Background

Screening individuals at increased risk for pancreatic cancer (PC) detects early, potentially curable, pancreatic neoplasia.

Objective

To develop consortium statements on screening, surveillance and management of high-risk individuals with an inherited predisposition to PC.

Methods

A 49-expert multidisciplinary international consortium met to discuss pancreatic screening and vote on statements. Consensus was considered reached if ≥75% agreed or disagreed.

Results

There was excellent agreement that, to be successful, a screening programme should detect and treat T1N0M0 margin-negative PC and high-grade dysplastic precursor lesions (pancreatic intraepithelial neoplasia and intraductal papillary mucinous neoplasm). It was agreed that the following were candidates for screening: first-degree relatives (FDRs) of patients with PC from a familial PC kindred with at least two affected FDRs; patients with Peutz–Jeghers syndrome; and p16, BRCA2 and hereditary non-polyposis colorectal cancer (HNPCC) mutation carriers with ≥1 affected FDR. Consensus was not reached for the age to initiate screening or stop surveillance. It was agreed that initial screening should include endoscopic ultrasonography (EUS) and/or MRI/magnetic resonance cholangiopancreatography not CT or endoscopic retrograde cholangiopancreatography. There was no consensus on the need for EUS fine-needle aspiration to evaluate cysts. There was disagreement on optimal screening modalities and intervals for follow-up imaging. When surgery is recommended it should be performed at a high-volume centre. There was great disagreement as to which screening abnormalities were of sufficient concern to for surgery to be recommended.

Conclusions

Screening is recommended for high-risk individuals, but more evidence is needed, particularly for how to manage patients with detected lesions. Screening and subsequent management should take place at high-volume centres with multidisciplinary teams, preferably within research protocols.

BACKGROUND

Genetic influences may be discerned in families that have multiple affected members and may manifest as an earlier age of cancer diagnosis. In this study we determine whether cancers develop at an earlier age in multiplex Familial Barrett’s Esophagus (FBE) kindreds, defined by 3 or more members affected by Barrett’s esophagus (BE) or esophageal adenocarcinoma (EAC).

METHODS

Information on BE/EAC risk factors and family history was collected from probands at eight tertiary care academic hospitals. Age of cancer diagnosis and other risk factors were compared between non-familial (no affected relatives), duplex (two affected relatives), and multiplex (three or more affected relatives) FBE kindreds.

RESULTS

The study included 830 non-familial, 274 duplex and 41 multiplex FBE kindreds with 274, 133 and 43 EAC and 566, 288 and 103 BE cases, respectively. Multivariable mixed models adjusting for familial correlations showed that multiplex kindreds were associated with a younger age of cancer diagnosis (p = 0.0186). Median age of cancer diagnosis was significantly younger in multiplex compared to duplex and non-familial kindreds (57 vs. 62 vs. 63 yrs, respectively, p = 0.0448). Mean body mass index (BMI) was significantly lower in multiplex kindreds (p = 0.0033) as was smoking (p < 0.0001), and reported regurgitation (p = 0.0014).

CONCLUSIONS

Members of multiplex FBE kindreds develop EAC at an earlier age compared to non-familial EAC cases. Multiplex kindreds do not have a higher proportion of common risk factors for EAC, suggesting that this aggregation might be related to a genetic factor.

IMPACT

These findings indicate that efforts to identify susceptibility genes for BE and EAC will need to focus on multiplex kindreds.

There is a critical need to identify molecular markers that can reliably aid in stratifying esophageal adenocarcinoma (EAC) risk in patients with Barrett's esophagus. MicroRNAs (miRNA/miR) are one such class of biomolecules. In the present cross-sectional study, we characterized miRNA alterations in progressive stages of neoplastic development, i.e., metaplasia–dysplasia–adenocarcinoma, with an aim to identify candidate miRNAs potentially associated with progression. Using next generation sequencing (NGS) as an agnostic discovery platform, followed by quantitative real-time PCR (qPCR) validation in a total of 20 EACs, we identified 26 miRNAs that are highly and frequently deregulated in EACs (≥4-fold in >50% of cases) when compared to paired normal esophageal squamous (nSQ) tissue. We then assessed the 26 EAC-derived miRNAs in laser microdissected biopsy pairs of Barrett's metaplasia (BM)/nSQ (n = 15), and high-grade dysplasia (HGD)/nSQ (n = 14) by qPCR, to map the timing of deregulation during progression from BM to HGD and to EAC. We found that 23 of the 26 candidate miRNAs were deregulated at the earliest step, BM, and therefore noninformative as molecular markers of progression. Two miRNAs, miR-31 and –31*, however, showed frequent downregulation only in HGD and EAC cases suggesting association with transition from BM to HGD. A third miRNA, miR-375, showed marked downregulation exclusively in EACs and in none of the BM or HGD lesions, suggesting its association with progression to invasive carcinoma. Taken together, we propose miR-31 and –375 as novel candidate microRNAs specifically associated with early- and late-stage malignant progression, respectively, in Barrett's esophagus.

Barrett's esophagus (BE) is a metaplastic process whereby the normal stratified, squamous esophageal epithelium is replaced by specialized intestinal epithelium. Barrett's is the only accepted precursor lesion for esophageal adenocarcinoma (EAC), a solid tumor that is rapidly increasing in incidence in western countries. BE evolves into EAC through intermediate steps that involve increasing degrees of dysplasia. Current histologic criteria are quite subjective and the clinical behavior of BE is highly variable and difficult to predict using these standards. It is widely believed that molecular alterations present in BE and EAC will provide more precise prognostic and predictive markers for these conditions than the current clinical and histologic features in use. In order to further define molecular alterations that can classify unique groups of BE and EAC, we utilized methylation microarrays to compare the global gene methylation status of a collection of normal squamous, BE, BE + high-grade dysplasia (HGD), and EAC cases. We found distinct global methylation signatures, as well as differential methylation of specific genes, that discriminated these histological groups. We also noted high and low methylation epigenotypes among the BE and EAC cases. Additional validation of those CpG sites that distinguished BE from BE + HGD and EAC may lead to the discovery of useful biomarkers with potential clinical applications in the diagnosis and prognosis of BE and EAC.

Aim

Aim of this study is to determine the prevalence of Barrett's Esophagus (BE) in first degree relatives of patients with esophageal adenocarcinoma (EAC) and Barrett's' high grade dysplasia (HGD).

Methods

After Institutional Review board approval first degree relatives of patients with EAC/HGD underwent unsedated ultrathin trans-nasal endoscopy (UUTNE) with biopsy. BE was suspected if any salmon colored epithelial tongues were seen above the gastro-esophageal junction. A diagnosis of BE was made only if biopsy from these areas confirmed columnar lined epithelium with intestinal metaplasia.

Results

From 23 families 47 first degree relative underwent UUTNE and one patient underwent routine upper endoscopy with sedation as part of this study. The mean age of cases was 44.4 yrs. All patients tolerated the procedure well and there were no procedure related complications. BE was suspected in 16 (34%) patients and confirmed in 13/16 (27.7%) patients. There was 4 long segment (> 3cm) and 9 short segment (<3 cm) of BE.

Conclusion

There is a significantly higher than expected prevalence of BE in first degree relatives of EAC/HGD patients. This should be taken in to consideration to develop further screening guidelines. Further work is need to confirm these findings. Un-sedated trans-nasal endoscopy is a safe and well-tolerated method for BE screening.

Background

Preliminary research suggests that rectally administered nonsteroidal antiinflammatory drugs may reduce the incidence of pancreatitis after endoscopic retrograde cholangiopancreatography (ERCP).

Methods

In this multicenter, randomized, placebo-controlled, double-blind clinical trial, we assigned patients at elevated risk for post-ERCP pancreatitis to receive a single dose of rectal indomethacin or placebo immediately after ERCP. Patients were determined to be at high risk on the basis of validated patient- and procedure-related risk factors. The primary outcome was post-ERCP pancreatitis, which was defined as new upper abdominal pain, an elevation in pancreatic enzymes to at least three times the upper limit of the normal range 24 hours after the procedure, and hospitalization for at least 2 nights.

Results

A total of 602 patients were enrolled and completed follow-up. The majority of patients (82%) had a clinical suspicion of sphincter of Oddi dysfunction. Post-ERCP pancreatitis developed in 27 of 295 patients (9.2%) in the indomethacin group and in 52 of 307 patients (16.9%) in the placebo group (P = 0.005). Moderate-to-severe pancreatitis developed in 13 patients (4.4%) in the indomethacin group and in 27 patients (8.8%) in the placebo group (P = 0.03).

Conclusions

Among patients at high risk for post-ERCP pancreatitis, rectal indomethacin significantly reduced the incidence of the condition. (Funded by the National Institutes of Health; ClinicalTrials.gov number, NCT00820612.)

3-D optical coherence tomography (OCT) has been extensively investigated as a potential screening and/or surveillance tool for Barrett’s esophagus (BE). Understanding and correcting motion artifact may improve image interpretation. In this work, the motion trace was analyzed to show the physiological origin (respiration and heart beat) of the artifacts. Results showed that increasing balloon pressure did not sufficiently suppress the physiological motion artifact. An automated registration algorithm was designed to correct such artifacts. The performance of the algorithm was evaluated in images of normal porcine esophagus and demonstrated in images of BE in human patients.

Background & Aims

Radiofrequency ablation (RFA) can eradicate dysplasia and intestinal metaplasia in patients with dysplastic Barrett’s esophagus (BE), and reduce rates of esophageal adenocarcinoma. We assessed long-term rates of eradication, durability of neosquamous epithelium, disease progression, and safety of RFA in patients with dysplastic BE.

Methods

We performed a randomized trial of 127 subjects with dysplastic BE; after cross-over subjects were included 119 received RFA. Subjects were followed for a mean time of 3.05 years; the study was extended to 5 years for patients with eradication of intestinal metaplasia at 2 years. Outcomes included eradication of dysplasia or intestinal metaplasia after 2 and 3 years, durability of response, disease progression, and adverse events.

Results

After 2 years, 101/106 patients had complete eradication of all dysplasia (95%) and 99/106 had eradication of intestinal metaplasia (93%). After 2 years, among subjects with initial low-grade dysplasia, all dysplasia was eradicated in 51/52 (98%) and intestinal metaplasia was eradicated in 51/52 (98%); among subjects with initial high-grade dysplasia, all dysplasia was eradicated in 50/54 (93%) and intestinal metaplasia was eradicated in 48/54 (89%). After 3 years, dysplasia was eradicated in 55/56 of subjects (98%) and intestinal metaplasia was eradicated in 51/56 (91%). Kaplan-Meier analysis showed that dysplasia remained eradicated in >85% of patients and intestinal metaplasia in >75%, without maintenance RFA. Serious adverse events occurred in 4/119 subjects (3.4%); the rate of stricture was 7.6%. The rate of esophageal adenocarcinoma was 1/181 pt-yrs (0.55%/pt-yr); there was no cancer-related morbidity or mortality. The annual rate of any neoplastic progression was 1/73 pt-yrs (1.37%/pt-yr).

Conclusion

In subjects with dysplastic BE, RFA therapy has an acceptable safety profile, is durable, and is associated with a low rate of disease progression, for up to 3 years.

AIM: To determine if there were any interactions between cardiac devices and small bowel capsules secondary to electromagnetic interference (EMI) in patients who have undergone small bowel capsule endoscopy (SBCE).

METHODS: Authors conducted a chart review of 20 patients with a cardiac pacemaker (CP) or implantable cardioverter defibrillator (ICD) who underwent continuous electrocardiographic monitoring during their SBCE from 2003-2008. authors searched for unexplained electrocardiogram (ECG) findings, changes in CP and ICD set parameters, any abnormality in transmitted capsule data, and adverse clinical events.

RESULTS: There were no adverse events or hemodynamically significant arrhythmias reported. CP and ICD set parameters were preserved. The majority of ECG abnormalities were also found in pre- or post- SBCE ECG tracings and the CP behavior during arrhythmias appeared appropriate. Two patients seemed to have episodes of undersensing by the CP. However, similar findings were documented in ECGs taken outside the time frame of the SBCE. One patient was observed to have a low signal encountered from the capsule resulting in lack of localization, but no images were lost.

CONCLUSION: Capsule-induced EMI remains a possibility but is unlikely to be clinically important. CP-induced interference of SBCE is also possible, but is infrequent and does not result in loss of images transmitted by the capsule.

Background

After endoscopic radiofrequency ablation (RFA) of dysplastic Barrett's esophagus (BE), endoscopic biopsy samples are obtained to assess response to therapy. Whether these biopsies are of adequate depth to assess efficacy is unknown.

Objective

To compare the depth of endoscopic biopsy samples after RFA with those of untreated controls and to determine the prevalence of subepithelial structures in endoscopic biopsy fragments.

Design

Secondary analysis of the AIM Dysplasia Trial, a multicenter, randomized, sham-controlled study.

Setting

Nineteen treatment centers.

Patients

Subjects with dysplastic BE, either status post RFA or ablation naïve (sham).

Main Outcome Measurements

The proportion of biopsy samples demonstrating subepithelial structures, stratified by tissue type (columnar vs squamous) in sham- and RFA-treated subjects.

Results

A total of 5648 biopsy fragments were analyzed from 113 subjects (78 RFA, 35 sham; mean 50.0 fragments per subject). Most fragments (4653, 82.4%) contained subepithelium. Squamous biopsy samples from RFA and sham subjects demonstrated subepithelium at similar rates (78.4% vs 79.1%, respectively, P = not significant [NS]). Columnar biopsy samples from RFA and sham subjects also included subepithelium at similar rates (99.0% vs 98.8%, respectively, P = NS). Regardless of treatment assignment, more columnar than squamous biopsy samples demonstrated subepithelium (98.8% vs 78.5%, P < .001).

Limitations

Biopsy samples were not individually mounted.

Conclusions

In both squamous and columnar tissue, endoscopic biopsy samples after RFA were as likely to demonstrate subepithelium as untreated controls. Almost 80% of all biopsy samples were adequate to evaluate for subsquamous intestinal metaplasia. The primary determinant of biopsy depth is the type of epithelium that underwent biopsy, with squamous less likely to yield subepithelium than columnar. Biopsy samples after RFA appear to be of adequate depth to assess response to therapy.

Fourier-domain optical coherence tomography (OCT) and balloon-based catheters have furthered the potential of OCT as a real-time surveillance tool for Barrett’s esophagus (BE). However, a balloon catheter, which expands the esophagus and centers the catheter, applies direct pressure on the esophagus. This may affect the tissue appearance and the ability to detect dysplasia in BE. To study this effect, we propose a double-balloon catheter to allow imaging with and without balloon-tissue contact. A system design based on a spectral-domain OCT platform is reported and validated by acquisition of high quality, volumetric images of swine esophagus in vivo.

Barrett’s esophagus (BE) increases the risk for development of esophageal adenocarcinoma. Because of the rapid rise in incidence of esophageal adenocarcinoma, screening for BE with subsequent surveillance when found has been proposed as a method of early detection. Sedated endoscopy, however, is too expensive for wide spread screening. As a result, other techniques including unsedated transnasal esophagoscopy and capsule esophagoscopy have been proposed to expand screening programs.

Familial aggregation of esophageal adenocarcinomas, esophagogastric junction adenocarcinomas, and their precursor Barrett’s esophagus has been termed Familial Barrett’s Esophagus (FBE). Numerous studies documenting increased familial risk for these diseases raise the hypothesis that there may be an inherited susceptibility to the development of BE and its associated cancers. In this study, using segregation analysis for a binary trait as implemented in S.A.G.E. 6.0.1, we analyzed data on 881singly ascertained pedigrees in order to determine whether FBE is caused by a common environmental or genetic agent and, if genetic, to identify the mode of inheritance of FBE. The inheritance models were compared by likelihood ratio tests and Akaike’s A Information Criterion. Results indicated that random environmental and/or multifactorial components were insufficient to fully explain the familial nature of FBE, but rather there is segregation of a major type transmitted from one generation to the next (p-value < 10−10). An incompletely dominant inheritance model together with a polygenic component fits the data best. For this dominant model, the estimated penetrance of the dominant allele is 0.1005 (95% confidence interval, CI: 0.0587 to 0.1667) and the sporadic rate is 0.0012 (95% CI: 0.0004 to 0.0042), corresponding to a relative risk of 82.53 (95% CI: 28.70 to 237.35), or odds ratio of 91.63 (95% CI: 32.01 to 262.29). This segregation analysis provides epidemiological evidence in support of one or more rare autosomally inherited dominant susceptibility allele(s) in FBE families, and hence motivates linkage analyses.

Background

Quantitative spectral analysis of the radio-frequency (RF) signals that underlie grayscale EUS images can be used to provide additional, objective information about tissue state.

Objective

Our purpose was to validate RF spectral analysis as a method to distinguish between (1) benign and malignant lymph nodes and (2) normal pancreas (NP), chronic pancreatitis (CP) and pancreatic cancer (PC).

Design & Setting

A prospective validation study of eligible patients was conducted to compare with pilot study RF data.

Patients

Forty-three patients underwent EUS of the esophagus, stomach, pancreas, and surrounding intra-abdominal and mediastinal lymph nodes (19 from previous pilot study and 24 additional patients).

Main Outcome Measurements

Midband fit, slope, intercept, and correlation coefficient from a linear regression of the calibrated RF power spectra were determined.

Results

Discriminant analysis of mean pilot-study parameters was then performed to classify validation-study parameters. For benign vs. malignant lymph nodes, midband-fit and intercept (both with t-test p < 0.058) provided classification with 67% accuracy and area under ROC curve (AUC) of 0.86. For diseased vs. NP, midband-fit and correlation coefficient (both with ANOVA p < 0.001) provided 93% accuracy and AUC of 0.98. For PC vs. CP, the same parameters provided 77% accuracy and AUC of 0.89. Results improved further when classification was performed with all data.

Limitations

Moderate sample size and spatial averaging inherent to the technique.

Conclusions

This study confirms that mean spectral parameters provide a non-invasive method to quantitatively discriminate benign and malignant lymph nodes as well as normal and diseased pancreas.

BACKGROUND AND AIMS

Adenocarcinomas of the esophagus and adenocarcinomas of the gastroesophageal junction are postulated to be complex genetic diseases. Combined influences of environmental factors and genetic susceptibility likely influence the age at which these cancers develop. The aim of this study was to determine whether familiality and other recognized risk factors are associated with the development of these cancers at an earlier age.

METHODS

A structured validated questionnaire was utilized to collect self reported data on gastro-esophageal reflux symptoms, risk factors for Barrett’s esophagus (BE) and family history, including age of cancer diagnosis in affected relatives from probands with BE, adenocarcinoma of the esophagus, or adenocarcinoma of the gastro-esophageal junction, at five tertiary care academic hospitals. Medical records of all relatives reported to be affected were requested from hospitals providing this cancer care to confirm family histories. Familiality of BE/cancer, obesity (defined as body mass index > 30), gastro-esophageal reflux symptoms, and other risk factors were assessed for association with a young age of cancer diagnosis.

RESULTS

A total of 356, 216 non-familial and 140 familial, cancers were studied. The study population consisted of 292 (82%) men and 64 (18%) women. Mean age of cancer diagnosis was no different comparing familial and non-familial cancers, 62.6 yrs vs. 61.9 yrs, p = 0.70. There were also no significant differences in symptoms of gastroesophageal reflux, body mass index, race, gender, and smoking history between familial and non-familial cancers. Mean age of cancer diagnosis was significantly younger comparing those who were obese one year prior to diagnosis with those who were non-obese, mean age 58.99 yrs vs. 63.6 yrs, p = 0.008. Multivariable modeling of age at cancer diagnosis showed that obesity 1 year before diagnosis was associated with a younger age of cancer diagnosis (p=0.005) after adjustment for heartburn and regurgitation duration.

CONCLUSIONS

Obesity is associated with the development of esophageal and gastro-esophageal junctional adenocarcinomas at an earlier age. Familial cancers arise at the same age as non-familial cancers and have a similar risk factor profile.

OBJECTIVE

Determine the relation of race and gender to outcome from bleeding peptic ulcer.

DESIGN

Retrospective cohort study.

SETTING

All acute care hospitals in the United States.

PATIENTS

A 100% sample of hospitalized Medicare beneficiaries older than 64 years (n = 82,868) with a primary discharge diagnosis of peptic ulcer with hemorrhage.

MEASUREMENTS AND MAIN RESULTS

Surgical treatment was performed in 6.9% of patients, 30-day mortality was 8.5%, and average length of stay was 9.4 days. Surgery was somewhat more common in men than women (7.3% vs 6.5%, p < .001), and in whites than African Americans (6.9% vs 6.3%, p < .001), but neither race nor gender was associated with surgery in multivariable analysis adjusting for potentially confounding factors. Mortality rates were similar in African Americans and whites (8.5%), and somewhat higher in men than women (10.7% vs 9.3%, p < .001). In multivariable analysis, there was no difference in mortality across gender and racial groups. Although unadjusted and adjusted lengths of stay were longer for African Americans and shorter for men, the differences were modest (i.e., 16% increase and 6% decrease in multivariable analysis, respectively, p < .0001).

CONCLUSIONS

In this national sample, there is no significant gender or racial difference in therapy and outcome for patients with hemorrhagic peptic ulcer. The findings raise the possibility that studies that have shown race and gender differences in management of coronary artery disease and cancer may not be generalizable to other common diagnoses.