Stratified survival of resected and overall pancreatic cancer patients in Europe and the USA in the early twenty-first century: a large, international population-based study

Abstract: Background The prognosis of pancreatic cancer (PaC) strongly varies across different stages and age groups, which has unfortunately not been well recorded in the literature. This international population-based study aimed to provide tumor-node-metastasis (TNM) stage- and age-specific survival estimates and trends in resected and overall (resected and unresected) PaC in the early twenty-first century. Methods: Using data from the US Surveillance, Epidemiology, and End Results-18 Program and the national cancer registries of the Netherlands, Belgium, Norway, and Slovenia, short-term and long-term overall survival results stratified by TNM stage and age in resected and overall primary PaC, irrespective of being microscopically confirmed or not, in 2003–2014 were computed using the Kaplan-Meier method. The temporal survival trends over three predefined periods (2003–2005, 2006–2008, and 2009–2011) were further examined using the log-rank test. Results: In total, data for 125,183 patients were analyzed. Overall, age-stratified 3-year survival was 20–34% (< 60 years), 14–25% (60–69 years), and 9–13% (≥ 70 years) in stages I–II PaC; and 2–5% (< 60 years), 1–2% (60–69 years), and < 1–1% (≥ 70 years) in stages III–IV cancer. Patients who underwent operation had higher 3-year survival in each stage and age group (stages I–II: 23–39% (< 60 years), 16–31% (60–69 years), and 17–30% (≥ 70 years); stages III–IV: 5–19% (< 70 years) and 2–14% (≥ 70 years)). Perioperative survival also decreased with advancing stage and older age (stages I–II: 98–100% (< 60 years), 97–99% (60–69 years), and 94–99% (≥ 70 years); stages III–IV: 94–99% (< 70 years) and 81–96% (≥ 70 years)). Between 2003 and 2005 and 2009–2011, for overall PaC, both short-term and long-term survival improvements were observed in all countries except Belgium; for resected disease, short-term improvements were present only in the USA and Slovenia, but long-term improvements were observed in all countries except Slovenia, with stage-specific variations. Conclusions: Our large international study provides TNM stage- and age-specific population-based survival in overall and resected PaC that will facilitate clinical counseling. While the survival expectations for patients with resected PaC are substantially higher than the widely available and known dismal survival predictions for overall patients, conclusions on the benefits of resection cannot be made from this observational study. Patients with advanced-stage disease and/or older age should undergo careful risk assessment before treatment. Limited but inspiring improvement in survival is observed

Development and validation of a prognostic model to predict the prognosis of patients who underwent chemotherapy and resection of pancreatic adenocarcinoma: a large international population-based cohort study

Background: Pancreatic cancer (PaC) remains extremely lethal worldwide even after resection. PaC resection rates are low, making prognostic studies in resected PaC difficult. This large international population-based study aimed at exploring factors associated with survival in patients with resected TNM stage I–II PaC receiving chemotherapy and at developing and internationally validating a survival-predicting model. Methods: Data of stage I–II PaC patients resected and receiving chemotherapy in 2003–2014 were obtained from the national cancer registries of Belgium, the Netherlands, Slovenia, and Norway, and the US Surveillance, Epidemiology, and End Results (SEER)-18 Program. Multivariable Cox proportional hazards models were constructed to investigate the associations of patient and tumor characteristics with overall survival, and analysis was performed in each country respectively without pooling. Prognostic factors remaining after backward selection in SEER-18 were used to build a nomogram, which was subjected to bootstrap internal validation and external validation using the European datasets. Results: A total of 11,837 resected PaC patients were analyzed, with median survival time of 18–23 months and 3-year survival rates of 21–31%. In the main analysis, patient age, tumor T stage, N stage, and differentiation were associated with survival across most countries, with country-specific association patterns and strengths. However, tumor location was mostly not significantly associated with survival. Resection margin, hospital type, tumor size, positive and harvested lymph node number, lymph node ratio, and comorbidity number were associated with survival in certain countries where the information was available. A median survival time- and 1-, 2-, 3-, and 5-year survival probability-predictive nomogram incorporating the backward-selected variables in the main analysis was established. It fits each European national cohort similarly well. Calibration curves showed very good agreement between nomogram-prediction and actual observation. The concordance index of the nomogram (0.60) was significantly higher than that of the T and N stage-based model (0.56) for predicting survival. Conclusions: In these large international population-based cohorts, patients with resected PaC receiving chemotherapy have distinct characteristics independently associated with survival, with country-specific patterns and strengths. A robust benchmark population-based survival-predicting model is established and internationally validated. Like previous models predicting survival in resected PaC, our nomogram performs modestly

One-carbon metabolites, B vitamins and associations with systemic inflammation and angiogenesis biomarkers among colorectal cancer patients:results from the ColoCare Study

B-vitamins involved in one-carbon metabolism have been implicated in the development of inflammation- A nd angiogenesis-related chronic diseases, such as colorectal cancer. Yet, the role of one-carbon metabolism in inflammation and angiogenesis among colorectal cancer patients remains unclear.The objective of this study was to investigate associations of components of one-carbon metabolism with inflammation and angiogenesis biomarkers among newly diagnosed colorectal cancer patients (n=238) in the prospective ColoCare Study, Heidelberg.We cross-sectionally analyzed associations between 12 B-vitamins and one-carbon metabolites and 10 inflammation and angiogenesis biomarkers from pre-surgery serum samples using multivariable linear regression models. We further explored associations among novel biomarkers in these pathways with Spearman partial correlation analyses. We hypothesized that pyridoxal-5'-phosphate (PLP) is inversely associated with inflammatory biomarkers.We observed that PLP was inversely associated with CRP (r=-0.33, plinearlinear=0.003), IL-6 (r=-0.39, plinear linear=0.02) and TNFα (r=-0.12, plinear=0.045). Similar findings were observed for 5-methyl-tetrahydrofolate and CRP (r=-0.14), SAA (r=-0.14) and TNFα (r=-0.15) among colorectal cancer patients. Folate catabolite apABG was positively correlated with IL-6 (r= 0.27, plinearlinear<0.0001), indicating higher folate utilization during inflammation.Our data support the hypothesis of inverse associations between PLP and inflammatory biomarkers among colorectal cancer patients. A better understanding of the role and inter-relation of PLP and other one-carbon metabolites with inflammatory processes among colorectal carcinogenesis and prognosis could identify targets for future dietary guidance for colorectal cancer patients.</p

Mendelian randomization analysis of C-reactive protein on colorectal cancer risk

Background: Chronic inflammation is a risk factor for colorectal cancer (CRC). Circulating C-reactive protein (CRP) is also moderately associated with CRC risk. However, observational studies are susceptible to unmeasured confounding or reverse causality. Using genetic risk variants as instrumental variables, we investigated the causal relationship between genetically elevated CRP concentration and CRC risk, using a Mendelian randomization approach. Methods: Individual-level data from 30 480 CRC cases and 22 844 controls from 33 participating studies in three international consortia were used: the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO), the Colorectal Transdisciplinary Study (CORECT) and the Colon Cancer Family Registry (CCFR). As instrumental variables, we included 19 single nucleotide polymorphisms (SNPs) previously associated with CRP concentration. The SNP-CRC associations were estimated using a logistic regression model adjusted for age, sex, principal components and genotyping phases. An inverse-variance weighted method was applied to estimate the causal effect of CRP on CRC risk. Results: Among the 19 CRP-associated SNPs, rs1260326 and rs6734238 were significantly associated with CRC risk (P = 7.5 × 10-4, and P = 0.003, respectively). A genetically predicted one-unit increase in the log-transformed CRP concentrations (mg/l) was not associated with increased risk of CRC [odds ratio (OR) = 1.04; 95% confidence interval (CI): 0.97, 1.12; P = 0.256). No evidence of association was observed in subgroup analyses stratified by other risk factors. Conclusions: In spite of adequate statistical power to detect moderate association, we found genetically elevated CRP concentration was not associated with increased risk of CRC among individuals of European ancestry. Our findings suggested that circulating CRP is unlikely to be a causal factor in CRC development

Genome-Wide Interaction Analyses between Genetic Variants and Alcohol Consumption and Smoking for Risk of Colorectal Cancer

Genome-wide association studies (GWAS) have identified many genetic susceptibility loci for colorectal cancer (CRC). However, variants in these loci explain only a small proportion of familial aggregation, and there are likely additional variants that are associated with CRC susceptibility. Genome-wide studies of gene-environment interactions may identify variants that are not detected in GWAS of marginal gene effects. To study this, we conducted a genome-wide analysis for interaction between genetic variants and alcohol consumption and cigarette smoking using data from the Colon Cancer Family Registry (CCFR) and the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO). Interactions were tested using logistic regression. We identified interaction between CRC risk and alcohol consumption and variants in the 9q22.32/HIATL1 (Pinteraction = 1.76×10−8; permuted pvalue 3.51x10-8) region. Compared to non-/occasional drinking light to moderate alcohol consumption was associated with a lower risk of colorectal cancer among individuals with rs9409565 CT genotype (OR, 0.82 [95% CI, 0.74±0.91]; P = 2.1×10−4) and TT genotypes (OR,0.62 [95% CI, 0.51±0.75]; P = 1.3×10−6) but not associated among those with the CC genotype (p = 0.059). No genome-wide statistically significant interactions were observed for smoking. If replicated our suggestive finding of a genome-wide significant interaction between genetic variants and alcohol consumption might contribute to understanding colorectal cancer etiology and identifying subpopulations with differential susceptibility to the effect of alcohol on CRC risk

Just Follow Your Heart: A 5-Year Journey

t is winter 1997. It is the year of my PhD ... a big step for me, and yet nothing special these days. Everybody around you seems to have a PhD, and at least half of your friends are looking for the same as you, this dream job where you finally get recognised as somebody with experience, at least in your own field. Where you get paid properly, not just for a half-time job or with a stipend, and where you have better working hours, less than 16 hours a day. In a dream place, where you work in a team and share results, and publishing is no problem. Will the experience, and title, I\u27ve gained help me find my dream position? I know how to work hard, how to guide my own project, and how to work independently. On you go ... it can only get better

Correlation of Repeat Measurements of 27 Candidate Protein Markers for Colorectal Cancer Screening Taken Three Years and Multiple Freeze&ndash;Thaw Cycles Apart

In recent years the blood proteome has been increasingly researched for biomarkers for early detection of colorectal cancer (CRC). Blood samples from screening studies are often subject to preanalytical variability and repeated freeze&ndash;thaw cycles. We aimed to assess the correlation of repeat measurements of 27 candidate protein markers for CRC screening taken three years and multiple freeze&ndash;thaw cycles apart. The concentrations of 27 protein markers were measured in plasma samples of 39 newly detected CRC cases from a cohort of 9245 participants of screening colonoscopies. The proteins were measured using proximity extension assays (PEA) carried out on the same set of samples twice, three years apart, with an average of three freeze&ndash;thaw cycles in between the two measurements. Pearson&rsquo;s product moment correlation coefficients were calculated. Correlation coefficients ranged from +0.43 to +0.97, with a median of 0.67 and an interquartile range of +0.58 to +0.84, with all p-values of correlation being &lt;0.01 (&lt;0.0005 for 22 proteins, &lt;0.001 for 4 proteins). Repeat measurements of the 27 protein biomarkers for CRC screening performed three years later, and on average three freeze&ndash;thaw cycles apart, showed moderate to high levels of correlation. Apart from the effects of freeze&ndash;thaw cycles, slightly different preprocessing performed on the data may have contributed to recorded differences between measurements

Whole-blood DNA Methylation Markers for Risk Stratification in Colorectal Cancer Screening: A Systematic Review

DNA methylation profiles within whole-blood samples have been reported to be associated with colorectal cancer (CRC) occurrence and might enable risk stratification for CRC. We systematically reviewed and summarized studies addressing the association of whole-blood DNA methylation markers and risk of developing CRC or its precursors. We searched PubMed and ISI Web of Knowledge to identify relevant studies published until 12th November 2018. Two reviewers independently extracted data on study population characteristics, candidate genes, methylation measurement methods, methylation levels of patients in comparison to healthy controls, p-values, and odds ratios of the markers. Overall, 19 studies reporting 102 methylation markers for risk assessment of colorectal neoplasms met our inclusion criteria. The studies mostly used Methylation Specific Polymerase Chain Reaction (MS-PCR) for assessing the methylation status of a defined set of genes. Only two studies applied array-based genome-wide assays to assess the methylation levels. Five studies incorporated panels consisting of 2&ndash;10 individual methylation markers to assess their potential for stratifying the risk of developing colorectal neoplasms. However, none of these associations was confirmed in an independent cohort. In conclusion, whole-blood DNA methylation markers may be useful as biomarkers for risk stratification in CRC screening, but reproducible risk prediction algorithms are yet to be established by large scale epigenome-wide studies with thorough validation of results in prospective study cohorts including large screening populations. The possibilities of enhancing predictive power by combining methylation data with polygenetic risk scores and environmental risk factors need to be explored

Cell Line Secretome and Tumor Tissue Proteome Markers for Early Detection of Colorectal Cancer: A Systematic Review

Objective: In order to find low abundant proteins secretome and tumor tissue proteome data have been explored in the last few years for the diagnosis of colorectal cancer (CRC). In this review we aim to summarize the results of studies evaluating markers derived from the secretome and tumor proteome for blood based detection of colorectal cancer. Methods: Observing the preferred reporting items for systematic reviews and meta-analysis (PRISMA) guidelines PubMed and Web of Science databases were searched systematically for relevant studies published up to 18 July 2017. After screening for predefined eligibility criteria a total of 47 studies were identified. Information on diagnostic performance indicators, methodological procedures and validation was extracted. Functions of proteins were identified from the UniProt database and the the Quality Assessment of Diagnostic Accuracy Studies-2 (QUADAS-2) tool was used to assess study quality. Results: Forty seven studies meeting inclusion criteria were identified. Overall, 83 different proteins were identified, with carcinoembryonic Antigen (CEA) being by far the most commonly reported (reported in 24 studies). Evaluation of the markers or marker combinations in blood samples from CRC cases and controls yielded apparently very promising diagnostic performances, with area under the curve &gt;0.9 in several cases, but lack of internal or external validation, overoptimism due to overfitting and spectrum bias due to evaluation in clinical setting rather than screening settings are major concerns. Conclusions: Secretome and tumor proteome-based biomarkers when validated in blood yield promising candidates. However, for discovered protein markers to be clinically applicable as screening tool they have to be specific for early stages and need to be validated externally in larger studies with participants recruited in true screening setting

Comparison of Proteomic Technologies for Blood-Based Detection of Colorectal Cancer

Blood-based protein biomarkers are increasingly being explored as supplementary or efficient alternatives for population-based screening of colorectal cancer (CRC). The objective of the current study was to compare the diagnostic potential of proteins measured with different proteomic technologies. The concentrations of protein biomarkers were measured using proximity extension assays (PEAs), liquid chromatography/multiple reaction monitoring&ndash;mass spectrometry (LC/MRM-MS) and quantibody microarrays (QMAs) in plasma samples of 56 CRC patients and 99 participants free of neoplasms. In another approach, proteins were measured in serum samples of 30 CRC cases and 30 participants free of neoplasm using immunome full-length functional protein arrays (IpAs). From all the measurements, 9, 6, 35 and 14 protein biomarkers overlapped for comparative evaluation of (a) PEA and LC/MRM-MS, (b) PEA and QMA, (c) PEA and IpA, and (d) LC/MRM-MS and IpA measurements, respectively. Correlation analysis was performed, along with calculation of the area under the curve (AUC) for assessing the diagnostic potential of each biomarker. DeLong&rsquo;s test was performed to assess the differences in AUC. Evaluation of the nine biomarkers measured with PEA and LC/MRM-MS displayed correlation coefficients &gt;+0.6, similar AUCs and DeLong&rsquo;s p-values indicating no differences in AUCs for biomarkers like insulin-like growth factor binding protein 2 (IGFBP2), matrix metalloproteinase 9 (MMP9) and serum paraoxonase lactonase 3 (PON3). Comparing six proteins measured with PEA and QMA showed good correlation and similar diagnostic performance for only one protein, growth differentiation factor 15 (GDF15). The comparison of 35 proteins measured with IpA and PEA and 14 proteins analyzed with IpA and LC/MRM-MS revealed poor concordance and comparatively better AUCs when measured with PEA and LC/MRM-MS. The comparison of different proteomic technologies suggests the superior performance of novel technologies like PEA and LC/MRM-MS over the assessed array-based technologies in blood-protein-based early detection of CRC