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BACKGROUND AND OBJECTIVE The role of endothelial progenitor cells in patients with cirrhosis has seldom been investigated. This study was conducted to assess the clinical significance of circulating endothelial progenitor cells in patients with liver cirrhosis with or without hepatocellular carcinoma. METHODS A blood sample was collected once from patients with cirrhosis alone (n = 34) or cirrhosis and hepatocellular carcinoma (n = 46) and healthy controls (n = 27) for assessing levels of endothelial progenitor cells and vascular endothelial growth factor. Blood cells staining positive for CD34/CD133/KDR using flow cytometry were characterized as endothelial progenitor cells. Plasma vascular endothelial growth factor was quantified by ELISA. RESULTS The levels of CD34/KDR-positive endothelial progenitor cells, CD133/KDR-positive endothelial progenitor cells, and vascular endothelial growth factor were higher in patients with cirrhosis ± hepatocellular carcinoma than in healthy controls (P = 0.017, P < 0.001 and P < 0.001, respectively). The levels of endothelial progenitor cells and vascular endothelial growth factor did not show statistical difference according to Child-Turcotte-Pugh class. There was a moderately significant correlation between vascular endothelial growth factor levels and hepatocellular carcinoma stage (ρ = 0.464, P = 0.001). Smoking, ascites, and portal vein thrombosis were independently related to lower levels of circulating CD34/KDR-positive endothelial progenitor cells, higher levels of CD133/KDR-positive endothelial progenitor cells, and higher levels of vascular endothelial growth factor, respectively (P = 0.041, P = 0.023, and P < 0.001, respectively). CONCLUSION Circulating endothelial progenitor cells and plasma vascular endothelial growth factor levels were higher in patients with liver cirrhosis ± hepatocellular carcinoma compared to healthy controls. The increase in endothelial progenitor cells and vascular endothelial growth factor may have a possible role in the development of complications, especially ascites and portal vein thrombosis, or in progression of hepatocellular carcinoma.

Background and aim Hepatic encephalopathy (HE) is a frequent complication of cirrhosis, characterized by cognitive deficits that negatively impact patients' quality of life. The mild, minimal hepatic encephalopathy (mHE) can only be detected by psychometric tests and early mHE detection can prevent more severe complications or even survival times. Here, we aimed to investigate the feasibility and validity of the novel-developed electronic number connection test (eNCT), which is designed as a fast and easy-to-perform mHE patient self-test. Methods The eNCT design was inspired by the paper-pencil number connection test version A, showing 25 numbers on the screen (1-25), in a random order. The time required to tap on all digits in the correct order was measured. A total of 238 individuals (112 patients with liver cirrhosis) were enrolled in this study and eNCT times were compared with well-established paper-pencil tests. The Psychometric Hepatic Encephalopathy Score test battery was used to detect mHE and cut-off values for mHE detection by the eNCT were defined. Results Overall, cirrhotic patients showed significantly slower test completion times compared with control participants. The eNCT performance was inversely correlated with Psychometric Hepatic Encephalopathy Score test performance in cirrhotic patients, independent of the HE status. Thirty cirrhotic patients fulfilled the mHE criteria and receiver operating characteristic curve analysis showed high sensitivity (>82%) and specificity (>85%) for mHE detection. Finally, the eNCT showed excellent test-retest reliability (intraclass correlation coefficient=0.94). Conclusion The novel eNCT is a reliable HE self-test to monitor cognitive function and detect cognitive impairment in cirrhotic patients.

We read with concern the paper of McNicholl et al. 1 on the accuracy of GastroPanel (GP) in the diagnosis of atrophic gastritis (AG). The major conclusions of the paper are in sharp contrast with the earlier literature 2–6 and the most recent international consensus statements. The skewed GP results reported in the study 1 could be due to any or all of three main reasons: (a) poor laboratory techniques; (b) misclassification bias of the study endpoint (AG); and (c) inadequate statistical power (n=85, 10 with AG). First of all, it should be noted that the ‘Biohit-Deltaclon GastroPanel’s Lab’ in Spain, where the authors reported their analyses had been carried out 1, has no contract in force with Biohit Oyj (Helsinki, Finland), and accordingly no rights to use either the name Biohit or GastroPanel in this context. It is emphasized that the GP test (Biohit Oyj) is an enzyme-linked immunosorbent assay test and has not been optimized (or even tested) by the manufacturer for use as a chemiluminescent enzyme immunoassay 1. This type of technical modification inevitably entails that the manufacturer-recommended cutoff values are not valid in the new application. Chemiluminescent assay should have been validated against the reference GP test to confirm the appropriateness of the cutoff values that the authors have used (Figure 1) 1. Even minor deviations from the appropriately validated cutoff values in a study with a limited number of cases (only 10 with AG) would lead to markedly distorted results. Plasma pepsinogen I (PGI) levels and severity of AG show a practically linear relationship 2–5. PGI levels less than 25 µg/l and PGI/PGII ratio less than 3.0 are consistent with moderate or severe AG of the corpus 3. Therefore, it is surprising that the mean serum level of PGI for patients with AG of the corpus reported in this study is 101 µg/l (Table 1) 1. On the basis of extensive clinical series, such PGI values are impossible in patients with biopsy-confirmed moderate or severe AG of the corpus 2–6. The GP test is optimized to be used in context with the Updated Sydney System (USS) for classification of gastritis 2,6. The five diagnostic categories – (a) normal mucosa, (b) superficial gastritis, (c) atrophic antrum gastritis, (d) atrophic corpus gastritis, and (e) atrophic pangastritis – are common to both the GP test and the USS, which enables direct assessment of their concordance using, for example, weighted κ (intraclass correlation coefficient) testing. When this is done in an adequately powered study based on validated USS classification, an interassay (GP-to-USS) agreement is usually in the range of 0.7 to greater than 0.8 (substantial to almost perfect) 2,6. This information on the overall test agreement was missing in the present report 1. The lack of this key information invalidates the correct interpretation of the GP results and also precludes any meaningful calculations on GP performance as an indicator of the AG (study endpoint). Mild AG of the corpus should never be used as the study endpoint in calculating the performance indicators of the PGI, PGI/PGII, as repeatedly emphasized 2–6. This fact has been neglected in the present study, in which the GP cutoff values presented in Figure 1 algorithm are indicated for AG in general and not stratified according to the grade of AG 1. The only appropriate way of calculating the predictive indicators of PGI and PGI/PGII ratio for AG of the corpus is to use the combined moderate/severe AG as the study endpoint. This approach in an adequately powered study with validated USS classification gives receiver operating characteristic (area under the curve) values above 0.970 for PGI and greater than 0.950 for the PGI/PGII ratio 2–6. Another unique feature of the GP test is the interpretation of the results by specific software (GastroSoft Biohit Oyj, Helsinki, Finland), which is almost mandatory in their correct interpretation. The authors did not report using GastroSoft in their study 1. The role of the G-17 biomarker is more complex. Low levels of G-17 are not exclusively inherent to antral AG, but may also reflect high gastric acid output, whereas high volumes may result from the use of proton pump inhibitors 2,7,8. In fact, the use of G-17 is not recommended by the GP manufacturer for the diagnosis of antral AG. Finally, in a study including only 10 patients with (unclassified) AG in a clinical setting, one cannot draw any conclusions whatsoever on the use of the GP test in a screening setting. Such a setting would necessitate an adequately powered cohort of population-derived (asymptomatic) individuals, all being tested by GP, with all test positives (and random 5% of test negatives) to be confirmed by gastroscopy and validated biopsy classification, and, importantly, all performance indicators being corrected for verification bias by special statistical treatment.

In recent years, panintestinal capsule endoscopy (PCE) with double-headed capsules has been used to perform complete, single-sitting exploration of both small bowel and colon in different clinical conditions. Double-headed capsules for colonic examination (CCE) have been exploited first in this setting, followed by newer generations of capsules (i.e. PillCam Crohn, PCC) specifically engineered for this purpose. The aim of this study was to evaluate the feasibility of PCE in the form of a systematic review. We performed a comprehensive literature search to identify papers in which CE was specifically used for a PCE of the gastrointestinal tract. Data on CE, bowel preparation regimen, rate of cleanliness and completeness, and data on transit times were analyzed. The primary outcome was to assess the feasibility of a whole-gut exploration with CE. Sixteen (n = 16) studies including 915 CE procedures with CCE1 (n = 134), CCE2 (n = 357) and PCC (n = 424) were included. 13/16 studies were performed in the setting of Crohn's disease. Cleanliness and completeness rates were acceptable in all studies, ranging from 63.9% and 68.6% to 100%, respectively. In conclusion, PCE is a feasible technique, although further structured studies are needed to explore its full potential.

Objectives Anti-TNFα agents have been a staple of Crohn's disease treatment for 20 years, but they have weaknesses. New treatments have more recently become available. The aim of this paper is to examine the Crohn's disease patient population for whom anti-TNF treatments are not preferred and where new mechanisms of action should be considered. Methods A representative sample of 100 Italian physicians with documented expertise with biological treatment of moderate-to-severe Crohn's disease were interviewed. A literature review on Crohn's disease treatment was also conducted to identify patient populations for whom anti-TNFs are unsuitable. Results On the basis of the interviewed physicians, about 9% of moderate-to-severe Crohn's disease patients were noneligible to anti-TNFα due to contraindication or possible risk of intolerance, while 11% had discontinued anti-TNFα treatment due to complications or intolerance/hypersensitivity. Patients with severe heart disease and at high risk of infections were more frequently considered unsuitable. The proportion of patients considered unsuitable among elderly patients and in those with recurrent infections, cancer, and other comorbidities ranged between 40 and 60%. Conclusions We provided additional quantitative and qualitative information to help identify patients who are less suitable to anti-TNF agents, who could benefit from newer biologic agents with different mechanisms of action.

Hepatic encephalopathy (HE) is associated with a poor prognosis. There is no study on the prevention of recurrence of encephalopathy with L-ornithine L-aspartate (LOLA).We conducted a double-blind randomized controlled trial at a tertiary center. Consecutive patients with cirrhosis who had recovered from HE were randomized to receive LOLA (6 g thrice daily) or similar amount of placebo by computer-based randomization for 6 months. Patients were assessed by psychometric HE scores using five paper-pencil tests, critical flicker frequency test, arterial ammonia, and sickness impact profile scores at inclusion. Primary end point was development of overt HE.Of 306 patients, 150 patients were enrolled. HE recurred in nine (12.3%) of 73 and in 20 (27.7%) of 72 patients receiving LOLA and placebo, respectively (P=0.02), with hazard ratio of 0.389 (95% confidence interval=0.174-0.870). Mortality was similar in both groups (6.8 vs. 13.8%, P=0.18). At 6 months follow-up, there was a significant change in the psychometric hepatic encephalopathy score (2.53±2.18 vs. -0.01±1.92, P0.001), ammonia level (-23.58±14.8 vs. 1.41±13.34 μmol/l, P0.001), CFF (5.85±4.82 vs. 0.58±4.53, P0.001), and SIP scores (-7.89±5.52 vs. -0.95±4.25, P0.001) in patients treated with LOLA compared with placebo. On multivariate analysis, only MELD score predicted the recurrence of overt HE, with odds ratio of 2.21 (95% confidence interval: 1.526-3.204, P0.001).LOLA is effective in the secondary prophylaxis of HE and is associated with significant improvements in psychometric hepatic encephalopathy score, ammonia level, critical flicker frequency scores, and health-related quality of life.

BACKGROUND Adenoma detection rate (ADR) is defined as the number of colonoscopies with at least one adenoma, expressed as the ratio of the total number of colonoscopies performed. Recently, an application of a conversion factor to estimate the ADR from the polyp detection rate (PDR) was described. AIM In this meta-analysis, we examined the correlation between ADR and PDR in the published studies and assessed the relative ratio of these ratios for a better and more accurate estimation. METHODS English Medical literature searches were performed for 'PDR' AND 'ADR'. A meta-analysis was carried out for papers that fulfilled the inclusion criteria using comprehensive meta-analysis software. RESULTS Twenty-five studies and 42 sets of data, including 31 623 patients, from nine countries published till 31 August 2017, were found. Funnel plot did not indicate a significant publication bias. relative ratio for ADR calculated from PDR was 0.688, 95% confidence intervals: 0.680-0.695, P value of less than 0.0001 in the meta-analysis fixed model. Heterogeneity (the proportion of inconsistency in individual studies) between studies was significant, with Q=492.753, d.f. (Q) 41, P

Aim/Objective/Background Direct-acting oral anticoagulant drugs are marketed worldwide for the primary and secondary prevention and treatment of thromboembolic disorders. Rivaroxaban, an oral, direct factor Xa inhibitor, is one of the most used. Rivaroxaban-induced hepatotoxicity is unusual, although a number of adverse reports have recently been reported. Here, we report two new cases of rivaroxaban-induced hepatitis. Methods A systematic search of case reports on the MEDLINE database encompassing the years 2008–2016 was carried out.Additional references were obtained following a manual search of the retrieved papers. We report two new cases of adverse events occurred in patients treated with rivaroxaban (20 mg/die) to prevent systemic embolism, who presented with hepatocellular liver injury with onset at 8 weeks after initiation of the drug intake. Results Twenty-six cases were retrieved from MEDLINE (57.7% female, 42.3% male). Using the Roussel Uclaf Causality Assessment Method (RUCAM) scale, liver injury was classified as hepatocellular (42.3%), cholestatic (26.9%), or mixed (15.4%). Older age (≥65 years) was present as a risk factor in 57.7%. The time lapse between initiation of treatment and onset of hepatic injury ranged from 2 to 180 days (median: 15 days). Our two new patients were diagnosed with drug-induced liver injury (hepatocellular pattern) using the ‘consensus criteria’, for drug-induced liver injury. Their RUCAM scores were calculated and assessed as highly probable and probable, respectively. A clinical recovery after rivaroxaban withdrawal was observed. Conclusion Direct-acting oral anticoagulants have been commonly prescribed, even if safety issues regarding the use of these drugs are still an ongoing concern, especially in patients experiencing chronic liver disease. Dedicated postauthorization safety studies should be undertaken to better define rivaroxaban-induced drug-induced liver injury.

Patients with cirrhosis have a high incidence of portal vein thrombosis (PVT), and optimal management of PVT in cirrhotic patients remains unclear. Currently, there is no paper on optimal doses of enoxaparin for the management of PVT with cirrhosis.To evaluate the efficacy and safety of anticoagulation therapy with different doses of enoxaparin for PVT in cirrhotic patients with hepatitis B.Sixty-five patients with hepatitis B-related cirrhosis and acute PVT were treated by different doses of enoxaparin. All the patients were assigned randomly to two groups: one group received enoxaparin 1 mg/kg subcutaneously every 12 h and the other group received enoxaparin 1.5 mg/kg subcutaneously every 24 h. Clinical, biochemical evaluation, Doppler ultrasound, and contrast-enhanced computed tomography were performed during the anticoagulation treatment.Of the 65 patients, 51 patients (78.5%) achieved complete/partial recanalization of PVT after 6 months of anticoagulation therapy. Child-Pugh scores were lower in the 51 patients who achieved complete/partial recanalization than those of the 14 nonresponders (P0.01). No patients showed variceal bleeding during anticoagulation therapy in the two groups. The rates of nonvariceal bleeding with the use of 1.5 mg/kg every 24 h (23.5%) were higher than those with the use of 1 mg/kg every 12 h (6.4%).Anticoagulation therapy with different doses of enoxaparin for PVT in hepatitis B patients with cirrhosis is efficient and safe, and 1 mg/kg enoxaparin subcutaneously every 12 h is a better anticoagulation regimen in the treatment of PVT in cirrhotic patients.

Background and study aims The wide use of PET-CT for the staging of neoplasms has extended to enlarged lymph nodes of unknown origin. Nevertheless, upper abdominal and mediastinal nodes are accessible to endoscopic ultrasonography-fine needle aspiration (EUS-FNA), providing a cytological diagnosis, with a high diagnostic yield in previous reports. In this paper, we have compared the accuracy of both procedures in this particular setting. Patients and methods After the finding of a lymphadenopathy in a conventional CT, both PET-CT and EUS-FNA were performed. The endoscopist had no information about PET-CT results. FNA was performed after a systematic EUS exam, with a 25 G needle and no suction. We considered the pathologic results as the gold standard or, if not available, the patients' outcome as a surrogate marker. Results A total of 54 patients were included. Common locations of nodes included subcarinal space (33.3%), porta hepatis (31.5%), upper mediastinum (15%), peripancreatic (7.4%), and other locations (12.8%). Adequate specimens were obtained in 48/54 patients (89%). The most common diagnoses based on cytology were benign/reactive (42%), epidermoid carcinoma (8.4%), lymphoma (8.4%), and ductal adenocarcinoma of pancreatic origin (6.3%). PET was positive in 67% of patients. The sensitivity, specificity, positive predictive value, negative predictive value, and overall accuracy of EUS-FNA were 91.3, 100, 100, 92.5, and 95.8%, respectively. The same values for PET-CT were 75, 25, 50, 50, and 50%, respectively. Conclusion In our series, EUS-FNA has proven to be the best diagnostic procedure to accurately establish the etiology of isolated adenopathies, showing a much better diagnostic yield than PET-CT, the role of which should be re-evaluated in this setting.