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Decades have passed since the underlying molecular etiologies of the most common hereditary forms of colorectal cancer (CRC), Lynch syndrome, and familial adenomatous polyposis (FAP) were first described. With the advent of next-generation sequencing (NGS) panels, the landscape of hereditary CRC testing has changed dramatically. We review available screening strategies, novel CRC predisposition genes, and challenges and opportunities in this field. Improved sensitivity and availability of NGS panel testing have greatly expanded our understanding regarding the number of CRC syndromes and their phenotypic expression. A variety of screening strategies are available to identify heritable CRC syndromes, potentially decreasing morbidity and mortality in this population. However, these screening strategies remain imperfect and present challenges regarding their implementation in clinical practice. Screening strategies include universal screening of CRC tumors for Lynch syndrome, clinical prediction algorithms, and risk assessment questionnaires. Additionally, there remains a gap in our understanding of the clinical implications of novel gene mutations of variable penetrance and unexpected NGS panel test results. Incorporation of single nucleotide polymorphisms (SNPs) may help to further refine cancer risk assessment, and the clinical introduction of RNA analysis may allow us to clarify variants of unknown significance (VUSs) and identify deep intronic mutations that would otherwise be missed. Recognition of genetic predisposition to CRC is critical for the practicing gastroenterologist. The evolving field of cancer genetics offers great challenges and opportunities for improved CRC management.

Though improved screening practices have reduced the incidence and mortality of colorectal cancer (CRC), screening rates continue to be suboptimal. This is especially true of high-risk individuals, who are difficult for clinicians to identify during a typical health care encounter. The authors developed an electronic patient questionnaire that determined an individual's CRC screening status and identified high-risk individuals. The questionnaire was administered to employees through the Department of Human Resources. The response rate was 44.7%; 81.2% of respondents aged ≥50 years were up-to-date on CRC screening; 878 high-risk individuals were identified, 77.7% of whom were up-to-date on CRC screening. However, among high-risk individuals aged 40 to 49 years, only 45.8% reported up-to-date CRC screening. The questionnaire was effective in measuring CRC screening rates and identifying high-risk individuals. Dissemination by the Department of Human Resources was novel, effective, and was not dependent on a health care encounter to assess screening or high-risk status.

Aim To evaluate the efficacy and safety of liquid nitrogen cryotherapy as a primary or rescue treatment for BE, with and without dysplasia, or intramucosal adenocarcinoma (IMC). Methods This was a retrospective, single-center study carried out in a tertiary care center including 45 patients with BE who was treatment-naive or who had persistent intestinal metaplasia (IM), dysplasia, or IMC despite prior therapy. Barrett's mucosa was resected via EMR when clinically appropriate, then patients underwent cryotherapy until eradication or until deemed to have failed treatment. Surveillance biopsies were taken at standard intervals. Results From 2010 through 2014, 33 patients were studied regarding the efficacy of cryotherapy. Overall, 29 patients (88%) responded to cryotherapy, with 84% having complete regression of all dysplasia and cancer. Complete eradication of cancer and dysplasia was seen in 75% of subjects with IMC; the remaining two subjects did not respond to cryotherapy. Following cryotherapy, 15 patients with high-grade dysplasia (HGD) had 30% complete regression, 50% IM, and 7% low-grade dysplasia (LGD); one subject had persistent HGD. Complete eradication of dysplasia occurred in all 5 patients with LGD. In 5 patients with IM, complete regression occurred in 4, and IM persisted in one. In 136 cryotherapy sessions amongst 45 patients, adverse events included chest pain (1%), stricture (4%), and one gastrointestinal bleed in a patient on dual antiplatelet therapy who had previously undergone EMR. Conclusion Cryotherapy is an efficacious and safe treatment modality for Barrett's esophagus with and without dysplasia or intramucosal adenocarcinoma.

Background & Aims Endoscopic ultrasound (EUS)−guided chemoablation with ethanol lavage followed by infusion of paclitaxel is effective for the treatment of mucinous pancreatic cysts. However, complications arise in 3%−10% of patients, presumably linked to the inflammatory effects of ethanol. We aimed to determine whether alcohol is required for effective pancreatic cyst ablation, if removing alcohol from the ablation process would improve complication rates, and whether a multi-agent chemotherapeutic cocktail could increase the rate of complete cyst resolution compared with findings reported from previous trials using alcohol followed by paclitaxel alone. Methods Between November 2011 and December 2016, we conducted a single-center, prospective, double-blind trial of 39 patients with mucinous-type pancreatic cysts. Patients were randomly assigned to 1 of 2 groups that underwent EUS-guided pancreatic cyst lavage with either 80% ethanol (control) or normal saline (alcohol-free group). Cysts in both groups were then infused with an admixture of paclitaxel and gemcitabine. Primary outcomes were the rates of complete ablation 12 months after the procedure, and rates of serious and minor adverse events within 30 days of the procedure. Results At 12 months, 67% of patients who underwent alcohol-free EUS-guided cyst chemoablation had complete ablation of cysts compared with 61% of patients in the control group. Serious adverse events occurred in 6% of patients in the control group vs none of the patients in the alcohol-free group. Minor adverse events occurred in 22% of patients in the control group and none of the patients in the alcohol-free group. The overall rate of complete ablation was 64%. Conclusions In this prospective, randomized, controlled trial, we found that alcohol is not required for effective EUS-guided pancreatic cyst ablation, and when alcohol is removed from the ablation process, there is a significant reduction in associated adverse events. A multi-agent chemotherapeutic ablation admixture did not appear to significantly improve rates of complete ablation compared with the current standard of alcohol lavage followed by paclitaxel alone. ClinicalTrials.gov ID: NCT01475331.

Background A disparity in colorectal cancer (CRC) incidence and mortality has been reported for black men and women in the United States.

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The double layer stent (DLS) has a unique design and has been used for palliation of malignant biliary obstruction, but literature on this stent is limited. Our aim was to compare plastic (PS), DLS and metal stents (MS) in terms of complication rates, time to occlusion, and patency rate in patients with malignant biliary obstruction (MBO). A retrospective review of stents placed for MBO at our institution in the period between January 2009 and April 2011 was conducted. A total of 114 stents were identified, of which 44 were MS (39 %), 37 DLS (32 %), and 33 PS (29 %). A stent was considered occluded when an unplanned stent removal or intervention occurred due to clinical suspicion of biliary obstruction. Stents remained patent for 95 days (range 7–359 days) in the DLS group and 59 days (range 7–228 days) in the PS group (P = 0.014) and 128.7 days (range 4–602 days) in the metal stent group. Twenty-seven percent (n = 9) of PS occluded after a mean of 60 days while 16 % (n = 7) of MS occluded after a mean of 87 days and 5 % (n = 2) of DLS occluded after a mean of 85 days (DLS vs. PS P = 0.012, DLS vs. MS P = 0.13, MS vs. PS P = 0.22). DLS are superior to PS in patients with MBO and appear to be comparable to MS. MS had a longer patency rate but were comparable to DLS in early and late complications. We speculate that the less expensive DLS may be a cost effective alternative in the palliation of MBO.

Background & Aims EPIC-3 is a prospective, international study that has demonstrated the efficacy of PEG-IFN alfa-2b plus weight-based ribavirin in patients with chronic hepatitis C and significant fibrosis who previously failed any interferon–alfa/ribavirin therapy. The aim of the present study was to assess FibroTest (FT), a validated non-invasive marker of fibrosis in treatment-naive patients, as a possible alternative to biopsy as the baseline predictor of subsequent early virologic (EVR) and sustained virologic response (SVR) in previously treated patients. Methods Of 2312 patients enrolled, 1459 had an available baseline FT, biopsy, and complete data. Uni- (UV) and multi-variable (MV) analyses were performed using FT and biopsy. Results Baseline characteristics were similar as in the overall population; METAVIR stage: 28% F2, 29% F3, and 43% F4, previous relapsers 29%, previous PEG-IFN regimen 41%, high baseline viral load (BVL) 64%. 506 patients (35%) had undetectable HCV-RNA at TW12 (TW12neg), with 58% achieving SVR. The accuracy of FT was similar to that in naive patients: AUROC curve for the diagnosis of F4 vs F2=0.80 ( p p p ⩽0.001) with EVR. Among patients TW12neg, two independent factors remained highly predictive of SVR by MV analysis ( p ⩽0.001): genotype 2/3 (odds ratio=2.9), fibrosis estimated with FT (4.3) or by biopsy (1.5). Conclusions FibroTest at baseline is a possible non-invasive alternative to biopsy for the prediction of EVR at 12weeks and SVR, in patients with previous failures and advanced fibrosis, retreated with PEG-IFN alfa-2b and ribavirin.

Background and study aims: Direct percutaneous endoscopic necrosectomy has been described as a minimally invasive intervention for the debridement of walled-off pancreatic necrosis (WOPN). In this retrospective cohort study, we aimed to confirm these findings in a US referral center and evaluate the clinical value of this modality in the treatment of pancreatic necrosis as well as other types of intra-abdominal fluid collections and necrosis. Patients and methods: Twelve consecutive patients with WOPN or other abdominal abscess requiring debridement and washout underwent computed tomography (CT)-guided drainage catheter placement. Each patient then underwent direct percutaneous endoscopic necrosectomy and washout with repeat debridement performed until complete. Drains were then removed once output fell below 30 mL/day and imaging confirmed resolution. The primary endpoints were time to clinical resolution and sustained resolution at 1-year follow up. Results: Ten patients were treated for WOPN, one for necrotic hepatic abscesses, and one for omental necrosis. The median time to intervention was 85 days with an average of 2.3 necrosectomies performed. Complete removal of drains was accomplished in 11 patients (92 %). The median time to resolution was 57 days. No serious adverse events occurred; however, one patient developed pancreaticocutaneous fistulas. Ten patients completed 1-year surveillance of which none required drain replacement. No patients required surgery or repeat endoscopy. Conclusions: This series supports the premise that direct percutaneous endoscopic necrosectomy is a safe and effective intervention for intra-abdominal fluid collections and necrosis in appropriately selected patients. Our study demonstrates a high clinical success rate with minimal adverse events. This modality offers several potential advantages over surgical and transgastric approaches including use of improved accessibility, an excellent safety profile, and requirement for only deep or moderate sedation.

Patients with the hamartomatous polyposis Peutz-Jeghers and familial juvenile polyposis syndromes are predisposed to colorectal cancer but lack early genetic alterations found in adenomatous premalignant lesions. We studied hamartomatous polyps for the expression of an early preneoplastic colorectal neoplasia risk marker also found in familial adenomatous polyposis patients. Retrospective, genetic, and hospital archival tissue immunohistochemistry using Adnab-9, a premalignant marker often found in Paneth-like cells (PCs), was performed on sections of polyps from eight patients with Peutz-Jeghers syndrome, eight patients with familial juvenile polyposis, and 36 hyperplastic polyp control sections. Anti-alpha-defensin 5 (AD5), a universal PC marker, was also used to label a subgroup of sections. Hamartomatous polyposis patients also underwent specific genetic analysis. Eighty-nine percent of Peutz-Jeghers syndrome polyps labeled with Adnab-9 compared with 63% for AD5; 88% of familial juvenile polyposis sections also labeled with Adnab-9. Of the 36 hyperplastic polyp sections, only four (11%) labeled with Adnab-9 and one (3%) with AD5. Adnab-9 labeling of PCs in the epithelial elements of hamartomatous colonic lesions of hereditary hamartomatous syndrome patients reflects the predisposition to colorectal cancer, further justifying early intervention strategies.

Hepatitis C virus (HCV) infection refractory to previous therapy is common. Treatment of patients with refractory disease is difficult and less studied. Pegylated interferon alpha-2b plus ribavirin is used for treatment of HCV patients naïve to therapy. We conducted a randomized study for refractory HCV patients using a high- vs. a low-dose pegylated interferon alpha-2b and ribavirin protocol. Our aim was (1) to determine the efficacy of pegylated interferon alpha-2b plus ribavirin to eradicate HCV in previously treated individuals and (2) to compare a low-dose to a high-dose regimen. One hundred fifty-two patients were initiated in the study, 112 (74%) were male and 40 (26%) female. Nineteen percent of patients obtained a sustained viral response (SVR) in the high-dose arm. Prior relapsers had the highest SVR rates: 50% in non-genotype 1 and 34% in genotype 1. The odds of achieving a SVR were six times higher in previous relapsers. The rate of SVR in genotype 1 patients who were nonresponders to prior therapy was only 8%. All patients who achieved a SVR had no detectable virus at week 24. However, only half of those who had undetectable viral titers at week 24 achieved a SVR. In conclusion, retreatment of patients with refractory hepatitis C infection with interferon alpha-2b and ribavirin combination therapy is well tolerated and gives modest response rates. The most important factor in predicting response to therapy is the manner of response to previous treatment. The likelihood of response to treatment can be predicted from the viral titers at 24 weeks.

Background and aims: Peutz-Jeghers syndrome (PJS) is a dominantly inherited disorder often caused by mutations in STK11. Time to onset of symptoms was characterised for a large collection of individuals with PJS who had been tested for STK11 mutations and genotype–phenotype correlations were evaluated. Methods: We characterised mutations in 42 independent probands and also used a historical cohort design to study 51 individuals with Peutz-Jeghers syndrome who had completed self-administered questionnaires. Results: Mutations were detected in 22/32 (69%) probands with PJS and 0/10 probands referred to rule out PJS. Real-time PCR analysis to quantitate DNA failed to detect any large deletions in PJS participants without STK11 mutations. The median time to onset for gastrointestinal symptoms or polypectomy was 13 years of age but showed a wide variability. Gastric polyps were frequent in PJS participants, with a median age at onset of 16 years. Individuals with missense mutations had a significantly later time to onset of first polypectomy (p = 0.04) and of other symptoms compared with those participants either with truncating mutations or no detectable mutation. Conclusion: STK11 mutation analysis should be restricted to individuals who meet PJS criteria or their close relatives. Direct sequencing of STK11 yields a high rate of point mutations in individuals who meet phenotypic PJS criteria. Individuals with missense mutations of STK11 typically had a later time to onset for PJS symptoms. The common occurrence of gastric polyps may facilitate chemopreventive studies for this disorder.

Germline mutations of the LKB1 gene lead to Peutz-Jeghers syndrome (PJS), which is associated with a predisposition to gastrointestinal polyposis and cancer. In this study we tested for germline mutations of LKB1 in 11 patients with PJS from nine families and analyzed the expression patterns of the LKB1 and cyclo-oxygenase-2 (COX-2) proteins in 28 Peutz-Jeghers polyps (PJPs) and five carcinomas from these patients by immunohistochemical (IHC) analysis. In eight of those families we identified seven different mutations, which consisted of two splice site mutations, two nonsense mutations, one small in-frame deletion, one frame-shift mutation, and one silent mutation. Immunostaining revealed nuclear and cytoplasmic expression of LKB1 protein in 23 PJPs and five carcinomas, nuclear expression alone in one PJP, and loss of LKB1 protein expression in four PJPs, indicating a heterogeneous LKB1 expression pattern in PJPs. Overexpression of COX-2 was detected in 23 (82%) of 28 PJPs and in all carcinomas. Despite heterogeneity in staining of LKB1 among individuals and even among samples from the same individual, we found statistically significant correlations in staining of LKB1 relative to COX-2. These results suggest that COX-2 plays a role in tumorigenesis in PJS and may therefore be considered as a potential target for PJS chemoprevention.

OBJECTIVE: Peutz-Jeghers syndrome (PJS) is an autosomal-dominant hamartomatous polyposis syndrome. Affected individuals are at risk for intestinal and extraintestinal malignancies. Prostaglandins and polyamines are small molecules believed to be important in tumor formation and growth. Cyclooxygenase (COX) and ornithine decarboxylase (ODC) are key enzymes in the prostaglandin and polyamine biosynthetic pathways, respectively. The aim of this study was to measure and compare COX-1 and COX-2 expression in normal and hamartomatous tissue of PJS patients. METHODS: We measured COX-1 and COX-2 protein expression in normal and hamartomatous GI tissues from affected PJS individuals and compared it with that in normal controls. COX-2 RNA in these tissues was also measured and compared by reverse transcription polymerase chain reaction (PCR). In addition, COX-2 expression was detected in tissue slides by immunostaining. ODC activity was measured between normal and hamartomatous tissues of PJS compared with control tissues. RESULTS: COX-1 expression was similar in normal and control GI tissues. In contrast, COX-2 overexpression was noted in hamartomatous polyp tissue from PJS patients compared with normal control and PJS tissue. COX-2 expression by reverse transcription PCR was 10-fold greater in a hamartoma compared with other tissues. COX-2 expression was noted in the epithelial cells of hamartomatous polyps, and also coursing throughout the stromal tissue of the lamina propria, including muscle cells. ODC activity was similar in the tissues studied. CONCLUSIONS: Selective COX-2 overexpression was noted in hamartomatous polyp tissue from PJS individuals. The results of the study provide an avenue for possible effective chemoprevention of polyp formation and growth in PJS.

The prevalence of polyps and cancer in the proximal colon among patients who have polyps detected on sigmoidoscopy was determined in a large rural referral hospital in north central Pennsylvania. Eleven thousand one hundred sixty patients underwent sigmoidoscopy between 1991 and 1997. Polyps were detected in 709 patients. Five hundred twenty-three patients who had a polyp at sigmoidoscopy and full colonoscopy completed within one year were included in this study. 120 patients (23%) had a proximal polyp detected at colonoscopy. The prevalence of proximal polyps and histologically advanced polyps was related to the size, number, and histology of the distal index polyp found at sigmoidoscopy. However, the absolute difference in prevalence of proximal polyps stratified by dings at sigmoidoscopy was small. A total of 5 adenocarcinomas were detected in the proximal colon. All proximal cancers detected at colonoscopy occurred in patients with a distal polyp less than 10 mm. Our data emphasize the importance of colonoscopy in all patients with a polyp detected at sigmoidoscopy independent of its size and histology.

Background Hepatocellular carcinoma is the most common primary liver malignancy, commonly a sequelae of hepatitis C infection, but can complicate cirrhosis of any cause. Whether metabolic syndrome and its components, type II diabetes, hypertension, and hyperlipidemia increase the risk of hepatocellular carcinoma independent of cirrhosis is unknown. Methods A retrospective cohort study was conducted using the MarketScan insurance claims database from 2008-2012. Individuals with hepatocellular carcinoma aged 19-64 years and age and sex-matched controls were included. Multivariate analysis of hepatocellular carcinoma risk factors was performed. Results Hepatitis C (odds ratio [OR] 2.102) was the largest risk factor for hepatocellular carcinoma. Other independent risk factors were type II diabetes (OR 1.353) and hypertension (OR 1.229). Hyperlipidemia was protective against hepatocellular carcinoma (OR 0.885). The largest risk increase occurred with hypertension with type II diabetes and hepatitis C (OR 4.580), although hypertension and type II diabetes without hepatitis C still incurred additional risk (OR 3.399). Type II diabetes and hyperlipidemia had a similar risk if hepatitis C was present (OR 2.319) or not (OR 2.395). Metformin (OR 0.706) and cholesterol medications (OR 0.645) were protective in diabetics. Insulin (OR 1.640) increased the risk of hepatocellular carcinoma compared with the general type II diabetes population. Conclusion In the absence of cirrhosis, type II diabetes and hypertension were independent risk factors for hepatocellular carcinoma. Hyperlipidemia and medical management of type II diabetes with metformin and cholesterol medication appeared to reduce the incidence of hepatocellular carcinoma. In contrast, insulin was associated with a higher risk of hepatocellular carcinoma.

Tumor cell death in vitro by photodynamic therapy (PDT) has been related to the induction of apoptosis. We measured and compared changes in apoptosis and caspase 3 activity, an effector of apoptosis, in normal and neoplastic esophageal tissues during PDT. Apoptosis index, caspase 3 cleavage activity, pro-caspase 3, p53, and bcl-2 levels were measured in normal and neoplastic tissues of patients with esophageal adenocarcinoma before, during, and after PDT with Photofrin. The apoptotic index was greater in carcinoma tissue compared to adjacent normal tissues. In concert, pro-caspase 3 immunoreactivity was absent and caspase 3-like cleavage activity was over 30-fold greater in carcinoma tissue compared to normal esophageal tissues. These parameters were unaffected by PDT. Variable changes in bcl-2 and p53 immunoreactivity were noted in normal and carcinoma tissues during PDT. Greater levels of apoptosis and caspase 3 activity are hallmarks of esophageal adenocarcinoma compared to normal esophageal tissue. These differences were unaffected by PDT. This may be due to the fact that tissues were obtained 72 h post-PDT therapy. Changes in these parameters may have occurred early after PDT therapy. An assessment of apoptosis and caspase 3 activity prior to 72 h post-PDT may provide further insight into the mechanism involved, although no sustained effects on these parameters by PDT were noted.

OBJECTIVE: We determined the outcome of patients with chronic abdominal pain of unknown etiology referred by gastroenterologists to a chronic pain clinic. METHODS: A retrospective chart review of 43 consecutive patients seen by a university-based gastroenterology group was referred to our Chronic Pain Clinic for evaluation and treatment. Pain character and location, the referring diagnosis, and initial Chronic Pain Clinic diagnosis was compared between responders and nonresponders. Early and long-term pain relief was scored by standard questionnaire. RESULTS: Of the 43 patients with chronic abdominal pain of undetermined etiology, 70% reported complete or substantial pain relief by the end of chronic pain management. Pain character and location and the referring diagnosis were not predictors of pain relief. Long-term pain relief was reported by 35% of patients. CONCLUSION: A substantial group of patients with chronic abdominal pain of unknown etiology benefited from Chronic Pain Clinic services.

Herpes simplex-induced fulminant hepatitis is an infrequently reported cause of hepatitis in adults. Pregnant females and patients with impaired cellular immunity may be at increased risk, although healthy adults have been affected. The diagnosis may be underrecognized due to nonspecific presenting symptoms and lack of typical cutaneous herpes lesions. We present three cases of fatal herpes simplex fulminant hepatitis. Our review of case reports of herpes simplex hepatitis in adults demonstrates improved survival with intravenous acyclovir therapy. We believe that empiric use of acyclovir should be considered while the diagnostic evaluation of non-acetaminophen-induced fulminant hepatitis is underway. Recognition of characteristic liver function abnormalities seen with fulminant herpes simplex hepatitis include marked elevation of transaminases with AST > ALT and a mild hyperbilirubinemia (anicteric hepatitis), and they should prompt acyclovir therapy. This is especially true when there are no obvious risk factors for other forms of hepatitis.

Peutz-Jeghers syndrome is characterized bygastrointestinal hamartomatous polyposis, mucocutaneouspigmentation, and a predisposition to cancer. Theetiology of this syndrome is unknown. We investigated the expression of epidermal growth factorreceptor (EGFr), transforming growth factor-α(TGF-α), transforming growthfactor-β1 (TGF-β1) andtransforming growth factor-β receptor (TGF-β RII) between normal and Peutz-Jeghers smallbowel tissues. In addition, immunoprecipitation byphosphotyrosine antibodies followed by EGFr westernblotting was measured and compared between aPeutz-Jeghers hamartoma and normal duodenal tissue. EGFrexpression was increased 2.5-fold in normal andhamartomatous tissue of Peutz-Jeghers patients comparedto normal small bowel tissue. In Peutz-Jeghers tissues, the major EGFr immunoreactive band wasincreased size from 170 to approximately 200 kDa. Usingan antibody specific for activated EGFr, this largersize band was predominant in Peutz-Jeghers tissue.Immunoprecipitation of a hamartoma by a phosphotyrosine specificantibody followed by western blotting for EGFrdemonstrated this 200-kDa band. Expression ofTGF-α, TGF-β1, TGF-β RII wasnot significantly different between normal and Peutz-Jeghers tissues. Inconclusion, EGFr was overexpressed in normal andhamartomatous small bowel tissue of Peutz-Jegherspatients, which suggests that EGFr in Peutz-Jegherstissue is persistently activated or highly stimulatedby endogenous ligands and also suggests a possible rolefor EGFr in the pathogenesis of Peutz-Jeghers syndrome.

There is limited information about colorectal cancer (CRC) screening trends in high-risk groups, including the black, obese, diabetic, and smoking populations. For this study, the authors evaluated national CRC screening trends in these high-risk groups to provide insights into whether screening resources are being appropriately used.This was a nationally representative, population-based study using the Behavioral Risk Factor Surveillance System from the Centers for Disease Control. Data analysis was performed using bivariate analyses with weighted logistic regression.In the general population, CRC screening increased significantly from 59% to 65% during the years 2006 to 2010. The screening prevalence in non-Hispanic blacks was 58% in 2006 and 65% in 2010. Among obese individuals, the prevalence of up-to-date CRC screening increased significantly from 59% in 2006 to 66% in 2010. Screening prevalence in individuals with diabetes was 63% in 2006 and 69% in 2010. The CRC screening prevalence in current smokers was 45% in 2006 and 50% in 2010. The odds of CRC screening in the non-Hispanic black population, the obese population, and the diabetic population were higher than in non-Hispanic whites, normal weight individuals, and the population without diabetes, respectively. Current smokers had significantly lower odds of CRC screening than never-smokers in the years studied (2006: odds ratio [OR], 0.71; 95% confidence interval [CI], 0.66-0.76; 2008: OR, 0.67; 95% CI, 0.63-0.71; 2010: OR, 0.69; 95% CI, 0.66-0.73).The prevalence of CRC screening in high-risk groups is trending upward. Despite this, current smokers have significantly lower odds of CRC screening compared with the general population.

The secondary bile acid deoxycholic acid isbelieved to be a promoter of large bowel cancer, in partby inducing colonic epithelial proliferation. Theeffects of deoxycholic acid on [3H]thymidineincorporation by the human colon cancer cell line HT29 andtwo differentiated subclones were measured and compared.The subclone HT29-C1 has features of mature absorptivecells and HT29-N2 cells secrete mucus under cholinergic control. The three cell lines were treated withdeoxycholic acid (DCA) at concentrations of 0, 5, 10,50, 100, 150, and 300 μM for 3, 6, 9, 15, 24, and 48hr. A significant increase in proliferation was noted in HT29 cells only at 6 hr with 5 and 10muM deoxycholic acid. Neither the subclone HT29-C1, norHT29-N2 cells exhibited significant change in[3H]thymidine incorporation with DCA at theseconcentrations or time points. Higher doses of deoxycholicacid above 50 μM and duration of exposure greaterthan 24 hr were cytotoxic to all three cell lines. Theproliferative effects of DCA in HT29 cells were not paralleled by changes in protein kinase Cactivity or protein kinase C isoform expression.Quantitative and qualitative differences in PKC isoformexpression were not noted in the three cell lines used in this study. The proliferative effects of DCAon HT29 cells appear to be independent of the PKC signaltransduction pathway.

BACKGROUND: Peutz-Jeghers syndrome (PJS) is characterized by intestinal polyposis, mucocutaneous pigmentation and an increased cancer risk, usually caused by mutations of the STK11 gene. This study collected epidemiological, clinical and genetic data from all Uruguayan PJS patients. METHODS: Clinical data were obtained from public and private medical centers and updated annually. Sequencing of the STK11 gene in one member of each family was performed. RESULTS AND DISCUSSION: 25 cases in 11 unrelated families were registered (15 males, 10 females). The average age of diagnosis and death was 18 and 41 years respectively. All patients had characteristic PJS pigmentation and gastrointestinal polyps. 72% required urgent surgery due to intestinal obstruction. 3 families had multiple cases of seizure disorder, representing 20% of cases. 28% developed cancer and two patients had more than one cancer. An STK11 mutation was found in 8 of the 9 families analyzed. A unique M136K missense mutation was noted in one family. Comparing annual live births and PJS birth records from 1970 to 2009 yielded an incidence of 1 in 155,000. CONCLUSION: The Uruguayan Registry for Peutz-Jeghers patients showed a high chance of emergent surgery, epilepsy, cancer and shortened life expectancy. The M136K missense mutation is a newly reported STK 11 mutation.

Endogenous opioid peptides serve as growth factors in normal and neoplastic cells and tissues, and both opioids and their receptors have been identified in human colon cancer. This study examined the hypothesis that opioids serve to modulate the growth of human colon cancer. Daily administration of the native opioid growth factor (OGF), [Met5]enkephalin, at dosages of 0.5, 5, or 25 mg/kg prevented the occurrence of human colon cancer HT-29 xenografts in nude mice. More than 80% of the mice receiving OGF beginning at the time of tumor cell inoculation did not exhibit neoplasias within 3 wk, in comparison with a tumor incidence of 93% in control subjects. Even 7 wk after cancer cell inoculation, 57% of the mice given OGF did not display a tumor. OGF delayed tumor appearance and growth in animals developing colon cancer with respect to the control group. The suppressive effects of OGF on oncogenicity were opioid receptor mediated. OGF and its receptor, zeta (zeta), were detected in transplanted human HT-29 colon tumors. Surgical specimens of human colon cancers also contained OGF. These results show that a naturally occurring opioid peptide acts as a potent negative regulator of human gastrointestinal cancer and may suggest pathways for tumor etiology, progression, treatment, and prophylaxis.

BACKGROUND: While it is clear that luminal epidermal growth factor (EGF) stimulates repair of the damaged bowel, its significance in maintaining normal gut growth remains uncertain. If EGF is important in maintaining normal gut growth, the EGF receptor (EGF-R) should be present on the apical (luminal) surface in addition to the basolateral surface. AIMS/SUBJECTS/METHODS: This study examined the distribution of the EGF-R in the epithelium throughout the human gastro-intestinal tract using immunohistochemistry, electron microscopy, and western blotting of brush border preparations. RESULTS: Immunostaining of the oesophagus showed circumferential EGF-R positivity in the cells of the basal portions of the stratified squamous epithelium but surface cells were EGF-R negative. In the normal stomach, small intestine, and colon, immunostaining localised the receptor to the basolateral surface with the apical membranes being consistently negative. EGF-R positivity within the small intestine appeared to be almost entirely restricted to the proliferative (crypt) region. Western blotting demonstrated a 170 kDa protein in whole tissue homogenates but not in the brush border vesicle preparations. CONCLUSIONS: As the EGF-R is located only on the basolateral surfaces in the normal adult gastrointestinal tract, the major role of luminal EGF is probably to stimulate repair rather than to maintain normal gut growth.

The incidence of esophageal adenocarcinoma (EAC) has increased exponentially in the last 3 decades. Barrett’s esophagus (BE) is the only known precursor of EAC. Patients with BE have a greater than 40 folds higher risk of EAC compared with the general population. Recent years have witnessed a revolution in the clinical and molecular research related to BE. However, several aspects of this condition remain controversial. Data regarding the true prevalence of BE have varied widely. Recent studies have suggested a lower incidence of EAC in nondysplastic BE (NDBE) than previously reported. There is paucity of prospective data showing a survival benefit of screening or surveillance for BE. Furthermore, the ever-increasing emphasis on healthcare cost containment has called for reexamination of the screening and surveillance strategies for BE. There is a need for identification of reliable clinical predictors or molecular biomarkers to risk-stratify patients who might benefit the most from screening or surveillance for BE. Finally, new therapies have emerged for the management of dysplastic BE. In this paper, we highlight the key areas of controversy and uncertainty surrounding BE. The paper discusses, in detail, the current literature about the molecular pathogenesis, biomarkers, histopathological diagnosis, and management strategies for BE.

Purpose. We evaluated a questionnaire to aid in the recognition of CRC risk, as well as patient interest in their risk status within an open-access endoscopy center. Methods. A questionnaire was administered to new patients presenting for colonoscopy from May 2007 to February 2008. 287 patients were enrolled. Family history was evaluated using Amsterdam 1, II, and Revised Bethesda criteria. Recognition of risk and referral for counseling was assessed. Patients' interest to be contacted by a genetic counselor was also assessed. Results. 13.2 % (38/287) of patients met Revised Bethesda criteria. Of these, 18 (47.4 %) were previously told about their increased risk for CRC. Only 1 patient who met Revised Bethesda criteria (2.6 %) was previously referred for genetics, whereas none of the 3 patients who met Amsterdam I or II criteria were referred. 23.7 % of high-risk patients did not want to be contacted if found to be at increased risk for cancer. Conclusion. In our open-access endoscopy system, a significant number of high-risk patients remain unidentified and underreferred for genetic counseling due to numerous barriers. Our findings lend support to taking a public health approach to identifying those at risk for Lynch syndrome by implementing universal screening of all CRC specimens.

Watermelon stomach is an unusual cause of gastrointestinal bleeding and iron deficiency anemia. Its etiology is unknown, but it has been reported to be associated with a variety of diseases, including autoimmune disorders and cirrhosis. We report on the long-term outcome of 15 patients (13 women, 2 men) treated with neodymium-yttrium-aluminum-garnet (Nd:YAG) laser therapy. The mean age of patients at presentation was 71.6 years (range, 59 to 85 years). Fourteen patients were transfusion-dependent, requiring an average of 9.6 units of blood in the 12 months preceding diagnosis and treatment. Associated diseases included scleroderma (3 patients), mixed connective tissue disease (1 patient), history of cancer (3 patients), cryptogenic cirrhosis (3 patients), and chronic renal failure (3 patients). In 7 of 9 patients who had an antinuclear antibody test, an elevated titer greater than 1:160 in a speckled pattern was noted. Nd:YAG laser coagulation therapy was administered to all patients without complications and was successful in reducing bleeding in every case. Five patients died during the course of follow-up without signs of recurrent gastrointestinal bleeding. The remaining 10 patients have had both endoscopic and hematologic improvement during a mean follow-up period of 4.4 years from the time of initial diagnosis (range, 2 to 8 years). The 10 survivors are no longer transfusion-dependent and have stable hematocrits.

Protein kinase C (PKC) is a mediator of transmembrane signal transduction, important in cell growth and differentiation. Cell activation by extracellular signals is associated with a translocation of PKC from the cytosol to the membrane. We measured and compared PKC activity in cytosol and membrane fractions of normal and neoplastic colorectal tissue. Total and membrane-associated PKC activity in normal colorectal tissue was greater in patients (N = 16) with colorectal cancer compared to that from patients with a normal colonoscopy (N = 16), P0.01. A similar trend was noted in PKC activity of normal colorectal tissue from patients with adenomas compared to patients with a normal colonoscopy. PKC activity (total, membrane-associated, percent membrane) was not different in neoplastic colorectal tissue compared to that of adjacent normal tissue. However, there was a considerable range of PKC activity noted in all groups, which would limit the utility of PKC activity as a marker for colorectal neoplasia.

Background In 1996, the National Cancer Institute hosted an international workshop to develop criteria to identify patients with colorectal cancer who should be offered microsatellite instability (MSI) testing due to an increased risk for Hereditary Nonpolyposis Colorectal Cancer (HNPCC). These criteria were further modified in 2004 and became known as the revised Bethesda Guidelines. Our study aimed to retrospectively evaluate the percentage of patients diagnosed with HNPCC tumors in 2004 who met revised Bethesda criteria for MSI testing, who were referred for genetic counseling within our institution. Methods All HNPCC tumors diagnosed in 2004 were identified by accessing CoPath, an internal database. Both the Tumor Registry and patients' electronic medical records were accessed to collect all relevant family history information. The list of patients who met at least one of the revised Bethesda criteria, who were candidates for MSI testing, was then cross-referenced with the database of patients referred for genetic counseling within our institution. Results A total of 380 HNPCC-associated tumors were diagnosed at our institution during 2004 of which 41 (10.7%) met at least one of the revised Bethesda criteria. Eight (19.5%) of these patients were referred for cancer genetic counseling of which 2 (25%) were seen by a genetics professional. Ultimately, only 4.9% of patients eligible for MSI testing in 2004 were seen for genetic counseling. Conclusion This retrospective study identified a number of barriers, both internal and external, which hindered the identification of individuals with HNPCC, thus limiting the ability to appropriately manage these high risk families.

A variety of syndromes confer increased risk for intestinal polyp development, outside the more commonly occurring syndromes. Each of these uncommon syndromes predispose to pathognomonic histologies that are uncommonly observed. Accurate diagnosis of these syndromes is contingent on higher-level pathology review, evaluation of signs and symptoms beyond sole consideration of the polyps, and collection of a detailed family history. When a genetic mutation can be identified in the proband, the management of intestinal and extra-intestinal cancer screening can be more appropriately tailored.

The effects of unsaturated fat and fiber (cellulose) on the growth of human colon cancer explanted to athymic nude mice was evaluated. Eighty-seven male nude mice bearing xenografts of human HT29 or WiDr colon cancer were divided into three groups of equal weight and tumor volume. Each group was fed one of three diets: normal fat/no fiber (N/N), high fat/no fiber (H/N) or high fat/high fiber (H/H). To equalize caloric intake, animals in the H/N group received 4 g of food per day and the other animals were fed 5 g of food per day. At sacrifice tumor volume and weight was recorded, and tumors were analyzed for protein and DNA content and ornithine decarboxylase activity. Tumor volume, weight, and protein were greater in the H/N group compared to the N/N group for both colon cancer cell lines. Tumor DNA content was greater in the HT29 H/N group compared to the N/N group (P less than 0.05) and tumor ornithine decarboxylase activity in the WiDr H/N group was greater than the N/N animals (P less than 0.002). The tumor growth-promoting effects of the high unsaturated fat diet were attenuated by the addition of fiber. Animal weight was higher in the H/N group compared to the N/N and H/H groups. This study suggested that a high-fat diet stimulated and fiber decreased the growth of human colon cancer explanted to athymic nude mice. The growth-promoting effects of a high-fat diet in colorectal cancer may be due in part to a circulating trophic factor since these tumors were remote from the large intestine.

Peutz-Jeghers Syndrome (PJS) is an autosomal dominant inherited cancer predisposition syndrome and gastrointestinal hamartomatous polyposis syndrome characterized by the presence of distinct perioral freckling. To date, we have not found any tool that specifically assesses the psychosocial impact of PJS on patients. We developed a PJS quality of life questionnaire using expert opinions of 3 cancer genetic counselors and a survey of patients with PJS through recruitment of participants involved in a support group over the internet. We measured and compared our questionnaire results to the widely used Center for Epidemiologic Studies and Depression Scale (CES-D) and the Short Form 36 (SF-36). We recruited 38 patients for our study. Volunteers were mailed a consent form, the self-administered CES-D, SF-36 and our developed PJS questionnaire and were instructed to return the completed questionnaires by mail. Results showed that PJS patients suffer from mild depression even though physically they did not feel impacted by their condition compared to the general population. However, having PJS caused them to alter many important life decisions. The PJS Questionnaire correlated with data obtained from analysis of CES-D, as well as the SF-36. More uniquely, it provided specific information regarding the burden of disease and quality of life in patients affected with Peutz-Jeghers syndrome. Its ability to do so for other polyposis syndrome populations remains to be studied. These results are important in developing plan of care for these patients regarding genetic counseling and surveillance strategies for PJS patients.

Polyamine content (putrescine, spermidine, and spermine) or ornithine decarboxylase (ODC) activity was measured in normal-appearing colonic mucosa from patients undergoing colonoscopy. Comparisons were made between those with and those without adenomatous polyps. Colonic mucosal polyamine content was measured in 44 persons. Mean putrescine content was 1.25 +/- 0.26 (SE) nmol/mg protein in 22 patients with adenomatous polyps compared with 0.53 +/- 0.12 nmol/mg protein in patients without polyps (P less than 0.02). Tissue content of spermidine and spermine did not differ between these two groups. Ornithine decarboxylase activity was measured in tissue from 45 patients. Mean ODC activity was 2.84 +/- 0.73 pmol/hr/mg protein in 23 persons with adenomatous polyps compared with 1.15 +/- 0.18 pmol/hr/mg protein in persons without polyps (P less than 0.05). Mucosal putrescine and ODC activity are elevated in patients with adenomatous polyps compared with patients without polyps. These biochemical markers may prove helpful in improving surveillance methods for colorectal cancer and premalignant adenomatous polyps.