J.L. Tang

PIK3CA exon 20 mutations as a potential biomarker for resistance to anti-EGFR monoclonal antibodies in KRAS wild-type metastatic colorectal cancer: a systematic review and meta-analysis

BACKGROUNDnWe conducted a systematic review and meta-analysis to dissect the association between PIK3CA mutations and resistance to anti-epidermal growth factor receptor (EGFR) monoclonal antibodies (MoAbs) according to PIK3CA exon of mutations in metastatic colorectal cancer (mCRC).nnnMETHODSnWe systematically identified studies exploring the association between PIK3CA mutations and clinical outcomes of mCRC patients treated with anti-EGFR MoAbs. The primary clinical outcomes included objective response rate (ORR), progression-free survival (PFS), and overall survival (OS). The pooled relative risk (RR) or hazard ratio (HR) was estimated by using fixed effect model or random effect model according to heterogeneity between studies.nnnRESULTSnThirteen studies were considered eligible, with 576 mCRC patients included. In KRAS wild-type mCRC patients, we observed a lower ORR in patients with PIK3CA exon 20 mutations [3 studies, 377 patients; ORR = 0% versus 37%; RR = 0.25; 95% confidence interval (CI) 0.05-1.19; P = 0.082], although the result was not statistically significant because of the small sample size. Only one study provided survival data according to the PIK3CA exon of the mutations, in which PIK3CA exon 20 mutations were statistically significantly associated with shorter PFS (HR = 2.52; 95% CI 1.33-4.78; P = 0.013) and OS (HR = 3.29; 95% CI 1.60-6.74; P = 0.006) in KRAS wild-type mCRC patients treated with anti-EGFR MoAbs. The predictive power of exon 20 mutation is greater than exon 9 mutations and all exons mutations in terms of ORR, PFS, and OS.nnnCONCLUSIONnThese analyses suggest that PIK3CA exon 20 mutations may be a potential biomarker for resistance to anti-EGFR MoAbs in KRAS wild-type mCRC.

KRAS, BRAF and PIK3CA Mutations and the Loss of PTEN Expression in Chinese Patients with Colorectal Cancer

BACKGROUNDnTo investigate the frequency and relationship of the KRAS, BRAF and PIK3CA mutations and the loss of PTEN expression in Chinese patients with colorectal cancer (CRC).nnnMETHODOLOGY/PRINCIPAL FINDINGSnGenomic DNA was extracted from the formalin-fixed paraffin-embedded (FFPE) tissues of 69 patients with histologically confirmed CRC. Automated sequencing analysis was conducted to detect mutations in the KRAS (codons 12, 13, and 14), BRAF (codon 600) and PIK3CA (codons 542, 545 and 1047). PTEN protein expression was evaluated by immunohistochemistry on 3 mm FFPE tissue sections. Statistical analysis was carried out using SPSS 16.0 software. The frequency of KRAS, BRAF and PIK3CA mutations and loss of PTEN expression was 43.9% (25/57), 25.4% (15/59), 8.2% (5/61) and 47.8% (33/69), respectively. The most frequent mutation in KRAS, BRAF and PIK3CA was V14G (26.7% of all mutations), V600E (40.0% of all mutations) and V600L (40.0% of all mutations), and H1047L (80.0% of all mutations), respectively. Six KRAS mutant patients (24.0%) harbored BRAF mutations. BRAF and PIK3CA mutations were mutually exclusive. No significant correlation was observed between the four biomarkers and patients characteristics.nnnCONCLUSIONS/SIGNIFICANCEnBRAF mutation rate is much higher in this study than in other studies, and overlap a lot with KRAS mutations. Besides, the specific types of KRAS and PIK3CA mutations in Chinese patients could be quite different from that of patients in other countries. Further studies are warranted to examine their impact on prognosis and response to targeted treatment.

Associations of apolipoprotein E exon 4 and lipoprotein lipase S447X polymorphisms with acute ischemic stroke and myocardial infarction

Abstract Background: Because apolipoprotein E (apoE) and lipopoprotein lipase (LPL) polymorphisms interact with each other and with other factors to affect lipid metabolism, we sought to determine their separate and combined effects in association with ischemic vascular disease. Methods: We performed a case-control study of 816 subjects: 246 acute ischemic stroke patients, 234 acute myocardial infarction patients, and 336 controls. APOE exon 4 and LPL S447X genotypes were determined. Results: APOE ɛ2 and ɛ4 homozygotes were increased in stroke (4.5% vs. 1.0%, p=0.008), while in myocardial infarction the ɛ4 allele was increased (12.6% vs. 9.5%, p=0.006) but ɛ2 was decreased (3.7% vs. 12.1%, p=0.000006). For subjects with either APOE ɛ2 or ɛ4 alleles, LPL X alleles were increased in vascular disease (OR=2.2, p=0.01). LPL X alleles displayed opposite tendencies toward association with disease when subjects were divided by sex, smoking, or APOE genotype. Meta-analysis and regression analysis of previous studies supported the sex and smoking dichotomies. Conclusion: This is the first report of an association of vascular disease with an interaction of APOE exon 4 and LPL S447X genotypes. Therefore, APOE genotypes and LPL S447X interactions with apoE, sex, and smoking may affect the risk of myocardial infarction and ischemic stroke.

Interventions for preventing infection in nephrotic syndrome

BACKGROUNDnInfection is one of the most common complications and still remains a significant cause of morbidity and occasionally mortality in patients, especially children with nephrotic syndrome. Many different prophylactic interventions have been used or recommended for reducing the risks of infection in nephrotic syndrome in clinical practice. Whether the existing evidence is scientifically rigorous and which prophylactic intervention can be recommended for routine use based on the current evidence is still unknown.nnnOBJECTIVESnTo assess the benefits and harms of any prophylactic intervention for reducing the risk of infection in children and adults with nephrotic syndrome.nnnSEARCH METHODSnWe searched the Cochrane Renal Groups specialised register, the Cochrane Central Register of Controlled Trials (CENTRAL) (in The Cochrane Library), MEDLINE and Pre-MEDLINE (from 1966), EMBASE (from 1980), China Biological Medicine Database (1979 to December 2009), Chinese Science and Technique Journals Database (to December 2009), China National Infrastructure (to December 2009), WangFang database (to December 2009), reference lists of nephrology textbooks, review articles, relevant studies and abstracts from nephrology meetings without language restriction.Date of last search: 6 February 2012nnnSELECTION CRITERIAnRandomised controlled trials (RCTs) and quasi-RCTs comparing any prophylactic interventions (pharmacological or non-pharmacological) for preventing any infection in children and adults with nephrotic syndrome.nnnDATA COLLECTION AND ANALYSISnTwo authors independently assessed and extracted information. Information was collected on methods, participants, interventions and outcomes (appearance of infection, mortality, quality of life and adverse events). Results were expressed as risk ratios (RR) for dichotomous outcomes or as mean differences (MD) for continuous data with 95% confidence intervals (CI).nnnMAIN RESULTSnTwelve studies conducted in China, including 762 children with nephrotic syndrome were identified. No studies were identified in adults. All studies compared one kind of prophylactic pharmacotherapy (intravenous immunoglobulin (IVIG), thymosin, oral transfer factor, mannan peptide tablet, Bacillus Calmette-Guerin (BCG) vaccine injection, polyvalent bacterial vaccine (Lantigen B) and two kinds of Chinese medicinal herbs: a compound of Chinese medicinal herbs (TIAOJINING) and Huangqi (astragalus) granules) plus baseline treatment with baseline treatment alone. No RCTs were identified comparing antibiotics, non-pharmacological prophylaxis, or pneumococcal vaccination. Four studies showed a significantly beneficial effect of IVIG on preventing nosocomial or unspecified infection in children with nephrotic syndrome (RR 0.47, 95% CI 0.31 to 0.73). Thymosin (RR 0.50, 95% CI 0.26 to 0.97), oral transfer factor (RR 0.51, 95% CI 0.35 to 0.73), BCG vaccine injection (RR 0.68, 95% CI 0.48 to 0.95), Huangqi granules (RR 0.62, 95% CI 0.47 to 0.83) and TIAOJINING (RR 0.59, 95% CI 0.43 to 0.81) were also effective in reducing the risk of infection in children with nephrotic syndrome. However mannan peptide tablet (RR 0.46, 95% CI 0.21 to 1.01) and polyvalent bacterial vaccine (RR 0.24, 95% CI 0.06 to1.00) were not superior to baseline treatment in reducing the risk of infection for nephrotic children. No serious adverse events were reported.nnnAUTHORS CONCLUSIONSnIVIG, thymosin, oral transfer factor, BCG vaccine, Huangqi granules and TIAOJINING may have positive effects on the prevention of nosocomial or unspecified infection with no obvious serious adverse events in children with nephrotic syndrome. However the methodological quality of all studies was poor, the sample sizes small, and all studies were from China, and thus there is no strong evidence on the effectiveness of these interventions.

Review paper: epidemiology, evidence-based medicine, and public health.

This article reviews the relation between evidence-based medicine and epidemiology and the recent evolution of the former. The meaning of evidence and the international efforts to collect, summarize, and disseminate findings from scientific research that are relevant for medical decision making are discussed. Evidence, current resources, and peoples values, all play a role in making evidence-based medical decisions. This also has important implications for public health practice. However, decision making differs considerably between clinical care of individual patients and public health decision and policies that normally apply to populations. Although more closely related to epidemiology than clinical medicine, public health should also adopt a more systematic approach to evidence-based practice.

Performance comparison among the major healthcare financing systems in six cities of the Pearl River Delta region, mainland China.

Background The healthcare system of mainland China is undergoing drastic reform and the optimal models for healthcare financing for provision of primary care will need to be identified. This study compared the performance indicators of the community health centres (CHCs) under different healthcare financing systems in the six cities of the Pearl River Delta region. Methods Approximately 300 hypertensive patients were randomly recruited from the computerized chronic disease management records provided by one CHC in each of the six cities in 2011 using a multi-stage cluster random sampling method. The major outcome measures included the treatment rate of hypertension, defined as prescription of ≥ one antihypertensive agent; and the control rate of hypertension, defined as systolic blood pressure levels <140 mmHg and diastolic blood pressure levels <90 mmHg in patients without diabetes mellitus, or <130/80 mmHg among patients with concomitant diabetes. Binary logistic regression analyses were conducted with these two measures as outcome variables, respectively, controlling for patients’ socio-demographic variables. The financing system (Hospital- vs. Government- vs. private-funded) was the independent variable tested for association with the outcomes. Results From 1,830 patients with an average age of 65.9 years (SD 12.8), the overall treatment and control rates were 75.4% and 20.2%, respectively. When compared with hospital-funded CHCs, patients seen in the Government-funded (adjusted odds ratio [AOR] 0.462, 95% C.I. 0.325–0.656) and private-funded CHCs (AOR 0.031, 95% C.I. 0.019–0.052) were significantly less likely to be prescribed antihypertensive medication. However, the Government-funded CHC was more likely to have optimal BP control (AOR 1.628, 95% C.I. 1.157–2.291) whilst the privately-funded CHC was less likely to achieve BP control (AOR 0.146, 95% C.I. 0.069–0.310), irrespective of whether antihypertensive drugs were prescribed. Conclusions Privately-funded CHCs had the lowest rates of BP treatment and control due to a variety of potential factors as discussed.

Toremifene versus tamoxifen for advanced breast cancer

BACKGROUNDnToremifene (TOR) and tamoxifen (TAM) can both be used as treatments for advanced breast cancer.nnnOBJECTIVESnTo compare the efficacy and safety of TOR with TAM in patients with advanced breast cancer.nnnSEARCH METHODSnThe Cochrane Breast Cancer Groups Specialised Register was searched (1 July 2011) using the codes for toremifene, fareston, tamoxifen, nolvadex, and breast cancer. We also searched MEDLINE (via PubMed) (from inception to 1 July 2011), EMBASE (via Ovid) (from inception to 1 July 2011), The Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library, Issue 7, 2011), and the WHO International Clinical Trials Registry Platform search portal (1 July 2011). In addition, we screened the reference lists of relevant trials or reviews.nnnSELECTION CRITERIAnRandomised controlled trials (RCTs) that compared the efficacy and safety, or both of TOR with TAM in women with advanced breast cancer. Trials that provided sufficient data on one of the following items: objective response rate (ORR), time to progression (TTP), overall survival (OS), and adverse events, were considered eligible for inclusion.nnnDATA COLLECTION AND ANALYSISnStudies were assessed for eligibility and quality. Two review authors independently extracted the following details: first author, publication year, country, years of follow-up, treatment arms, intention-to-treat (ITT) population size, menopausal status of patients, hormone receptor status, response criteria, efficacy and safety outcomes of TOR and TAM arms. Hazard ratios (HR) were derived for time-to-event outcomes, where possible, and response and adverse events were analysed as dichotomous variables. We used a fixed-effect model for meta-analysis unless there was significant between-study heterogeneity.nnnMAIN RESULTSnA total of 2061 patients from seven RCTs were included for final analysis, with 1226 patients in the TOR group and 835 patients in the TAM group. The ORR for the TOR group was 25.8% (316/1226) whereas, the ORR for the TAM group was 26.9% (225/835). The pooled risk ratio (RR) suggested that the ORRs were not statistically different between the two groups (RR 1.02, 95% confidence interval (CI) 0.88 to 1.18, P = 0.83). The median TTP was 6.1 months for the TOR group and 5.8 months for the TAM group. The median OS was 27.8 months for the TOR group and 27.6 months for the TAM group. There were no significant differences in TTP and OS between the two therapeutic groups (for TTP: HR 1.08, 95% CI 0.94 to 1.24; for OS: HR 1.02, 95% CI 0.86 to 1.20). The frequencies of most adverse events were also similar in the two groups, while headache seemed to occur less in the TOR group than in the TAM group (RR 0.14, 95% CI 0.03 to 0.74, P = 0.02). There was no significant heterogeneity between studies in most of the above meta-analyses. Sensitivity analysis did not alter the results.nnnAUTHORS CONCLUSIONSnTOR and TAM are equally effective and the safety profile of the former is at least not worse than the latter in the first-line treatment of patients with advanced breast cancer. Thus, TOR may serve as a reasonable alternative to TAM when anti-oestrogens are applicable but TAM is not the preferred choice for some reason.

Association between ATM 5557G>A polymorphism and breast cancer risk: a meta-analysis

Epidemiological studies have evaluated the association between ATM 5557G>A (p.D1853N) polymorphism and breast cancer risk. However, the results remain conflicting rather than conclusive. To derive a more precise estimation of the relationship, we performed this meta-analysis. Systematic searches of PubMed and Medline databases were performed. A total of nine studies included 3155 cases and 2752 controls were identified. When all nine studies were pooled into the meta-analysis, there was no evidence for significant association between 5557G>A mutation and breast cancer risk(for G/A vs. G/G: ORxa0=xa01.05, 95% CIxa0=xa00.83–1.34; for A/A vs. G/G: ORxa0=xa00.77, 95% CIxa0=xa00.58–1.03; for dominant model: ORxa0=xa01.04, 95% CIxa0=xa00.82–1.31; for recessive model: ORxa0=xa00.87, 95% CIxa0=xa00.69–1.09). In the subgroup analyses by family history and ethnicity, significant associations were found among Amerindians (for G/A vs. G/G: ORxa0=xa02.19, 95% CIxa0=xa01.38–3.47; for dominant model: ORxa0=xa02.15, 95% CIxa0=xa01.37–3.38). In summary, the meta-analysis suggest that ATM 5557G>A polymorphism is associated with increased breast cancer risk among Amerindians. However, due to the small subjects included in analysis and the selection bias existed in some studies, the results for Amerindians should be interpreted with caution.

Tong-xin-luo capsule for patients with coronary heart disease after percutaneous coronary intervention

BACKGROUNDnPercutaneous coronary intervention (PCI) is a standard treatment for coronary heart disease (CHD). Restenosis, defined as a 50% reduction in luminal diameter at six months after PCI, indicates a need for revascularisation. Restenosis has proven to be a major drawback to PCI. Tong-xin-luo is one of the prophylactic strategies for cardiovascular events in patients after PCI that is widely used in China, but its efficacy and safety have not been systematically evaluated.nnnOBJECTIVESnTo systematically assess the efficacy and safety of Tong-xin-luo capsules in preventing cardiovascular events after PCI in patients with CHD.nnnSEARCH METHODSnWe searched the Cochrane Central Register of Controlled Trials in The Cochrane Library, MEDLINE (OVID), EMBASE (OVID), WanFang, Chinese Biomedical Database, Chinese Medical Current Contents, and China National Knowledge Infrastructure from their inception to June 2014. We also searched other resources, including ongoing trials and research registries. We applied no language restrictions.nnnSELECTION CRITERIAnRandomised controlled trials of participants with CHD after PCI were included. Participants in the intervention group received Tong-xin-luo capsules for at least three months.nnnDATA COLLECTION AND ANALYSISnTwo review authors independently extracted data and assessed the risk of bias. Any disagreements were resolved by discussion with a third review author. The primary outcomes included occurrence of angiographic restenosis and adverse events; the secondary outcomes included myocardial infarction, heart failure, angina, all cause mortality, mortality due to any cardiovascular event, use of revascularisation, patient acceptability, quality of life and cost-effectiveness. Dichotomous data were measured with risk ratios (RRs) with 95% confidence intervals (CIs).nnnMAIN RESULTSnSixteen studies involving 1063 participants were identified. The risk of bias for fifteen studies was high and along with imprecision and possible publication bias, this lowered our confidence in the results. There was low quality evidence that Tong-xi-luo reduced the rates of angiographic restenosis (RR 0.16, 95% CI 0.07 to 0.34), myocardial infarction (RR 0.32, 95% CI 0.16 to 0.66), heart failure (RR 0.26, 95% CI 0.11 to 0.62), and use of revascularisation (RR 0.26, 95% CI 0.15 to 0.45). There was very low quality evidence for the effect of Tong-xin-luo on all-cause mortality (RR 0.38, 95% CI 0.06 to 2.56), angina (RR 0.24, 95% CI 0.17 to 0.34) and death due to any cardiovascular event (RR 0.31, 95% CI 0.08 to 1.12). Adverse events were seldom reported, and included gastrointestinal reactions and nausea.nnnAUTHORS CONCLUSIONSnThe addition of Tong-xin-luo to conventional Western medicine may possibly prevent restenosis and recurrence of cardiovascular events in patients with CHD after PCI. However, the data are limited by publication bias and high risk of bias for included studies. Further high-quality trials are required to evaluate the potential effects of this intervention.

The impact of cardiovascular multimorbidity on healthcare service utilisation under three primary care organisational models in China

Purpose China’s current healthcare reform leads to the emergence of community health centres (CHCs) of different models for delivering primary care services especially for patients with chronic conditions. Cardiovascular multimorbidity is a frequent phenomenon among such patients, yet less is known on its impact on healthcare service utilization in the primary care setting. This study aimed to compare the healthcare utilization patterns with cardiovascular multimorbidity under different CHC organisational models in China. n nMethods Cardiovascular multimorbidity was defined as the presence of two or more medical conditions related to cardiovascular diseases. Data on patients with cardiovascular multimorbidity who had a regularly attended CHC were extracted from a previous multicentre study in Guangdong province in southern China. Healthcare service utilization was measured in terms of primary care consultations in the previous 6 months, and a 4-point liker-type scale was developed to measure the continuity of care. Analysis of covariance was performed after Bonferroni-corrected adjustments were made for covariates. n nResults A total number of 383 primary care patients fulfilled all the inclusion criteria and the average number of cardiovascular diseases is 2.22 (95% CI: 2.18–2.27). Multiple linear regression analysis showed that healthcare service utilization was significantly increased among patients with cardiovascular multimorbidity (2.10; 95% CI: 0.73–3.47, p=0.003). After adjustment weremade for age and gender, patients of government-owned CHCs exhibited superior scores in the continuity of care (13.83; 95% CI: 13.51–14.14), compared to patients of privately-owned CHCs (12.93; 95% CI: 12.66–13.20, p n nConclusion The study suggested government-owned primary care providers might perform better continuous primary care services for patients with cardiovascular multimorbidity. Further in-depth understanding of the impact of cardiovascular multimorbidity and multimortality is needed to inform the way in which primary care providers are performed to correspond to the challenge from cardiovascular multimorbidity.