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A dedicated ultrasound (US) score, the Gemelli Ultrasound Chronic Pancreatitis (USCP) score, could be useful in the follow-up of patients with chronic pancreatitis (CP). However, its role in the diagnosis of CP has not been investigated. We aimed to evaluate the role of the Gemelli USCP score in the diagnosis of CP and the agreement with standard imaging techniques. Ninety-three patients clinically suspected of having CP and referred to the pancreatic outpatient clinic of A. Gemelli Hospital for endoscopic ultrasound (EUS) were prospectively enrolled. All patients underwent pancreatic US to calculate the Gemelli USCP score. A receiver operating characteristic curve analysis was also performed to assess the performance of the US score in CP diagnosis. The Gemelli USCP score was inversely related to the Rosemont score for both total value (p0.0001) and each parameter evaluated (p0.0001). This score was significantly higher in patients with CP with an excellent area under the receiver operating characteristic curve (0.946) and the optimal cutoff of 5. Moreover, we found a significant correlation between the Gemelli USCP score and laboratory parameters related to pancreatic exocrine insufficiency (p0.0001). The development of a dedicated ultrasound score could be useful as a non-invasive tool in the diagnosis of CP.

Chronic inflammation due to hepatitis C virus (HCV) infection leads to liver fibrosis and rearrangement of liver tissue, which is responsible for the development of portal hypertension (PH) and hepatocellular carcinoma (HCC). The advent of direct-acting antiviral drugs has revolutionized the natural history of HCV infection, providing an overall eradication rate of over 90%. Despite a significant decrease after sustained virological response (SVR), the rate of HCC and liver-related complications is not completely eliminated in patients with advanced liver disease. Although the reasons are still unclear, cirrhosis itself has a residual risk for the development of HCC and other PH-related complications. Ultrasound elastography is a recently developed non-invasive technique for the assessment of liver fibrosis. Following the achievement of SVR, liver stiffness (LS) usually decreases, as a consequence of reduced inflammation and, possibly, fibrosis. Recent studies emphasized the application of LS assessment in the management of patients with SVR in order to define the risk for developing the complications of chronic liver disease (functional decompensation, gastrointestinal bleeding, HCC) and to optimize long-term prognostic outcomes in clinical practice.

BACKGROUND: The use of umbilical venous catheters (UVCs) in the perinatal period may be associated with severe complications, including the occurrence of portal vein thrombosis (PVT). AIM: To assess the incidence of UVC-related PVT in infants with postnatal age up to three months. METHODS: A systematic and comprehensive database searching (PubMed, Cochrane Library, Scopus, Web of Science) was performed for studies from 1980 to 2020 (the search was last updated on November 28, 2020). We included in the final analyses all peer-reviewed prospective cohort studies, retrospective cohort studies and case-control studies. The reference lists of included articles were hand-searched to identify additional studies of interest. Studies were considered eligible when they included infants with postnatal age up to three months with UVC-associated PVT. Incidence estimates were pooled by using random effects meta-analyses. The quality of included studies was assessed using the Newcastle-Ottawa scale. The systematic review was performed according to the Preferred Reporting Items for Systematic reviews and Meta-Analysis (PRISMA) guidelines. RESULTS: Overall, 16 studies were considered eligible and included in the final analyses. The data confirmed the relevant risk of UVC-related thrombosis. The mean pooled incidence of such condition was 12%, although it varied across studies (0%-49%). In 15/16 studies (94%), diagnosis of thrombosis was made accidentally during routine screening controls, whilst in 1/16 study (6%) targeted imaging assessments were carried out in neonates with clinical concerns for a thrombus. Tip position was investigated by abdominal ultrasound (US) alone in 1/16 (6%) studies, by a combination of radiography and abdominal US in 14/16 (88%) studies and by a combination of radiography, abdominal US and echocardiography in 1/16 (6%) studies. CONCLUSION: To the best of our knowledge, this is the first systematic review specifically investigating the incidence of UVC-related PVT. The use of UVCs requires a high index of suspicion, because its use is significantly associated with PVT. Well-designed prospective studies are required to assess the optimal approach to prevent UVC-related thrombosis of the portal system.

Hepatic venous pressure gradient (HVPG) is the gold standard for assessing the degree of portal hypertension (PH), but it is not suitable for routine clinical use. The recently developed ultrasonography techniques, dynamic contrast-enhanced ultrasound (D-CEUS) and liver stiffness (LS), have expanded the possibilities for noninvasive evaluation.To investigate the usefulness of D-CEUS and elastographic parameters in assessing the presence and degree of PH.This is a prospective monocentric study. Patients with liver cirrhosis referred for HVPG measurements underwent hepatic Doppler ultrasound, LS measurement, and D-CEUS with a second-generation contrast agent. Pearson's correlation and a receiver operating characteristic (ROC) curve analysis were performed to assess the role of noninvasive findings in predicting clinically significant PH (CSPH) and severe PH (SPH).46 consecutive patients (31 men; mean age±SD: 57±11 years) were enrolled. A significant positive correlation was noted between LS and HVPG (r = 0.809, p0.0001) with an area under the ROC curve of 0.923. A cut-off value of 24.2 kPa best predicted CSPH with a positive predictive value of 85%. Among the D-CEUS features, the area under the ROC curves of liver parenchyma peak intensity (PI-LP) was greater than the other indices both for CSPH and SPH (1.000 and 0.981, respectively). A PI-LP under 23.3 arbitrary units indicated the presence of CSPH with a sensitivity and a specificity of 100%.A multimodal ultrasound approach based on D-CEUS and LS might become a reliable predictor of CSPH and SPH and a useful alternative to HVPG.Der hepatische Venendruckgradient (HVPG) ist der Goldstandard zur Beurteilung des Schweregrads der portalen Hypertonie (PH), eignet sich jedoch nicht für den Einsatz in der klinischen Praxis. Die kürzlich entwickelten Ultraschalltechniken, der dynamische kontrastverstärkte Ultraschall (D-CEUS) und die Lebersteifigkeit (LS), haben die Möglichkeiten der nicht invasiven Untersuchung erweitert. ZIEL: Untersuchung des Nutzens von D-CEUS und elastografischen Parametern bei der Diagnose einer PH und Beurteilung ihres Schweregrads.Dies ist eine prospektive monozentrische Studie. Bei Patienten mit Leberzirrhose, die zur HVPG-Messung überwiesen wurden, wurden hepatischer Doppler-Ultraschall, LS-Messung und D-CEUS mit einem Kontrastmittel der 2. Generation durchgeführt. Es wurden eine Pearson-Korrelation und eine ROC-Kurvenanalyse (Receiver Operating Characteristic) durchgeführt, um die Rolle nicht invasiver Befunde bei der Vorhersage einer klinisch signifikanten PH (CSPH) und der schweren PH (SPH) zu bewerten.Es wurden 46 konsekutive Patienten (31 Männer; Durchschnittsalter ±SD: 57 ±11 Jahre) eingeschlossen. Eine signifikante positive Korrelation wurde zwischen LS und HVPG (r = 0,809, p0,0001) mit einer Fläche unter der ROC-Kurve von 0,923 festgestellt. Ein Cut-Off-Wert von 24,2 kPa erlaubte die beste Vorhersage für CSPH mit einem positiven Vorhersagewert von 85%. Unter den D-CEUS-Merkmalen war die Fläche unter den ROC-Kurven der Peak-Intensität des Leberparenchyms (PI-LP) sowohl für CSPH als auch für SPH größer (1,000 bzw. 0,981) als die anderen Indizes. Eine PI-LP unter 23,3 arbiträren Einheiten sprach für eine CSPH mit einer Sensitivität und einer Spezifität von 100%.Ein multimodaler Ultraschallansatz, basierend auf D-CEUS und LS, könnte ein zuverlässiger Prädiktor für CSPH und SPH sowie eine nützliche Alternative zum HVPG werden.

ObjectiveClinical diagnosis and approval of new medications for non-alcoholic steatohepatitis (NASH) require invasive liver biopsies. The aim of our study was to identify non-invasive biomarkers of NASH and/or liver fibrosis.DesignThis multicentre study includes 250 patients (discovery cohort, n=100 subjects (Bariatric Surgery Versus Non-alcoholic Steato-hepatitis - BRAVES trial); validation cohort, n=150 (Liquid Biopsy for NASH and Liver Fibrosis - LIBRA trial)) with histologically proven non-alcoholic fatty liver (NAFL) or NASH with or without fibrosis. Proteomics was performed in monocytes and hepatic stellate cells (HSCs) with iTRAQ-nano- Liquid Chromatography - Mass Spectrometry/Mass Spectrometry (LC-MS/MS), while flow cytometry measured perilipin-2 (PLIN2) and RAB14 in peripheral blood CD14+CD16−monocytes. Neural network classifiers were used to predict presence/absence of NASH and NASH stages. Logistic bootstrap-based regression was used to measure the accuracy of predicting liver fibrosis.ResultsThe algorithm for NASH using PLIN2 mean florescence intensity (MFI) combined with waist circumference, triglyceride, alanine aminotransferase (ALT) and presence/absence of diabetes as covariates had an accuracy of 93% in the discovery cohort and of 92% in the validation cohort. Sensitivity and specificity were 95% and 90% in the discovery cohort and 88% and 100% in the validation cohort, respectively.The area under the receiver operating characteristic (AUROC) for NAS level prediction ranged from 83.7% (CI 75.6% to 91.8%) in the discovery cohort to 97.8% (CI 95.8% to 99.8%) in the validation cohort.The algorithm including RAB14 MFI, age, waist circumference, high-density lipoprotein cholesterol, plasma glucose and ALT levels as covariates to predict the presence of liver fibrosis yielded an AUROC of 95.9% (CI 87.9% to 100%) in the discovery cohort and 99.3% (CI 98.1% to 100%) in the validation cohort, respectively. Accuracy was 99.25%, sensitivity 100% and specificity 95.8% in the discovery cohort and 97.6%, 99% and 89.6% in the validation cohort. This novel biomarker was superior to currently used FIB4, non-alcoholic fatty liver disease fibrosis score and aspartate aminotransferase (AST)-to-platelet ratio and was comparable to ultrasound two-dimensional shear wave elastography.ConclusionsThe proposed novel liquid biopsy is accurate, sensitive and specific in diagnosing the presence and severity of NASH or liver fibrosis and is more reliable than currently used biomarkers.Clinical trialsDiscovery multicentre cohort: Bariatric Surgery versus Non-Alcoholic Steatohepatitis, BRAVES, ClinicalTrials.gov identifier:NCT03524365.Validation multicentre cohort: Liquid Biopsy for NASH and Fibrosis, LIBRA, ClinicalTrials.gov identifier:NCT04677101.

Ultrasound (US) is frequently the first line imaging technique used in patients with abdominal pain and clinical suspicion of chronic pancreatitis (CP), but its role in the diagnosis and follow-up of CP is still controversial.We aimed to develop a dedicated score for the US staging of CP and to evaluate the agreement of this score with standard imaging techniques.Ninety consecutive patients with a diagnosis of CP referred to the pancreatic outpatient clinic of A. Gemelli Hospital between June and September 2018 were recruited in the study. Patients underwent pancreatic US to evaluate different morphological parameters to develop an US based score system, called the Gemelli UltraSound Chronic Pancreatitis (USCP) score.The Gemelli USCP score significantly increased according to the Cambridge score for both mean value (p0.0001) and each parameter evaluated (p0.0001). Moreover, we found a significant correlation between the score and laboratory parameters related to pancreatic exocrine insufficiency such as vitamin D, B9, and B12 deficiency and fecal elastase values (p0.0001).The development of a dedicated US score could be useful in the follow up of patients with CP as alternative non-invasive technique to standard radiological imaging.

Background: Contrast-enhanced ultrasound (CEUS) with second-generation contrast agents performed 1 month after hepatocellular carcinoma (HCC) treatment is almost as sensitive as contrast-enhanced computed tomography (CECT) in depicting the residual tumor. However, the efficacy of CEUS performed early after the procedure is still debated. Aim: We evaluated the diagnostic accuracy (DA) of CEUS for the assessment of tumor response shortly after locoregional therapy in patients with unresectable HCC. Methods: Ninety-four patients with 104 HCC lesions who were scheduled to receive percutaneous ethanol injection, radiofrequency ablation, transcatheter arterial chemoembolization, or combined treatment were enrolled in this study. With CECT at 1-month as the reference standard, the DA of CEUS performed 48-h after the procedure was evaluated. Patients were followed-up to look for tumor or disease progression. Results: Based on CECT findings, 43/104 lesions were diagnosed as having residual viability after 1 month. CEUS performed 48 h after treatment detected residual tumor in 34/43 nodules with treatment failure at CECT with a sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of 79.1, 96.7, 94.4, 86.8, and 89%, respectively. There was a high degree of concordance between CEUS and CECT (kappa coefficient = 0.78). A hyperemic halo was detectable in 35 lesions without a statistically significant difference between concordant and discordant cases. In patients with uninodular disease responders according to 48 h CEUS had a significantly longer mean overall survival and time to progression compared to nonresponders. Conclusion: CEUS performed 48 h after treatment can be considered a reliable modality for the evaluation of the real extent of necrosis and has prognostic value in the assessment of HCC.

OBJECTIVES Intersystem variability in liver stiffness (LS) quantification with ultrasound shear wave elastography (SWE) precludes direct comparison of results obtained with different equipment. The aim of this study was to investigate the agreement between point-SWE and 2-dimensional-SWE with Esaote-MyLab 9 (p-QElaXto and 2D-QElaXto, respectively) and 2D-SWE with SuperSonic Imagine (SSI) in order to assess specific LS thresholds for fibrosis staging with QElaXto techniques, using SSI as a reference standard. METHODS A total of 235 compensated chronic liver disease (CLD) patients without comorbidities potentially affecting LS were enrolled in the study. Among them, 101 patients underwent also liver biopsy. Agreement between the equipment was assessed with Pearson coefficient and Bland-Altman analysis, while cut-off values were calculated with receiver operating characteristics analysis. RESULTS Correlation between 2D-QElaXto and p-QElaXto with SSI resulted very good (r = 0.898 and r = 0.866), especially in precirrhotic stages, with a mean difference between LS values of -1.3 kPa for 2D-QElaXto and -0.6 kPa for p-QElaXto compared with SSI. Cut-off thresholds for diagnosing fibrosis ≥F2, ≥F3, and F4 in non-HBV-related CLD were, respectively, 5.5, 8.0, and 10.6 kPa for 2D-QElaXto and 6.1, 8.1, and 11.7 kPa for p-QElaXto. All three SWE techniques were effective in differentiating significant fibrosis ≥F2 from mild or absent fibrosis in the subgroup of patients submitted to biopsy and showed good feasibility. CONCLUSIONS Correlation between QElaXto techniques and SSI in LS measurements is very good. Our study identifies for the first time cut-off thresholds for fibrosis staging in non-HBV-related CLD using two QElaXto techniques.

Portal vein thrombosis (PVT) represents a well-known complication during the natural course of liver cirrhosis (LC), ranging from asymptomatic cases to life-threating conditions related to portal hypertension and hepatic decompensation. Portal flow stasis, complex acquired hypercoagulable disorders and exogenous factors leading to endothelial dysfunction have emerged as key factors for PVT development. However, PVT occurrence remains unpredictable and many issues regarding its natural history, prognostic significance and treatment are still elusive. In particular although spontaneous resolution or disease stability occur in most cases of PVT, factors predisposing to disease progression or recurrence after spontaneous recanalization are not clarified as yet. Moreover, PVT impact on LC outcome is still debated, as PVT may represent itself a consequence of liver fibrosis and hepatic dysfunction progression. Anticoagulation and transjugular intrahepatic portosystemic shunt are considered safe and effective in this setting and are recommended in selected cases, even if the safer therapeutic option and the optimal therapy duration are still unknown. Nevertheless, their impact on mortality rates should be addressed more extensively. In this review we present the most debated questions regarding PVT, whose answers should come from prospective cohort studies and large sample-size randomized trials.

Background & Aims Although the discriminative ability of the model for end-stage liver disease (MELD) score is generally considered acceptable, its calibration is still unclear. In a validation study, we assessed the discriminative performance and calibration of 3 versions of the model: original MELD-TIPS, used to predict survival after transjugular intrahepatic portosystemic shunt (TIPS); classic MELD-Mayo; and MELD-UNOS, used by the United Network for Organ Sharing (UNOS). We also explored recalibrating and updating the model. Methods In total, 776 patients who underwent elective TIPS (TIPS cohort) and 445 unselected patients (non-TIPS cohort) were included. Three, 6 and 12-month mortality predictions were calculated by the 3 MELD versions: discrimination was assessed by c-statistics and calibration by comparing deciles of predicted and observed risks. Cox and Fine and Grey models were used for recalibration and prognostic analyses. Results In the TIPS/non-TIPS cohorts, the etiology of liver disease was viral in 402/188, alcoholic in 185/130, and non-alcoholic steatohepatitis in 65/33; mean follow-up±SD was 25±9/19±21 months; and the number of deaths at 3-6-12 months was 57-102-142/31-47-99, respectively. C-statistics ranged from 0.66 to 0.72 in TIPS and 0.66 to 0.76 in non-TIPS cohorts across prediction times and scores. A post hoc analysis revealed worse c-statistics in non-viral cirrhosis with more pronounced and significant worsening in the non-TIPS cohort. Calibration was acceptable with MELD-TIPS but largely unsatisfactory with MELD-Mayo and -UNOS whose performance improved much after recalibration. A prognostic analysis showed that age, albumin, and TIPS indication might be used to update the MELD. Conclusions In this validation study, the performance of the MELD score was largely unsatisfactory, particularly in non-viral cirrhosis. MELD recalibration and candidate variables for an update to the MELD score are proposed. Lay summary While the discriminative performance of the model for end-stage liver disease (MELD) score is credited to be fair to good, its calibration, the correspondence of observed to predicted mortality, is still unsettled. We found that application of 3 different versions of the MELD in 2 independent cirrhosis cohorts yielded largely imprecise mortality predictions particularly in non-viral cirrhosis. Thus, we propose a recalibration and suggest candidate variables for an update to the model.

Aim To evaluate whether changes in bowel perfusion parameters measured by dynamic-CEUS (D-CEUS) can be used for monitoring response to therapy in active Crohn disease (CD). Methods Fifty-four CD patients were evaluated with d -CEUS before (T0) and after 2 (T1), 6 (T2) and 12 weeks (T3) of anti-TNFα therapy. Variations from baseline were calculated for: peak intensity, PI; area under the curve, AUC; slope of wash in, Pw; time to peak, TP; mean transit time, MTT (median percentage values) and were correlated with combined endoscopic/clinical response after 12 weeks and clinical relapse within 6 months. Results 70% of patients achieved combined endoscopic/clinical response (responders). The reduction in PI, AUC, Pw and MTT between T1 and T0 was higher in responders. Relapsers (21%) showed significantly lower reduction in delta PI and Pw at T1 and T2. At T3 they showed a new increase in PI and lower reduction in delta Pw. In relapsers, AUC showed a significantly lower decrease at T2 and T3, TP showed a significant reduction at T3 and MTT showed a progressive increase at the different time-points, reaching the statistical significance at T3. Conclusions d -CEUS might become a reliable predictor of combined endoscopic/clinical response and clinical relapse in CD.

Importance Interleukin-6 signal blockade has shown preliminary beneficial effects in treating aberrant host inflammatory response against SARS-CoV-2 leading to severe respiratory distress. Objective to describe the effect of off-label intravenous use of Sarilumab in patients with severe SARS-CoV-2-related pneumonia. Design Observational clinical cohort study. Setting Fondazione Policlinico Universitario A. Gemelli IRCCS as Italian Covid reference center. Participants Patients with laboratory-confirmed SARS-CoV-2 infection and respiratory distress with PaO2/FiO2 ratio Main outcomes and measures We describe the clinical outcomes of 53 patients with SARS-CoV-2 severe pneumonia treated with intravenous Sarilumab in terms of pulmonary function improvement or Intensive Care Unit (ICU) admission rate in medical wards setting and of live discharge rate in ICU treated patients as well as in terms of safety. Each patient received Sarilumab 400 mg administered intravenously on day 1, with eventual additional infusion based on clinical judgement, and was followed for at least 14 days, unless previously discharged or dead. No gluco-corticosteroids were used at baseline. Results Of the 53 SARS-CoV-2pos patients receiving Sarilumab, 39 (73.6%) were treated in medical wards (66.7% with a single infusion) while 14 (26.4%) in ICU (92.6% with a second infusion). The median PaO2/FiO2 of patients in the Medical Ward was 146(IQR:120-212) while the median PaO2/FiO2 of patients in ICU was 112(IQR:100-141.5), respectively. Within the medical wards, 7(17.9%) required ICU admission, 4 of whom were re-admitted to the ward within 5-8 days. At 19 days median follow-up, 89.7% of medical inpatients significantly improved (46.1% after 24 hours, 61.5% after 3 days), 70.6% were discharged from the hospital and 85.7% no longer needed oxygen therapy. Within patients receiving Sarilumab in ICU, 64.2% were discharged from ICU to the ward and 35.8% were still alive at the last follow-up. Overall mortality rate was 5.7% after Sarilumab administration: 1(2.5%) patient died in the Medical Ward whilst 2(14.2%) patients died in ICU, respectively. Conclusions and relevance IL-6R inhibition appears to be a potential treatment strategy for severe SARS-CoV-2 pneumonia and intravenous Sarilumab seems a promising treatment approach showing, in the short term, an important clinical benefit and good safety. Key points Question SARS-CoV-2 infection remains a disease with many unknown aspects for which there are no therapies with proven efficacy. To date, it is recognized that COVID-19 disease may lead to the development of a cytokine storm for which drugs as IL-6R inhibitors may have beneficial effect. Findings In this observational clinical study, we reported the efficacy and safety of intravenous Sarilumab use in SARS-CoV-2 severe pneumonia with a global resolution rate of 83.0% (89.7% in medical wards and 64.3% in ICU) and an overall mortality rate of 5.7%. Meaning IL-6R-inhibition is an effective approach for severe SARS-CoV-2 pneumonia and intravenous Sarilumab is a promising treatment approach leading to an important clinical benefit and good safety in the short term.

To date, no study has explored the potential role of ElastPQ, a novel point-SWE technique, in the assessment of clinically significant portal hypertension. The aim of our study was to determine a liver stiffness (LS) cut-off value measured by ElastPQ and laboratory parameters that could help to identify those patients who can safely avoid screening endoscopy.Data were collected on 1422 patients who underwent ElastPQ measurement from January 2013 to January 2016 in our Department. Inclusion criteria were a LS value of ≥7 kPa, an upper gastrointestinal endoscopy within 12 months and a diagnosis of compensated chronic liver disease. Exclusion criteria were history of decompensated liver disease, evidence of porto-spleno-mesenteric vein thrombosis and non-cirrhotic portal hypertension. Varices were graded as low-risk varices (grade2) or varices needing treatment (VNT, grade ≥2).The study included 195 patients (120 [61%] HCV, 171 [88%] Child-Pugh A). Varices were present in 35% cases, with 10% prevalence of VNT. According to ROC curve analysis, LS measurement and platelet count were evaluated as predictors of VNT. Overall, 75/195 (38%) met the 'BAVElastPQ' criteria (that is, LS 12 kPa and platelet count150 000/μL). Within this group, 11/75 (15%) had any grade of varices and only 1/75 (1%) had VNT. The BAVElastPQ criteria gave sensitivity of 0.95, specificity of 0.42, positive predictive value of 0.15 and negative predictive value of 0.99.The BAVElastPQ criteria correctly identified 99% of patients without VNT. By applying such criteria, we could have potentially avoided 38% of surveillance endoscopies in our cohort.

• Clinicians are looking for a reliable prognostic marker for patients with COVID-19. • In our cohort, clinical improvement was predicted by younger age and a NLR below 3. • Transfer to ICU was instead predicted by a NLR over 4 (p=0.046). • NLR is a fast, widely available and relatively inexpensive assessment. • NLR may be a useful tool in the early screening of patients with COVID-19.

PURPOSE: Hepatocellular adenoma (HCA) is a rare benign monoclonal neoplasm, recently categorized on genetic and histopathological basis into four subtypes with different biological behaviors. Since contrast-enhanced ultrasonography (CEUS) is nowadays a well-established technique for liver nodule characterization, the aim of our study was to assess CEUS features of HCAs to identify criteria that correlate with different HCA subtypes as compared to histopathologic examination and other imaging modalities. METHODS: We retrospectively analyzed data of patients with histology-proven HCA who underwent CEUS, computed tomography or magnetic resonance imaging (MRI) in seven different Italian ultrasound units. RESULTS: The study enrolled 19 patients (16 females; 69% with concomitant/prior use of oral contraceptives): the mean size of all HCAs was 4.2 cm (range 1.6–7.1 cm); 14/19 had inflammatory HCAs (I-HCA), 1/19 β-catenin-activated HCA, and the others unclassified HCAs. On CEUS, during the arterial phase, all but one HCA displayed a rapid enhancement, with 89% of these showing centripetal and 11% centrifugal filling pattern, whereas during the portal and late venous phase 58% of HCA showed washout and the remaining 42% displayed persistent enhancement. In particular, among I-HCAs 7/14 showed no washout, 3/14 and 4/14 showed washout in the portal or late phase, respectively. CONCLUSIONS: This dataset represents one of the few published experiences on HCAs and CEUS in Italy and shows that HCAs are hypervascularized in the arterial phase usually with a centripetal flow pattern and have a heterogeneous behavior in portal and late phase. In particular, occurrence of delayed washout on CEUS but not on MRI is frequently observed in the subtype of I-HCA.

Intestinal ultrasonography has emerged as a cheap, non-invasive and readily accessible modality for the assessment of a number of gastroenterological diseases. Over the last decade, particularly due to the widespread use of biological agents in Inflammatory Bowel Disease (IBD), guidelines regarding management and follow-up advise more regular disease assessment and surveillance in order to guide treatment adjustments, and provide more personalised care. Given the young age of the majority of patients with IBD the availability of an alternative modality to harmful radiation or the risks of endoscopy for this indication offers an appealing advantage. Intestinal ultrasonography has been shown to be as sensitive and specific for detecting IBD as both computed tomography and magnetic resonance enterography, and endoscopic evaluation. More recent developments in the technology of ultrasonography equipment and the use of intravenous contrast agents (contrast enhanced ultrasonography, known as CEUS), have significantly increased the ability to both detect disease location, determine the disease activity and also potentially the difference between fibrotic and inflammatory segments. This review focusses specifically on the value of CEUS for the diagnosis of both Crohn's disease and Ulcerative Colitis, in determining disease activity, extraintestinal complications, determination of fibrosis as well as its more recent use in assessing and predicting response to biological and immunosuppressive therapies.

Hepatocellular carcinoma (HCC) is one of the most common cancers in the world. A careful multidisciplinary assessment of tumor characteristics, liver function and physical status is required for proper therapeutic management. In recent years, several studies have supported the feasibility and benefit of combined therapy in the treatment of single large HCC, defined as those exceeding 3 cm in size. We present a case of combined treatment using radiofrequency ablation followed by trans-arterial chemoembolization with radiopaque embolic beads. The aim of this technical report was to describe the radiologic findings during combined radiofrequency ablation and radiopaque bead embolization, pointing out the differences and the potential advantages of using radiopaque beads compared with non-radiopaque beads. Furthermore, it is also the first report on using radiopaque beads in combined treatment for HCC.

Purpose To evaluate the diagnostic accuracy of shear-wave elastography (SWE) in identifying different degrees of fibrosis in a cohort of consecutive children and adolescents with nonalcoholic steatohepatitis (NASH). Materials and Methods Consecutive pediatric patients scheduled to undergo liver biopsy were studied with an ultrasonography-based SWE system. Elastography was performed in 68 of 69 patients with biopsy-proved NASH (37 boys and 31 girls; mean age, 12.6 years ± 2.48; age range, 8-17 years). The correlations among laboratory findings, liver stiffness, and fibrosis score were analyzed, and the area under the receiver operating characteristic curve (AUC) was used to assess the presence of any fibrosis (score ≥F1) or significant fibrosis (score ≥F2). Findings from histologic examination were used as the standard of reference. Results SWE showed a very high correlation with liver fibrosis (P.001) at univariate and multivariate analyses. The AUCs for the association of any and significant fibrosis were 0.92 (95% confidence interval [CI]: 0.86, 0.98) and 0.97 (95% CI: 0.95, 0.99), respectively. The intraclass correlation coefficient for absolute agreement was 0.95 (95% CI: 0.90, 0.97). Conclusion SWE is an accurate and reproducible noninvasive technique that efficiently depicts the presence of significant liver fibrosis and, less accurately, mild liver fibrosis in pediatric patients with nonalcoholic fatty liver disease. Larger clinical prospective studies are warranted to confirm SWE accuracy and establish threshold values for fibrosis grading in comparison or in combination with other noninvasive methods.

To date, there is no approved second-line treatment for patients dismissing sorafenib or ineligible for this treatment, so it would be useful to find an effective alternative treatment option. The aim of our study was to evaluate safety, feasibility and effectiveness of transarterial chemoembolisation with degradable starch microspheres (DSM-TACE) in the treatment of patients with advanced hepatocellular carcinoma (HCC) dismissing or ineligible for multikinase-inhibitor chemotherapy administration (sorafenib) due to unbearable side effects or clinical contraindications. Forty consecutive BCLC stage B or C patients (31 male; age, 70.6 ± 13.6 years), with intermediate or locally advanced HCC dismissing or ineligible for sorafenib administration, who underwent DSM-TACE treatment cycle via lobar approach were prospectively enrolled. Tumour response was evaluated on multidetector computed tomography based on mRECIST criteria. Primary endpoints were safety, tolerance and overall disease control (ODC); secondary endpoints were progression-free survival (PFS) and overall survival (OS). Technical success was achieved in all patients. No intra/peri-procedural death/major complications occurred. No signs of liver failure or systemic toxicity were detected. At 1-year follow-up, ODC of 52.5% was registered. PFS was 6.4 months with a median OS of 11.3 months. DSM-TACE is safe and effective as a second-line treatment in HCC patients dismissing or ineligible for sorafenib. • DSM-TACE is safe and effective as second-line treatment in HCC patients dismissing or ineligible for sorafenib • DSM-TACE allows the temporary occlusion of the smaller arterial vessels, improving overall therapeutic effectiveness by reducing the immediate wash-out of the cytostatic agent • DSM-TACE also decreases the risk of systemic toxicity and post-embolic syndrome

This study was designed to assess the feasibility and safety of a single-step combined therapy using radiofrequency ablation and transarterial chemoembolization (RFA + TACE) in patients with hepatocellular carcinoma (HCC) and uncontrolled coagulopathy. The study also aimed to compare the effectiveness of this approach with TACE alone, performed in a control group.One hundred and forty-three consecutive cirrhotic patients having a single HCC 8 cm were enrolled in this observational prospective single-center study from January 2010 to June 2017 and were divided, according to coagulation tests, into three groups (A: low risk; B: intermediate risk and C: high risk of bleeding). The feasibility and safety of a single-step combined treatment (RFA followed by TACE) were evaluated in terms of technical success rate, periprocedural complications, and laboratory values variations. Tumor response obtained at 1-month CT follow-up for group C was compared with that of control group, composed by 16 matched patients with severe coagulopathy and single HCC 8 cm, who underwent only TACE in a previous period, performed by the same operator.Technical success was achieved in all patients, without any major complications. Minor complications rate was significantly higher in group C after RFA; however, the patients were successfully treated with subsequent TACE therapy, without any differences between pre- and post-procedural laboratory values. One-month complete response rates were similar in all the three groups; however, the response rates of group C were significantly higher as compared to that of the control TACE Group (p .001).The single-step RFA plus TACE therapy allows expansion of the indication for percutaneous thermal ablation, allowing to also include cases previously contraindicated due to the procedural high-risk of complications associated with bleeding, thus improving short-term patient outcome.

Atopic dermatitis (AD) is the most frequent chronic inflammatory skin disorder in children and is usually accompanied by genetic and environmental factors. Effective management and treatment of AD is challenging and often requires systemic immunosuppressive therapy when refractory to topical treatments. We report a rare association between chronic hepatitis C virus (HCV) and severe AD, management of which required systemic cyclosporine because of its favorable effects on inflammatory and viral-related clinical outcomes.

To compare transfemoral approach (TFA) and transradial approach (TRA) in patients undergoing hepatic chemoembolization in terms of safety, feasibility, and procedural variables, including fluoroscopy time, radiation dose (reference air kerma [RAK]), and patient preference.A single-center prospective intrapatient comparative study was conducted with 42 consecutive patients with hepatic malignancies who received 2 consecutive treatment sessions of unilobar hepatic chemoembolization within a 4-week interval over a 6-month period with both TRA and TFA. All procedures were performed by 1 interventional radiologist who assessed the eligibility of patients for inclusion in the study. The primary endpoint was intraprocedural conversion rate. Secondary endpoints were access site complications, angiographic and procedural variables, and evaluation of patient discomfort and preferences.A 100% technical success rate and a crossover rate of 0% were recorded. There were no major vascular complications and similar rates of minor complications (4.8% for TRA, 7.1% for TFA; P = .095), which were self-limited and without any clinical sequelae. TRA treatments required a significantly longer preparation time for the procedure (P = .008) with no significant differences for other procedural variables. Greater discomfort at the access route and patient inability to perform basic activities after the procedure were recorded for TFA (P.001). TRA was preferred by 35 patients (35/42) for potential future transarterial procedures.TRA is safe and feasible for transarterial hepatic chemoembolization, with high technical success, low overall complications, and improved patient comfort.

Treatment of Helicobacter pylori infection is becoming a very relevant problem especially in industrialized Countries. Although different therapeutic regimens are currently available, treatment failure remains a growing problem in daily medical practice. Several factors could play a role in the eradication failure, but the most relevant are antibiotic resistance and patient's compliance. While Helicobacter pylori resistance to amoxicillin is rare, clarithromycin and metronidazole resistance varies significantly from close to zero up to 25%. However, metronidazole in vitro resistance exhibits a lower impact on eradication success because resistance in vitro does not reflect that in vivo. Specific guidelines have then been published, mostly based on antibiotic resistance among different geographic areas. Basically, first-line and second-line regimens have been well defined; concerning third-line treatment Maastricht III guidelines suggest to adopt a culture-based approach. Culture is, however, expensive, invasive and available only in few specialized centres. An alternative approach may be to use an empirical strategy, based on the avoidance of repeating similar eradicating schemes in the same patients during the course of different eradicating regimens. For this approach we propose the acronym DANCE (Different Antibiotic No Culture Eradicating) strategy. When correctly applied, this approach showed to reach successful eradication in up to 99.5% of Helicobacter pylori-positive patients.

We assessed the prognostic significance of infections in relation to current prognostic scores and explored if infection could be considered per se a distinct clinical stage in the natural history of cirrhosis.We included consecutive patients with cirrhosis admitted to a tertiary referral liver unit for at least 48 h over a 2-year period. Diagnosis of infection was based on positive cultures or strict established criteria. We used competing risk analysis and propensity score matching for data analysis.501 patients (63% male, 48% alcoholic liver disease, median Model of End-stage Liver Disease (MELD)=17) underwent 781 admissions over the study period. Portal hypertensive bleeding and complicated ascites were the commonest reasons of admission. The incidence of proven bacterial infection was 25.6% (60% community acquired and 40% nosocomial). Survival rates at 3, 6, 12, and 30 months were 83%, 77%, 71%, and 62% in patients without diagnosis of infection, vs. 50%, 46%, 41%, and 34% in patients with diagnosis of infection. Overall survival was independently associated with MELD score (hazards ratio (HR) 1.099), intensive care (ITU) stay (HR 1.967) and bacterial infection (HR 2.226). Bacterial infection was an independent predictor of survival even when patients who died within the first 30 days were excluded from the analysis in Cox regression (HR 2.013) and competing risk Cox models in all patients (HR 1.46) and propensity risk score-matched infected and non-infected patients (HR 1.67).Infection most likely represents a distinct prognostic stage of cirrhosis, which affects survival irrespective of disease severity, even after recovery from the infective episode.

Current expressions based on serum creatinine concentration overestimate kidney function in cirrhosis, leading to significant differences between "true" and calculated glomerular filtration rate (GFR). We compared the performance of the four-variable and six-variable Modification of Diet in Renal Disease and chronic kidney disease epidemiology with "true," or measured, GFR (mGFR) and the impact of this difference on Model for End-Stage Liver Disease (MELD) calculation. We subsequently developed and validated a GFR equation specifically for cirrhosis and compared the performance of the new derived formula with existing GFR formulae. We included 469 consecutive patients who had a transplant assessment between 2011 and 2014. mGFR was measured using plasma isotope clearance according to a technique validated in patients with ascites. A corrected creatinine was derived from the mGFR after application of the Modification of Diet in Renal Disease formula. Subsequently, a corrected MELD was calculated and compared with the conventionally calculated MELD. Stepwise multiple linear regression was used to derive a GFR equation. This was compared with the mGFR in independent external and internal validation sets of 82 and 174 patients with cirrhosis, respectively. A difference >20 mL/minute/1.73 m2 between existing formulae and mGFR was observed in 226 (48.2%) patients. The corrected MELD score was ≥3 points higher in 177 (37.7%) patients. The predicted equation (r2 = 74.6%) was GFR = 45.9 × (creatinine-0·836 ) × (urea-0·229 ) × (international normalized ratio-0·113 ) × (age-0.129 [Corrected November 29, 2016: originally written as "age-129."]) × (sodium0·972 ) × 0.809 (if female) × 0.92 (if moderate/severe ascites). An online calculator is available at http://rfh-cirrhosis-gfr.ucl.ac.uk. The model was a good fit and showed the greatest accuracy compared to that of existing formulae. Conclusion We developed and validated a new accurate model for GFR assessment in cirrhosis, the Royal Free Hospital cirrhosis GFR, using readily available variables; this remains to be tested and incorporated in prognostic scores in patients with cirrhosis. (Hepatology 2017;65:582-591).

When end stage liver disease occurs, liver transplantation is the only effective treatment available. In the past, liver transplantation was frequently accompanied by considerable bleeding complications and massive transfusion requirements, while only in recent years advances in operative management and a better understanding of the pathophysiology of coagulation have determined a better outcome for this major surgery. In addition, accumulating evidence shows that the overall haemostatic function in patients with cirrhosis facing liver transplantation may not be shifted towards a bleeding diathesis as traditionally believed, but that both bleeding episodes and thrombotic events may take place as major peri- and post-operative complications in patients undergoing liver surgery. The aim of this review paper is to offer an overview of recent developments that have gradually improved our understanding about the changes that may occur in the haemostatic system of patients undergoing liver transplantation, taking into account the best way to monitor them.

In the last years, the development in the oncology field has been huge and rapid. In particular, the evaluation of response to anti-tumour treatments has been being object of intense research, producing significant changes. Response assessment after therapy in solid neoplasias has always used radiological imaging techniques, with tumour size reduction representing a presumed therapeutic efficacy. However, with the introduction of anti-angiogenetic drugs the evaluation of tumour size has become unsuitable because some tumours, under treatment, show only tumour perfusion changes rather than lesion shrinkage. Between different imaging techniques with contrast-enhancement, contrast-enhanced ultrasound (CEUS) and, in particular, dynamic CEUS have arisen as a promising and non-invasive device for monitoring cancer treatments. Moreover, the introduction of perfusion software has even more refined the technique since it is able to provide quantitative parameters related to blood flow and blood volume that can be associated with tumour response and clinical outcome such as the progression free survival and the overall survival. Here, we give an overview of the current status of CEUS in monitoring hepatocellular carcinoma response to different kind of treatments.

The association of chronic hepatitis C virus (HCV) infection with a wide spectrum of cutaneous manifestations has been widely reported in the literature, with varying strength of epidemiological association. Skin diseases which are certainly related with chronic HCV infection due to a strong epidemiological and pathogenetic association are mixed cryoglobulinemia, lichen planus and porphyria cutanea tarda. Chronic pruritus and necrolytic acral erythema are conditions that may share a possible association with HCV infection, while several immune-mediated inflammatory skin conditions, such as psoriasis, chronic urticaria and vitiligo, have been only anecdotally reported in the setting of chronic HCV infection. Traditional interferon-based treatment regimens for HCV infection are associated with substantial toxicity and a high-risk of immune-related adverse events, while the advent of new direct-acting antivirals with sustained virological response and improved tolerability will open the door for all-oral, interferon-free regimens. In the new era of these direct acting antivirals there will be hopefully a renewed interest in extra-hepatic manifestations of HCV infection. The aim of the present paper is to review the main cutaneous HCV-related disorders - mixed cryoglobulinemia, lichen planus, porphyria cutanea tarda and chronic pruritus - and to discuss the potential impact of new antiviral treatments on the course of these extra-hepatic manifestations of chronic HCV infection.

Celiac disease (CD) is a chronic disease causing the inflammation of the proximal small intestine, in genetically predisposed individuals. This is triggered by the consumption of the gluten protein and the side effects of the disease are mitigated by a lifelong gluten-free diet (GFD) treatment. The predominant consequence of CD is malnutrition due to malabsorption (with diarrhea, weight loss, nutritional deficiencies, and altered blood parameters), especially in patients who do not show strict adherence to GFD treatment. Recent evidence shows that, despite a lifelong GFD, some functional disorders persist, such as compromised gallbladder function and motility, exocrine pancreatic insufficiency, increased gut permeability, small-intestinal bowel overgrowth, nonalcoholic fatty liver disease (NAFLD), lactose intolerance, and milk allergy. These abnormalities may predispose to the occurrence of overweight and obesity even in CD patients. This review focuses on the principal functional and metabolic disorders in both treated and untreated CD, ranging from alterations of the gastrointestinal system to impaired glucose and lipid metabolism and insulin secretion with the aim of providing new implications beyond a GFD, for an ad hoc nutrition treatment in these patients.

Examinations with a visualisation of the anatomy and pathology of the gastrointestinal (GI) tract are often necessary for the diagnosis of GI diseases. Traditional radiology played a crucial role for many years. Endoscopy, despite some limitations, remains the main technique in the differential diagnosis and treatment of GI diseases. In the last decades, the introduction of, and advances in, non-invasive cross-sectional imaging modalities, including ultrasound (US), computed tomography (CT), positron-emission tomography (PET), and magnetic resonance imaging, as well as improvements in the resolution of imaging data, the acquisition of 3D images, and the introduction of contrast-enhancement, have modified the approach to the examination of the GI tract. Moreover, additional co-registration techniques, such as PET-CT and PET-MRI, allow multimodal data acquisition with better sensitivity and specificity in the study of tissue pathology. US has had a growing role in the development and application of the techniques for diagnosis and management of GI diseases because it is inexpensive, non-invasive, and more comfortable for the patient, and it has sufficient diagnostic accuracy to provide the clinician with image data of high temporal and spatial resolution. Moreover, Doppler and contrast-enhanced ultrasound (CEUS) add important information about blood flow. This article provides a general review of the current literature regarding imaging modalities used for the evaluation of bowel diseases, highlighting the role of US and recent developments in CEUS.

Sorafenib has become the standard first-line treatment for patients with advanced HCC and acts by inducing alterations in tumor vascularity. We wanted to evaluate the feasibility of dynamic CEUS (D-CEUS) as a predictor of early tumor response to sorafenib and to correlate functional parameters with clinical efficacy end points.Twenty-eight HCC patients treated with sorafenib 400mg bid were prospectively enrolled. CEUS was performed at baseline (T0) and after 15 (T1) and 30 (T2) days of treatment. Tumor vasculature was assessed in a specific harmonic mode associated with a perfusion and quantification software (Q-Lab, Philips). Variations between T1/T2 and T0 were calculated for five D-CEUS functional parameters (peak intensity, PI; time to PI, TP; area under the curve, AUC; slope of wash in, Pw; mean transit time, MTT) and were compared for responders and non-responders. The correlation between D-CEUS parameters, overall survival (OS), and progression-free survival (PFS) was also assessed. A p value0.05 was considered statistically significant.The percentage variation at T1 significantly correlated with response in three D-CEUS parameters (AUC, PI and Pw; p=0.002,0.001, and 0.003, respectively). A decrease of AUC (p=0.045) and an increased/unchanged value of TP (p=0.029) and MTT (p=0.010) were associated with longer survival. Three D-CEUS parameters (AUC, TP, Pw) were significantly associated with PFS.D-CEUS provides a reliable and early measure of efficacy for anti-angiogenic therapies and could be an excellent tool for selecting patients who will benefit from treatment.

To the Editor: We read with great interest the article by Pozzoni et al. (1) about the effectiveness of Saccharomyces boulardii (S. boulardii) in the prevention of antibiotic-associated diarrhea (AAD) in adults. This is a carefully designed clinical trial, which was conducted with good methodology and low risk of bias. We agree with the authors that AAD prevention is an important topic, especially in hospitalized patients, since it increases costs and hospital length of stay. However, the results of the trial should be interpreted within the context of some limitations.

Background & Aims: Neo-adjuvant transarterial therapies are commonlyused for patients with HCC in the waiting list for liver transplantation (LT)to delay tumour progression, however, their effectiveness is not well-estab-lished. We studied the effect of pre-LT transarterial therapies on post-LTHCC recurrence, using the explanted liver histology to assess therapeutic effi-cacy and the predictors of response to these therapies. Methods: Weincluded 150 consecutive patients from our prospectively compiled database,listed for liver transplantation using the Milan criteria. Transarterial emboli-zation without chemotherapeutic agents was the transarterial therapyused as standard of care. PVA particles were the embolizing agent of choi-ce. Results: Sixty-seven (45%) patients had TAE as bridging therapy to livertransplantation, of which 60 were transplanted after 2001. The majority ofpatients (36, 54%) had partial tumour necrosis after transarterial therapy,whereas 22 (33%) had complete tumour necrosis and 9 (13%) had no necro-sis. HCC post-transplant recurrence was independently associated with noneo-adjuvant transarterial therapy (OR 5.395, 95% CI 1.289–22.577;P = 0.021) and the total radiological size of HCC nodules (OR 1.037, 95%CI 1.006–1.069; P = 0.020). Conclusions: Pre-transplant TAE with the morepermanently occluding PVA particles significantly reduces post-transplantHCC recurrence in patients within the Milan criteria.Hepatocellular carcinoma (HCC) is a major indicationfor liver transplantation (LT) in Europe, representing14% of transplants(1). The selection criteria currentlyused in most centres for listing patients with HCC arethe Milan criteria, i.e. a single lesion up to 5 cm diame-ter or up to three lesions all 3 cm (2). As livertransplantation has become an effective treatment forend-stage liver disease, there is increased organ demandwhich results in prolonged waiting list times (3). Longwaiting list times may result in tumour progression andthus high dropout rates as patients become ineligible,because of increasing tumour size, such that 6- and 12-month dropout rate because of tumour progression are11 and 57% respectively (4).Therefore, neo-adjuvant treatments while the patientis on the waiting list are used in many centres to delaytumour progression and decrease waiting list dropouts.Transarterial therapies [chemo-embolization (TACE) orbland embolization (TAE)], are probably the mostwidely used neo-adjuvant modalities (5). TACE is nor-mally considered as a palliative procedure in patientswho do not have surgical or transplant options andincreases survival in this setting as shown in randomizedcontrolled trials and meta-analyses (6, 7). However, arecent Cochrane meta-analysis has not shown benefit(8), but this evaluation has been disputed (9). In theneo-adjuvant setting, there is no robust evidence of effi-cacy, but there is some evidence of benefit from cohortstudies (10–13). It should be noted that TACE is not astandardized procedure, as reports document differentuse of embolic and chemotherapeutic agents, differentarterial selectivity before embolization, variable emboli-zation particle sizes and different schedules and indica-tions for repeat sessions (14). On the other hand, thetransplant population offers a unique opportunity tostudy objective responses to transarterial therapies basedon explant histology.In this study, we used a cohort of consecutivepatients transplanted for HCC to evaluate (a) the effectsof a uniform protocol of pre-LT transarterial therapies