Rates of Downstream Procedures and Complications Associated With Lung Cancer Screening in Routine Clinical Practice : A Retrospective Cohort Study.

BACKGROUND: Lung cancer screening (LCS) using low-dose computed tomography (LDCT) reduces lung cancer mortality but can lead to downstream procedures, complications, and other potential harms. Estimates of these events outside NLST (National Lung Screening Trial) have been variable and lacked evaluation by screening result, which allows more direct comparison with trials. OBJECTIVE: To identify rates of downstream procedures and complications associated with LCS. DESIGN: Retrospective cohort study. SETTING: 5 U.S. health care systems. PATIENTS: Individuals who completed a baseline LDCT scan for LCS between 2014 and 2018. MEASUREMENTS: Outcomes included downstream imaging, invasive diagnostic procedures, and procedural complications. For each, absolute rates were calculated overall and stratified by screening result and by lung cancer detection, and positive and negative predictive values were calculated. RESULTS: Among the 9266 screened patients, 1472 (15.9%) had a baseline LDCT scan showing abnormalities, of whom 140 (9.5%) were diagnosed with lung cancer within 12 months (positive predictive value, 9.5% [95% CI, 8.0% to 11.0%]; negative predictive value, 99.8% [CI, 99.7% to 99.9%]; sensitivity, 92.7% [CI, 88.6% to 96.9%]; specificity, 84.4% [CI, 83.7% to 85.2%]). Absolute rates of downstream imaging and invasive procedures in screened patients were 31.9% and 2.8%, respectively. In patients undergoing invasive procedures after abnormal findings, complication rates were substantially higher than those in NLST (30.6% vs. 17.7% for any complication; 20.6% vs. 9.4% for major complications). LIMITATION: Assessment of outcomes was retrospective and was based on procedural coding. CONCLUSION: The results indicate substantially higher rates of downstream procedures and complications associated with LCS in practice than observed in NLST. Diagnostic management likely needs to be assessed and improved to ensure that screening benefits outweigh potential harms. PRIMARY FUNDING SOURCE: National Cancer Institute and Gordon and Betty Moore Foundation.

Association between racial residential segregation and screening uptake for colorectal and cervical cancer among Black and White patients in five US health care systems.

BACKGROUND: Despite increased recognition that structural racism contributes to poorer health outcomes for racial and ethnic minorities, there are knowledge gaps about how current patterns of racial residential segregation are associated with cancer screening uptake. The authors examined associations between Black residential segregation and screening for colorectal cancer (CRC) and cervical cancer among non-Hispanic Black and non-Hispanic White adults. METHODS: This was a retrospective study of CRC and cervical cancer screening-eligible adults from five health care systems within the Population-Based Research to Optimize the Screening Process (PROSPR II) Consortium (cohort entry, 2010-2012). Residential segregation was measured using site-specific quartiles of the Black local isolation score (LIS). The outcome was receipt of CRC or cervical cancer screening within 3 years of cohort entry (2010-2015). Logistic regression was used to calculate associations between the LIS and screening completion, adjusting for patient-level covariates. RESULTS: Among CRC (n = 642,661) and cervical cancer (n = 163,340) screening-eligible patients, 456,526 (71.0%) and 106,124 (65.0%), respectively, received screening. Across PROSPR sites, living in neighborhoods with higher LIS tended to be associated with lower odds of CRC screening (Kaiser Permanente Northern California: adjusted odds ratio [aOR] LIS trend in Black patients, 0.95 [p < .001]; aOR LIS trend in White patients, 0.98 [p < .001]; Kaiser Permanente Southern California: aOR LIS trend in Black patients, 0.98 [p = .026]; aOR LIS trend in White patients, 1.01 [p = .023]; Kaiser Permanente Washington: aOR LIS trend in White patients, 0.97 [p = .002]. However, for cervical cancer screening, associations with the LIS varied by site and race (Kaiser Permanente Washington: aOR LIS trend in White patients, 0.95 [p < .001]; Mass General Brigham: aOR LIS trend in Black patients, 1.12 [p < .001]; aOR LIS trend in White patients, 1.03 [p < .001]). CONCLUSIONS: Across five diverse health care systems, the direction of the association between Black residential segregation and screening varied by PROSPR site, race, and screening type. Additional research, including studies that examine multiple dimensions of segregation and structural racism using intersectional approaches, are needed to further disentangle these relationships.

Predicting Risk of Colorectal Cancer After Adenoma Removal in a Large Community-Based Setting.

INTRODUCTION: Colonoscopy surveillance guidelines categorize individuals as high or low risk for future colorectal cancer (CRC) based primarily on their prior polyp characteristics, but this approach is imprecise, and consideration of other risk factors may improve postpolypectomy risk stratification. METHODS: Among patients who underwent a baseline colonoscopy with removal of a conventional adenoma in 2004-2016, we compared the performance for postpolypectomy CRC risk prediction (through 2020) of a comprehensive model featuring patient age, diabetes diagnosis, and baseline colonoscopy indication and prior polyp findings (i.e., adenoma with advanced histology, polyp size ≥10 mm, and sessile serrated adenoma or traditional serrated adenoma) with a polyp model featuring only polyp findings. Models were developed using Cox regression. Performance was assessed using area under the receiver operating characteristic curve (AUC) and calibration by the Hosmer-Lemeshow goodness-of-fit test. RESULTS: Among 95,001 patients randomly divided 70:30 into model development (n = 66,500) and internal validation cohorts (n = 28,501), 495 CRC were subsequently diagnosed; 354 in the development cohort and 141 in the validation cohort. Models demonstrated adequate calibration, and the comprehensive model demonstrated superior predictive performance to the polyp model in the development cohort (AUC 0.71, 95% confidence interval [CI] 0.68-0.74 vs AUC 0.61, 95% CI 0.58-0.64, respectively) and validation cohort (AUC 0.70, 95% CI 0.65-0.75 vs AUC 0.62, 95% CI 0.57-0.67, respectively). DISCUSSION: A comprehensive CRC risk prediction model featuring patient age, diabetes diagnosis, and baseline colonoscopy indication and polyp findings was more accurate at predicting postpolypectomy CRC diagnosis than a model based on polyp findings alone.

Identifying factors and causal chains associated with optimal implementation of Lynch syndrome tumor screening: An application of coincidence analysis.

PURPOSE: This study compared Lynch syndrome universal tumor screening (UTS) across multiple health systems (some of which had 2 or more distinct UTS programs) to understand multilevel factors that may affect the successful implementation of complex programs. METHODS: Data from 66 stakeholder interviews were used to conduct multivalue coincidence analysis and identify key factors that consistently make a difference in whether UTS programs were implemented and optimized at the system level. RESULTS: The selected coincidence analysis model revealed combinations of conditions that distinguish 4 optimized UTS programs, 10 nonoptimized programs, and 4 systems with no program. Fully optimized UTS programs had both a maintenance champion and a positive inner setting. Two independent paths were unique to nonoptimized programs: (1) positive attitudes and a mixed inner setting or (2) limited planning and engaging among stakeholders. Negative views about UTS evidence or lack of knowledge about UTS led to a lack of planning and engaging, which subsequently prevented program implementation. CONCLUSION: The model improved our understanding of program implementation in health care systems and informed the creation of a toolkit to guide UTS implementation, optimization, and changes. Our findings and toolkit may serve as a use case to increase the successful implementation of other complex precision health programs.

Uptake of Lung Cancer Screening CT After a Provider Order for Screening in the PROSPR-Lung Consortium.

BACKGROUND: Uptake of lung cancer screening (LCS) has been slow with less than 20% of eligible people who currently or formerly smoked reported to have undergone a screening CT. OBJECTIVE: To determine individual-, health system-, and neighborhood-level factors associated with LCS uptake after a provider order for screening. DESIGN AND SUBJECTS: We conducted an observational cohort study of screening-eligible patients within the Population-based Research to Optimize the Screening Process (PROSPR)-Lung Consortium who received a radiology referral/order for a baseline low-dose screening CT (LDCT) from a healthcare provider between January 1, 2015, and June 30, 2019. MAIN MEASURES: The primary outcome is screening uptake, defined as LCS-LDCT completion within 90 days of the screening order date. KEY RESULTS: During the study period, 18,294 patients received their first order for LCS-LDCT. Orders more than doubled from the beginning to the end of the study period. Overall, 60% of patients completed screening after receiving their first LCS-LDCT order. Across health systems, uptake varied from 41 to 87%. In both univariate and multivariable analyses, older age, male sex, former smoking status, COPD, and receiving care in a centralized LCS program were positively associated with completing LCS-LDCT. Unknown insurance status, other or unknown race, and lower neighborhood socioeconomic status, as measured by the Yost Index, were negatively associated with screening uptake. CONCLUSIONS: Overall, 40% of patients referred for LCS did not complete a LDCT within 90 days, highlighting a substantial gap in the lung screening care pathway, particularly in decentralized screening programs.

Dietary Factors Differ Between Young-Onset and Older-Onset Colorectal Cancer Patients.

We aimed to evaluate differences in dietary factors between young-onset (diagnosed at ages <50) and older-onset colorectal cancer (CRC). CRC patients diagnosed from 1998 to 2018 reported to the Puget Sound Surveillance, Epidemiology, and End Results registry were recruited using mail and telephone. Consented patients completed questionnaires assessing demographics, medical history, and CRC risk factors, including dietary factors. We used multi-variable logistic regression to calculate adjusted odds ratios (ORs) and 95% confidence intervals (CIs) comparing dietary intake in young-onset vs. older-onset CRC. Analyses included 1,087 young- and 2,554 older-onset CRC patients. Compared to older-onset CRC, young-onset CRC patients had lower intake of vegetables (OR for highest intake vs. lowest = 0.59 CI: 0.55, 0.64) and fruit (OR for highest intake vs. lowest = 0.94 CI: 0.88, 0.99) and higher intake of processed meat (OR for highest intake vs. lowest = 1.82 CI: 1.11, 2.99) and spicy food (OR for highest intake vs. lowest = 1.69 CI: 1.09, 2.61). There was no statistically significant difference between young- and older-onset CRC patients for red meat consumption. Dietary patterns differed between young- and older-onset CRC; young-onset CRC patients had lower intake of vegetables and fruit and higher intakes of processed meat and spicy food.

Colorectal cancer pre-diagnostic symptoms are associated with anatomic cancer site.

BACKGROUND: Signs and red flag symptoms in colorectal cancer (CRC) patients who are below the recommended screening age are often overlooked, leading to delayed diagnosis and worse prognosis. This study investigates how patient pre-diagnostic symptoms are associated with anatomic site of their cancer and whether the association varies by age at CRC diagnosis. METHODS: We ascertained CRC patients' experienced symptoms and screening through medical abstractions from an ongoing population-based study of CRC patients identified through a SEER cancer registry (N = 626). We used logistic regression to estimate odds ratios and 95% confidence intervals for the association between symptoms and CRC anatomic site. Additional analyses were stratified by age at diagnosis. Early-onset was defined as less than 50 years of age at CRC diagnosis. RESULTS: Participants who experienced blood in stool were more likely (odds ratio (95% confidence interval)) to have rectal (vs. colon) cancer (4.37 (3.02, 6.33)), as were patients who experienced changes to stool (1.78 (1.21, 2.60)). Patients diagnosed with colon cancer were more likely to present with abdominal pain (0.30 (0.19, 0.47)), anemia (0.40 (0.21, 0.75)), other symptoms (0.33 (0.19, 0.55)) and no symptoms (0.68 (0.44, 1.04)). When stratifying by age at diagnosis, we found that the association between blood in stool and rectal tumor location was particularly pronounced for patients with early-onset CRC (6.48 (2.73, 15.41)). CONCLUSIONS: Common pre-diagnostic red flag symptoms are associated with CRC anatomic site. These findings can inform best practices for gastroenterologist triage of care and early evaluation of CRC and are of key importance given the rise of early-onset (pre-screening age) CRC. TRIAL REGISTRATION: Not applicable to this study and analysis.

Depression, anxiety, & loneliness among cancer survivors during the COVID-19 pandemic.

PURPOSE: To assess the impact of the COVID-19 pandemic on depression, anxiety, and loneliness between those with and without a history of cancer. DESIGN: This prospective observational study used a quantitative approach. PARTICIPANTS: Adult members of the Kaiser Permanente Research Bank (N = 104,640). METHODS: Participants completed a series of surveys from May to December 2020. The difference in score of depression, anxiety, and loneliness were estimated using linear mixed regression. FINDINGS: Among cancer survivors, 21% and 19% met the thresholds for increased risk of depression and anxiety. Among cancer survivors, younger age groups and females reported increased depression, anxiety, and loneliness scores. CONCLUSIONS: This study highlights the continued necessity of addressing mental health needs and social support in cancer survivors during and after a public health emergency. IMPLICATIONS FOR PSYCHOSOCIAL PROVIDERS: Cancer survivors may need particular resources after cancer treatment to strengthen resilience and improve quality of life.

Genome-wide Modeling of Polygenic Risk Score in Colorectal Cancer Risk.

Accurate colorectal cancer (CRC) risk prediction models are critical for identifying individuals at low and high risk of developing CRC, as they can then be offered targeted screening and interventions to address their risks of developing disease (if they are in a high-risk group) and avoid unnecessary screening and interventions (if they are in a low-risk group). As it is likely that thousands of genetic variants contribute to CRC risk, it is clinically important to investigate whether these genetic variants can be used jointly for CRC risk prediction. In this paper, we derived and compared different approaches to generating predictive polygenic risk scores (PRS) from genome-wide association studies (GWASs) including 55,105 CRC-affected case subjects and 65,079 control subjects of European ancestry. We built the PRS in three ways, using (1) 140 previously identified and validated CRC loci; (2) SNP selection based on linkage disequilibrium (LD) clumping followed by machine-learning approaches; and (3) LDpred, a Bayesian approach for genome-wide risk prediction. We tested the PRS in an independent cohort of 101,987 individuals with 1,699 CRC-affected case subjects. The discriminatory accuracy, calculated by the age- and sex-adjusted area under the receiver operating characteristics curve (AUC), was highest for the LDpred-derived PRS (AUC = 0.654) including nearly 1.2 M genetic variants (the proportion of causal genetic variants for CRC assumed to be 0.003), whereas the PRS of the 140 known variants identified from GWASs had the lowest AUC (AUC = 0.629). Based on the LDpred-derived PRS, we are able to identify 30% of individuals without a family history as having risk for CRC similar to those with a family history of CRC, whereas the PRS based on known GWAS variants identified only top 10% as having a similar relative risk. About 90% of these individuals have no family history and would have been considered average risk under current screening guidelines, but might benefit from earlier screening. The developed PRS offers a way for risk-stratified CRC screening and other targeted interventions.

Quantitative Pathologic Analysis of Digitized Images of Colorectal Carcinoma Improves Prediction of Recurrence-Free Survival.

BACKGROUND & AIMS: To examine whether quantitative pathologic analysis of digitized hematoxylin and eosin slides of colorectal carcinoma (CRC) correlates with clinicopathologic features, molecular alterations, and prognosis. METHODS: A quantitative segmentation algorithm (QuantCRC) was applied to 6468 digitized hematoxylin and eosin slides of CRCs. Fifteen parameters were recorded from each image and tested for associations with clinicopathologic features and molecular alterations. A prognostic model was developed to predict recurrence-free survival using data from the internal cohort (n = 1928) and validated on an internal test (n = 483) and external cohort (n = 938). RESULTS: There were significant differences in QuantCRC according to stage, histologic subtype, grade, venous/lymphatic/perineural invasion, tumor budding, CD8 immunohistochemistry, mismatch repair status, KRAS mutation, BRAF mutation, and CpG methylation. A prognostic model incorporating stage, mismatch repair, and QuantCRC resulted in a Harrell's concordance (c)-index of 0.714 (95% confidence interval [CI], 0.702-0.724) in the internal test and 0.744 (95% CI, 0.741-0.754) in the external cohort. Removing QuantCRC from the model reduced the c-index to 0.679 (95% CI, 0.673-0.694) in the external cohort. Prognostic risk groups were identified, which provided a hazard ratio of 2.24 (95% CI, 1.33-3.87, P = .004) for low vs high-risk stage III CRCs and 2.36 (95% CI, 1.07-5.20, P = .03) for low vs high-risk stage II CRCs, in the external cohort after adjusting for established risk factors. The predicted median 36-month recurrence rate for high-risk stage III CRCs was 32.7% vs 13.4% for low-risk stage III and 15.8% for high-risk stage II vs 5.4% for low-risk stage II CRCs. CONCLUSIONS: QuantCRC provides a powerful adjunct to routine pathologic reporting of CRC. A prognostic model using QuantCRC improves prediction of recurrence-free survival.

Evaluation of Harms Reporting in U.S. Cancer Screening Guidelines.

BACKGROUND: Cancer screening should be recommended only when the balance between benefits and harms is favorable. This review evaluated how U.S. cancer screening guidelines reported harms, within and across organ-specific processes to screen for cancer. OBJECTIVE: To describe current reporting practices and identify opportunities for improvement. DESIGN: Review of guidelines. SETTING: United States. PATIENTS: Patients eligible for screening for breast, cervical, colorectal, lung, or prostate cancer according to U.S. guidelines. MEASUREMENTS: Information was abstracted on reporting of patient-level harms associated with screening, diagnostic follow-up, and treatment. The authors classified harms reporting as not mentioned, conceptual, qualitative, or quantitative and noted whether literature was cited when harms were described. Frequency of harms reporting was summarized by organ type. RESULTS: Harms reporting was inconsistent across organ types and at each step of the cancer screening process. Guidelines did not report all harms for any specific organ type or for any category of harm across organ types. The most complete harms reporting was for prostate cancer screening guidelines and the least complete for colorectal cancer screening guidelines. Conceptualization of harms and use of quantitative evidence also differed by organ type. LIMITATIONS: This review considers only patient-level harms. The authors did not verify accuracy of harms information presented in the guidelines. CONCLUSION: The review identified opportunities for improving conceptualization, assessment, and reporting of screening process-related harms in guidelines. Future work should consider nuances associated with each organ-specific process to screen for cancer, including which harms are most salient and where evidence gaps exist, and explicitly explore how to optimally weigh available evidence in determining net screening benefit. Improved harms reporting could aid informed decision making, ultimately improving cancer screening delivery. PRIMARY FUNDING SOURCE: National Cancer Institute.

"Go ahead and screen" - advice to healthcare systems for routine lynch syndrome screening from interviews with newly diagnosed colorectal cancer patients.

BACKGROUND: Lynch syndrome (LS) is the most common cause of inherited colorectal cancer (CRC). Universal tumor screening (UTS) of newly diagnosed CRC cases is recommended to aid in diagnosis of LS and reduce cancer-related morbidity and mortality. However, not all health systems have adopted UTS processes and implementation may be inconsistent due to system and patient-level complexities. METHODS: To identify barriers, facilitators, and suggestions for improvements of the UTS process from the patient perspective, we conducted in-depth, semi-structured interviews with patients recently diagnosed with CRC, but not screened for or aware of LS. Patients were recruited from eight regionally diverse US health systems. Interviews were conducted by telephone, 60-minutes, audio-recorded, and transcribed. An inductive, constant comparative analysis approach was employed.  RESULTS: We completed 75 interviews across the eight systems. Most participants were white (79%), about half (52%) were men, and the mean age was 60 years. Most self-reported either no (60%) or minimal (40%) prior awareness of LS. Overall, 96% of patients stated UTS should be a routine standard of care for CRC tumors, consistently citing four primary motivations for wanting to know their LS status and engage in the process for LS identification: "knowledge is power"; "family knowledge"; "prevention and detection"; and "treatment and surveillance." Common concerns pertaining to the process of screening for and identifying LS included: creating anticipatory worry for patients, the potential cost and the accuracy of the genetic test, and possibly having one's health insurance coverage impacted by the LS diagnosis. Patients suggested health systems communicate LS results in-person or by phone from a trained expert in LS; offer proactive verbal and written education about LS, the screening steps, and any follow-up surveillance recommendations; and support patients in communicating their LS screening to any of their blood relatives. CONCLUSION: Our qualitative findings demonstrate patients with CRC have a strong desire for healthcare systems to regularly implement and offer UTS. Patients offer key insights for health systems to guide future implementation and optimization of UTS and other LS screening programs and maximize diagnosis of individuals with LS and improve cancer-related surveillance and outcomes. TRIAL REGISTRATION: Not available: not a clinical trial.

An Update on the Epidemiology, Molecular Characterization, Diagnosis, and Screening Strategies for Early-Onset Colorectal Cancer.

Rising trends in the incidence and mortality of early-onset colorectal cancer (CRC) in those who are younger than 50 years have been well established. These trends have spurred intense investigation focused on elucidating the epidemiology and characteristics of early-onset CRC, as well as on identifying strategies for early detection and prevention. In this review, we provide a contemporary update on early-onset CRC with a particular focus on epidemiology, molecular characterization, red flag signs and symptoms, and screening for early-onset CRC.

Identifying Novel Susceptibility Genes for Colorectal Cancer Risk From a Transcriptome-Wide Association Study of 125,478 Subjects.

BACKGROUND AND AIMS: Susceptibility genes and the underlying mechanisms for the majority of risk loci identified by genome-wide association studies (GWAS) for colorectal cancer (CRC) risk remain largely unknown. We conducted a transcriptome-wide association study (TWAS) to identify putative susceptibility genes. METHODS: Gene-expression prediction models were built using transcriptome and genetic data from the 284 normal transverse colon tissues of European descendants from the Genotype-Tissue Expression (GTEx), and model performance was evaluated using data from The Cancer Genome Atlas (n = 355). We applied the gene-expression prediction models and GWAS data to evaluate associations of genetically predicted gene-expression with CRC risk in 58,131 CRC cases and 67,347 controls of European ancestry. Dual-luciferase reporter assays and knockdown experiments in CRC cells and tumor xenografts were conducted. RESULTS: We identified 25 genes associated with CRC risk at a Bonferroni-corrected threshold of P < 9.1 × 10-6, including genes in 4 novel loci, PYGL (14q22.1), RPL28 (19q13.42), CAPN12 (19q13.2), MYH7B (20q11.22), and MAP1L3CA (20q11.22). In 9 known GWAS-identified loci, we uncovered 9 genes that have not been reported previously, whereas 4 genes remained statistically significant after adjusting for the lead risk variant of the locus. Through colocalization analysis in GWAS loci, we additionally identified 12 putative susceptibility genes that were supported by TWAS analysis at P < .01. We showed that risk allele of the lead risk variant rs1741640 affected the promoter activity of CABLES2. Knockdown experiments confirmed that CABLES2 plays a vital role in colorectal carcinogenesis. CONCLUSIONS: Our study reveals new putative susceptibility genes and provides new insight into the biological mechanisms underlying CRC development.

The Kaiser Permanente Research Bank Cancer Cohort: a collaborative resource to improve cancer care and survivorship.

BACKGROUND: The Kaiser Permanente Research Bank (KPRB) is collecting biospecimens and surveys linked to electronic health records (EHR) from approximately 400,000 adult KP members. Within the KPRB, we developed a Cancer Cohort to address issues related to cancer survival, and to understand how genetic, lifestyle and environmental factors impact cancer treatment, treatment sequelae, and prognosis. We describe the Cancer Cohort design and implementation, describe cohort characteristics after 5 years of enrollment, and discuss future directions. METHODS: Cancer cases are identified using rapid case ascertainment algorithms, linkage to regional or central tumor registries, and direct outreach to KP members with a history of cancer. Enrollment is primarily through email invitation. Participants complete a consent form, survey, and donate a blood or saliva sample. All cancer types are included. RESULTS: As of December 31, 2020, the cohort included 65,225 cases (56% female, 44% male) verified in tumor registries. The largest group was diagnosed between 60 and 69 years of age (31%) and are non-Hispanic White (83%); however, 10,076 (16%) were diagnosed at ages 18-49 years, 4208 (7%) are Hispanic, 3393 (5%) are Asian, and 2389 (4%) are Black. The median survival time is 14 years. Biospecimens are available on 98% of the cohort. CONCLUSIONS: The KPRB Cancer Cohort is designed to improve our understanding of treatment efficacy and factors that contribute to long-term cancer survival. The cohort's diversity - with respect to age, race/ethnicity and geographic location - will facilitate research on factors that contribute to cancer survival disparities.

Patient and tumour characteristics of screening-age adults diagnosed with screen-detected versus symptomatic colon cancer.

AIM: International studies have shown that most colon cancers are diagnosed among people with symptoms, but research is limited in the United States. Here, we conducted a retrospective study of adults aged 50-85 years diagnosed with stage I-IIIA colon cancer between 1995 and 2014 in two US healthcare systems. METHODS: Mode of detection (screening or symptomatic) was ascertained from medical records. We estimated unadjusted odds ratios (OR) and 95% confidence intervals (CI) comparing detection mode by patient factors at diagnosis (year, age, sex, race, smoking status, body mass index [BMI], Charlson score), prediagnostic primary care utilization, and tumour characteristics (stage, location). RESULTS: Of 1,675 people with colon cancer, 38.4% were screen-detected, while 61.6% were diagnosed following symptomatic presentation. Screen-detected cancer was more common among those diagnosed between 2010 and 2014 versus 1995-1999 (OR 1.65, 95% CI: 1.19-2.28), and those with a BMI of 25-<30 kg/m2 (OR 1.54, 95% CI: 1.21-1.98) or ≥30 kg/m2 (OR 1.52, 95% CI: 1.18-1.96) versus <25 kg/m2 . Screen-detected cancer was less common among people aged 76-85 (OR 0.50, 95% CI: 0.39-0.65) versus 50-64, those with comorbidity scores >0 (OR 0.71, 95% CI: 0.56-0.91 for score = 1, OR 0.34, 95% CI: 0.26-0.45 for score = 2+), and those with 2+ prediagnostic primary care visits (OR 0.53, 95% CI: 0.37-0.76) versus 0 visits. The odds of screen detection were lower among patients diagnosed with stage IIA (OR 0.33, 95% CI = 0.27-0.41) or IIB (OR 0.12, 95% CI: 0.06-0.24) cancers versus stage I. CONCLUSIONS: Most colon cancers among screen-eligible adults were diagnosed following symptomatic presentation. Even with increasing screening rates over time, research is needed to better understand why specific groups are more likely to be diagnosed when symptomatic and identify opportunities for interventions.

The association of bowel function, participation in life activities, and quality of life in rectal cancer survivors.

PURPOSE: To evaluate whether limited participation in life activities is associated with quality of life (QOL) in rectal cancer survivors, and if so, whether this association is independent of bowel function difficulties. METHODS: We surveyed rectal cancer survivors from four healthcare systems about their QOL, bowel function, and participation in life activities. Additional demographic and clinical variables were extracted from the electronic health record. We examined independent associations between bowel function, participation in life activities, and QOL, controlling for potential confounders. We also identified factors, including ostomy status, that correlate with participation in life activities. RESULTS: Of the 527 respondents, 52% were male, 80% were non-Hispanic white, and the mean age was 63. In fully adjusted models for all rectal cancer survivors, participation in life activities was positively associated with QOL, while bowel function was not. Bowel function retained an independent association with QOL for those who previously had an ostomy and were therefore more likely to have a low rectal anastomosis. Lower participation in life activities was correlated with lower self-reported physical and cognitive function, younger age, financial difficulty, and being non-Hispanic white. CONCLUSIONS: Rectal cancer survivors' participation in life activities was strongly associated with QOL, even when controlling for numerous confounders, including bowel function. Identifying ways to improve participation in life activities may be critical to developing rehabilitative and other supportive interventions that optimize QOL among rectal cancer survivors.

Genetic architectures of proximal and distal colorectal cancer are partly distinct.

OBJECTIVE: An understanding of the etiologic heterogeneity of colorectal cancer (CRC) is critical for improving precision prevention, including individualized screening recommendations and the discovery of novel drug targets and repurposable drug candidates for chemoprevention. Known differences in molecular characteristics and environmental risk factors among tumors arising in different locations of the colorectum suggest partly distinct mechanisms of carcinogenesis. The extent to which the contribution of inherited genetic risk factors for CRC differs by anatomical subsite of the primary tumor has not been examined. DESIGN: To identify new anatomical subsite-specific risk loci, we performed genome-wide association study (GWAS) meta-analyses including data of 48 214 CRC cases and 64 159 controls of European ancestry. We characterised effect heterogeneity at CRC risk loci using multinomial modelling. RESULTS: We identified 13 loci that reached genome-wide significance (p<5×10-8) and that were not reported by previous GWASs for overall CRC risk. Multiple lines of evidence support candidate genes at several of these loci. We detected substantial heterogeneity between anatomical subsites. Just over half (61) of 109 known and new risk variants showed no evidence for heterogeneity. In contrast, 22 variants showed association with distal CRC (including rectal cancer), but no evidence for association or an attenuated association with proximal CRC. For two loci, there was strong evidence for effects confined to proximal colon cancer. CONCLUSION: Genetic architectures of proximal and distal CRC are partly distinct. Studies of risk factors and mechanisms of carcinogenesis, and precision prevention strategies should take into consideration the anatomical subsite of the tumour.

Circulating Levels of Insulin-like Growth Factor 1 and Insulin-like Growth Factor Binding Protein 3 Associate With Risk of Colorectal Cancer Based on Serologic and Mendelian Randomization Analyses.

BACKGROUND & AIMS: Human studies examining associations between circulating levels of insulin-like growth factor 1 (IGF1) and insulin-like growth factor binding protein 3 (IGFBP3) and colorectal cancer risk have reported inconsistent results. We conducted complementary serologic and Mendelian randomization (MR) analyses to determine whether alterations in circulating levels of IGF1 or IGFBP3 are associated with colorectal cancer development. METHODS: Serum levels of IGF1 were measured in blood samples collected from 397,380 participants from the UK Biobank, from 2006 through 2010. Incident cancer cases and cancer cases recorded first in death certificates were identified through linkage to national cancer and death registries. Complete follow-up was available through March 31, 2016. For the MR analyses, we identified genetic variants associated with circulating levels of IGF1 and IGFBP3. The association of these genetic variants with colorectal cancer was examined with 2-sample MR methods using genome-wide association study consortia data (52,865 cases with colorectal cancer and 46,287 individuals without [controls]) RESULTS: After a median follow-up period of 7.1 years, 2665 cases of colorectal cancer were recorded. In a multivariable-adjusted model, circulating level of IGF1 associated with colorectal cancer risk (hazard ratio per 1 standard deviation increment of IGF1, 1.11; 95% confidence interval [CI] 1.05-1.17). Similar associations were found by sex, follow-up time, and tumor subsite. In the MR analyses, a 1 standard deviation increment in IGF1 level, predicted based on genetic factors, was associated with a higher risk of colorectal cancer risk (odds ratio 1.08; 95% CI 1.03-1.12; P = 3.3 × 10-4). Level of IGFBP3, predicted based on genetic factors, was associated with colorectal cancer risk (odds ratio per 1 standard deviation increment, 1.12; 95% CI 1.06-1.18; P = 4.2 × 10-5). Colorectal cancer risk was associated with only 1 variant in the IGFBP3 gene region (rs11977526), which also associated with anthropometric traits and circulating level of IGF2. CONCLUSIONS: In an analysis of blood samples from almost 400,000 participants in the UK Biobank, we found an association between circulating level of IGF1 and colorectal cancer. Using genetic data from 52,865 cases with colorectal cancer and 46,287 controls, a higher level of IGF1, determined by genetic factors, was associated with colorectal cancer. Further studies are needed to determine how this signaling pathway might contribute to colorectal carcinogenesis.

Changes in the expression of genes encoding type IV pili-associated proteins are seen when Clostridium perfringens is grown in liquid or on surfaces.

BACKGROUND: Clostridium perfringens is a Gram-positive anaerobic pathogen that causes multiple diseases in humans and animals. C. perfringens lack flagella but have type IV pili (TFP) and can glide on agar surfaces. When C. perfringens bacteria are placed on surfaces, they become elongated, flexible and have TFP on their surface, traits not seen in liquid-grown cells. In addition, the main pilin in C. perfringens TFP, PilA2, undergoes differential post-translational modification when grown in liquid or on plates. To understand the mechanisms underlying these phenotypes, bacteria were grown in three types of liquid media and on agar plates with the same medium to compare gene expression using RNA-Seq. RESULTS: Hundreds of genes were differentially expressed, including transcriptional regulatory protein-encoding genes and genes associated with TFP functions, which were higher on plates than in liquid. Transcript levels of TFP genes reflected the proportion of each protein predicted to reside in a TFP assembly complex. To measure differences in rates of translation, the Escherichia coli reporter gene gusA gene (encoding ß-glucuronidase) was inserted into the chromosome downstream of TFP promoters and in-frame with the first gene of the operon. ß-glucuronidase expression was then measured in cells grown in liquid or on plates. ß-glucuronidase activity was proportional to mRNA levels in liquid-grown cells, but not plate-grown cells, suggesting significant levels of post-transcriptional regulation of these TFP-associated genes occurs when cells are grown on surfaces. CONCLUSIONS: This study reveals insights into how a non-flagellated pathogenic rod-shaped bacterium senses and responds to growth on surfaces, including inducing transcriptional regulators and activating multiple post-transcriptional regulatory mechanisms associated with TFP functions.