This study aims to assess trends in patient-related factors and treatment strategies in Dutch colorectal cancer (CRC) patients and their effect on survival.Data were obtained from the Rotterdam study, an ongoing population-based study of individuals aged ≥45 years. Between 1990 and 2014, incident, pathology-confirmed CRC cases were divided into two groups based on date of diagnosis (either before or after January 1, 2003). Patient characteristics, initial treatment, and date of mortality were collected. Analyses were performed using Kaplan-Meier and Cox proportional hazard models.Of 14,928 individuals, 272 developed colon cancer and 124 rectal cancer. Median follow-up was 13.2 years. Patients diagnosed after January 1, 2003 were treated chemotherapeutically more often than those diagnosed prior to this date in colon cancer (28.6% vs. 9.1%, p = 0.02) and treated more often with chemotherapy (38.6% vs. 12.3%, p = 0.02) and radiotherapy (41.3% vs. 10.2%, p = 0.001) in rectal cancer. Overall survival, adjusted for patient, tumor characteristics, and treatment, improved in rectal cancer (HR, 0.31; 95% CI, 0.13-0.74) but remained stable in colon cancer (HR, 1.28; 95% CI, 0.84-1.95).Chemotherapeutic agents and radiotherapy are increasingly used in CRC patients. Survival in rectal cancer improved, whereas in colon cancer this was not observed.
Immunity has been suggested to be important in the pathogenesis of dementia. However, the contribution of innate versus adaptive immunity in the development of dementia is not clear. In this study, we aimed to investigate (1) the association between components of innate immunity (granulocytes and platelets) and adaptive immunity (lymphocytes) with risk of dementia and (2) the association between their derived ratios (granulocyte-to-lymphocyte ratio [GLR], platelet-to-lymphocyte ratio [PLR], and systemic immune-inflammation index [SII]), reflecting the balance between innate and adaptive immunity, with risk of dementia.Blood cell counts were measured repeatedly between 2002 and 2015 in dementia-free participants of the prospective population-based Rotterdam Study. Participants were followed-up for dementia until 1 January 2016. Joint models were used to determine the association between granulocyte, platelets, and lymphocyte counts, and their derived ratios with risk of dementia.Of the 8313 participants (mean [standard deviation] age 61.1 [7.4] years, 56.9% women), 664 (8.0%) developed dementia during a median follow-up of 8.6 years. Doubling of granulocyte and platelet counts tended to be associated with an increased risk of dementia (HR [95%CI] 1.22 [0.89-1.67] and 1.45 [1.07-1.95], respectively). Doubling of the derived ratios GLR, PLR, and SII were all associated with an increased dementia risk (HR [95%CI] 1.26 [1.03-1.53], 1.27 [1.05-1.53], and 1.15 [0.98-1.34], respectively).GLR, PLR, and SII are associated with an increased risk of dementia in the general population. This supports the role of an imbalance in the immune system towards innate immunity in the pathogenesis of dementia.
Several studies found that the systemic immune‐inflammation index (SII) is a prognostic factor for mortality in patients with solid tumors. It is unknown whether an increased SII in generally healthy individuals reflects a risk for developing cancer. Our objective was to investigate the association between the SII and incident cancers in a prospective cohort study. Data were obtained from the Rotterdam Study; a population‐based study of individuals aged ≥45 years, between 2002 and 2013. The SII at baseline was calculated from absolute blood counts. The association between the SII and the risk of any solid incident cancer during follow‐up was assessed using Cox proportional hazard models. Individuals with a prior cancer diagnosis were excluded. Data of 8,024 individuals were included in the analyses. The mean age at baseline was 65.6 years (SD 10.5 years) and the majority were women. During a maximum follow‐up period of 10.7 years, 733 individuals were diagnosed with cancer. A higher SII at baseline was associated with a 30% higher risk of developing a solid cancer (HR of 1.30 [95% CI; 1.11–1.53]), after adjustment for age, sex, socioeconomic status, smoking, BMI and type 2 diabetes. The absolute cumulative 10‐year cancer risk increased from 9.7% in the lowest quartile of SII to 14.7% in the highest quartile ( p ‐value = 0.009). The risk of developing cancer was persistent over time and increased for individuals with the longest follow‐up. In conclusion, a high SII is a strong and independent risk indicator for developing a solid cancer.
Abstract Novel prognostic inflammatory markers of cancer survival and cardiovascular disease are; the neutrophil-to-lymphocyte ratio (NLR), the platelet-to-lymphocyte ratio (PLR) and the systemic immune-inflammation index (SII). As normal values for these markers are unknown, our objective was to obtain reference values in the general population. We obtained data from a population-based prospective cohort study of individuals aged 45 years and over between 2002 and 2014. Absolute blood counts were used to calculate the NLR, PLR and SII. All inflammatory indices followed a log-normal distribution. We calculated the mean and 95% reference intervals in an unselected population. Furthermore we studied whether the inflammatory markers differed between age categories and gender. In total 8,711 participants (57.1% female; mean age 65.9 years, standard deviation 10.5 years) were included. Mean values and corresponding 95% reference intervals for the NLR were: 1.76 (0.83–3.92), for PLR: 120 (61–239) and for SII: 459 (189–1168). The inflammatory markers increased with age. The PLR and SII were higher in females, whilst the NLR was higher in males. In conclusion, we provided reference values for new inflammatory markers. All increase with age and vary with gender. This provides context that allows for proper interpretation of their potential value in future clinical practice and research.
Abstract Background: Pancreatic ductal adenocarcinoma is a highly lethal disease and for the past few decades no new advances in treatment have been made. A new potential target for therapy may be the STAT-JAK signaling pathway. This pathway plays a critical role in the regulation of cell survival, proliferation and migration. Recently, high levels of pSTAT3 expression have been associated with a poor outcome in pancreatic cancer. Therefore our main goal was to study the role of the JAK-STAT pathway in various human pancreatic cancer cell lines and its suitability for targeted therapy. Methods: Protein levels of phosphorylated STAT1 and STAT3 were determined in eight human pancreatic adenocarcinoma cell lines. A JAK1/3-inhibitor (Tofacitinib) was used to inhibit pSTAT1 and pSTAT3 at clinically relevant doses. Its effect on proliferation and migration was evaluated by means of an MTT assay, total DNA levels and a scratch assay. Photomicrographs were taken and compared at starting time point and after eight hours. To study the effect of STAT3 levels on drug-resistance for Gemcitabine, MTT assays were performed in the presence of Tofacitinib. Results: Levels of phosphorylated STAT1 and STAT3 varied widely amongst the eight cell lines. In five cell lines both STATs were activated. Inhibition with Tofacitinib (200ng/mL) was shown for both, ranging from 26.5% to 77.8% for pSTAT1 and 8.1% to 67.3% for pSTAT3 respectively. No significant effect on proliferation was observed after treatment with 100ng/mL, 200ng/mL and 400ng/mL Tofacitinib for 24, 48 and 72 hours by MTT assay or 200ng/mL Tofacitinib for 24 and 72 hours by DNA measurements. Migration was significantly reduced by Tofacitinib treatment (200ng/mL) in three cell lines: BxPC3 (44.0%, p = 0.0443 ), MIA PaCa2 (62.5%, p = 0.0224 ) and PANC1 (52.4 %, p = 0.0336) when treated with Tofacitinib (200ng/mL), but levels of inhibition did not correspond to STAT1/3 phosphorylation levels in these cell lines. No effect on drug-resistance for Gemcitabine was observed after combined treatment with Tofacitinib. Conclusion: Contrary to recent publications, suggesting that the JAK-STAT pathway may be involved in the tumor biology of pancreatic cancer, we show no effect of divergent STAT activity levels on cellular behavior in pancreatic cell lines and susceptibility of cells to Tofacitinib. Thus, while STAT1 and STAT3 activity levels vary considerably between tumors, our data suggest that these STATs do not provide a target for precision medicine. Citation Format: Jesse Fest, Gwenny M. Fuhler, Peter M. van Koetsveld, Maikel P. Peppelenbosch, Casper HJ van Eijck.{Authors}. Involvement of JAK-STAT signaling in human pancreatic adenocarcinoma cell lines and suitability for targeted therapy. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2016 May 12-15; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2016;76(24 Suppl):Abstract nr A29.
The appendix, an organ of immunological and microbiological importance, could be involved in the pathogenesis of cancers, but results are inconclusive. Our objective was to assess the association between appendectomy and the subsequent risk of cancer.Data were obtained from the Rotterdam Study; a long-term prospective population-based study of individuals aged 55 years and older, of which the first cohort started in 1990 and included 7983 participants. Information on appendectomy was obtained through either medical interview at baseline or linkage with the national automated pathology center (PALGA). Cancer cases were pathology based. End of follow-up was January 1st, 2015. The association between appendectomy and risk of cancer was assessed using Cox proportional hazard models, adjusted for known confounders.Of 7135 included participants, 1373 (19.2%) had undergone an appendectomy and 1632 individuals developed cancer. After adjustment for age, sex, socioeconomic status, BMI, smoking, prevalent diabetes mellitus and alcohol intake, a history of appendectomy was associated with a significantly lower risk of cancer [hazard ratio (HR) 0.86, 95% confidence interval (CI) 0.75-0.98]. Subgroup analyses showed similar results for gastrointestinal cancer (HR 0.75, 95% CI 0.56-0.99), in particular colon cancer (HR 0.65, 95% 0.43-0.97), and cancer of the female reproductive organs (HR 0.35, 95% CI 0.15-0.80).Participants who underwent an appendectomy had a reduced risk of cancer in general after adjustment for potential confounders. Therefore, these results contradict earlier studies suggestive of an increased risk. Further research is necessary to replicate these results and reveal its underlying mechanism.
Most patients with pancreatic cancer present with advanced disease and die within the first year after diagnosis. Predictive biomarkers that signal the presence of pancreatic cancer in an early stage are desperately needed. We aimed to identify new and validate previously found plasma metabolomic biomarkers associated with early stages of pancreatic cancer. Prediagnostic blood samples from individuals who were to receive a diagnosis of pancreatic cancer between 1 month and 17 years after sampling (N = 356) and age- and sex-matched controls (N = 887) were collected from five large population cohorts (HUNT2, HUNT3, FINRISK, Estonian Biobank, Rotterdam Study). We applied proton nuclear magnetic resonance-based metabolomics on the Nightingale platform. Logistic regression identified two interesting hits: glutamine (P = 0.011) and histidine (P = 0.012), with Westfall-Young family-wise error rate adjusted P values of 0.43 for both. Stratification in quintiles showed a 1.5-fold elevated risk for the lowest 20% of glutamine and a 2.2-fold increased risk for the lowest 20% of histidine. Stratification by time to diagnosis suggested glutamine to be involved in an earlier process (2 to 5 years before diagnosis), and histidine in a process closer to the actual onset (<2 years). Our data did not support the branched-chain amino acids identified earlier in several US cohorts as potential biomarkers for pancreatic cancer. Thus, although we identified glutamine and histidine as potential biomarkers of biological interest, our results imply that a study at this scale does not yield metabolomic biomarkers with sufficient predictive value to be clinically useful per se as prognostic biomarkers.
Abstract Background A very high erythrocyte sedimentation rate ( ESR ) is usually an indication of underlying pathology. Additionally, a moderately elevated ESR may also be attributable to biological ageing. Whether the ESR is a prognostic factor for mortality, regardless of age, has been scarcely investigated. Therefore, the objective was to analyse the association between elevated ESR levels and the risk of mortality in a prospective cohort of the general population. Methods We studied data from the Rotterdam Study (1990–2014). ESR levels were measured at baseline and individuals were followed until death or end of study. Associations between moderately (20–50 mm h −1 ) and markedly (>50 mm h −1 ) elevated ESR levels and all‐cause mortality were assessed using multivariate Cox proportional hazard models. Results In total, 5226 participants were included, and the mean age was 70.3 years. During a median follow‐up time of 14.9 years, 3749 participants died (71.7%). After adjustment, both a moderately elevated ESR and a markedly elevated ESR were associated with a significantly higher risk of overall mortality [hazard ratio ( HR ) 1.23, 95% confidence interval ( CI ) 1.12–1.35 and HR 1.89, 95% CI 1.38–2.60, respectively]. Although the ESR becomes higher with age, in a group aged above 75 years, without any comorbidities, an ESR > 20 mm h −1 remained associated with a significantly increased risk of mortality ( HR 1.29, 95% CI 1.01–1.64). Conclusion An elevated ESR is an independent prognostic factor for mortality. Despite the fact that ESR increases with age, it remains associated with an increased risk of mortality and warrants close follow‐up.
