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Racial differences in diabetes-associated pancreatic cancer (PC) and the interaction of diabetes with other risk factors are not well established. We determined the association between diabetes and risk of PC in 2,192 cases and 5,113 controls in three large case-control studies conducted at the National Cancer Institute, the University of California San Francisco, and the M.D. Anderson Cancer Center. In multivariable analyses, diabetes was associated with a 1.8-fold risk of PC [95% confidence interval (CI) = 1.5-2.1]. Risk estimates decreased with increasing years with diabetes (≤2 years OR = 2.9, 95% CI = 2.1-3.9; 3-5 years OR = 1.9, 95% CI = 1.3-2.6; 6-10 years OR = 1.6, 95% CI = 1.2-2.3; 11-15 years OR = 1.3, 95% CI = 0.9-2.0; > 15 years OR = 1.4, 95% CI = 1.0-2.0 (p for trend < 0.0001). Among diabetics, risk was higher in insulin ever users compared with nonusers (OR = 2.2, 95% CI = 1.6-3.7) and was restricted to insulin use of ≤3 years (OR = 2.4). Insulin use of >10 years was associated with a reduced risk of pancreatic cancer (OR = 0.5, 95% CI = 0.3-0.9; p for trend < 0.0001). Hispanic men and Asians had a higher risk of diabetes-associated PC than did whites and blacks, but the differences were not statistically significant. No significant interaction between diabetes and cigarette smoking, alcohol consumption and body mass index was observed. Although reverse causation may explain the association between diabetes diagnosed in close temporal proximity to PC, our results show that long-term diabetes, even though risk diminishes over time, remains a risk factor for PC independent of obesity and smoking.

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. 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.

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.

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.

Background/objective: Amyotrophic lateral sclerosis (ALS) is a diagnosis that incorporates a heterogeneous set of neurodegenerative processes into a single progressive and uniformly fatal disease making the development of a uniformly applicable therapeutic difficult. Recent multinational ALS natural history incidence studies have identified systemic chronic activation of the innate immune system as a major risk factor for developing ALS. Persistent immune activation in patients with ALS leads to loss of muscle and lowering of serum creatinine. The goal of the current study was to test whether the slowing of nerve and muscle destruction in NP001-treated ALS patients compared with controls in phase 2 studies would lead to extension of survival. Methods: Phase 2 clinical studies with NP001, an intravenously administered form of the innate immune system regulator NaClO2, are now reporting long-term survival benefits for drug recipients vs. placebo controls after only six months of intermittent treatment. As a prodrug, NP001 is converted by macrophages to taurine chloramine, a long-lived regulator of inflammation. We performed a pooled analysis of all patients who had completed the studies in two six-month NP001 phase 2 trials. Changes in respiratory vital capacity and the muscle mass product, creatinine, defined treated patients who, compared to placebo, had up to a year of extended survival. Conclusions: The observed longer survival in ALS patients with the greatest inflammation-associated muscle loss provides further evidence that ALS is a disease of ongoing innate immune dysfunction and that NP001 is a disease-modifying drug with sustained clinical activity.

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.

Background/Objectives: The aim of this study was to estimate the effect of a 6 months’ treatment course of the innate immune modulator NP001 (a pH-adjusted intravenous formulation of purified sodium chlorite), on disease progression, as measured by overall survival (OS) in patients with amyotrophic lateral sclerosis. Methods: Blinded survival data were retrospectively collected for 268 of the 273 patients who had participated in two phase 2 placebo-controlled clinical trials of NP001 (ClinicalTrials.gov: NCT01281631 and NCT02794857) and received at least one dose of either 1 mg/kg or 2 mg/kg of NP001 as chlorite based on actual body weight, or placebo. Kaplan–Meier methods were used on the intent-to-treat population to estimate survival probabilities. Results: In the overall population, the median OS was 4.8 months (2.7 years [95% CI: 2.3, 3.5] in the 2 mg/kg NP001group and 2.3 years [95% CI: 1.8, 2.9] in the placebo group). Hazard ratio (HR): 0.77 (95% CI: 0.57, 1.03), p = 0.073. Among patients aged ≤ 65 years, the median OS for the 2 mg/kg NP001 group was 10.8 months (3.3 years [95% CI: 2.4, 3.8] in the 2 mg/kg NP001 group and 2.4 years [95% CI: 1.7, 3.3] in the placebo group). HR: 0.69 (95% CI: 0.50, 0.95). No differences were observed in the 1 mg/kg NP001 group or in patients aged > 65 years. Conclusions: The findings from this study suggest that a 6 months’ treatment course of NP001 resulted in a 4.8-month increase in overall survival in patients with ALS. The findings from this study indicate that targeting inflammation associated with the innate immune system may provide a pathway for new therapeutic options for the treatment of ALS.

Recent GWAS have identified several susceptibility loci for NHL. Despite these successes, much of the heritable variation in NHL risk remains to be explained. Common copy-number variants are important genomic sources of variability, and hence a potential source to explain part of this missing heritability. In this study, we carried out a CNV analysis using GWAS data from 681 NHL cases and 749 controls to explore the relationship between common structural variation and lymphoma susceptibility. Here we found a novel association with diffuse large B-cell lymphoma (DLBCL) risk involving a partial duplication of the C-terminus region of the LOC283177 long non-coding RNA that was further confirmed by quantitative PCR. For chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), known somatic deletions were identified on chromosomes 13q14, 11q22-23, 14q32 and 22q11.22. Our study shows that GWAS data can be used to identify germline CNVs associated with disease risk for DLBCL and somatic CNVs for CLL/SLL.

There are well-established disparities in cancer incidence and outcomes by race/ethnicity that result from the interplay between structural, socioeconomic, socio-environmental, behavioural and biological factors. However, large research studies designed to investigate factors contributing to cancer aetiology and progression have mainly focused on populations of European origin. The limitations in clinicopathological and genetic data, as well as the reduced availability of biospecimens from diverse populations, contribute to the knowledge gap and have the potential to widen cancer health disparities. In this review, we summarise reported disparities and associated factors in the United States of America (USA) for the most common cancers (breast, prostate, lung and colon), and for a subset of other cancers that highlight the complexity of disparities (gastric, liver, pancreas and leukaemia). We focus on populations commonly identified and referred to as racial/ethnic minorities in the USA—African Americans/Blacks, American Indians and Alaska Natives, Asians, Native Hawaiians/other Pacific Islanders and Hispanics/Latinos. We conclude that even though substantial progress has been made in understanding the factors underlying cancer health disparities, marked inequities persist. Additional efforts are needed to include participants from diverse populations in the research of cancer aetiology, biology and treatment. Furthermore, to eliminate cancer health disparities, it will be necessary to facilitate access to, and utilisation of, health services to all individuals, and to address structural inequities, including racism, that disproportionally affect racial/ethnic minorities in the USA.

: Overall survival in patients with amyotrophic lateral sclerosis (ALS) is linked to the rate of predicted respiratory vital capacity (PVC) loss. The objective of this study was to test whether changes in quantitative PVC measures over time linked to survival would define an immunopathogenic subset of ALS responsive to NP001, a regulator of innate immunity. : In a retrospective study, data from intent-to-treat (ITT) population of two phase 2 trials of NP001 were evaluated for over time changes in PVC, time-to-event (TTE) loss of 15% PVC and PVC change from baseline, as linked to survival outcomes in patients treated with NP001 vs placebo. : Treatment with NP001 was associated with a significantly lower risk compared to placebo in the loss of 15% PVC over six months ( = 0.01; HR = 0.60, 95% CI: 0.39, 0.90). Data from the two trials were subsequently divided by a disease progression rate (DPR) value of 0.50 units of ALSFRS-R score lost per month for analysis of slow vs. rapid disease. In ALS patients with slowly progressive disease (DPR < 0.50), TTE PVC changes from baseline were slowed ( < 0.0005) and overall survival extended significantly (18.5 months) in NP001-treated vs. placebo groups. The rapidly progressive ALS patients (DPR ≥ 0.50) treated with NP001 showed no significant difference in PVC change or survival from the placebo group. : These hypothesis-generating observations suggest that inflammation might play a significant role in the loss of respiratory function in a major subset of ALS patients.