Barrett's esophagus in 2016: From pathophysiology to treatment

Esophageal complications caused by gastroesophageal reflux disease (GERD) include reflux esophagitis and Barrett's esophagus (BE). BE is a premalignant condition with an increased risk of developing esophageal adenocarcinoma (EAC). The carcinogenic sequence may progress through several steps, from normal esophageal mucosa through BE to EAC. A recent advent of functional esophageal testing (particularly multichannel intraluminal impedance and pH monitoring) has helped to improve our knowledge about GERD pathophysiology, including its complications. Those findings (when properly confirmed) might help to predict BE neoplastic progression. Over the last few decades, the incidence of EAC has continued to rise in Western populations. However, only a minority of BE patients develop EAC, opening the debate regarding the cost-effectiveness of current screening/surveillance strategies. Thus, major efforts in clinical and research practice are focused on new methods for optimal risk assessment that can stratify BE patients at low or high risk of developing EAC, which should improve the cost effectiveness of screening/surveillance programs and consequently significantly affect health-care costs. Furthermore, the area of BE therapeutic management is rapidly evolving. Endoscopic eradication therapies have been shown to be effective, and new therapeutic options for BE and EAC have emerged. The aim of the present review article is to highlight the status of screening/surveillance programs and the current progress of BE therapy. Moreover, we discuss the recent introduction of novel esophageal pathophysiological exams that have improved the knowledge of the mechanisms linking GERD to BE

SLC22A3 polymorphisms do not modify pancreatic cancer risk, but may influence overall patient survival

Expression of the solute carrier (SLC) transporter SLC22A3 gene is associated with overall survival of pancreatic cancer patients. This study tested whether genetic variability in SLC22A3 associates with pancreatic cancer risk and prognosis. Twenty four single nucleotide polymorphisms (SNPs) tagging the SLC22A3 gene sequence and regulatory elements were selected for analysis. Of these, 22 were successfully evaluated in the discovery phase while six significant or suggestive variants entered the validation phase, comprising a total study number of 1,518 cases and 3,908 controls. In the discovery phase, rs2504938, rs9364554, and rs2457571 SNPs were significantly associated with pancreatic cancer risk. Moreover, rs7758229 associated with the presence of distant metastases, while rs512077 and rs2504956 correlated with overall survival of patients. Although replicated, the association for rs9364554 did not pass multiple testing corrections in the validation phase. Contrary to the discovery stage, rs2504938 associated with survival in the validation cohort, which was more pronounced in stage IV patients. In conclusion, common variation in the SLC22A3 gene is unlikely to significantly contribute to pancreatic cancer risk. The rs2504938 SNP in SLC22A3 significantly associates with an unfavorable prognosis of pancreatic cancer patients. Further investigation of this SNP effect on the molecular and clinical phenotype is warranted

Efficacy of EGFR Inhibition Is Modulated by Model, Sex, Genetic Background and Diet: Implications for Preclinical Cancer Prevention and Therapy Trials

Molecule-targeted therapies are being widely developed and deployed, but they are frequently less effective in clinical trials than predicted based upon preclinical studies. Frequently, only a single model or genetic background is utilized using diets that are not relevant to that consumed by most cancer patients, which may contribute to the lack of predictability of many preclinical therapeutic studies. Inhibition of epidermal growth factor receptor (EGFR) in colorectal cancer was used to investigate potential causes for low predictive values of many preclinical studies. The efficacy of the small molecule EGFR inhibitor AG1478 was evaluated using two mouse models, ApcMin/+ and azoxymethane (AOM), both sexes on three genetic backgrounds, C57BL/6J (B6) and A/J (A) inbred strains and AB6F1 hybrids, and two diets, standard chow (STD) or Western-style diet (WD). AG1478 has significant anti-tumor activity in the B6-ApcMin/+ model with STD but only moderately on the WD and in the AOM model on an A background with a WD but not STD. On the F1 hybrid background AG1478 is effective in the ApcMin/+ model with either STD or WD, but has only moderate efficacy in the AOM model with either diet. Sex differences were also observed. Unexpectedly, the level of liver EGFR phosphorylation inhibition by AG1478 was not positively correlated with inhibition of tumor growth in the AOM model. Model-dependent interactions between genetic background and diet can dramatically impact preclinical results, and indicate that low predictive values of preclinical studies can be attributed to study designs that do not account for the heterogeneous patient population or the diets they consume. Better-designed preclinical studies should lead to more accurate predictions of therapeutic response in the clinic

Common germline variants within the CDKN2A/2B region affect risk of pancreatic neuroendocrine tumors

Pancreatic neuroendocrine tumors (PNETs) are heterogeneous neoplasms which represent only 2% of all pancreatic neoplasms by incidence, but 10% by prevalence. Genetic risk factors could have an important role in the disease aetiology, however only a small number of case control studies have been performed yet. To further our knowledge, we genotyped 13 SNPs belonging to the pleiotropic CDKN2A/B gene region in 320 PNET cases and 4436 controls, the largest study on the disease so far. We observed a statistically significant association between the homozygotes for the minor allele of the rs2518719 SNP and an increased risk of developing PNET (ORhom = 2.08, 95% CI 1.05-4.11, p = 0.035). This SNP is in linkage disequilibrium with another polymorphic variant associated with increased risk of several cancer types. In silico analysis suggested that the SNP could alter the sequence recognized by the Neuron-Restrictive Silencer Factor (NRSF), whose deregulation has been associated with the development of several tumors. The mechanistic link between the allele and the disease has not been completely clarified yet but the epidemiologic evidences that link the DNA region to increased cancer risk are convincing. In conclusion, our results suggest rs2518719 as a pleiotropic CDKN2A variant associated with the risk of developing PNETs

Gastrin stabilises β-catenin protein in mouse colorectal cancer cells

As gastrin may play a role in the pathophysiology of gastrointestinal (GI) malignancies, the elucidation of the mechanisms governing gastrin-induced proliferation has recently gained considerable interest. Several studies have reported that a large percentage of colorectal tumours overexpress or stabilise the β-catenin oncoprotein. We thus sought to determine whether gastrin might regulate β-catenin expression in colorectal tumour cells. Amidated gastrin-17 (G-17), one of the major circulating forms of gastrin, not only enhanced β-catenin protein expression, but also one of its target genes, cyclin D1. Furthermore, activation of β-catenin-dependent transcription by gastrin was confirmed by an increase in LEF-1 reporter activity, as well as enhanced cyclin D1 promoter activity. Finally, G-17 prolonged the τ1/2 of β-catenin protein, demonstrating that gastrin appears to exert its mitogenic effects on colorectal tumour cells, at least in part, by stabilising β-catenin

Persistent Megalocystic Ovary Following in Vitro Fertilization in a Postpartum Patient with Polycystic Ovarian Syndrome

SummaryObjectiveOvarian hyperstimulation syndrome (OHSS) is more severe when pregnancy occurs, as the developing pregnancy produces human chorionic gonadotropin, which stimulates the ovary's persistent growth. If no pregnancy occurs, the syndrome will typically resolve within 1 week. In a maintained pregnancy, slow resolution of symptoms usually occurs over 1-2 months.Case ReportA 31-year-old woman, gravida 2, para 1, aborta 1, with polycystic ovary syndrome underwent in vitro fertilization (IVF) with clomiphene citrate and follicle-stimulating hormone/gonadotropin releasing hormone-antagonist stimulation. During transvaginal oocyte retrieval, enlarged bilateral ovaries were noted. She had an episode of OHSS after IVF/embryo transfer, for which paracentesis was performed three times. Pregnancy was achieved. Throughout antenatal examinations, bilateral ovaries were enlarged. She delivered a healthy baby by cesarean section at term. However, 1 month after delivery, the bilateral ovary had not shrunk, and levels of tumor markers CA125 and CA199 were 50.84 and 41.34 U/mL, respectively. At laparotomy for suspected malignancy, both adnexae formed “kissing ovaries”, which were multinodulated with yellow serous fluid. Specimens from wedge resection submitted for frozen section showed a benign ovarian cyst. The final pathology report showed bilateral follicle cysts.ConclusionWith the increasing use of gonadotropins in the management of infertility, ovarian enlargement secondary to hyperstimulation is common. Generally, symptoms appear between the 6th and 13th weeks of pregnancy and disappear thereafter. The hyperstimulated ovary often subsides after the first trimester. This case is unusual as the megalocystic ovary persisted after delivery. To the best of our knowledge, we report the first case of enlarged bilateral ovaries persisting 2 months after delivery

Functional single nucleotide polymorphisms within the cyclin-dependent kinase inhibitor 2A/2B region affect pancreatic cancer risk

The CDKN2A (p16) gene plays a key role in pancreatic cancer etiology. It is one of the most commonly somatically mutated genes in pancreatic cancer, rare germline mutations have been found to be associated with increased risk of developing familiar pancreatic cancer and CDKN2A promoter hyper-methylation has been suggested to play a critical role both in pancreatic cancer onset and prognosis. In addition several unrelated SNPs in the 9p21.3 region, that includes the CDNK2A, CDNK2B and the CDNK2B-AS1 genes, are associated with the development of cancer in various organs. However, association between the common genetic variability in this region and pancreatic cancer risk is not clearly understood. We sought to fill this gap in a case-control study genotyping 13 single nucleotide polymorphisms (SNPs) in 2,857 pancreatic ductal adenocarcinoma (PDAC) patients and 6,111 controls in the context of the Pancreatic Disease Research (PANDoRA) consortium. We found that the A allele of the rs3217992 SNP was associated with an increased pancreatic cancer risk (ORhet=1.14, 95% CI 1.01-1.27, p=0.026, ORhom=1.30, 95% CI 1.12-1.51, p=0.00049). This pleiotropic variant is reported to be a mir-SNP that, by changing the binding site of one or more miRNAs, could influence the normal cell cycle progression and in turn increase PDAC risk. In conclusion, we observed a novel association in a pleiotropic region that has been found to be of key relevance in the susceptibility to various types of cancer and diabetes suggesting that the CDKN2A/B locus could represent a genetic link between diabetes and pancreatic cancer risk

Common genetic variants associated with pancreatic adenocarcinoma may also modify risk of pancreatic neuroendocrine neoplasms (vol 39, pg 360, 2018)

Pancreatic neuroendocrine neoplasms (pNEN) account for less than 5% of all pancreatic neoplasms and genetic association studies on susceptibility to the disease are limited. We sought to identify possible overlap of genetic susceptibility loci between pancreatic ductal adenocarcinoma (PDAC) and pNEN; therefore, PDAC susceptibility variants (n=23) from Caucasian genome-wide association studies (GWAS) were genotyped in 369 pNEN cases and 3,277 controls from the PANcreatic Disease ReseArch (PANDoRA) consortium to evaluate the odds associated with pNEN risk, disease onset and tumor characteristics. Main effect analyses showed four PDAC susceptibility variants – rs9854771, rs1561927, rs9543325 and rs10919791 to be associated with pNEN risk. Subsequently, only associations with rs9543325, rs10919791 and rs1561927 were noteworthy with false positive report probability (FPRP) tests. Stratified analyses considering age at onset (50 year threshold), showed rs2736098, rs16986825 and rs9854771 to be associated with risk of developing pNEN at a younger age. Stratified analyses also showed some SNPs to be associated with different degrees of tumor grade, metastatic potential and functionality. Our results identify known GWAS PDAC susceptibility loci, which may also be involved in sporadic pNEN etiology and suggest that some genetic mechanisms governing pathogenesis of these two entities may be similar, with few of these loci being more influential in younger cases or tumor subtypes

The role of prostaglandin E2 (PGE 2) in toll-like receptor 4 (TLR4)-mediated colitis-associated neoplasia

<p>Abstract</p> <p>Background</p> <p>We have previously found that TLR4-deficient (TLR4-/-) mice demonstrate decreased expression of mucosal PGE ₂and are protected against colitis-associated neoplasia. However, it is still unclear whether PGE ₂is the central factor downstream of TLR4 signaling that promotes intestinal tumorigenesis. To further elucidate critical downstream pathways involving TLR4-mediated intestinal tumorigenesis, we examined the effects of exogenously administered PGE ₂in TLR4-/- mice to see if PGE ₂bypasses the protection from colitis-associated tumorigenesis.</p> <p>Method</p> <p>Mouse colitis-associated neoplasia was induced by azoxymethane (AOM) injection followed by two cycles of dextran sodium sulfate (DSS) treatment. Two different doses of PGE ₂(high dose group, 200 μg, n = 8; and low dose group, 100 μg, n = 6) were administered daily during recovery period of colitis by gavage feeding. Another group was given PGE ₂during DSS treatment (200 μg, n = 5). Inflammation and dysplasia were assessed histologically. Mucosal Cox-2 and amphiregulin (AR) expression, prostanoid synthesis, and EGFR activation were analyzed.</p> <p>Results</p> <p>In control mice treated with PBS, the average number of tumors was greater in WT mice (n = 13) than in TLR4-/- mice (n = 7). High dose but not low dose PGE ₂treatment caused an increase in epithelial proliferation. 28.6% of PBS-treated TLR4-/- mice developed dysplasia (tumors/animal: 0.4 ± 0.2). By contrast, 75.0% (tumors/animal: 1.5 ± 1.2, P < 0.05) of the high dose group and 33.3% (tumors/animal: 0.3 ± 0.5) of the low dose group developed dysplasia in TLR4-/- mice. Tumor size was also increased by high dose PGE ₂treatment. Endogenous prostanoid synthesis was differentially affected by PGE ₂treatment during acute and recovery phases of colitis. Exogenous administration of PGE ₂increased colitis-associated tumorigenesis but this only occurred during the recovery phase. Lastly, PGE ₂treatment increased mucosal expression of AR and Cox-2, thus inducing EGFR activation and forming a positive feedback mechanism to amplify mucosal Cox-2.</p> <p>Conclusions</p> <p>These results highlight the importance of PGE ₂as a central downstream molecule involving TLR4-mediated intestinal tumorigenesis.</p