Alastair Hayes

Diabetes, Smoking, Alcohol Use, and Family History of Cancer as Risk Factors for Pancreatic Neuroendocrine Tumors: A Systematic Review and Meta-Analysis

Background and Aims: Risk factors for pancreatic neuroendocrine tumors (PNETs) are not well understood. The aim of this systematic review was to assess if diabetes mellitus, smoking, alcohol use, and family history of cancer are risk factors for PNETs. Methods: MEDLINE and abstracts from the European and North American Neuroendocrine Tumor Societies (ENETS and NANETS) were searched for studies published until October 2013. Eligible studies were selected according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. Results: Five studies evaluating 4 individual populations were included (study accrual period 2000-2011) into the meta-analysis, involving 827 cases (range 160-309 per study) and 2,407 controls (range 233-924 per study). All studies had a case-control design and described regional series. The pooled adjusted odds ratio was 2.74 (95% CI: 1.63-4.62; p < 0.01; I2 = 60.4%) for history of diabetes, 1.21 (95% CI: 0.92-1.58; p = 0.18; I2 = 45.8%) for ever smoking, 1.37 (95% CI: 0.99-1.91; p = 0.06; I2 = 0.0%) for heavy smoking, 1.09 (95% CI: 0.64-1.85; p = 0.75; I2 = 85.2%) for ever alcohol use, 2.72 (95% CI: 1.25-5.91; p = 0.01; I2 = 57.8%) for heavy alcohol use, and 2.16 (95% CI: 1.64-2.85; p < 0.01; I2 = 0.0%) for first-degree family history of cancer. Conclusions: Diabetes mellitus and first-degree family history of cancer are associated with an increased risk of sporadic PNET. There was also a trend for diagnosis of sporadic PNET associated with heavy smoking. Alcohol use may be a risk factor for PNET, but there was considerable heterogeneity in the meta-analysis. These results suggest the need for a larger, homogeneous, international study for the clarification of risk factors for the occurrence of PNET.

Risk and protective factors for the occurrence of sporadic pancreatic endocrine neoplasms

Pancreatic neuroendocrine neoplasms (PNENs) represent 10% of all pancreatic tumors by prevalence. Their incidence has reportedly increased over recent decades in parallel with that of pancreatic adenocarcinoma. PNENs are relatively rare, and of the few institutions that have published potential risk factors, findings have been heterogeneous. Our objective was to investigate the association between potential risk and protective factors for the occurrence of sporadic PNENs across a European population from several institutions. A multinational European case-control study was conducted to examine the association of selected environmental, family and medical exposure factors using a standardized questionnaire in face-to-face interviews. A ratio of 1:3 cases to controls were sex and age matched at each study site. Adjusted univariate and multivariate logistic regression analysis were performed for statistically significant factors. The following results were obtained: In 201 cases and 603 controls, non-recent onset diabetes (OR 2.09, CI 1.27-3.46) was associated with an increased occurrence of PNENs. The prevalence of non-recent onset diabetes was higher both in cases with metastatic disease (TNM stage III-IV) or advanced grade (G3) at the time of diagnosis. The use of metformin in combination with insulin was also associated with a more aggressive phenotype. Drinking coffee was more frequent in cases with localized disease at diagnosis. Our study concluded that non-recent onset diabetes was associated with an increased occurrence of PNENs and the combination of metformin and insulin was consistent with a more aggressive PNEN phenotype. In contrast to previous studies, smoking, alcohol and first-degree family history of cancer were not associated with PNEN occurrence.

Early organ dysfunction affects long-term survival in acute pancreatitis patients.

BACKGROUND The effect of early organ dysfunction on long-term survival in acute pancreatitis (AP) patients is unknown. OBJECTIVE The aim of this study was to ascertain whether early organ dysfunction impacts on long-term survival after an episode of AP. METHODS A retrospective analysis was performed using survival data sourced from a prospectively maintained database of patients with AP admitted to the Royal Infirmary of Edinburgh during a 5-year period commencing January 2000. A multiple organ dysfunction syndrome (MODS) score of ≥ 2 during the first week of admission was used to define early organ dysfunction. After accounting for in-hospital deaths, long-term survival probabilities were estimated using the Kaplan-Meier test. The prognostic significance of patient characteristics was assessed by univariate and multivariate analyses using Coxs proportional hazards methods. RESULTS A total of 694 patients were studied (median follow-up: 8.8 years). Patients with early organ dysfunction (MODS group) were found to have died prematurely [mean survival: 10.0 years, 95% confidence interval (CI) 9.4-10.6 years] in comparison with the non-MODS group (mean survival: 11.6 years, 95% CI 11.2-11.9 years) (log-rank test, P = 0.001) after the exclusion of in-hospital deaths. Multivariate analysis confirmed MODS as an independent predictor of long-term survival [hazard ratio (HR): 1.528, 95% CI 1.72-2.176; P = 0.019] along with age (HR: 1.062; P < 0.001), alcohol-related aetiology (HR: 2.027; P = 0.001) and idiopathic aetiology (HR: 1.548; P = 0.048). CONCLUSIONS Early organ dysfunction in AP is an independent predictor of long-term survival even when in-hospital deaths are accounted for. Negative predictors also include age, and idiopathic and alcohol-related aetiologies.

Increased levels of 3-hydroxykynurenine parallel disease severity in human acute pancreatitis

Inhibition of kynurenine 3-monooxygenase (KMO) protects against multiple organ dysfunction (MODS) in experimental acute pancreatitis (AP). We aimed to precisely define the kynurenine pathway activation in relation to AP and AP-MODS in humans, by carrying out a prospective observational study of all persons presenting with a potential diagnosis of AP for 90 days. We sampled peripheral venous blood at 0, 3, 6, 12, 24, 48, 72 and 168 hours post-recruitment. We measured tryptophan metabolite concentrations and analysed these in the context of clinical data and disease severity indices, cytokine profiles and C-reactive protein (CRP) concentrations. 79 individuals were recruited (median age: 59.6 years; 47 males, 59.5%). 57 met the revised Atlanta definition of AP: 25 had mild, 23 moderate, and 9 severe AP. Plasma 3-hydroxykynurenine concentrations correlated with contemporaneous APACHE II scores (R2 = 0.273; Spearman rho = 0.581; P < 0.001) and CRP (R2 = 0.132; Spearman rho = 0.455, P < 0.001). Temporal profiling showed early tryptophan depletion and contemporaneous 3-hydroxykynurenine elevation. Furthermore, plasma concentrations of 3-hydroxykynurenine paralleled systemic inflammation and AP severity. These findings support the rationale for investigating early intervention with a KMO inhibitor, with the aim of reducing the incidence and severity of AP-associated organ dysfunction.

Smoking, alcohol and family history of cancer as risk factors for small intestinal neuroendocrine tumors: a systematic review and meta-analysis

Abstract Objectives: Risk factors for small intestinal neuroendocrine tumors (SI-NETs) are not well understood. The aim of this systematic literature review was to identify risk factors for SI-NET and to further assess these by meta-analysis. Material and methods: PubMed and abstracts from the ENETS and NANETS were searched for studies published until May 2015. Eligible studies were selected according to the PRISMA statement. Results: Seven studies evaluating six individual populations were included (study accrual period 1980–2012) in the meta-analysis, involving 765 (range 17–325) cases and 502,282 (range 52–498,376) controls. All studies were case–control by design. The following risk factors were reported in ≥2 studies: family history of any cancer, family history of colorectal cancer, ever alcohol use and ever smoking. The pooled OR was 1.34 (95% CI: 1.12–1.60; p < .01; I2 = 0.0%) for family history of any cancer, 1.43 (95% CI: 1.15–1.79; p < .01; I2 = 0.0%) for family history of colorectal cancer, 1.04 (95% CI: 0.63–1.72; p = .87; I2 = 65.0%) for ever alcohol use and 1.40 (95% CI: 1.06–1.86; p < .05; I2 = 49.3%) for ever smoking. Conclusions: Family history of any cancer, family history of colorectal cancer and history of ever smoking were associated with an increased risk of SI-NET by meta-analysis. Alcohol consumption was not a significant risk factor for SI-NET. However, the studies reporting smoking and alcohol had a high degree of heterogeneity. Therefore, further studies are needed for clarification of smoking and alcohol as risk factors for the occurrence of SI-NET.