Changes in the Prevalence of Hepatitis C Virus Infection, Nonalcoholic Steatohepatitis, and Alcoholic Liver Disease Among Patients With Cirrhosis or Liver Failure on the Waitlist for Liver Transplantation.

BACKGROUND & AIMS: Concurrent to development of more effective drugs for treatment of hepatitis C virus (HCV) infection, there has been an increase in the incidence of nonalcoholic fatty liver disease. Data indicate that liver transplantation prolongs survival times of patient with acute hepatitis associated with alcoholic liver disease (ALD). We compared data on disease prevalence in the population with data from liver transplantation waitlists to evaluate changes in the burden of liver disease in the United States. METHODS: We collected data on the prevalence of HCV from the 2010 and 2013-2014 cycles of the National Health and Nutrition Examination Survey. We also collected data from the HealthCore Integrated Research Database on patients with cirrhosis and chronic liver failure (CLF) from 2006 through 2014, and data on patients who received transplants from the United Network for Organ Sharing from 2003 through 2015. We determined percentages of new waitlist members and transplant recipients with HCV infection, stratified by indication for transplantation, modeling each calendar year as a continuous variable using the Spearman rank correlation, nonparametric test of trends, and linear regression models. RESULTS: In an analysis of data from the National Health and Nutrition Examination Survey (2013-2014), we found that the proportion of patients with a positive HCV antibody who had a positive HCV RNA was 0.5 (95% confidence interval, 0.42-0.55); this value was significantly lower than in 2010 (0.64; 95% confidence interval, 0.59-0.73) (P = .03). Data from the HealthCore database revealed significant changes (P < .05 for all) over time in percentages of patients with compensated cirrhosis (decreases in percentages of patients with cirrhosis from HCV or ALD, but increase in percentages of patients with cirrhosis from nonalcoholic steatohepatitis [NASH]), CLF (decreases in percentages of patients with CLF from HCV or ALD, with an almost 3-fold increase in percentage of patients with CLF from NASH), and hepatocellular carcinoma (HCC) (decreases in percentages of patients with HCC from HCV or ALD and a small increase in HCC among persons with NASH). Data from the United Network for Organ Sharing revealed that among patients new to the liver transplant waitlist, or undergoing liver transplantation, for CLF, there was a significant decrease in the percentage with HCV infection and increases in percentages of patients with nonalcoholic fatty liver disease or ALD. Among patients new to the liver transplant waitlist or undergoing liver transplantation for HCC, proportions of those with HCV infection, nonalcoholic fatty liver disease, or ALD did not change between 2003 and 2015. CONCLUSIONS: In an analysis of 3 different databases (National Health and Nutrition Examination Survey, HealthCore, and United Network for Organ Sharing), we found the proportion of patients on the liver transplant waitlist or undergoing liver transplantation for chronic HCV infection to be decreasing and fewer patients to have cirrhosis or CLF. However, the percentages of patients on the waitlist or receiving liver transplants for NASH or ALD are increasing, despite different relative burdens of disease among the entire population of patients with cirrhosis.

Effects of carbon dioxide insufflation during direct cholangioscopy on biliary pressures and vital parameters: a pilot study in porcine models.

BACKGROUND AND AIMS: Direct per-oral cholangioscopy allows endoscopic visualization of the biliary tract. Insufflation with carbon dioxide (CO2) is an alternative to saline solution irrigation during direct cholangioscopy. There are no data on maximal CO2 insufflation in direct cholangioscopy without causing biliary barotrauma or fatal gas embolism. We aimed to evaluate the safety of increasing CO2 insufflation in direct cholangioscopy without causing biliary barotrauma or fatal gas embolism. METHODS: This was an in vivo animal study. Four domestic pigs, under general endotracheal anesthesia, were used. The first animal was used to validate the feasibility of direct cholangioscopy and biliary pressure measurements, after which all animals underwent laparotomy, insertion of a pressure transducer in the cystic duct, and direct transpapillary placement of the cholangioscope. The common bile duct (CBD) and cystic duct were ligated to contain the instilled gas and exclusively expose the biliary tree. Insufflation of CO2 started at 200 mL/min and was continuously increased until there was evidence of bile duct rupture (as measured by a drop in intraductal pressures) or instability of vital signs (hypotension, bradycardia, bradypnea, O2 desaturation). Necropsy was performed on all animals to assess the liver and biliary system for evidence of barotrauma. RESULTS: CO2 was insufflated up to 8 L/min without causing bile duct rupture or instability in vital signs despite increasing CBD pressure with insufflation. There was significant correlation between CO2 flow with partial pressure of CO2 in arterial blood (PaCO2) (coefficient, 0.96-1.00; P < .01) and end tidal expired CO2 (EtCO2) (coefficient, 0.94-1.00; P < .01). However, the pulse rate, respiratory rate, arterial blood pressure, and O2 did not correlate with the amount of CO2 flow. There was no evidence of hepatic or biliary barotrauma on necropsy. CONCLUSIONS: This pilot experience in porcine models suggests that CO2 insufflation is safe for direct cholangioscopy and does not result in biliary barotrauma or vital signs instability.

Comparative diagnostic performance of volumetric laser endomicroscopy and confocal laser endomicroscopy in the detection of dysplasia associated with Barrett's esophagus.

BACKGROUND AND AIMS: Probe-based confocal laser endomicroscopy (pCLE) and volumetric laser endomicroscopy (VLE) (also known as frequency domain optical coherence tomography) are advanced endoscopic imaging modalities that may be useful in the diagnosis of dysplasia associated with Barrett's esophagus (BE). We performed pCLE examination in ex-vivo EMR specimens and compared the diagnostic performance of using the current VLE scoring index (previously established as OCT-SI) and a novel VLE diagnostic algorithm (VLE-DA) for the detection of dysplasia. METHODS: A total of 27 patients with BE enrolled in a surveillance program at a tertiary-care center underwent 50 clinically indicated EMRs that were imaged with VLE and pCLE and classified into neoplastic (N = 34; high-grade dysplasia, intramucosal adenocarcinoma) and nonneoplastic (N = 16; low-grade dysplasia, nondysplastic BE), based on histology. Image datasets (VLE, N = 50; pCLE, N = 50) were rated by 3 gastroenterologists trained in the established diagnostic criteria for each imaging modality as well as a new diagnostic algorithm for VLE derived from a training set that demonstrated association of specific VLE features with neoplasia. Sensitivity, specificity, and diagnostic accuracy were assessed for each imaging modality and diagnostic criteria. RESULTS: The sensitivity, specificity, and diagnostic accuracy of pCLE for detection of BE dysplasia was 76% (95% confidence interval [CI], 59-88), 79% (95% CI, 53-92), and 77% (95% CI, 72-82), respectively. The optimal diagnostic performance of OCT-SI showed a sensitivity of 70% (95% CI, 52-84), specificity of 60% (95% CI, 36-79), and diagnostic accuracy of 67%; (95% CI, 58-78). The use of the novel VLE-DA showed a sensitivity of 86% (95% CI, 69-96), specificity of 88% (95% CI, 60-99), and diagnostic accuracy of 87% (95% CI, 86-88). The diagnostic accuracy of using the new VLE-DA criteria was significantly superior to the current OCT-SI (P < .01). CONCLUSION: The use of a new VLE-DA showed enhanced diagnostic performance for detecting BE dysplasia ex vivo compared with the current OCT-SI. Further validation of this algorithm in vivo is warranted.

Outcomes of double-balloon enteroscopy-assisted direct percutaneous endoscopic jejunostomy tube placement.

BACKGROUND AND STUDY AIMS: In a large series, conventional direct percutaneous endoscopic jejunostomy (DPEJ) tube placement with push endoscopes failed in approximately one-third of patients. In a pilot study, double-balloon enteroscopy (DBE)-assisted DPEJ tube placement was successful in all patients in whom attempted conventional DPEJ had failed. The study aim was to assess the technical success of and adverse events related to DBE-DPEJ tube placement in a large cohort of patients. PATIENTS AND METHODS: The medical records of all patients who underwent DBE-DPEJ tube placement between July 2010 and November 2013 were reviewed using a prospectively maintained electronic database. Data were abstracted for patient demographics, indications for DPEJ, gut anatomy, technical success rate, causes of failure, and adverse events. RESULTS: The study comprised a total of 94 patients (39 men; mean age 56 years; body mass index [BMI] 23 ±â€Š6.4 kg/m(2)). The most common indication for DPEJ was gastroparesis (n = 29). Altered gut anatomy was present in 36 patients (38 %). DBE-DPEJ tube placement was technically successful in 87 patients (93 %). The mean procedure duration was 33 minutes (range 15 - 88). DBE-DPEJ tube placement failed in seven patients (7 %), primarily because of limited instrument advancement in the setting of presumed surgical adhesions. Post-procedural adverse events occurred in eight patients (9 %), with one serious adverse event, which was a gastric interposition requiring surgical repair. CONCLUSIONS: Compared with the published outcomes of DPEJ by conventional endoscopy, DBE-DPEJ tube placement was technically successful in a high proportion of patients (93 %) and with a relatively low rate of significant adverse events.

Outcomes and Predictors of Rebleeding After 2-Octyl Cyanoacrylate Injection in Acute Gastric Variceal Hemorrhage.

BACKGROUND AND AIM: Endoscopic injection of 2-octyl cyanoacrylate (2-OCA) is used on an off-label basis for gastric variceal hemorrhage (GVH) in the United States. We assessed the efficacy, safety, and predictors of rebleeding after gastric variceal obturation (GVO) with 2-OCA in patients with acute GVH. MATERIALS AND METHODS: A retrospective analysis was performed of patients with GVH who underwent 2-OCA injection for GVO over a 15-year period. Rates of acute hemostasis, predictors of rebleeding, and cyanoacrylate-related adverse events were assessed. RESULTS: A total of 95 patients (63 males, median age 59±14 y) were analyzed. Gastric varices were categorized as GOV-1 (3%), GOV-2 (61%), and isolated gastric varices type 1 (36%) per Sarin classification. Initial hemostasis was achieved in all patients. Successful GVO, defined as sustained hemostasis within a month after injection, was achieved in 87 (92%) patients. Failed GVO with in-hospital rebleeding was observed in 8 (8%) patients. On univariate analysis, only the model for end-stage liver disease score was associated with an increased risk of rebleeding (odds ratio 1.2; 95% confidence interval, 1.1-1.4; P<0.01). Glue-related adverse events consisted of pulmonary emboli in 2 patients (2.1%), resulting in death in 1 patient. All cause in-hospital mortality was 13% due to uncontrolled gastric variceal rebleeding (n=3), renal failure (n=6), metastatic hepatocellular carcinoma (n=1), hemorrhagic stroke (n=1), and pulmonary embolism (n=1). CONCLUSIONS: Injection of 2-OCA was effective at achieving hemostasis in a high proportion of patients (92%) admitted for acute GVH. The risk of glue-related pulmonary embolism approximated 2% in our patient cohort, including 1 fatality.

Obstructive sleep apnea is a risk factor for Barrett's esophagus.

BACKGROUND & AIMS: Common risk factors for obstructive sleep apnea (OSA) and Barrett's esophagus (BE) include obesity and gastroesophageal reflux disease (GERD). The aims of this study were to assess the association between OSA and BE and to determine whether the association is independent of GERD and body mass index (BMI). METHODS: Patients who had undergone a diagnostic polysomnogram and esophagogastroduodenoscopy were identified by using Mayo Clinic (Rochester, Minnesota) databases from January 2000-November 2011. They were randomly matched for age, sex, and BMI at time of polysomnogram into the following groups: BE but no OSA (n = 36), OSA but no BE (n = 78), both (n = 74), or neither (n = 74). Clinical and demographic variables were abstracted from medical records. The association between OSA and BE was assessed by using a multiple variable logistic model that incorporated age, sex, BMI, clinical diagnosis of GERD, and smoking history. RESULTS: Subjects with OSA had an 80% increased risk for BE compared with subjects without OSA (odds ratio, 1.8; 95% confidence interval, 1.1-3.2; P = .03). These findings were independent of age, sex, BMI, GERD, and smoking history. Increasing severity of OSA, measured by using the apnea-hypopnea index, was associated with an increased risk of BE (odds ratio, 1.2 per 10-unit increase in apnea-hypopnea index; 95% confidence interval, 1.0-1.3; P = .03). CONCLUSIONS: In this case-control study, OSA was associated with an increased risk of BE, potentially through BMI and GERD independent mechanisms. Patients with OSA may benefit from evaluation for BE.

Recurrence of esophageal intestinal metaplasia after endoscopic mucosal resection and radiofrequency ablation of Barrett's esophagus: results from a US Multicenter Consortium.

BACKGROUND & AIMS: Radiofrequency ablation (RFA) is an established treatment for dysplastic Barrett's esophagus (BE). Although short-term end points of ablation have been ascertained, there have been concerns about recurrence of intestinal metaplasia (IM) after ablation. We aimed to estimate the incidence and identify factors that predicted the recurrence of IM after successful RFA. METHODS: We analyzed data from 592 patients with BE treated with RFA from 2003 through 2011 at 3 tertiary referral centers. Complete remission of intestinal metaplasia (CRIM) was defined as eradication of IM (in esophageal and gastroesophageal junction biopsy specimens), documented by 2 consecutive endoscopies. Recurrence was defined as the presence of IM or dysplasia after CRIM in surveillance biopsies. Two experienced gastrointestinal pathologists confirmed pathology findings. RESULTS: Based on histology analysis, before RFA, 71% of patients had high-grade dysplasia or esophageal adenocarcinoma, 15% had low-grade dysplasia, and 14% had nondysplastic BE. Of patients treated, 448 (76%) were assessed after RFA. Fifty-five percent of patients underwent endoscopic mucosal resection before RFA. The median time to CRIM was 22 months, with 56% of patients in CRIM by 24 months. Increasing age and length of BE segment were associated with longer times to CRIM. Twenty-four months after CRIM, the incidence of recurrence was 33%; 22% of all recurrences observed were dysplastic BE. There were no demographic or endoscopic factors associated with recurrence. Complications developed in 6.5% of subjects treated with RFA; strictures were the most common complication. CONCLUSIONS: Of patients with BE treated by RFA, 56% were in complete remission after 24 months. However, 33% of these patients had disease recurrence within the next 2 years. Most recurrences were nondysplastic and endoscopically manageable, but continued surveillance after RFA is essential.

Prediction of response to endoscopic therapy of Barrett's dysplasia by using genetic biomarkers.

BACKGROUND: Endoscopic therapy for the treatment of high-grade dysplasia (HGD) and intramucosal cancer (IMC) in Barrett's esophagus (BE) may not always result in complete remission of dysplasia (CRD). OBJECTIVE: To determine whether genetic alterations in the Barrett's mucosa can predict response to endoscopic therapy. DESIGN: Retrospective cohort study. SETTING: Tertiary-care institution. PATIENTS: Selected patients who underwent endoscopic therapy for BE containing HGD/IMC between 2003 and 2010. INTERVENTIONS: Endoscopic therapy combining mucosal resection and different ablation modalities was performed based on patient characteristics, endoscopic findings, and technique evolution. Fluorescence in situ hybridization was used to evaluate genetic alterations on baseline endoscopic cytology brushings by using probes directed to loci 8q24 (MYC), 9p21 (CDKN2A; alias P16), 17q12 (ERBB2; alias Her-2/neu), and 20q13.2 (ZNF217). MAIN OUTCOME MEASUREMENTS: Genetic biomarkers predicting achievement of CRD after endoscopic therapy. RESULTS: A total of 181 patients were included (145 men; 66 ± 10 years of age). There were 130 patients (72%) who responded to endoscopic therapy with CRD. Multiple gains detected by fluorescence in situ hybridization was found to be a negative predictor (hazard ratio 0.57; 95% confidence interval, 0.40-0.82) after adjusting for potential clinical confounders. Similar results were found when analyses were restricted to patients (n = 66) undergoing radiofrequency ablation (hazard ratio 0.58; 95% confidence interval, 0.31-1.09). LIMITATIONS: Retrospective study, heterogeneity of treatment modalities. CONCLUSION: Patients with multiple gains detected by brush cytology specimens may have a lower response rate to endoscopic therapy. The presence of multiple gains can be an adjunct to standard histology in prognosticating BE patients with HGD/IMC undergoing endoscopic therapy.

Endpoints for radiofrequency ablation in Barrett's dysplasia.

The need to combat the rising incidence of esophageal adenocarcinoma with its dismal prognosis has led to increasing development of many endoscopic treatments for Barrett's esophagus (BE). Radiofrequency ablation (RFA) has been shown to be a safe and effective endoscopic treatment modality for dysplastic BE. The durability of successful eradication of dysplastic BE has been reported by earlier studies with limited sample size, follow-up time, and inadequate cohort of patients with high-grade dysplasia or intramucosal cancer. In this issue, Orman and colleagues present their findings from their single center, retrospective cohort of patients who underwent RFA with post-treatment surveillance. They report a low recurrence rate of 5.2% per year. There were no clinical characteristics found to be associated with BE recurrence in terms of length of segment or degree of dysplasia. Complete eradication of dysplasia (CE-D) or intestinal metaplasia was determined after a single post-RFA endoscopic examination with biopsies. This is an area of controversy as previous studies have used a minimum of two negative examinations before CE can be claimed. There are also limitations from sampling error during surveillance biopsies and the loss of a third of all post-RFA patients during surveillance. Multicenter, prospective studies with adequate follow-up are still needed before we can draw recommendations when to adequately cease post-treatment surveillance and to identify patients with increased risk of either recurrence or progression.

A new era: endoscopic tissue transplantation.

PURPOSE OF REVIEW: To describe basic principles of tissue engineering with emphasis on the potential role of gastrointestinal endoscopy in regenerative medicine. RECENT FINDINGS: Stricturing associated with endoscopic submucosal resection and circumferential endoscopic mucosal resection can be prevented through transplantation of autologous epidermal cell sheets or seeded decellularized biological scaffolds. Lower esophageal sphincter augmentation through injection of muscle-derived cells is a novel potential treatment for gastroesophageal reflux disease. Stem cell derived tissue has been used to repair injured colon in a mouse model of colitis. A bioengineered internal anal sphincter has been successfully implanted in mice and showed preserved functionality. SUMMARY: The immediate foreseeable application of tissue engineering in gastrointestinal endoscopy is in the field of mucosal repair after acute injury. Tissue regeneration can be achieved through expansion of autologous somatic cells or by induction of multipotent or pluripotent stem cells. Advances in cellular scaffolding have made bioengineering of complex tissues a reality. Tissue engineering in endoscopy is also being pioneered by studies looking at enteral sphincter augmentation and regeneration. The availability of engineered tissue for endoscopic application will increase with advances in cell-culturing techniques.

Performance of double-balloon enteroscopy for the management of small bowel polyps in hamartomatous polyposis syndromes.

BACKGROUND AND AIM: Hamartomatous polyposis syndromes (HPS) are a group of rare inherited autosomal dominant disorders. Small bowel polyposis is one of the manifestations of HPS. Double-balloon enteroscopy (DBE) with polypectomy may obviate repeated small bowel surgeries for polyp intussusception, obstruction, or bleeding. The efficacy and safety of DBE-assisted polypectomy in HPS patients with clinically significant small bowel polyposis were evaluated. METHODS: All HPS patients who underwent DBE from January 2007 to April 2011 were identified using a prospectively maintained database. Data on patient demographics, pre-DBE radiological studies, polyp characteristics, procedural outcomes, and complications were abstracted. RESULTS: Twenty-two patients underwent a total of 34 DBE procedures. Pre-DBE imaging included computed tomography enterography (n = 15), computed tomography enteroclysis (n = 5), small bowel follow-through (n = 1), and magnetic resonance enterography (n = 1). Any small bowel polyp ≥ 1 cm in size on radiological imaging was referred for DBE-assisted polypectomy. Antegrade and retrograde DBE were successful in reaching and resecting targeted polyps in 90% (18/20) and 71.4% (10/14) of procedures, respectively. The overall success rate for DBE-assisted polypectomy was 82.3% (95% confidence interval: 66.5-91.6%). The median size of resected polyps was 2 cm (range 1-5 cm) and all were hamartomas. Minor adverse events occurred in four (11.8%) procedures, including abdominal pain (n = 2), immediate post-polypectomy bleeding (n = 1), and self-limited hematochezia (n = 1). CONCLUSIONS: DBE-assisted polypectomy was successful in over 80% of HPS patients with an acceptable margin of safety. To the knowledge of the authors, this is one of the largest single-center studies to report on the performance and safety of DBE-assisted polypectomy in HPS patients.

Utility of baseline positron emission tomography with computed tomography for predicting endoscopic resectability and survival outcomes in patients with early esophageal adenocarcinoma.

BACKGROUND AND AIMS: Positron emission tomography with computed tomography (PET/CT) has been used to detect metastasis in the diagnosis of esophageal adenocarcinoma (EAC). However, the utility of PET/CT to assess primary tumor for endoscopic resectability and prognosis in early EAC remains unclear. We conducted a retrospective study to determine the association of PET/CT findings with histopathological tumor invasion depth and survival outcomes. METHODS: EAC patients who underwent PET/CT followed by endoscopic mucosal resection (EMR) were included. Pathology on EMR and survival outcomes from a prospectively maintained database was retrieved. Two radiologists independently reviewed the PET/CT using the following parameters: detection of malignancy, fluorodeoxyglucose (FDG) uptake intensity, FDG focality, FDG eccentricity, esophageal thickness, maximal standard uptake value (SUVmax), and SUVmax ratio (lesion/liver). RESULTS: There were 72 eligible patients: 42 (58.3%) had T1a lesions, and 30 (41.7%) had ≥ T1b. Only SUVmax ratio was associated with tumor invasion depth (odds ratio=2.77, 95% confidence interval 1.26-7.73, P=0.0075). Using a cut-off of 1.48, the sensitivity and specificity of SUVmax ratio for identification of T1a lesions were 43.3% and 80.9%, respectively. Adjusting the SUVmax ratio to 2.14, 16.7% (5/30) of ≥ T1b patients were identified without any false-positive cases. Multivariate analysis showed SUVmax ratio, Charlson comorbidity index, and esophagectomy were independent predictors for survival. CONCLUSIONS: SUVmax ratio (lesion/liver) is more accurate in predicting endoscopic resectability and mortality for EAC than other PET/CT parameters and appears promising as a useful adjunct to the current diagnostic work-up.

Barrett's esophagus in 2012: updates in pathogenesis, treatment, and surveillance.

Barrett's esophagus (BE) is the only established precursor lesion in the development of esophageal adenocarcinoma (EAC) and it increases the risk of cancer by 11-fold. It is regarded as a complication of gastroesophageal reflux disease. There is an ever-increasing body of knowledge on the pathogenesis, diagnosis, treatment, and surveillance of BE and its associated dysplasia. In this review, we summarize the latest advances in BE research and clinical practice in the past 2 years. It is critical to understand the molecular underpinnings of this disorder to comprehend the clinical outcomes of the disease. For clinical gastroenterologists, there is also continuous growth of endoscopic approaches which is daunting, and further improvements in the detection and treatment of BE and early EAC are anticipated. In the future, we may see the increased role of biomarkers, both molecular and imaging, in both diagnostic and therapeutic strategies for BE.

Pediatric case of mesalazine-induced interstitial nephritis with literature review.

We present the case of a 14-year-old boy with ulcerative colitis who was diagnosed with mesalazine-induced interstitial nephritis (M-IIN). Improvement in renal function occurred with discontinuation of mesalazine and corticosteroid therapy. We systematically searched the literature for pediatric cases of M-IIN. There were eight cases. Majority of the cases were boys (75%) with ulcerative colitis (75%). Average duration of mesalazine use prior to the diagnosis of interstitial nephritis was 24 ± 18 months. The median dose was 1.5 g/day. M-IIN appears to be an idiosyncratic reaction without any relation to dose or duration of mesalazine use. Although there are no guidelines to recommend routine surveillance of renal function, monitoring of serum creatinine in patients on mesalazine remains an inexpensive and non-invasive test that may lead to early detection and treatment of renal injury.

Diagnostic performance of two confocal endomicroscopy systems in detecting Barrett's dysplasia: a pilot study using a novel bioprobe in ex vivo tissue.

BACKGROUND: There are currently 2 existing confocal laser endomicroscopy (CLE) platforms: probe-based CLE (pCLE) and endoscope-based CLE (eCLE) systems, each with its own criteria for identifying dysplasia in Barrett's esophagus (BE). The diagnostic performance of these 2 systems has not been directly compared. DESIGN: Preclinical, feasibility study. OBJECTIVES: We compared the interrater agreement and diagnostic performance of the pCLE and eCLE systems. In addition, we evaluated a new BE endomicroscopy criteria based on fluorescent glucose intensity uptake. PATIENTS: Thirteen patients with Barrett's esophagus and high-grade dysplasia or early cancer undergoing 16 EMR. INTERVENTION: CLE imaging was performed using two different probes with 2-[N-(7-nitrobenz-2-oxa-1,3-diaxol-4-yl)amino]-2-deoxyglucose, a fluorescent glucose analog with preferential uptake in dysplastic mucosa to supply contrast. Four quadrants were imaged per specimen with a total of 64 imaged mucosal sites presented to three gastroenterologists. MAIN OUTCOME MEASUREMENTS: Interobserver agreement and accuracy for dysplasia was assessed of images classified according to Miami criteria, stacked eCLE images classified using the Mainz criteria and a novel fluorescence intensity criteria. RESULTS: The interrater agreements were 0.17, 0.68, and 0.87 for the Miami, Mainz, and the fluorescence intensity criteria, respectively. Overall accuracy in detecting dysplasia was 37% (95% CI, 30.3-43.9), 44.3% (95% CI, 37.3-50.9), and 78.6% (95% CI, 72.2-83.3) for the Miami, Mainz, and the fluorescence intensity criteria, respectively. LIMITATIONS: This imaging technique and proposed fluorescence intensity criteria using 2-[N-(7-nitrobenz-2-oxa-1,3-diaxol-4-yl)amino]-2-deoxyglucose in EMR tissue will require in vivo validation and cannot be directly used with the current eCLE and pCLE clinical applications. CONCLUSIONS: In this preclinical feasibility study, the use of an eCLE system with a topical fluorescent contrast in ex vivo EMR tissue demonstrated higher interrater agreement and accuracy.

Synergistic effects of photodynamic therapy with HPPH and gemcitabine in pancreatic cancer cell lines.

BACKGROUND AND OBJECTIVE: Photodynamic therapy (PDT) is a potential treatment for pancreatic cancer. A second-generation photosensitizer, 2-[1-hexyloxyethyl]-2-devinyl pyropheophorbide (HPPH) has a long wavelength absorption, high-tumor selectivity, and shorter duration of skin photosensitivity. We investigated the efficacy of PDT with HPPH and gemcitabine in inducing cell death in multiple pancreatic cancer cell lines. METHODS: We used three pancreatic cancer cell lines (PANC-1, MIA PaCa-2, and BXPC-3) incubated with HPPH concentration of 0, 0.005, 0.01, 0.025, 0.05, 0.1, 0.25, and 0.5 µg/ml for 6 hours, followed by photoradiation at a light dose of 60 J/cm(2). Afterwards, each cell line was treated with gemcitabine at concentrations of 0, 1, 10, and 100 µM and incubated for another 96 hours. Cell death was detected with SYTOX green staining. We also assessed the difference in cytotoxicity in adding gemcitabine before and after PDT. RESULTS: HPPH-PDT can effectively induce cell death in all cell lines in a dose-dependent manner, with a 100% of cell death at the 0.5 µg/ml HPPH concentration. In contrast, monotherapy with gemcitabine alone (100 µM) only achieved <45% cell death. Combining gemcitabine to HPPH-PDT resulted in synergistic cytotoxic effect with 20-50% more cell death across all cell lines. There was no difference in cytotoxicity in adding gemcitabine before or after PDT. CONCLUSION: This is the first study on HPPH-PDT for pancreatic cancer. HPPH-PDT-induced cell death occurs in a dose-dependent manner. HPPH-PDT and gemcitabine have synergistic effects in inducing cell death in multiple pancreatic cancer cell lines.

A multi-analyte cell-free DNA-based blood test for early detection of hepatocellular carcinoma.

The limited performance of guideline-recommended abdominal ultrasound and serum alpha-fetoprotein (AFP) highlights the urgent, unmet need for new biomarkers for more accurate detection of early hepatocellular carcinoma (HCC). To this end, we have conducted a prospective clinical validation study to evaluate the performance of the HelioLiver Test, a multi-analyte blood test combining cell-free DNA methylation patterns, clinical variables, and protein tumor markers. A blinded, multicenter validation study was performed with 247 subjects, including 122 subjects with HCC and 125 control subjects with chronic liver disease. The performance of the HelioLiver Test was compared with AFP and the GALAD score as established HCC surveillance blood tests. The performance of the HelioLiver Test (area under the receiver operating characteristic curve [AUROC] = 0.944) was superior to both AFP (AUROC = 0.851; p < 0.0001) and GALAD (AUROC = 0.899; p < 0.0001). Using a prespecified diagnostic algorithm, the HelioLiver Test showed sensitivities of 85% (95% confidence interval [CI], 78%-90%) for HCC of any stage and 76% (95% CI, 60%-87%) for early stage (American Joint Committee on Cancer [AJCC] I and II) HCC. In contrast, AFP (≥20 ng/mL) alone and the GALAD score (≥-0.63) showed lower sensitivities of 62% (95% CI, 54%-70%) and 75% (95% CI, 67%-82%) for HCC overall, and 57% (95% CI, 40%-71%) and 65% (95% CI, 49%-79%) for early stage (AJCC I and II) HCC, respectively. The specificities of the HelioLiver Test (91%; 95% CI, 85%-95%), AFP (97%; 95% CI, 92%-99%), and the GALAD score (94%; 95% CI, 88%-97%) were similar for control subjects. The HelioLiver Test showed superior performance for HCC detection compared to with both AFP and the GALAD score and warrants further evaluation in HCC surveillance settings.

A randomized controlled trial of double versus triple therapy with amantadine for genotype 1 chronic hepatitis C in Latino patients.

BACKGROUND: With only a third of Latinos achieving sustained virologic response (SVR), there is a need for enhanced HCV treatment. Amantadine has been proposed to improve response rates in addition to standard therapy with peginterferon alpha and ribavirin. Our objective is to evaluate whether triple therapy with amantadine improves SVR rates in this special population. METHOD: Treatment-naïve Latino subjects with HCV genotype 1 infection were randomized to receive peginterferon alpha-2a plus weight-based ribavirin for 48 weeks (double therapy) or the same regimen plus amantadine 200 mg daily (triple therapy). The primary endpoint was SVR. Predictors of liver fibrosis using APRI and Forns indices were also evaluated. RESULTS: We enrolled 124 patients with chronic hepatitis C genotype 1. Sixty-three received conventional therapy and 61 patients had triple therapy with amantadine. SVR at week 72 was achieved in 25 patients (39.7%) vs. 26 patients (42.6%) in the double and triple regimen, respectively (p=0.561). After multivariate analysis, advanced fibrosis, obesity, and low pretreatment ALT levels were associated with non-response in both groups (p=0.0234, p=0.0012, p=0.0249, respectively). APRI values delimited an area under the ROC curve (AUROC) of 0.724 and Forns index with AUROC of 0.733. There was no difference between both indices in predicting significant fibrosis (Knodell index: F3-F4). CONCLUSION: Our study demonstrates that the addition of amantadine to standard treatment of chronic HCV does not improve SVR rates in Latino patients with genotype 1. Further research to improve response rates in this special population is needed.

Localized hepatosplenic sarcoidosis with an elevated serum CA-125 level.

Sarcoidosis, a granulomatous disorder of unknown etiology, primarily affects the lungs and lymph nodes. Extrapulmonary disease without any pulmonary involvement is rare. Sarcoidosis with an elevated serum CA-125 level has only been reported five times in the literature. We describe a case of localized hepatosplenic sarcoidosis, confirmed by biopsy, with associated CA-125 elevation. In our review of the current literature, this is the first reported case of localized hepatosplenic sarcoidosis with associated serum CA-125 elevation.