomes in unselected patients (estimated 43%). Results The ORR in genotype-selected patients was 39.1% (9 partial responses out of 23 evaluable patients, 95% CI, 22.2 to 59.2), not achieving the primary objective of improving ORR. An encouraging disease control rate (DCR, consisting of partial responses and stable diseases) of 95.7% was noted and patients with homozygous TSER*2 genotype showed better tumor response. Conclusions In this first prospective, multi-institutional study in patients with gastric or GEJ cancers, selecting patients with at least one TSER*2 allele did not improve the ORR but led to an encouraging DCR. Further studies are needed to investigate the utility of selecting patients homozygous for the TSER*2 allele and additional genomic markers in improving clinical outcomes for patients with gastric and GEJ cancers. Trial Registration ClinicalTrials.gov NCT00515216

Weather, pollution, and acute myocardial infarction in Hong Kong and Taiwan

BACKGROUND Several previous studies examined the association between acute myocardial infarction (AMI) incidence and temperature and/or air pollution. Results of these studies have been inconsistent and few studies have been done in cities with sub-tropical or tropical climates. METHODS Daily data on AMI hospitalizations, mean temperature and humidity, and pollutants, were collected for 2000-2009 for three warm-climate Asian cities. Poisson Generalized Additive Models were used to regress daily AMI counts on temperature, humidity, and pollutants while controlling for day of the week, long-term trends and seasonal effects. Smoothing splines allowing non-linear associations were used for temperature and humidity while pollutants were modeled as linear terms. RESULTS A 1°C drop below a threshold temperature of 24°C was significantly (p<.0001) associated with AMI hospitalization increases of 3.7% (average lag 0-13 temperature) in Hong Kong, 2.6% (average lag 0-15) in Taipei, and 4.0% (average lag 0-11) in Kaohsiung. No significant heat effects were observed. Among pollutants same day nitrogen dioxide (NO2) levels were the strongest predictors in all three cities, with a 10mg/m(3) increase in NO2 being associated with a 1.1% rise in AMI hospitalization in Hong Kong, and a 10 ppb rise being associated with 4.4% and 2.6% rises in Taipei and Kaohsiung, respectively. CONCLUSIONS Cool temperatures and higher NO2 levels substantially raised AMI risk in these warm-climate cities and the effect sizes we observed were stronger than those found in previous studies. More attention should be paid to the health dangers of cold weather in warm-climate cities.

One-year delayed effect of fog on malaria transmission: a time-series analysis in the rain forest area of Mengla County, south-west China

BackgroundMalaria is a major public health burden in the tropics with the potential to significantly increase in response to climate change. Analyses of data from the recent past can elucidate how short-term variations in weather factors affect malaria transmission. This study explored the impact of climate variability on the transmission of malaria in the tropical rain forest area of Mengla County, south-west China.MethodsEcological time-series analysis was performed on data collected between 1971 and 1999. Auto-regressive integrated moving average (ARIMA) models were used to evaluate the relationship between weather factors and malaria incidence.ResultsAt the time scale of months, the predictors for malaria incidence included: minimum temperature, maximum temperature, and fog day frequency. The effect of minimum temperature on malaria incidence was greater in the cool months than in the hot months. The fog day frequency in October had a positive effect on malaria incidence in May of the following year. At the time scale of years, the annual fog day frequency was the only weather predictor of the annual incidence of malaria.ConclusionFog day frequency was for the first time found to be a predictor of malaria incidence in a rain forest area. The one-year delayed effect of fog on malaria transmission may involve providing water input and maintaining aquatic breeding sites for mosquitoes in vulnerable times when there is little rainfall in the 6-month dry seasons. These findings should be considered in the prediction of future patterns of malaria for similar tropical rain forest areas worldwide.

MSH2 c.1452-1455delAATG Is a Founder Mutation and an Important Cause of Hereditary Nonpolyposis Colorectal Cancer in the Southern Chinese Population

Hereditary nonpolyposis colorectal cancer (HNPCC) accounts for approximately 2% of all colorectal cancer (CRC) cases and is the most common hereditary CRC syndrome. We have previously reported a high incidence of microsatellite instability (MSI) and germline mismatch repair (MMR) gene mutations in young Hong Kong Chinese with CRC. Ongoing studies at the Hereditary Gastrointestinal Cancer Registry in Hong Kong have revealed a unique germline MSH2 c.1452-1455delAATG mutation that has not been reported in other ethnic groups. Detailed analysis showed that this specific MSH2 mutation constituted 21% of all germline MMR gene mutations and 36% of all MSH2 germline mutations identified. We designed a specific PCR-based diagnostic test on paraffin-embedded tissues and identified this germline mutation in 2 (1.5%) of 138 consecutive patients with early-onset CRC (<46 years of age at diagnosis). Haplotype analysis was performed using 11 microsatellite markers located between D2S391 and D2S123. All 10 families had the same disease haplotype, suggesting a founder effect. These 10 families all originated from the Chinese province of Guangdong, which historically included Hong Kong. It is the most populous of the Chinese provinces, with a population of >93 million. Further analysis suggested that this founder mutation may date back to between 22 and 103 generations ago. The identification of this MSH2 founder mutation has important implications for the design of mutation-detection strategies for the southern Chinese population. Since there were major emigrations from Hong Kong and Guangdong province during the 19th and 20th centuries, this finding is also significant for Chinese communities worldwide.

Medical interventions following natural disasters: missing out on chronic medical needs.

Although natural disasters may cause massive loss of human life and destruction of resources, they also present affected populations with a rare opportunity to access external resources. Nevertheless, many post-disaster medical relief intervention programmes only focus on the provision of acute medical services and the control of communicable diseases. Currently, no specific study has examined why chronic medical needs seem to be insufficiently addressed in disaster relief interventions. This paper review current knowledge about how natural disasters affect peuple with chronic medical needs, assess possible factors in disaster preparedness and response that pre-empt addressing chronic medical needs and suggest possible ways to overcome these barriers. Unawareness and insensitivity of relief workers towards chronic medical conditions, the practice of risk rather than need-based assessments, a focus on acute needs, the lack of reliable indicators and baseline information, and the multidimensional characteristics or chronic medical problems all pose serious challenges and probably deter the government and post-disaster relief agencies to deal with diseases of a chronic nature. It is important to increase the awareness and sensitivity of the stakeholders towards chronic medical problems during all phases of planning and intervention. Relevant assessment tools should be developed to rapidly identify chronic medical needs in resource deficit settings. Community partnership and collaboration that promote local ownership and technical transfer of chronic disease management skills will be essential for the sustainability of services beyond the disaster relief period. Potential programmes might include the technical training of local staff, establishment of essential drug and supply lists, and the provision of a range of medical services that may address chronic health needs. Asia Pac J Public Health 2007; 19(Special Issue): 45–51.