Consensus on precision medicine for metastatic cancers: a report from the MAP conference.

Recent advances in biotechnologies have led to the development of multiplex genomic and proteomic analyses for clinical use. Nevertheless, guidelines are currently lacking to determine which molecular assays should be implemented in metastatic cancers. The first MAP conference was dedicated to exploring the use of genomics to better select therapies in the treatment of metastatic cancers. Sixteen consensus items were covered. There was a consensus that new technologies like next-generation sequencing of tumors and ddPCR on circulating free DNA have convincing analytical validity. Further work needs to be undertaken to establish the clinical utility of liquid biopsies and the added clinical value of expanding from individual gene tests into large gene panels. Experts agreed that standardized bioinformatics methods for biological interpretation of genomic data are needed and that precision medicine trials should be stratified based on the level of evidence available for the genomic alterations identified.

Bioaccumulation of heavy metals in fish and Ardeid at Pearl River Estuary, China.

Sediment, fish (tilapia, Oreochromis mossambicus and snakehead, Channa asiatica), eggs and eggshells of Little Egrets (Egretta garzetta) and Chinese Pond Herons (Ardeola bacchus) were collected from Mai Po Ramsar site of Hong Kong, as well as from wetlands in the Gu Cheng County, Shang Hu County and Dafeng Milu National Nature Reserve of Jiangsu Province, China between 2004 and 2007 (n=3-9). Concentrations of six heavy metals were analyzed, based on inductively coupled plasma optical emission spectrometry (ICP-OES). Significant bioaccumulations of Cd (BAF: 165-1271 percent) were observed in the muscle and viscera of large tilapia and snakehead, suggesting potential health risks to the two bird species, as the fishes are the main preys of waterbirds. Significant (p<0.01) linear relationships were obtained between concentrations of Cd, Cr, Cu, Mn, Pb and Zn in the eggs and eggshells of various Ardeid species, and these regression models were used to extrapolate the heavy metal concentrations in the Ardeid eggs of Mai Po. Extrapolated concentrations are consistent with data in the available literature, and advocate the potential use of these models as a non-invasive sampling method for predicting heavy metal contamination in Ardeid eggs.

Role of gender disparity of circulating high-sensitivity C-reactive protein concentrations and obesity on asthma in Taiwan.

BACKGROUND: Several studies have suggested that the association between obesity and asthma may be stronger in females than in males, but the reason is still unclear. OBJECTIVE: The aim of this study was to investigate whether differences in high-sensitivity C-reactive protein (hs-CRP) levels explain why obesity is associated with asthma in females but not in males. METHODS: This study prospectively enrolled 754 subjects ≥ 18 years old from hospital-based asthma patients and population-based controls. We measured adiposity factors [body mass index (BMI), waist circumference and waist-hip ratio], hs-CRP and total IgE levels. RESULTS: After adjusting for potential confounding factors, we found a significant association between BMI and asthma in females with a significant interaction of gender and BMI on asthma (χ(2) =10.2, P=0.004). If hs-CRP was added to the logistic model, the interaction was attenuated but still significant (χ(2) =7.02, P=0.03). After adjusting for BMI, we did not find that circulating hs-CRP concentrations were significantly associated with asthma in males and females. CONCLUSION: We found that BMI was associated with asthma in females, but our results do not support the suggestion that hs-CRP levels contribute significantly to the link between obesity and asthma with respect to gender disparity.

Use of nutritional health supplements and associated factors among parents with children at kindergartens in Hong Kong.

OBJECTIVES. To estimate the prevalence of so-called nutritional health supplement consumption among kindergarten children; secondarily to explore potential factors associated with such consumption. DESIGN. Cross-sectional, self-administered questionnaire survey. SETTING. One kindergarten each in Hong Kong island, Kowloon, and the New Territories region. SUBJECTS. Parents who had a child studying at the three sampled kindergartens in April 2010. RESULTS. Of 951 sets of parents, 730 (77%) responded. Approximately 52% (95% confidence interval, 47-58%) of the respondents gave regular health supplements to their child. The commonest type of supplement given was cod fish oil (69%). Approximately 36% of the respondents did not know the upper limit dosage of their supplement. Parents of only 66% of regular health supplements consumers, compared to 75% of non-regular users, knew that there was an inherent risk from over-consumption (P=0.018). Parental beliefs that "It is useful/important for normal child development" (adjusted odds ratio=1.93; 95% confidence interval, 1.18-3.16; P=0.009), "It is useful/important for immune function" (1.79; 1.05-3.05; P=0.032) were associated with consumption of health such supplements. CONCLUSION. There is high rate of health supplement consumption among healthy kindergarten children in Hong Kong. There are wrong beliefs from parents that health supplements are important for normal-growing children for their normal growth and body immunity. About one-third of parents has limited knowledge on potential side-effects of overdose and do not know the limit of consumption. Education on "Less (health supplement) is more (health)" is recommended.

Ecotoxicological study on sediments of Mai Po marshes, Hong Kong using organisms and biomarkers.

Sediments from Mai Po Ramsar site, Hong Kong were in general shown to be highly toxic based on the results of four toxicity tests (Microtox solid-phase test, Daphnia mortality test, algal [Microcystis aeruginosa] growth inhibition test and ryegrass [Lolium perenne] seed germination/root elongation test). Sediment of the mudflat (which is open to Deep Bay, i.e., the pollution source) was the most toxic while sediment of gei wai 24g (an enclosed freshwater pond) was the least toxic. Results of biomarker studies (tilapia hepatic metallothionein; glutathione (GSH) and EROD activity using H4IIE rat hepatoma cell) were also concordant with those in the toxicity tests. Significant liner relationships (p<0.01) were found between GSH contents in the rat hepatoma cells and PAHs, OCPs contents in the sediment extracts. It is recommended that the present suite of bioassays is useful and is biologically relevant for future ecotoxicological studies focusing on similar wetlands.

Risk assessment of residual DDTs in freshwater and marine fish cultivated around the Pearl River Delta, China.

Six species of freshwater fish collected from 10 fishponds in Shunde and Zhongshan, China, four species of marine fishes collected from different mariculture farms [four in Hong Kong (Tung Lung Chau, Ma Wan, Cheung Chau and Kat O) and two in mainland China (Daya Bay and Shenzhen)] together with feed (both trash fish and commercial pellets) and sediment were analyzed for DDTs. Total DDTs in freshwater fish flesh decreased in the order of: carnivores [1742 microg/kg lipid weight (l.w.)] > herbivores (165 microg/kg, l.w.) > omnivores (42.5 microg/kg, l.w.), with the highest concentration detected in mandarin fish (Siniperca chuatsi) (2641 microg/kg, l.w.). For marine fish, snubnose pompano (Trachinotus blochii) and orange-spotted grouper (Epinephelus coioides) collected in Ma Wan contained elevated levels of total DDTs (2590 and 2034 microg/kg l.w., respectively). Trash fish used in both freshwater and marine fish farms contained significantly higher levels (86.5-641 microg/kg l.w.) (p < 0.05) of DDTs than in commercial pellets, but correlations between DDT levels in fish feed and muscle were not significant. The elevated biota-sediment accumulating factor for tilapia (Tilapia mossambicus) (24.1) indicated that accumulation of DDTs from sediment to the fish was evident. It can be concluded that trash fish should not be used for fish culture in order to lower the level of residual DDTs in fish muscle.

Outbreak of intestinal infection due to Rhizopus microsporus.

Sinopulmonary and rhinocerebral zygomycosis has been increasingly found in patients with hematological malignancies and bone marrow transplantation, but intestinal zygomycosis remains very rare in the literature. We investigated an outbreak of intestinal infection due to Rhizopus microsporus in 12 patients on treatment for hematological malignancies over a period of 6 months in a teaching hospital. The intake of allopurinol during hospitalization (P < 0.001) and that of commercially packaged ready-to-eat food items in the preceding 2 weeks (P < 0.001) were found to be independently significant risk factors for the development of intestinal zygomycosis. A total of 709 specimens, including 378 environmental and air samples, 181 food samples, and 150 drug samples, were taken for fungal culture. Among them, 16 samples of allopurinol tablets, 3 prepackaged ready-to-eat food items, and 1 pair of wooden chopsticks were positive for Rhizopus microsporus, which was confirmed by ITS1-5.8S-ITS2 rRNA gene cluster (internal transcribed spacer [ITS]) sequencing. The mean viable fungal counts of allopurinol obtained from wards and pharmacy were 4.22 x 10(3) CFU/g of tablet (range, 3.07 x 10(3) to 5.48 x 10(3)) and 3.24 x 10(3) CFU/g of tablet (range, 2.68 x 10(3) to 3.72 x 10(3)), respectively, which were much higher than the mean count of 2 x 10(2) CFU/g of food. Phylogenetic analysis by ITS sequencing showed multiple clones from isolates of contaminated allopurinol tablets and ready-to-eat food, of which some were identical to patients' isolates, and with one isolate in the cornstarch used as an excipient for manufacture of this drug. We attempted to type the isolates by random amplification of polymorphic DNA analysis, with limited evidence of clonal distribution. The primary source of the contaminating fungus was likely to be the cornstarch used in the manufacturing of allopurinol tablets or ready-to-eat food. Rhizopus microsporus is thermotolerant and can multiply even at 50 degrees C. The long holding time of the intermediates during the manufacturing process of allopurinol amplified the fungal load. Microbiological monitoring of drugs manufactured for highly immunosuppressed patients should be considered.

The use of complementary non-destructive evaluation methods to evaluate the integrity of the cement-bone interface.

The integrity of the cement-bone interface is vital to the long-term stability of cemented hip arthroplasty. Most of the previous studies investigating the interface have been confined to the continuum level, neglecting the effects of microstructure. Microscopic damage at the interface may eventually lead to macroscopic loosening of the implant. However, as the strength of the interface depends on the interlock of the cement with bone and because the properties of cancellous bone depend on its microstructure, the study of the behaviour of the interface at the microstructural level may help to gain an understanding of the factors governing initiation of loosening. In this study, two complementary non-destructive methods, acoustic emission (AE) and computed tomography (CT), have been implemented to study the initiation and progression of damage of an analogue cement-bone interface sample under four-point bending. Early failure was detected, localized, and characterized using AE. CT images of the sample before and after loading were used to visualize damage in three dimensions. Damage initiated at the interface and was found to be related to stress-raising microstructural features in the cement. These were caused by irregularities in the geometry of the bone analogue and recesses and notches formed by the flow of cement.

Asia Pacific consensus recommendations for colorectal cancer screening.

Colorectal cancer (CRC) is rapidly increasing in Asia, but screening guidelines are lacking. Through reviewing the literature and regional data, and using the modified Delphi process, the Asia Pacific Working Group on Colorectal Cancer and international experts launch consensus recommendations aiming to improve the awareness of healthcare providers of the changing epidemiology and screening tests available. The incidence, anatomical distribution and mortality of CRC among Asian populations are not different compared with Western countries. There is a trend of proximal migration of colonic polyps. Flat or depressed lesions are not uncommon. Screening for CRC should be started at the age of 50 years. Male gender, smoking, obesity and family history are risk factors for colorectal neoplasia. Faecal occult blood test (FOBT, guaiac-based and immunochemical tests), flexible sigmoidoscopy and colonoscopy are recommended for CRC screening. Double-contrast barium enema and CT colonography are not preferred. In resource-limited countries, FOBT is the first choice for CRC screening. Polyps 5-9 mm in diameter should be removed endoscopically and, following a negative colonoscopy, a repeat examination should be performed in 10 years. Screening for CRC should be a national health priority in most Asian countries. Studies on barriers to CRC screening, education for the public and engagement of primary care physicians should be undertaken. There is no consensus on whether nurses should be trained to perform endoscopic procedures for screening of colorectal neoplasia.

Modulation of ozone-induced airway hyperresponsiveness and inflammation by interleukin-13.

The present study aimed to determine whether the T-helper cell type 2-derived cytokines, interleukin (IL)-4 and -13, can modulate the lung response to ozone exposure. IL-13(-/-), IL-4/13(-/-) and IL-13-overexpressing transgenic (Tg) mice were exposed to ozone (3 ppm; 3 h) or air. Wild-type (Wt) Balb/c mice and transgenic-negative littermates (IL-13Wt) were used as controls for gene-deficient and IL-13Tg mice, respectively. IL-4/13(-/-) and IL-13(-/-) mice developed a lesser degree of ozone-induced airway hyperresponsiveness (AHR) while IL-13Tg mice developed a greater degree of AHR compared with ozone-exposed wild-type or IL-13Wt mice, respectively. Ozone caused a time-dependent increase of bronchoalveolar lavage (BAL) neutrophils and macrophages in wild-type mice, maximal at 20-24 h, which was attenuated in the IL-13(-/-) and IL-4/13(-/-) mice. In IL-13Tg mice, there was a greater increase in BAL neutrophils after ozone exposure compared with IL-13Wt mice. Using quantitative real-time PCR, ozone-induced mRNA expression for IL-6 and keratinocyte chemokine was further enhanced in IL-13(-/-) and IL-4/13(-/-) mice, and was inhibited in IL-13Tg mice. Macrophage inflammatory protein (MIP)-3alpha/CCL20 expression was enhanced after ozone exposure in wild-type mice, inhibited in IL-13(-/-) and IL-4/13(-/-) mice, while in IL-13Tg mice it was enhanced. A similar pattern of expression was observed with lipopolysaccharide-induced cytokine (LIX/CXCL5/ENA-78) expression. In conclusion, interleukin-13 augments ozone-induced airway hyperresponsiveness and neutrophilic inflammation, possibly through modulation of certain cytokines induced by ozone exposure.

Smooth surface micro finite element modelling of a cancellous bone analogue material.

Tetrahedral finite element meshes with smooth surfaces can be created from computed tomography scans of cancellous bone in order to evaluate its mechanical properties. Image processing before creation of the mesh can affect the accuracy of determined mechanical properties. For a cancellous bone analogue, threshold, mesh density and surface smoothing parameters used in mesh generation were varied and the mechanical properties predicted by the resulting meshes were compared to experimental results. This study has shown that threshold selection is vital for accurate determination of volume fraction and resulting mechanical properties.

Derivation of V function for LR 115 SSNTD from its partial sensitivity to 222Rn and its short-lived progeny.

Solid-state nuclear track detectors (SSNTDs) have been widely applied for measurements of environmental concentrations of 222Rn and its progeny. The V function for an SSNTD is important for understanding the track development in the SSNTD as well as for real life applications. The partial sensitivity rhoi of the LR 115 detector applied in the bare mode to 222Rn and its short-lived progeny is related to the equilibrium factor F through the proxy equilibrium factor Fp. On the other hand, rhoi is also dependent on the removed active layer thickness during chemical etching, which is related to the V function for the LR 115 detector. In the present paper, the experimentally obtained rhoi values of the LR 115 detector for different removed active layer thickness are used to derive the V function for the LR 115 SSNTD, which took the form of the Durrani--Green's function, i.e., [formula: see text] , with the best-fitted constants as a1=14.23; a2=0.48; a3=5.9 and a4=0.077 (a5=1).

Derivation of V function for LR 115 SSNTD from its sensitivity to 220Rn in a diffusion chamber.

The sensitivity of the LR 115 detector inside a diffusion chamber to (220)Rn gas concentration is dependent on the removed active layer thickness during chemical etching. This dependence is related to the V function for the LR 115 detector (where V is the ratio between the track etch velocity V(t) and the bulk etch velocity V(b)) and the geometry of the diffusion chamber. The present paper presents the experimentally determined relationship between the sensitivity of the LR 115 detector inside a Karlsruhe diffusion chamber (determined from the number of etched tracks completely penetrating the active cellulose nitrate layer) and the removed active layer thickness. These data were used to derive the V function for the LR 115 detector, which took the functional form of the Durrani-Green's function, i.e., V=1+((a1e-)(a2R+a3e(-a)4R))(1(-e)(-a5R)), with the best-fitted constants as a(1)=14.50, a(2)=0.50, a(3)=3.9 and a(4)=0.066.

Frequent microsatellite instability and mismatch repair gene mutations in young Chinese patients with colorectal cancer.

BACKGROUND: The incidence of colorectal cancer in persons under 46 years of age is substantially higher in Hong Kong than in Scotland and many other countries. Consequently, we examined whether there is a hereditary predisposition for colorectal cancer in this Southern Chinese population. METHODS: We investigated the incidence of microsatellite instability (MSI) at 10 DNA sites in 117 colorectal cancer specimens from Chinese patients of various ages. Those tumors with new alleles at 40% or more of the sites investigated were identified as highly unstable MSI (MSI-H). In young patients, we also searched for germline mutations in three mismatch repair genes (hMSH2, hMLH1, and hMSH6). RESULTS: The incidence of MSI-H varied statistically significantly with age, being observed in more than 60% of those younger than age 31 years at diagnosis and in fewer than 15% of those age 46 years or older. In 15 patients (<46 years old) whose colorectal cancers showed MSI-H, eight possessed germline mutations in either hMSH2 or hMLH1. When mutations in hMSH6 were included, more than 80% of Chinese colorectal cancer patients younger than 31 years had germline mutations in mismatch repair genes. We found a novel germline missense mutation in hMSH6 in a 29-year-old man whose tumor showed no MSI. Two patients had a 4-base-pair insertion in exon 10 causing a truncated protein; this insertion is a common polymorphism with a population allele frequency in Chinese of 5.6%. CONCLUSIONS: Our results indicate that germline mutations in mismatch repair genes contribute substantially to the pathogenesis and high incidence of colorectal cancer in young Hong Kong Chinese. However, because young Chinese and Caucasians show similar proportions of colorectal cancers with MSI-H, despite the higher incidence in the former, additional factors may underlie the high susceptibility of young Chinese to colorectal cancer.

Intrarectal administration of lidocaine gel versus plain lubricant gel for pain control during transrectal ultrasound-guided extensive 10-core prostate biopsy in Hong Kong Chinese population: prospective double-blind randomised controlled trial.

OBJECTIVE: To compare the level of pain experienced by patients during transrectal ultrasound-guided prostatic biopsy using intrarectal 2% lidocaine gel versus plain lubricant gel. DESIGN: Prospective double-blind randomised controlled trial. SETTING: Regional hospital, Hong Kong. PATIENTS: From March 2002 to December 2003, patients who underwent ultrasound-guided prostate biopsy at a Geriatric Urology Centre. MAIN OUTCOME MEASURES: Pain and discomfort scores measured by horizontal visual analogue scales. RESULTS: A total of 338 consecutive patients were randomised to lidocaine gel or plain lubricant gel groups. The two groups were statistically similar in demographic and disease characteristics. There were no significant statistical differences in pain or discomfort score in the lidocaine gel and plain lubricant groups--pain score: 1.75 versus 1.79 (P=0.66) on day 0 and 0.21 versus 0.15 (P=0.97) on day 1; discomfort score: 0.79 versus 0.77 (P=0.86) on day 0 and 0.12 versus 0.12 (P=0.76) on day 1. No major complications were recorded in this cohort. CONCLUSIONS: Transrectal ultrasound-guided trucut biopsy of the prostate can be safely performed with no anaesthesia in Chinese patients. Pain and discomfort are minimal. It was found that 2% lidocaine gel has no statistical therapeutic or analgesic benefit over plain lubricant gel.

Obstructive sleep apnoea in children with Down syndrome.

INTRODUCTION: Children with Down syndrome (DS) are prone to develop obstructive sleep apnoea (OSA) for a combination of reasons, including small upper airway, midfacial hypoplasia, micrognathia and muscular hypotonia. The objective of this study was to compare the prevalence of OSA in DS children, with or without snoring, with snoring children matched for gender, age and weight for height. METHODS: DS children were prospectively recruited from the Hong Kong Down Syndrome Association. All recruited DS children underwent a sleep polysomnography (PSG) in our sleep laboratory. The same number of patients without DS who underwent sleep PSG in the same period were enrolled as controls after they were matched for gender, age and weight for height. OSA was defined as apnoea-hypopnoea index (AHI) greater than 1.5. RESULTS: 22 DS patients and 22 snoring controls completed the overnight PSG. The mean age of DS children and snoring controls was 10.82 +/- 5.93 and 10.27 +/- 5.68 years, respectively. The prevalence of OSA was 59 percent in DS children and 32 percent in snoring controls. Median and interquartile range (IQR) of AHI of DS children (median 1.80, IQR is 0.40 to 7.10) were significantly higher than those of controls (median 0.50, IQR is 0.00 to 2.03, p-value equals 0.041). Out of 13 DS children with OSA, eight of them (61.5 percent) had no habitual snoring. CONCLUSION: 59 percent of DS children in the current series were found to have OSA and they were more likely to develop OSA than controls. Nearly 40 percent of DS children with OSA did not have habitual snoring.

hMLH1 promoter methylation and lack of hMLH1 expression in sporadic gastric carcinomas with high-frequency microsatellite instability.

Mutation of DNA mismatch repair genes has rarely been documented in sporadic gastric carcinoma with microsatellite instability (MSI). In sporadic colorectal carcinoma, hMLH1 promoter methylation associated with protein loss is found in the majority of high-frequency MSI cases. We investigated a series of 35 sporadic gastric carcinomas stratified into high-frequency MSI (MSI-H), low-frequency MSI (MSI-L) and microsatellite stable (MSS) groups and found that hypermethylation of the CpG island in the hMLH1 promoter region was present in 100% of MSI-H sporadic gastric carcinomas. In 90% of cases, there was an associated complete loss of hMLH1 protein, as detected by immunohistochemistry, and a markedly lowered hMLH1 mRNA level. This loss of hMLH1 protein occurred in the MSI-H invasive tumor but not in the adjacent carcinoma-in situ or dysplastic components that were MSS. The MSI-L and MSS forms of gastric carcinoma all showed predominantly unmethylated hMLH1 promoter, positive hMLH1 protein and high hMLH1 mRNA level. On the other hand, hMSH2 protein was expressed in all of the tumors irrespective of the MSI status. Our results suggest that high-frequency MSI in sporadic gastric cancer is mostly due to epigenetic inactivation of hMLH1 in association with promoter methylation, and the loss of hMLH1 protein is a significant event in the development of invasive tumor.

A novel germline 1.8-kb deletion of hMLH1 mimicking alternative splicing: a founder mutation in the Chinese population.

We have previously reported that there is a high incidence of microsatellite instability (MSI) and germline mismatch repair gene mutation in colorectal cancer arising from young Hong Kong Chinese. Most of the germline mutations involve hMSH2, which is different from the mutation spectrum in the Western population. It is well known that alternative splicing is common in hMLH1, which complicates RNA based mutation detection methods. In contrast, large deletions in hMLH1, commonly observed in some ethnic groups, tend to escape detection by exon-by-exon direct DNA sequencing. Here we report the detection of a novel germline 1.8 kb deletion involving exon 11 of hMLH1 in a local hereditary non-polyposis colorectal cancer family. This mutation generates a mRNA transcript with deletion of exons 10-11, which is indistinguishable from one of the most common and predominant hMLH1 splice variants. A diagnostic test based on PCR of the breakpoint region led to the identification of an additional young colorectal cancer patient with this mutation. Haplotype analysis suggests that they may share a common ancestral mutation. Our results caution investigators in the interpretation of alternative splicing and have important implications for the design of hMLH1 mutation detection strategy in the Chinese population.