Aye Moa

The Aetiological Role of Human Papillomavirus in Oesophageal Squamous Cell Carcinoma: A Meta-Analysis

Background The aetiological role of human papillomavirus (HPV) in oesophageal squamous cell carcinoma (OSCC) has been widely researched for more than three decades, with conflicting findings. In the absence of a large, adequately powered single case-control study, a meta-analysis of all available case-control studies is the most rigorous way of identifying any potential association between HPV and OSCC. We present the first global meta-analysis of case-control studies investigating the role of HPV in OSCC. Methods Case-control studies investigating OSCC tissue for presence of HPV DNA were identified. 21 case-control studies analyzing a total of 1223 cases and 1415 controls, met our inclusion criteria. HPV detection rates were tabulated for each study and all studies were assessed for quality. The random effects method was used to pool the odds ratios (OR). Results From all OSCC specimens included in this meta-analysis, 35% (426/1223) were positive for HPV DNA. The pooled OR for an HPV-OSCC association was 3.04 (95% CI 2.20 to 4.20). Meta-regression analysis did not find a significant association between OR and any of the quality domains. Influence analysis was non-significant for the effect of individual studies on the pooled estimate. Studies conducted in countries with low to medium OSCC incidence showed a stronger relationship (OR 4.65, 95% CI 2.47 to 8.76) than regions of high OSCC incidence (OR 2.65, 95% CI 1.80 to 3.91). Conclusions Uncertainty around the aetiological role of HPV in OSCC is due largely to the small number and scale of appropriately designed studies. Our meta-analysis of these studies suggests that HPV increases the risk of OSCC three-fold. This study provides the strongest evidence to date of an HPV-OSCC association. The importance of these findings is that prophylactic vaccination could be of public health benefit in prevention of OSCC in countries with high OSCC incidence.

Sustained lower rates of HRT prescribing and breast cancer incidence in Australia since 2003.

We previously reported a 6.7% drop in breast cancer incidence rates from 2001 to 2003 in women aged C50 years in Australia, and no significant change in incidence in women younger than 50 years [1]. This was in the context of a substantial and rapid fall of 40% in hormone replacement therapy (HRT) prescribing over the same period. We report here on the results of an updated analysis using national statistics on HRT prescribing and on breast cancer in Australia up to 2005. We used the same data sources and methods as previously described [1]. Figure 1 shows that the total number of HRT prescriptions in Australia remained low after 2003, with an overall 55% drop in prescribing occurring between 2001 and 2005. Figure 1 also shows that breast cancer incidence rates in women C50 years have remained at a sustained lower level in 2003–2005 compared to 2001. The incidence rates in this age group were lower by 8.8% (95% CI: 6.1–11.4%; P \ 0.0001) in 2005 compared to 2001, equivalent to 790 (95% CI: 550–1,020) fewer breast cancers (out of about 9,000 incident breast cancers for women of this age). Over the same period, there was no change in incidence in women aged 20–49 years (non-significant increase of 4.5%; P = 0.07). Rates for women\50 years in Fig. 1 are slightly higher than previously reported because of different weightings of the population at risk. The changes in breast cancer incidence in women aged C50 years occurred at a time of largely stable screening mammography rates in Australia. Age-standardised biennial breast cancer screening participation rates for Australian women aged 50–69 years were 56.9% in 2000–2001, slightly decreasing to 56.2% in 2002–2003 and thereafter remaining unchanged at 56.2% in 2004–2005 [2]. The trends in breast cancer incidence in Australia are strikingly similar to those reported in the USA [3, 4]. In both countries a rapid fall in use of HRT after 2001 was followed by a substantial drop in breast cancer rates in women aged C50 years between 2001 and 2003, with sustained lower rates observed after 2003. Declining trends in both HRT use and breast cancer incidence have now been reported in many countries [5] and are consistent with evidence from studies in individuals that the HRT-associated risk of breast cancer is reversible soon after ceasing use of HRT [6, 7, 8]. K. Canfell (&) Y. J. Kang A. Moa Cancer Epidemiology Research Unit, Cancer Council NSW, 153 Dowling Street, Woolloomooloo, Sydney, NSW, Australia e-mail: karenc@nswcc.org.au

Immunogenicity and safety of inactivated quadrivalent influenza vaccine in adults: A systematic review and meta-analysis of randomised controlled trials

BACKGROUND A quadrivalent influenza vaccine (QIV) includes two A strains (A/H1N1, A/H3N2) and two B lineages (B/Victoria, B/Yamagata). The presence of both B lineages eliminate potential B lineage mismatch of trivalent influenza vaccine (TIV) with the circulating strain. METHODS Electronic database searches of Medline, Embase, Cochrane Central Register of Controlled Trials (CCRCT), Scopus and Web of Science were conducted for articles published until June 30, 2015 inclusive. Articles were limited to randomised controlled trials (RCTs) in adults using inactivated intramuscular vaccine and published in English language only. Summary estimates of immunogenicity (by seroprotection and seroconversion rates) and adverse events outcomes were compared between QIV and TIV, using a risk ratio (RR). Studies were pooled using inverse variance weights with a random effect model and the I(2) statistic was used to estimate heterogeneity. RESULTS A total of five RCTs were included in the meta-analysis. For immunogenicity outcomes, QIV had similar efficacy for the three common strains; A/H1N1, A/H3N2 and the B lineage included in the TIV. QIV also showed superior efficacy for the B lineage not included in the TIV; pooled seroprotection RR of 1.14 (95%CI: 1.03-1.25, p=0.008) and seroconversion RR of 1.78 (95%CI: 1.24-2.55, p=0.002) for B/Victoria, and pooled seroprotection RR of 1.12 (95%CI: 1.02-1.22, p=0.01) and seroconversion RR of 2.11 (95%CI: 1.51-2.95, p<0.001) for B/Yamagata, respectively. No significant differences were found between QIV and TIV for aggregated local and systemic adverse events within 7days post-vaccination. There were no vaccine-related serious adverse events reported for either QIV or TIV. Compared to TIV, injection-site pain was more common for QIV, with a pooled RR of 1.18 (95%CI: 1.03-1.35, p=0.02). CONCLUSION In adults, inactivated QIV was as immunogenic as seasonal TIV, with equivalent efficacy against the shared three strains included in TIV, and a superior immunogenicity against the non-TIV B lineage.

A Randomized Clinical Trial of the Immunogenicity of 7-Valent Pneumococcal Conjugate Vaccine Compared to 23-Valent Polysaccharide Vaccine in Frail, Hospitalized Elderly

Background Elderly people do not mount strong immune responses to vaccines. We compared 23-valent capsular polysaccharide (23vPPV) alone versus 7-valent conjugate (PCV7) vaccine followed by 23vPPV 6 months later in hospitalized elderly. Methods Participants were randomized to receive 23vPPV or PCV7-23vPPV. Antibodies against serotypes 3, 4, 6A, 6B, 9V, 14, 18C, 19A, 19F, 23F were measured by enzyme-linked immunosorbent (ELISA) and opsonophagocytic (OPA) assays at baseline, 6 months and 12 months. Results Of 312 recruited, between 40% and 72% of subjects had undetectable OPA titres at baseline. After one dose, PCV7 recipients had significantly higher responses to serotypes 9V (both assays) and 23F (OPA only), and 23vPPV recipients had significantly higher responses to serotype 3 (ELISA), 19F and 19A (OPA only). In subjects with undetectable OPA titres at baseline, a proportionately greater rise in OPA titre (P<0.01) was seen for all serotypes after both vaccines. The GMT ratio of OPA was significantly higher at 12 months in the PCV7-23vPPV group for serotypes 6A, 9V, 18C and 23F. OPA titre levels for these serotypes increased moderately after 6 months, whereas immunity waned in the 23vPPV only arm. Conclusion We did not show overwhelming benefit of one vaccine over the other. Low baseline immunity does not preclude a robust immune response, reiterating the importance of vaccinating the frail elderly. A schedule of PCV7-23vPPV prevents waning of antibody, suggesting that both vaccines could be useful in the elderly. Follow up studies are needed to determine persistence of immunity. Trial Registration The Australian Clinical Trials Registry ACTRN12607000387426

Efficacy of face masks and respirators in preventing upper respiratory tract bacterial colonization and co-infection in hospital healthcare workers.

Abstract Objective We compared the efficacy of medical masks (MM) and N95 respirators (N95) in preventing bacterial colonization/infection in healthcare workers (HCWs). Methods A cluster randomized clinical trial (RCT) of 1441 hospital HCWs randomized to medical masks or N95 respirators, and compared to 481 control HCWs, was performed in Beijing, China, during the winter season of 2008–2009. Participants were followed for development of clinical respiratory illness (CRI). Symptomatic subjects were tested for Streptococcus pneumoniae, Bordetella pertussis, Chlamydia pneumoniae, Mycoplasma pneumoniae or Haemophilus influenza type B by multiplex polymerase chain reaction (PCR). Results The rate of bacterial colonization was 2.8% in the N95 group (p=0.02), 5.3% among medical mask users (p<0.01) and 7.5% among the controls (p=0.16). N95 respirators were significantly protective (adjusted RR 0.34, 95% CI: 0.21–0.56) against bacterial colonization. Co-infections of two bacteria or a virus and bacteria occurred in up to 3.7% of HCWs, and were significantly lower in the N95 arm. Conclusions N95 respirators were significantly protective against bacterial colonization, co-colonization and viral-bacterial co-infection. We showed that dual respiratory virus or bacterial-viral co-infections can be reduced by the use of N95 respirators. This study has occupational health and safety implications for health workers.

Influenza vaccine as a coronary intervention for prevention of myocardial infarction

Cardiovascular disease (CVD) is the leading cause of morbidity and mortality globally. Influenza is one of the leading infectious causes of morbidity and mortality globally, and evidence is accumulating that it can precipitate acute myocardial infarction (AMI). This is thought to be due to a range of factors including inflammatory release of cytokines, disruption of atherosclerotic plaques and thrombogenesis, which may acutely occlude a coronary artery. There is a large body of observational and clinical trial evidence that shows that influenza vaccine protects against AMI. Estimates of the efficacy of influenza vaccine in preventing AMI range from 15% to 45%. This is a similar range of efficacy compared with the accepted routine coronary prevention measures such as smoking cessation (32–43%), statins (19–30%) and antihypertensive therapy (17–25%). Influenza vaccine should be considered as an integral part of CVD management and prevention. While it is recommended in many guidelines for patients with CVD, rates of vaccination in risk groups aged <65 years are very low, in the range of 30%. The incorporation of vaccination into routine CVD prevention in patient care requires a clinical practice paradigm change.

Quantifying the risk of respiratory infection in healthcare workers performing high-risk procedures

SUMMARY This study determined the risk of respiratory infection associated with high-risk procedures (HRPs) performed by healthcare workers (HCWs) in high-risk settings. We prospectively studied 481 hospital HCWs in China, documented risk factors for infection, including performing HRPs, measured new infections, and analysed whether HRPs predicted infection. Infection outcomes were clinical respiratory infection (CRI), laboratory-confirmed viral or bacterial infection, and an influenza infection. About 12% (56/481) of the study participants performed at least one HRP, the most common being airway suctioning (7·7%, 37/481). HCWs who performed a HRP were at significantly higher risk of developing CRI and laboratory-confirmed infection [adjusted relative risk 2·9, 95% confidence interval (CI) 1·42–5·87 and 2·9, 95% CI 1·37–6·22, respectively]. Performing a HRP resulted in a threefold increase in the risk of respiratory infections. This is the first time the risk has been prospectively quantified in HCWs, providing data to inform occupational health and safety policies.

Evidence for the aetiology of human papillomavirus in oesophageal squamous cell carcinoma in the Chinese population: a meta-analysis

Objectives We aimed to conduct a meta-analysis of human papillomavirus (HPV) as a risk factor for oesophageal squamous cell carcinoma (OSCC) in China, using all eligible studies published in the English and Chinese language literature. Design The random effect model was used to analyse the pooled OR. The I2 and Q tests were included in the subgroup analyses. Setting Literature searches of databases including MEDLINE, PUBMED, EMBASE and Chinese National Knowledge Infrastructure (CNKI) and other available resources were performed to retrieve studies investigating OSCC tissue from Chinese participants for the presence of HPV DNA. Primary outcome measure A collective analysis of OSCC cases and control specimens was carried out from 15 case–control studies (6 in the English language and 9 in the Chinese language) for HPV prevalence. Results Of a total of 1177 OSCC and 1648 oesophageal control samples, 55% (642/1177) of cancer specimens and 27% (445/1648) of control samples were positive for HPV DNA. A positive strong association between HPV DNA and OSCC was observed among the included studies, with a pooled OR of 3.69 (95% CI 2.74 to 4.96). Heterogeneity and publication bias were not observed in the analysis. Subgroup analyses of the included studies also supported the measure of association of causal links between HPV and OSCC. Conclusions This meta-analysis provides the strongest evidence until now of an association between HPV and OSCC in the Chinese population. China has a high burden of OSCC, making this an important research finding. A strength and new contribution of this study is combining data from the English and Chinese language literature to analyse all studies conducted in China. These findings may inform the population level use of prophylactic HPV vaccination to reduce the burden of OSCC in China.

Normal endometrial cells in cervical cytology: systematic review of prevalence and relation to significant endometrial pathology

Objectives To estimate the prevalence of normal endometrial cells (NECs) and the proportion of NECs associated with significant endometrial pathology in conventional and liquid-based cytology (LBC) cervical smears; and to assess the association between NECs and clinical symptoms in women with endometrial hyperplasia or carcinoma. Methods Systematic review of the literature and meta-analysis of prevalence and proportion data. The review was confined to studies reporting on NECs in smears from postmenopausal women or women aged 40+. Results A total of 22 relevant primary studies were identified from 1970 to 2007. The overall summary estimate for the prevalence of NECs in smears from postmenopausal women or women aged 40+ in all screening smears was 0.4% (95% CI 0.2–0.7%); this was 0.3% (95% CI 0.1–0.5%) and 0.9% (95% CI 0.5–1.4%) for conventional and LBC smears, respectively; P = 0.003 for difference. The overall estimate for the proportion of NECs associated with significant endometrial pathology was 7% (95% CI 4–10%); this was 11% (95% CI 8–14%) and 2% (95% CI 1–2%) for conventional and LBC smears, respectively; P < 0.001 for difference. In women with significant endometrial pathology, the presence of NECs in followed-up women was associated with abnormal uterine bleeding in 79% (95% CI 68–87%) of cases. Conclusion Compared with conventional cytology, LBC may be associated with a higher prevalence of NECs but these are less likely to be associated with endometrial pathology. This finding might be explained by more consistent use of sampling instruments for LBC with better access to the endocervical canal or alternatively by changes over time, broadly coincident with the introduction of LBC, in the population in which NECs are reported. In followed-up women with NECs, most endometrial pathology is accompanied by symptoms, implying that a relatively smaller number of additional cases are identified through follow-up of asymptomatic women.

Immunogenicity and persistence of immunity of a quadrivalent Human Papillomavirus (HPV) vaccine in immunocompromised children.

AIM The aim of this study was to determine the immunogenicity and reactogenicity of HPV vaccine in immunocompromised children. METHODS A multi-centre clinical trial was conducted in three paediatric hospitals in Australia. Unvaccinated children 5-18years of age attending one of three paediatric hospitals with a range of specified conditions associated with immunosuppression were included. Quadrivalent HPV vaccine (Gardasil) was given to the participants and serum anti-HPV antibody levels were measured at baseline (before first dose), 7 and 24months after the first dose of vaccine. RESULTS Fifty-nine participants were enrolled across the three paediatric hospitals and among those one was seropositive to types 6, 11 and 16 at baseline. Seven months after the first dose, seroconversion rates were 93.3%, 100%, 100% and 88.9% for type 6, 11, 16 and 18 respectively. The corresponding rates at 24month follow up were 82.2%, 91.1%, 91.1% and 68.9%. The greatest increase in geometric mean titre (GMT) was for type 16, followed by type 11. GMTs declined over the following months, but remained more than fourfold higher for all serotypes compared to baseline titres at 24months post vaccination. Injection site erythema, pain and swelling were commonly reported local adverse events and were less common after each dose. Few participants reported systemic adverse events, and minor disease flare occurred in two participants. One child developed a squamous cell oral carcinoma during follow up, but tissue was unable to be tested for HPV. CONCLUSION Immunosuppressed children had an adequate immunogenic response to Quadrivalent HPV vaccine regardless of age and the cause of immunosuppression. HPV related cancers occur at higher frequency and earlier in immunosuppressed patients, so early vaccination and optimal scheduling should be further studied in such children. CLINICAL TRIAL REGISTRATION NCT02263703 (ClinicalTrials.gov).