Physical activity and the risk of non-Hodgkin lymphoma subtypes: A pooled analysis.

Non-Hodgkin lymphoma (NHL) is composed of a heterogeneous collection of subtypes with considerable differences in genetics, biology and aetiology. Studies to date on physical activity and NHL risk have not had sufficient sample size to evaluate whether associations differ by subtype. We pooled data from nine case-control studies to examine the association between moderate-to-vigorous intensity physical activity (MVPA) and risk of NHL overall and by subtype (diffuse large B-cell lymphoma, follicular lymphoma, chronic lymphocytic leukaemia/small lymphocytic lymphoma, marginal zone lymphoma and mature T-cell lymphoma). A total of 5653 cases and 9115 controls were included in the pooled analysis. Physical activity was harmonised across nine studies and modelled as study-specific tertiles. Multinomial logistic regression was used to estimate the association between physical activity and NHL, adjusting for confounders. The overall odds of NHL was 13% lower among participants in the most active tertile of MVPA compared to the least active tertile (adjusted odds ratio = 0.87, 95% CI = 0.80, 0.95). Similar decreases were observed across NHL subtypes. In summary, in this pooled analysis of case-control studies, physical activity was associated with a modest risk reduction for each NHL subtype examined and with overall NHL.

Association of polygenic risk score with the risk of chronic lymphocytic leukemia and monoclonal B-cell lymphocytosis.

Inherited loci have been found to be associated with risk of chronic lymphocytic leukemia (CLL). A combined polygenic risk score (PRS) of representative single nucleotide polymorphisms (SNPs) from these loci may improve risk prediction over individual SNPs. Herein, we evaluated the association of a PRS with CLL risk and its precursor, monoclonal B-cell lymphocytosis (MBL). We assessed its validity and discriminative ability in an independent sample and evaluated effect modification and confounding by family history (FH) of hematological cancers. For discovery, we pooled genotype data on 41 representative SNPs from 1499 CLL and 2459 controls from the InterLymph Consortium. For validation, we used data from 1267 controls from Mayo Clinic and 201 CLL, 95 MBL, and 144 controls with a FH of CLL from the Genetic Epidemiology of CLL Consortium. We used odds ratios (ORs) to estimate disease associations with PRS and c-statistics to assess discriminatory accuracy. In InterLymph, the continuous PRS was strongly associated with CLL risk (OR, 2.49; P = 4.4 × 10-94). We replicated these findings in the Genetic Epidemiology of CLL Consortium and Mayo controls (OR, 3.02; P = 7.8 × 10-30) and observed high discrimination (c-statistic = 0.78). When jointly modeled with FH, PRS retained its significance, along with FH status. Finally, we found a highly significant association of the continuous PRS with MBL risk (OR, 2.81; P = 9.8 × 10-16). In conclusion, our validated PRS was strongly associated with CLL risk, adding information beyond FH. The PRS provides a means of identifying those individuals at greater risk for CLL as well as those at increased risk of MBL, a condition that has potential clinical impact beyond CLL.

Fatty acids found in dairy, protein and unsaturated fatty acids are associated with risk of pancreatic cancer in a case-control study.

Although many studies have investigated meat and total fat in relation to pancreatic cancer risk, few have investigated dairy, fish and specific fatty acids (FAs). We evaluated the association between intake of meat, fish, dairy, specific FAs and related nutrients and pancreatic cancer. In our American-based Mayo Clinic case-control study 384 cases and 983 controls frequency matched on recruitment age, race, sex and residence area (Minnesota, Wisconsin or Iowa, USA) between 2004 and 2009. All subjects provided demographic information and completed 144-item food frequency questionnaire. Logistic regression-calculated odds ratios (ORs) and 95% confidence intervals (95% CIs) were adjusted for age, sex, cigarette smoking, body mass index and diabetes mellitus. Significant inverse association (trend p-value < 0.05) between pancreatic cancer and the groupings (highest vs. lowest consumption quintile OR [95% CI]) was as follows: meat replacement (0.67 [0.43-1.02]), total protein (0.58 [0.39-0.86]), vitamin B12 (0.67 [0.44, 1.01]), zinc (0.48 [0.32, 0.71]), phosphorus (0.62 [0.41, 0.93]), vitamin E (0.51 [0.33, 0.78]), polyunsaturated FAs (0.64 [0.42, 0.98]) and linoleic acid (FA 18:2) (0.62 [0.40-0.95]). Increased risk associations were observed for saturated FAs (1.48 [0.97-2.23]), butyric acid (FA 4:0) (1.77 [1.19-2.64]), caproic acid (FA 6:0) (2.15 [1.42-3.27]), caprylic acid (FA 8:0) (1.87 [1.27-2.76]) and capric acid (FA 10:0) (1.83 [1.23-2.74]). Our study suggests that eating a diet high in total protein and certain unsaturated FAs is associated with decreased risk of developing pancreatic cancer in a dose-dependent manner, whereas fats found in dairy increase risk.

Medical history and lifestyle factors have limited impact on time-to-first-treatment in patients with chronic lymphocytic leukemia.

Background: Chronic lymphocytic leukemia (CLL) is a heterogeneous disease. Whereas some patients have an indolent disease, others experience an aggressive course and early death. Our aim was to investigate if modifiable and non-modifiable medical history and lifestyle factors prior to diagnosis had an impact on the natural course of the disease. Method: In 1154 CLL patients, we assessed if the weight, physical activity, smoking, and alcohol consumption or non-modifiable characteristics including family history of lymphoid malignancy and medical history were associated with time-to-first-treatment (TTFT) and adjusted all results for the CLL-International Prognostic Index (CLL-IPI). Results: TTFT was shorter for patients with high/very high-risk CLL-IPI than those with low/intermediate risk CLL-IPI. In the adjusted analysis we did not find additional impact on TTFT besides CLL-IPI from any environmental characteristics assessed. Conclusions: We found limited impact of environmental factors on the natural course of CLL (measured as the TTFT in treatment naïve patients) providing valuable knowledge, and potential relief, to share with patients at the time of diagnosis.

Vaccination History and Risk of Lymphoma and Its Major Subtypes.

BACKGROUND: Vaccinations have been hypothesized to play a role in lymphoma etiology, but there are few studies, mixed results, and limited data on lymphoma subtypes. Herein, we investigate the association of vaccinations with risk of major lymphoma subtypes. METHODS: We studied 2,461 lymphoma cases and 2,253 controls enrolled from 2002 to 2014. Participants self-reported history of vaccinations against hepatitis A, hepatitis B, yellow fever, and influenza. Polytomous logistic regression was used to estimate OR and 95% confidence intervals (CI), adjusting for potential confounders. RESULTS: After multivariable adjustment, vaccination against influenza was inversely associated with lymphoma (OR = 0.82; 95% CI, 0.66-1.02), which was stronger for last vaccination 1+ years before enrollment (OR = 0.71; 95% CI, 0.56-0.91) and for >5 influenza vaccinations (OR = 0.56; 95% CI, 0.46-0.68). Ever vaccination against hepatitis A (OR = 0.81; 95% CI, 0.66-1.00) but not hepatitis B (OR = 0.97; 95% CI, 0.81-1.18) was associated with lymphoma risk, although more recent vaccinations were inversely associated with lymphoma risk for both hepatitis A (<6 years before enrollment, OR = 0.56; 95% CI, 0.40-0.77) and hepatitis B (<9 years before enrollment, OR = 0.72; 95% CI, 0.55-0.93). Ever vaccination against yellow fever was inversely associated with risk (OR = 0.73; 95% CI, 0.55-0.96), and this did not vary by time since last vaccination. Although there was no overall statistical evidence for heterogeneity of vaccination history by lymphoma subtype, the only statistically significant inverse associations were observed for influenza and yellow fever vaccinations with diffuse large B-cell and follicular lymphoma. CONCLUSIONS: Selected vaccinations were inversely associated with lymphoma risk, with time since last vaccination relevant for some of these vaccines. IMPACT: Vaccinations against hepatitis A, hepatitis B, yellow fever, and influenza are unlikely to increase lymphoma risk.

Polygenic risk score and risk of monoclonal B-cell lymphocytosis in caucasians and risk of chronic lymphocytic leukemia (CLL) in African Americans.

Monoclonal B-cell lymphocytosis (MBL) is a precursor to CLL. Other than age, sex, and CLL family-history, little is known about factors associated with MBL risk. A polygenic-risk-score (PRS) of 41 CLL-susceptibility variants has been found to be associated with CLL risk among individuals of European-ancestry(EA). Here, we evaluate these variants, the PRS, and environmental factors for MBL risk. We also evaluate these variants and the CLL-PRS among African-American (AA) and EA-CLL cases and controls. Our study included 560 EA MBLs, 869 CLLs (696 EA/173 AA), and 2866 controls (2631 EA/235 AA). We used logistic regression, adjusting for age and sex, to estimate odds ratios (OR) and 95% confidence intervals within each race. We found significant associations with MBL risk among 21 of 41 variants and with the CLL-PRS (OR = 1.86, P = 1.9 × 10-29, c-statistic = 0.72). Little evidence of any association between MBL risk and environmental factors was observed. We observed significant associations of the CLL-PRS with EA-CLL risk (OR = 2.53, P = 4.0 × 10-63, c-statistic = 0.77) and AA-CLL risk (OR = 1.76, P = 5.1 × 10-5, c-statistic = 0.62). Inherited genetic factors and not environmental are associated with MBL risk. In particular, the CLL-PRS is a strong predictor for both risk of MBL and EA-CLL, but less so for AA-CLL supporting the need for further work in this population.

Does a Multiple Myeloma Polygenic Risk Score Predict Overall Survival of Patients with Myeloma?

BACKGROUND: Genome-wide association studies (GWAS) of multiple myeloma in populations of European ancestry (EA) identified and confirmed 24 susceptibility loci. For other cancers (e.g., colorectum and melanoma), risk loci have also been associated with patient survival. METHODS: We explored the possible association of all the known risk variants and their polygenic risk score (PRS) with multiple myeloma overall survival (OS) in multiple populations of EA [the International Multiple Myeloma rESEarch (IMMEnSE) consortium, the International Lymphoma Epidemiology consortium, CoMMpass, and the German GWAS] for a total of 3,748 multiple myeloma cases. Cox proportional hazards regression was used to assess the association between each risk SNP with OS under the allelic and codominant models of inheritance. All analyses were adjusted for age, sex, country of origin (for IMMEnSE) or principal components (for the others) and disease stage (ISS). SNP associations were meta-analyzed. RESULTS: SNP associations were meta-analyzed. From the meta-analysis, two multiple myeloma risk SNPs were associated with OS (P < 0.05), specifically POT1-AS1-rs2170352 [HR = 1.37; 95% confidence interval (CI) = 1.09-1.73; P = 0.007] and TNFRSF13B-rs4273077 (HR = 1.19; 95% CI = 1.01-1.41; P = 0.04). The association between the combined 24 SNP MM-PRS and OS, however, was not significant. CONCLUSIONS: Overall, our results did not support an association between the majority of multiple myeloma risk SNPs and OS. IMPACT: This is the first study to investigate the association between multiple myeloma PRS and OS in multiple myeloma.

Fruit and vegetable consumption is inversely associated with having pancreatic cancer.

OBJECTIVE: Studies on fruit, vegetable, fiber, and grain consumption and pancreatic cancer risk are inconclusive. We used a clinic-based case-control study specifically designed to address limitations of both cohort and case-control studies to examine the relationship. METHODS: Participants were excluded who reported changing their diet within 5 years prior to study entry. And 384 rapidly ascertained cases and 983 controls (frequency matched on age (±5 years), race, sex, and residence) completed epidemiologic surveys and 144-item food frequency questionnaires. Odds ratios (OR) and 95% confidence intervals were calculated using logistic regression adjusted for age, sex, smoking, body mass index, energy intake, and alcohol consumption. RESULTS: Comparing highest to lowest quintiles, we observed significant inverse associations (OR < 0.8) with significant trends (p (trend) < 0.05) for citrus, melon, and berries, other fruits, dark green vegetables, deep yellow vegetables, tomato, other vegetables, dry bean and pea, insoluble fiber, soluble fiber, whole grains, and orange/grapefruit juice, and an increased association with non-whole grains. Results were similar after adjusting for diabetes or total sugar intake. CONCLUSIONS: We provide evidence that lower consumption of fruits, vegetables, whole grains, and fiber is associated with having pancreatic cancer. This may have a role in developing prevention strategies.

The association of health behaviors with quality of life in lymphoma survivors.

The impact of change in health behaviors (physical activity [PA], alcohol and smoking) on quality of life (QOL) in lymphoma survivors is not well understood. We evaluated the associations of health behaviors with QOL domains at diagnosis and at 3-year follow-up (FU3) in 2805 lymphoma survivors. We report clinically significant QOL score differences, defined as scores that exceeded a minimally important difference threshold and were statistically significant. Current smoking was associated with lower QOL at baseline (p < 0.01) and at FU3 (p < 0.01). Meeting the American Cancer Society PA guidelines was associated with better functional wellbeing and overall QOL at FU3 (p < 0.01). An increase in PA from baseline to FU3 was associated with improvement in physical, functional wellbeing and overall QOL at FU3 compared to baseline (p < 0.01). Thus, QOL in lymphoma survivors is associated with their health behaviors and active interventions to promote positive lifestyle changes in lymphoma survivors are needed.

Body mass index and survival of patients with lymphoma.

The impact of body mass index (BMI) on survival in lymphoma remains controversial. We leveraged a prospective cohort of lymphoma patients enrolled to SPORE Molecular Epidemiology Resource between 2002 and 2015 to assess the association of BMI before diagnosis, BMI at diagnosis, and BMI change over time with lymphoma-specific survival (LSS). A total of 4009 lymphoma patients (670 diffuse large B-cell lymphoma (DLBCL), 689 follicular lymphoma (FL), 1018 chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), and 1632 other subtypes) were included. Significantly shorter LSS after diagnosis was observed for FL patients who were obese before diagnosis (HR: 3.02, 95%CI: 1.43-6.41, p=.004) and for those with a ≥ 5% increase in BMI from diagnosis to 3-year follow-up (HR: 3.53, 95%CI: 1.22-10.2, p=.020). In contrast, obesity prior to or at the time of diagnosis was not associated with LSS in DLBCL and CLL/SLL. The impact of weight control after diagnosis in FL patient warrants investigation.

Coinherited genetics of multiple myeloma and its precursor, monoclonal gammopathy of undetermined significance.

So far, 23 germline susceptibility loci have been associated with multiple myeloma (MM) risk. It is unclear whether the genetic variation associated with MM susceptibility also predisposes to its precursor, monoclonal gammopathy of undetermined significance (MGUS). Leveraging 2434 MM cases, 754 MGUS cases, and 2 independent sets of controls (2567/879), we investigated potential shared genetic susceptibility of MM and MGUS by (1) performing MM and MGUS genome-wide association studies (GWAS); (2) validating the association of a polygenic risk score (PRS) based on 23 established MM loci (MM-PRS) with risk of MM, and for the first time with MGUS; and (3) examining genetic correlation of MM and MGUS. Heritability and genetic estimates yielded 17% (standard error [SE] ±0.04) and 15% (SE ±0.11) for MM and MGUS risk, respectively, and a 55% (SE ±0.30) genetic correlation. The MM-PRS was associated with risk of MM when assessed continuously (odds ratio [OR], 1.17 per SD; 95% confidence interval [CI], 1.13-1.21) or categorically (OR, 1.70; 95% CI, 1.38-2.09 for highest; OR, 0.71; 95% CI, 0.55-0.90 for lowest compared with middle quintile). The MM-PRS was similarly associated with MGUS (OR, 1.19 per SD; 95% CI, 1.14-1.26 as a continuous measure, OR, 1.77, 95%CI: 1.29-2.43 for highest and OR, 0.70, 95%CI: 0.50-0.98 for lowest compared with middle quintile). MM and MGUS associations did not differ by age, sex, or MM immunoglobulin isotype. We validated a 23-SNP MM-PRS in an independent series of MM cases and provide evidence for its association with MGUS. Our results suggest shared common genetic susceptibility to MM and MGUS.

A physiologically based pharmacokinetic (PBPK) model to characterize and predict the disposition of monoclonal antibody CC49 and its single chain Fv constructs.

Optimization of the use of monoclonal antibodies (MAbs) as diagnostic tools and therapeutic agents in the treatment of cancer is aided by quantitative characterization of the transport and tissue disposition of these agents in whole animals. This characterization may be effectively achieved by the application of physiologically based pharmacokinetic (PBPK) models. The purpose of this study was to develop a PBPK model to characterize the biodistribution of the pancarcinoma MAb CC49 IgG in normal and neoplastic tissues of nude mice, and to further apply the model to predict the disposition of multivalent single chain Fv (scFv) constructs in mice. Since MAbs are macromolecules, their transport is membrane-limited and a two-pore formalism is employed to describe their extravasation. The influence of binding of IgG to the protective neonatal Fc receptor (FcRn) on its disposition is also accounted for in the model. The model successfully described (131)I-CC49 IgG concentrations in blood, tumor and various organs/tissues in mice. Sensitivity analysis revealed the rate of transcapillary transport to be a critical determinant of antibody penetration and localization in the tumor. The applicability of the model was tested by predicting the disposition of di- and tetravalent scFv constructs of CC49 in mice. The model gave reasonably good predictions of the disposition of the scFv constructs. Since the model employs physiological parameters, it can be used to scale-up mouse biodistribution data to predict antibody distribution in humans. Therefore, the clinical utility of the model was tested with data for (131)I-CC49 obtained in patients, by scaling up murine parameter values according to known empirical relationships. The model gave satisfactory predictions of CC49 disposition and tumor uptake in man.

Polymer relationships during preparation of chitosan-alginate and poly-l-lysine-alginate nanospheres.

The preparation of chitosan-alginate nanospheres is described and their properties compared to the poly-L-lysine-alginate system. The mass ratio range of sodium alginate:CaCl(2):cationic polymer (poly-L-lysine [PLL] or chitosan) to prepare nanospheres was 100:17:10. This mass ratio ensured that the calcium alginate was maintained in the pre-gel phase and sufficient cationic polymer was present to form nanospheres. At low cationic polymer concentrations, nanospheres were not formed, whereas microspheres were formed at higher concentrations. The release of entrapped methylene blue from the nanospheres was directly proportional (R(2)=0.98) to the sodium chloride concentration in the dissolution medium. The sodium ions more efficiently displace PLL compared to chitosan; hence, the mass of drug released from the chitosan-alginate nanospheres is slow for equivalent sodium ion concentration. Isothermal titration calorimetry studies determined that the primary binding affinity between calcium and alginate was 1.33 x 10(6)/mole and entropically driven, whereas, the second binding affinity was weaker (1.03 x 10(4)/mole) and driven by both enthalpy and entropy. This binding was competitively inhibited by sodium ions. Similarly, the binding of PLL to calcium alginate pre-gel was electrostatic and competitively inhibited by sodium, although, the thermodynamic parameters for this interaction could not be determined.

Solution equilibria of deferoxamine amides.

The physico-chemical solution properties of deferoxamine were modified by acylating the terminal amino group with short-chain aliphatic, succinic, and methylsulphonic moieties. The analog iron(III)-binding constants and stabilities under physiological conditions were determined to confirm that the iron binding ability of the parent molecule was retained following modification. The proton dissociation constants of the lipophilic deferoxamine analogs were determined by potentiometric titration and nonlinear least-squares analysis. However, because the iron(III) binding complex is fully formed below pH 2, the metal-ligand equilibria could not be studied using potentiometric methods. The iron binding constants of the deferoxamine analogs were determined by spectrophotometrically following the proton-dependent exchange of iron with EDTA in the pH range of 4.0 to 6.5 and solving mass balance equations. The proton-dissociation constants and the iron binding constants of the lipophilic deferoxamine analogs were comparable to those of deferoxamine. However, at physiological conditions, the iron-binding complex of the most lipophilic butylamide derivative was slightly less stable and the succinamide derivative complex was slightly more stable. Like deferoxamine, the hydroxamate groups of the analogs were unhindered and free to form a 1:1 coordination complex with iron(III). Consequently, changes in aqueous solvation, conformation, and steric interference, imparted by the modifications at the terminal amino group of deferoxamine, may have affected the stabilities of the iron(III) complex and the efficiency of iron binding.

Particle size and temperature effect on the physical stability of PLGA nanospheres and microspheres containing Bodipy.

The purpose of this study was to investigate the effect of particle size, storage temperature, and duration of storage on the physical stability and morphology of polylactic-co-glycolic acid (PLGA) nanospheres and microspheres. PLGA nanospheres and microspheres containing the fluorescent dye, Bodipy, were prepared in varying sizes by controlling the method and degree of agitation during the emulsification phase of preparation. Mean diameters of the particles were measured by dynamic light scattering. To evaluate the effect of storage temperature and duration of storage on the extent of aggregation, nanospheres and microspheres were stored at 4 degrees C, 25 degrees C, 37 degrees C, and 50 degrees C for 6 days and then monitored using both confocal and scanning electron microscopy. The mean +/- SD diameters of PLGA particles containing Bodipy were: 266.9 +/- 2.8, 351.6 +/- 1.8, 988.8 +/- 14.1, and 1865.9 +/- 67.0 nm. The extent of aggregation of the particulate delivery system decreased as the mean diameter increased, and increased as the storage temperature increased. The maximum extent of aggregation was observed with the smallest (266 nm) nanospheres. Microspheres did not aggregate. The aggregation of nanospheres was significantly reduced by introducing an additional evaporation step during preparation, suggesting that migration of residual dichloromethane from within the nanospheres may have dissolved the PLGA on the surface. The extent of aggregation of nanospheres increased as the temperature was increased from 4 degrees C to 50 degrees C, and decreased as particle size increased. To avoid aggregation, PLGA nanospheres should be stored at 4 degrees C.

Rationale and Design of the International Lymphoma Epidemiology Consortium (InterLymph) Non-Hodgkin Lymphoma Subtypes Project.

BACKGROUND: Non-Hodgkin lymphoma (NHL), the most common hematologic malignancy, consists of numerous subtypes. The etiology of NHL is incompletely understood, and increasing evidence suggests that risk factors may vary by NHL subtype. However, small numbers of cases have made investigation of subtype-specific risks challenging. The International Lymphoma Epidemiology Consortium therefore undertook the NHL Subtypes Project, an international collaborative effort to investigate the etiologies of NHL subtypes. This article describes in detail the project rationale and design. METHODS: We pooled individual-level data from 20 case-control studies (17471 NHL cases, 23096 controls) from North America, Europe, and Australia. Centralized data harmonization and analysis ensured standardized definitions and approaches, with rigorous quality control. RESULTS: The pooled study population included 11 specified NHL subtypes with more than 100 cases: diffuse large B-cell lymphoma (N = 4667), follicular lymphoma (N = 3530), chronic lymphocytic leukemia/small lymphocytic lymphoma (N = 2440), marginal zone lymphoma (N = 1052), peripheral T-cell lymphoma (N = 584), mantle cell lymphoma (N = 557), lymphoplasmacytic lymphoma/Waldenström macroglobulinemia (N = 374), mycosis fungoides/Sézary syndrome (N = 324), Burkitt/Burkitt-like lymphoma/leukemia (N = 295), hairy cell leukemia (N = 154), and acute lymphoblastic leukemia/lymphoma (N = 152). Associations with medical history, family history, lifestyle factors, and occupation for each of these 11 subtypes are presented in separate articles in this issue, with a final article quantitatively comparing risk factor patterns among subtypes. CONCLUSIONS: The International Lymphoma Epidemiology Consortium NHL Subtypes Project provides the largest and most comprehensive investigation of potential risk factors for a broad range of common and rare NHL subtypes to date. The analyses contribute to our understanding of the multifactorial nature of NHL subtype etiologies, motivate hypothesis-driven prospective investigations, provide clues for prevention, and exemplify the benefits of international consortial collaboration in cancer epidemiology.

pH-dependent stability of creatine ethyl ester: relevance to oral absorption.

Creatine ethyl ester hydrochloride (CEE) was synthesized as a prodrug of creatine (CRT) to improve aqueous solubility, gastrointestinal permeability, and ultimately the pharmacodynamics of CRT. We used high-performance liquid chromatography (HPLC) and proton nuclear magnetic resonance (NMR) to characterize the pH-dependent stability of CEE in aqueous solution and compared the permeability of CEE to CRT and creatinine (CRN) across Caco-2 human epithelial cell monolayers and transdermal permeability across porcine skin. CEE was most stable in a strongly acidic condition (half-life = 570 hours at pH 1.0) where it undergoes ester hydrolysis to CRT and ethanol. At pH ≥ 1.0, CEE cyclizes to CRN with the logarithm of the first order rate constant increasing linearly with pH. Above pH 8.0 (half-life = 23 sec) the rate of degradation was too rapid to be determined. The rate of degradation of CEE in cell culture media and simulated intestinal fluid (SIF) was a function of pH and correlated well with the stability in aqueous buffered solutions. The permeability of CEE across Caco-2 monolayers and porcine skin was significantly greater than that of CRT or CRN. The stability of CEE in acidic media together with its improved permeability suggests that CEE has potential for improved oral absorption compared to CRT.

Polymorphisms in metabolism/antioxidant genes may mediate the effect of dietary intake on pancreatic cancer risk.

OBJECTIVES: A source of variation for inconsistent dietary-pancreatic cancer associations may be individuals carrying constitutional metabolism/antioxidant gene variants that differentially benefit compared to homozygous individuals. Seventy-six tag single-nucleotide polymorphisms were genotyped in 13 candidate genes to test differential associations with pancreatic adenocarcinoma. METHODS: A clinic-based case-control design was used to rapidly ascertain 251 cases and 970 frequency matched controls who provided blood samples and completed a 144-item food frequency questionnaire. Single-nucleotide polymorphisms were evaluated using a dominant genetic model and dietary categories split on controls' median intake. Logistic regression was used to calculate odds ratios and 95% confidence intervals, adjusted for potential confounders. RESULTS: Significant increased associations (Bonferroni corrected P ≤ 0.0007) were observed for carriers of greater than or equal to 1 minor allele for rs3816257 (glucosidase, α; acid [GAA]) and lower intake of deep-yellow vegetables (1.90 [1.28-2.83]); and carriers of no minor allele for rs12807961 (catalase [CAT]) and high total grains intake (2.48 [1.50-4.09]), whereas those with greater than or equal to 1 minor allele had a decreasing slope (across grains). The reference group was no minor alleles with low dietary intake. CONCLUSIONS: Interindividual variation in metabolism/antioxidant genes could interact with dietary intake to influence pancreatic cancer risk.

Meat-related mutagens and pancreatic cancer: null results from a clinic-based case-control study.

BACKGROUND: Pancreatic cancer is a devastating disease for which the role of dietary factors remains inconclusive. The study objective was to evaluate risk of pancreatic cancer associated with meat preparation methods and meat-related mutagen consumption using a clinic-based case-control design. METHODS: There were 384 cases and 983 controls; subjects provided demographic information and completed a 144-item food frequency questionnaire, which was used to estimate meat mutagen intake using the National Cancer Institute's CHARRED database (Bethesda, MD). Logistic regression was used to calculate ORs and 95% confidence intervals (CI), adjusted for factors including age, sex, cigarette smoking, body mass index, and diabetes mellitus. RESULTS: Overall, the findings were null with respect to meat mutagen intake and pancreatic cancer. CONCLUSIONS: The results do not support an association between well-done meat or meat-related mutagen intake and pancreatic cancer and contrast with generally increased risks reported in previous studies. IMPACT: These data contribute to evidence about pancreatic cancer and potentially carcinogenic compounds in meat.