Further decompensation in cirrhosis: Results of a large multicenter cohort study supporting Baveno VII statements.

BACKGROUND AND AIMS: The prognostic weight of further decompensation in cirrhosis is still unclear. We investigated the incidence of further decompensation and its effect on mortality in patients with cirrhosis. APPROACH AND RESULTS: Multicenter cohort study. The cumulative incidence of further decompensation (development of a second event or complication of a decompensating event) was assessed using competing risks analysis in 2028 patients. A 4-state model was built: first decompensation, further decompensation, liver transplant, and death. A cause-specific Cox model was used to assess the adjusted effect of further decompensation on mortality. Sensitivity analyses were performed for patients included before or after 1999. In a mean follow-up of 43 months, 1192 patients developed further decompensation and 649 died. Corresponding 5-year cumulative incidences were 52% and 35%, respectively. The cumulative incidences of death and liver transplant after further decompensation were 55% and 9.7%, respectively. The most common further decompensating event was ascites/complications of ascites. Five-year probabilities of state occupation were 24% alive with first decompensation, 21% alive with further decompensation, 7% alive with a liver transplant, 16% dead after first decompensation without further decompensation, 31% dead after further decompensation, and <1% dead after liver transplant. The HR for death after further decompensation, adjusted for known prognostic indicators, was 1.46 (95% CI: 1.23-1.71) ( p <0.001). The significant impact of further decompensation on survival was confirmed in patients included before or after 1999. CONCLUSIONS: In cirrhosis, further decompensation occurs in ~60% of patients, significantly increases mortality, and should be considered a more advanced stage of decompensated cirrhosis.

Accurate liquid biopsy for the diagnosis of non-alcoholic steatohepatitis and liver fibrosis.

OBJECTIVE: Clinical 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. DESIGN: This 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. RESULTS: The 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. CONCLUSIONS: The 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 TRIALS: Discovery 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.

Noninvasive Evaluation of Clinically Significant Portal Hypertension in Patients with Liver Cirrhosis: The Role of Contrast-Enhanced Ultrasound Perfusion Imaging and Elastography.

BACKGROUND: 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. AIMS: To investigate the usefulness of D-CEUS and elastographic parameters in assessing the presence and degree of PH. METHODS: 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). RESULTS: 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, p<0.0001) 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%. CONCLUSION: 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.

Multiparametric Dynamic Ultrasound Approach for Differential Diagnosis of Primary Liver Tumors.

A correct differentiation between hepatocellular carcinoma (HCC) and intracellular cholangiocarcinoma (ICC) is essential for clinical management and prognostic prediction. However, non-invasive differential diagnosis between HCC and ICC remains highly challenging. Dynamic contrast-enhanced ultrasound (D-CEUS) with standardized software is a valuable tool in the diagnostic approach to focal liver lesions and could improve accuracy in the evaluation of tumor perfusion. Moreover, the measurement of tissue stiffness could add more information concerning tumoral environment. To explore the diagnostic performance of multiparametric ultrasound (MP-US) in differentiating ICC from HCC. Our secondary aim was to develop an US score for distinguishing ICC and HCC. Between January 2021 and September 2022 consecutive patients with histologically confirmed HCC and ICC were enrolled in this prospective monocentric study. A complete US evaluation including B mode, D-CEUS and shear wave elastography (SWE) was performed in all patients and the corresponding features were compared between the tumor entities. For better inter-individual comparability, the blood volume-related D-CEUS parameters were analyzed as a ratio between lesions and surrounding liver parenchyma. Univariate and multivariate regression analysis was performed to select the most useful independent variables for the differential diagnosis between HCC and ICC and to establish an US score for non-invasive diagnosis. Finally, the diagnostic performance of the score was evaluated by receiver operating characteristic (ROC) curve analysis. A total of 82 patients (mean age ± SD, 68 ± 11 years, 55 men) were enrolled, including 44 ICC and 38 HCC. No statistically significant differences in basal US features were found between HCC and ICC. Concerning D-CEUS, blood volume parameters (peak intensity, PE; area under the curve, AUC; and wash-in rate, WiR) showed significantly higher values in the HCC group, but PE was the only independent feature associated with HCC diagnosis at multivariate analysis (p = 0.02). The other two independent predictors of histological diagnosis were liver cirrhosis (p < 0.01) and SWE (p = 0.01). A score based on those variables was highly accurate for the differential diagnosis of primary liver tumors, with an area under the ROC curve of 0.836 and the optimal cut-off values of 0.81 and 0.20 to rule in or rule out ICC respectively. MP-US seems to be a useful tool for non-invasive discrimination between ICC and HCC and could prevent the need for liver biopsy at least in a subgroup of patients.

Correlation Between QElaXto Techniques and Supersonic Imagine for Liver Stiffness Quantification in Chronic Liver Disease.

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.

Performance of the model for end-stage liver disease score for mortality prediction and the potential role of etiology.

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.

Assessing Baveno VI criteria with liver stiffness measured using a new point-shear wave elastography technique (BAVElastPQ study).

BACKGROUND AND AIMS: 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. METHODS: 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 (grade <2) or varices needing treatment (VNT, grade ≥2). RESULTS: 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 count >150 000/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. CONCLUSIONS: 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.

Contrast-Enhanced Ultrasound in the Short-Term Evaluation of Hepatocellular Carcinoma after Locoregional Treatment.

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.

TACE with degradable starch microspheres (DSM-TACE) as second-line treatment in HCC patients dismissing or ineligible for sorafenib.

OBJECTIVES: 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. METHODS: 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). RESULTS: 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. CONCLUSIONS: DSM-TACE is safe and effective as a second-line treatment in HCC patients dismissing or ineligible for sorafenib. KEY POINTS: • 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.

Development and validation of a mathematical equation to estimate glomerular filtration rate in cirrhosis: The royal free hospital cirrhosis glomerular filtration rate.

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).

Bacterial Infections Change Natural History of Cirrhosis Irrespective of Liver Disease Severity.

OBJECTIVES: 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. METHODS: 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. RESULTS: 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). CONCLUSIONS: Infection most likely represents a distinct prognostic stage of cirrhosis, which affects survival irrespective of disease severity, even after recovery from the infective episode.

Liver Stiffness in Pediatric Patients with Fatty Liver Disease: Diagnostic Accuracy and Reproducibility of Shear-Wave Elastography.

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. © RSNA, 2016.

Transradial versus Transfemoral Access for Hepatic Chemoembolization: Intrapatient Prospective Single-Center Study.

PURPOSE: 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. MATERIALS AND METHODS: 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. RESULTS: 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. CONCLUSIONS: TRA is safe and feasible for transarterial hepatic chemoembolization, with high technical success, low overall complications, and improved patient comfort.

Low-Dose Cyclosporine A in the Treatment of Severe Atopic Dermatitis Complicated by Chronic Hepatitis C Virus Infection.

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.

Prognostic value of liver stiffness in patients hospitalized for acute decompensated heart failure: a meta-analysis.

PURPOSE: Heart failure (HF) is a major health problem affecting millions of people worldwide. In the latest years, many efforts have been made to identify predictors of poor prognosis in these patients. The aim of this systematic review and meta-analysis was to enlighten the correlation between liver stiffness (LS), assessed by Shear Wave Elastography techniques, and HF, particularly focusing on the prognostic value of LS on cardiovascular outcomes. METHODS: We searched the PUBMED databases (up to May 1st, 2023) for studies that enlightened the correlation between LS and cardiovascular outcomes in patients hospitalized for acute decompensated heart failure (ADHF). We performed a meta-analysis to estimate the efficacy of LS in predicting the prognosis of patients with ADHF. RESULTS: We analyzed data from 7 studies, comprising 677 patients, that assessed the prognostic value of LS in predicting cardiovascular outcomes in patients hospitalized for ADHF. The pooled analysis showed that increased liver stiffness was associated with higher risk of adverse cardiac events (hazard ratio 1.07 [1.03, 1.12], 95% CI). CONCLUSION: Increased LS is associated with poor prognosis in patients hospitalized for HF and might help effectively identify those patients at high risk for worse outcomes.

Dynamic Contrast-Enhanced Ultrasound in the Prediction of Advanced Hepatocellular Carcinoma Response to Systemic and Locoregional Therapies.

Hepatocellular carcinoma (HCC) is the most frequent primary liver cancer and the sixth most common malignant tumor in the world, with an incidence of 2-8% per year in patients with hepatic cirrhosis or chronic hepatitis. Despite surveillance schedules, it is sometimes diagnosed at an advanced stage, requiring complex therapeutic efforts with both locoregional and systemic treatments. Traditional radiological tools (computed tomography and magnetic resonance) are used for the post-treatment follow-up of HCC. The first follow-up imaging is performed at 4 weeks after resection or locoregional treatments, or after 3 months from the beginning of systemic therapies, and subsequently every 3 months for the first 2 years. For this reason, these radiological methods do not grant the possibility of an early distinction between good and poor therapeutic response. Contrast-enhanced ultrasound (CEUS) and dynamic contrast-enhanced ultrasound (DCE-US) have gained the interest of several researchers for their potential role in the early assessment of response to locoregional treatments (chemoembolization) or antiangiogenic therapies in patients with advanced HCC. In fact, DCE-US, through a quantitative analysis performed by specific software, allows the construction of time-intensity curves, providing an evaluation of the parameters related to neoplastic tissue perfusion and its potential changes following therapies. It has the invaluable advantage of being easily repeatable, minimally invasive, and able to grant important evaluations regarding patients' survival, essential for well-timed therapeutic changes in case of unsatisfying response, and eventual further treatment planning.

Multimodal dynamic ultrasound approach as predictor of response in patients with Crohn's disease treated with ustekinumab.

Background: The approval of ustekinumab (UST) has opened new options for the treatment of Crohn's disease (CD), but potential markers predicting the efficacy of this interleukin-12/23 inhibitor are lacking. Contrast-enhanced ultrasound (CEUS) is non-invasive alternative to endoscopy, demonstrating early transmural changes after treatment induction. Objectives: We conducted a prospective monocentric study aiming to explore the value of multimodal intestinal ultrasound (IUS) in predicting the response to UST in patients with active CD who have been previously exposed to anti-tumour necrosis factor α (TNFα). Design and methods: Consecutive patients with moderate-to-severe CD involving the terminal ileum who were scheduled to begin UST therapy were enrolled between January 2020 and October 2021 in the inflammatory bowel diseases outpatient centre. A complete IUS evaluation, including B-mode, Doppler, dynamic CEUS and elastography, was performed at the time of induction (T0) and after 8 (T1), 16 (T2), 24 (T3) and 48 (T4) weeks of therapy. Each IUS parameter and their variations from baseline were correlated with endoscopic response and mucosal healing after 1 year. Results: A total of 52 patients were included, 29 (55.8%) of which reached endoscopic response at T4. The univariate analysis revealed that, between T3 and T0, the percentage changes of bowel wall thickness, Limberg score, mean signal intensity, rise time, wash-in rate, C reactive protein and Harvey-Bradshaw Index were associated with long-term therapeutic outcome. Based on the above parameters, we developed an IUS score that showed a good performance in predicting 1 year-endoscopic response (area under the curve: 0.91). Conclusion: Multimodal ultrasound could be helpful to predict long-term therapeutic outcome in patients with CD treated with UST. Registration: NCT05987501.

Using ultrasound to predict how well ustekinumab works in Crohn's disease patients Background:The introduction of Ustekinumab (UST) as a treatment for Crohn's disease (CD) has provided new options, but there's a need for reliable markers predicting how well this interleukin-12/23 inhibitor will work. Contrast-enhanced ultrasound (CEUS) is a non-invasive alternative to endoscopy, showing early transmural changes post-treatment. Objectives: In a prospective monocentric study, researchers aimed to explore the value of multimodal intestinal ultrasound (IUS) in predicting UST response in patients with active CD who had previous exposure to anti-tumor necrosis factor α (TNFα). The study involved patients with moderate to severe CD in the terminal ileum, scheduled for UST therapy. Design and methods: Consecutive patients were enrolled between January 2020 and October 2021. Complete IUS evaluations, including B mode, Doppler, dynamic CEUS, and elastography, were conducted at induction (T0) and after 8 (T1), 16 (T2), 24 (T3), and 48 (T4) weeks of therapy. Various IUS parameters and their changes from baseline were correlated with endoscopic response and mucosal healing after 1 year. Results: Of the 52 patients, 29 (55.8%) achieved endoscopic response at T4. The analysis showed that changes in bowel wall thickness, Limberg score, mean signal intensity, rise time, wash-in rate, C-reactive protein, and Harvey-Bradshaw Index between T3 and T0 were associated with long-term therapeutic outcomes. An IUS score developed from these parameters demonstrated good performance in predicting 1-year endoscopic response (area under the curve: 0.91). Conclusion: The study suggests that multimodal ultrasound could be a valuable tool in predicting the long-term therapeutic outcome for patients with CD treated with UST. This non-invasive approach offers insights into treatment response, potentially aiding in personalized treatment strategies for individuals with Crohn's disease.

Early prediction of response to sorafenib in patients with advanced hepatocellular carcinoma: the role of dynamic contrast enhanced ultrasound.

BACKGROUND & AIMS: 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. METHODS: 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 value <0.05 was considered statistically significant. RESULTS: 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. CONCLUSIONS: 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.

Transarterial embolization as neo-adjuvant therapy pretransplantation in patients with hepatocellular carcinoma.

BACKGROUND & AIMS: Neo-adjuvant transarterial therapies are commonly used for patients with HCC in the waiting list for liver transplantation (LT) to delay tumour progression, however, their effectiveness is not well-established. We studied the effect of pre-LT transarterial therapies on post-LT HCC recurrence, using the explanted liver histology to assess therapeutic efficacy and the predictors of response to these therapies. METHODS: We included 150 consecutive patients from our prospectively compiled database, listed for liver transplantation using the Milan criteria. Transarterial embolization without chemotherapeutic agents was the transarterial therapy used as standard of care. PVA particles were the embolizing agent of choice. RESULTS: Sixty-seven (45%) patients had TAE as bridging therapy to liver transplantation, of which 60 were transplanted after 2001. The majority of patients (36, 54%) had partial tumour necrosis after transarterial therapy, whereas 22 (33%) had complete tumour necrosis and 9 (13%) had no necrosis. HCC post-transplant recurrence was independently associated with no neo-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 more permanently occluding PVA particles significantly reduces post-transplant HCC recurrence in patients within the Milan criteria.