Cumulative risk of cervical intraepithelial neoplasia for women with normal cytology but positive for human papillomavirus: Systematic review and meta-analysis.

Most women positive for human papillomavirus (HPV) are cytology normal. The optimal screen-management of these women is unclear given their risk of developing precancer. We performed a systematic review and meta-analysis of progression rates to precancer and cancer for HPV-positive, cytology normal women. We searched MEDLINE, EMBASE and Scopus for prospective studies measuring the cumulative incidence of precancer and cervical cancer in HPV-positive, cytology/histology normal women. Record screening was performed independently by two reviewers. We modeled the cumulative incidence over time using a multilevel random-effects meta-regression model. We used the model to predict HPV type-specific risks of precancer and cancer over follow-up. Data from 162 unique records were used in our analysis. The average incidence rate of cervical intraepithelial neoplasia grade 3 or cancer (CIN3+) in high-risk HPV positive but cytology/histology normal women was 1.0 per 100 women-years (95% CI: 1.0-1.1). This corresponds to an average cumulative risk at 1, 3 and 5 years of 2.1% (95% prediction interval 0.0-9.5), 4.3% (95% prediction interval 0.0-11.5) and 6.4% (95% prediction interval 0.0-13.5). HPV type was a strong predictor of the risk of oncogenic progression. There was substantial heterogeneity in the background precancer risk across studies (P-value < .0001). Our HPV type-specific progression risk estimates can help inform risk-based cervical cancer screening guidelines for HPV-positive women. However, precancer and cervical cancer risks are highly variable and may not be generalizable between populations.

Estimates of the future burden of cancer attributable to infections in Canada.

More than 7000 incident cancers diagnosed in Canada in 2015 were attributable to infections. The future infection-associated cancer burden can be lowered by reducing the prevalence of major cancer-causing infections; hepatitis B virus (HBV), hepatitis C virus (HCV), Helicobacter pylori (H. pylori) and human papillomavirus (HPV). We modeled the future impact of (1) 10%, 25%, and 50% relative reductions in the prevalence of HBV, HCV and H. pylori and (2) different school-based HPV vaccination coverage levels (lower, current, higher) on Canadian cancer incidence by the year 2042. We modeled counterfactual reductions in HBV, HCV and H. pylori prevalence in 2018, assuming a latency period of 15-years, to estimate the impact on cancer incidence starting in 2033. The number of HPV-attributable cancers among vaccinated cohorts was a function of pre-2018 vaccine coverage levels and the 2018 counterfactuals. A 50% counterfactual reduction in the prevalence of HBV, HCV and H. pylori could prevent an estimated 10,585 cancers from 2018 to 2042; a 25% reduction could prevent 5293 cancers and a 10% reduction could prevent 2117 cancers. Assuming continuity of current estimated country-wide HPV vaccine coverage, 3977 anogenital and 1073 head and neck cancers could be prevented from 2018 to 2042, whereas vaccine coverage of 80% in girls and boys could prevent an additional 311 cancers. Almost 16,000 cancers could be prevented in Canada from 2018 to 2042 with a 50% relative reduction in HBV, HCV and H. pylori prevalence and 80% HPV vaccine coverage of girls and boys.

Cancers attributable to infections in Canada.

Infections are estimated to cause approximately 15% of the world's cancers with large geographic variations. Yet, Canadian estimates for specific cancer-causing infections are not available. To estimate the number of infection-associated cancers diagnosed among Canadian adults in 2015, we calculated population attributable risks (PARs) and the number of attributable cases for seven carcinogenic infections and their 20 associated cancers. A systematic literature search was performed for each infection to obtain data on infection prevalence in the population and the relative risk or odds ratio associated with the cancer it causes. When mechanistic evidence suggested that detection of a given infection within cancer tissue was sufficient to attribute the cancer to the infection, prevalence among cancer cases was used to approximate the PAR. Data from 61 studies formed the basis of our analyses. The estimated number of infection-attributable cancer cases for 2015 was: 3828 for human papillomavirus (HPV), 2052 for Helicobacter pylori, 578 for Epstein-Barr virus, 509 for hepatitis B and C viruses (HBV, HCV), 100 for human herpesvirus type 8, and 30 cases for human T-cell lymphotropic virus type 1. These seven infections were responsible for 3.7% of cancers diagnosed among Canadian adults in 2015; 3.5% among men and 4.0% among women. The infections with the highest number of attributable cases are largely preventable or treatable through vaccination (HBV and HPV), antibiotic therapy (H. pylori), or a combination of interventions (HCV), thereby representing an important target for reducing the infection-caused cancer burden among Canadians.

The current and future burden of cancer attributable to modifiable risk factors in Canada: Summary of results.

Nearly one in two Canadians are expected to be diagnosed with cancer in their lifetime. However, there are opportunities to reduce the impact of modifiable cancer risk factors through well-informed interventions and policies. Since no comprehensive Canadian estimates have been available previously, we estimated the proportion of cancer diagnosed in 2015 and the future burden in 2042 attributable to lifestyle and environmental factors, and infections. Population-based historical estimates of exposure prevalence and their associated risks for each exposure-cancer site pair were obtained to estimate population attributable risks, assuming the exposures were distributed independently and that the risk estimates were multiplicative. We estimated that between 33 and 37% (up to 70,000 cases) of incident cancer cases among adults aged 30 years and over in 2015 were attributable to preventable risk factors. Similar proportions of cancer cases in males (34%) and females (33%) were attributable to these risk factors. Tobacco smoking and a lack of physical activity were associated with the highest proportions of cancer cases. Cancers with the highest number of preventable cases were lung (20,100), colorectal (9800) and female breast (5300) cancer. If current trends in the prevalence of preventable risk factors continue into the future, we project that by 2042 approximately 102,000 incident cancer cases are expected to be attributable to these risk factors per year, which would account for roughly one-third of all incident cancers. Through various risk reduction interventions, policies and public health campaigns, an estimated 10,600 to 39,700 cancer cases per year could be prevented by 2042.

The burden of cancer attributable to modifiable risk factors in Canada: Methods overview.

Up-to-date estimates of current and projected future cancer burden attributable to various exposures are essential for planning and implementing cancer prevention initiatives. The Canadian Population Attributable Risk of Cancer (ComPARe) study was conducted to: i) estimate the number and proportion of cancers diagnosed among adults in Canada in 2015 that are attributable to modifiable risk factors and ii) project the future avoidable cancers by 2042 under various intervention targets. We estimated the population attributable risk (with 95% confidence intervals) and the potential impact fraction of cancers associated with selected lifestyle, environmental, and infectious factors. Exposure-specific sensitivity analyses were also completed where appropriate. Several exposures of interest included active and passive smoking, obesity and abdominal adiposity, leisure-time physical inactivity, sedentary behaviour, alcohol consumption, insufficient fruit and vegetable intake, red and processed meat consumption, air pollution (PM2.5, NO2), indoor radon gas, ultraviolet radiation (UVR), hepatitis B and C virus, Helicobacter pylori, Epstein-Barr virus, human papillomavirus, human herpesvirus type 8 and human T-cell lymphotropic virus type 1. We used the 2015 cancer incidence data for 35 cancer sites from the Canadian Cancer Registry and projected cancer incidence to 2042 using historical data from 1983 to 2012. Here, we provide an overview of the data sources and methods used in estimating the current and future cancer burden in Canada. Specific methodologic details for each exposure are included in the individual articles included as part of this special issue.

Merger mania: mergers and acquisitions in the generic drug sector from 1995 to 2016.

BACKGROUND: Drug shortages and increasing generic drug prices are associated with low levels of competition. Mergers and acquisitions impact the level of competition. Record merger and acquisition activity was reported for the pharmaceutical sector in 2014/15, yet information on mergers and acquisitions in the generic drug sector are absent from the literature. This information is necessary to understand if and how such mergers and acquisitions can be a factor in drug shortages and increasing prices. METHODS: Data on completed merger and acquisition deals that had a generic drug company being taken over (i.e. 'target') were extracted from Bloomberg Finance L.P. The number and announced value of deals are presented globally, for the United States, and globally excluding the United States annually from 1995 to 2016 in United States dollars. RESULTS: Generic drug companies comprised 9.3% of the value of all deals with pharmaceutical targets occurring from 1995 to 2016. Globally, in 1995 there were no deals, in 2014 there were 22 deals worth $1.86 billion, in 2015 there were 34 deals totalling $33.56 billion, and in 2016 there were 42 deals worth in excess of $44 billion. This substantial increase was partially attributed to Teva's 2016 acquisition of Allergan's generic drug business. The surge in mergers and acquisitions for 2015/16 was driven by deals in the United States, where they represented 89.7% of the dollar value of deals in those years. CONCLUSIONS: The recent blitz in mergers and acquisitions signals that the generic drug industry is undergoing a transformation, especially in the United States. This restructuring can negatively affect the level of competition that might impact prices and shortages for some products, emphasizing the importance of updating regulations and procurement policies.

Examining screening mammography participation among women aged 40 to 74.

OBJECTIVE: To examine participation in screening mammography among women aged 40 to 74 and identify which factors are associated with those women who participate in screening. DESIGN: Secondary analysis of the cross-sectional 2012 Canadian Community Health Survey. SETTING: Canada. PARTICIPANTS: A population-based national sample of 18 312 women aged 40 to 74. MAIN OUTCOME MEASURES: Women's participation in screening mammography in the 2 years preceding the 2012 Canadian Community Health Survey; women's preventive health activities (ie, having a regular doctor, a recent physical checkup, and a Papanicolaou test), which were adjusted for sociodemographic factors. RESULTS: Participation in recent screening mammography was highest among women aged 60 to 69 (70.3%), followed by those aged 50 to 59 (63.4%) and those aged 70 to 74 (58.4%). Almost one-third (31.4%) of women aged 40 to 49 had had a screening mammogram in the past 2 years. Having a regular doctor (odds ratio [OR] = 3.30, 95% CI 2.90 to 3.73), a physical checkup in the past year (OR = 3.06, 95% CI 2.30 to 4.08), or a Pap test in the past 3 years (OR = 3.47, 95% CI 3.18 to 3.79) more than tripled the odds that women had had a recent screening mammogram. CONCLUSION: Aside from age being a factor associated with women's participation in screening mammography, factors related to women's health care use (having a regular doctor, a recent physical checkup, and a recent Pap test) demonstrated a stronger association with women aged 40 to 74 having had recent mammograms. The association between women's participation in screening and their preventive health activities implies that the doctor's office is an appropriate venue for conversations regarding the potential benefits and harms of screening mammography.

Clinical Performance of the BD Onclarity Extended Genotyping Assay for the Management of Women Positive for Human Papillomavirus in Cervical Cancer Screening.

BACKGROUND: Among women whose cervical specimens tested positive for high-risk human papillomaviruses (hrHPV) via the Hybrid Capture 2 assay in the Canadian Cervical Cancer Screening Trial (CCCaST), we assessed hrHPV genotype concordance between BD Onclarity HPV Assay and Roche's Linear Array, overall and stratified by hrHPV viral load. We also evaluated the performance of cytology, cytology combined with hrHPV genotyping (Onclarity assay) for HPV16/18 and non-HPV16/18 types, and hrHPV genotyping triage strategies for the detection of cervical intraepithelial neoplasia grade 2 or 3 and worse (CIN2+/CIN3+). METHODS: Standard measures (expected agreement, agreement, and κ values) were used to compare Onclarity to the reference test, Linear Array. Twenty-four triage strategies were evaluated by calculating their sensitivities, specificities, and positive and negative predictive values for CIN2+ and CIN3+ detection. RESULTS: Among 734 hrHPV+ samples tested, there was near perfect concordance irrespective of viral load between the Onclarity and Linear Array assays for the individual genotypes [human papillomaviruses (HPV) 16, 18, 31, 45, 51, 52] by Onclarity (κ values ranged from 0.92-0.98). Strategies with adequate specificity (>75%) and the highest sensitivities to detect CIN3+ among 617 women positive for hrHPV, were positivity to HPV16 and/or 31 (Sensitivity: 65.2%, Specificity: 76.9%) and HPV16 and/or 18 (Sensitivity: 58.7%, Specificity: 81.6%). CONCLUSIONS: While confirming the importance of HPV16, we found that HPV31 was comparable with HPV18 for the detection of CIN2/3+ in the triage of women positive for hrHPV. IMPACT: HPV31 may be an important genotype in the triage of women positive for hrHPV.

Is Hodgkin Lymphoma Associated with Hepatitis B and C Viruses? A Systematic Review and Meta-analysis.

BACKGROUND: Apart from the Epstein-Barr virus (EBV), the etiology of the hematologic malignancy Hodgkin lymphoma (HL) is not well defined. Hepatitis B virus (HBV) and hepatitis C virus (HCV) are associated with some lymphoproliferative diseases with similarities to HL. METHODS: We performed a systematic review and meta-analysis, by searching Embase, MEDLINE, and Web of Science databases on March 9, 2021, for studies reporting a measure of association for HBV and HL or HCV and HL. We calculated pooled relative risks (RR) and their 95% confidence intervals (CI). RESULTS: Pooling nine HBV studies with 1,762 HL cases yielded an RR of 1.39 (95% CI, 1.00-1.94) and pooling 15 HCV studies with 4,837 HL cases resulted in an RR of 1.09 (95% CI, 0.88-1.35). Meta-analyzing by study design, hepatitis detection method, and region revealed two subgroups with statistically significant associations-HCV studies that used hospital-based controls and/or were conducted in the West Pacific. No included study assessed age or EBV tumor status in relation to HL. CONCLUSIONS: Although we did not find an association between HBV or HCV and HL, research assessing the impact of age and EBV tumor status was lacking. IMPACT: The effect of HBV or HCV infection in the development of HL remains unclear.

Estimating the future cancer management costs attributable to modifiable risk factors in Canada.

OBJECTIVES: An estimated 33-37% of incident cancers in Canada are attributable to modifiable risk factors. Interventions targeting these risk factors would minimize the substantial health and economic burdens Canadians face due to cancer. We estimate the future health and economic burden of cancer in Canada by incorporating data from the Canadian Population Attributable Risk of Cancer (ComPARe) study into OncoSim, a web-based microsimulation tool. METHODS: Using the integrated OncoSim population attributable risk and population impact measures, we evaluated risk factor-targeted intervention scenarios implemented in 2020, assuming the targeted risk factor prevalence reduction would be achieved by 2032 with a 12-year latency period. RESULTS: We estimate that smoking will be the largest contributor to cancer-related costs, with a cost of CAD $44.4 billion between 2032 and 2044. An estimated CAD $3.3 billion of the cost could be avoided with a 30% reduction in smoking prevalence by 2022. Following smoking, the next highest cancer management costs are associated with inadequate physical activity and excess body weight, accounting for CAD $10.7 billion ($2.7 billion avoidable) and CAD $9.8 billion ($3.2 billion avoidable), respectively. Avoidable costs for other risk factors range from CAD $90 million to CAD $2.5 billion. CONCLUSION: Interventions targeting modifiable cancer risk factors could prevent a substantial number of incident cancer cases and billions of dollars in cancer management costs. With limited budgets and rising costs in cancer care in Canada, these simulation models and results are valuable for researchers and policymakers to inform decisions and prioritize and evaluate intervention programs.

RéSUMé: OBJECTIFS: Il est estimé que de 33 % à 37 % des cancers incidents au Canada sont imputables à des facteurs de risque modifiables. Des interventions ciblant ces facteurs de risque réduiraient le fardeau sanitaire et économique considérable du cancer dans la population canadienne. Nous avons estimé le futur fardeau sanitaire et économique du cancer au Canada en intégrant les données de l'étude ComPARe (Canadian Population Attributable Risk of Cancer) dans l'outil de microsimulation en ligne OncoSim. MéTHODE: À l'aide des indicateurs d'impact dans la population et du risque attribuable dans la population intégrés dans OncoSim, nous avons évalué des scénarios d'intervention mis en œuvre en 2020 axés sur les facteurs de risque, en partant de l'hypothèse que la réduction de la prévalence des facteurs de risque ciblés serait atteinte d'ici 2032 avec une période de latence de 12 ans. RéSULTATS: Nous estimons que le tabagisme sera le facteur qui contribuera le plus aux coûts du cancer, avec un coût de 44,4 milliards $ CA entre 2032 et 2044. Il est estimé qu'une part de 3,3 milliards $ CA de ce coût pourrait être évitée en réduisant de 30 % la prévalence du tabagisme d'ici 2022. Après le tabagisme, les coûts de prise en charge du cancer les plus élevés sont associés à l'inactivité physique et au surpoids, qui représentent respectivement 10,7 milliard $ CA (dont 2,7 milliards $ évitables) et 9,8 milliards $ CA (dont 3,2 milliards $ évitables). Les coûts évitables pour d'autres facteurs de risque vont de 90 millions $ CA à 2,5 milliards $ CA. CONCLUSION: Des interventions ciblant les facteurs de risque de cancer modifiables pourraient prévenir un nombre considérable de cas de cancers incidents et épargner des milliards de dollars en coûts de prise en charge du cancer. Avec les budgets serrés et la hausse des coûts des soins du cancer au Canada, ces modèles de simulation et leurs résultats permettent aux chercheurs et aux responsables des politiques d'éclairer les décisions et de hiérarchiser et d'évaluer les programmes d'intervention.

Estimates of future cancer mortality attributable to modifiable risk factors in Canada.

OBJECTIVES: Modifiable lifestyle, environmental, and infectious risk factors associated with cancer impact both cancer incidence and mortality at the population level. Most studies estimating this burden focus on cancer incidence. However, because these risk factors are associated with cancers of disparate mortality rates, the burden associated with cancer incidence could differ from cancer mortality. Therefore, estimating the cancer mortality attributable to these risk factors provides additional insight into cancer prevention. Here, we estimated future cancer deaths and the number of avoidable deaths in Canada due to modifiable risk factors. METHODS: The projected cancer mortality data came from OncoSim, a web-based microsimulation tool. These data were applied to the methodological framework that we previously used to estimate the population attributable risks and the potential impact fractions of modifiable risk factors on Canadian cancer incidence. RESULTS: We estimated that most cancer deaths will be attributed to tobacco smoking with an average of 27,900 deaths annually from 2024 to 2047. If Canada's current trends in excess body weight continue, cancer deaths attributable to excess body weight would double from 2786 deaths in 2024 to 5604 deaths in 2047, becoming the second leading modifiable cause of cancer death. Applying targets to reduce these risk factors, up to 34,600 cancer deaths could be prevented from 2024 to 2047. CONCLUSION: Our simulated results complement our previous findings on the cancer incidence burden since decreasing the overall burden of cancer will be accelerated through a combination of decreasing cancer incidence and improving survival outcomes through improved treatments.

RéSUMé: OBJECTIFS: Les facteurs de risque modifiables associés au cancer (liés au mode de vie, à l'environnement, aux maladies infectieuses) ont des effets à la fois sur l'incidence du cancer et sur la mortalité par cancer à l'échelle de la population. La plupart des études qui estiment ce fardeau portent sur l'incidence du cancer. Cependant, comme les facteurs de risque susmentionnés sont associés à des cancers dont les taux de mortalité sont disparates, le fardeau associé à l'incidence du cancer pourrait différer de la mortalité par cancer. En conséquence, l'estimation de la mortalité par cancer imputable à ces facteurs de risque pourrait éclairer la prévention du cancer. Nous estimons ici les décès futurs par cancer et le nombre de décès évitables au Canada dus à des facteurs de risque modifiables. MéTHODE: Les données projetées sur la mortalité par cancer proviennent d'OncoSim, un outil de microsimulation en ligne. Elles ont été appliquées au cadre méthodologique que nous avions déjà utilisé pour estimer les risques attribuables dans la population et les fractions de l'incidence potentielle des facteurs de risque modifiables sur l'incidence canadienne du cancer. RéSULTATS: Selon nos estimations, entre 2024 et 2047, la plupart des décès par cancer seront imputés au tabagisme, qui causera en moyenne 27 900 décès par année. Si les tendances actuelles au Canada en matière de surpoids se maintiennent, les décès par cancer attribuables au surpoids doubleraient, passant de 2 786 décès en 2024 à 5 604 en 2047, et le surpoids deviendrait la deuxième cause modifiable de décès par cancer. En appliquant des cibles de réduction de ces facteurs de risque, jusqu'à 34 600 décès par cancer pourraient être évités entre 2024 et 2047. CONCLUSION: Les résultats de notre simulation confirment nos constatations antérieures sur le fardeau de l'incidence du cancer, car la diminution du fardeau global du cancer sera accélérée par une combinaison de la diminution de l'incidence du cancer et de l'amélioration des résultats de survie grâce à l'amélioration des traitements.

The future burden of cancer in Canada: Long-term cancer incidence projections 2013-2042.

BACKGROUND: Cancer is the leading cause of death in Canada and the estimated annual spending associated with cancer is approximately $7.5 billion. Projecting the future burden of cancer in Canada is essential for health planning and evaluation. We aimed to estimate the future incidence of cancer in Canada to 2042. METHODS: Age-sex-region-specific cancer incidence data were obtained for the years 1983-2012 and cancer incidence was projected from 2013 to 2042 for the top five cancer sites. The modelling algorithm combined a mixture of cancer projection methods to select the best-fitted model. When the chosen model produced by the modelling algorithm resulted in estimates that were not consistent with expert opinion, an alternate model was selected that took into consideration historical changes in policy, screening and lifestyle behaviours. Incidence projections were made for Canada and its provinces. RESULTS: Lung cancer incidence is estimated to rise to 14,866 cases in men and 19,162 in women in 2042. Colorectal cancer incidence is estimated to rise to 28,146 in men and 21,102 in women. Cases of bladder cancer are projected to rise to 10,708 and 3,364 in men and women, respectively. Breast cancer incidence is predicted to rise to 40,712 and prostate cancer incidence is projected to rise to 92,949. CONCLUSION: These cancer incidence projections up to 2042 can be used for planning cancer control strategies and prevention programs. Given the ongoing changes in the prevalence of risk factors and in cancer prevention policies, these estimates should be interpreted with caution.

The influence of three e-cigarette models on indoor fine and ultrafine particulate matter concentrations under real-world conditions.

Electronic cigarette (e-cigarette) use has steadily increased since 2010. Indoor e-cigarette use exposes bystanders to a new source of particulate matter (PM) air pollution. Elevated short-term exposures to PM with a lower measuremented aerodynamic diameter (≤2.5 µm), PM2.5 and ultrafine particles (UFPs) have been linked to increased risk of adverse respiratory and cardiac events. This exposure study estimated concentrations of PM2.5 and UFPs from indoor e-cigarette use at 0.5 meters (m) and 1 m away from an e-cigarette user and investigated whether these indoor concentrations varied across three common e-cigarette models. One e-cigarette user tested three different e-cigarettes containing the same nicotine solution on three separate occasions and measured concentrations on PM2.5 and UFPs at 0.5 and 1 m in a ∼38 m3 office. Continuous measures of PM2.5 and UFPs were taken for 5.5 min before e-cigarette use, then the user puffed seven times for 6.5 min (exposure), and for 10 min after ceasing e-cigarette use. Following the initiation of e-cigarette use, levels of PM2.5 increased 160-fold at a distance of 0.5 m, and 103-fold at 1 m. The corresponding increases in UFP counts were 5.2, and 3.0-fold higher, respectively. The PM2.5 concentrations and UFP counts between e-cigarette models were statistically significantly different at 1 m, but not at 0.5 m. There was substantial variability between distances, e-cigarettes, and replicates. This study indicates that e-cigarette vapors influence PM2.5 and UFPs concentrations/counts at close proximity distances indoors; additional research is needed to characterize the composition of those particles and evaluate the impacts of other e-cigarette solutions on indoor air quality.