The public child welfare system is plagued with high turnover, which is consistently associated with job-related stress. However, the COVID-19 pandemic introduced challenges that impact both the work ...and caseworkers’ decision to stay in their job. To better understand stressors and intention to stay amid the COVID-19 pandemic, one state-level agency implemented a survey, completed by forty-eight percent of public child welfare caseworkers in the state. The current analysis employs multinomial logistic regression to predict intention to stay in the job and in the field and narrative analysis to describe caseworker experiences. Expanding on prior research, findings suggest that caseworker perception of an organization’s response to COVID-19 challenges is associated with a caseworker’s intent to leave. Further, this study highlights the distinction in commitment to the field compared to commitment to one’s job, introduces challenges associated with work during the COVID-19 pandemic, and describes worker-identified benefits of those work changes.
The risk of colorectal cancer after a previous negative colonoscopy is very low. Nevertheless, interval cancers occur. We aimed to assess the characteristics and predictors of interval cancers after ...negative colonoscopy.
A population-based case-control study was conducted in Southern Germany in 2003-7. Sociodemographic and tumour characteristics were compared among 78 patients with interval cancers occurring 1-10 years after a negative colonoscopy and 433 colorectal cancers detected at screening. In addition, the indication for the preceding negative colonoscopy and its completeness were compared between patients with interval cancers and 515 controls with a preceding negative colonoscopy.
56.4% of interval cancers occurred among women compared with 33.7% of cases detected by screening (p=0.0001). After adjustment for covariates, female sex (OR 2.28, 95% CI 1.35 to 3.83) and location in the caecum or ascending colon (OR 1.98, 95% CI 1.17 to 3.35) were independently associated with occurrence of interval cancers. The preceding negative colonoscopy was more commonly conducted because of a positive faecal occult blood test (26.0% vs 12.9%, p=0.009) and was more often incomplete (caecum not reached: 18.1% vs 6.7%, p=0.001) among interval cancer cases than among controls. Characteristics of the preceding negative colonoscopy strongly and independently associated with occurrence of interval cancers were follow-up of a positive faecal occult blood test among men (OR 5.49, 95% CI 2.10 to 14.35) and incompleteness among women (OR 4.38, 95% CI 1.69 to 11.30).
The observed patterns suggest that a substantial proportion of interval cancers are due to neoplasms missed at colonoscopy and are potentially preventable by enhanced performance of colonoscopy.
Endothelial cells (ECs) provide angiocrine factors orchestrating tumor progression. Here, we show that activated Notch1 receptors (N1ICD) are frequently observed in ECs of human carcinomas and ...melanoma, and in ECs of the pre-metastatic niche in mice. EC N1ICD expression in melanoma correlated with shorter progression-free survival. Sustained N1ICD activity induced EC senescence, expression of chemokines and the adhesion molecule VCAM1. This promoted neutrophil infiltration, tumor cell (TC) adhesion to the endothelium, intravasation, lung colonization, and postsurgical metastasis. Thus, sustained vascular Notch signaling facilitates metastasis by generating a senescent, pro-inflammatory endothelium. Consequently, treatment with Notch1 or VCAM1-blocking antibodies prevented Notch-driven metastasis, and genetic ablation of EC Notch signaling inhibited peritoneal neutrophil infiltration in an ovarian carcinoma mouse model.
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•Tumor ECs frequently have activated Notch1 and this correlates with poor prognosis•Sustained EC Notch1 activity promotes TC migration across the vessel wall•Endothelial Notch1 hyperactivation promotes neutrophil infiltration and metastasis•Neutrophil infiltration and metastasis depend on Notch1-induced VCAM1 expression
Wieland, Rodriguez-Vita et al. reveal that activated Notch1 signaling in endothelial cells (ECs) in tumors and in the pre-metastatic niche induces VCAM1 expression, leading to increased neutrophil infiltration and metastasis. Inhibition of Notch1 or VCAM1 reduces metastasis driven by EC Notch1 in mouse models.
Circulating microRNAs (miRNAs) have been proposed as minimally invasive prognostic markers for various types of cancers, including colorectal cancer (CRC), the third most diagnosed cancer worldwide. ...We aimed to evaluate the levels of circulating miRNAs that might serve as markers for CRC prognosis and survival. We included plasma samples of 543 CRC patients with stage I‐IV disease from a population‐based study carried out in Germany. After comprehensive evaluation of current literature, 95 miRNAs were selected and measured with Custom TaqMan® Array MicroRNA Cards. Plasma samples of non‐metastatic and metastatic colon cancer patients, each group consisting of ten patients with ‘good’ and ten patients with ‘bad’ prognosis were screened. Identified candidate miRNAs were further validated by RT‐qPCR in the whole study cohort. The association of the miRNA levels with patients' survival and the prognostic subtypes was analyzed with uni‐ and multivariate logistic regression and Cox proportional hazards regression models. Increased miR‐122 levels were associated with a ‘bad’ prognostic subtype in metastatic CRC (Odds ratio: 1.563, 95% confidence interval (CI): 1.038‐2.347) and a shorter relapse‐free survival and overall survival for non‐metastatic (Hazard ratio (HR): 1.370, 95% CI: 1.028‐1.825; HR: 1.353, 95% CI: 1.002‐1.828) and metastatic (HR: 1.264, 95% CI: 1.050‐1.520; HR: 1.292, 95% CI: 1.078‐1.548) CRC patients. Additionally, several members of the miR‐200 family showed associations with patients' prognosis and correlations to clinicopathological characteristics. The here identified miRNA markers, miR‐122 and the miR‐200 family members, could be of use in the development of a multi‐marker blood test for CRC prognosis.
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Metastasis is the major cause of death for colorectal cancer (CRC) patients. Prognostic markers that are constantly measurable using liquid biopsies could facilitate the earlier prediction of relapse events and metastasis formation. In a prospective study cohort of 543 colorectal cancer patients, the authors evaluated the role of circulating miRNAs as potential prognostic markers for CRC with a specific focus on miRNAs known to be involved in tumor progression and metastasis formation. MiR‐122 and several members of the miR‐200 family were identified as prognostic markers, suggesting their potential use in the development of a multi‐marker blood test for CRC prognosis.
Background & Aims The adenoma detection rate (ADR) is an important quality indicator of screening colonoscopy; it is inversely associated with risk of interval cancers and colorectal cancer ...mortality. We assessed trends in the ADR in the first 10 years of the German screening colonoscopy program. Methods We calculated age-adjusted and age-specific detection rates of nonadvanced adenomas and advanced adenomas for each calendar year based on 4.4 million screening colonoscopies conducted from 2003 through 2012 and reported to the German screening colonoscopy registry. Results We observed a steady and strong increase in rate of detection of nonadvanced adenomas in both sexes and all age groups. Age-adjusted rates of detection of nonadvanced adenomas increased from 13.3% to 22.3% among men and from 8.4% to 14.9% among women. This increase was mostly due to an increase in detection rates of adenomas <0.5 cm, and it is partly explained by an innovation effect (higher ADRs among incoming colonoscopists than among leaving colonoscopists, and relatively stable ADRs among continuing colonoscopists). Only modest increases were observed in detection rates of advanced adenomas (from 7.4% to 9.0% among men, and from 4.4% to 5.2% among women) and colorectal cancer. In 2012, overall ADR reached 31.3% and 20.1% in men and women, respectively. Conclusions We observed a strong increase in ADRs from 2003 through 2012 in Germany. Although we cannot exclude the effects of secular trends in colorectal neoplasm prevalence, the observed increase was mainly the result of a steady increase in detection of nonadvanced adenomas (especially adenomas <0.5 cm). Further research should address potential implications for defining screening and surveillance intervals.
High red and processed meat intake (RPMI) is an established risk factor for colorectal cancer (CRC). We aimed to assess the impact of RPMI on CRC risk according to and in comparison with genetically ...determined risk, which was quantified by a polygenic risk score (PRS). RPMI and potential confounders (ascertained by questionnaire) and a PRS (based on 140 CRC-related loci) were obtained from 5109 CRC cases and 4134 controls in a population-based case−control study. Associations of RPMI with CRC risk across PRS levels were assessed using logistic regression models and compared to effect estimates of PRS using “genetic risk equivalent” (GRE), a novel metric for effective risk communication. RPMI multiple times/week, 1 time/day, and >1 time/day was associated with 19% (95% CI 1% to 41%), 41% (18% to 70%), and 73% (30% to 132%) increased CRC risk, respectively, when compared to RPMI ≤ 1 time/week. Associations were independent of PRS levels (pinteraction = 0.97). The effect of RPMI > 1 time/day was equivalent to the effect of having 42 percentiles higher PRS level (GRE 42, 95% CI 20−65). RPMI increases CRC risk regardless of PRS levels. Avoiding RPMI can compensate for a substantial proportion of polygenic risk for CRC.
Colorectal cancer (CRC) is a heterogeneous disease with different mechanisms of pathogenesis. Classification systems have been proposed based on molecular features of tumors, but none are used in ...clinical practice. We performed a systematic review of studies on the associations between molecular classifications of CRC and patient survival.
We searched the PubMed, Embase, Cochrane, and Web of Science databases for combinations of terms related to CRC, molecular markers, subtype classifications, and survival (overall survival, disease-specific survival, disease-free survival). We included only studies that used at least 3 molecular markers to classify tumors and provided an estimate of survival associated with each subtype. Data extraction and quality assessment were performed independently by 2 reviewers.
We identified 6 studies that fulfilled the inclusion criteria. In these studies, molecular subtypes were assigned based on pathways associated with tumor development or findings from gene expression clustering analyses. Most studies proposed classification systems with 5 subtypes, including information on microsatellite instability, mutations in BRAF, and mutations in KRAS. None of the studies included TNM stage in their classification system. Three classification systems used similar definitions. Only 3 studies provided internal or external validation of the proposed classification schemes. Tumors with microsatellite stability and mutations in KRAS or BRAF were associated with decreased survival times, compared with tumors with microsatellite stability and no mutations.
In a systematic review of studies of molecular classifications of CRC and patient survival, we found that most subtypes were not significantly or not differentially associated with survival. None of the systems integrated TNM staging. Further research and validation are needed to develop molecular subtype classification systems for clinical practice.
Smoking and alcohol increase risk for colorectal malignancies. However, colorectal cancer (CRC) is a heterogenic disease and associations with the molecular pathological pathways are unclear.
This ...population-based case-control study includes 2444 cases with first-diagnosis CRC and 2475 controls. Tumour tissue was analysed for MSI (microsatellite instability), CIMP (CpG island methylator phenotype), BRAF (B-Raf proto-oncogene serine/threonine kinase gene) and KRAS (Kirsten rat sarcoma viral oncogene homologue gene) mutations. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were estimated for associations between alcohol and smoking and CRC molecular subtypes and pathways.
Current smoking showed higher ORs for MSI-high (OR = 2.79, 95% CI: 1.86-4.18) compared to MSS (OR = 1.41, 1.14-1.75, p-heterogeneity (p-het) = 0.001), BRAF-mutated (mut) (OR = 2.40, 1.41-4.07) compared to BRAF-wild type (wt) (OR = 1.52, 1.24-1.88, p-het = 0.074), KRAS-wt (OR = 1.70, 1.36-2.13) compared to KRAS-mut (OR = 1.26, 0.95-1.68, p-het = 0.039) and CIMP-high (OR = 2.01, 1.40-2.88) compared to CIMP-low/negative CRC (OR = 1.50, 1.22-1.85, p-het=0.101). Current smoking seemed more strongly associated with sessile serrated pathway (CIMP-high + BRAF-mut; OR = 2.39, 1.27-4.52) than with traditional pathway CRC (MSS + CIMP-low/negative + BRAF-wt; OR = 1.50, 1.16-1.94) and no association was observed with alternate pathway CRC (MSS + CIMP-low/negative + KRAS-wt; OR = 1.08, 0.77-1.43). No heterogeneity was observed in alcohol consumption association by molecular subtypes.
In this large case-control study, smoking was more strongly associated with MSI-high and KRAS-wt CRC and with cases showing features of the sessile serrated pathway. Association patterns were less clear for alcohol consumption.
AbstractObjectiveTo review and summarise the evidence on the prevalence of colorectal adenomas and cancers at a follow-up screening colonoscopy after negative index colonoscopy, stratified by ...interval between examinations and by sex.DesignSystematic review and meta-analysis of all available studies.Data sourcesPubMed, Web of Science, and Embase. Two investigators independently extracted characteristics and results of identified studies and performed standardised quality ratings.Eligibility criteriaStudies assessing the outcome of a follow-up colonoscopy among participants at average risk for colorectal cancer with a negative previous colonoscopy (no adenomas).Results28 studies were identified, including 22 cohort studies, five cross sectional studies, and one case-control study. Findings for an interval between colonoscopies of one to five, five to 10, and more than 10 years were reported by 17, 16, and three studies, respectively. Summary estimates of prevalences of any neoplasm were 20.7% (95% confidence interval 15.8% to 25.5%), 23.0% (18.0% to 28.0%), and 21.9% (14.9% to 29.0%) for one to five, five to 10, and more than 10 years between colonoscopies. Corresponding summary estimates of prevalences of any advanced neoplasm were 2.8% (2.0% to 3.7%), 3.2% (2.2% to 4.1%), and 7.0% (5.3% to 8.7%). Seven studies also reported findings stratified by sex. Summary estimates stratified by interval and sex were consistently higher for men than for women.ConclusionsAlthough detection of any neoplasms was observed in more than 20% of participants within five years of a negative screening colonoscopy, detection of advanced neoplasms within 10 years was rare. Our findings suggest that 10 year intervals for colonoscopy screening after a negative colonoscopy, as currently recommended, may be adequate, but more studies are needed to strengthen the empirical basis for pertinent recommendations and to investigate even longer intervals.Study registrationProspero CRD42019127842.
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