Search

Background and Aims: Circulating albumin in cirrhosis can be dysfunctional because of accumulating structural damages, leading to the concept of effective albumin concentration (eAlb), referring to the albumin portion presenting structural and functional integrity. We aimed to estimate eAlb in patients with decompensated cirrhosis and analyze its relationships with albumin function and clinical outcomes as compared to total albumin concentration (tAlb). Approach and Results: We evaluated 319 patients with cirrhosis hospitalized for acute decompensation (AD) with and without acute-on-chronic liver failure (ACLF) and 18 age- and sex-comparable outpatients with compensated cirrhosis. tAlb was quantified by standard assay, whereas eAlb was estimated combining liquid chromatography/electrospray ionization/mass spectrometry and standard methods. Albumin binding and detoxification efficiency were evaluated by electron paramagnetic resonance analysis. Circulating albumin in patients with decompensated cirrhosis displayed multiple structural abnormalities, with reversible oxidation and glycation being the most frequent. As a result, eAlb progressively declined with the worsening of cirrhosis and was superior to tAlb in stratifying patients between compensated cirrhosis, AD, and ACLF, as well as patients with and without complications. Moreover, eAlb, but not tAlb, was closely associated with binding capacities in ACLF. Finally, eAlb at admission predicted the occurrence of ACLF within 30 days and mortality at 90 days better than tAlb. Conclusions: This large, observational study provides the evidence in patients with decompensated cirrhosis that eAlb can be quantified and differentiated from tAlb routinely measured in clinical practice. As compared to tAlb, eAlb is more closely associated with disease severity and albumin dysfunction and carries a greater prognostic power. These results prompt future research assessing eAlb as a biomarker for predicting prognosis and treatment response.

Aging with multimorbidity and polytherapy are the most significant factors that could led to inappropriate prescribing of contraindicated medications in patients with chronic kidney disease (CKD). The aim of this study was to evaluate the prescriptions of contraindicated drugs in older adults in CKD and to identify their associated factors in a hospital context. An observational retrospective study was carried out considering all patients ≥65 years with at least one serum creatinine value recorded into the REPOSI register into 2010–2016 period. The estimated glomerular filtration rate (eGFR) was applied to identify CKD. A descriptive analysis was performed to compare demographic and clinical characteristics; logistic regression models were used to estimate factors of inappropriate and percentage changes of drug use during hospitalization. A total of 4,713 hospitalized patients were recorded, of which 49.8% had an eGFR 2; the 21.9% were in treatment with at least one inappropriate drug at the time of hospital admission with a decrease of 3.0% at discharge (p = 0.010). The probability of using at least one contraindicated drug was significantly higher in patients treated with more several drugs (OR 1.21, 95% CI 1.16–1.25, p p < 0.001; G5: 19.38, 11.51–32.64, p < 0.001). Low-dose acetylsalicylic acid was the contraindicated drug mainly used at the time of admission, reducing 1.2% at discharge. An overall increase in therapeutic appropriateness in hospitalized older patients with CKD was observed, despite a small percentage of therapeutic inappropriateness at discharge that underlines the need for a closer collaboration with the pharmacologist to improve the drug management.

Background: The results of the pivotal RESORCE trial led to the approval of the tyrosine kinase inhibitor regorafenib as second-line treatment in advanced hepatocellular carcinoma (HCC) after sorafenib failure. Data about prognostic factors in a second-line HCC setting are scarce. Objective: The aim of the present study was to investigate prognostic factors in a cohort of patients with advanced HCC treated with regorafenib after progressing on sorafenib. Methods: We retrieved the data of 259 patients affected by advanced HCC treated with regorafenib as second-line treatment from four different Italian institutions and one South Korean institution and performed a recursive partitioning analysis to build a score system. Results: At the first-step univariate analysis for overall survival (OS), alkaline phosphatase (ALP) was the most significant parameter and was chosen as the first node in our tree model. In the subpopulation of patients presenting with ALP ≤122 U/L (n=155) at baseline, the most statistically significant split was by progression-free survival (PFS) on previous sorafenib treatment, between patients with a PFS ≥ 6 months (n = 59) and patients with a PFS < 6 months (n = 96). In the subpopulation of patients with ALP ≤ 122 U/L and PFS to sorafenib ≥ 6 months, the final split was determined between patients with hepatitis B virus (HBV)-related liver disease (n = 22) and patients with no HBV-related liver disease (n = 37). In the subpopulation of patients presenting ALP >122 U/L (n = 104) at baseline, the most statistically significant split was by aspartate aminotransferase (AST) value, between patients with AST ≤ 56 U/L (n = 48) and patients with AST > 56 U/L (n = 56). We built the Regorafenib Prognostic Index (REP index) stratifying the population into “low-risk,” “medium-risk,” and “high-risk” groups. The difference in median OS between the three risk groups was statistically significant, being 20.8 months (95% confidence interval [CI] 10.0–46.3) in the “low-risk” group, 8.4 months (95% CI 7.2–1435.8) in the “medium-risk” group, and 5.5 months (95% CI 3.5–13.2) in the “high risk” group. The median PFS was 7.7 months (95% CI 3.7–19.3), 2.5 months (95% CI 2.1–28.8), and 2.4 months (95% CI 1.6–9.1) for the “low-risk,” “medium-risk,” and “high-risk” groups, respectively. Conclusion: The REP index is an independent prognostic factor for OS and PFS in patients with advanced HCC treated with regorafenib.

Background: To know burden disease of a patient is a key point for clinical practice and research, especially in the elderly. Charlson’s Comorbidity Index (CCI) is the most widely used rating system, but when diagnoses are not available therapy-based comorbidity indices (TBCI) are an alternative. However, their performance is debated. This study compares the relations between Drug Derived Complexity Index (DDCI), Medicines Comorbidity Index (MCI), Chronic Disease Score (CDS), and severe multimorbidity, according to the CCI classification, in the elderly. Methods: Logistic regression and Receiver Operating Characteristic (ROC) analysis were conducted on two samples from Italy: 2579 nursing home residents (Korian sample) and 7505 older adults admitted acutely to geriatric or internal medicine wards (REPOSI sample). Results: The proportion of subjects with severe comorbidity rose with TBCI score increment, but the Area Under the Curve (AUC) for the CDS (Korian: 0.70, REPOSI: 0.79) and MCI (Korian: 0.69, REPOSI: 0.81) were definitely better than the DDCI (Korian: 0.66, REPOSI: 0.74). All TBCIs showed low Positive Predictive Values (maximum: 0.066 in REPOSI and 0.317 in Korian) for the detection of severe multimorbidity. Conclusion: CDS and MCI were better predictors of severe multimorbidity in older adults than DDCI, according to the CCI classification. A high CCI score was related to a high TBCI. However, the opposite is not necessarily true probably because of non-evidence-based prescriptions or physicians’ prescribing attitudes. TBCIs did not appear selective for detecting of severe multimorbidity, though they could be used as a measure of disease burden, in the absence of other solutions.

Combined hepatocellular and cholangiocarcinoma (HCC-CC) is a rare primary liver cancer. It is constituted by neoplastic cells of both hepatocellular and cholangiocellular derivation. Different histology types of HCC-CC have been reported, hinting at heterogeneous carcinogenic pathways leading to the development of this cancer. Due to its rarity and complexity, mixed HCC-CC is a scantly investigated condition with unmet needs and unsatisfactory outcomes. Surgery remains the preferred treatment in resectable patients. The risk of recurrence, however, is high, especially in comparison with other primary liver cancers such as hepatocellular carcinoma. In unresectable or recurring patients, the therapeutic options are challenging due to the dual nature of the neoplastic cells. Consequently, the odds of survival of patients with HCC-CC remains poor. We analysed the literature systematically about the treatment of mixed HCC-CC, reviewing the main therapeutic options and their outcomes and analysing the most interesting developments in this topic with a focus on new potential therapeutic avenues.

The current epidemic of non-alcoholic fatty liver disease (NAFLD) is reshaping the field of hepatology all around the world. The widespread diffusion of metabolic risk factors such as obesity, type2-diabetes mellitus, and dyslipidemia has led to a worldwide diffusion of NAFLD. In parallel to the increased availability of effective anti-viral agents, NAFLD is rapidly becoming the most common cause of chronic liver disease in Western Countries, and a similar trend is expected in Eastern Countries in the next years. This epidemic and its consequences have prompted experts from all over the word in identifying effective strategies for the diagnosis, management, and treatment of NAFLD. Different scientific societies from Europe, America, and Asia-Pacific regions have proposed guidelines based on the most recent evidence about NAFLD. These guidelines are consistent with the key elements in the management of NAFLD, but still, show significant difference about some critical points. We reviewed the current literature in English language to identify the most recent scientific guidelines about NAFLD with the aim to find and critically analyse the main differences. We distinguished guidelines from 5 different scientific societies whose reputation is worldwide recognised and who are representative of the clinical practice in different geographical regions. Differences were noted in: the definition of NAFLD, the opportunity of NAFLD screening in high-risk patients, the non-invasive test proposed for the diagnosis of NAFLD and the identification of NAFLD patients with advanced fibrosis, in the follow-up protocols and, finally, in the treatment strategy (especially in the proposed pharmacological management). These difference have been discussed in the light of the possible evolution of the scenario of NAFLD in the next years.

Introduction Pain and frailty are prevalent conditions in the older population. Many chronic diseases are likely involved in their origin, and both have a negative impact on quality of life. However, few studies have analysed their association. Methods In light of this knowledge gap, 3577 acutely hospitalized patients 65 years or older enrolled in the REPOSI register, an Italian network of internal medicine and geriatric hospital wards, were assessed to calculate the frailty index (FI). The impact of pain and some of its characteristics on the degree of frailty was evaluated using an ordinal logistic regression model after adjusting for age and gender. Results The prevalence of pain was 24.7%, and among patients with pain, 42.9% was regarded as chronic pain. Chronic pain was associated with severe frailty (OR = 1.69, 95% CI 1.38–2.07). Somatic pain (OR = 1.59, 95% CI 1.23–2.07) and widespread pain (OR = 1.60, 95% CI 0.93–2.78) were associated with frailty. Osteoarthritis was the most common cause of chronic pain, diagnosed in 157 patients (33.5%). Polymyalgia, rheumatoid arthritis and other musculoskeletal diseases causing chronic pain were associated with a lower degree of frailty than osteoarthritis (OR = 0.49, 95%CI 0.28–0.85). Conclusions Chronic and somatic pain negatively affect the degree of frailty. The duration and type of pain, as well as the underlying diseases associated with chronic pain, should be evaluated to improve the hospital management of frail older people. Electronic Supplementary Material The online version of this article (10.1007/s40122-020-00202-3) contains supplementary material, which is available to authorized users.

Based on the assumption that characterizing the history of a disease will help in improving practice while offering a clue to research, this article aims at reviewing the history of nonalcoholic fatty liver disease (NAFLD) in adults and children. To this end, we address the history of NAFLD histopathology, which begins in 1980 with Ludwig’s seminal studies, although previous studies date back to the 19th century. Moreover, the principal milestones in the definition of genetic NAFLD are summarized. Next, a specific account is given of the evolution, over time, of our understanding of the association of NAFLD with metabolic syndrome, spanning from the outdated concept of “NAFLD as a manifestation of the Metabolic Syndrome”, to the more appropriate consideration that NAFLD has, with metabolic syndrome, a mutual and bi-directional relationship. In addition, we also report on the evolution from first intuitions to more recent studies, supporting NAFLD as an independent risk factor for cardiovascular disease. This association probably has deep roots, going back to ancient Middle Eastern cultures, wherein the liver had a significance similar to that which the heart holds in contemporary society. Conversely, the notions that NAFLD is a forerunner of hepatocellular carcinoma and extra-hepatic cancers is definitely more modern. Interestingly, guidelines issued by hepatological societies have lagged behind the identification of NAFLD by decades. A comparative analysis of these documents defines both shared attitudes (e.g., ultrasonography and lifestyle changes as the first approaches) and diverging key points (e.g., the threshold of alcohol consumption, screening methods, optimal non-invasive assessment of liver fibrosis and drug treatment options). Finally, the principal historical steps in the general, cellular and molecular pathogenesis of NAFLD are reviewed. We conclude that an in-depth understanding of the history of the disease permits us to better comprehend the disease itself, as well as to anticipate the lines of development of future NAFLD research.

Long non-coding RNAs (lncRNAs) are ncRNAs more than 200 nucleotides long that participate to a wide range of biological functions. However, their role in cancer is poorly known. By using an NGS-based approach we analyzed the intragenic and poliA-lncRNAs in hepatocellular carcinoma (HCC) and we assayed the relationships between their deregulated expression and clinical-pathological characteristics. The expression profile of lncRNAs was studied in a discovery series of 28 HCC and matched cirrhosis and was validated in an independent cohort of 32 HCC patients both in tissue and serum. The correlation between lncRNA expression and clinical-pathological variables, EMT markers and putative sponged microRNAs level were investigated. Functional experiments were performed in HCC-derived cell lines to clarify the role of selected lncRNAs in HCC. A panel of deregulated lncRNAs differentiated HCC from cirrhotic tissue. CASC9 and LUCAT1 were up-regulated in a subset of HCC-derived cell lines and in half of HCCs which displayed a lower recurrence after surgery. LUCAT1 and CASC9 silencing increased cell motility and invasion capability in HCC cells and influenced the EMT phenotype. LUCAT1 was demonstrated to directly sponge the onco-miR-181d-5p. Both LUCAT1 and CASC9 were secreted in exosomes, and higher circulating CASC9 levels were associated with tumor size and HCC recurrence after surgery, suggesting its potential usage as putative non-invasive prognostic biomarker of recurrence.

Background & Aims The use of contrast enhanced ultrasound (CEUS) for the diagnosis of hepatocellular carcinoma (HCC) in cirrhosis was questioned because of the risk of a false positive diagnosis in cases of cholangiocarcinoma. The American College of Radiology has recently released a scheme (CEUS Liver Imaging Reporting and Data System [LI-RADS®]) to classify lesions at risk of HCC investigated by CEUS. The aim of the present study was to validate this LI-RADS scheme for the diagnosis of HCC. Methods A total of 1,006 nodules from 848 patients with chronic liver disease at risk of HCC were collected in five Italian centers and retrospectively analyzed. Nodules were classified as LR-5, (HCC) if ≥1 cm with arterial phase hyperenhancement, and late washout (onset ≥60 s after contrast injection) of mild degree. Rim enhancement and/or early and/or marked washout qualified lesions as LR-M (malignant, but not specific for HCC). Other combinations qualified lesions at intermediate risk for HCC (LR-3) or probable HCC (LR-4). Diagnostic reference standard was CT/MRI diagnosis of HCC (n = 506) or histology (n = 500). Results The median nodule size was 2 cm. Of 1,006 nodules, 820 (81%) were HCC, 40 (4%) were cholangiocarcinoma, 116 (11%) regenerative nodules (±dysplastic). The LR-5 category (52% of all nodules) was 98.5% predictive of HCC, with no risk of misdiagnosis for pure cholangiocarcinoma. Sensitivity for HCC was 62%. All LR-M nodules were malignant and the majority of non-hepatocellular origin. Over 75% of cholangiocarcinomas were LR-M. The LR-3 category included 203 lesions (HCC 96 [47%]) and the LR-4 202 (HCC 173 [87%]). Conclusions The CEUS LI-RADS class LR-5 is highly specific for HCC, enabling its use for a confident non-invasive diagnosis. Lay summary This is a retrospective study of approximately 1,000 focal lesions at risk for hepatocellular carcinoma (HCC). Herein, we demonstrate that the refined definition of the typical contrast enhanced ultrasound pattern of HCC introduced by the Liver Imaging Reporting and Data System (LI-RADS®) practically abolishes the risk of misdiagnosis of other malignant entities ( e.g. cholangiocarcinoma) for HCC with negligible reduction in sensitivity. These data support the use of contrast enhanced ultrasound to diagnose HCC in cirrhosis.

SUMMARY Contrast-enhanced ultrasound (CEUS) is a sure, noninvasive, repeatable imaging technique widely used in the characterization of benign and malignant liver lesions. The European Federation of Societies for Ultrasound in Medicine and Biology guidelines suggest the typical CEUS features of liver lesions as criteria for the noninvasive diagnosis in cirrhotic and not-cirrhotic patients. The clinical application of CEUS in the liver study is summarized in this review; the contrast-enhanced patterns of the most frequent liver lesions are described (hepatocellular and cholangiocellular carcinoma, liver metastases, hemangioma, focal nodular hyperplasia, adenoma). The role of this imaging technique in the diagnostic algorithm of liver malignancy is illustrated and the CEUS application in hepatologic and oncological settings is depicted.

Background Few data exist on real-life adherence to international guidelines for the treatment of hepatocellular carcinoma. We analysed the rate of adherence to American Association for the Study of Liver Diseases guidelines, to identify reasons for discrepancy with treatments performed in our centre. Methods 227 consecutive cirrhotics with a first hepatocellular carcinoma diagnosis (2005–2010) were retrospectively evaluated and stratified based on Barcelona Clinic Liver Cancer system: 126 early, 50 intermediate, 40 advanced, and 11 end stage. Results Early hepatocellular carcinomas were theoretically eligible for resection ( n = 27), liver transplantation ( n = 36), and percutaneous treatment ( n = 63). In practice, 15/27 (55.5%), 31/36 (86.1%), and 22/63 (34.9%) respectively were treated as recommended. Reasons for discrepancy were age/comorbidity, tumour location, ultrasound visibility, surgical contraindications. Transarterial chemoembolisation was performed in 25/126 early hepatocellular carcinomas (19.8%), resection in 11/63 early hepatocellular carcinomas eligible for percutaneous treatment (17.5%). Transarterial chemoembolisation was excluded in 16/50 intermediate hepatocellular carcinomas (32%). Resection or transarterial chemoembolisation was performed in 6/40 advanced hepatocellular carcinomas (15%). Conclusion Overall, 60% of patients were treated according to American Association for the Study of Liver Diseases guidelines. Approximately 28% of hepatocellular carcinomas were “under-treated” and 7% treated more aggressively than recommended. Peculiarities of individual patients can lead the multidisciplinary team to personalise real-life treatments.

a b s t r a c t Background: The frequency with which patients in Child-Pugh B having hepatocellular carcinoma are treated following the international guidelines according to the Barcelona Clinic Liver Cancer stages is unknown. Aims: To investigate treatment allocation for Child-Pugh B patients in different tumour stages, with particular interest in the intermediate stage. Methods: Patients were retrospectively identified from a consecutively collected series. Treatment was carried out primarily according to the guidelines. Results: Of 86 Child-Pugh B patients, 45 were Barcelona early stage, of which the Child-Pugh scores were 46.7% B7, 33.3% B8, 20.0% B9; 27 patients were intermediate stage (B7 59.3%, B8 37.0% and B9 3.7% respectively), 12 were advanced (41.7% B7, 25.0% B8 and 33.3% B9) and 2 were terminal (both B9). In the intermediate stage, transarterial chemoembolization (or ablation) was performed in 68.8% of the Child- Pugh B7 patients, 50% of the B8 patients and 0% of the B9 patients. Median survival of the intermediate patients was 8.0 months (9.0 in B7 vs. 6.0 in -B8/B9, P = 0.048). Survival of the intermediate stage patients undergoing chemoembolisation was 22.0 months in Child-Pugh B7 and 6.0 in B8. Conclusions: Approximately half of the intermediate stage patients can undergo locoregional treatment with good survival when in the Child-Pugh B7. The Child-Pugh numeric score impacts survival, suggesting that this tumour stage be refined. © 2013 Published by Elsevier Ltd on behalf of Editrice Gastroenterologica Italiana S.r.l.

Noninvasive criteria for the diagnosis of hepatocellular carcinoma (HCC) in cirrhosis, recommended by the European Association for the Study of Liver (EASL) in 2001 and by the American Association for the Study of Liver Diseases (AASLD) in 2005, have left a number of small liver neoplastic nodules undefined. We designed this prospective study in 2003 with the aims of assessing the diagnostic contribution of vascular contrast-enhanced techniques and investigating the possible additional contribution of superparamagnetic iron oxide magnetic resonance (SPIO-MR) in this setting.Between 2003 and 2005, 75 consecutive small (10-30 mm) liver nodules detected at ultrasonography in 60 patients with cirrhosis were prospectively submitted to contrast-enhanced ultrasound (CEUS), helical-computed tomography (helical-CT), and gadolinium magnetic resonance (gad-MR), each blinded to the other. A total of 68 nodules were also studied with SPIO-MR at the same time as gad-MR.Using the EASL noninvasive criteria, the diagnosis of HCC was established in 44 of 55 (80%) nodules with a final diagnosis of HCC. Gad-MR was the most sensitive technique for detecting the typical vascular pattern. SPIO-MR showed a pattern consistent with HCC in 5 of 10 HCCs, not satisfying the EASL noninvasive criteria, and was negative in 17 of 18 (94.4%) nonmalignant nodules. The review of the present case series according to the AASLD criteria for the noninvasive diagnosis of HCC yielded a sensitivity rate of 81.8%.This study shows that both EASL and AASLD noninvasive recall strategies for nodules of 10-30 mm in the cirrhotic liver, based on the vascular pattern of nodules, have a false-negative rate of approximately 20%. SPIO-MR may increase the diagnostic potential of noninvasive techniques, contributing to the diagnosis of HCC lacking a typical vascular pattern.

The best prioritization of patients with hepatocellular carcinoma (HCC) waiting for liver transplantation under the model for end-stage liver disease (MELD) allocation system is still being debated. We analyzed the impact of a MELD adjustment for HCC, which consisted of the addition of an extra score (based on the HCC stage and waiting time) to the native MELD score. The outcome was analyzed for 301 patients with chronic liver disease listed for liver transplantation between March 1, 2001 and February 28, 2003 [United Network for Organ Sharing (UNOS)-Child-Turcotte-Pugh (CTP) era, 163 patients, 28.8% with HCC] and between March 1, 2003 and February 28, 2004 (HCC-MELD era, 138 patients, 29.7% with HCC). In the HCC-MELD era, the cumulative dropout risk at 6 months was 17.6% for patients with HCC versus 22.3% for those patients without HCC (P = NS), similar to that in the UNOS-CTP era. The cumulative probability of transplantation at 6 months was 70.3% versus 39.0% (P = 0.005), being higher than that in the UNOS-CTP era for patients with HCC (P = 0.02). At the end of the HCC-MELD era, 12 patients with HCC (29.3%) versus 57 without HCC (58.8%) were still on the list (P = 0.001). Both native and adjusted MELD scores were higher (P < 0.05) and progressed more in patients with HCC who dropped out than in those who underwent transplantation or remained on the list (the initial-final native MELD scores were 17.3-23.1, 15.5-15.6, and 12.8-14.1, respectively). The patients without HCC remaining on the list showed stable MELD scores (initial-final: 15.1-15.4). In conclusion, the present data support the strategy of including the native MELD scores in the allocation system for HCC. This model allows the timely transplantation of patients with HCC without severely affecting the outcome of patients without HCC. Liver Transpl 13:857–866, 2007. © 2007 AASLD.

a b s t r a c t This review illustrates the state of the art clinical applications and the future perspectives of ultrasound elastographic methods for the evaluation of chronic liver diseases, including the most widely used and validated technique, transient elastography, followed by shear wave elastography and strain imaging elastography. Liver ultrasound elastography allows the non-invasive evaluation of liver stiffness, provid- ing information regarding the stage of fibrosis, comparable to liver biopsy which is still considered the gold standard; in this way, it can help physicians in managing patients, including the decision as to when to start antiviral treatment. The characterization of focal liver lesions and the prognostic role of the elastographic technique in the prediction of complications of cirrhosis are still under investigation. © 2013 Elsevier Ireland Ltd. All rights reserved.

In a prospective study, we examined the impact of arterial hypervascularity, as established by the European Association for the Study of the Liver (EASL) recommendations, as a criterion for characterizing small (1-3 cm) nodules in cirrhosis. A total of 72 nodules (1-2 cm, n = 41; 2.1-3 cm, n = 31) detected by ultrasonography in 59 patients with cirrhosis were included in the study. When coincidental arterial hypervascularity was detected at contrast perfusional ultrasonography and helical computed tomography, the lesion was considered to be hepatocellular carcinoma (HCC) according to EASL criteria. When one or both techniques showed negative results, ultrasound-guided biopsy was performed. In cases with negative results for malignancy or high-grade dysplasia, biopsy was repeated when an increase in size was detected at the 3-month follow-up examination. Coincidental hypervascularity was found in 44 of 72 nodules (61%; 44% of 1-2-cm nodules and 84% of 2-3-cm nodules). Fourteen nodules (19.4%) had negative results with both techniques (hypovascular nodules). Biopsy showed HCC in 5 hypovascular nodules and in 11 of 14 nodules with hypervascularity using only one technique. All nodules larger than 2 cm finally resulted to be HCC. Not satisfying the EASL imaging criteria for diagnosis were 38% of HCCs 1 to 2 cm (17% hypovascular) and 16% of those 2 to 3 cm (none hypovascular). In conclusion, the noninvasive EASL criteria for diagnosis of HCC are satisfied in only 61% of small nodules in cirrhosis; thus, biopsy frequently is required in this setting. Relying on imaging techniques in nodules of 1 to 2 cm would miss the diagnosis of HCC in up to 38% of cases. Any nodule larger than 2 cm should be regarded as highly suspicious for HCC.

Tenosynovitis is an inflammation of the synovial sheath surrounding a tendon. This may be caused by a variety of etiological factors. Here we describe the case of a 40 year old diabetic patient who two months after liver transplantation developed left-hand purulent tenosynovitis. Tenosynovitis was diagnosed using ultrasound, found to be caused by cryptococcus neoformans, and successfully treated using antifungal therapy combined with ultrasound follow-up.

Purpose: To assess the impact of different vascular patterns at contrast-enhanced ultrasound (CEUS) on the characterization of small liver nodules (10 – 30 mm) in cirrhosis and to determine whether primary nodules and recurrent nodules (after a previously treated hepatocellular carcinoma) display variations in enhancement pattern. Materials and Methods: A total of 135 cirrhotic patients were evaluated. A diagnosis of hepatocellular carcinoma (HCC) was established according to AASLD Guidelines, based on imaging (computed tomography and/or magnetic resonance) or liver biopsy. All patients underwent CEUS. Different CEUS patterns were evaluated in terms of diagnostic accuracy: HYPER-HYPO: Arterial hyperenhancement followed by washout (hypoechoic appearance compared with surrounding parenchyma) in late phase; HYPER-ISO: Arterial hyperenhancement followed by isoenhancement (isoechoic appearance) in late phase; ISO-ISO: Isoenhancement in all vascular phases. Results: A total of 155 consecutive primary (n = 90) or recurrent (n = 65) nodules were detected. HCC was diagnosed in 127 nodules (71 primary, 56 recurrent). A characteristic HYPER-HYPO CEUS pattern was revealed in 52/127 (40.9 %) HCCs (31 primary, 21 recurrent) giving a positive predictive value (PPV) of 98 % (97 % primary, 100 % recurrent) and an accuracy of 51 % (54 % primary, 46 % recurrent). A HYPER-ISO pattern was noted in 46 HCCs (31 primary, 15 recurrent). Assuming this pattern to also be indicative of HCC, the PPV and accuracy were 94 % (93 % primary, 97 % recurrent) and 77 % (84 % primary, 68 % recurrent), respectively. An ISO-ISO pattern was present in 29 HCCs (9 primary, 20 recurrent) and 22 non-HCCs (14 primary, 8 recurrent). Conclusion: These data confirm that the HYPER-HYPO pattern at CEUS is definitely diagnostic for HCC in cirrhosis and that the HYPER-ISO pattern has a similar PPV, indicating that this pattern is highly suspicious for HCC. The ISO-ISO pattern was found in > 50 % of recurrent nodules and indicates a high risk of HCC.

To the Editor: The study by Suh and coworkers [1] addresses a hot topic, namely the possibility to predict prognosis (recurrence and survival) in patients submitted to curative treatments for early hepatocellular carcinoma (HCC). The authors conclude that patients submitted to radiofrequency ablation are at higher risk of local intrahepatic recurrence in comparison to surgery and that survival is compromised in case of increased production of a-fetoprotein (AFP) by prothrombin, induced by vitamin K absence-II (PIVKA-II), compared to all other groups (not increased AFP by PIVKA-II product or surgical resection). We agree with the conclusion of the higher risk of recurrence, as we recently demonstrated [2], but in our view the second conclusion is not sufficiently supported by evidence. Moreover, some incorrect reporting of data prevent a full understanding of the study. Regarding the latter point, results about AFP and PIVKA-II were reported as mean values. This is unacceptable, as such data are not expected to follow a Gaussian distribution, thus, mean values are poorly or totally non-informative or may even be misleading under these circumstances. Median values have to be reported. Moreover, readers cannot understand how many patients had normal values of these two parameters. Secondly, the authors themselves point out that patients submitted to ablation had a slightly more compromised liver function than surgical patients. It is evident that cirrhotic patients with poorer liver function have a worse overall survival, regardless of the tumours status. We have recently shown in this Journal that resection may apparently provide better survival in early HCC, but only when entire patient series are analysed [2]. Such difference disappeared in very early HCC when patients were balanced in terms of background liver function and tumour features [2]. Suh and colleagues [1] did not show whether the four subgroups were superimposable in terms of highly relevant factors, such as liver function variables, tumour size and number, thus making the issue of survival questionable. This would be recommendable, especially in the two groups of patients, submitted to ablation, for which the information, derived from histology on which prognosis was designed, was not available. Thus, a re-analysis of the Korean data appears to be well-deserved before the conclusions, proposed by the authors, can be adopted.

AIM: Primary aim was to validate the percentage of intrahepatic cholangiocarcinomas (ICC) which have a contrast vascular pattern at contrast enhanced ultrasound (CEUS) at risk of misdiagnosis with hepatocellular carcinoma (HCC) and, secondary aim, to verify if any characteristics in the CEUS pattern helps to identify ICC. METHODS: All ICC on cirrhosis seen in three Italian centres (Bologna, Milan and Pavia) between 2003 and 2011, in which CEUS and at least another imaging technique (CT or MRI) had been performed, were retrospectively identified. Those patients with ICC size comparable to the early HCC stage (Milan criteria, considered as small ICC) were enrolled for this study. The enhancement pattern at CEUS was analysed and compared with CT or MRI. RESULTS: A total of 25 small ICC made this study group. CEUS was at risk of misdiagnosis of ICC for HCC in a significantly higher number of cases than in CT (performed in 24 ICC) (52% vs. 4.2%, P = 0.009) and MRI (11 ICC) (52% vs. 9.1%, P = 0.02). A different contrast pattern among all techniques was found in 6 of 10 ICC lesions submitted to the three imaging methods. In the arterial phase, ICC lacked global hyperenhacement in approximately 50% of cases at CEUS and the degree of intensity of wash-out in the late phase was marked in 24% of nodules. CONCLUSIONS: CEUS misdiagnosed as HCC a significantly higher number of ICC lesions in cirrhotic patients than CT and MRI. However, some CEUS contrast features can help suspect ICC, especially in some cases with inconclusive CT or MRI.

Background & Aims Aim of the study was to assess the clinical impact of conventional transarterial chemoembolization (cTACE) repeated "on demand" on HCC outcome. Outcome measures were: response rate to first and repeated cTACE, recurrence rates and overall survival. Methods The outcome of 151 consecutive HCC patients submitted to a first cTACE from January 2004 to December 2005 was retrospectively analyzed. Results Complete radiological response (CR) was observed in 72/151 (48%), 34/60 (52%) and 12/22 (55%) patients after first, second and third cTACE, respectively. Recurrence rates at 6 and 12months were 37% and 61% after the first cTACE, and 40% and 59% after the second cTACE, respectively. Patients not achieving CR or with a recurrence after CR not treated with curative therapies were 94 and 84 after first and second cTACE, respectively. Of these, 60/94 (64%) and 22/84 (26%) were submitted to a second and third cTACE, respectively. Median overall survival was 32.0months but 25.0months excluding transplanted patients. Factors at the time of first cTACE associated with overall shorter survival at multivariate analysis were higher bilirubin, higher AFP and not achieving CR. Conclusions CR and recurrence rates after first and second cTACE were similar. About 64% of patients were submitted to second cTACE, while only few patients (26%) were submitted to third cTACE using an "on demand" policy. These figures may be also useful for planning trials for the evaluation of the efficacy of repeated TACE vs . TACE combined with adjuvant treatments or vs . systemic treatments.

Background Which is the least expensive recall policy for nodules in the cirrhotic liver remains unclear. Aim Aim of the study was to analyze the costs of different recall diagnostic strategies of hepatocellular carcinoma (HCC) on cirrhosis on a real series of patients. Methods 75 consecutive small liver nodules (10–30 mm) detected at conventional ultrasonography in 60 patients with cirrhosis were submitted to contrast-enhanced ultrasound, computed tomography and gadolinium-magnetic resonance imaging with a final diagnosis established according to the latest guidelines which include different strategies for nodules 10–19 mm or ≥20 mm. The actual costs required to fully characterise any nodule and staging HCC in every patient, if one or the other imaging modality had been used as the first diagnostic step, were calculated. The theoretical hypothesis that each nodule was present in each patient was also investigated from an economical point of view. Results The recall strategy starting with contrast-enhanced ultrasound plus computed tomography is the least expensive strategy for patients with at least one nodule 10–19 mm in size, in nearly all combinations (single or double nodules). In patients with single 20–30 mm nodules the least expensive strategy is to start with computed tomography and to use contrast-enhanced ultrasound as a second step technique. Conclusions wider use of contrast-enhanced ultrasound has the potential to save healthcare costs after first ultrasound detection of a single small nodule in cirrhosis.

The aim of this study was to identify the most common patterns of various common liver lesions at real-time contrast-enhanced ultrasonography with second-generation contrast agents and their role in the differentiation of malignant from benign lesions.The enhancement pattern in the arterial phase and its modifications in subsequent portal and sinusoidal phases were separately evaluated in (i) 171 liver lesions detected at conventional ultrasonography in 125 noncirrhotic patients (87 metastases, six cholangiocellular carcinoma, 38 focal nodular hyperplasia, 30 hemangiomas, seven focal fatty sparing/changes, two hepatocellular adenomas and one hepatocellular carcinoma) and (ii) 75 lesions detected in 67 cirrhotic patients (66 hepatocellular carcinoma and nine dysplastic nodules). The final diagnosis was made by contrast-enhanced helical computed tomography and/or magnetic resonance imaging or by ultrasonography-guided biopsy when the diagnosis was equivocal at conventional imaging techniques (45 lesions).In noncirrhotic patients, the hypoechoic pattern in portal and sinusoidal phase (rapid washout) or the markedly hypoechoic or anechoic pattern in sinusoidal phase (marked late washout) showed a sensitivity, specificity and accuracy of 96.8, 100 and 98.2% for the diagnosis of malignancy. In cirrhotic patients, early arterial enhancement showed a sensitivity of 93.9% for the diagnosis of malignancy, with a specificity as low as 55.5% given the presence of arterial enhancement in 5/9 nodules resulted dysplastic at histological analysis.Real-time contrast-enhanced ultrasonography provides sensitive and specific criteria for the differential diagnosis between benign and malignant liver lesions, and in most cases it may replace more expensive and invasive imaging techniques.

Fitz-Hugh-Curtis is a rare syndrome characterised by perihepatitis following pelvic inflammatory disease. We report the case of a patient with a right ovarian teratoma, abnormal liver tests and pain in the right abdomen and shoulder, initially attributed to an acalculous cholecystitis. Before gynaecological surgery, a repeat ultrasound scan found several small avascular peritoneal masses at the upper dome of the liver, not reported in the initial examination. This prompted laparoscopic exploration of the subdiaphragmatic space, and the final diagnosis of Fitz-Hugh-Curtis-syndrome was made. Such ultrasound finding appears to be a new diagnostic feature of this syndrome.

A case is reported in which a several-fold increase in transaminases and gamma-GT was detected in an elderly male patient with fatty liver. The patient was regularly taking a mixture of herbal products, used as a laxative, for a number of years, with no alteration of blood chemistry until 6 months before the present observation. However, the composition of the mixture had been modified by the manufacturer in the past 5 months, with addition of boldo leaf extracts. Transaminases promptly returned to normal after withdrawal of the laxative. It is concluded that boldo leaf extracts might be hepatotoxic, at least in elderly patients with fatty liver.

The action pathways of nitrates are hypothesised to be deranged in cirrhosis.In order to confirm it, the acute haemodynamic effects of isosorbide-5-mononitrate in cirrhotic patients and controls was investigated.Nine cirrhotics and nine healthy controls.Evaluation in the fasting state, 90 min after isosorbide-5-mononitrate or placebo (double-blind on two different days) and then 30 and 120 min after eating a standard meal. Various systemic and splanchnic haemodynamic parameters, including arterial impedance, assessed as Doppler pulsatility index, were measured.isosorbide-5-mononitrate reduced arterial pressure and increased heart rate and mesenteric pulsatility index both in controls and in cirrhotics, whereas the following parameters behaved differently in the two groups (P0.05): hepatic pulsatility index decreased (-9%) and the portal velocity increased (+13%) in controls, whereas hepatic pulsatility increased (+18%) and portal velocity decreased (-18%) in cirrhotics. The two groups presented a similar pattern of changes in most variables under placebo after a meal. In controls, the administration of isosorbide-5-mononitrate blunted the postprandial mesenteric vasodilation and related changes in splanchnic and systemic circulation, expected at 30 min, in comparison to those observed under placebo. In cirrhotics, instead, the postprandial pattern was similar under placebo and isosorbide-5-mononitrate.The acute administration of isosorbide-5-mononitrate produces different haemodynamic effects in healthy and diseased livers, both in the fasting state and after a meal, consistent with the hypothesis of a deranged response of the intrahepatic microcirculation to nitrates in cirrhosis.

Epithelioid hemangioendothelioma (EH) is a rare tumor arising from the vascular endothelial cells of soft tissue or visceral organs. The most common visceral site is the liver, where it is often involved in a multifocal manner known as hepatic EH (HEH). Surgical resection with curative intent represents the gold standard therapy. When surgery is not feasible, or in cases of metastatic disease, no standard medical treatment is currently indicated. In small series, drugs with anti-angiogenic activity (such as bevacizumab, sorafenib, thalidomide, and lenalidomide) have been proposed with promising results. We describe a 73-year-old man with multifocal non-resectable HEH treated with lenalidomide. Disease status was evaluated by abdominal ultrasound and magnetic resonance every four months. The patient was treated for a total of 39 mo with prolonged disease stabilization and, at the time of writing, is still under treatment with a good tolerance profile. During a short period of treatment discontinuation, the disease showed slight progression that immediately resolved after the reintroduction of lenalidomide. Lenalidomide may represent a valid treatment option for HEH due to its anti-angiogenic and antineoplastic activities. This preliminary result merits further study in a large series.

Background: Antibodies to a cytosolic soluble liver antigen (SLA) are specifically detected in patients with autoimmune hepatitis (AIH). The target of anti-SLA has been identified as a ~50 kDa UGA serine tRNA-associated protein complex (tRNP(Ser)Sec), through the screening of cDNA libraries. A recent report questioned the identity of tRNP(Ser)Sec as the real SLA antigen. The latter study identified α-enolase as a major anti-SLA target, through proteomic analysis. Methods: In an attempt to explain the observed discrepancy we have investigated reactivity of SLA positive sera against α-enolase and tRNP(Ser)Sec using rat and primate liver homogenate and the recombinant antigens. Thirtythree serum samples, 11 from SLA-positive patients and 22 from SLA negative controls were investigated. SLA antibodies were detected by an inhibition ELISA and confirmed by immunoblot using human liver homogenate. Autoantibody reactivity was further evaluated using preparations of primate and rat liver homogenates. Anti-αenolase antibody reactivity has been tested by immunoblot using recombinant α-enolase. An affinity purified goat polyclonal anti-α-enolase IgG antibody was used as reference serum sample. Anti-tRNP(Ser)Sec antibody reactivity was detected by ELISA or dot blot using recombinant tRNP (Ser)Sec antigen.

e15149 Background: Sorafenib is the only drug approved for the treatment of hepatocellular carcinoma (HCC). Little is known about clinical-laboratoristic parameters predicting treatment benefit. Methods: Between 2008-2012, 94 consecutiveclinically compensatedcirrhoticpatients [M/F=85/9, median age 69-years (38-88)] with advanced HCC (BCLC-C, n=57) and those with an intermediate HCC (BCLC-B, n=37) who failed to respond or not eligible to locoregional therapies, received sorafenib. Clinical-laboratoristic data were reviewed. RECIST criteria were used to assess objective benefit. Toxicities were classified using NCIC Toxicity Criteria v-3.0 and treatment managed according to drug label. Results: The median treatment duration (TD) was 3.9 months (range 0.1-48). The median survival was 9.2 months (range 0.4-45). On the basis of TD we identified two groups of patients with a significant different overall survival (OS): group A (TD>6.6 months, median-TD 11.4, 33 patients) and group B (TD19 ng/ml) remained predictor of shortened OS (p=0.028, OR=4). Conclusions: Development of nausea and fatigue on sorafenib is associated with poorer OS. AFP basal levels