Ashley H. Davis-Yadley

Vitamins in Pancreatic Cancer: A Review of Underlying Mechanisms and Future Applications

Although there is increasing evidence that vitamins influence pancreatic adenocarcinoma biology and carcinogenesis, a comprehensive review is lacking. In this study, we performed a PubMed literature search to review the anticancer mechanisms and the preclinical and clinical studies that support the development of the bioactive vitamins A, C, D, E, and K in pancreatic cancer intervention. Preclinical studies have shown promising results for vitamin A in pancreatic cancer prevention, with clinical trials showing intriguing responses in combination with immunotherapy. For vitamin C, preclinical studies have shown slower tumor growth rates and/or increased survival when used alone or in combination with gemcitabine, with clinical trials with this combination revealing decreased primary tumor sizes and improved performance status. Preclinical studies with vitamin D analogues have shown potent antiproliferative effects and repression of migration and invasion of pancreatic cancer cells, with a clinical trial showing increased time to progression when calciferol was added to docetaxel. For vitamin E, preclinical studies have shown that δ-tocotrienol and γ-tocotrienol inhibited tumor cell growth and survival and augmented gemcitabine activity. Early-phase clinical trials with δ-tocotrienol are ongoing. Vitamin K demonstrates activation of apoptosis and inhibition of cellular growth in pancreatic tumor cells; however, there are no clinical studies available for further evaluation. Although preclinical and clinical studies are encouraging, randomized controlled trials with endpoints based on insights gained from mechanistic and preclinical studies and early-phase clinical trials are required to determine the efficacy of bioactive vitamin interventions in pancreatic cancer.

Metabolic Activity by 18F-FDG-PET/CT Is Prognostic for Stage I and II Pancreatic Cancer.

Purpose Metabolic activity, as defined by 18F-FDG uptake on PET, is a prognostic marker for multiple malignancies; however, no study has examined the prognostic value of imaging with FDG PET in stage I and II pancreatic cancer. We examined the value of PET FDG uptake in early-stage pancreatic cancer patients. Methods We identified patients with early-stage pancreatic cancer (I-II) who had FDG PET scan performed as part of their preoperative evaluation. The patients were divided into either high or low FDG uptake according to the median primary tumor standard uptake value (SUVmax). Our primary end points were overall survival (OS) and recurrence-free survival (RFS). Kaplan-Meier estimate was used for survival analysis. Pathologic data were compared using the Fisher exact and &khgr;2 tests. Results One hundred five patients were identified: 51 patients with low FDG uptake and 54 patients with high FDG uptake. Eighty-five patients (81%) had PET avid tumors, whereas 20 (19%) patients did not. High FDG uptake correlated with pathologic stage (P = 0.012). Patients with low FDG uptake had significantly better median OS than patients with high FDG uptake (28 vs. 16 months; P = 0.036). Patients with low-FDG uptake had significantly longer median RFS than patients with high FDG uptake (14 vs. 12 months; P = 0.049). Conclusions Low FDG uptake in PET scans in patients with stage I and II pancreatic cancer correlates with improved OS and RFS. This supports the concept that glucose metabolic pathways are important in pancreatic cancer biology and that PET scan activity can be used as a prognostic biomarker after pancreatectomy.

Prognostic Fifteen-Gene Signature for Early Stage Pancreatic Ductal Adenocarcinoma

The outcomes of patients treated with surgery for early stage pancreatic ductal adenocarcinoma (PDAC) are variable with median survival ranging from 6 months to more than 5 years. This challenge underscores an unmet need for developing personalized medicine strategies to refine the current treatment decision-making process. To derive a prognostic gene signature for patients with early stage PDAC, a PDAC cohort from Moffitt Cancer Center (n = 63) was used with overall survival (OS) as the primary endpoint. This was further evaluated using an independent microarray cohort dataset (Stratford et al: n = 102). Technical validation was performed by NanoString platform. A prognostic 15-gene signature was developed and showed a statistically significant association with OS in the Moffitt cohort (hazard ratio [HR] = 3.26; p<0.001) and Stratford et al cohort (HR = 2.07; p = 0.02), and was independent of other prognostic variables. Moreover, integration of the signature with the TNM staging system improved risk prediction (p<0.01 in both cohorts). In addition, NanoString validation showed that the signature was robust with a high degree of reproducibility and the association with OS remained significant in the two cohorts. The gene signature could be a potential prognostic tool to allow risk-adapted stratification of PDAC patients into personalized treatment protocols; possibly improving the currently poor clinical outcomes of these patients.

Increased Expression of the Glucose Transporter Type 1 Gene Is Associated With Worse Overall Survival in Resected Pancreatic Adenocarcinoma.

Objectives There is currently no reliable method to predict the risk of relapse after curative resection of early-stage pancreatic adenocarcinoma. Increased glucose metabolism observed on 18F-fluorodeoxyglucose positron emission tomography (PET) by malignant cells, the Warburg effect, is a well-known characteristic of the malignant phenotype. We investigated the role of glucose transporter type 1 (GLUT-1) gene expression, a glucose cell plasma membrane transporter, in early-stage pancreatic cancer. Methods Associations between GLUT-1 gene expression with PET maximum standardized uptake values and histologic grade were investigated in early-stage pancreatic adenocarcinoma patients. Multivariate analysis was conducted to determine predictors of prognosis. Cox proportional hazard model was used for survival analysis. Results Sixty-three patients had GLUT-1 gene analysis performed, and 50 patients had both GLUT-1 analysis and PET scan. Patients with high GLUT-1 gene expression had a decreased overall survival by univariate analysis using Cox proportional hazard model (hazard ratio, 2.82; P = 0.001) and remained significant on multivariate analysis (hazard ratio, 2.54; P = 0.03). There was no correlation of GLUT-1 gene expression with histologic grade or PET maximum standardized uptake values. Conclusions Increased GLUT-1 gene expression was associated with a decreased overall survival in pancreatic adenocarcinoma. This supports increased GLUT-1 gene expression as a potential prognostic marker in resected pancreatic adenocarcinoma.

Advances in the Endoscopic Diagnosis of Barrett Esophagus.

BACKGROUND Barrett esophagus (BE) continues to be a major risk factor for developing esophageal adenocarcinoma. METHODS We review the risk factors, diagnosis, and management of BE, with an emphasis on the most current endoscopic diagnostic modalities for BE. RESULTS Novel diagnostic modalities have emerged to address the inadequacies of standard, untargeted biopsies, such as dye-based and virtual chromoendoscopy, endoscopic mucosal resection, molecular biomarkers, optical coherence tomography, confocal laser endomicroscopy, volumetric laser endomicroscopy, and endocytoscopy. Treatment of BE depends on the presence of intramucosal cancer or dysplasia, particularly high-grade dysplasia with or without visible mucosal lesions. CONCLUSIONS Recent advances in endoscopic diagnostic tools demonstrate promising results and help to mitigate the shortcomings of the Seattle protocol. Future research as well as refining these tools may help aid them in replacing standard untargeted biopsies.

Low bone mineral density linked to colorectal adenomas: a cross-sectional study of a racially diverse population

BACKGROUND Epidemiologic studies suggest that lower bone mineral density (BMD) is associated with an increased risk for colorectal adenoma/cancer, especially in postmenopausal women. The aim of this study is to investigate the association between osteopenia and/or osteoporosis and colorectal adenomas in patients from a New York community hospital. METHODS We performed a cross-sectional observational study on 200 patients who underwent screening colonoscopies and bone density scan (dual-energy X-ray absorptiometry) at Nassau University Medical Center from November 2009 to March 2011. Among these, 83 patients were identified as osteoporosis (T score of -2.5 or below) and 67 were osteopenia (T score between -1.0 and -2.5). Logistic regression model was performed to assess the association between osteopenia and/or osteoporosis and colorectal adenomas. RESULTS Among the patients with osteopenia and osteoporosis, the mean ages were 59.1 years [standard deviation (SD) =8.9] and 61.5 (SD =8.9), respectively. There were 94.0%, 85.1% and 74.7% women, respectively, in normal BMD, osteopenia and osteoporosis groups. The prevalence of colorectal adenomas was 17.9% and 25.3% in the osteopenia and osteoporosis groups, respectively, and 18.0% in the normal BMD group. After adjustment for potential confounders including age, sex, race, body mass index (BMI), tobacco use, alcohol use, history of diabetes, hypertension, or dyslipidemia, osteoporosis was found to be associated with presence of colorectal adenomas more than 2, compared to the normal BMD group. No significant associations were found for the prevalence, size, and location of adenomas. CONCLUSIONS Our study suggests that osteoporosis is significantly associated with the presence of multiple colorectal adenomas. Prospective studies with a larger sample size are warranted in the future.

Establishing the link between hepatitis B virus infection and colorectal adenoma

BACKGROUND Chronic hepatitis B (CHB) infection has been associated with malignancy, most notably hepatocellular carcinoma. Previous research has shown that hepatitis C is associated with increased colorectal adenomas and neoplasia. Currently, there are no studies on the association of CHB and colorectal adenomas. We aimed to identify a possible link between CHB and colorectal adenoma. METHODS A retrospective chart review was performed on 588 consecutive patients undergoing screening or diagnostic colonoscopy that were previously screened or diagnosed with hepatitis B. Comparisons between categorical variables were analyzed with Chi Square test and t-test for continuous variables. Unconditional logistic regression was used to generate age-, gender-and race-adjusted odds ratios and their 95% confidence intervals (CI) comparing medication users with non-users. Statistical analyses were performed with SAS 9.3 software. RESULTS A total of 487 patients were analyzed in the control group vs. 71 in the hepatitis B group. The adenoma detection rate was 23.9% in hepatitis B vs. 15.9% in the non-hepatitis B group for all cause colonoscopy; however this did not reach statistical significance. There was a significantly higher number of adenomas present in the distal colon compared to control (OR =2.16; 95% CI, 1.06-4.43; P=0.04). There were no significant findings between hepatitis B infection with size, multiplicity or presence of proximal adenomas. There was a significant difference noted in regards to smoking history, BMI and age between two groups. CONCLUSIONS Although the adenoma detection rate was higher in hepatitis B population vs. the non-hepatitis B group this did not reach statistical significance. However, we did find an association between CHB infection and the presence of distal colorectal adenomas. Larger prospective studies are needed to strengthen our findings along with future studies examining hepatitis B virus (HBV) and mechanisms inducing colorectal carcinogenesis.

The safety and efficacy of single balloon enteroscopy in the elderly.

Background: Single balloon enteroscopy (SBE) is an important tool in the management of small bowel disease with limited data available on its performance in the elderly. We aimed to evaluate the safety, efficacy, diagnostic and therapeutic outcomes of SBE in the elderly. Methods: A retrospective review was performed on 366 patients undergoing 428 SBEs from 2010 to 2014. Patients were divided into different age groups: control <55, 55–64, 65–74 and ⩾75 years. Data on comorbidities, complications, findings, diagnostic and therapeutic yield were compared between groups. Results: Anterograde and retrograde SBE were performed in 340 and 49 patients, respectively, with 63 patients requiring more than 1 procedure. Diagnostic yield was significantly higher for age ⩾75 years compared with <55, 66.3% versus 50%, odds ratio (OR) 1.97 [95% confidence interval (CI) 1.14–3.41]. Therapeutic yield was significantly higher in all three older age groups compared with <55 years, 20.3%: 55–64 years, 44.4%, OR 3.13(95% CI 1.7–5.78); 65–74 years, 42%, OR 2.84 (95% CI 1.59–5.06); and >75 years, 47.5%, OR 3.55 (95% CI 1.96–6.43). No significant difference was seen between age groups in complications or failures. Our overall complication rate was 2.3% with 5 minor and 5 major complications. There was a higher yield of angioectasias in the elderly. Argon plasma coagulation (APC) and multipolar electrocoagulation were used more often in older age groups. Conclusion: SBE is safe in elderly patients and delivers higher diagnostic and therapeutic yields compared to younger patients. The elderly are more likely to have angioectasias and undergo APC and electrocoagulation.

Timing of single balloon enteroscopy: significant or not?

Background: The development of balloon assisted enteroscopy (BAE) has revolutionized diagnostic and therapeutic modalities for small-bowel disorders. Although the role of emergent esophagogastroduodenoscopy and colonoscopy for upper and lower gastrointestinal bleeding is well defined, there is scarce data with regard to emergent BAE for gastrointestinal bleeding. Study: We performed a retrospective cohort study including 110 hospitalized patients with obscure gastrointestinal bleeding who underwent single balloon enteroscopy (SBE) between January 2010 and August 2013. Patients were divided into two groups based on procedures performed emergently (within 24 hours) versus non-emergently (greater than 24 hours). Data on patient demographics, hemodynamic characteristics, type of obscure bleed, lesions identified, location of lesions, endoscopic intervention performed, need for further surgical or radiological intervention, diagnostic and therapeutic yield, and adverse events were compared between groups. Independent samples t test and Fisher’s exact test were used to assess the association between dependent and independent variables. For continuous data, the results were summarized as mean difference and 95 % confidence intervals (CI), and for binary as odds ratio and 95 %CI. Results: Although patients in the group where enteroscopy was performed within 24 hours had a significantly higher incidence of radiological intervention (10.0 % vs. 0.0 %, P = 0.019), the diagnostic and therapeutic yields between the two groups were not significantly different. Additionally, there were no statistically significant differences between the groups for overt and occult bleeding, transfusion requirements, type and location of lesions, endoscopic intervention performed, or adverse events. Hospital stay was shorter in the patients who had SBE within 24 hours of admission (6.2 vs. 11.3 days, P < 0.001). Conclusions: Although the diagnostic and therapeutic yields of SBE were not significantly different between patients having the procedure within 24 hours and those having it later, the early SBE group required more interventional radiology procedures. While endoscopists may not necessarily have to perform emergent assessment within 24 hours in patients with obscure gastrointestinal bleeding (OGIB) for greater diagnostic or therapeutic yield, early intervention may allow for earlier stabilization and thus shorter hospital stays. Prospective studies further evaluating these findings are indicated.

Ethnic disparities in the risk of colorectal adenomas associated with aspirin and statin use: a retrospective multiethnic study.

BACKGROUND Although data on the inverse association between colorectal adenomas (CRA) and daily aspirin or statin therapy exists in white and black patients, scarce data exists on these associations in the Hispanic population. With a rapidly increasing Hispanic population in the United States, defining the association in Hispanics is crucial. METHODS The study sample included 1,843 consecutive patients who underwent a colonoscopy (screening or diagnostic) from 2009 to 2011 at a community hospital in East Meadow, New York. Data was then extracted from patient charts regarding aspirin and/or statin use. Adjusted odds ratios (OR) and their 95% confidence intervals (CI) were calculated to assess the association between colonoscopy findings and aspirin, statin, or aspirin/statin use. RESULTS In our total population including all races, aspirin user had an increased risk for having two or more adenomas (OR =1.73, 95% CI: 1.00, 2.99, P=0.05) and presence of an adenoma in the proximal colon (OR =1.66, 95% CI: 1.07, 2.58, P=0.02). In the total study population, those who used both statin and aspirin had an increased risk for having two or more adenomas (OR =2.56, 95% CI: 1.21, 5.39, P=0.01). In the Hispanic population, users of both medications had an increased risk for having two or more adenomas (OR =19.04, 95% CI: 1.30, 280.09, P=0.03), adenoma present in the distal colon (OR =5.75, 95% CI: 1.64, 20.21, P=0.01) and largest adenoma in distal colon (OR =5.75, 95% CI: 1.64, 20.21, P=0.01). CONCLUSIONS Aspirin use and aspirin/statin use was associated with abnormal colonoscopy findings, particularly in the Hispanic population. These findings may be due to environmental factors such as dietary, colonic flora, or genetic susceptibility. The findings warrant further investigational research, particularly in Hispanics.