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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.

Abstract Rationale The NELSON (Nederlands Leuvens Longkanker Screenings Onderzoek) trial is, with 15,822 participants, the largest European lung cancer computer tomography screening trial. A volumetry-based screening strategy, stringent criteria for a positive screening, and an increasing length of screening interval are particular features of the NELSON trial. Objectives To determine the effect of stringent referral criteria and increasing screening interval on the characteristics of screen-detected lung cancers, and to compare this across screening rounds, between sexes, and with other screening trials. Methods All NELSON participants with screen-detected lung cancer in the first three rounds were included. Lung cancer stage at diagnosis, histological subtype, and tumor localization were compared between the screening rounds, the sexes, and with other screening trials. Measurements and Main Results In the first three screening rounds, 200 participants were diagnosed with 209 lung cancers. Of these lung cancers, 70.8% were diagnosed at stage I and 8.1% at stage IIIB–IV, and 51.2% were adenocarcinomas. There was no significant difference in cancer stage, histology, or tumor localization across the screening rounds. Women were diagnosed at a significantly more favorable cancer stage than men. Compared with other trials, the screen-detected lung cancers of the NELSON trial were relatively more often diagnosed at stage I and less often at stage IIIB–IV. Conclusions Despite stringent criteria for a positive screening, an increasing length of screening interval, and few female participants, the screening strategy of the NELSON trial resulted in a favorable cancer stage distribution at diagnosis, which is essential for the effectiveness of our screening strategy. Clinical trial registered with www.trialregister.nl (ISRCTN63545820).

Objectives To provide an early risk assessment of extending screening intervals beyond five years for a human papillomavirus (HPV) based cervical screening programme in the Netherlands.Design 14 year follow-up of a population based randomised cohort from the POBASCAM randomised trial. Setting Organised cervical screening in the Netherlands, based on a programme of three screening rounds (each round done every five years).Participants 43 339 women aged 29-61 years with a negative HPV and/or negative cytology test participating in the POBASCAM trial. Interventions Women randomly assigned to HPV and cytology co-testing (intervention) or cytology testing only (control), and managed accordingly.Main outcome measures Cumulative incidence of cervical cancer and cervical intraepithelial neoplasia (CIN) grade 3 or worse (CIN3+). Associations with age were expressed as incidence rate ratios. In HPV positive women, reductions in CIN3+ incidence after negative cytology, HPV type 16/18 genotyping, and/or repeat cytology were estimated.Results The cumulative incidence of cervical cancer (0.09%) and CIN3+ (0.56%) among HPV negative women in the intervention group after three rounds of screening were similar to the cumulative among women with negative cytology in the control group after two rounds (0.09% and 0.69%, respectively). Cervical cancer and CIN3+ risk ratios were 0.97 (95% confidence interval 0.41 to 2.31, P=0.95) and 0.82 (0.62 to 1.09, P=0.17), respectively. CIN3+ incidence was 72.2% (95% confidence interval 61.6% to 79.9%, P<0.001) lower among HPV negative women aged at least 40 years than among younger women. No significant association between cervical cancer incidence and age could be demonstrated. CIN3+ incidence among HPV positive women with negative cytology, HPV 16/18 genotyping, and/or repeat cytology was 10.4 (95% confidence interval 5.9 to 18.4) times higher than among HPV negative women.Conclusions Long term incidences of cervical cancer and CIN3+ were low among HPV negative women in this study cohort, and supports an extension of the cervical screening interval beyond five years for women aged 40 years and older. HPV positive women with subsequent negative cytology, HPV16/18 genotyping, and/or repeat cytology have at least a fivefold higher risk of CIN3+ than HPV negative women, indicating that HPV based programmes with long intervals (>five years) should be implemented with risk stratification.Trial registration POBASCAM trial number ISRCTN20781131.

Daily aspirin reduces the long-term incidence of some adenocarcinomas, but effects on mortality due to some cancers appear after only a few years, suggesting that it might also reduce growth or metastasis. We established the frequency of distant metastasis in patients who developed cancer during trials of daily aspirin versus control. Our analysis included all five large randomised trials of daily aspirin (≥75 mg daily) versus control for the prevention of vascular events in the UK. Electronic and paper records were reviewed for all patients with incident cancer. The effect of aspirin on risk of metastases at presentation or on subsequent follow-up (including post-trial follow-up of in-trial cancers) was stratified by tumour histology (adenocarcinoma vs other) and clinical characteristics. Of 17 285 trial participants, 987 had a new solid cancer diagnosed during mean in-trial follow-up of 6·5 years (SD 2·0). Allocation to aspirin reduced risk of cancer with distant metastasis (all cancers, hazard ratio [HR] 0·64, 95% CI 0·48–0·84, p=0·001; adenocarcinoma, HR 0·54, 95% CI 0·38–0·77, p=0·0007; other solid cancers, HR 0·82, 95% CI 0·53–1·28, p=0·39), due mainly to a reduction in proportion of adenocarcinomas that had metastatic versus local disease (odds ratio 0·52, 95% CI 0·35–0·75, p=0·0006). Aspirin reduced risk of adenocarcinoma with metastasis at initial diagnosis (HR 0·69, 95% CI 0·50–0·95, p=0·02) and risk of metastasis on subsequent follow-up in patients without metastasis initially (HR 0·45, 95% CI 0·28–0·72, p=0·0009), particularly in patients with colorectal cancer (HR 0·26, 95% CI 0·11–0·57, p=0·0008) and in patients who remained on trial treatment up to or after diagnosis (HR 0·31, 95% CI 0·15–0·62, p=0·0009). Allocation to aspirin reduced death due to cancer in patients who developed adenocarcinoma, particularly in those without metastasis at diagnosis (HR 0·50, 95% CI 0·34–0·74, p=0·0006). Consequently, aspirin reduced the overall risk of fatal adenocarcinoma in the trial populations (HR 0·65, 95% CI 0·53–0·82, p=0·0002), but not the risk of other fatal cancers (HR 1·06, 95% CI 0·84–1·32, p=0·64; difference, p=0·003). Effects were independent of age and sex, but absolute benefit was greatest in smokers. A low-dose, slow-release formulation of aspirin designed to inhibit platelets but to have little systemic bioavailability was as effective as higher doses. That aspirin prevents distant metastasis could account for the early reduction in cancer deaths in trials of daily aspirin versus control. This finding suggests that aspirin might help in treatment of some cancers and provides proof of principle for pharmacological intervention specifically to prevent distant metastasis. None.

Application of the principles of total mesorectal excision to colon cancer by undertaking complete mesocolic excision (CME) has been proposed to improve oncological outcomes. We aimed to investigate whether implementation of CME improved disease-free survival compared with conventional colon resection. Data for all patients who underwent elective resection for Union for International Cancer Control (UICC) stage I–III colon adenocarcinomas in the Capital Region of Denmark between June 1, 2008, and Dec 31, 2011, were retrieved for this population-based study. The CME group consisted of patients who underwent CME surgery in a centre validated to perform such surgery; the control group consisted of patients undergoing conventional colon resection in three other hospitals. Data were collected from the Danish Colorectal Cancer Group (DCCG) database and medical charts. Patients were excluded if they had stage IV disease, metachronous colorectal cancer, rectal cancer (≤15 cm from anal verge) in the absence of synchronous colon adenocarcinoma, tumour of the appendix, or R2 resections. Survival data were collected on Nov 13, 2014, from the DCCG database, which is continuously updated by the National Central Office of Civil Registration. The CME group consisted of 364 patients and the non-CME group consisted of 1031 patients. For all patients, 4-year disease-free survival was 85·8% (95% CI 81·4–90·1) after CME and 75·9% (72·2–79·7) after non-CME surgery (log-rank p=0·0010). 4-year disease-free survival for patients with UICC stage I disease in the CME group was 100% compared with 89·8% (83·1–96·6) in the non-CME group (log-rank p=0·046). For patients with UICC stage II disease, 4-year disease-free survival was 91·9% (95% CI 87·2–96·6) in the CME group compared with 77·9% (71·6–84·1) in the non-CME group (log-rank p=0·0033), and for patients with UICC stage III disease, it was 73·5% (63·6–83·5) in the CME group compared with 67·5% (61·8–73·2) in the non-CME group (log-rank p=0·13). Multivariable Cox regression showed that CME surgery was a significant, independent predictive factor for higher disease-free survival for all patients (hazard ratio 0·59, 95% CI 0·42–0·83), and also for patients with UICC stage II (0·44, 0·23–0·86) and stage III disease (0·64, 0·42–1·00). After propensity score matching, disease-free survival was significantly higher after CME, irrespective of UICC stage, with 4-year disease-free survival of 85·8% (95% CI 81·4–90·1) after CME and 73·4% (66·2–80·6) after non-CME (log-rank p=0·0014). Our data indicate that CME surgery is associated with better disease-free survival than is conventional colon cancer resection for patients with stage I–III colon adenocarcinoma. Implementation of CME surgery might improve outcomes for patients with colon cancer. Tvergaards Fund and Edgar and Hustru Gilberte Schnohrs Fund.

In this large, randomized, placebo-controlled trial, a quadrivalent vaccine (including human papillomavirus types 6, 11, 16 and 18) given at day 1, month 2, and month 6 was associated with a significant reduction in the occurrence of cervical intraepithelial neoplasia. No beneficial effect was observed on prevalent lesions. The prevention benefit for incident lesions associated with HPV-16 and HPV-18 appears to increase with time. A quadrivalent vaccine (including human papillomavirus types 6, 11, 16 and 18) was associated with a significant reduction in the occurrence of cervical intraepithelial neoplasia. The prevention benefit for incident lesions associated with HPV-16 and HPV-18 appears to increase with time. Cervical cancer is the second most common cancer in women and the leading cause of cancer-related death in many developing countries. 1 Although well-organized programs for Papanicolaou screening have led to a significant decline in mortality from cervical cancer in developed countries, 1 such programs are costly 2 and have not been effectively implemented in most developing countries. 3 Human papillomaviruses (HPVs) cause virtually all cervical cancers, with HPV types 16 (HPV-16) and 18 (HPV-18) responsible for approximately 70%. 4 When phase 3 trials of prophylactic HPV vaccines were in the planning stages, the vaccine advisory committee of the Food and Drug Administration (FDA) recommended . . .

Supplemental calcium and vitamin D have been associated with a reduced risk of colorectal cancer in epidemiologic and polyp-prevention studies, but evidence from randomized trials was lacking. Although the long latency involved in colorectal cancer may be relevant, this Women's Health Initiative trial involving 36,282 postmenopausal women showed that daily calcium plus vitamin D supplementation for an average of seven years had no effect on the incidence of colorectal cancer. Although the long latency involved in colorectal cancer may be relevant, this trial involving postmenopausal women showed that daily calcium plus vitamin D supplementation for an average of seven years had no effect on the incidence of colorectal cancer. As the second leading cause of death from cancer in the United States, 1 colorectal cancer is the focus of considerable preventive effort. 2 Most observational studies have associated increased calcium and vitamin D intake with a decreased risk of colorectal cancer 3 – 6 and recurrent polyps. 7 , 8 Although the results are somewhat mixed, one pooled analysis of 10 cohort studies that assessed dietary consumption and total calcium intake (diet plus supplements) reported a reduction in the incidence of colorectal cancer of 10 to 15 percent, 9 whereas an earlier pooled analysis found no effect. 10 The suggestion that increased calcium intake helped prevent colorectal . . .

Gastric cancer is not a recognised extra-colonic manifestation of FAP, except in countries with a high prevalence of gastric cancer. Data regarding gastric adenomas in FAP are sparse. The aim of this study was to review the clinical characteristics of gastric tumours occurring within an FAP population from the largest European polyposis registry. All patients that developed a gastric adenoma or carcinoma were identified from a prospectively maintained registry database. The primary outcome measure was the occurrence of gastric adenoma or adenocarcinoma. Secondary outcomes included APC mutation, tumour stage, management and survival. Eight patients developed gastric cancer and 21 an adenoma (median age 52 and 44 years, respectively). Regular oesophagogastroduodenoscopy surveillance was performed in 6/8 patients who developed cancer. Half were advanced T3/4 tumours and 6/8 had nodal or metastatic spread at diagnosis. All cancer cases died within a median of 13.5 months from diagnosis. Gastric adenomas were evenly distributed: 11/21 (52%) in the distal and 10/21 (48%) proximal stomach, whereas 5/8 (63%) cancers were located proximally. An association between gastric tumour and desmoid development was observed; 7/8 (88%) cancer and 11/21 (52%) adenoma cases had a personal or family history of desmoid. It would appear from this small, retrospective study that gastric cancer is not a prominent extra-colonic feature of FAP in the Western world. It seems to present at an advanced stage with a poor prognosis. There may be an association between gastric tumour and desmoid occurrence but a large multicentre cohort is necessary to investigate this further.

Cervical cancer is a serious health problem, with nearly 500 000 women developing the disease each year worldwide. Most cases occur in less developed countries where no effective screening systems are available. Risk factors include exposure to human papillomavirus, smoking, and immune-system dysfunction. Most women with early-stage tumours can be cured, although long-term morbidity from treatment is common. Results of randomised clinical trials have shown that for women with locally advanced cancers, chemoradiotherapy should be regarded as the standard of care; however, the applicability of this treatment to women in less developed countries remains largely untested. Many women with localised (stage IB) tumours even now receive various combinations of surgery and radiotherapy, despite unresolved concern about the morbidity of this approach compared with definitive radiotherapy or radical surgery. Treatment of recurrent cervical cancer remains largely ineffective. Quality of life should be taken into account in treatment of women with primary and recurrent cervical cancer.

Objective To compare the detection rates of precancerous and cancerous cervical lesions by human papillomavirus (HPV) DNA testing and by conventional cytology screening. Design Prospective randomised trial. Two cohorts were followed over one screening round of five years, screened initially by primary HPV DNA testing or by primary Pap test.Setting Population based programme for cervical cancer screening in Finland. Participants Women aged 25-65 years invited for screening in 2003-07 (101 678 in HPV arm; 101 747 in conventional cytology arm). Intervention Women were randomly allocated (1:1) to primary HPV DNA screening followed by cytology triage if they had positive results, or to primary cytology screening. Screening method was disclosed at the screening visit. Trial personnel involved were aware of all test results.Main outcome measures Cumulative detection rates of cervical intraepithelial neoplasia (CIN), adenocarcinoma in situ (AIS), and invasive cervical cancer before the second screening (after five years) or before 31 December 2008. Lesions detected at screening and during the five year interval were included.Results 1010 and 701 precancerous or cancerous lesions were detected during an average follow-up of 3.6 years in the HPV and cytology arms, respectively. Among invited women, the hazard ratio was 1.53 (95% confidence interval l.28 to 1.84) for CIN grade 1, 1.54 (1.33 to 1.78) for CIN 2, 1.32 (1.09 to 1.59) for CIN 3 or AIS, and 0.81 (0.48 to 1.37) for cervical cancer. In 25-34 year old participants, the cumulative hazard (or cumulative detection rate) was 0.0057 (0.0045 to 0.0072) for HPV screening versus 0.0046 (0.0035 to 0.0059) for conventional screening; corresponding data for women aged 35 years and older were 0.0022 (0.0019 to 0.0026) and 0.0017 (0.0014 to 0.0021), respectively.Conclusions Primary HPV DNA screening detects more cervical lesions than primary cytology within one screening round of five years. Even if the detection rate of CIN 3 or AIS increased in the HPV arm in both age groups, the absolute difference in cumulative rates in women aged 35 years or older was small. By carefully selecting age groups and screening intervals, HPV screening could increase the overall detection rate of cervical precancerous lesions only slightly. However, these findings should be interpreted in the context of the high level of opportunistic screening that occurs in Finland.Trial registration International Standard Randomised Controlled Trial ISRCTN23885553.