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Supplemental Digital Content is available in the text Objective: This large international cohort study aimed to investigate the associations of examined lymph node (ELN) number with accurate staging and long-term survival in pancreatic adenocarcinoma (PaC) and to robustly determine the minimal and optimal ELN thresholds. Summary Background Data: ELN number is an important quality metric in cancer care. The recommended minimal ELN number in PaC to accurately stage cancer varies greatly across guidelines, and the optimal number especially to adequately stratify patient survival has not yet been established. Methods: Population-based data on patients with stage I to II PaC resected in 2003 to 2015 from the US Surveillance, Epidemiology, and End Results (SEER)-18 Program and Netherlands National Cancer Registry (NCR) were analyzed. Associations of ELN number with stage migration and survival were evaluated using multivariable-adjusted logistic and Cox regression models, respectively. The series of odds ratios (ORs) for negative-to-positive node stage migration and hazard ratios (HRs) for survival with more ELNs were fitted using a LOWESS smoother, and structural breakpoints were determined by Chow test. Results: Overall 16,241 patients were analyzed. With increasing ELN number, both cohorts exhibited significant proportional increases from nodenegative to node-positive disease [OR SEER-18 = 1.05, 95% confidence interval (CI) = 1.04–1.05; ORNCR = 1.10, 95% CI = 1.08–1.12] and serial improvements in survival (HR SEER-18 = 0.98, 95% CI = 0.98–0.99; HRNCR = 0.98, 95% CI = 0.97–0.99) per additional ELN after controlling for confounders. Associations for stage migration and survival remained significant in most stratifications by patient, tumor, and treatment factors. Cut-point analyses suggested a minimal threshold ELN number of 11 and an optimal number of 19, which were validated both internally in the derivative US cohort and externally in the Dutch cohort with the ability to well discriminate different probabilities of both survival and stage migration. Conclusions: In stage I to II PaC, more ELNs are associated with more precise nodal staging, which might largely explain the survival association. Our observational study does not suggest causality, and does not encourage more extended lymphadenectomy before further randomized evidence is obtained. Our results robustly conclude 11 ELNs as the minimal and suggest 19 ELNs as the optimal cut-points, for evaluating quality of lymph node examination and possibly for stratifying postoperative prognosis. [ABSTRACT FROM AUTHOR]

Supplemental Digital Content is available in the text Objective: The aim of this study was to evaluate outcomes of metastases at various time intervals after colorectal cancer (CRC) diagnosis. Background: Earlier studies have indicated a short time interval between CRC diagnosis and distant metastases to be associated with poor prognosis. The majority of studies assessed outcome from CRC diagnosis or metastasis resection rather than from metastasis diagnosis and might be subject to immortal time bias. Methods: Patients in the population-based DACHS study were stratified: metastases at/within 1 month (immediate), 2 to 6 months (early), 7 to 12 months (intermediate), and >12 months (late) after CRC diagnosis. The primary endpoint was overall survival (OS) from metastasis diagnosis. Cox proportional hazards regression models were used to calculate hazard ratios (HRs) and 95% confidence intervals (CI). HRs were adjusted for important confounders and immortal time. Results: A total of 1027 patients were included. T4 (P < 0.0001) and node-positive tumors (P < 0.0001) were more frequent in the immediate group. Lung metastases (P < 0.0001) and single-site metastases (P < 0.0001) were more prevalent in the late group. In multivariable analysis, immediate metastases were not associated with poor OS compared to metastases at later time points (late vs immediate: HR 1.21; 95% CI, 0.98–1.48). Subgroup analyses revealed poor OS of late versus immediate metastases for females (1.45; 1.08–1.96), proximal colon cancer (1.54; 1.09–2.16), and N0 (1.46; 1.00–2.12) or N1 disease (1.88; 1.17–3.05). Conclusions: Immediate or early metastases are not associated with unfavorable outcome compared to late metastases. These findings challenge the current notion of poor outcome for CRC with immediate or early metastases. [ABSTRACT FROM AUTHOR]

Background: Flexible sigmoidoscopy and fecal immunochemical tests are established diagnostic tests for colorectal cancer (CRC) screening and less invasive, less expensive, and easier to conduct than colonoscopy. However, little is known about their joint diagnostic performance compared with colonoscopy. We aimed to assess the expected diagnostic performance of joint use of flexible sigmoidoscopy and fecal immunochemical test.Methods: We assessed the overall and site-specific prevalences of colorectal neoplasms and the overall sensitivity, specificity, area under the receiver operating characteristics curve of a quantitative fecal immunochemical test (FOB Gold, Sentinel Diagnostics, Milano, Italy) among 3,466 participants in screening colonoscopy in Germany. Results were used to model the expected diagnostic performance of joint use of flexible sigmoidoscopy and fecal immunochemical testing.Results: CRC and advanced adenomas were found in 29 (1%) and 354 (10%) participants, respectively. The area under the curve of fecal immunochemical testing for these outcomes could be raised from 96% to 100% and from 70% to 89%, respectively, by combining it with flexible sigmoidoscopy. At 90% specificity, sensitivity of fecal immunochemical testing would increase from 97% to 100% for CRC and from 40% to 79% for advanced adenomas.Conclusions: Combining flexible sigmoidoscopy and fecal immunochemical testing might strongly enhance diagnostic performance of each single test to a level close to the diagnostic performance of screening colonoscopy while avoiding many unnecessary colonoscopies. [ABSTRACT FROM AUTHOR]

Link between obesity and early onset colorectal cancers: Importance of accounting for BMI trajectories in early life. All studies included in our review considered body mass index (BMI) at late adolescence, young or middle adulthood, i.e., at ages during which BMI trajectories are rather stable ([[3]]). Nevertheless, we agree that timing of BMI measurements and BMI trajectories are crucial factors to be considered in the study of the role of overweight and obesity for colorectal cancer (CRC), including early-onset colorectal cancer (EOCRC). [Extracted from the article]

Background: Vitamin D insufficiency is common among older adults. Genome-wide association studies have found an association between variants in the vitamin D binding protein and serum levels of vitamin D. The quantification of this association among older women and men and its potential variation by season remain unexplored.Methods: Serum levels of 25-hydroxyvitamin D [25(OH)D] and genetic variants in the vitamin D binding protein were analyzed in 2160 women and 1581 men age 50 to 74 years participating in a large population-based cohort study (ESTHER study-epidemiologic study assessing chances of prevention and early detection of various chronic diseases, including cancer among older adults) in Germany. Serum levels of 25(OH)D were assessed in relation to four single nucleotide polymorphisms (SNPs; rs4588, rs2282679, rs1155563, and rs12512631) by descriptive and multivariate analysis.Results: Both heterozygous and homozygous women and men carrying the rare allele with SNPs rs4588, rs2282679, or rs1155563 had lower levels of 25(OH)D in summer months than those homozygous for the wild-type alleles. Adjusted differences ranged from 5.1 to 5.4 nmol/l among heterozygous carriers of the rare alleles and from 8.8 to 9.6 nmol/l among homozygous carriers of the rare alleles. During winter months, 25(OH)D differences by genotype were smaller among women and not apparent among men.Conclusions: Older women and men living in a high-latitude region and carrying the rare alleles of SNPs rs4588, rs2282679, or rs1155563 seem to benefit less from higher levels of ultraviolet radiation during the summer season. [ABSTRACT FROM AUTHOR]

Helicobacter pylori infection is an established risk factor for chronic atrophic gastritis. However, estimates of the strength of this association have varied widely, possibly due to clearance of the infection in severe stages of chronic atrophic gastritis, which may lead to underestimation of the association. We assessed the association of H. pylori infection with chronic atrophic gastritis according to severity of disease.We measured serum pepsinogen I and II (as surrogates for chronic atrophic gastritis) and antibodies against H. pylori by ELISA in 9444 men and women aged 50-74 years in a population-based study in Saarland, a state of Germany. The association between H. pylori and chronic atrophic gastritis (defined as pepsinogen I <70 ng/mL and pepsinogen I/II-ratio <3) was analyzed after stratification of chronic atrophic gastritis cases by quintiles of pepsinogen I as proxy marker for severity of chronic atrophic gastritis.When all cases were included, the odds ratio for the association with Chronic atrophic gastritis for H. pylori infection alone was 2.9 (95% confidence interval 2.3-3.6); it was 4.1 (3.2-5.2), for H. pylori infection that was positive for the presence of Ig G antibodies specific to the cytotoxin-associated gene A (CagA) protein—a well-established virulence factor of H. pylori. These ORs ranged from 11 (5.2-22) and 16 (7.7-34) for the quintile of cases with highest pepsinogen I (least severe cases) to 1.0 (0.7-1.6) and 0.9 (0.5-1.5) for the quintile of cases with lowest pepsinogen I (most severe cases). Five of 7 cases with CagA-seropositivity but negative H. pylori serostatus (a pattern indicative of past infection) were in the group of most severe cases.Our results support the hypothesis of major underestimation of the association of H. pylori and chronic atrophic gastritis, due to clearance of the infection in advanced stages of the disease. These results suggest that the association is much stronger than estimated by most epidemiologic studies to date. [ABSTRACT FROM AUTHOR]

Background: Examination of the genetic structure of complex diseases by a "genomic pathway approach"--which applies stepwise model selection to sets of more than 1000 polymorphisms in studies of several hundred subjects--has recently been proposed. Models constructed through extensive selection procedures may yield misleading test statistics and measures of predictive performance; we aimed to quantify the extent of such problems inherent to stepwise regression on the genomic pathway scale.Methods: We performed permutation analyses and data-splitting approaches using one of the datasets examined in the paper that originally suggested this approach (n = 536; 1195 SNPs in 22 genes) (Lesnick et al. PLoS Genet. 2007;3:e98).Results: The P values for the genetic effects produced by standard testing severely overestimated the significance, resulting in our example in a standard P value of 3.5 x 10(-69) and a permutation P of 0.003 (95% confidence interval = 0.001 to 0.009). Furthermore, the apparent validity as measured by the area under the receiver operating characteristic curve in 90% training datasets (0.935 [interquartile range = 0.918-0.951]) was extremely overoptimistic when compared with the validity estimated from the excluded 10% validation subsets (0.564 [0.518-0.614]). This validated area under the receiver operating characteristic curve was lower than for models predicting case/control status solely from age and sex while excluding any genetic effects (median difference = -0.040 [95% confidence interval = -0.049 to -0.031]).Conclusions: The application of stepwise model selection on the genomic pathway scale--at least in the simple form currently put forward--is prone to yield highly misleading results. We provide pointers to some promising alternatives. [ABSTRACT FROM AUTHOR]

Background: Multiple studies have suggested that breast-feeding can prevent obesity, but the evidence remains inconclusive. The concentrations of specific constituents of human milk, such as adipokines, may play a role in this relationship, and these have rarely been considered. We assessed the role of adiponectin and leptin in human milk in childhood overweight.Methods: Between November 2000 and November 2001 all women delivering at the Department of Gynecology and Obstetrics at the University of Ulm, Germany were invited to participate in the study together with their healthy newborns. Milk samples were collected 6 weeks postpartum. Adiponectin and leptin levels were determined by commercially available ELISA. Active follow-up was performed at age 12 and 24 months.Results: Of the 674 breast-fed children, 56 (8%) were overweight at the age of 2 years. Median adiponectin and leptin levels in milk were 10.9 ng/mL and 174.5 pg/mL, respectively. Adjusted odds ratio for overweight at the age of 2 was 1.6 (95% confidence interval = 1.0-2.6) per unit increase of log adiponectin and 1.1 (0.8-1.5) per unit increase of log leptin. Among children who were breast-fed for at least 6 months, adjusted odds ratios were 2.1 (1.1-4.2) per unit increase of log adiponectin, and 1.1 (0.7-1.6) per unit increase of log leptin.Conclusion: High levels of adiponectin in maternal milk may be a risk factor for childhood overweight. [ABSTRACT FROM AUTHOR]