CONTEXT Immunochemical fecal occult blood tests (iFOBTs) are potentially promising tools for colorectal cancer screening. Low-dose aspirin use, which increases the likelihood of gastrointestinal ...bleeding, is common in the target population for colorectal cancer screening. OBJECTIVE To assess the association of low-dose aspirin use with the performance of 2 quantitative iFOBTs in a large sample of patients undergoing colorectal cancer screening. DESIGN, SETTING, AND PARTICIPANTS Diagnostic study conducted from 2005 through 2009 at internal medicine and gastroenterology practices in southern Germany including 1979 patients (mean age, 62.1 years): 233 regular users of low-dose aspirin (167 men, 67 women) and 1746 who never used low-dose aspirin (809 men, 937 women). MAIN OUTCOME MEASURES Sensitivity, specificity, positive and negative predictive values, and area under receiver operating characteristic (ROC) curves in detecting advanced colorectal neoplasms (colorectal cancer or advanced adenoma) with 2 quantitative iFOBTs. RESULTS Advanced neoplasms were found in 24 users (10.3%) and 181 nonusers (10.4%) of low-dose aspirin. At the cut point recommended by the manufacturer, sensitivities of the 2 tests were 70.8% (95% confidence interval CI, 48.9%-87.4%) for users compared with 35.9% (95% CI, 28.9%-43.4%) for nonusers and 58.3% (95% CI, 36.6%-77.9%) for users compared with 32.0% (95% CI, 25.3%-39.4%) for nonusers (P = .001 and P = .01, respectively). Specificities were 85.7% (95% CI, 80.2%-90.1%) for users compared with 89.2% (95% CI, 87.6%-90.7%) for nonusers and 85.7% (95% CI, 80.2%-90.1%) for users compared with 91.1% (95% CI, 89.5%-92.4%) for nonusers (P = .13 and P = .01, respectively). The areas under the ROC curve were 0.79 (95% CI, 0.68-0.90) for users compared with 0.67 (95% CI, 0.62-0.71) for nonusers and 0.73 (95% CI, 0.62-0.85) for users compared with 0.65 (95% CI, 0.61-0.69) for nonusers (P = .05 and P = .17, respectively). Among men, who composed the majority of low-dose aspirin users, the areas under the ROC curve were 0.87 (95% CI, 0.76-0.98) for users compared with 0.68 (95% CI, 0.63-0.74) for nonusers and 0.81 (95% CI, 0.68-0.93) for users compared with 0.67 (95% CI, 0.61-0.72) for nonusers (P = .003 and P = .04, respectively). CONCLUSION For 2 iFOBTs, use of low-dose aspirin compared with no aspirin was associated with a markedly higher sensitivity for detecting advanced colorectal neoplasms, with only a slightly lower specificity.
Gestational weight gain (GWG) is an important modifiable factor known to influence fetal outcomes including birth weight and adiposity. Unlike behaviors such as smoking and alcohol consumption, the ...effect of GWG throughout pregnancy on fetal development and other outcomes has not been extensively studied. The aim of this study was to investigate the relationship of GWG with endocrine factors such as adiponectin, leptin, and C-reactive protein which may be associated with inflammatory response, fetal growth, and adiposity later in life. Data were obtained from the Ulm Birth Cohort Study (UBCS) and the Ulm SPATZ Health Study, two methodologically similar birth cohort studies including newborns and their mothers recruited from 11/2000-11/2001 and 04/2012-05/2013. In the two included birth cohorts we consistently observed statistically significant positive associations between GWG beginning as early as the second trimester with fetal cord blood leptin and stronger association beginning as early as the first trimester with post-delivery maternal serum leptin. Total weight gain exceeding commonly accepted recommended guidelines was consistently associated with higher leptin levels in both cord blood and post-delivery maternal serum. These results suggest a potential pathomechanistic link between fetal environment and surrogate markers of long-term health.
Summary
Background
Faecal immunochemical test (FIT) is emerging as a valid test to rule‐out the presence of colorectal cancer (CRC). However, the accuracy of FIT is dependent on the cut‐off applied. ...An additional low‐cost test could improve further detection of CRC.
Aims
To evaluate the efficacy of combined FIT and volatile organic compounds (VOC) in the detection of CRC within symptomatic populations.
Methods
Systematic reviews on the diagnostic accuracy of FIT and VOC, for the detection of CRC, were updated. Meta‐analyses were performed adopting a bivariate model for sensitivity and specificity. Clinical utility of combined FIT and VOC was estimated using Fagan's nomogram. Post‐test probability of FIT negatives was used as a pre‐test probability for VOC.
Results
The pooled sensitivity and specificity of FIT at 10 µg/g faeces, for the detection of CRC, were 0.914 (95% confidence interval CI = 0.894‐0.936) and 0.783 (CI = 0.850‐0.696), respectively. For VOC, the sensitivity was 0.837 (CI = 0.781‐0.881) and the specificity was 0.803 (CI = 0.870‐0.712). The area under the curve for FIT and VOC were 0.926 and 0.885, respectively. In a population with 5% CRC prevalence, the estimated probability of having CRC following a negative FIT was 0.5% and following both negative FIT and VOC was 0.1%.
Conclusions
In a FIT‐negative symptomatic population, VOC can be a good test to rule‐out the presence of CRC. The estimated probability reduction by 0.4% when both tests being negative offers adequate safety netting in primary care for the exclusion of CRC. The number needed to colonoscope to identify one CRC is eight if either FIT or VOC positive. Cost‐effectiveness and clinical accuracy of this approach will need further evaluation.
A diagnostic tree approach, utilising non‐invasive tests in triaging patients with symptoms for colonoscopy.
Chronic low-grade inflammation has been proposed as a linking mechanism between obesity and the development of inflammation-related conditions such as insulin resistance and cardiovascular disease. ...Despite major advances in the last 2 decades, the complex relationship between inflammation and obesity remains poorly understood. Therefore, we aimed to identify novel inflammation-related proteins associated with adiposity. We investigated the association between BMI and waist circumference and 72 circulating inflammation-related proteins, measured using the Proximity Extension Assay (Olink Proteomics), in 3,308 participants of four independent European population-based studies (KORA-Fit, BVSII, ESTHER, and Bialystok PLUS). In addition, we used body fat mass measurements obtained by Dual-energy X-ray absorptiometry (DXA) in the Bialystok PLUS study to further validate our results and to explore the relationship between inflammation-related proteins and body fat distribution. We found 14 proteins associated with at least one measure of adiposity across all four studies, including four proteins for which the association is novel: DNER, SLAMF1, RANKL, and CSF-1. We confirmed previously reported associations with CCL19, CCL28, FGF-21, HGF, IL-10RB, IL-18, IL-18R1, IL-6, SCF, and VEGF-A. The majority of the identified inflammation-related proteins were associated with visceral fat as well as with the accumulation of adipose tissue in the abdomen and the trunk. In conclusion, our study provides new insights into the immune dysregulation observed in obesity that might help uncover pathophysiological mechanisms of disease development.
The value of KI67 in breast cancer prognostication has been questioned due to concerns on the analytical validity of visual KI67 assessment and methodological limitations of published studies. Here, ...we investigate the prognostic value of automated KI67 scoring in a large, multicentre study, and compare this with pathologists' visual scores available in a subset of patients.
We utilised 143 tissue microarrays containing 15,313 tumour tissue cores from 8088 breast cancer patients in 10 collaborating studies. A total of 1401 deaths occurred during a median follow-up of 7.5 years. Centralised KI67 assessment was performed using an automated scoring protocol. The relationship of KI67 levels with 10-year breast cancer specific survival (BCSS) was investigated using Kaplan-Meier survival curves and Cox proportional hazard regression models adjusted for known prognostic factors.
Patients in the highest quartile of KI67 (>12 % positive KI67 cells) had a worse 10-year BCSS than patients in the lower three quartiles. This association was statistically significant for ER-positive patients (hazard ratio (HR) (95 % CI) at baseline = 1.96 (1.31-2.93); P = 0.001) but not for ER-negative patients (1.23 (0.86-1.77); P = 0.248) (P-heterogeneity = 0.064). In spite of differences in characteristics of the study populations, the estimates of HR were consistent across all studies (P-heterogeneity = 0.941 for ER-positive and P-heterogeneity = 0.866 for ER-negative). Among ER-positive cancers, KI67 was associated with worse prognosis in both node-negative (2.47 (1.16-5.27)) and node-positive (1.74 (1.05-2.86)) tumours (P-heterogeneity = 0.671). Further classification according to ER, PR and HER2 showed statistically significant associations with prognosis among hormone receptor-positive patients regardless of HER2 status (P-heterogeneity = 0.270) and among triple-negative patients (1.70 (1.02-2.84)). Model fit parameters were similar for visual and automated measures of KI67 in a subset of 2440 patients with information from both sources.
Findings from this large-scale multicentre analysis with centrally generated automated KI67 scores show strong evidence in support of a prognostic value for automated KI67 scoring in breast cancer. Given the advantages of automated scoring in terms of its potential for standardisation, reproducibility and throughput, automated methods appear to be promising alternatives to visual scoring for KI67 assessment.
LINKED CONTENT
This article is linked to Chandrapalan et al and Hanna & Cross papers. To view these articles, visit https://doi.org/10.1111/apt.16405 and https://doi.org/10.1111/apt.16471
AIM.Infected parents, especially infected mothers, may play a key role in transmission of Helicobacter pylori within the family. The aim of this population-based study was to determine the role of ...parental infection status in transmission of H. pylori to the child by taking into consideration the infection status of both parents simultaneously.
METHODS.Study subjects were a sample of preschool children in the city of Ulm, located in Southern Germany, who were screened for school fitness between January and July, 1998. The infection status of the children was determined by the C-urea breath test (UBT). Parental infection status was determined by measurement of specific H. pylori IgG antibodies in saliva using a modified immunoassay (Milenia H. pylori IgG; DPC, Biermann, Germany). The parents provided additional information through a standardized questionnaire.
RESULTS.We included 305 children ages 5 to 7 years (mean age, 5.8 years) and their parents in the analysis. Prevalence of H. pylori infection in children by means of UBT was 10.2% 95% confidence interval (CI) 7.0–14.1%. The prevalence of infection was 5.1% if the mother showed no salivary antibody response against H. pylori and 17.3% if she did. Prevalence of infection in children was 6.8% if the father showed no salivary antibody response and 19.1% if he did. After adjustment for potential confounders (including infection of the spouse), the odds ratio for H. pylori infection of the child was 3.9 (95% CI 1.4 to 10.6) when the mother was saliva-positive and 2.0 (95% CI 0.8 to 5.3) when the father was saliva-positive.
CONCLUSION.This study strengthens previous evidence that in the population studied infected parents, in particular mothers may play a key role in transmission of H. pylori to the child.
Automated methods are needed to facilitate high‐throughput and reproducible scoring of Ki67 and other markers in breast cancer tissue microarrays (TMAs) in large‐scale studies. To address this need, ...we developed an automated protocol for Ki67 scoring and evaluated its performance in studies from the Breast Cancer Association Consortium. We utilized 166 TMAs containing 16,953 tumour cores representing 9,059 breast cancer cases, from 13 studies, with information on other clinical and pathological characteristics. TMAs were stained for Ki67 using standard immunohistochemical procedures, and scanned and digitized using the Ariol system. An automated algorithm was developed for the scoring of Ki67, and scores were compared to computer assisted visual (CAV) scores in a subset of 15 TMAs in a training set. We also assessed the correlation between automated Ki67 scores and other clinical and pathological characteristics. Overall, we observed good discriminatory accuracy (AUC = 85%) and good agreement (kappa = 0.64) between the automated and CAV scoring methods in the training set. The performance of the automated method varied by TMA (kappa range= 0.37–0.87) and study (kappa range = 0.39–0.69). The automated method performed better in satisfactory cores (kappa = 0.68) than suboptimal (kappa = 0.51) cores (p‐value for comparison = 0.005); and among cores with higher total nuclei counted by the machine (4,000–4,500 cells: kappa = 0.78) than those with lower counts (50–500 cells: kappa = 0.41; p‐value = 0.010). Among the 9,059 cases in this study, the correlations between automated Ki67 and clinical and pathological characteristics were found to be in the expected directions. Our findings indicate that automated scoring of Ki67 can be an efficient method to obtain good quality data across large numbers of TMAs from multicentre studies. However, robust algorithm development and rigorous pre‐ and post‐analytical quality control procedures are necessary in order to ensure satisfactory performance.
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