Marcel Zwahlen

Body-mass index and incidence of cancer: a systematic review and meta-analysis of prospective observational studies.

BACKGROUND Excess bodyweight, expressed as increased body-mass index (BMI), is associated with the risk of some common adult cancers. We did a systematic review and meta-analysis to assess the strength of associations between BMI and different sites of cancer and to investigate differences in these associations between sex and ethnic groups. METHODS We did electronic searches on Medline and Embase (1966 to November 2007), and searched reports to identify prospective studies of incident cases of 20 cancer types. We did random-effects meta-analyses and meta-regressions of study-specific incremental estimates to determine the risk of cancer associated with a 5 kg/m2 increase in BMI. FINDINGS We analysed 221 datasets (141 articles), including 282,137 incident cases. In men, a 5 kg/m2 increase in BMI was strongly associated with oesophageal adenocarcinoma (RR 1.52, p<0.0001) and with thyroid (1.33, p=0.02), colon (1.24, p<0.0001), and renal (1.24, p <0.0001) cancers. In women, we recorded strong associations between a 5 kg/m2 increase in BMI and endometrial (1.59, p<0.0001), gallbladder (1.59, p=0.04), oesophageal adenocarcinoma (1.51, p<0.0001), and renal (1.34, p<0.0001) cancers. We noted weaker positive associations (RR <1.20) between increased BMI and rectal cancer and malignant melanoma in men; postmenopausal breast, pancreatic, thyroid, and colon cancers in women; and leukaemia, multiple myeloma, and non-Hodgkin lymphoma in both sexes. Associations were stronger in men than in women for colon (p<0.0001) cancer. Associations were generally similar in studies from North America, Europe and Australia, and the Asia-Pacific region, but we recorded stronger associations in Asia-Pacific populations between increased BMI and premenopausal (p=0.009) and postmenopausal (p=0.06) breast cancers. INTERPRETATION Increased BMI is associated with increased risk of common and less common malignancies. For some cancer types, associations differ between sexes and populations of different ethnic origins. These epidemiological observations should inform the exploration of biological mechanisms that link obesity with cancer.

Insulin-like growth factor (IGF)-I, IGF binding protein-3, and cancer risk: systematic review and meta-regression analysis

BACKGROUND Insulin-like growth factor (IGF)-I and its main binding protein, IGFBP-3, modulate cell growth and survival, and are thought to be important in tumour development. Circulating concentrations of IGF-I might be associated with an increased risk of cancer, whereas IGFBP-3 concentrations could be associated with a decreased cancer risk. METHODS We did a systematic review and meta-regression analysis of case-control studies, including studies nested in cohorts, of the association between concentrations of IGF-I and IGFBP-3 and prostate, colorectal, premenopausal and postmenopausal breast, and lung cancer. Study-specific dose-response slopes were obtained by relating the natural log of odds ratios for different exposure levels to blood concentrations normalised to a percentile scale. FINDINGS We identified 21 eligible studies (26 datasets), which included 3609 cases and 7137 controls. High concentrations of IGF-I were associated with an increased risk of prostate cancer (odds ratio comparing 75th with 25th percentile 1.49, 95% CI 1.14-1.95) and premenopausal breast cancer (1.65, 1.26-2.08) and high concentrations of IGFBP-3 were associated with increased risk of premenopausal breast cancer (1.51, 1.01-2.27). Associations were larger in assessments of plasma samples than in serum samples, and in standard case-control studies compared with nested studies. INTERPRETATION Circulating concentrations of IGF-I and IGFBP-3 are associated with an increased risk of common cancers, but associations are modest and vary between sites. Although laboratory methods need to be standardised, these epidemiological observations could have major implications for assessment of risk and prevention of cancer.

Outcomes associated with drug-eluting and bare-metal stents: a collaborative network meta-analysis

BACKGROUND Whether the two drug-eluting stents approved by the US Food and Drug Administration-a sirolimus-eluting stent and a paclitaxel-eluting stent-are associated with increased risks of death, myocardial infarction, or stent thrombosis compared with bare-metal stents is uncertain. Our aim was to compare the safety and effectiveness of these stents. METHODS We searched relevant sources from inception to March, 2007, and contacted investigators and manufacturers to identify randomised controlled trials in patients with coronary artery disease that compared drug-eluting with bare-metal stents, or that compared sirolimus-eluting stents head-to-head with paclitaxel-eluting stents. Safety outcomes included mortality, myocardial infarction, and definite stent thrombosis; the effectiveness outcome was target lesion revascularisation. We included 38 trials (18,023 patients) with a follow-up of up to 4 years. Trialists and manufacturers provided additional data on clinical outcomes for 29 trials. We did a network meta-analysis with a mixed-treatment comparison method to combine direct within-trial comparisons between stents with indirect evidence from other trials while maintaining randomisation. FINDINGS Mortality was similar in the three groups: hazard ratios (HR) were 1.00 (95% credibility interval 0.82-1.25) for sirolimus-eluting versus bare-metal stents, 1.03 (0.84-1.22) for paclitaxel-eluting versus bare-metal stents, and 0.96 (0.83-1.24) for sirolimus-eluting versus paclitaxel-eluting stents. Sirolimus-eluting stents were associated with the lowest risk of myocardial infarction (HR 0.81, 95% credibility interval 0.66-0.97, p=0.030 vs bare-metal stents; 0.83, 0.71-1.00, p=0.045 vs paclitaxel-eluting stents). There were no significant differences in the risk of definite stent thrombosis (0 days to 4 years). However, the risk of late definite stent thrombosis (>30 days) was increased with paclitaxel-eluting stents (HR 2.11, 95% credibility interval 1.19-4.23, p=0.017 vs bare-metal stents; 1.85, 1.02-3.85, p=0.041 vs sirolimus-eluting stents). The reduction in target lesion revascularisation seen with drug-eluting stents compared with bare-metal stents was more pronounced with sirolimus-eluting stents than with paclitaxel-eluting stents (0.70, 0.56-0.84; p=0.0021). INTERPRETATION The risks of mortality associated with drug-eluting and bare-metal stents are similar. Sirolimus-eluting stents seem to be clinically better than bare-metal and paclitaxel-eluting stents.

Sexual transmission of HIV according to viral load and antiretroviral therapy: systematic review and meta-analysis

Objectives:To synthesize the evidence on the risk of HIV transmission through unprotected sexual intercourse according to viral load and treatment with combination antiretroviral therapy (ART). Design:Systematic review and meta-analysis. Methods:We searched Medline, Embase and conference abstracts from 1996–2009. We included longitudinal studies of serodiscordant couples reporting on HIV transmission according to plasma viral load or use of ART and used random-effects Poisson regression models to obtain summary transmission rates [with 95% confidence intervals, (CI)]. If there were no transmission events we estimated an upper 97.5% confidence limit. Results:We identified 11 cohorts reporting on 5021 heterosexual couples and 461 HIV-transmission events. The rate of transmission overall from ART-treated patients was 0.46 (95% CI 0.19–1.09) per 100 person-years, based on five events. The transmission rate from a seropositive partner with viral load below 400 copies/ml on ART, based on two studies, was zero with an upper 97.5% confidence limit of 1.27 per 100 person-years, and 0.16 (95% CI 0.02–1.13) per 100 person-years if not on ART, based on five studies and one event. There were insufficient data to calculate rates according to the presence or absence of sexually transmitted infections, condom use, or vaginal or anal intercourse. Conclusion:Studies of heterosexual discordant couples observed no transmission in patients treated with ART and with viral load below 400 copies/ml, but data were compatible with one transmission per 79 person-years. Further studies are needed to better define the risk of HIV transmission from patients on ART.

A systematic review of the survival and complication rates of fixed partial dentures (FPDs) after an observation period of at least 5 years

OBJECTIVES The objective of this systematic review was to assess the 5- and 10-year survival of implant supported fixed partial dentures (FPDs) and to describe the incidence of biological and technical complications. METHODS An electronic MEDLINE search complemented by manual searching was conducted to identify prospective and retrospective cohort studies on FPDs with a mean follow-up time of at least 5 years. Patients had to have been examined clinically at the follow-up visit. Assessment of the identified studies and data abstraction was performed independently by two reviewers. Failure and complication rates were analyzed using random-effects Poisson regression models to obtain summary estimates of 5- and 10-year survival proportions. RESULTS The search provided 3844 titles and 560 abstracts. Full-text analysis was performed for 176 articles resulting in 21 studies that met the inclusion criteria. Meta-analysis of these studies indicated an estimated survival of implants in implant-supported FPDs of 95.4% (95 percent confidence interval (95% CI): 93.9-96.5%) after 5 and 92.8% (95% CI: 90-94.8%) after 10 years. The survival rate of FPDs supported by implants was 95% (95% CI: 92.2-96.8%) after 5 and 86.7% (95% CI: 82.8-89.8%) after 10 years of function. Only 61.3% (95% CI: 55.3-66.8%) of the patients were free of any complications after 5 years. Peri-implantitis and soft tissue complications occurred in 8.6% (95% CI: 5.1-14.1%) of FPDs after 5 years. Technical complications included implant fractures, connection-related and suprastructure-related complications. The cumulative incidence of implant fractures after 5 years was 0.4% (95% CI: 0.1-1.2%). After 5 years, the cumulative incidence of connection-related complications (screw loosening or fracture) was 7.3% and 14% for suprastructure-related complications (veneer and framework fracture). CONCLUSION Despite a high survival of FPDs, biological and technical complications are frequent. This, in turn, means that substantial amounts of chair time have to be accepted by the clinician following the incorporation of implant-supported FPDs. More studies with follow-up times of 10 and more years are needed as only few studies have described the long-term outcomes.

Incidence and correlates of drug-eluting stent thrombosis in routine clinical practice. 4-year results from a large 2-institutional cohort study.

OBJECTIVES We sought to determine the risk of late stent thrombosis (ST) during long-term follow-up beyond 3 years, searched for predictors, and assessed the impact of ST on overall mortality. BACKGROUND Late ST was reported to occur at an annual rate of 0.6% up to 3 years after drug-eluting stent (DES) implantation. METHODS A total of 8,146 patients underwent percutaneous coronary intervention with a sirolimus-eluting stent (SES) (n=3,823) or paclitaxel-eluting stent (PES) (n=4,323) and were followed up to 4 years after stent implantation. Dual antiplatelet treatment was prescribed for 6 to 12 months. RESULTS Definite ST occurred in 192 of 8,146 patients with an incidence density of 1.0/100 patient-years and a cumulative incidence of 3.3% at 4 years. The hazard of ST continued at a steady rate of 0.53% (95% confidence interval [CI]: 0.44 to 0.64) between 30 days and 4 years. Diabetes was an independent predictor of early ST (hazard ratio [HR]: 1.96; 95% CI: 1.18 to 3.28), and acute coronary syndrome (HR: 2.21; 95% CI: 1.39 to 3.51), younger age (HR: 0.97; 95% CI: 0.95 to 0.99), and use of PES (HR: 1.67; 95% CI: 1.08 to 2.56) were independent predictors of late ST. Rates of death and myocardial infarction at 4 years were 10.6% and 4.6%, respectively. CONCLUSIONS Late ST occurs steadily at an annual rate of 0.4% to 0.6% for up to 4 years. Diabetes is an independent predictor of early ST, whereas acute coronary syndrome, younger age, and PES implantation are associated with late ST.

A systematic review of the survival and complication rates of all-ceramic and metal–ceramic reconstructions after an observation period of at least 3 years. Part II: fixed dental prostheses.

OBJECTIVES The objective of this systematic review was to assess the 5-year survival rates and incidences of complications of all-ceramic fixed dental prostheses (FDPs) and to compare them with those of metal-ceramic FDPs. METHODS An electronic MEDLINE and Dental Global Publication Research System search complemented by manual searching was conducted to identify prospective and retrospective cohort studies on all-ceramic and metal-ceramic reconstructions with a mean follow-up time of at least 3 years. Patients had to have been examined clinically at the follow-up visit. Assessment of the identified studies and data abstraction was performed independently by three reviewers. Failure rates were analyzed using standard and random-effects Poisson regression models to obtain summary estimates of 5-year survival proportions. RESULTS The search provided 3473 titles for single crowns and FDPs and resulted in 100 abstracts for all-ceramic FDPs. Full-text analysis was performed for 39 articles, resulting in nine studies of ceramic FDPs that met the inclusion criteria. The data on survival and complication rates of metal-ceramic FDPs were obtained from a previous systematic review of Tan et al. (2004) and the updated version from the same authors (Pjetursson et al. 2007). In Poisson regression meta-analysis, the 5-year survival of metal-ceramic FDPs was significantly (P<0.0001) higher with 94.4% [95 confidence interval (CI): 91.1-96.5%] than the survival of all-ceramic FDPs, being 88.6% (95 CI: 78.3-94.2%). The frequencies of material fractures (framework and veneering material) were significantly (P<0.0001) higher for all-ceramic FDPs (6.5% and 13.6%) compared with those of metal-ceramic FDPs (1.6% and 2.9%). Other technical complications like loss of retention and biological complications like caries and loss of pulp vitality were similar for the two types of reconstructions over the 5-year observation period. CONCLUSION Based on the present systematic review of all-ceramic FDPs, significantly lower survival rates at 5 years were seen compared with metal-ceramic FDPs. The most frequent reason for failure of FDPs made out of glass-ceramics or glass-infiltrated ceramics was fracture of the reconstruction (framework and veneering ceramic). However, when zirconia was used as framework material, the reasons for failure were primarily biological and technical complications other than framework fracture.

A systematic review of the success of sinus floor elevation and survival of implants inserted in combination with sinus floor elevation.

OBJECTIVES The objectives of this systematic review were to assess the survival rate of grafts and implants placed with sinus floor elevation. MATERIAL AND METHODS An electronic search was conducted to identify studies on sinus floor elevation, with a mean follow-up time of at least 1 year after functional loading. RESULTS The search provided 839 titles. Full-text analysis was performed for 175 articles resulting in 48 studies that met the inclusion criteria, reporting on 12,020 implants. Meta-analysis indicated an estimated annual failure rate of 3.48% [95% confidence interval (CI): 2.48%-4.88%] translating into a 3-year implant survival of 90.1% (95% CI: 86.4%-92.8%). However, when failure rates was analyzed on the subject level, the estimated annual failure was 6.04% (95% CI: 3.87%-9.43%) translating into 16.6% (95% CI: 10.9%-24.6%) of the subjects experiencing implant loss over 3 years. CONCLUSION The insertion of dental implants in combination with maxillary sinus floor elevation is a predictable treatment method showing high implant survival rates and low incidences of surgical complications. The best results (98.3% implant survival after 3 years) were obtained using rough surface implants with membrane coverage of the lateral window.

Recombinant human erythropoiesis-stimulating agents and mortality in patients with cancer: a meta-analysis of randomised trials.

BACKGROUND Erythropoiesis-stimulating agents reduce anaemia in patients with cancer and could improve their quality of life, but these drugs might increase mortality. We therefore did a meta-analysis of randomised controlled trials in which these drugs plus red blood cell transfusions were compared with transfusion alone for prophylaxis or treatment of anaemia in patients with cancer. METHODS Data for patients treated with epoetin alfa, epoetin beta, or darbepoetin alfa were obtained and analysed by independent statisticians using fixed-effects and random-effects meta-analysis. Analyses were by intention to treat. Primary endpoints were mortality during the active study period and overall survival during the longest available follow-up, irrespective of anticancer treatment, and in patients given chemotherapy. Tests for interactions were used to identify differences in effects of erythropoiesis-stimulating agents on mortality across prespecified subgroups. FINDINGS Data from a total of 13 933 patients with cancer in 53 trials were analysed. 1530 patients died during the active study period and 4993 overall. Erythropoiesis-stimulating agents increased mortality during the active study period (combined hazard ratio [cHR] 1.17, 95% CI 1.06-1.30) and worsened overall survival (1.06, 1.00-1.12), with little heterogeneity between trials (I(2) 0%, p=0.87 for mortality during the active study period, and I(2) 7.1%, p=0.33 for overall survival). 10 441 patients on chemotherapy were enrolled in 38 trials. The cHR for mortality during the active study period was 1.10 (0.98-1.24), and 1.04 (0.97-1.11) for overall survival. There was little evidence for a difference between trials of patients given different anticancer treatments (p for interaction=0.42). INTERPRETATION Treatment with erythropoiesis-stimulating agents in patients with cancer increased mortality during active study periods and worsened overall survival. The increased risk of death associated with treatment with these drugs should be balanced against their benefits. FUNDING German Federal Ministry of Education and Research, Medical Faculty of University of Cologne, and Oncosuisse (Switzerland).

Domains of physical activity and all-cause mortality: systematic review and dose–response meta-analysis of cohort studies

BACKGROUND The dose-response relation between physical activity and all-cause mortality is not well defined at present. We conducted a systematic review and meta-analysis to determine the association with all-cause mortality of different domains of physical activity and of defined increases in physical activity and energy expenditure. METHODS MEDLINE, Embase and the Cochrane Library were searched up to September 2010 for cohort studies examining all-cause mortality across different domains and levels of physical activity in adult general populations. We estimated combined risk ratios (RRs) associated with defined increments and recommended levels, using random-effects meta-analysis and dose-response meta-regression models. RESULTS Data from 80 studies with 1 338 143 participants (118 121 deaths) were included. Combined RRs comparing highest with lowest activity levels were 0.65 [95% confidence interval (95% CI) 0.60-0.71] for total activity, 0.74 (95% CI 0.70-0.77) for leisure activity, 0.64 (95% CI 0.55-0.75) for activities of daily living and 0.83 (95% CI 0.71-0.97) for occupational activity. RRs per 1-h increment per week were 0.91 (95% CI 0.87-0.94) for vigorous exercise and 0.96 (95% CI 0.93-0.98) for moderate-intensity activities of daily living. RRs corresponding to 150 and 300 min/week of moderate to vigorous activity were 0.86 (95% CI 0.80-0.92) and 0.74 (95% CI 0.65-0.85), respectively. Mortality reductions were more pronounced in women. CONCLUSION Higher levels of total and domain-specific physical activity were associated with reduced all-cause mortality. Risk reduction per unit of time increase was largest for vigorous exercise. Moderate-intensity activities of daily living were to a lesser extent beneficial in reducing mortality.