Publications by authors named "Chor-Wing Sing"

26 Publications

  • Page 1 of 1

Comparative Treatment Persistence with Bone-Targeting Agents Among Asian Patients with Bone Metastases from Solid Tumors: A Multinational Retrospective Cohort Study.

BioDrugs 2022 Apr 12. Epub 2022 Apr 12.

School of Pharmacy, Institute of Clinical Pharmacy and Pharmaceutical Sciences, College of Medicine, National Cheng Kung University, No. 1, University Road, Tainan 701, Taiwan.

Background: The efficacy of bone-targeting agents has been confirmed, but the generalizability of results to Asia is in question.

Objective: We aimed to evaluate and compare treatment persistence and re-initiation with different bone-targeting agents among patients with bone metastases from solid tumors.

Methods: This population-based cohort study included patients with bone metastasis with breast, lung, or prostate cancer who initiated bone-targeting agents, including denosumab, zoledronic acid, and pamidronate in Taiwan (2013-17), Hong Kong (2013-17), and Korea (2012-16). We described the patients' persistence with bone-targeting agents, by evaluating the interruption probability, and compared risks of treatment interruption. The rates of re-initiation with index bone-targeting agents were evaluated.

Results: We included 5127 patients (denosumab: 3440, zoledronic acid: 1210, pamidronate: 477) from Taiwan, 883 patients (denosumab: 458, zoledronic acid: 357, pamidronate: 68) from Hong Kong, and 4800 patients (zoledronic acid: 4068, pamidronate: 732) from Korea. Compared with zoledronic acid, denosumab had a lower risk of interruption in Taiwan (adjusted hazard ratio: 0.44; 95% confidence interval 0.40-0.48) and Hong Kong (0.36; 0.28-0.45). However, pamidronate was more likely to be interrupted than zoledronic acid in Taiwan (1.31; 1.11-1.54) and Korea (2.06; 1.83-2.32), but not in Hong Kong (1.13; 0.71-1.78). After discontinuation, original treatments with denosumab in Taiwan and zoledronic acid in Hong Kong were more likely to be resumed, while in Korea, the rates were similar among the bisphosphonates.

Conclusions: Denosumab was associated with a lower risk of interruption than bisphosphonates in patients with bone metastases in Taiwan and Hong Kong. Further investigations may be required to verify patients' actual reasons for discontinuation.
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http://dx.doi.org/10.1007/s40259-022-00528-8DOI Listing
April 2022

Validation of diagnostic coding for interstitial lung diseases in an electronic health record system in Hong Kong.

Pharmacoepidemiol Drug Saf 2022 May 9;31(5):519-523. Epub 2022 Mar 9.

Department of Medicine, The University of Hong Kong, Pokfulam, Hong Kong SAR, China.

Objective: Large electronic medical record (EMR) databases can facilitate epidemiology research into uncommon diseases such as interstitial lung disease (ILD). Given the rarity and diagnostic difficulty of ILD, the validity of the coding in EMR requires clarification. We aimed to assess the validity of International Classification of Diseases, 9th Revision (ICD-9) code algorithms for identifying ILD in the territory-wide electronic medical health record system of Clinical Data Analysis and Reporting System (CDARS) in Hong Kong.

Method: Patients who visited the Queen Mary Hospital in 2005-2018 with ILD were identified using the following ICD-9 codes: post-inflammatory pulmonary fibrosis (PPF; ICD-9: 515), idiopathic fibrosing alveolitis (IFA; ICD-9: 516.3), connective tissue disease-associated interstitial lung disease (CTD-ILD; ICD-9: 517.2, 517.8, 714.81), sarcoidosis (ICD-9: 135) and extrinsic allergic alveolitis (EAA; ICD-9: 495). A random selection was conducted in cases with diagnostic code of PPF and IFA, where a relative higher case number was identified. All the cases of CTD-ILD, sarcoidosis and EAA were included in validation for relatively small case number.

Results: Two hundred and sixty nine cases were validated using medical record review by a respiratory specialist. The overall positive predictive value (PPV) was 79% (95% CI, 74%-84%). In subgroup analysis, true positive case numbers of PPF, IFA, CTD-ILD, sarcoidosis and EAA were 74/100 (74%), 95/100 (95%), 11/15 (73%), 27/32 (84%) and 6/22 (27%), respectively.

Conclusions: This was the first ICD-9 coding validation for ILD in Hong Kong CDARS. Our study demonstrated that using ICD-9 algorithms 515, 516.3, 517.2, 517.8, 714.81 and 135 enhanced identifications of ILDs with PPV that was reliable to support utility of CDARS database for further clinical research on ILDs. The validity is particularly high with 516.3.
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http://dx.doi.org/10.1002/pds.5421DOI Listing
May 2022

Bone-targeting agents in major solid tumour metastases: a multinational cohort study.

BMJ Support Palliat Care 2022 Feb 17. Epub 2022 Feb 17.

School of Pharmacy, Institute of Clinical Pharmacy and Pharmaceutical Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan

Objective: To describe the epidemiology, clinical characteristics and utilisation patterns of bone-targeting agents (BTAs) in patients with bone metastases from breast, prostate and lung cancer.

Methods: This is a multinational retrospective cohort study including patients with three major solid tumours (breast, prostate and lung cancer) and newly initiated on BTAs (ie, denosumab, zoledronic acid and pamidronate). Records were retrieved from nationwide health databases from Hong Kong and Taiwan (HK and TW: 2013-2017) and Korea (KR: 2012-2016). Descriptive analyses included the annual incidence rates of bone metastases and the cumulative incidence curves of BTA initiation. We used Sankey diagrams to visualise the dynamic BTA utilisation patterns.

Results: The annual incidence rate of bone metastases ranged from 3.5% to 4.5% in TW, from 9.6% to 10.3% in HK and from 2.9% to 3.8% in KR. We identified 14.1% (5127), 9.3% (883) and 9.4% (4800) of patients with bone metastases newly initiated on BTAs in TW, HK and KR, respectively. The most frequently used BTA in TW (67.1%) and HK (51.9%) was denosumab, while in KR (84.8%) it was zoledronic acid. Sankey diagrams indicated the proportion of patients remaining on denosumab was highest in TW and HK, while it was zoledronic acid in KR. Specifically, in TW, patients who were on bisphosphonates or had discontinued treatment frequently switched to or reinitiated denosumab.

Conclusions: We found the rate of BTA utilisation remained low across all sites and tumour types in recent years. The dynamic utilisation patterns of BTAs provide better understanding of the treatment landscape for future evaluation of associated outcomes of patients.
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http://dx.doi.org/10.1136/bmjspcare-2021-003062DOI Listing
February 2022

COVID-19 vaccines and risks of hematological abnormalities: Nested case-control and self-controlled case series study.

Am J Hematol 2022 04 9;97(4):470-480. Epub 2022 Feb 9.

Laboratory of Data Discovery for Health (D24H), Hong Kong Science Park, Hong Kong Special Administrative Region, China.

Several studies reported hematological abnormalities after vaccination against the coronavirus disease 2019 (COVID-19). We evaluated the association between COVID-19 vaccines (CoronaVac and BNT162b2) and hematological abnormalities. We conducted nested case-control and self-controlled case series analyses using the data from the Hong Kong Hospital Authority and the Department of Health, HKSAR. Outcomes of interest were thrombocytopenia, leukopenia, and neutropenia. Adjusted odds ratios (aORs), incidence rate ratios (IRRs), and 95% confidence intervals (CIs) were estimated using conditional logistic regression. In total, 1 643 419 people received COVID-19 vaccination (738 609 CoronaVac; 904 810 BNT162b2). We identified 457 and 422 cases after CoronaVac and BNT162b2 vaccination, respectively. For CoronaVac, the incidence of thrombocytopenia, leukopenia, and neutropenia was 2.51, 1.08, and 0.15 per 10 000 doses. For BNT162b2, the corresponding incidence was 1.39, 1.17, and 0.26 per 10 000 doses. The incidence per 10 000 COVID-19 cases were 1254, 2341, and 884, respectively. We only observed an increased risk of leukopenia following the second dose of BNT162b2 (aOR 1.58, 95% CI 1.24-2.02; day 0-14, IRR 2.21; 95% CI 1.59-3.08). There was no increased risk of any hematological abnormalities after CoronaVac vaccination. We observed an increased risk of leukopenia shortly after the second dose of BNT162b2. However, the incidence was much lower than the incidence following severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections. There was no association between CoronaVac and hematological abnormalities. The benefits of vaccination against COVID-19 still outweigh the risk of hematological abnormalities.
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http://dx.doi.org/10.1002/ajh.26478DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9011752PMC
April 2022

Immediate Risk for Cardiovascular Events in Hip Fracture Patients: A Population-Based Cohort Study.

J Gerontol A Biol Sci Med Sci 2021 Nov 8. Epub 2021 Nov 8.

Department of Pharmacology and Pharmacy, The University of Hong Kong, Pokfulam, Hong Kong.

Background: Emerging evidence showed that bone metabolism and cardiovascular diseases (CVD) are closely related. We previously observed a potential immediate risk of cardiovascular mortality after hip fracture. However, whether there is an immediate risk of cardiovascular events after hip fracture is unclear. The aim of this study was to evaluate the risk for major adverse cardiovascular events (MACEs) between patients having experienced falls with and without hip fracture.

Methods: This retrospective population-based cohort study used data from a centralized electronic health record database managed by Hong Kong Hospital Authority. Patients having experienced falls with and without hip fracture were matched by propensity score (PS) at a 1:1 ratio. Adjusted associations between hip fracture and risk of MACEs were evaluated using competing risk regression after accounting for competing risk of death.

Results: Competing risk regression showed that hip fracture was associated with increased one-year risk of MACEs (hazard ratio [HR], 1.27; 95% CI, 1.21 to 1.33; p<0.001), with a 1-year cumulative incidence difference of 2.40% (1.94% to 2.87%). The HR was the highest in the first 90-day after hip fracture (HR of 1.32), and such an estimate was continuously reduced in 180-day, 270-day, and 1-year after hip fracture.

Conclusions: Hip fracture was associated with increased immediate risk of MACEs. This study suggested that a prompt evaluation of MACE among older adults aged 65 years and older who are diagnosed with hip fracture irrespectively of cardiovascular risk factors may be important, as early management may reduce subsequent risk of MACE.
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http://dx.doi.org/10.1093/gerona/glab336DOI Listing
November 2021

Secular trends in fall-related hospitalizations in adolescents, youth and adults: a population-based study.

Lancet Reg Health West Pac 2021 Jul 9;12:100183. Epub 2021 Jun 9.

Department of Pharmacology and Pharmacy, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China.

Background: Falls are one of the major causes of injury globally. However, there is a lack of population-based studies on falls among adolescents, young and middle-aged adults. We therefore aimed to conduct a large-scale population study on the secular trend in incidence of fall-related hospitalization.

Methods: A population-wide electronic database, Hong Kong's Clinical Data Analysis and Reporting System (CDARS), was used in this retrospective cohort study. Patients aged≥10, hospitalized with diagnosis of accidental falls (ICD-9-CM E880-E888) from 2005-2018, were included. Outcome measures included the number, age- and sex-standardized incidence rate of fall-related hospital admissions, their length of stay (LOS) and 1-year all-cause mortality. Linear regression and average annual percentage change (AAPC) using joinpoint regression were computed for trend analysis.

Findings: From 2005 to 2018, a total of 336,439 patients aged≥10 were identified with fall-related hospitalization. Among these fall patients, 33.7% occurred at age<60. The number of fall-related hospital admissions episodes increased significantly by 83.7% during the study period. The standardized incidence rate of falls per 1000 person-years increased from 3.67 (95% CI 3.62-3.72) in 2005 to 4.79 (95% CI 4.74-4.84) in 2018. Although the total hospitalized bed-days increased from 178,723 days in 2005, to 299,273 days in 2018 (+67.5%,p<.0001), the median length of stay per episode of falls decreased from 4.90 days to 3.79 days (p<.0001).

Interpretation: Continuous increase in the incidence of fall-related hospitalization in people aged≥10 was observed. This suggested that falls are a public health issue in all ages. Further studies on the differences in the underlying risk factors and comorbidities between younger and older fall patients are warranted.

Funding: None.
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http://dx.doi.org/10.1016/j.lanwpc.2021.100183DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8356129PMC
July 2021

Global epidemiology of hip fractures: a study protocol using a common analytical platform among multiple countries.

BMJ Open 2021 07 28;11(7):e047258. Epub 2021 Jul 28.

School of Pharmacy, Sungkyunkwan University, Suwon, South Korea.

Introduction: Hip fractures are associated with a high burden of morbidity and mortality. Globally, there is wide variation in the incidence of hip fracture in people aged 50 years and older. Longitudinal and cross-geographical comparisons of health data can provide insights on aetiology, risk factors, and healthcare practices. However, systematic reviews of studies that use different methods and study periods do not permit direct comparison across geographical regions. Thus, the objective of this study is to investigate global secular trends in hip fracture incidence, mortality and use of postfracture pharmacological treatment across Asia, Oceania, North and South America, and Western and Northern Europe using a unified methodology applied to health records.

Methods And Analysis: This retrospective cohort study will use a common protocol and an analytical common data model approach to examine incidence of hip fracture across population-based databases in different geographical regions and healthcare settings. The study period will be from 2005 to 2018 subject to data availability in study sites. Patients aged 50 years and older and hospitalised due to hip fracture during the study period will be included. The primary outcome will be expressed as the annual incidence of hip fracture. Secondary outcomes will be the pharmacological treatment rate and mortality within 12 months following initial hip fracture by year. For the primary outcome, crude and standardised incidence of hip fracture will be reported. Linear regression will be used to test for time trends in the annual incidence. For secondary outcomes, the crude mortality and standardised mortality incidence will be reported.

Ethics And Dissemination: Each participating site will follow the relevant local ethics and regulatory frameworks for study approval. The results of the study will be submitted for peer-reviewed scientific publications and presented at scientific conferences.
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http://dx.doi.org/10.1136/bmjopen-2020-047258DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8319985PMC
July 2021

Treatment with direct oral anticoagulants or warfarin and the risk for incident diabetes among patients with atrial fibrillation: a population-based cohort study.

Cardiovasc Diabetol 2021 03 25;20(1):71. Epub 2021 Mar 25.

Department of Pharmacology and Pharmacy, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong, China.

Background: Diabetes mellitus is a common comorbidity of atrial fibrillation (AF), which can complicate the management of AF. The pharmacology of oral anticoagulants (OACs) have been implicated in pathogenesis of diabetes, but the relationship between different OACs and risk of diabetes remains unexamined. This study aimed to evaluate the risk of diabetes with use of different OACs in AF patients.

Methods: Population-based retrospective cohort study using an electronic healthcare database managed by the Hong Kong Hospital Authority. Patients newly diagnosed with AF from 2014 through 2018 and prescribed OACs were included and followed till December 31, 2019. Inverse probability of treatment weighting based on the propensity score (PS) is used to address potential bias due to nonrandomized allocation of treatment. The risks ofdiabetes were compared between different new OAC users using propensity score-weighted cumulative incidence differences (CID).

Results: There were 13,688 new users of OACs (warfarin: n = 3454; apixaban: n = 3335; dabigatran: n = 4210; rivaroxaban: n = 2689). The mean age was 75.0 (SD, 11.2), and 6,550 (47.9%) were women. After a median follow-up of 0.93 years (interquartile range, 0.21-1.92 years), 698 incident diabetes cases were observed. In Cox-regression analysis, dabigatran use was significantly associated with reduced risk of diabetes when compared with warfarin use [HR 0.69 (95% CI 0.56-0.86; P < 0.001)], with statistically insignificant associations observed for use of apixaban and rivaroxaban. The corresponding adjusted CIDs at 2 years after treatment with apixaban, dabigatran, and rivaroxaban users when compared with warfarin were - 2.06% (95% CI - 4.08 to 0.16%); - 3.06% (95% CI - 4.79 to - 1.15%); and - 1.8% (- 3.62 to 0.23%). In head-to-head comparisons between women DOAC users, dabigatran was also associated with a lower risk of diabetes when compared with apixaban and rivaroxaban.

Conclusions: Among adults with AF receiving OACs, the use of dabigatran had the lowest risk of diabetes when compared with warfarin use.
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http://dx.doi.org/10.1186/s12933-021-01263-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7993481PMC
March 2021

Long-term Outcome of Short-course High-dose Glucocorticoids for Severe Acute Respiratory Syndrome (SARS): A 17-Year Follow-up in SARS Survivors.

Clin Infect Dis 2021 05;72(10):1830-1833

Department of Pharmacology and Pharmacy, University of Hong Kong, Pokfulam, Hong Kong, Special Administrative Region, China.

Use of high-dose glucocorticoids for COVID-19 (caused by SARS-CoV-2) is controversial because of safety concerns. We examined the long-term consequences of glucocorticoid use in severe acute respiratory syndrome (caused by SARS-CoV-1) survivors. Results showed that high-dose glucocorticoids greatly increased the long-term risk of avascular necrosis but not other major diseases.
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http://dx.doi.org/10.1093/cid/ciaa992DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7454482PMC
May 2021

Nitrogen-Containing Bisphosphonates Are Associated With Reduced Risk of Pneumonia in Patients With Hip Fracture.

J Bone Miner Res 2020 09 2;35(9):1676-1684. Epub 2020 Jun 2.

Department of Pharmacology and Pharmacy, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong.

The objective of this work was to study the risk of pneumonia and pneumonia mortality among patients receiving nitrogen-containing bisphosphonates (N-BPs), non-N-BP anti-osteoporosis medications, and no anti-osteoporosis medications after hip fracture. We studied a historical cohort using a population-wide database. Patients with first hip fracture during 2005-2015 were identified and matched by time-dependent propensity score. The cohort was followed until December 31, 2016, to capture any pneumonia and pneumonia mortality. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using Cox-proportional hazards regression. Absolute risk difference (ARD) and number needed to treat (NNT) were calculated. We identified 54,047 patients with hip fracture. Of these, 4041 patients who received N-BPs and 11,802 without anti-osteoporosis medication were propensity score-matched. N-BPs were associated with a significantly lower risk of pneumonia compared with no treatment (6.9 versus 9.0 per 100 person-years; HR 0.76; 95% CI, 0.70 to 0.83), resulting in an ARD of 0.02 and NNT of 46. A similar association was observed with pneumonia mortality (HR 0.65; 95% CI, 0.56 to 0.75). When N-BPs were compared with non-N-BP anti-osteoporosis medications, the association remained significant. N-BPs were associated with lower risks of pneumonia and pneumonia mortality. Randomized controlled trials are now required to determine whether N-BPs, non-vaccine-based medications, can reduce pneumonia incidence in high risk groups. © 2020 American Society for Bone and Mineral Research.
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http://dx.doi.org/10.1002/jbmr.4030DOI Listing
September 2020

Association Between Treatment With Apixaban, Dabigatran, Rivaroxaban, or Warfarin and Risk for Osteoporotic Fractures Among Patients With Atrial Fibrillation: A Population-Based Cohort Study.

Ann Intern Med 2020 07 19;173(1):1-9. Epub 2020 May 19.

UCL School of Pharmacy, London, United Kingdom, Centre for Safe Medication and Practice Research, The University of Hong Kong, Hong Kong, and The University of Hong Kong Shenzhen Hospital, Shenzhen, Guangdong, China (I.C.W.).

Background: It is unclear whether anticoagulant type is associated with the risk for osteoporotic fracture, a deleterious complication of anticoagulants among patients with atrial fibrillation (AF).

Objective: To compare the risk for osteoporotic fracture between anticoagulants.

Design: Population-based cohort study.

Setting: Territory-wide electronic health record database of the Hong Kong Hospital Authority.

Participants: Patients newly diagnosed with AF between 2010 and 2017 who received a new prescription for warfarin or a direct oral anticoagulant (DOAC) (apixaban, dabigatran, or rivaroxaban). Follow-up ended on 31 December 2018.

Measurements: Osteoporotic hip and vertebral fractures in anticoagulant users were compared using propensity score-weighted cumulative incidence differences (CIDs).

Results: There were 23 515 patients identified (3241 apixaban users, 6867 dabigatran users, 3866 rivaroxaban users, and 9541 warfarin users). Overall mean age was 74.4 years (SD, 10.8), ranging from 73.1 years (warfarin) to 77.9 years (apixaban). Over a median follow-up of 423 days, 401 fractures were identified (crude event number [weighted rate per 100 patient-years]: apixaban, 53 [0.82]; dabigatran, 95 [0.76]; rivaroxaban, 57 [0.67]; and warfarin, 196 [1.11]). After 24-month follow-up, DOAC use was associated with a lower risk for fracture than warfarin use (apixaban CID, -0.88% [95% CI, -1.66% to -0.21%]; dabigatran CID, -0.81% [CI, -1.34% to -0.23%]; and rivaroxaban CID, -1.13% [CI, -1.67% to -0.53%]). No differences were seen in all head-to-head comparisons between DOACs at 24 months (apixaban vs. dabigatran CID, -0.06% [CI, -0.69% to 0.49%]; rivaroxaban vs. dabigatran CID, -0.32% [CI, -0.84% to 0.18%]; and rivaroxaban vs. apixaban CID, -0.25% [CI, -0.86% to 0.40%]).

Limitation: Residual confounding is possible.

Conclusion: Among patients with AF, DOAC use may result in a lower risk for osteoporotic fracture compared with warfarin use. Fracture risk does not seem to be altered by the choice of DOAC. These findings may help inform the benefit-risk assessment when choosing between anticoagulants.

Primary Funding Source: The University of Hong Kong and University College London Strategic Partnership Fund.
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http://dx.doi.org/10.7326/M19-3671DOI Listing
July 2020

Serum Metabolome of Coffee Consumption and its Association With Bone Mineral Density: The Hong Kong Osteoporosis Study.

J Clin Endocrinol Metab 2020 03;105(3)

Department of Pharmacology and Pharmacy, the University of Hong Kong, Pokfulam, Hong Kong, China.

Background: Inconsistent associations between coffee consumption and bone mineral density (BMD) have been observed in epidemiological studies. Moreover, the relationship of bioactive components in coffee with BMD has not been studied. The aim of the current study is to identify coffee-associated metabolites and evaluate their association with BMD.

Methods: Two independent cohorts totaling 564 healthy community-dwelling adults from the Hong Kong Osteoporosis Study (HKOS) who visited in 2001-2010 (N = 329) and 2015-2016 (N = 235) were included. Coffee consumption was self-reported in an food frequency questionnaire. Untargeted metabolomic profiling on fasting serum samples was performed using liquid chromatography-mass spectrometry platforms. BMD at lumbar spine and femoral neck was measured by dual-energy X-ray absorptiometry. Multivariable linear regression and robust regression were used for the association analyses.

Results: 12 serum metabolites were positively correlated with coffee consumption after Bonferroni correction for multiple testing (P < 4.87 × 10-5), with quinate, 3-hydroxypyridine sulfate, and trigonelline (N'-methylnicotinate) showing the strongest association. Among these metabolites, 11 known metabolites were previously identified to be associated with coffee intake and 6 of them were related to caffeine metabolism. Habitual coffee intake was positively and significantly associated with BMD at the lumbar spine and femoral neck. The metabolite 5-acetylamino-6-formylamino-3-methyluracil (AFMU) (β = 0.012, SE = 0.005; P = 0.013) was significantly associated with BMD at the lumbar spine, whereas 3-hydroxyhippurate (β = 0.007, SE = 0.003, P = 0.027) and trigonelline (β = 0.007, SE = 0.004; P = 0.043) were significantly associated with BMD at the femoral neck.

Conclusions: 12 metabolites were significantly associated with coffee intake, including 6 caffeine metabolites. Three of them (AFMU, 3-hydroxyhippurate, and trigonelline) were further associated with BMD. These metabolites could be potential biomarkers of coffee consumption and affect bone health.
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http://dx.doi.org/10.1210/clinem/dgz210DOI Listing
March 2020

The lipid-lowering effect of once-daily soya drink fortified with phytosterols in normocholesterolaemic Chinese: a double-blind randomized controlled trial.

Eur J Nutr 2020 Sep 23;59(6):2739-2746. Epub 2019 Oct 23.

Department of Medicine, Faculty of Medicine, Queen Mary Hospital, The University of Hong Kong, 102 Pokfulam Road, Pokfulam, Hong Kong.

Purpose: Phytosterols reduce intestinal cholesterol absorption and help to lower LDL-cholesterol. Many Chinese adults are lactose-intolerant and cannot tolerate bovine milk enriched with phytosterol. Soya-milk is a common beverage in Asia and it has beneficial effects on general health. We therefore conducted a randomized double-blind controlled trial to assess the effectiveness of a phytosterols-enriched soya drink in lowering serum LDL-cholesterol level (primary outcome) and other cardiovascular parameters (secondary outcomes).

Methods: One hundred and fifty-nine normocholesterolaemic participants (85 men and 74 women; aged 19-79) were randomized to daily intake of one serving of phytosterols-enriched soya drink (N = 82), equivalent to 2 g of phytosterol per day, or a matched soya drink without phytosterols (N = 77) for 3 weeks. Adverse events, withdrawal and compliance were documented.

Results: Among the treatment group (N = 82), phytosterols-enriched soya drink significantly decreased LDL-cholesterol by 5.96% (SE 1.48, 95% CI - 8.91%, - 3.00%) with a median of 6.74% compared with baseline, resulting in a significant reduction of 4.70% (95% CI - 8.89%, - 0.51%; p = 0.028) with a median of 5.20% compared with placebo (N = 77). In contrast, there were no significant changes in other lipid parameters, blood glucose, blood pressure, body weight or waist circumference. Remarkably, 95% of the participants randomized to the fortified drink reported no adverse events at all.

Conclusions: Daily consumption of a phytosterols-enriched soya drink may be a simple and cost-neutral means of lowering LDL-cholesterol in individuals in China, with massive population and rising incidence of coronary heart disease (ClinicalTrials.gov identifier: NCT02881658; date of registration: 14 Aug 2016).
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http://dx.doi.org/10.1007/s00394-019-02119-wDOI Listing
September 2020

Development and Validation of a Risk Score to Predict the First Hip Fracture in the Oldest Old: A Retrospective Cohort Study.

J Gerontol A Biol Sci Med Sci 2020 04;75(5):980-986

Department of Pharmacology and Pharmacy, The University of Hong Kong, China.

Background: To evaluate whether the common risk factors and risk scores (FRAX, QFracture, and Garvan) can predict hip fracture in the oldest old (defined as people aged 80 and older) and to develop an oldest-old-specific 10-year hip fracture prediction risk algorithm.

Methods: Subjects aged 80 years and older without history of hip fracture were studied. For the derivation cohort (N = 251, mean age = 83), participants were enrolled with a median follow-up time of 8.9 years. For the validation cohort (N = 599, mean age = 85), outpatients were enrolled with a median follow-up of 2.6 years. A five-factor risk score (the Hong Kong Osteoporosis Study [HKOS] score) for incident hip fracture was derived and validated, and its predictive accuracy was evaluated and compared with other risk scores.

Results: In the derivation cohort, the C-statistics were .65, .61, .65, .76, and .78 for FRAX with bone mineral density (BMD), FRAX without BMD, QFracture, Garvan, and the HKOS score, respectively. The category-less net reclassification index and integrated discrimination improvement of the HKOS score showed a better reclassification of hip fracture than FRAX and QFracture (all p < .001) but not Garvan, while Garvan, but not HKOS score, showed a significant over-estimation in fracture risk (Hosmer-Lemeshow test p < .001). In the validation cohort, the HKOS score had a C-statistic of .81 and a considerable agreement between expected and observed fracture risk in calibration.

Conclusion: The HKOS score can predict 10-year incident hip fracture among the oldest old in Hong Kong. The score may be useful in identifying the oldest old patients at risk of hip fracture in both community-dwelling and hospital settings.
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http://dx.doi.org/10.1093/gerona/glz178DOI Listing
April 2020

Association of Alendronate and Risk of Cardiovascular Events in Patients With Hip Fracture.

J Bone Miner Res 2018 08 9;33(8):1422-1434. Epub 2018 May 9.

Department of Pharmacology and Pharmacy, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong.

The risk of cardiovascular events (CVEs) with alendronate use in real-world hip fracture patients is unknown. This study aimed to investigate the risk of CVE with and without use of alendronate in patients with hip fracture. We conducted a retrospective cohort study using a population-wide database managed by the Hong Kong Hospital Authority. Patients newly diagnosed with hip fracture from 2005 through 2013 were followed until November 6, 2016. Alendronate and other antiosteoporosis medications use during the study period were examined. We matched treated and nontreated patients based on time-dependent propensity score. The risks of cardiovascular mortality, myocardial infarction, and stroke between treatment groups were evaluated using conditional Cox regression stratified by match pairs. To examine the associations over time, outcomes were assessed at 1 year, 3 years, 5 years, and 10 years. Among 34,991 patients with newly diagnosed hip fracture, 4602 (13.2%) received antiosteoporosis treatment during follow-up. Physical functioning or survival prospect was not significantly different between treated and nontreated patients. A total of 4594 treated patients were matched with 13,568 nontreated patients. Results of Cox regression analysis revealed that alendronate was associated with a significantly lower risk of 1-year cardiovascular mortality (HR 0.33; 95% CI, 0.17 to 0.65) and incident myocardial infarction (HR 0.55; 95% CI, 0.34 to 0.89), whereas marginally significant reduction in risk of stroke was observed at 5 years and 10 years (HR at 5 years: 0.82; 95% CI, 0.67 to 1.00; p = 0.049; HR at 10 years: 0.83; 95% CI, 0.69 to 1.01; p = 0.065). The strength of the association declined over time but remained significant. Similar results were observed when all nitrogen-containing bisphosphonates (N-BPs) were analyzed together. These findings were robust in multiple sensitivity analyses. Additional studies in other population samples and randomized clinical trials may be warranted to further understand the relationship between use of various antiosteoporosis medication and risk of CVE in patients with hip fracture. © 2018 American Society for Bone and Mineral Research.
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http://dx.doi.org/10.1002/jbmr.3448DOI Listing
August 2018

Validity of major osteoporotic fracture diagnosis codes in the Clinical Data Analysis and Reporting System in Hong Kong.

Pharmacoepidemiol Drug Saf 2017 Aug 3;26(8):973-976. Epub 2017 Apr 3.

Department of Pharmacology and Pharmacy, The University of Hong Kong, Hong Kong.

Purpose: Large medical record databases facilitate epidemiology research in fracture. However, the validity of fracture in the databases is needed to ensure the reliability of data. We aimed to assess the validity of International Classification of Diseases, 9th Revision (ICD-9) code algorithms for identifying major osteoporotic fracture in the Clinical Data Analysis and Reporting System (CDARS) in Hong Kong.

Methods: The CDARS is a database developed by the Hong Kong Hospital Authority for research purpose. We used ICD-9 code algorithm for identifying major osteoporotic fracture, including vertebral fracture, humerus fracture, forearm/wrist fracture, and hip fracture, in CDARS in 2005-2016. As high positive predictive value (PPV) is critically important in epidemiology research, we sought to determine the PPV of fracture diagnostic code in terms of ICD-9 relative to the radiography imaging and clinical notes. A total of 380 major osteoporotic fracture cases (vertebral fracture: 101 cases; humerus fracture: 81 cases; forearm/wrist fracture: 94 cases; and hip fracture: 104 cases) were randomly selected and validated.

Results: In 380 fracture cases, the overall PPV was 96.8%. In subgroup analysis, PPV of 100% was observed for hip, humerus, and forearm/wrist fractures, whereas PPV of 86% was observed for vertebral fracture.

Conclusions: The use of ICD-9 code algorithm to identify major osteoporotic fracture in CDARS is a valid tool with a very high PPV. However, cautious interpretation is required when the study focuses on incident vertebral fracture. Copyright © 2017 John Wiley & Sons, Ltd.
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http://dx.doi.org/10.1002/pds.4208DOI Listing
August 2017

Association Between Dabigatran vs Warfarin and Risk of Osteoporotic Fractures Among Patients With Nonvalvular Atrial Fibrillation.

JAMA 2017 03;317(11):1151-1158

Department of Pharmacology and Pharmacy, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China8Research Department of Practice and Policy, UCL School of Pharmacy, London, United Kingdom.

Importance: The risk of osteoporotic fracture with dabigatran use in patients with nonvalvular atrial fibrillation (NVAF) is unknown.

Objective: To investigate the risk of osteoporotic fracture with dabigatran vs warfarin in patients with NVAF.

Design, Setting, And Participants: Retrospective cohort study using a population-wide database managed by the Hong Kong Hospital Authority. Patients newly diagnosed with NVAF from 2010 through 2014 and prescribed dabigatran or warfarin were matched by propensity score at a 1:2 ratio with follow-up until July 31, 2016.

Exposures: Dabigatran or warfarin use during the study period.

Main Outcomes And Measures: Risk of osteoporotic hip fracture and vertebral fracture was compared between dabigatran and warfarin users using Poisson regression. The corresponding incidence rate ratio (IRR) and absolute risk difference (ARD) with 95% CIs were calculated.

Results: Among 51 496 patients newly diagnosed with NVAF, 8152 new users of dabigatran (n = 3268) and warfarin (n = 4884) were matched by propensity score (50% women; mean [SD] age, 74 [11] years). Osteoporotic fracture developed in 104 (1.3%) patients during follow-up (32 dabigatran users [1.0%]; 72 warfarin users [1.5%]). Results of Poisson regression analysis showed that dabigatran use was associated with a significantly lower risk of osteoporotic fracture compared with warfarin (0.7 vs 1.1 per 100 person-years; ARD per 100 person-years, -0.68 [95% CI, -0.38 to -0.86]; IRR, 0.38 [95% CI, 0.22 to 0.66]). The association with lower risk was statistically significant in patients with a history of falls, fractures, or both (dabigatran vs warfarin, 1.6 vs 3.6 per 100 person-years; ARD per 100 person-years, -3.15 [95% CI, -2.40 to -3.45]; IRR, 0.12 [95% CI, 0.04 to 0.33]), but not in those without a history (0.6 vs 0.7 per 100 person-years; ARD per 100 person-years, -0.04 [95% CI, 0.67 to -0.39]; IRR, 0.95 [95% CI, 0.45 to 1.96]) (P value for interaction, <.001).

Conclusions And Relevance: Among adults with NVAF receiving anticoagulation, the use of dabigatran compared with warfarin was associated with a lower risk of osteoporotic fracture. Additional study, perhaps including randomized clinical trials, may be warranted to further understand the relationship between use of dabigatran vs warfarin and risk of fracture.
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http://dx.doi.org/10.1001/jama.2017.1363DOI Listing
March 2017

Randomized controlled trial of the effect of phytosterols-enriched low-fat milk on lipid profile in Chinese.

Sci Rep 2017 01 24;7:41084. Epub 2017 Jan 24.

Department of Medicine, University of Hong Kong, Pokfulam, Hong Kong.

Phytosterols found naturally in plants are known to reduce cholesterol absorption in the gut. The traditional southern Chinese diet typically contains many vegetables and not much meat, and there is high prevalence of lactose intolerance in Chinese; we therefore aimed to test if phytosterols-enriched milk is effective in lowering serum LDL-cholesterol in Chinese. Two hundred and twenty-one participants (41 men and 180 women; age 24-79) without cholesterol-lowering drugs or diabetes mellitus were randomized to daily intake of phytosterols-enriched low-fat milk which contained 1.5 g phytosterols per day (N = 110) or a conventional low-fat milk (N = 111) for three weeks. Fasting bloods were taken before and at the end of the study for the measurement of lipid and glucose profile. Physical examination was also performed. Comparing treatment with control, treatment group had significant decrease in serum LDL-cholesterol level (9.5 ± 2.0%; p < 0.0001). Phytosterols intake also decreased total cholesterol (P < 0.0001) and diastolic blood pressure (P = 0.01). Consumption of a phytosterols-enriched low-fat milk led to a significant fall in LDL-cholesterol, total cholesterol, and diastolic blood pressure in Chinese. This can be recommended as part of a healthy diet for people. (ClinicalTrials.gov identifier: NCT02541201; Date of registration: 26 Aug 2015).
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http://dx.doi.org/10.1038/srep41084DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5259797PMC
January 2017

Incidence and risk estimate of drug-induced agranulocytosis in Hong Kong Chinese. A population-based case-control study.

Pharmacoepidemiol Drug Saf 2017 Mar 13;26(3):248-255. Epub 2017 Jan 13.

Department of Pharmacology and Pharmacy, The University of Hong Kong, Hong Kong.

Purpose: Drug-induced agranulocytosis is a rare but life-threatening adverse drug reaction. Its epidemiology in Chinese is largely unknown. This study aimed to estimate the incidence, mortality, and risk of the drugs associated with agranulocytosis in Hong Kong Chinese.

Methods: A population-based case-control study was conducted using the Clinical Data Analysis and Reporting System, a database managed by the Hong Kong Hospital Authority. Patients with drug-induced agranulocytosis from 1 January 2004 to 31 December 2013 were identified. World Health Organization causality assessment was used to evaluate the possible drug aetiology of each case. Odd ratios (ORs) of the drug exposure were calculated using exact conditional logistic regression.

Results: A total of 155 cases of drug-induced agranulocytosis were identified. Mean age was 51.4 years, and 95 cases were female. Incidence rate was estimated to be 2.2 cases per million person-years, and the all-cause mortality of patients with drug-induced agranulocytosis was 3.9%. Among the cases, the most common associated drug groups were antithyroid drugs (41.9%), antimicrobials (20%), anticonvulsants (10.3%), and antipsychotics (6.5%). Carbimazole had the highest risk of agranulocytosis (adjusted OR 416.7, 95% confidence interval (CI) 51.5-3372.9) with an incidence of 9.2 (95%CI 6.9-12.1) per 10 000 users and 3.6 (95%CI 2.7-4.8) per 10 000 user-years. Other drugs with significant risk included cephalosporins, clozapine, penicillins, phenytoin, and propyl thiouracil.

Conclusions: The incidence and mortality in Hong Kong Chinese were relatively low compared to Caucasians. Antithyroid drugs were the most common implicated drug class, and carbimazole had the highest risk of agranulocytosis. Copyright © 2017 John Wiley & Sons, Ltd.
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http://dx.doi.org/10.1002/pds.4156DOI Listing
March 2017

Safety profiles of iron chelators in young patients with haemoglobinopathies.

Eur J Haematol 2017 Mar 19;98(3):198-217. Epub 2017 Jan 19.

Department of Paediatrics and Adolescent Medicine, Faculty of Medicine, Friedrich-Alexander University Erlangen-Nürnberg (FAU), Erlangen, Germany.

Background: This review describes the safety of deferoxamine (DFO), deferiprone (DFP), deferasirox (DFX) and combined therapy in young patients less than 25 yr of age with haemoglobinopathies.

Methods: Searches in electronic literature databases were performed. Studies reporting adverse events associated with iron chelation therapy were included. Study and reporting quality was assessed using AHRQ Risk of Bias Assessment Tool and McMaster Quality Assessment Scale of Harms. Prospective clinical studies were pooled in a random-effects meta-analysis of proportions.

Results: Safety data of 2040 patients from 34 studies were included. Ninety-two case reports of 246 patients were identified. DFX (937 patients) and DFP (667 patients) possess the largest published safety evidence. Fewer studies on combination regimens are available. Increased transaminases were seen in all regimens (3.9-31.3%) and gastrointestinal disorders with DFP and DFX (3.7-18.4% and 5.8-18.8%, respectively). Therapy discontinuations due to adverse events were low (0-4.1%). Reporting quality was selective and poor in most of the studies.

Conclusion: Iron chelation therapy is generally safe in young patients, and published data correspond to summary of product characteristics. Each iron chelation regimen has its specific safety risks. DFO seems not to be associated with serious adverse effects in recommended doses. In DFP and DFX, rare, but serious, adverse reactions can occur. Data on combined therapy are scarce, but it seems equally safe compared to monotherapy.
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http://dx.doi.org/10.1111/ejh.12833DOI Listing
March 2017

Serum 25-hydroxyvitamin D and the risk of stroke in Hong Kong Chinese.

Thromb Haemost 2017 01 27;117(1):158-163. Epub 2016 Oct 27.

Ching-Lung Cheung, PhD, Department of Pharmacology and Pharmacy, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, Tel.: +852 2831 5085, Fax: +852 2816 2095, Email:

Low vitamin D levels have been associated with various cardiovascular diseases; however, whether it is associated with stroke remains inconclusive. We aimed to evaluate the association between serum 25-hydroxyvitamin D and risk of stroke. We conducted a cohort study consisting of 3,458 participants from the Hong Kong Osteoporosis Study aged ≥45 at baseline, examined between 1995 and 2010 and followed up using electronic medical records. Ischaemic and haemorrhagic stroke were defined using the ICD-9 code. In multivariable Cox-proportional hazard regression, quintiles 1 and 4 were significantly associated with increased risk of stroke when compared to the highest quintile (Quintile 1: HR, 1.78; 95 % CI, 1.16-2.74 and quintile 4: HR, 1.61; 95 % CI, 1.07-2.43). A similar association was observed in both men and women. In subgroup analysis, the association was specifically observed for ischaemic stroke, but not haemorrhagic stroke. Using a penalized regression spline, the association between vitamin D and risk of stroke was in a reverse J-shape, with the lowest risk of stroke being observed at 25(OH)D levels between 70 and 80 nmol/l. In conclusion, a low vitamin D level is associated with increased risk of ischaemic stroke; however, whether high vitamin D level is also associated with increased risk of stroke requires further study.
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http://dx.doi.org/10.1160/TH16-07-0551DOI Listing
January 2017

Pharmacogenomics--how close/far are we to practising individualized medicine for children?

Br J Clin Pharmacol 2015 Mar;79(3):419-28

The translation of pharmacogenomics into clinical practice is a key approach for practising individualized medicine, which aims to maximize drug efficacy and minimize drug toxicity. Since the completion of both the Human Genome Project and the International HapMap project, the development of pharmacogenomics has been greatly facilitated. However, progress in translating pharmacogenomics into clinical practice, especially in paediatric medicine, is unexpectedly slow. Many challenges from different areas remain. This paper discusses the existing applications and the limitations to the implementation of paediatric pharmacogenomics, as well as possible solutions for overcoming these limitations and challenges.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4345952PMC
http://dx.doi.org/10.1111/bcp.12338DOI Listing
March 2015

Adverse drug reactions - examples of detection of rare events using databases.

Br J Clin Pharmacol 2015 Oct 1;80(4):855-61. Epub 2015 Jun 1.

Centre for Safe Medication Practice and Research, Department of Pharmacology and Pharmacy, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China.

It is recognised that randomised controlled trials are not feasible for capturing rare adverse events. There is an increasing trend towards observational research methodologies using large population-based health databases. These databases offer more scope for adequate sample sizes, allowing for comprehensive patient characterisation and assessment of the associated factors. While direct causality cannot be established and confounders cannot be ignored, databases present an opportunity to explore and quantify rare events. The use of databases for the detection of rare adverse events in the following conditions, sudden death associated with attention deficit hyperactivity disorder (ADHD) treatment, retinal detachment associated with the use of fluoroquinolones and toxic epidermal necrolysis associated with drug exposure, are discussed as examples. In general, rare adverse events tend to have immediate and important clinical implications and may be life-threatening. An understanding of the causative factors is therefore important, in addition to the research methodologies and database platforms that enable the undertaking of the research.
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http://dx.doi.org/10.1111/bcp.12474DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4594728PMC
October 2015

Vitamin K intake and mortality in people with chronic kidney disease from NHANES III.

Clin Nutr 2015 Apr 2;34(2):235-40. Epub 2014 Apr 2.

Department of Pharmacology and Pharmacy, The University of Hong Kong, Pokfulam, Hong Kong, China; Centre for Safe Medication Practice and Research, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong, China. Electronic address:

Background & Aims: Cardiovascular disease (CVD) is the leading cause of death in patients with chronic kidney disease (CKD), partly due to increased vascular calcification. Vitamin K plays a role in preventing vascular calcification in CKD yet the relationship between vitamin K intake and mortality in CKD patients remains unclear.

Methods: This observational cohort study included 3401 participants with CKD from the Third National Health and Nutrition Examination Survey. Vitamin K intake was estimated from 24-h dietary recalls (1988-94). Mortality was determined from the National Death Index records through 2006. Cox-proportional hazards regression was used to estimate Hazard Ratios (HR) by comparing those with adequate intake of vitamin K to those with low intake, adjusting for advanced CKD covariates. For sensitivity analysis, these associations were also examined among those with different renal status.

Results: During a median follow-up of 13.3 years (37,408 person-years), 1815 and 876 participants died from all-cause and CVD causes, respectively. 72% of the participants had vitamin K intake lower than the recommended adequate intake. Participants with vitamin K intake higher than recommended adequate intake for vitamin K were associated with lower risk of all-cause (HR = 0.85; 95%: 0.72-1; P = 0.047) and CVD mortality (HR = 0.78; 95%: 0.64-95; P = 0.016). Sensitivity analyses in subgroups with advanced CKD revealed similar findings.

Conclusions: This observational study suggests that adequate intake of vitamin K may be associated with reduced all-cause and CVD mortality in CKD patients. However, vitamin K may be a marker of a healthy diet; therefore clinical trials may help in clarifying the effect of vitamin K independent of a healthy diet.
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http://dx.doi.org/10.1016/j.clnu.2014.03.011DOI Listing
April 2015

Differential expression of type 2 3α/type 5 17β-hydroxysteroid dehydrogenase (AKR1C3) in tumors of the central nervous system.

Int J Clin Exp Pathol 2010 Mar 25;3(8):743-54. Epub 2010 Mar 25.

College of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA.

Human aldo-keto reductase (AKR) 1C3, type 2 3α-hydroxysteroid dehydrogenase (HSC)/ type 5 17β-HSD, is known to be involved in steroids, prostaglandins, and lipid aldehydes metabolism. The expression of AKR1C3 has been demonstrated in hormone-dependent normal tissues such as breast, endometrium, prostate, and testis; and de -regulated AKR1C3 expression has been shown in breast carcinoma, endometrial hyperplasia, endometrial carcinoma, and prostate carcinoma. AKR1C3 expression has also been demonstrated in hormone-independent normal tissues (renal tubules and urothelium) and neoplastic tissues (renal cell carcinoma, Wilm's tumor, and urothelial cell carcinoma). Extensive expression of AKR1C3 in normal and neoplastic as well as hormone-dependent and hormone-independent tissues indicates that AKR1C3 may have functions beyond steroid hormone metabolism. In this report, we describe a widespread expression of AKR1C3 in glial neoplasms and meningiomas, with limited expression in medulloblastoma and no expression in Schwannoma. These tumors, except meningioma, are not classically considered to be sex hormone-dependent or related brain tumors. The current results corroborate our earlier observations that AKR1C3 is expressed in both sex hormone-dependent and hormone-independent malignancies. Similar to AKR1C3 distribution in Wilm's tumor, we also demonstrate that expression of AKR1C3 is reduced in tumors with embryonic phenotypes.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2993224PMC
March 2010
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