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John Martin tells the history of Newfoundland's fluorspar mines from their founding to the last shipment of fluorspar in 1990 and declaration of bankruptcy a year later. He focuses on the health hazards experienced by the miners, and how the mining companies, workers, governments, and health services came to terms with the unfolding human tragedy. He also covers such matters as the improvement of methods for dust quantification and radiation surveillance in the mines, battles for compensation, and the influence of the St Lawrence case on the development of labour law in the province.

High-risk persons were screened for lung cancer in a population-based, randomized, controlled trial that involved volume-based nodule management for further testing. At 10 years of follow-up, lung-cancer mortality was significantly lower in the screening group than in the control group (2.5 vs. 3.3 per 1000 person-years among male participants).

BackgroundITALUNG is contributing to the European evaluation of low-dose CT (LDCT) screening for lung cancer (LC).MethodsEligible subjects aged 55–69 years, smokers or ex-smokers (at least 20 pack-years in the last 10 years), were randomised to receive an annual invitation for LDCT screening for 4 years (active group) or to usual care (control group). All participants were followed up for vital status and cause of death (at the end of 2014) and LC incidence (at the end of 2013). Pathological and clinical information was collected from the Tuscan Cancer Registry data.Results1613 subjects were randomly assigned to the active group and 1593 to the control group. At the end of the follow-up period 67 LC cases were diagnosed in the active group and 71 in the control group (rate ratio (RR)=0.93; 95% CI 0.67 to 1.30). A greater proportion of stage I LC was observed in the active group (36% vs 11%, p<0.001). Non-significant reductions of 17% (RR=0.83; 95% CI 0.67 to 1.03) for overall mortality and 30% (RR=0.70; 95% CI 0.47 to 1.03) for LC-specific mortality were estimated.ConclusionsDespite the lack of statistical significance, the ITALUNG trial outcomes suggest that LDCT screening could reduce LC and overall mortality. Moreover, the comparison of the number of LC cases diagnosed in the two groups does not show overdiagnosis after an adequate follow-up period. A pooled analysis of all European screening trials is advocated to assess the benefit-to-harm ratio of LDCT screening and its implementation in public health settings.Trial registration numberResults, NCT02777996.

Objective To estimate the cumulative radiation exposure and lifetime attributable risk of cancer incidence associated with lung cancer screening using annual low dose computed tomography (CT).Design Secondary analysis of data from a lung cancer screening trial and risk-benefit analysis.Setting 10 year, non-randomised, single centre, low dose CT, lung cancer screening trial (COSMOS study) which took place in Milan, Italy in 2004-15 (enrolment in 2004-05). Secondary analysis took place in 2015-16.Participants High risk asymptomatic smokers aged 50 and older, who were current or former smokers (≥20 pack years), and had no history of cancer in the previous five years.Main outcome measures Cumulative radiation exposure from low dose CT and positron emission tomography (PET) CT scans, calculated by dosimetry software; and lifetime attributable risk of cancer incidence, calculated from the Biological Effects of Ionizing Radiation VII (BEIR VII) report.Results Over 10 years, 5203 participants (3439 men, 1764 women) underwent 42 228 low dose CT and 635 PET CT scans. The median cumulative effective dose at the 10th year of screening was 9.3 mSv for men and 13.0 mSv for women. According to participants’ age and sex, the lifetime attributable risk of lung cancer and major cancers after 10 years of CT screening ranged from 5.5 to 1.4 per 10 000 people screened, and from 8.1 to 2.6 per 10 000 people screened, respectively. In women aged 50-54, the lifetime attributable risk of lung cancer and major cancers was about fourfold and threefold higher than for men aged 65 and older, respectively. The numbers of lung cancer and major cancer cases induced by 10 years of screening in our cohort were 1.5 and 2.4, respectively, which corresponded to an additional risk of induced major cancers of 0.05% (2.4/5203). 259 lung cancers were diagnosed in 10 years of screening; one radiation induced major cancer would be expected for every 108 (259/2.4) lung cancers detected through screening.Conclusion Radiation exposure and cancer risk from low dose CT screening for lung cancer, even if non-negligible, can be considered acceptable in light of the substantial mortality reduction associated with screening.

Inflammation in the tumour microenvironment mediated by interleukin 1β is hypothesised to have a major role in cancer invasiveness, progression, and metastases. We did an additional analysis in the Canakinumab Anti-inflammatory Thrombosis Outcomes Study (CANTOS), a randomised trial of the role of interleukin-1β inhibition in atherosclerosis, with the aim of establishing whether inhibition of a major product of the Nod-like receptor protein 3 (NLRP3) inflammasome with canakinumab might alter cancer incidence. We did a randomised, double-blind, placebo-controlled trial of canakinumab in 10 061 patients with atherosclerosis who had had a myocardial infarction, were free of previously diagnosed cancer, and had concentrations of high-sensitivity C-reactive protein (hsCRP) of 2 mg/L or greater. To assess dose–response effects, patients were randomly assigned by computer-generated codes to three canakinumab doses (50 mg, 150 mg, and 300 mg, subcutaneously every 3 months) or placebo. Participants were followed up for incident cancer diagnoses, which were adjudicated by an oncology endpoint committee masked to drug or dose allocation. Analysis was by intention to treat. The trial is registered with ClinicalTrials.gov, NCT01327846. The trial is closed (the last patient visit was in June, 2017). Baseline concentrations of hsCRP (median 6·0 mg/L vs 4·2 mg/L; p<0·0001) and interleukin 6 (3·2 vs 2·6 ng/L; p<0·0001) were significantly higher among participants subsequently diagnosed with lung cancer than among those not diagnosed with cancer. During median follow-up of 3·7 years, compared with placebo, canakinumab was associated with dose-dependent reductions in concentrations of hsCRP of 26–41% and of interleukin 6 of 25–43% (p<0·0001 for all comparisons). Total cancer mortality (n=196) was significantly lower in the pooled canakinumab group than in the placebo group (p=0·0007 for trend across groups), but was significantly lower than placebo only in the 300 mg group individually (hazard ratio [HR] 0·49 [95% CI 0·31–0·75]; p=0·0009). Incident lung cancer (n=129) was significantly less frequent in the 150 mg (HR 0·61 [95% CI 0·39–0·97]; p=0·034) and 300 mg groups (HR 0·33 [95% CI 0·18–0·59]; p<0·0001; p<0·0001 for trend across groups). Lung cancer mortality was significantly less common in the canakinumab 300 mg group than in the placebo group (HR 0·23 [95% CI 0·10–0·54]; p=0·0002) and in the pooled canakinumab population than in the placebo group (p=0·0002 for trend across groups). Fatal infections or sepsis were significantly more common in the canakinumab groups than in the placebo group. All-cause mortality did not differ significantly between the canakinumab and placebo groups (HR 0·94 [95% CI 0·83–1·06]; p=0·31). Our hypothesis-generating data suggest the possibility that anti-inflammatory therapy with canakinumab targeting the interleukin-1β innate immunity pathway could significantly reduce incident lung cancer and lung cancer mortality. Replication of these data in formal settings of cancer screening and treatment is required. Novartis Pharmaceuticals.

US guidelines now recommend lung cancer screening with low-dose CT for high-risk individuals. Reports of new nodules after baseline screening have been scarce and are inconsistent because of differences in definitions used. We aimed to identify the occurrence of new solid nodules and their probability of being lung cancer at incidence screening rounds in the Dutch-Belgian Randomized Lung Cancer Screening Trial (NELSON). In the ongoing, multicentre, randomised controlled NELSON trial, between Dec 23, 2003, and July 6, 2006, 15 822 participants who had smoked at least 15 cigarettes a day for more than 25 years or ten cigarettes a day for more than 30 years and were current smokers, or had quit smoking less than 10 years ago, were enrolled and randomly assigned to receive either screening with low-dose CT (n=7915) or no screening (n=7907). From Jan 28, 2004, to Dec 18, 2006, 7557 individuals underwent baseline screening with low-dose CT; 7295 participants underwent second and third screening rounds. We included all participants with solid non-calcified nodules, registered by the NELSON radiologists as new or smaller than 15 mm3 (study detection limit) at previous screens. Nodule volume was generated semiautomatically by software. We calculated the maximum volume doubling time for nodules with an estimated percentage volume change of 25% or more, representing the minimum growth rate for the time since the previous scan. Lung cancer diagnosis was based on histology, and benignity was based on histology or stable size for at least 2 years. The NELSON trial is registered at trialregister.nl, number ISRCTN63545820. We analysed data for participants with at least one solid non-calcified nodule at the second or third screening round. In the two incidence screening rounds, the NELSON radiologists registered 1222 new solid nodules in 787 (11%) participants. A new solid nodule was lung cancer in 49 (6%) participants with new solid nodules and, in total, 50 lung cancers were found, representing 4% of all new solid nodules. 34 (68%) lung cancers were diagnosed at stage I. Nodule volume had a high discriminatory power (area under the receiver operating curve 0·795 [95% CI 0·728–0·862]; p<0·0001). Nodules smaller than 27 mm3 had a low probability of lung cancer (two [0·5%] of 417 nodules; lung cancer probability 0·5% [95% CI 0·0–1·9]), nodules with a volume of 27 mm3 up to 206 mm3 had an intermediate probability (17 [3·1%] of 542 nodules; lung cancer probability 3·1% [1·9–5·0]), and nodules of 206 mm3 or greater had a high probability (29 [16·9%] of 172 nodules; lung cancer probability 16·9% [12·0–23·2]). A volume cutoff value of 27 mm3 or greater had more than 95% sensitivity for lung cancer. Our study shows that new solid nodules are detected at each screening round in 5–7% of individuals who undergo screening for lung cancer with low-dose CT. These new nodules have a high probability of malignancy even at a small size. These findings should be considered in future screening guidelines, and new solid nodules should be followed up more aggressively than nodules detected at baseline screening. Zorgonderzoek Nederland Medische Wetenschappen and Koningin Wilhelmina Fonds Kankerbestrijding.

ObjectivesTo evaluate malignancies and their associations with baseline risk factors and cardiovascular risk scores with tofacitinib versus tumour necrosis factor inhibitors (TNFi) in patients with rheumatoid arthritis (RA).MethodsIn an open-label, randomised controlled trial (ORAL Surveillance; NCT02092467), 4362 patients with RA aged ≥50 years with ≥1 additional cardiovascular risk factor received tofacitinib 5 (N=1455) or 10 mg two times per day (N=1456) or TNFi (N=1451). Incidence rates (IRs; patients with first events/100 patient-years) and HRs were calculated for adjudicated malignancies excluding non-melanoma skin cancer (NMSC), NMSC and subtypes. Post hoc analyses for malignancies excluding NMSC, lung cancer and NMSC included risk factors identified via simple/multivariable Cox models and IRs/HRs categorised by baseline risk factors, history of atherosclerotic cardiovascular disease (HxASCVD) and cardiovascular risk scores.ResultsIRs for malignancies excluding NMSC and NMSC were higher with tofacitinib (combined and individual doses) versus TNFi. Risk of lung cancer (most common subtype with tofacitinib) was higher with tofacitinib 10 mg two times per day versus TNFi. In the overall study population, the risk of malignancies excluding NMSC was similar between both tofacitinib doses and TNFi until month 18 and diverged from month 18 onwards (HR (95% CIs) for combined tofacitinib doses: 0.93 (0.53 to 1.62) from baseline to month 18 vs 1.93 (1.22 to 3.06) from month 18 onwards, interaction p=0.0469). Cox analyses identified baseline risk factors across treatment groups for malignancies excluding NMSC, lung cancer and NMSC; interaction analyses generally did not show statistical evidence of interaction between treatment groups and risk factors. HxASCVD or increasing cardiovascular risk scores were associated with higher malignancy IRs across treatments.ConclusionsRisk of malignancies was increased with tofacitinib versus TNFi, and incidence was highest in patients with HxASCVD or increasing cardiovascular risk. This may be due to shared risk factors for cardiovascular risk and cancer.Trial registration numbers NCT02092467, NCT01262118, NCT01484561, NCT00147498, NCT00413660, NCT00550446, NCT00603512, NCT00687193, NCT01164579, NCT00976599, NCT01059864, NCT01359150, NCT02147587, NCT00960440, NCT00847613, NCT00814307, NCT00856544, NCT00853385, NCT01039688, NCT02281552, NCT02187055, NCT02831855, NCT00413699, NCT00661661

Angiotensin-receptor blockers (ARBs) are a widely used drug class approved for treatment of hypertension, heart failure, diabetic nephropathy, and, recently, for cardiovascular risk reduction. Experimental studies implicate the renin-angiotensin system, particularly angiotensin II type-1 and type-2 receptors, in the regulation of cell proliferation, angiogenesis, and tumour progression. We assessed whether ARBs affect cancer occurrence with a meta-analysis of randomised controlled trials of these drugs. We searched Medline, Scopus (including Embase), Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, and the US Food and Drug Administration website for studies published before November, 2009, that included any of the seven currently available ARBs. Randomised controlled trials with an ARB given in at least one group, with a follow-up of at least 1 year, and that enrolled at least 100 patients were included. New-cancer data were available for 61 590 patients from five trials. Data on common types of solid organ cancers were available for 68 402 patients from five trials, and data on cancer deaths were available for 93 515 patients from eight trials. Telmisartan was the study drug in 30 014 (85·7%) patients who received ARBs as part of the trials with new cancer data. Patients randomly assigned to receive ARBs had a significantly increased risk of new cancer occurrence compared with patients in control groups (7·2% vs 6·0%, risk ratio [RR] 1·08, 95% CI 1·01–1·15; p=0·016). When analysis was limited to trials where cancer was a prespecified endpoint, the RR was 1·11 (95% CI 1·04–1·18, p=0·001). Among specific solid organ cancers examined, only new lung-cancer occurrence was significantly higher in patients randomly assigned to receive ARBs than in those assigned to receive control (0·9% vs 0·7%, RR 1·25, 1·05–1·49; p=0·01). No statistically significant difference in cancer deaths was observed (1·8% vs 1·6%, RR 1·07, 0·97–1·18; p=0·183). This meta-analysis of randomised controlled trials suggests that ARBs are associated with a modestly increased risk of new cancer diagnosis. Given the limited data, it is not possible to draw conclusions about the exact risk of cancer associated with each particular drug. These findings warrant further investigation. None.

Abstract Rationale Smoking is the largest contributor to lung cancer risk, and those who continue to smoke after diagnosis have a worse survival. Screening for lung cancer with low-dose computed tomography (LDCT) reduces mortality in high-risk individuals. Smoking cessation is an essential component of a high-quality screening program. Objectives To quantify the effects of smoking history and abstinence on mortality in high-risk individuals who participated in the NLST (National Lung Screening Trial). Methods This is a secondary analysis of a randomized controlled trial (NLST). Measurements and Main Results Measurements included self-reported demographics, medical and smoking history, and lung cancer–specific and all-cause mortality. Cox regression was used to study the association of mortality with smoking status and pack-years. Kaplan-Meier survival curves were examined for differences in survival based on trial arm and smoking status. Current smokers had an increased lung cancer–specific (hazard ratio [HR], 2.14–2.29) and all-cause mortality (HR, 1.79–1.85) compared with former smokers irrespective of screening arm. Former smokers in the control arm abstinent for 7 years had a 20% mortality reduction comparable with the benefit reported with LDCT screening in the NLST. The maximum benefit was seen with the combination of smoking abstinence at 15 years and LDCT screening, which resulted in a 38% reduction in lung cancer–specific mortality (HR, 0.62; 95% confidence interval, 0.51–0.76). Conclusions Seven years of smoking abstinence reduced lung cancer–specific mortality at a magnitude comparable with LDCT screening. This reduction was greater when abstinence was combined with screening, highlighting the importance of smoking cessation efforts in screening programs.

BackgroundLung cancer screening using low-dose CT (LDCT) was shown to reduce lung cancer mortality by 20% in the National Lung Screening Trial.MethodsThe pilot UK Lung Cancer Screening (UKLS) is a randomised controlled trial of LDCT screening for lung cancer versus usual care. A population-based questionnaire was used to identify high-risk individuals. CT screen-detected nodules were managed by a pre-specified protocol. Cost effectiveness was modelled with reference to the National Lung Cancer Screening Trial mortality reduction.Results247 354 individuals aged 50–75 years were approached; 30.7% expressed an interest, 8729 (11.5%) were eligible and 4055 were randomised, 2028 into the CT arm (1994 underwent a CT). Forty-two participants (2.1%) had confirmed lung cancer, 34 (1.7%) at baseline and 8 (0.4%) at the 12-month scan. 28/42 (66.7%) had stage I disease, 36/42 (85.7%) had stage I or II disease. 35/42 (83.3%) had surgical resection. 536 subjects had nodules greater than 50 mm3 or 5 mm diameter and 41/536 were found to have lung cancer. One further cancer was detected by follow-up of nodules between 15 and 50 mm3 at 12 months. The baseline estimate for the incremental cost-effectiveness ratio of once-only CT screening, under the UKLS protocol, was £8466 per quality adjusted life year gained (CI £5542 to £12 569).ConclusionsThe UKLS pilot trial demonstrated that it is possible to detect lung cancer at an early stage and deliver potentially curative treatment in over 80% of cases. Health economic analysis suggests that the intervention would be cost effective—this needs to be confirmed using data on observed lung cancer mortality reduction.Trial registrationISRCTN 78513845.