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The aim of this study was to provide the most comprehensive and up-to-date evidence on the association between cigarette smoking and colorectal cancer (CRC) risk. We conducted a systematic review and meta-analysis of epidemiological studies on the association between cigarette smoking and CRC risk published up to September 2018. We calculated relative risk (RR) of CRC according to smoking status, intensity, duration, pack-years, and time since quitting, with a focus on molecular subtypes of CRC. The meta-analysis summarizes the evidence from 188 original studies. Compared with never smokers, the pooled RR for CRC was 1.14 (95% confidence interval [CI] 1.10-1.18) for current smokers and 1.17 (95% CI 1.15-1.20) for former smokers. CRC risk increased linearly with smoking intensity and duration. Former smokers who had quit smoking for more than 25 years had significantly decreased risk of CRC compared with current smokers. Smoking was strongly associated with the risk of CRC, characterized by high CpG island methylator phenotype (RR 1.42; 95% CI 1.20-1.67; number of studies [n] = 4), BRAF mutation (RR 1.63; 95% CI 1.23-2.16; n = 4), or high microsatellite instability (RR 1.56; 95% CI 1.32-1.85; n = 8), but not characterized by KRAS (RR 1.04; 95% CI 0.90-1.20; n = 5) or TP53 (RR 1.13; 95% CI 0.99-1.29; n = 5) mutations. Cigarette smoking increases the risk of CRC in a dose-dependent manner with intensity and duration, and quitting smoking reduces CRC risk. Smoking greatly increases the risk of CRC that develops through the microsatellite instability pathway, characterized by microsatellite instability-high, CpG island methylator phenotype positive, and BRAF mutation.

Chronic stress induces signalling from the sympathetic nervous system (SNS) and drives cancer progression, although the pathways of tumour cell dissemination are unclear. Here we show that chronic stress restructures lymphatic networks within and around tumours to provide pathways for tumour cell escape. We show that VEGFC derived from tumour cells is required for stress to induce lymphatic remodelling and that this depends on COX2 inflammatory signalling from macrophages. Pharmacological inhibition of SNS signalling blocks the effect of chronic stress on lymphatic remodelling in vivo and reduces lymphatic metastasis in preclinical cancer models and in patients with breast cancer. These findings reveal unanticipated communication between stress-induced neural signalling and inflammation, which regulates tumour lymphatic architecture and lymphogenous tumour cell dissemination. These findings suggest that limiting the effects of SNS signalling to prevent tumour cell dissemination through lymphatic routes may provide a strategy to improve cancer outcomes. Adverse life events have been associated with reduced survival in cancer patients. Here, the authors explore the mechanism responsible and show that chronic stress in mice activates a signalling cascade in macrophages and tumour cells, which results in restructuring of the tumour lymphatic system, promoting metastasis.

INTRODUCTION:To examine the association between low-dose aspirin use and risk of colorectal cancer (CRC).METHODS:In this nationwide cohort study, we identified individuals aged 50 years or older residing for 6 months or more in Norway in 2004-2018 and obtained data from national registers on drug prescriptions, cancer occurrence, and sociodemographic factors. Multivariable Cox regression models were used to estimate the association between low-dose aspirin use and CRC risk. In addition, we calculated the number of CRC potentially averted by low-dose aspirin use.RESULTS:We included 2,186,390 individuals. During the median follow-up of 10.9 years, 579,196 (26.5%) used low-dose aspirin, and 38,577 (1.8%) were diagnosed with CRC. Current use of aspirin vs never use was associated with lower CRC risk (hazard ratio [HR] 0.87, 95% confidence interval [CI] 0.84-0.90). The association was more pronounced for metastatic CRC (HR 0.79; 95% CI 0.74-0.84) than regionally advanced (HR 0.89; 95% CI 0.85-0.92) and localized CRC (HR 0.93; 95% CI 0.87-1.00; P heterogeneity = 0.001). A significant trend was found between duration of current use and CRC risk: HR 0.91 (95% CI 0.86-0.95) for <3 years, HR 0.85 (0.80-0.91) for ≥3 and <5 years, and HR 0.84 (0.80-0.88) for ≥5 years of use vs never use (P trend < 0.001). For past use, HR were 0.89 (95% CI 0.84-0.94) for <3 years, 0.90 (0.83-0.99) for ≥3 and <5 years, and 0.98 (0.91-1.06) for ≥5 years since last use vs never use (P-trend < 0.001). We estimated that aspirin use averted 1,073 cases of CRC (95% CI 818-1,338) in the study period.DISCUSSION:In this nationwide cohort, use of low-dose aspirin was associated with a lower risk of CRC.

ObjectivesAccurate identification of adverse events after colonoscopy is essential for quality assurance in colorectal cancer (CRC) screening. Review of medical records is labour intensive as adverse events are infrequent. The object of this study was to investigate the accuracy of claims data in identifying adverse events after colonoscopy in CRC screening.DesignCross-sectional, retrospective.Setting and participantsMales and females aged 50–74 years were randomised to once-only sigmoidoscopy or biennial faecal immunochemical test in a CRC screening trial at two screening centres in Norway. Participants in the present study underwent follow-up colonoscopy from 2012 to April 2020 after initial positive screening test. We reviewed medical records for adverse events within 30 days following 11 205 colonoscopies.Primary and secondary outcome measuresThe primary outcome of the study was to assess the sensitivity of claims data from the Norwegian Patient Registry to identify lower gastrointestinal bleeding using emergency contact International Statistical Classification of Diseases and Related Health Problems 10th Revision diagnostic code sets under two definitions: a stringent definition (codes explicitly identifying bleeding) and a broad definition (including suggestive codes). Secondary outcome measures included the sensitivity to identify perforation using a stringent and a broad definition. Additionally, we assessed whether incorporating procedure codes and non-emergency contacts improved accuracy.Results87 cases of lower gastrointestinal bleeding and eight perforations were confirmed. Sensitivity for bleeding differed between the centres (p<0.001). At centre 1, sensitivity was 48.6% (95% CI 31.9% to 65.6%) using the stringent and 89.2% (95% CI 74.6% to 97.0%) using the broad definition. At centre 2, sensitivity was 36.0% (95% CI 22.9% to 50.8%) and 50.0% (95% CI 35.5% to 64.5%), respectively. Combined sensitivity for perforation was 37.5% (95% CI 8.5% to 75.5%) using the stringent and 62.5% (95% CI 24.5% to 91.5%) using the broad definition. Adding procedure codes and non-emergency contacts slightly increased sensitivity but increased false positives.ConclusionsUse of claims data underestimated adverse event rates following colonoscopy. Difference in coding practice across hospitals underscores the need for standardised reporting in screening programmes.Trial registration numberNCT01538550.

Background Aspirin and non-aspirin non-steroidal anti-inflammatory drugs (NA-NSAID) have been associated with improved survival in individuals with epithelial ovarian cancer (EOC); however, findings to date are inconsistent. Methods We conducted a registry-based cohort study evaluating survival following an incident invasive EOC diagnosis including individuals diagnosed between 2004–2018 (n = 4325; n = 2206 deaths; n = 1973 EOC deaths). Evaluated exposures were low-dose aspirin and NA-NSAIDs. Two primary post-diagnosis exposure windows were evaluated: fixed post-diagnostic baseline exposure ≤ 305 days after diagnosis (use, non-use) and updated “time-varying” exposure (never, past, current use; cumulative defined daily dose (DDD)). Pre-diagnostic exposure (use, non-use) was further evaluated. Multivariable Cox-proportional hazard models were used to estimate hazard ratios (HRs) and 95% confidence intervals [95% CIs]. The primary outcome was cause-specific survival. Restricted mean survival time (RMST) in exposure groups was estimated at 5 years following start of follow-up. Results Baseline post-diagnosis aspirin use was not associated with survival following an EOC diagnosis (e.g., use vs. no use: aspirin, HR = 1.02 [95% CI = 0.84–1.24]). Inverse associations were observed between current aspirin use post-diagnosis and survival in the time-varying exposure models (HR 0.68 [0.57–0.81]), and with higher post-diagnosis cumulative DDD of aspirin. Findings for NA-NSAIDs were less consistent. No associations were observed for pre-diagnostic use. Results for overall survival were similar to those for cause-specific survival. Compared to never use, post-diagnosis low-dose aspirin use was associated with a longer RMST (e.g., ever vs. never use, difference in RMST = 2.67 months). Conclusions This study provides further evidence of a potential beneficial effect of post-diagnosis low-dose aspirin use for ovarian cancer survival.

Background Cancer is a leading cause of premature death worldwide and incidence is expected to rise in the coming decades. Many cohort studies, measuring lifestyle factors at one time-point, have observed that overall healthy lifestyles were inversely related to cancer incidence. However, there is little knowledge on the impact of lifestyle modification within adulthood. Methods Using the Norwegian Women and Cancer study, two repeated self-reported assessments of lifestyle behaviours were used to calculate healthy lifestyle index scores at each time-point ( N  = 66 233). The associations between change in healthy lifestyle index score and lifestyle-related cancer incidence, including alcohol-, tobacco-, obesity-, and reproductive-related, and site-specific breast and colorectal cancer incidence were estimated using Cox proportional hazard regression models. To assess nonlinearity in the dose–response relationships, restricted cubic spline models were used. Results Independent of baseline lifestyle, positive lifestyle changes were inversely related to the incidence of overall lifestyle-related cancers, as well as alcohol-related, tobacco-related, obesity-related, and reproductive-related cancers, but not breast and colorectal site-specific cancers. An association between lifestyle worsening and cancer incidence compared to stable lifestyle was observed. Conclusions This study provides evidence that overall lifestyle changes among cancer-free women between the ages of 41 and 76 impact the incidence of many cancer types. Regardless of baseline lifestyle, there was a negative dose–response relationship between magnitude of positive lifestyle change and the incidence of overall lifestyle-related cancers. We observed that underlying this trend was an especially clear association between lifestyle worsening and increased risk compared to stable lifestyle. For adult women, maintaining a stable healthy lifestyle and lifestyle improvement are important for preventing the occurrence of many cancer types.

Background Previous studies assessed the prognostic effect of aspirin, statins, and metformin in breast cancer (BC) patients, with inconclusive results. Methods We performed a nationwide population-based cohort study to evaluate if post-diagnostic use of low-dose aspirin, statins, and metformin was associated with BC-specific survival. Women aged ≥ 50 years and diagnosed with BC in 2004–2017, who survived ≥ 12 months after diagnosis (follow-up started 12 months after diagnosis), were identified in the Cancer Registry of Norway. The Norwegian Prescription Database provided information on prescriptions. Multivariable Cox proportional hazard models were used to estimate hazard ratios (HR) and 95% confidence intervals (CI) for the association between post-diagnostic use and BC-specific survival, overall and by oestrogen receptor (ER) status. Results A total of 26,190 patients were included. Of these, 5324 (20%), 7591 (29%), and 1495 (6%) were post-diagnostic users of low-dose aspirin, statins, and metformin, respectively. The median follow-up was 6.1 years, and 2169 (8%) patients died from BC. HRs for use, compared to no use, were estimated at 0.96 (95% CI 0.85–1.08) for low-dose aspirin (ER+: HR = 0.97, 95% CI 0.83–1.13; ER−: HR = 0.97, 95% CI 0.73–1.29, p value for interaction = 0.562), 0.84 (95% CI 0.75–0.94) for statins (ER+: HR = 0.95, 95% CI 0.82–1.09; ER−: HR = 0.77, 95% CI 0.60–1.00, p value for interaction = 0.259), and 0.70 (95% CI 0.51–0.96) for metformin (compared to use of non-metformin antidiabetics) (ER+: HR = 0.67, 95% CI 0.45–1.01; ER−: HR = 1.62, 95% CI 0.72–3.62, p value for interaction = 0.077). Conclusion We found evidence supporting an association between post-diagnostic use of statins and metformin and survival, in patients with BC. Our findings indicate potential differences according to ER status.

Background We assessed associations between metformin use and survival in a nationwide Norwegian cohort of lung cancer (LC) patients. Methods The study linked 22,324 LC patients from the Cancer Registry of Norway diagnosed 2005–2014 with the Norwegian Prescription Database. We estimated associations of pre- and post-diagnostic metformin use with overall survival (OS) and LC-specific survival (LCSS) using multivariable time-fixed and time-dependent Cox regression. Results Pre-diagnostic metformin use was not associated with improved survival in all patients. Nevertheless, pre-diagnostic metformin use was associated with better LCSS in squamous cell carcinoma (SCC) patients (hazard ratio (HR) = 0.79; 95% confidence interval (CI) 0.62–0.99) and in patients with regional stage SCC (HR = 0.67; 95%CI 0.47–0.95). Post-diagnostic metformin use was associated with improved LCSS in all patients (HR = 0.83; 95%CI 0.73–0.95), in patients with SCC (HR = 0.75; 95%CI 0.57–0.98), regional stage LC (HR = 0.74; 95%CI 0.59–0.94), and regional stage SCC (HR = 0.57; 95%CI 0.38–0.86). OS showed similar results. Analyses of cumulative use showed a dose-response relationship in all patients, patients with adenocarcinoma and SCC, and with regional and metastatic LC. Conclusions Metformin use was associated with improved survival, especially LCSS in patients with regional stage SCC. Further prospective studies are required to clarify the role of metformin in LC treatment.

Background/Objectives: To evaluate the cost-effectiveness of β-blocker use in addition to standard care compared to standard care alone for women with triple-negative breast cancer (TNBC), with effectiveness measured by years of life lived (YLL), quality-adjusted life years (QALYs), and equal-value life years (evLYs) gained. Methods: A population cohort Markov model was developed to compare clinical and economic outcomes for TNBC treated with 1) lifelong β-blocker prescription initiated at diagnosis in addition to standard care versus 2) standard care alone. Life-table modelling was used to capture mortality over a lifetime horizon for the estimated eligible population of Australian women diagnosed with TNBC in 2022 (n = 767). Costs were derived from Australian healthcare perspective, and measured in Australian dollars (AUD) at 2022 prices with 5 percent annual discounting and AUD 28,000 willingness to pay threshold applied. Results: The model estimated 628 (95% CI 139, 1035) YLL, 526 (116, 865) QALYs, and 566 (125, 932) evLYs gained in the β-blocker group compared to standard care. The difference in health costs between β-blocker and standard care groups was AUD −935,116 (−2,365,417, 405,350). The β-blocker intervention was dominant over standard care in terms of both QALYs and evLYs gained. Conclusions: Preliminary modelling suggests that implementing β-blockers as an adjunct pharmacotherapy in the treatment of TNBC was more effective and less costly than current standard care. Further monitoring of long-term outcomes is recommended to validate the findings of observational and preclinical studies, and define the incidence, severity, and cost of β-blocker associated adverse events in cancer populations.