Racial/ethnic disparities in the trajectories of insomnia symptoms from childhood to young adulthood.

STUDY OBJECTIVES: To examine differences in the longitudinal prevalence of childhood insomnia symptoms across black/African American, Hispanic/Latinx, and non-Hispanic white groups. METHODS: Participants were 519 children from the Penn State Child Cohort (baseline [V1] from 2000-2005) who were followed up 8 years later as adolescents (V2) and 15 years later as young adults (S3). Mean age at S3 was 24.1 ±â€…2.7 years. Approximately, 76.5% identified as non-Hispanic white, 12.9% as black/African American, 7.1% as Hispanic/Latinx, and 3.5% as "other" race/ethnicity. Insomnia symptoms were defined as parent-reported (childhood) or self-reported (adolescence and young adulthood) moderate-to-severe difficulties initiating/maintaining sleep. Longitudinal trajectories of insomnia symptoms were identified across three-time points and the odds of each trajectory were compared between racial/ethnic groups, adjusting for sex, age, overweight, sleep apnea, periodic limb movements, psychiatric/behavioral disorders, and psychotropic medication use. RESULTS: Black/African Americans compared to non-Hispanic whites were at significantly higher odds of having a childhood-onset persistent trajectory through young adulthood (OR = 2.58, 95% CI [1.29, 5.14]), while Hispanics/Latinx were at nonsignificantly higher odds to have the same trajectory (OR = 1.81, 95% CI [0.77, 4.25]). No significant racial/ethnic differences were observed for remitted and waxing-and-waning trajectories since childhood or incident/new-onset trajectories in young adulthood. CONCLUSIONS: The results indicate that disparities in insomnia symptoms among black/African American and, to a lesser extent, Hispanic/Latinx groups start early in childhood and persist into young adulthood. Identifying and intervening upon upstream determinants of racial/ethnic insomnia disparities are warranted to directly address these disparities and to prevent their adverse health sequelae. CLINICAL TRIAL INFORMATION: N/A; Not a clinical trial.

The Effects of Black Raspberry as a Whole Food-Based Approach on Biomarkers of Oxidative Stress in Buccal Cells and Urine of Smokers.

Cigarette smoke is a rich source of free radicals that can promote oxidative stress and carcinogenesis, including head and neck squamous cell carcinoma (HNSCC) development; importantly, 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG) and 8-iso-prostaglandin F2α (8-isoprostane) are biomarkers of oxidative stress. Several mechanisms, including the antioxidant properties of black raspberry (BRB), account for their chemopreventive effects. In the present clinical trial, we tested the hypothesis that BRB administration reduces biomarkers levels of oxidative stress in buccal cells and urine of smokers. One week after enrolling 21 smokers, baseline buccal cells and urine samples were collected before the administration of BRB lozenges for 8 weeks (5/day, 1 gm BRB/lozenge). Buccal cells and urine samples were collected at the middle and the end of BRB administration. The last samples were collected after the BRB cessation (washout period). We analyzed levels of 8-oxodG and 8-isoprostane (LC/MS-MS), urinary cotinine (ELISA), and creatinine (spectrophotometry). BRB significantly reduced the levels of 8-oxodG by 17.08% (P = 0.00079) in buccal cells and 12.44% (P = 0.034) in urine at the middle of BRB administration as compared with baseline; the corresponding values at the end of BRB administration were 16.46% (P = 0.026) in buccal cells and 25.72% (P = 0.202) in urine. BRB had no significant effect on the levels of urinary 8-isoprostane. BRB's capacity to inhibit 8-oxodG formation of smokers' buccal cells and urine is clearly evident and the reduction in 8-oxodG suggests that antioxidant abilities are central to BRB's HNSCC chemopreventive properties. PREVENTION RELEVANCE: Cigarette smoke contains highly active components namely free radicals that can promote oxidative stress and oral cancer. We found that black raspberry (BRB) inhibited the formation of oxidative stress markers in the oral cavity and urine of smokers suggesting the antioxidant abilities of BRB in preventing oral cancer.

Self-sampling tools to increase cancer screening among underserved patients: a pilot randomized controlled trial.

BACKGROUND: Screening can reduce cancer mortality, but uptake is suboptimal and characterized by disparities. Home-based self-sampling can facilitate screening for colorectal cancer (with stool tests, eg, fecal immunochemical tests) and for cervical cancer (with self-collected human papillomavirus tests), especially among patients who face barriers to accessing health care. Additional data are needed on feasibility and potential effects of self-sampling tools for cancer screening among underserved patients. METHODS: We conducted a pilot randomized controlled trial with patients (female, ages 50-65 years, out of date with colorectal and cervical cancer screening) recruited from federally qualified health centers in rural and racially segregated counties in Pennsylvania. Participants in the standard-of-care arm (n = 24) received screening reminder letters. Participants in the self-sampling arm (n = 24) received self-sampling tools for fecal immunochemical tests and human papillomavirus testing. We assessed uptake of screening (10-week follow-up), self-sampling screening outcomes, and psychosocial variables. Analyses used Fisher exact tests to assess the effect of study arm on outcomes. RESULTS: Cancer screening was higher in the self-sampling arm than the standard-of-care arm (colorectal: 75% vs 13%, respectively, odds ratio = 31.32, 95% confidence interval = 5.20 to 289.33; cervical: 79% vs 8%, odds ratio = 72.03, 95% confidence interval = 9.15 to 1141.41). Among participants who returned the self-sampling tools, the prevalence of abnormal findings was 24% for colorectal and 18% for cervical cancer screening. Cancer screening knowledge was positively associated with uptake (P < .05). CONCLUSIONS: Self-sampling tools can increase colorectal and cervical cancer screening among unscreened, underserved patients. Increasing the use of self-sampling tools can improve primary care and cancer detection among underserved patients. CLINICAL TRIALS REGISTRATION NUMBER: STUDY00015480.

Concurrent durvalumab and radiation therapy (DUART) followed by adjuvant durvalumab in patients with localized urothelial cancer of bladder: results from phase II study, BTCRC-GU15-023.

BACKGROUND: Patients with bladder cancer (BC) who are cisplatin ineligible or have unresectable disease have limited treatment options. Previously, we showed targeting programmed death-ligand 1 (PD-L1) with durvalumab (durva) and radiation therapy (RT) combination was safe in BC. We now report results from a phase II study evaluating the toxicity and efficacy of durva and RT in localized BC. METHODS: This is a single-arm, multi-institutional phase II study; N=26. Enrolled patients had pure or mixed urothelial BC (T2-4 N0-2 M0) with unresectable tumors and were unfit for surgery or cisplatin ineligible. Patients received durva concurrently with RT ×7 weeks, followed by adjuvant durva × 1 year. PRIMARY ENDPOINTS: (A) progression-free survival (PFS) at 1 year and (B) disease control rate (DCR) post adjuvant durva. Key secondary endpoints: (A) complete response (CR) post durvaRT (8 weeks), (B) overall survival (OS), (C) PFS and (D) toxicity. Correlative studies included evaluation of baseline tumor and blood (baseline, post durvaRT) for biomarkers. RESULTS: Median follow-up was 27 months. Evaluable patients: 24/26 post durvaRT, 22/26 for DCR post adjuvant durva, all patients for PFS and OS. Post adjuvant durva, DCR was seen in 72.7%, CR of 54.5%. 1-year PFS was 71.5%, median PFS was 21.8 months. 1-year OS was 83.8%, median OS was 30.8 months. CR at 8 weeks post durvaRT was 62.5%. Node positive (N+) patients had similar median PFS and OS. DurvaRT was well tolerated. Grade ≥3 treatment-related adverse events: anemia, high lipase/amylase, immune-nephritis, transaminitis, dyspnea (grade 4-COPD/immune), fatigue, rash, diarrhea and scleritis. No difference in outcome was observed with PD-L1 status of baseline tumor. Patients with CR/PR or SD had an increase in naïve CD4 T cells, a decrease in PD-1+CD4 T cells at baseline and an increase in cytokine-producing CD8 T cells, including interferon gamma (IFNγ) producing cells, in the peripheral blood. CONCLUSION: Durva with RT followed by adjuvant durva was safe with promising efficacy in localized BC patients with comorbidities, including N+ patients. Larger randomized studies, like S1806 and EA8185, are needed to evaluate the efficacy of combining immunotherapy and RT in BC. TRIAL REGISTRATION NUMBER: NCT02891161.

Combined epigenetic and immunotherapy for blastic and classical mantle cell lymphoma.

Classical MCL (cMCL) constitutes 6-8% of all B cell NHL. Despite recent advances, MCL is incurable except with allogeneic stem cell transplant. Blastic mantle cell lymphoma (bMCL) is a rarer subtype of cMCL associated with an aggressive clinical course and poor treatment response, frequent relapse and poor outcomes. We treated 13 bMCL patients with combined epigenetic and immunotherapy treatment consisting of vorinostat, cladribine and rituximab (SCR). We report an increased OS greater than 40 months with several patients maintaining durable remissions without relapse for longer than 5 years. This is remarkably better then current treatment regimens which in bMCL range from 14.5-24 months with conventional chemotherapy regimens. We demonstrate that the G/A870 CCND1 polymorphism is predictive of blastic disease, nuclear localization of cyclinD1 and response to SCR therapy. The major resistance mechanisms to SCR therapy are loss of CD20 expression and evasion of treatment by sanctuary in the CNS. These data indicate that administration of epigenetic agents improves efficacy of anti-CD20 immunotherapies. This approach is promising in the treatment of MCL and potentially other previously treatment refractory cancers.

Trajectories of Insomnia Symptoms From Childhood Through Young Adulthood.

OBJECTIVES: Insomnia symptoms are transdiagnostic to physical and mental health disorders. Given the lack of population-based cohorts with objective sleep measures and long-term follow-ups, little is known about the chronicity of childhood insomnia symptoms. We determined the developmental trajectories of insomnia symptoms, their evolution into adult insomnia, and the role of objective sleep duration in the transition to adulthood. METHODS: A total of 502 children (median 9 years old, 71.7% response rate) were studied 7.4 years later as adolescents (median 16 years old) and 15 years later as adults (median 24 years old). Insomnia symptoms were ascertained as moderate-to-severe difficulties initiating and/or maintaining sleep via parent- or self reports at all 3 time points, adult insomnia via self-report in young adulthood, and objective short-sleep duration via polysomnography in childhood and adolescence. RESULTS: Among children with insomnia symptoms, the most frequent trajectory was persistence (43.3%), followed by remission (26.9% since childhood, 11.2% since adolescence) and a waxing-and-waning pattern (18.6%). Among children with normal sleep, the most frequent trajectory was persistence (48.1%), followed by developing insomnia symptoms (15.2% since adolescence, 20.7% in adulthood) and a waxing-and-waning pattern (16.0%). The odds of insomnia symptoms worsening into adult insomnia (22.0% of children, 20.8% of adolescents) were 2.6-fold and 5.5-fold among short-sleeping children and adolescents, respectively. CONCLUSIONS: Early sleep interventions are a health priority because pediatricians should not expect insomnia symptoms to developmentally remit in a high proportion of children. Objective sleep measures may be clinically useful in adolescence, a critical period for the adverse prognosis of the insomnia with short-sleep duration phenotype.

Variance reduction in the inverse probability weighted estimators for the average treatment effect using the propensity score.

The propensity methodology is widely used in medical research to compare different treatments in designs with a nonrandomized treatment allocation. The inverse probability weighted (IPW) estimators are a primary tool for estimating the average treatment effect but the large variance of these estimators is often a significant concern for their reliable use in practice. Inspired by Rao-Blackwellization, this paper proposes a method to smooth an IPW estimator by replacing the weights in the original estimator by their mean over a distribution of the potential treatment assignment. In our simulation study, the smoothed IPW estimator achieves a substantial variance reduction over its original version with only a small increased bias, for example two-to-sevenfold variance reduction for the three IPW estimators in Lunceford and Davidian [Statistics in Medicine, 23(19), 2937-2960]. In addition, our proposed smoothing can also be applied to the locally efficient and doubly robust estimator for added protection against model misspecification. An implementation in R is provided.

The Potential of Glioblastoma Patient Symptoms to Diagnose and Predict Survival.

Glioblastoma is a devastating malignancy with a dismal survival rate and median survival time of 14 months. Currently, the biomarkers for glioblastoma are mostly molecular and include EGFRvIII, ATRX, PTEN, IDH1, MGMT, and others. These prognostic tumor biomarkers are obtained through a surgical biopsy and thus are not easily attainable. Clinicians would benefit from a robust, non-invasive, and readily available indicator for early diagnosis and accurate prognostication for glioblastoma patients. In this study, we assessed whether specific patient symptoms could provide an early diagnosis of glioblastoma. Further, we also assessed if any patient symptomatology could provide clinicians with the ability to prognosticate patient survival more accurately. We retrospectively reviewed the clinical data for 218 patients. We determined whether symptoms including headache, weakness, seizure, memory loss/confusion, visual changes, speech changes, and loss of consciousness led to a patient being diagnosed earlier and if any of these symptoms predicted diminished patient survival. Our study determined that weakness and memory loss/confusion were the symptoms that predicted diminished survival, and weakness alone was the symptom that predicted an earlier diagnosis. This study further elucidates the complexities of glioblastoma and provides clinicians with more data for their patients when discussing prognostication after diagnosis of glioblastoma.

Racial/ethnic disparity in habitual sleep is modified by caloric intake in adolescents.

STUDY OBJECTIVES: We investigated the moderation of caloric intake on the association between race/ethnicity and habitual sleep in adolescents. METHODS: We analyzed the data obtained from 324 adolescents who completed the follow-up examination of the Penn State Child Cohort study. We collected actigraphy-measured sleep duration on 7 consecutive nights and computed their mean and standard deviation as habitual sleep duration (HSD) and habitual sleep variability (HSV), respectively. We also measured participants' daily intakes of total calorie, total fat, carbohydrates, and protein, through the Youth/Adolescent Food Frequency Questionnaire. Adjusted mean HSD and HSV among non-Hispanic whites and racial/ethnic minorities were compared by using analysis of covariance (ANCOVA), while controlling for age, sex, BMI percentile, total caloric intake, and socioeconomic status. The significance of the interaction between race/ethnicity and caloric intake was further tested in ANCOVA models. RESULTS: The study sample consisted of 79.3% non-Hispanic whites, 13.0% African American, 4.6% Hispanics, 2.2% Asian, and 0.9% American Indian. Adolescents who are racial/ethnic minorities showed shorter HSD (mean (SE): 6.80 (0.10) vs. 7.07 (0.05) hours/night, p = 0.02) and higher HSV (mean (SE): 1.31 (0.07) vs. 1.15 (0.04) hours/night, p = 0.04) than non-Hispanic whites. Racial/ethnic differences in HSV were significantly more pronounced among adolescents with high caloric intake (p interaction = 0.01), especially from carbohydrates (p interaction = 0.03) and fat (p interaction = 0.05). CONCLUSION: Adolescents who are racial/ethnic minorities slept objectively shorter and with greater night-to-night variability than non-Hispanic whites. The racial/ethnic disparity in habitual sleep variability was more pronounced among adolescents with high caloric intake, particularly from carbohydrates and fat.

Sorafenib and Quinacrine Target Anti-Apoptotic Protein MCL1: A Poor Prognostic Marker in Anaplastic Thyroid Cancer (ATC).

PURPOSE AND EXPERIMENTAL DESIGN: Anaplastic thyroid cancer (ATC) comprises approximately 2% of all thyroid cancers, and its median survival rate remains poor. It is responsible for more than one third of thyroid cancer-related deaths. ATC is frequently resistant to conventional therapy, and NFκB signaling has been proposed to be a feature of the disease. We aimed to assess the activity of the antimalaria drug quinacrine known to target NFκB signaling in combination with the clinically relevant kinase inhibitor sorafenib in ATC cells. The presence of NFκB-p65/RELA and its target MCL1 was demonstrated in ATC by meta-data gene set enrichment analysis and IHC. We assessed the responses of a panel of human ATC cell lines to quinacrine and sorafenib in vitro and in vivo RESULTS: We detected increased expression of NFκB-p65/RELA and MCL1 in the nucleus of a subset of ATC compared with non-neoplastic thyroid. ATC cells were found to respond with additive/synergistic tumor cell killing to the combination of sorafenib plus quinacrine in vitro, and the drug combination improves survival of immunodeficient mice injected orthotopically with ATC cells as compared with mice administered either compound alone or doxorubicin. We also demonstrate that the combination of sorafenib and quinacrine is well tolerated in mice. At the molecular level, quinacrine and sorafenib inhibited expression of prosurvival MCL1, pSTAT3, and dampened NFκB signaling. CONCLUSIONS: The combination of quinacrine and sorafenib targets emerging molecular hallmarks of ATC and shows promising results in clinically relevant models for the disease. Further testing of sorafenib plus quinacrine can be conducted in ATC patients. Clin Cancer Res; 22(24); 6192-203. ©2016 AACR.

Germline Mutation of the CCK Receptor: A Novel Biomarker for Pancreas Cancer.

OBJECTIVES: Today, genetic biomarkers have been demonstrated to play an important role in identifying at-risk subjects for familial or inherited cancers. We have identified a single-nucleotide polymorphism (SNP) that results in missplicing of the cholecystokinin (CCK) receptor gene and expressing a larger mutated receptor in pancreatic cancer. The purpose of this study was to evaluate the significance and specificity of this SNP as a potential biomarker in patients with pancreatic cancer compared with other gastrointestinal (GI) cancers that also have CCK receptors. METHODS: DNA was isolated and genotyped for the CCK receptor SNP from frozen tumor tissue from banked specimens of patients with pancreas, gastric, or colon cancer and from human cancer cell lines. Genotype and allelic frequencies were compared between the cancer cohort and two normal control databases using Fisher's exact test and odds ratio (OR). The Kaplan-Meier method was used to estimate the survival for patients with the CCK-B receptor SNP compared with those with the wild-type genotype. Immunohistochemical staining of cancer cells was done to detect the mutated receptor. RESULTS: Colon and gastric cancer patients had similar genotype frequencies for the CCK receptor SNP as that reported in the normal population. In contrast, the prevalence of the SNP in subjects with pancreatic cancer was twice that of controls and other GI cancers. Survival was adversely affected by the presence of the SNP only in those with pancreatic cancer. Immunoreactivity for the mutated receptor was positive in pancreatic cancer tissues with the SNP but absent in other GI cancers. CONCLUSIONS: A SNP of the CCK receptor is significantly increased in patients with pancreatic cancer but not in those with other GI malignancies. Therefore, this SNP may be a potential biomarker for pancreatic cancer.

Habitual sleep variability, mediated by nutrition intake, is associated with abdominal obesity in adolescents.

OBJECTIVE: To investigate habitual sleep duration (HSD) and habitual sleep variability (HSV) in relation to abdominal obesity and nutrient intake as mediating factors in adolescents. METHODS: We analyzed data from 305 adolescents who participated in the Penn State Child Cohort follow-up examination. An actigraphy device was used for seven consecutive nights to calculate HSD and HSV. Abdominal obesity was assessed by dual-energy x-ray absorptiometry. The Youth/Adolescent Food Frequency Questionnaire was used to obtain daily total caloric, protein, fat, and carbohydrates intakes. Linear regression models were used to associate HSD and HSV with abdominal obesity and to qualitatively identify mediating factors. The mediating effect was quantitatively estimated by mediation models. RESULTS: After adjusting for major covariates and HSD, higher HSV was significantly associated with abdominal obesity measures. For example, with 1-hour increase in HSV, android/gynoid fat ratio and visceral fat area increased by 0.02 cm(2) (standard error = 0.01, p = 0.03) and 6.86 cm(2) (standard error = 2.82, p = 0.02), respectively. HSD was not associated with abdominal obesity in HSV-adjusted models. Total caloric, fat, and carbohydrate intakes were significant mediating factors. For instance, 20% of the association between HSV and visceral fat can be attributed to carbohydrate intake. CONCLUSIONS: Higher HSV, not HSD, is significantly associated with abdominal obesity, which can be partially explained by increased caloric intake, especially from carbohydrate, in adolescents. This study suggests that more attention should be paid to establish and maintain regular sleep patterns in adolescents.

Distribution of cholecystokinin-B receptor genotype between patients with pancreatic cancer and controls and its impact on survival.

OBJECTIVE: Cholecystokinin (CCK) and gastrin stimulate growth of pancreatic cancer through the CCK-B receptor (CCK-BR). A splice variant of the CCK-BR that results from a single nucleotide polymorphism (SNP) has been identified. Because the splice variant receptor has an extended third intracellular loop, an area involved in cell signaling and growth, we hypothesized that this genetic variant could contribute to the poor prognosis and short survival of this malignancy. METHODS: DNA from 931 patients with pancreatic cancer was evaluated for the SNP (C > A; rs1800843) in the CCK-BR gene. For statistical analysis, the Fisher exact test was used to compare the genotype and allele frequency between the cancer cohort and normal controls and the dependence of genotype on factors, such as stage of disease and age, was analyzed using Cox proportional hazards models. RESULTS: Compared to the normal cohort, the frequency of the A-allele in pancreatic cancer subjects was increased (P = 0.01123; odds ratio, 2.283). Even after adjustment for stage of disease, survival of subjects with the minor allele was significantly shorter than those with the wild-genotype (hazard ratio, 1.83; P = 3.11 × 10(-11)). CONCLUSIONS: The CCK-BR SNP predicts survival and should be studied as a candidate genetic biomarker for those at risk of pancreatic cancer.

Cholecystokinin receptor antagonist halts progression of pancreatic cancer precursor lesions and fibrosis in mice.

OBJECTIVES: Exogenous administration of cholecystokinin (CCK) induces hypertrophy and hyperplasia of the pancreas with an increase in DNA content. We hypothesized that endogenous CCK is involved in the malignant progression of pancreatic intraepithelial neoplasia (PanIN) lesions and the fibrosis associated with pancreatic cancer. METHODS: The presence of CCK receptors in early PanIN lesions was examined by immunohistochemistry in mouse and human pancreas. Pdx1-Cre/LSL-Kras transgenic mice were randomized to receive either untreated drinking water or water supplemented with a CCK receptor antagonist (proglumide, 0.1 mg/mL). Pancreas from the mice were removed and examined histologically for number and grade of PanINs after 1, 2, or 4 months of antagonist therapy. RESULTS: Both CCK-A and CCK-B receptors were identified in early stage PanINs from mouse and human pancreas. The grade of PanIN lesions was reversed, and progression to advanced lesions arrested in mice treated with proglumide compared with the controls (P = 0.004). Furthermore, pancreatic fibrosis was significantly reduced in antagonist-treated animals compared with vehicle (P < 0.001). CONCLUSIONS: These findings demonstrate that endogenous CCK is in part responsible for the development and progression of pancreatic cancer. The use of CCK receptor antagonists may have a role in cancer prophylaxis in high-risk subjects and may reduce fibrosis in the microenvironment.

Comparative effects of two different forms of selenium on oxidative stress biomarkers in healthy men: a randomized clinical trial.

Epidemiologic and laboratory studies indicate that dietary selenium protects against prostate cancer. Results from clinical trials suggest that selenium-enriched yeast (SY) but not selenomethionine (SeMet) may be effective at reducing prostate cancer risk. Our objectives were to directly compare for the first time the effects of SeMet and SY on prostate cancer relevant biomarkers in men. We performed a randomized double blind, placebo-controlled trial of SY (200 or 285 µg/day) and SeMet (200 µg/day) administered for 9 months in 69 healthy men. Primary endpoints included blood levels of selenium-containing compounds and oxidative stress biomarkers [urine 8-hydroxy-2'-deoxyguanosine (8-OHdG) and 8-iso-prostaglandin-F2α (8-iso-PGF2α) and blood glutathione (GSH)]. Secondary endpoints included plasma glucose and PSA levels. Compliance was high in all groups (>95%). Plasma selenium levels were increased 93%, 54%, and 86% after 9 months in SeMet and low- and high-dose SY groups, respectively, and returned to baseline levels after a 3-month washout (P < 0.05). Levels of 8-OHdG and 8-iso-PGF2α were decreased 34% and 28%, respectively, after 9 months in the high-dose SY group (P < 0.05). These decreases were greatest in individuals with low baseline plasma levels of selenium (<127 ng/mL). No changes in serum PSA or blood glucose and GSH were observed. Overall, we showed for the first time, reductions in biomarkers of oxidative stress following supplementation with SY but not SeMet in healthy men. These findings suggest that selenium-containing compounds other than SeMet may account for the decrease in oxidative stress.

Cholecystokinin mediates progression and metastasis of pancreatic cancer associated with dietary fat.

BACKGROUND: Obesity and dietary fat are associated with increased risk of several malignancies including pancreatic cancer. The incidence of pancreatic cancer is increased in countries that consume diets high in fat. AIM: The purpose of this study was to assess the relationship and mechanism of action between dietary fat and endogenous cholecystokinin (CCK) on pancreatic tumor growth and metastasis in an immunocompetent animal model. METHODS: C57BL/6 mice were placed on regular, low-fat, or high-fat diets for 8 weeks before establishment of Panc-02 orthotopic pancreatic tumors. Mice were then treated with a CCK-A receptor antagonist, devazepide, or vehicle for an additional 2.5 weeks. Pancreas tumors were weighed and metastases counted. Blood CCK levels were measured by radioimmunoassay (RIA). Tissues were examined histologically and studied for genes associated with metastasis by RT-PCR array. Effects of the CCK antagonist on Panc-02 cells invasiveness was assessed in a Matrigel invasion assay. RESULTS: Mice that received the high-fat diet had larger tumors and tenfold higher serum CCK levels by RIA compared to normal diet controls (p < 0.01). Pancreatic tumors in high-fat diet mice treated with the antagonist had fewer intravascular tumor emboli and metastases compared to controls. The reduction in tumor emboli correlated with decreased vascular endothelial growth factor-A (VEGF-A) expression in tumors (p < 6 × 10(-9)). In vitro invasiveness of Panc-02 cells also was reduced by CCK-A receptor antagonist treatment (p = 1.33 × 10(-6)). CONCLUSION: CCK is a mediator of dietary fat-associated pancreatic cancer. CCK is also involved in the invasiveness of pancreatic tumors through a mechanism involving VEGF-A.

A single nucleotide polymorphism of the cholecystokinin-B receptor predicts risk for pancreatic cancer.

There currently are no tests available for early diagnosis or for the identification of patients at risk for development of pancreatic cancer. We report the discovery of single nucleotide polymorphism (SNP) in the cholecystokinin B receptor (CCKBR) gene predicts survival and risk of pancreatic cancer. Growth of human pancreatic cancer is stimulated by gastrin through the CCKBR and an alternatively spliced isoform of the CCKBR gene called CCKCR. One hundred and ten surgically resected benign and malignant pancreatic tissues as well as normal pancreas were prospectively evaluated for CCKBR genotype and protein expression. Analysis demonstrated the expression of the spliced isoform, CCKCR, was associated with a (SNP) (C > A) at position 32 of the intron 4 (IVS 4) of the CCKBR gene. Since the SNP is within an intron, it has not previously been identified in the GWAS studies. Only patients with the A/A or A/C genotypes, exhibited immunoreactivity to a selective CCKCR antibody. Survival among pancreatic cancer patients with the A-SNP was significantly shorter (p = 0.0001, hazard ratio = 3.63) compared with individuals with C/C genotype. Other variables such as surgical margins, lymph node status, histologic grade or adjuvant chemotherapy were not associated with survival. Furthermore, having one or two of the A-alleles was found to increase the risk of pancreatic adenocarcinoma by 174% (p = 0.0192) compared with the C/C wild type. Cancer cells transfected to overexpress the CCKCR demonstrated increased proliferation over controls. Genetic screening for this SNP may aid in early detection of pancreatic cancer in high risk subjects.