Vitamin D and pancreatic cancer: a pooled analysis from the Pancreatic Cancer Case-Control Consortium.

BACKGROUND: The potential role of vitamin D in the aetiology of pancreatic cancer is unclear, with recent studies suggesting both positive and negative associations. PATIENTS AND METHODS: We used data from nine case-control studies from the International Pancreatic Cancer Case-Control Consortium (PanC4) to examine associations between pancreatic cancer risk and dietary vitamin D intake. Study-specific odds ratios (ORs) were estimated using multivariable logistic regression, and ORs were then pooled using a random-effects model. From a subset of four studies, we also calculated pooled estimates of association for supplementary and total vitamin D intake. RESULTS: Risk of pancreatic cancer increased with dietary intake of vitamin D [per 100 international units (IU)/day: OR = 1.13, 95% confidence interval (CI) 1.07-1.19, P = 7.4 × 10(-6), P-heterogeneity = 0.52; ≥230 versus <110 IU/day: OR = 1.31, 95% CI 1.10-1.55, P = 2.4 × 10(-3), P-heterogeneity = 0.81], with the association possibly stronger in people with low retinol/vitamin A intake. CONCLUSION: Increased risk of pancreatic cancer was observed with higher levels of dietary vitamin D intake. Additional studies are required to determine whether or not our finding has a causal basis.

Diabetes, antidiabetic medications, and pancreatic cancer risk: an analysis from the International Pancreatic Cancer Case-Control Consortium.

BACKGROUND: Type 2 diabetes mellitus has been associated with an excess risk of pancreatic cancer, but the magnitude of the risk and the time-risk relationship are unclear, and there is limited information on the role of antidiabetic medications. PATIENTS AND METHODS: We analyzed individual-level data from 15 case-control studies within the Pancreatic Cancer Case-Control Consortium, including 8305 cases and 13 987 controls. Pooled odds ratios (ORs) were estimated from multiple logistic regression models, adjusted for relevant covariates. RESULTS: Overall, 1155 (15%) cases and 1087 (8%) controls reported a diagnosis of diabetes 2 or more years before cancer diagnosis (or interview, for controls), corresponding to an OR of 1.90 (95% confidence interval, CI, 1.72-2.09). Consistent risk estimates were observed across strata of selected covariates, including body mass index and tobacco smoking. Pancreatic cancer risk decreased with duration of diabetes, but a significant excess risk was still evident 20 or more years after diabetes diagnosis (OR 1.30, 95% CI 1.03-1.63). Among diabetics, long duration of oral antidiabetic use was associated with a decreased pancreatic cancer risk (OR 0.31, 95% CI 0.14-0.69, for ≥15 years). Conversely, insulin use was associated with a pancreatic cancer risk in the short term (OR 5.60, 95% CI 3.75-8.35, for <5 years), but not for longer duration of use (OR 0.95, 95% CI 0.53-1.70, for ≥15 years). CONCLUSION: This study provides the most definitive quantification to date of an excess risk of pancreatic cancer among diabetics. It also shows that a 30% excess risk persists for more than two decades after diabetes diagnosis, thus supporting a causal role of diabetes in pancreatic cancer. Oral antidiabetics may decrease the risk of pancreatic cancer, whereas insulin showed an inconsistent duration-risk relationship.

SOX2 promotes dedifferentiation and imparts stem cell-like features to pancreatic cancer cells.

SOX2 (Sex-determining region Y (SRY)-Box2) has important functions during embryonic development and is involved in cancer stem cell (CSC) maintenance, in which it impairs cell growth and tumorigenicity. However, the function of SOX2 in pancreatic cancer cells is unclear. The objective of this study was to analyze SOX2 expression in human pancreatic tumors and determine the role of SOX2 in pancreatic cancer cells regulating CSC properties. In this report, we show that SOX2 is not expressed in normal pancreatic acinar or ductal cells. However, ectopic expression of SOX2 is observed in 19.3% of human pancreatic tumors. SOX2 knockdown in pancreatic cancer cells results in cell growth inhibition via cell cycle arrest associated with p21(Cip1) and p27(Kip1) induction, whereas SOX2 overexpression promotes S-phase entry and cell proliferation associated with cyclin D3 induction. SOX2 expression is associated with increased levels of the pancreatic CSC markers ALDH1, ESA and CD44. Importantly, we show that SOX2 is enriched in the ESA(+)/CD44(+) CSC population from two different patient samples. Moreover, we show that SOX2 directly binds to the Snail, Slug and Twist promoters, leading to a loss of E-Cadherin and ZO-1 expression. Taken together, our findings show that SOX2 is aberrantly expressed in pancreatic cancer and contributes to cell proliferation and stemness/dedifferentiation through the regulation of a set of genes controlling G1/S transition and epithelial-to-mesenchymal transition (EMT) phenotype, suggesting that targeting SOX2-positive cancer cells could be a promising therapeutic strategy.

Alcohol consumption and pancreatic cancer: a pooled analysis in the International Pancreatic Cancer Case-Control Consortium (PanC4).

BACKGROUND: Heavy alcohol drinking has been related to pancreatic cancer, but the issue is still unsolved. METHODS: To evaluate the role of alcohol consumption in relation to pancreatic cancer, we conducted a pooled analysis of 10 case-control studies (5585 cases and 11,827 controls) participating in the International Pancreatic Cancer Case-Control Consortium. We computed pooled odds ratios (ORs) by estimating study-specific ORs adjusted for selected covariates and pooling them using random effects models. RESULTS: Compared with abstainers and occasional drinkers (< 1 drink per day), we observed no association for light-to-moderate alcohol consumption (≤ 4 drinks per day) and pancreatic cancer risk; however, associations were above unity for higher consumption levels (OR = 1.6, 95% confidence interval 1.2-2.2 for subjects drinking ≥ 9 drinks per day). Results did not change substantially when we evaluated associations by tobacco smoking status, or when we excluded participants who reported a history of pancreatitis, or participants whose data were based upon proxy responses. Further, no notable differences in pooled risk estimates emerged across strata of sex, age, race, study type, and study area. CONCLUSION: This collaborative-pooled analysis provides additional evidence for a positive association between heavy alcohol consumption and the risk of pancreatic cancer.

Cigarette smoking and pancreatic cancer: an analysis from the International Pancreatic Cancer Case-Control Consortium (Panc4).

BACKGROUND: To evaluate the dose-response relationship between cigarette smoking and pancreatic cancer and to examine the effects of temporal variables. METHODS: We analyzed data from 12 case-control studies within the International Pancreatic Cancer Case-Control Consortium (PanC4), including 6507 pancreatic cases and 12 890 controls. We estimated summary odds ratios (ORs) by pooling study-specific ORs using random-effects models. RESULTS: Compared with never smokers, the OR was 1.2 (95% confidence interval [CI] 1.0-1.3) for former smokers and 2.2 (95% CI 1.7-2.8) for current cigarette smokers, with a significant increasing trend in risk with increasing number of cigarettes among current smokers (OR=3.4 for ≥35 cigarettes per day, P for trend<0.0001). Risk increased in relation to duration of cigarette smoking up to 40 years of smoking (OR=2.4). No trend in risk was observed for age at starting cigarette smoking, whereas risk decreased with increasing time since cigarette cessation, the OR being 0.98 after 20 years. CONCLUSIONS: This uniquely large pooled analysis confirms that current cigarette smoking is associated with a twofold increased risk of pancreatic cancer and that the risk increases with the number of cigarettes smoked and duration of smoking. Risk of pancreatic cancer reaches the level of never smokers ∼20 years after quitting.

Cigar and pipe smoking, smokeless tobacco use and pancreatic cancer: an analysis from the International Pancreatic Cancer Case-Control Consortium (PanC4).

BACKGROUND: Cigarette smoking is the best-characterized risk factor for pancreatic cancer. However, data are limited for other tobacco smoking products and smokeless tobacco. MATERIALS AND METHODS: We conducted a pooled analysis of cigar and pipe smoking and smokeless tobacco use and risk of pancreatic cancer using data from 11 case-control studies (6056 cases and 11,338 controls) within the International Pancreatic Cancer Case-Control Consortium (PanC4). Pooled odds ratios (OR) and the corresponding 95% confidence intervals (CI) were estimated by unconditional multiple logistic regression models adjusted for study center and selected covariates. RESULTS: Compared with never tobacco users, the OR for cigar-only smokers was 1.6 (95% CI: 1.2-2.3), i.e. comparable to that of cigarette-only smokers (OR 1.5; 95% CI 1.4-1.6). The OR was 1.1 (95% CI 0.69-1.6) for pipe-only smokers. There was some evidence of increasing risk with increasing amount of cigar smoked per day (OR 1.82 for ≥ 10 grams of tobacco), although not with duration. The OR for ever smokeless tobacco users as compared with never tobacco users was 0.98 (95% CI 0.75-1.3). CONCLUSION: This collaborative analysis provides evidence that cigar smoking is associated with an excess risk of pancreatic cancer, while no significant association emerged for pipe smoking and smokeless tobacco use.

Subcutaneous IGF-1 is not beneficial in 2-year ALS trial.

BACKGROUND: Previous human clinical trials of insulin-like growth factor type I (IGF-1) in amyotrophic lateral sclerosis (ALS) have been inconsistent. This phase III, randomized, double-blind, placebo-controlled study was undertaken to address whether IGF-1 benefited patients with ALS. METHODS: A total of 330 patients from 20 medical centers were randomized to receive 0.05 mg/kg body weight of human recombinant IGF-1 given subcutaneously twice daily or placebo for 2 years. The primary outcome measure was change in their manual muscle testing score. Secondary outcome measures included tracheostomy-free survival and rate of change in the revised ALS functional rating scale. Intention to treat analysis was used. RESULTS: There was no difference between treatment groups in the primary or secondary outcome measures after the 2-year treatment period. CONCLUSIONS: Insulin-like growth factor type I does not provide benefit for patients with amyotrophic lateral sclerosis.

Factors predicting prognosis after decompressive hemicraniectomy for hemispheric infarction.

The authors reviewed 42 consecutive cases of decompressive hemicraniectomy after hemispheric ischemic stroke to assess predictors of outcome. On univariate analysis, advanced age and history of hypertension were significantly associated with unfavorable outcome, whereas thrombolysis was protective. Side of infarction, pupillary nonreactivity, degree of preoperative midline shift, and timing of surgery did not predict outcome. On multivariate analysis, older age independently predicted poor recovery (odds ratio 2.9 per 10-year increase in age).

Injuries due to seizures in persons with epilepsy: a population-based study.

BACKGROUND: Previous studies of injuries due to epileptic seizures predominantly involved patients with intractable epilepsy. These studies may have overestimated the risk of injuries in persons with epilepsy. METHODS: Patients consisted of 247 Rochester, MN, residents who were diagnosed with epilepsy between 1975 and 1984. Seizure-related injuries were defined as any injury, other than orolingual trauma, resulting from a seizure, sufficient for the patient to seek medical attention or for injury occurrence to be determined during the course of medical care. To identify risk factors for injury, characteristics of patients with seizure-related injury were compared with those without injury. RESULTS: During a total of 2,714 patient-years of follow-up, 62 seizure-related injuries were identified in 39 patients (16%, one injury in every 44 person-years). Most injuries involved cranial soft tissue contusions or lacerations (79%). The majority of seizure-related injuries (82%) occurred during generalized convulsive seizures. Univariate analyses identified five potential risk factors for seizure-related injury: greater number of antiepileptic drugs used, less independent living situation, higher Rankin score, history of generalized convulsive seizures or drop attacks, and higher seizure frequency score. Seizure frequency, however, was the only significant risk factor identified by multivariate analysis (p < 0.001; relative risk, 1.33). CONCLUSIONS: This population-based study shows that seizure-related injuries are infrequent and generally of minor severity. In most epilepsy patients, excessive restriction of daily activities to avoid injury is unnecessary. Effective seizure control reliably reduces the risk of seizure-related injuries.

Glutathione pathway genes and lung cancer risk in young and old populations.

Multiple enzymes with overlapping functions and shared substrates in the glutathione (GSH) metabolic pathway have been associated with host susceptibility to tobacco smoke carcinogens and in lung cancer etiology. However, few studies have investigated the differing and interacting roles of GSH pathway enzymes with tobacco smoke exposure on lung cancer risk in young (<50 years of age) and old (>80 years of age) populations. Between 1997 and 2001, 237 primary lung cancer patients (170 young, 67 old) and 234 controls (165 young, 69 old) were enrolled at the Mayo Clinic. Using PCR amplification of genomic DNA, polymorphic markers for gammaGCS, GPX1, GSTP1 (I105V and A114V), GSTM1 and GSTT1 were genotyped. Recursive partitioning and logistic regression models were used to build binary classification trees and to estimate odds ratios (OR) and 95% confidence intervals for each splitting factor. For the young age group, cigarette smoking had the greatest association with lung cancer (OR = 3.3). For never smokers, the dividing factors of recursive partitioning were GSTT1 (OR = 1.7), GPX1 (OR = 0.6) and GSTM1 (OR = 4.3). For the old age group, smoking had the greatest association with lung cancer (OR = 3.6). For smokers, the dividing factors were GPX1 (OR = 3.3) and GSTP1 (I105V) (OR = 4.1). Results from logistic regression analyses supported the results from RPART models. GSH pathway genes are associated with lung cancer development in young and old populations through differing interactions with cigarette smoking and family history. Carefully evaluating multiple levels of gene-environment and gene-gene interactions is critical in assessing lung cancer risk.

Accuracy of patient prediction of allergy skin test results.

BACKGROUND: The ability of patients to self-diagnose allergy is unknown. OBJECTIVE: To estimate the ability of patients to correctly predict the results of allergy skin tests. METHODS: We conducted a structured interview of 86 patients with chronic rhinitis or asthma undergoing aeroallergen skin tests. We asked, "Do you expect the skin tests to be positive or negative?" and "What do you expect the allergy tests to be positive for?" Responses to these questions were correlated with the results of aeroallergen skin tests. Skin tests were performed using the prick technique and included cat, grass pollen, tree pollen, weed pollen, dust mites, and molds. RESULTS: Seventy-three participants provided usable responses. Of those with a positive skin test, the number (percentage) of participants who predicted correctly was 10/18 (56%) for cat, 4/14 (29%) for tree, 7/26 (27%) for weeds, 5/23 (22%) for dust mite, 2/12 (17%) for grass, and 1/8 (12%) for mold. Of those with a negative skin test, the number (percentage) of participants who predicted correctly was 47/50 (94%) for dust mite, 51/59 (86%) for trees, 56/65 (86%) for mold, 52/61 (85%) for grass, 45/55 (82%) for cat, and 38/47 (81%) for weeds. CONCLUSIONS: (1) Patients have limited ability to correctly predict positive skin tests to aeroallergen. (2) Patients are able to predict negative skin tests with reasonable accuracy. (3) "What do you think you are allergic to?" may be a good screening question for patients with asthma and rhinitis.