Abstract Background To examine the influence of cigarette, cigar and pipe smoking, cessation of cigarette smoking and passive smoke exposure on the risk of pancreatic cancer. Methods Exposure data were collected during in-person interviews in a population-based case-control study of pancreatic cancer (N = 532 cases, N = 1701 controls) in the San Francisco Bay Area. Odds ratios (ORs) were adjusted for potential confounders. Results The adjusted odds ratio (OR) of pancreatic cancer among current smokers was 1.9 (95% confidence interval (CI), 1.4-2.7). A significant, positive trend in risk with increasing pack-years of smoking was observed (P-trend <0.0001). Compared with participants who continued to smoke, former smokers had no statistically significant elevation in risk of pancreatic cancer 10 years after smoking cessation, with risk reduced to that of never smokers regardless of prior smoking intensity. Both men and women experienced similar increased risk of pancreatic cancer with increasing smoking duration. Cigar and pipe smoking and exposure to passive smoke were not associated with pancreatic cancer. Conclusions Cigarette smoking is associated with an increased risk of pancreatic cancer. Smokers who had quit for ≥10 years no longer experienced an increased risk. Future work will help to determine the effect of declining smoking rates on pancreatic cancer incidence.

Alcohol consumption is postulated to be a risk factor for pancreatic cancer (PCA), but clarification of degree of risk related to consumption characteristics is lacking. We examined the association between alcohol consumption and PCA in a population-based case–control study (532 cases, 1,701 controls) in the San Francisco Bay Area. Population-based controls were frequency-matched by sex, age within 5-year categories and county of residence to cases identified by the cancer registry’s rapid case ascertainment. Detailed alcohol consumption data, including binge drinking (≥5 drinks/day), were collected during in-person interviews. Odds ratios (OR) and 95% confidence intervals (95% CI) were computed using adjusted unconditional logistic regression. Depending on dose, duration, and pattern of drinking, ORs were increased 1.5- to 6-fold among men but not women. In men, ORs increased with increasing overall alcohol consumption (22–35 drinks/week OR = 2.2, 95% CI = 1.1–4.0; ≥35 drinks/week OR = 2.6, 95% CI = 1.3–5.1, p-trend = 0.04). Most notable were effects with a history of binge drinking (OR = 3.5, 95% CI = 1.6–7.5) including increased number of drinks per day (p-trend = 0.002), and increased years of binge drinking (p-trend = 0.0006). In fully adjusted models that included smoking and other confounders, ORs for binge drinking in men were somewhat higher than in age-adjusted models. Results from our detailed analyses provide support for heavy alcohol consumption (including binge drinking) as a risk factor for PCA in men.

Pancreatic cancer is highly lethal, and identifying modifiable risk factors could have substantial public health impact. In this population-based case-control study (532 cases, 1701 controls), we used principal component analysis and multivariable unconditional logistic regression models to examine whether a particular dietary pattern was associated with risk of pancreatic cancer, adjusting for other known risk factors. A prudent dietary pattern, characterized by greater intake of vegetables, fruit, fish, poultry, whole grains, and low-fat dairy, was associated with an approximate 50% reduction in pancreatic cancer risk among men [odds ratio (OR) = 0.51, 95% confidence intervals (CI) = 0.31-0.84, P trend = 0.001] and women (OR = 0.51, 95% CI = 0.29-0.90, P trend = 0.04). A Western dietary pattern, characterized by higher intake of red and processed meats, potato chips, sugary beverages, sweets, high fat dairy, eggs, and refined grains, was associated with a 2.4-fold increased risk of pancreatic cancer among men (95% CI = 1.3-4.2, P trend = 0.008) but was not associated with risk among women. Among men, those in the upper quintiles of the Western diet and lower quintiles of the prudent diet had a threefold increased risk. Consistent with what has been recommended for several other chronic diseases, consuming a diet rich in plant-based foods, whole grains, and white meat, might reduce risk of pancreatic cancer.

The association between duration of pancreatitis and pancreatic cancer has not been well characterized in large population-based studies. We conducted detailed analyses to determine the association between pancreatitis onset and pancreatic cancer risk. Data from two case–control studies of pancreatic cancer (n = 4515) in the San Francisco Bay Area and the M.D. Anderson Cancer Center were pooled for analysis (1,663 cases, 2,852 frequency-matched controls). Adjusted odds ratios (OR) were estimated using a random-effects model. In the pooled multivariable model, history of pancreatitis was associated with a 7.2-fold increased risk estimate for pancreatic cancer [95% confidence interval (CI): 4.0, 13]. The risk estimate was nearly 10-fold in participants aged <55 years (OR = 9.9, 95% CI: 3.5, 28). A shorter temporal history of pancreatitis was more closely associated with pancreatic cancer than was a longer temporal history: <3 years (OR = 29, 95% CI: 12, 71), 3–10 years (OR = 2.6, 95% CI: 1.5, 5.6), and >10 years (OR = 1.8, 95% CI: 0.7, 4.5, p trend < 0.001). A short temporal history of pancreatitis was highly associated with pancreatic cancer, suggesting that pancreatitis may be an early manifestation of pancreatic cancer in some individuals. Pancreatic cancer should be considered in the differential diagnosis of individuals with an episode of pancreatitis.

Amyotrophic lateral sclerosis (ALS) is a clinical diagnosis used to define a neurodegenerative process that involves progressive loss of voluntary muscle function and leads to death within 2-5 years after diagnosis, in most cases because of respiratory function failure. Respiratory vital capacity (VC) measurements are reproducible and strong predictors of survival. To understand the role of the innate immune response in progressive VC loss we evaluated ALS clinical trial and biomarker results from a 6-month phase 2 study of NP001, a regulator of innate immune function. All ALS baseline values were similar between treated and controls except for those > 65 years old who were excluded from analysis. Treated patients with plasma CRP ≥ 1.13 mg/L (high CRP) showed a 64% slower rate of VC decline compared with placebo and those with plasma CRP < 1.13 mg/L (low CRP) who showed no response. High CRP patients showed no age associated loss of VC whereas low CRP patients showed an age dependent loss of VC function. Plasma levels of serum amyloid A (SAA) were similarly elevated in high CRP patients consistent with ongoing innate immune activation. Plasma TGFB1 in high CRP treated patients was 95% higher than placebo at 6-months, confirming the activation and release of this anti-inflammatory factor by the innate immune alpha 2 macroglobulin (A2M) system. This report is the first to link a biomarker confirmed regulation of the innate immune system with a therapeutic approach for controlling VC loss in ALS patients.

Amyotrophic lateral sclerosis (ALS) is a heterogeneous, progressive, and universally fatal neurodegenerative disease. A subset of ALS patients has measurable plasma levels of lipopolysaccharide (LPS) and C-reactive protein (CRP) consistent with low-grade microbial translocation (MT). Unless interrupted, MT sets up a self-perpetuating loop of inflammation associated with systemic macrophage activation. To test whether MT contributed to ALS progression, blood specimens from a phase 2 study of NP001 in ALS patients were evaluated for changes in activity in treated patients as compared to controls over the 6-month study. In this post hoc analysis, plasma specimens from baseline and six-month timepoints were analyzed. Compared with baseline values, biomarkers related to MT were significantly decreased (LPS, LPS binding protein (LBP), IL-18, Hepatocyte growth factor (HGF), soluble CD163 (sCD163)) in NP001-treated patients as compared to controls, whereas wound healing and immunoregulatory factors were increased (IL-10, Epidermal growth factor (EGF), neopterin) by the end of study. These biomarker results linked to the positive clinical trial outcome confirm that regulation of macrophage activation may be an effective approach for the treatment of ALS and, potentially, other neuroinflammatory diseases related to MT.

The objective of this article is to review the current status of the bacteria-virus interplay in Kaposi's sarcoma-associated herpesvirus (KSHV) infection and KSHV-driven cancers. KSHV is the etiological agent of several cancers, including Kaposi's sarcoma (KS) and primary effusion lymphoma. Due to immunosuppression, patients with KSHV are at an increased risk for bacterial infections. Moreover, among patients coinfected by HIV and KSHV, patients with KS have distinct oral microbiota compared to non-KS patients. Bacterial biomarkers associated with KSHV-driven cancers can provide insights in discerning the mechanisms of KSHV-induced oncogenesis. For example, pathogen-associated molecular patterns and bacterial products of certain bacterial species can regulate the expression of KSHV lytic and latent genes, thereby affecting viral replication and dissemination. In addition, infection with distinct opportunistic bacterial species have been associated with increased cell proliferation and tumorigenesis in KSHV-induced cancers through activation of pro-survival and -mitogenic cell signaling pathways. By elucidating the various mechanisms in which bacteria affect KSHV-associated pathogenesis, we will be able to pinpoint therapeutic targets for KSHV infection and KSHV-related cancers.

A better understanding of the association between diabetes and pancreatic cancer (PC) may inform prevention and/or early detection strategies. Metformin has been associated with reduced risk of certain cancers, including PC, in some observational clinical studies. We assessed whether metformin use was associated with PC risk among those with type 2 diabetes (DM2), and whether metformin use modulated the association between DM2 and risk of PC. In total, 536 PC cases and 869 frequency-matched controls were recruited predominantly from University of California San Francisco medical clinics from 2006 to 2011. Eligible participants completed direct interviews using a structured risk factor questionnaire. The association between metformin use and PC risk was assessed using propensity score-weighted unconditional logistic regression methods in analyses restricted to diabetics and adjusted multivariable logistic models in the total study population. Ever use of metformin was not associated with PC risk in analyses restricted to DM2 (N = 170) participants (adjusted OR: 1.01, 95% CI: 0.61-1.68). In the total study population (N = 1,405) using nondiabetics as the referent group, PC risk was inversely associated with diabetes duration (ptrend  < 0.001). Further, when DM2 participants were grouped by ever/never use of metformin and compared with nondiabetics, metformin use did not affect the association between DM2 and PC risk (never users: OR: 1.44, 95% CI: 0.78-2.67; ever users: OR: 1.19, 95% CI: 0.72-1.99). Results from our clinic-based case-control study suggest that metformin use is not associated with PC risk among those with DM2 and does not alter the association between DM2 and PC risk.

Inflammation triggered by innate immunity promotes carcinogenesis in cancer. Kaposi's sarcoma (KS), a hyperproliferative and inflammatory tumor caused by Kaposi's sarcoma-associated herpesvirus (KSHV) infection, is the most common cancer in AIDS patients. KSHV infection sensitizes cells to pathogen-associated molecular patterns (PAMPs). We examined the role of Pseudomonas aeruginosa, an opportunistic bacterium that can affect AIDS patients, in inflammation and cell proliferation of KSHV-transformed cells. P. aeruginosa stimulation increased cell proliferation and efficiency of colony formation in soft agar of KSHV-transformed rat primary mesenchymal precursor (KMM) cells but had no significant effect on the untransformed (MM) cells. P. aeruginosa stimulation also increased cell proliferation of KSHV-infected human B cells, BJAB, but not the uninfected cells. Mechanistically, P. aeruginosa stimulation resulted in increased inflammatory cytokines and activation of p38, ERK1/2, and JNK mitogen-activated protein kinase (MAPK) pathways in KMM cells while having no obvious effect on MM cells. P. aeruginosa induction of inflammation and MAPKs was observed with and without inhibition of the Toll-like receptor 4 (TLR4) pathway, while a flagellin-deleted mutant of P. aeruginosa required a functional TLR4 pathway to induce inflammation and MAPKs. Furthermore, treatment with either lipopolysaccharide (LPS) or flagellin alone was sufficient to induce inflammatory cytokines, activate MAPKs, and increase cell proliferation and efficiency of colony formation in soft agar of KMM cells. These results demonstrate that both LPS and flagellin are PAMPs that contribute to P. aeruginosa induction of inflammation in KSHV-transformed cells. Because AIDS-KS patients are susceptible to P. aeruginosa infection, our work highlights the preventive and therapeutic potential of targeting P. aeruginosa infection in these patients.IMPORTANCE Kaposi's sarcoma (KS), caused by infection with Kaposi's sarcoma-associated herpesvirus (KSHV), is one of the most common cancers in AIDS patients. KS is a highly inflammatory tumor, but how KSHV infection induces inflammation remains unclear. We have previously shown that KSHV infection upregulates Toll-like receptor 4 (TLR4), sensitizing cells to lipopolysaccharide (LPS) and Escherichia coli In the current study, we examined the role of Pseudomonas aeruginosa, an opportunistic bacterium that can affect AIDS patients, in inflammation and cell proliferation of KSHV-transformed cells. P. aeruginosa stimulation increased cell proliferation, inflammatory cytokines, and activation of growth and survival pathways in KSHV-transformed cells through two pathogen-associated molecular patterns, LPS and flagellin. Because AIDS-KS patients are susceptible to P. aeruginosa infection, our work highlights the preventive and therapeutic potential of targeting P. aeruginosa infection in these patients.

Background

Statins are cholesterol-lowering medications with pleiotropic effects, including alterations in growth signaling, as well as immunomodulatory and anti-inflammatory effects that may alter cancer risk. Evidence from previous epidemiologic studies is inconsistent about whether statin use is associated with a reduced risk of pancreatic cancer (PC).

Methods

Patients with confirmed diagnoses of PC (cases) were recruited from medical and surgical oncology clinics, with controls (frequency-matched by sex and age) recruited from general medicine clinics, at a high-volume academic medical center over a 6-year period (2006-2011). Direct interviews were conducted with an epidemiological risk factor questionnaire covering topics such as medical history, lifestyle factors, and medication usage. Adjusted multivariable logistic regression was used to compute odds ratios (ORs) and 95% confidence intervals (CIs) as estimates of the relative risk of PC.

Results

Data were obtained from 536 cases and 869 controls. Ever use of statins was associated with a 34% reduced PC risk (OR, 0.66; 95% CI, 0.47-0.92). In sex-stratified analyses, risk was statistically significantly reduced in men only (OR for men, 0.50; 95% CI, 0.32-0.79; OR for women, 0.86; 95% CI, 0.52-1.43). Duration of use was inversely associated with PC risk (>10-year use: overall OR, 0.51; OR for men, 0.41; 95% CI, 0.21-0.80; P(trend)  = .006).

Conclusions

This is the largest case-control study to demonstrate an inverse association between statin use and PC risk. Risk reduction in statin users appears to be sex-specific and is more pronounced in long-term users. Further research is warranted to better characterize this association and clarify the roles of underlying biologic mechanisms.