Screening for lung cancer: 2023 guideline update from the American Cancer Society.

Lung cancer is the leading cause of mortality and person-years of life lost from cancer among US men and women. Early detection has been shown to be associated with reduced lung cancer mortality. Our objective was to update the American Cancer Society (ACS) 2013 lung cancer screening (LCS) guideline for adults at high risk for lung cancer. The guideline is intended to provide guidance for screening to health care providers and their patients who are at high risk for lung cancer due to a history of smoking. The ACS Guideline Development Group (GDG) utilized a systematic review of the LCS literature commissioned for the US Preventive Services Task Force 2021 LCS recommendation update; a second systematic review of lung cancer risk associated with years since quitting smoking (YSQ); literature published since 2021; two Cancer Intervention and Surveillance Modeling Network-validated lung cancer models to assess the benefits and harms of screening; an epidemiologic and modeling analysis examining the effect of YSQ and aging on lung cancer risk; and an updated analysis of benefit-to-radiation-risk ratios from LCS and follow-up examinations. The GDG also examined disease burden data from the National Cancer Institute's Surveillance, Epidemiology, and End Results program. Formulation of recommendations was based on the quality of the evidence and judgment (incorporating values and preferences) about the balance of benefits and harms. The GDG judged that the overall evidence was moderate and sufficient to support a strong recommendation for screening individuals who meet the eligibility criteria. LCS in men and women aged 50-80 years is associated with a reduction in lung cancer deaths across a range of study designs, and inferential evidence supports LCS for men and women older than 80 years who are in good health. The ACS recommends annual LCS with low-dose computed tomography for asymptomatic individuals aged 50-80 years who currently smoke or formerly smoked and have a ≥20 pack-year smoking history (strong recommendation, moderate quality of evidence). Before the decision is made to initiate LCS, individuals should engage in a shared decision-making discussion with a qualified health professional. For individuals who formerly smoked, the number of YSQ is not an eligibility criterion to begin or to stop screening. Individuals who currently smoke should receive counseling to quit and be connected to cessation resources. Individuals with comorbid conditions that substantially limit life expectancy should not be screened. These recommendations should be considered by health care providers and adults at high risk for lung cancer in discussions about LCS. If fully implemented, these recommendations have a high likelihood of significantly reducing death and suffering from lung cancer in the United States.

Cervical cancer screening for individuals at average risk: 2020 guideline update from the American Cancer Society.

The American Cancer Society (ACS) recommends that individuals with a cervix initiate cervical cancer screening at age 25 years and undergo primary human papillomavirus (HPV) testing every 5 years through age 65 years (preferred); if primary HPV testing is not available, then individuals aged 25 to 65 years should be screened with cotesting (HPV testing in combination with cytology) every 5 years or cytology alone every 3 years (acceptable) (strong recommendation). The ACS recommends that individuals aged >65 years who have no history of cervical intraepithelial neoplasia grade 2 or more severe disease within the past 25 years, and who have documented adequate negative prior screening in the prior 10 years, discontinue all cervical cancer screening (qualified recommendation). These new screening recommendations differ in 4 important respects compared with the 2012 recommendations: 1) The preferred screening strategy is primary HPV testing every 5 years, with cotesting and cytology alone acceptable where access to US Food and Drug Administration-approved primary HPV testing is not yet available; 2) the recommended age to start screening is 25 years rather than 21 years; 3) primary HPV testing, as well as cotesting or cytology alone when primary testing is not available, is recommended starting at age 25 years rather than age 30 years; and 4) the guideline is transitional, ie, options for screening with cotesting or cytology alone are provided but should be phased out once full access to primary HPV testing for cervical cancer screening is available without barriers. Evidence related to other relevant issues was reviewed, and no changes were made to recommendations for screening intervals, age or criteria for screening cessation, screening based on vaccination status, or screening after hysterectomy. Follow-up for individuals who screen positive for HPV and/or cytology should be in accordance with the 2019 American Society for Colposcopy and Cervical Pathology risk-based management consensus guidelines for abnormal cervical cancer screening tests and cancer precursors.

Colorectal cancer screening for average-risk adults: 2018 guideline update from the American Cancer Society.

In the United States, colorectal cancer (CRC) is the fourth most common cancer diagnosed among adults and the second leading cause of death from cancer. For this guideline update, the American Cancer Society (ACS) used an existing systematic evidence review of the CRC screening literature and microsimulation modeling analyses, including a new evaluation of the age to begin screening by race and sex and additional modeling that incorporates changes in US CRC incidence. Screening with any one of multiple options is associated with a significant reduction in CRC incidence through the detection and removal of adenomatous polyps and other precancerous lesions and with a reduction in mortality through incidence reduction and early detection of CRC. Results from modeling analyses identified efficient and model-recommendable strategies that started screening at age 45 years. The ACS Guideline Development Group applied the Grades of Recommendations, Assessment, Development, and Evaluation (GRADE) criteria in developing and rating the recommendations. The ACS recommends that adults aged 45 years and older with an average risk of CRC undergo regular screening with either a high-sensitivity stool-based test or a structural (visual) examination, depending on patient preference and test availability. As a part of the screening process, all positive results on noncolonoscopy screening tests should be followed up with timely colonoscopy. The recommendation to begin screening at age 45 years is a qualified recommendation. The recommendation for regular screening in adults aged 50 years and older is a strong recommendation. The ACS recommends (qualified recommendations) that: 1) average-risk adults in good health with a life expectancy of more than 10 years continue CRC screening through the age of 75 years; 2) clinicians individualize CRC screening decisions for individuals aged 76 through 85 years based on patient preferences, life expectancy, health status, and prior screening history; and 3) clinicians discourage individuals older than 85 years from continuing CRC screening. The options for CRC screening are: fecal immunochemical test annually; high-sensitivity, guaiac-based fecal occult blood test annually; multitarget stool DNA test every 3 years; colonoscopy every 10 years; computed tomography colonography every 5 years; and flexible sigmoidoscopy every 5 years. CA Cancer J Clin 2018;68:250-281. © 2018 American Cancer Society.

Multilevel Interventions to Improve Colorectal Cancer Screening in an Urban Native American Community: A Pilot Randomized Clinical Trial.

Native Americans have the highest burden of colorectal cancer (CRC) and the lowest rates of CRC screening across the United States.1 The disparities in CRC screening were made worse during the pandemic, creating an unmet need to implement evidence-based, multilevel interventions to improve CRC screening uptake. This can be achieved through an organized outreach program with identification of screen-eligible individuals using health records from the clinic; and a screening program with the following: (1) a mailed invitation, (2) a package of materials so patients can complete a fecal immunochemical test (FIT) kit from their homes, (3) reminder calls and a letter, and (4) navigation to a diagnostic colonoscopy.2-5 We conducted a pilot randomized controlled trial of a program of outreach vs usual care for completion of CRC screening at an urban clinic serving the Native American community. Applying the Consolidated Framework for Implementation Research (CFIR),6 we also conducted patient and provider interviews to understand barriers and facilitators to the organized program and CRC screening in general.

Randomized Trial of Facilitated Adherence to Screening Colonoscopy vs Sequential Fecal-Based Blood Test.

BACKGROUND & AIMS: Colorectal cancer (CRC) screening guidelines include screening colonoscopy and sequential high-sensitivity fecal occult blood testing (HSgFOBT), with expectation of similar effectiveness based on the assumption of similar high adherence. However, adherence to screening colonoscopy compared with sequential HSgFOBT has not been reported. In this randomized clinical trial, we assessed adherence and pathology findings for a single screening colonoscopy vs sequential and nonsequential HSgFOBTs. METHODS: Participants aged 40-69 years were enrolled at 3 centers representing different clinical settings. Participants were randomized into a single screening colonoscopy arm vs sequential HSgFOBT arm composed of 4-7 rounds. Initial adherence to screening colonoscopy and sequential adherence to HSgFOBT, follow-up colonoscopy for positive HSgFOBT tests, crossover to colonoscopy, and detection of advanced neoplasia or large serrated lesions (ADN-SERs) were measured. RESULTS: There were 3523 participants included in the trial; 1761 and 1762 participants were randomized to the screening colonoscopy and HSgFOBT arms, respectively. Adherence was 1473 (83.6%) for the screening colonoscopy arm vs 1288 (73.1%) for the HSgFOBT arm after 1 round (relative risk [RR], 1.14; 95% CI, 1.10-1.19; P ≤ .001), but only 674 (38.3%) over 4 sequential HSgFOBT rounds (RR, 2.19; 95% CI, 2.05-2.33). Overall adherence to any screening increased to 1558 (88.5%) in the screening colonoscopy arm during the entire study period and 1493 (84.7%) in the HSgFOBT arm (RR, 1.04; 95% CI, 1.02-1.07). Four hundred thirty-six participants (24.7%) crossed over to screening colonoscopy during the first 4 rounds. ADN-SERs were detected in 121 of the 1473 participants (8.2%) in the colonoscopy arm who were adherent to protocol in the first 12 months of the study, whereas detection of ADN-SERs among those who were not sequentially adherent (n = 709) to HSgFOBT was subpar (0.6%) (RR, 14.72; 95% CI, 5.46-39.67) compared with those who were sequentially adherent (3.3%) (n = 647) (RR, 2.52; 95% CI, 1.61-3.98) to HSgFOBT in the first 4 rounds. When including colonoscopies from HSgFOBT patients who were never positive yet crossed over (n = 1483), 5.5% of ADN-SERs were detected (RR, 1.50; 95% CI, 1.15-1.96) in the first 4 rounds. CONCLUSIONS: Observed adherence to sequential rounds of HSgFOBT was suboptimal compared with a single screening colonoscopy. Detection of ADN-SERs was inferior when nonsequential HSgFOBT adherence was compared with sequential adherence. However, the greatest number of ADN-SERs was detected among those who crossed over to colonoscopy and opted to receive a colonoscopy. The effectiveness of an HSgFOBT screening program may be enhanced if crossover to screening colonoscopy is permitted. CLINICALTRIALS: gov, Number: NCT00102011.

Projected Colorectal Cancer Incidence and Mortality Based on Observed Adherence to Colonoscopy and Sequential Stool-Based Screening.

INTRODUCTION: Modeling supporting recommendations for colonoscopy and stool-based colorectal cancer (CRC) screening tests assumes 100% sequential participant adherence. The impact of observed adherence on the long-term effectiveness of screening is unknown. We evaluated the effectiveness of a program of screening colonoscopy every 10 years vs annual high-sensitivity guaiac-based fecal occult blood testing (HSgFOBT) using observed sequential adherence data. METHODS: The MIcrosimulation SCreening ANalysis (MISCAN) model used observed sequential screening adherence, HSgFOBT positivity, and diagnostic colonoscopy adherence in HSgFOBT-positive individuals from the National Colonoscopy Study (single-screening colonoscopy vs ≥4 HSgFOBT sequential rounds). We compared CRC incidence and mortality over 15 years with no screening or 10 yearly screening colonoscopy vs annual HSgFOBT with 100% and differential observed adherence from the trial. RESULTS: Without screening, simulated incidence and mortality over 15 years were 20.9 (95% probability interval 15.8-26.9) and 6.9 (5.0-9.2) per 1,000 participants, respectively. In the case of 100% adherence, only screening colonoscopy was predicted to result in lower incidence; however, both tests lowered simulated mortality to a similar level (2.1 [1.6-2.9] for screening colonoscopy and 2.5 [1.8-3.4] for HSgFOBT). Observed adherence for screening colonoscopy (83.6%) was higher than observed sequential HSgFOBT adherence (73.1% first round; 49.1% by round 4), resulting in lower simulated incidence and mortality for screening colonoscopy (14.4 [10.8-18.5] and 2.9 [2.1-3.9], respectively) than HSgFOBT (20.8 [15.8-28.1] and 3.9 [2.9-5.4], respectively), despite a 91% adherence to diagnostic colonoscopy with FOBT positivity. The relative risk of CRC mortality for screening colonoscopy vs HSgFOBT was 0.75 (95% probability interval 0.68-0.80). Findings were similar in sensitivity analyses with alternative assumptions for repeat colonoscopy, test performance, risk, age, and projection horizon. DISCUSSION: Where sequential adherence to stool-based screening is suboptimal and colonoscopy is accessible and acceptable-as observed in the national colonoscopy study, microsimulation, comparative effectiveness, screening recommendations.

Mortality and cancer incidence in perfluorooctanesulfonyl fluoride production workers.

BACKGROUND: Exposure to per- and polyfluoroalkyl substances (PFAS) has been associated with several health outcomes, though few occupationally-exposed populations have been studied. We evaluated mortality and cancer incidence in a cohort of perfluorooctanesulfonyl fluoride-based specialty chemical manufacturing workers. METHODS: The cohort included any employee who ever worked at the facility from 1961 to 2010 (N = 4045), with a primary interest in those who had 365 cumulative days of employment (N = 2659). Vital status and mortality records were obtained through 2014 and the cohort was linked to state cancer registries to obtain incident cancer cases from 1995 to 2014. Cumulative exposure was derived from a comprehensive exposure reconstruction that estimated job-specific perfluorooctanesulfonate (PFOS)-equivalents (mg/m3 ) exposure. Overall and exposure-specific standardized mortality ratios (SMR) were estimated in reference to the US population. Hazard ratios (HRs) and 95% confidence interval (CI) for cumulative PFOS-equivalent exposure (log2 transformed) were estimated within the cohort for specific causes of death and incident cancers using a time-dependent Cox model. RESULTS: Death rates were lower than expected except for cerebrovascular disease (SMR = 2.42, 95% CI = 1.25-4.22) and bladder cancer (SMR = 3.91, 95% CI = 1.07-10.02) in the highest exposure quartile. Within the cohort, the incidence of bladder, colorectal, and pancreatic cancer were positively associated with exposure, however except for lung cancer (HR = 1.05, 95% CI = 1.00-1.11) the CIs did not exclude an HR of 1. CONCLUSIONS: This study provides some evidence that occupational exposure to PFOS is associated with bladder and lung cancers and with cerebrovascular disease.

Strength training is more effective than aerobic exercise for improving glycaemic control and body composition in people with normal-weight type 2 diabetes: a randomised controlled trial.

AIMS/HYPOTHESIS: Type 2 diabetes in people in the healthy weight BMI category (<25 kg/m2), herein defined as 'normal-weight type 2 diabetes', is associated with sarcopenia (low muscle mass). Given this unique body composition, the optimal exercise regimen for this population is unknown. METHODS: We conducted a parallel-group RCT in individuals with type 2 diabetes (age 18-80 years, HbA1c 47.5-118.56 mmol/mol [6.5-13.0%]) and BMI <25 kg/m2). Participants were recruited in outpatient clinics or through advertisements and randomly assigned to a 9 month exercise programme of strength training alone (ST), aerobic training alone (AER) or both interventions combined (COMB). We used stratified block randomisation with a randomly selected block size. Researchers and caregivers were blinded to participants' treatment group; however, participants themselves were not. Exercise interventions were conducted at community-based fitness centres. The primary outcome was absolute change in HbA1c level within and across the three groups at 3, 6 and 9 months. Secondary outcomes included changes in body composition at 9 months. Per adherence to recommended exercise protocol (PP) analysis included participants who completed at least 50% of the sessions. RESULTS: Among 186 individuals (ST, n=63; AER, n=58; COMB, n=65) analysed, the median (IQR) age was 59 (53-66) years, 60% were men and 83% were Asian. The mean (SD) HbA1c level at baseline was 59.6 (13.1) mmol/mol (7.6% [1.2%]). In intention-to-treat analysis, the ST group showed a significant decrease in HbA1c levels (mean [95% CI] -0.44 percentage points [-0.78, -0.12], p=0.002), while no significant change was observed in either the COMB group (-0.35 percentage points, p=0.13) or the AER group (-0.24 percentage points, p=0.10). The ST group had a greater improvement in HbA1c levels than the AER group (p=0.01). Appendicular lean mass relative to fat mass increased only in the ST group (p=0.0008), which was an independent predictor of HbA1c change (beta coefficient -7.16, p=0.01). Similar results were observed in PP analysis. Only one adverse event, in the COMB group, was considered to be possibly associated with the exercise intervention. CONCLUSIONS/INTERPRETATION: In normal-weight type 2 diabetes, strength training was superior to aerobic training alone, while no significant difference was observed between strength training and combination training for HbA1c reduction. Increased lean mass relative to decreased fat mass was an independent predictor of reduction in HbA1c level. TRIAL REGISTRATION: ClinicalTrials.gov NCT02448498. FUNDING: This study was funded by the National Institutes of Health (NIH; R01DK081371).

Modeled residual current cancer risk after clinical investigation of a positive multicancer early detection test result.

BACKGROUND: Positive results of a multi-cancer early detection (MCED) test require confirmatory diagnostic workup. Here, residual current cancer risk (RR) during the process of diagnostic resolution, including situations where the initial confirmatory test does not provide resolution, was modeled. METHODS: A decision-tree framework was used to model conditional risk in a patient's journey through confirmatory diagnostic options and outcomes. The diagnostic journey assumed that cancer signal detection (a positive MCED test result) had already led to a transition from screening to diagnosis and began with an initial positive predictive value (PPV) from the positive result. Evaluation of a most probable (top) predicted cancer signal origin (CSO) and then a second-most probable predicted CSO followed. Under the assumption that the top- and second-predicted CSOs were each followed by a targeted confirmatory test, the RR was estimated for each subsequent scenario. RESULTS: For an initial MCED test result with typical performance characteristics modeled (PPV, 40%; top-predicted CSO accuracy, 90%), after a negative initial confirmatory test (sensitivity, 70%, 90%, or 100%) the RR ranged from 6% to 20%. A second-predicted CSO (accuracy, 50%), after a negative second confirmatory test, still provided a significant RR (3%-18%) in comparison with the National Institute for Health and Care Excellence-recommended cancer risk threshold warranting investigation in symptomatic individuals (3%). With a 40% PPV for an MCED test and 90% specificity for a confirmatory test, the risk of incidental findings after one or two confirmatory tests was 6% and 12%, respectively. CONCLUSIONS: These results may illustrate the impact of a positive MCED test on follow-up decision-making.

Computer-Aided Detection Improves Adenomas per Colonoscopy for Screening and Surveillance Colonoscopy: A Randomized Trial.

BACKGROUND & AIMS: Colonoscopy for colorectal cancer screening is endoscopist dependent, and colonoscopy quality improvement programs aim to improve efficacy. This study evaluated the clinical benefit and safety of using a computer-aided detection (CADe) device in colonoscopy procedures. METHODS: This randomized study prospectively evaluated the use of a CADe device at 5 academic and community centers by US board-certified gastroenterologists (n = 22). Participants aged ≥40 scheduled for screening or surveillance (≥3 years) colonoscopy were included; exclusion criteria included incomplete procedure, diagnostic indication, inflammatory bowel disease, and familial adenomatous polyposis. Patients were randomized by endoscopist to the standard or CADe colonoscopy arm using computer-generated, random-block method. The 2 primary endpoints were adenomas per colonoscopy (APC), the total number of adenomas resected divided by the total number of colonoscopies; and true histology rate (THR), the proportion of resections with clinically significant histology divided by the total number of polyp resections. The primary analysis used a modified intention-to-treat approach. RESULTS: Between January and September 2021, 1440 participants were enrolled to be randomized. After exclusion of participants who did not meet the eligibility criteria, 677 in the standard arm and 682 in the CADe arm were included in a modified intention-to-treat analysis. APC increased significantly with use of the CADe device (standard vs CADe: 0.83 vs 1.05, P = .002; total number of adenomas, 562 vs 719). There was no decrease in THR with use of the CADe device (standard vs CADe: 71.7% vs 67.4%, P for noninferiority < .001; total number of non-neoplastic lesions, 284 vs 375). Adenoma detection rate was 43.9% and 47.8% in the standard and CADe arms, respectively (P = .065). CONCLUSIONS: For experienced endoscopists performing screening and surveillance colonoscopies in the United States, the CADe device statistically improved overall adenoma detection (APC) without a concomitant increase in resection of non-neoplastic lesions (THR). CLINICALTRIALS: gov registration: NCT04754347.

Association between weight loss, change in physical activity, and change in quality of life following a corporately sponsored, online weight loss program.

BACKGROUND: The physiological benefits associated with corporately sponsored weight loss programs are increasingly well documented. However, less is known about how these programs affect employees' quality of life (QoL). The purpose of the present analysis was to examine the association between weight loss, change in physical activity, and change in QoL following a corporately sponsored, online weight loss program. METHODS: We examined the relationship between weight loss, self-reported change in physical activity, and change in several QoL indices in 26,658 participants (79% women) after the initial 10 weeks of the online weight loss program. The trend in changes in each QoL index with increasing weight loss and change in physical activity was examined using logistic regression analysis. RESULTS: We observed greater improvements in each QoL index with increasing weight loss (p-for-trend, < 0.001) as well as with progressive increases in physical activity (p-for-trend, < 0.001). The combination of increasing weight loss and increases in physical activity were associated with the greatest improvements in each QoL index (additive effect). The percentage of employees reporting improvements in QoL ("improved" or "very much improved") was 64% for energy, 63% for mood, 33% for sleep, 65% for self-confidence, 68% for indigestion, and 39% for musculoskeletal pain. CONCLUSIONS: Among people, who engage with a commercial weight loss program, greater weight loss during the program was associated with greater improvements in QoL, and increases in physical activity further enhanced the QoL-related benefits.

Impact of a Novel Training Approach on Hemodynamic and Vascular Profiles in Older Adults.

Exercise training beneficially moderates the effects of vascular aging. This study compared the efficacy of Peripheral Remodeling through Intermittent Muscular Exercise (PRIME), a novel training regimen, versus aerobic training on hemodynamic profiles in participants ≥70 years at risk for losing functional independence. Seventy-five participants (52 females, age: 76 ± 5 years) were assessed for hemodynamic and vascular function at baseline, after 4 weeks of either PRIME or aerobic training (Phase 1) and again after a further 8 weeks of aerobic and resistance training (Phase 2). Data were analyzed using 2 × 2 repeated-measures analysis of variance models on the change in each dependent variable. PRIME demonstrated reductions in brachial and aortic mean arterial pressure and diastolic blood pressure (p < .05) from baseline after Phase 1, which were sustained throughout Phase 2. Earlier and greater reductions in blood pressure following PRIME support the proposal that peripheral muscular training could beneficial for older individuals commencing an exercise program.

Effects of Screening Compliance on Long-term Reductions in All-Cause and Colorectal Cancer Mortality.

BACKGROUND & AIMS: Randomized trials have shown that biennial fecal occult blood test (FOBT) screening reduces mortality from colorectal cancer (CRC), but not overall mortality. Differences in benefit for men vs women, and by age, are unknown. We sought to evaluate long-term reduction in all-cause and CRC-specific mortality in men and women who comply with offered screening, and in different age groups, using individual participant data from 2 large randomized trials of biennial FOBT screening, compared with an intention to treat analysis. METHODS: We updated the CRC and all-cause mortality from the Danish CRC screening trial (n = 61,933) through 30 years of follow up and pooled individual participant data with individual 30-year follow-up data from the Minnesota Colon Cancer Control trial (n = 46,551). We compared the biennial screening groups to usual care (controls) in individuals 50-80 years old using Kaplan Meier estimates of relative risks and risk differences, adjusted for study differences in age, sex, and compliance. RESULTS: Through 30 years of follow up, there were 33,478 (71.9%) and 33,479 (72.2%) total deaths and 1023 (2.2%) and 1146 (2.5%) CRC deaths in the biennial screening (n = 46,553) and control groups (n = 46,358), respectively. Among compliers, biennial FOBT screening significantly reduced CRC mortality by 16% (relative risk [RR], 0.84; 95% CI, 0.74-0.96) and all-cause mortality by 2% (RR, 0.98; 95% CI, 0.97-0.99). Among compliers, the reduction in CRC mortality was larger for men (RR, 0.75; 95% CI, 0.62-0.90) than women (RR, 0.91; 95% CI, 0.75-1.09). The largest reduction in CRC mortality was in compliant men 60-69 years old (RR, 0.59; 95% CI, 0.42-0.81) and women 70 years and older (RR, 0.53; 95% CI, 0.30-0.94). CONCLUSIONS: Long-term CRC mortality outcomes of screening among compliers using biennial FOBT are sustained, with a statistically significant reduction in all-cause mortality. The reduction in CRC mortality is greater in men than women-the benefit in women lags that of men by about 10 years.

Associations between tissue-based CD3+ T-lymphocyte count and colorectal cancer survival in a prospective cohort of older women.

Tumor-infiltrating lymphocytes in colorectal cancer (CRC) predict better survival. However, associations between T-lymphocyte count in histologically normal tissues from patients with CRC and survival remain uncertain. We examined associations of CD3+ T-cells in colorectal tumor and histologically normal tissues with CRC-specific and all-cause mortality in the prospective Iowa Women's Health Study. Tissue microarrays were constructed using paraffin-embedded colorectal tissue samples from 464 women with tumor tissues and 314 women with histologically normal tissues (55-69 years at baseline) diagnosed with incident CRC from 1986 to 2002 and followed through 2014 (median follow-up 20.5 years). Three tumor and two histologically normal tissue cores for each patient were immunostained using CD3+ antibody and quantified, and the counts were averaged across the cores in each tissue. Cox proportional hazards regression estimated hazard ratios (HR) and 95% confidence interval (CI) for CRC-specific and all-cause mortality. After adjustment for age at diagnosis, body mass index, smoking status, tumor grade, and stage, HRs (95% CI) for the highest versus lowest tertile of tumor CD3+ score were 0.59 (0.38-0.89) for CRC-specific mortality and 0.82 (0.63-1.05) for all-cause mortality; for histologically normal CD3+ score, the corresponding HRs (95% CI) were 0.47 (0.19-1.17) and 0.50 (0.27-0.90), respectively. The CD3+ score combining the tumor and histologically normal scores was inversely associated with CRC-specific and all-cause mortality. Although the association between tumor CD3+ score and all-cause mortality was not significant, both higher CD3+ T-lymphocyte counts in tumor and histologically normal scores tended to be associated with lower CRC-specific and all-cause mortality.

dCas9-Based Scn1a Gene Activation Restores Inhibitory Interneuron Excitability and Attenuates Seizures in Dravet Syndrome Mice.

Dravet syndrome (DS) is a severe epileptic encephalopathy caused mainly by heterozygous loss-of-function mutations of the SCN1A gene, indicating haploinsufficiency as the pathogenic mechanism. Here we tested whether catalytically dead Cas9 (dCas9)-mediated Scn1a gene activation can rescue Scn1a haploinsufficiency in a mouse DS model and restore physiological levels of its gene product, the Nav1.1 voltage-gated sodium channel. We screened single guide RNAs (sgRNAs) for their ability to stimulate Scn1a transcription in association with the dCas9 activation system. We identified a specific sgRNA that increases Scn1a gene expression levels in cell lines and primary neurons with high specificity. Nav1.1 protein levels were augmented, as was the ability of wild-type immature GABAergic interneurons to fire action potentials. A similar enhancement of Scn1a transcription was achieved in mature DS interneurons, rescuing their ability to fire. To test the therapeutic potential of this approach, we delivered the Scn1a-dCas9 activation system to DS pups using adeno-associated viruses. Parvalbumin interneurons recovered their firing ability, and febrile seizures were significantly attenuated. Our results pave the way for exploiting dCas9-based gene activation as an effective and targeted approach to DS and other disorders resulting from altered gene dosage.

Younger Physicians and Longer Withdrawal Times Are Associated With Detection of Advanced Neoplasia in a Large Community Practice.

Studies assessing colonoscopic practice have demonstrated variation in adenoma detection rate,1 detection rates of advanced adenomas,2,3 and detection rates of sessile serrated lesions (SSLs).4,5 Our aims were to study the patient-, provider-, and procedure-level variables associated with detection rates of adenoma, SSLs, and advanced neoplasia in screening colonoscopies performed in large community practice.

Urinary N7-(1-hydroxy-3-buten-2-yl) guanine adducts in humans: temporal stability and association with smoking.

1,3-Butadiene (BD) is a known human carcinogen found in cigarette smoke, automobile exhaust, and urban air. Workers occupationally exposed to BD in the workplace have an increased incidence of leukemia and lymphoma. BD undergoes cytochrome P450-mediated metabolic activation to 3,4-epoxy-1-butene (EB), 1,2,3,4-diepoxybutane (DEB) and 1,2-dihydroxy-3,4-epoxybutane (EBD), which form covalent adducts with DNA. We have previously reported a quantitative nanoLC/ESI+-HRMS3 method for urinary N7-(1-hydroxy-3-buten-2-yl) guanine (EB-GII) adducts as a mechanism-based biomarker of BD exposure. In the present study, the method was updated to include high throughput 96-well solid phase extraction (SPE) and employed to establish urinary EB-GII biomarker stability and association with smoking. Urinary EB-GII levels were measured bimonthly for 1 year in 19 smokers to determine whether single adduct measurement provides reliable levels of EB-GII in an individual smoker. In addition, association of EB-GII with smoking was studied in 17 individuals participating in a smoking cessation program. EB-GII levels decreased 34% upon smoking cessation, indicating that it is associated with smoking status, but may also originate from sources other than exposure to cigarette smoke.

American Cancer Society lung cancer screening guidelines.

Findings from the National Cancer Institute's National Lung Screening Trial established that lung cancer mortality in specific high-risk groups can be reduced by annual screening with low-dose computed tomography. These findings indicate that the adoption of lung cancer screening could save many lives. Based on the results of the National Lung Screening Trial, the American Cancer Society is issuing an initial guideline for lung cancer screening. This guideline recommends that clinicians with access to high-volume, high-quality lung cancer screening and treatment centers should initiate a discussion about screening with apparently healthy patients aged 55 years to 74 years who have at least a 30-pack-year smoking history and who currently smoke or have quit within the past 15 years. A process of informed and shared decision-making with a clinician related to the potential benefits, limitations, and harms associated with screening for lung cancer with low-dose computed tomography should occur before any decision is made to initiate lung cancer screening. Smoking cessation counseling remains a high priority for clinical attention in discussions with current smokers, who should be informed of their continuing risk of lung cancer. Screening should not be viewed as an alternative to smoking cessation.

A marginal structural model approach to analyse work-related injuries: an example using data from the health and retirement study.

BACKGROUND: Biases may exist in the limited longitudinal data focusing on work-related injuries among the ageing workforce. Standard statistical techniques may not provide valid estimates when the data are time-varying and when prior exposures and outcomes may influence future outcomes. This research effort uses marginal structural models (MSMs), a class of causal models rarely applied for injury epidemiology research to analyse work-related injuries. METHODS: 7212 working US adults aged ≥50 years, obtained from the Health and Retirement Study sample in the year 2004 formed the study cohort that was followed until 2014. The analyses compared estimates measuring the associations between physical work requirements and work-related injuries using MSMs and a traditional regression model. The weights used in the MSMs, besides accounting for time-varying exposures, also accounted for the recurrent nature of injuries. RESULTS: The results were consistent with regard to directionality between the two models. However, the effect estimate was greater when the same data were analysed using MSMs, built without the restriction for complete case analyses. CONCLUSIONS: MSMs can be particularly useful for observational data, especially with the inclusion of recurrent outcomes as these can be incorporated in the weights themselves.