Pathophysiological-Based Nutritional Interventions in Cirrhotic Patients with Sarcopenic Obesity: A State-of-the-Art Narrative Review.

In recent decades, following the spread of obesity, metabolic dysfunction has come to represent the leading cause of liver disease. The classical clinical presentation of the cirrhotic patient has, therefore, greatly changed, with a dramatic increase in subjects who appear overweight or obese. Due to an obesogenic lifestyle (lack of physical activity and overall malnutrition, with an excess of caloric intake together with a deficit of proteins and micronutrients), these patients frequently develop a complex clinical condition defined as sarcopenic obesity (SO). The interplay between cirrhosis and SO lies in the sharing of multiple pathogenetic mechanisms, including malnutrition/malabsorption, chronic inflammation, hyperammonemia and insulin resistance. The presence of SO worsens the outcome of cirrhotic patients, affecting overall morbidity and mortality. International nutrition and liver diseases societies strongly agree on recommending the use of food as an integral part of the healing process in the comprehensive management of these patients, including a reduction in caloric intake, protein and micronutrient supplementation and sodium restriction. Based on the pathophysiological paths shared by cirrhosis and SO, this narrative review aims to highlight the nutritional interventions currently advocated by international guidelines, as well as to provide hints on the possible role of micronutrients and nutraceuticals in the treatment of this multifaceted clinical condition.

Deciphering cytopenias in internal medicine: a single-center observational study.

Cytopenia is a common finding in patients admitted to internal medicine wards and the clinical workup may be long and time-consuming. In this single-center observational study, we analyzed a series of 151 inpatients who received hematologist referral due to cytopenia observed during hospital admission. Patients were mainly elderly (median 71 years, 15-96) and 87% had at least one comorbidity. Anemia was the most common cytopenia (91%), followed by thrombocytopenia (51%), and neutropenia (22%); 73 (48%) patients had a bicytopenia and 5 (3%) pancytopenia. Cytopenias were mainly severe, 66% of cases required RBC transfusions, and 21% platelet pools. During a median hospital stay of 15 days (1-166), 53 subjects (35%) received a hematologic discharge diagnosis, whilst the two-thirds had secondary cytopenia mainly due to associated comorbidities. Only about 34% of 2,728 diagnostic tests performed (including laboratory, imaging, and histology) clearly informed the discharge diagnosis in this heterogenous setting. Specifically, bone-marrow evaluation indicated in 46 (30%) patients, was diagnostic in 32 (69.6%). Eleven percent of patients died due to progression of the oncohematologic disease (29%), sepsis (24%), and solid tumor progression (24%). In conclusion, cytopenias in the internal medicine setting are mainly severe, more frequently secondary to associated comorbidities (2/3 of patients) and deserve proper workup before second/third-level tests (immune-hematological assays and CT scan or PET and bone-marrow evaluation, respectively).

Therapeutic perspective for children and young adults living with thalassemia and sickle cell disease.

Hemoglobinopathies, including thalassemias and sickle cell disease, are the most common monogenic diseases worldwide, with estimated annual births of more than 330,000 affected infants. Hemoglobin disorders account for about 3.4% of deaths in children under 5 years of age. The distribution of these diseases is historically linked to current or previously malaria-endemic regions; however, immigration has led to a worldwide distribution of these diseases, making them a global health problem. During the last decade, new treatment approaches and novel therapies have been proposed, some of which have the potential to change the natural history of these disorders. Indeed, the first erythroid maturation agent, luspatercept, and gene therapy have been approved for beta-thalassemia adult patients. For sickle cell disease, molecules targeting vaso-occlusion and hemoglobin S polymerization include crizanlizumab, which has been approved for patients ≥ 16 years, voxelotor approved for patients ≥ 12 years, and L-glutamine for patients older than 5 years.    Conclusion: We herein present the most recent advances and future perspectives in thalassemia and sickle cell disease treatment, including new drugs, gene therapy, and gene editing, and the current clinical trial status in the pediatric populations. What is Known: • Red blood cell transfusions, iron chelation therapy and hematopoietic stem cell transplantation have been the mainstay of treatment of thalassemia patients for decades. • For sickle cell disease, until 2005, treatment strategies were mostly the same as those for thalassemia, with the option of simple transfusion or exchange transfusion. In 2007, hydroxyurea was approved for patients ≥ 2 years old. What is New: • In 2019, gene therapy with betibeglogene autotemcel (LentiGlobin BB305) was approved for TDT patients ≥ 12 years old non ß0/ß0 without matched sibling donor. • Starting from 2017 several new drugs, such as L-glutamine (approved only by FDA), crizanlizumab (approved by FDA and EMA for patients ≥ 16 years), and lastly voxelotor (approved by FDA and EMA for patients ≥ 12 years old).

Effects of COVID-19 Pandemic on Metabolic Status and Psychological Correlates of a Cohort of Italian NAFLD Outpatients.

Non-alcoholic fatty liver disease (NAFLD) is a potentially progressive condition characterized by the presence of fat in more than 5% of hepatocytes, representing the hepatic expression of metabolic syndrome (MetS). A reduction of at least 5-7% in initial body weight improves the metabolic profile underlying NAFLD. The aim of our study was to evaluate the effects of the COVID-19 lockdown on a cohort of non-advanced NAFLD Italian outpatients. We identified 43 patients with 3 available time point visits in our center: first visit (T0) when behavioral indications aimed at controlling MetS were provided, a pre-COVID visit (T1) and a post-COVID visit (T2). During the lockdown, an online compilation of validated psychological tests (SRQ-20, EQ5D, SF-12 and STAI) and a specifically formulated questionnaire for NAFLD was presented to our cohort and completed by 14 consenting patients. Patients who had lost more than 5% of the initial weight at T1 (9 subjects, 21%) maintained the results even at T2, with an overall reduction in BMI and liver stiffness; patients who had not lost the desired weight at T1 (34 subjects, 79%) displayed a further increase in BMI and visceral adiposity at T2. Of interest is that patients in the latter group reported signs of psychological suffering. Our data demonstrated that the setting of good counseling was effective in controlling the metabolic disorder underlying NAFLD in our cohort of outpatients. Given the need for patients to play an active role in the behavioral therapy for NAFLD, we advocate that a multidisciplinary approach be adopted, including a psychological support to obtain the best results over time.

Very Low Alcohol Consumption Is Associated with Lower Prevalence of Cirrhosis and Hepatocellular Carcinoma in Patients with Non-Alcoholic Fatty Liver Disease.

The role of moderate alcohol consumption in the evolution of NAFLD is still debated. The aim of this study is to evaluate the impact of current and lifelong alcohol consumption in patients with NAFLD. From 2015 to 2020, we enrolled 276 consecutive patients fulfilling criteria of NAFLD (alcohol consumption up to 140 g/week for women and 210 g/week for men). According to their current alcohol intake per week, patients were divided in: abstainers, very low consumers (C1: <70 g/week) and moderate consumers (C2). We created a new tool, called LACU (Lifetime Alcohol Consuming Unit) to estimate the alcohol exposure across lifetime: 1 LACU was defined as 7 alcohol units per week for 1 drinking year. Patients were divided into lifelong abstainers and consumers and the latter furtherly divided into quartiles: Q1-Q4. Stratification according to alcohol intake, both current and cumulative as estimated by LACU, showed that very low consumers (C1 and Q1-Q3) displayed lower frequency of cirrhosis and hepatocellular carcinoma compared to abstainers and moderate consumers (C2 and Q4). We can speculate that up to one glass of wine daily in the context of a Mediterranean diet may be a long-term useful approach in selected NAFLD patients.

Viral hepatitis: Innovations and expectations.

Viral hepatitis is a significant health problem worldwide, associated with morbidity and mortality. Hepatitis B, C, D, and occasionally E viruses (HBV, HCV, HDV, and HEV) can evolve in chronic infections, whereas hepatitis A virus (HAV) frequently produces acute self-limiting hepatitis. In the last years, different studies have been performed to introduce new antiviral therapies. The most important goal in the treatment of viral hepatitis is to avoid chronic liver disease and complications. This review analyzes currently available therapies, in particular for viruses associated with chronic liver disease. The focus is especially on HBV and HCV therapies, investigating new drugs already introduced in clinical practice and clinical trials. We also describe new entry inhibitors, developed for the treatment of chronic HDV and HBV and currently available treatments for HEV. The last drugs introduced have shown important efficacy in HCV, with achievable target HCV elimination by 2030. Concurrently, renewed interest in curative HBV therapies has been registered; current nucleotide/nucleoside analogs positively impact liver-related complications, ensuring high safety and tolerability. Novel approaches to HBV cure are based on new antivirals, targeting different steps of the HBV life cycle and immune modulators. The improved knowledge of the HDV life cycle has facilitated the development of some direct-acting agents, as bulevirtide, the first drug conditionally approved in Europe for HDV associated compensated liver disease. Further studies are required to identify a new therapeutic approach in hepatitis E, especially in immunosuppressed patients.

Prognosis of Single Early-Stage Hepatocellular Carcinoma (HCC) with CEUS Inconclusive Imaging (LI-RADS LR-3 and LR-4) Is No Better than Typical HCC (LR-5).

The American College of Radiology (ACR) released the Liver Imaging Report and Data System (LI-RADS) scheme, which categorizes hepatic nodules in risk classes from LR-1 to LR-5 (according to the degree of risk to be HCC) and LR-M (probable malignancy not specific for HCC). The aim of this study was to test whether HCC with different LR patterns on CEUS have different overall survival (OS) and recurrence-free survival (RFS). We retrospectively enrolled 167 patients with the first definitive diagnosis of single HCC (by using CT/MRI or histological techniques if CT/MRI were inconclusive) for whom CEUS examination was available. The median size of HCC lesions was 2.2 cm (range 1.0-7.2 cm). According to CEUS LI-RADS classification, 28 patients were in LR-3, 48 in LR-4, 83 in LR-5, and 8 in LR-M. Patient liver function and nodule characteristics were not statistically different between CEUS LI-RADS classes. Using univariate analysis, CEUS LI-RADS class was not found to be a predictor of survival (p = 0.347). In conclusion, HCC showing the CEUS LI-RADS classes LR-3 and LR-4 have no better clinical outcome than typical HCC. Such data support the EASL policy, aimed at conclusive diagnostic investigations of indeterminate nodules up to obtaining histological proof to avoid leaving aggressive HCC not timely treated.

Identification of Regorafenib Prognostic Index (REP Index) via Recursive Partitioning Analysis in Patients with Advanced Hepatocellular Carcinoma Receiving Systemic Treatment: A Real-World Multi-Institutional Experience.

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.

Determination of Effective Albumin in Patients With Decompensated Cirrhosis: Clinical and Prognostic Implications.

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.

History of Nonalcoholic Fatty Liver Disease.

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.

Treatment of Combined Hepatocellular and Cholangiocarcinoma.

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.

Direct antiviral agents for HCV infection and hepatocellular carcinoma: facts and FADs.

The advent of directly acting antivirals (DAA) has determined a showy change in the management of hepatitis C virus (HCV) infection, the most common cause of hepatocellular carcinoma (HCC) in many countries. It was demonstrated that the achievement of sustained virologic response (SVR) with interferon (IFN) reduces the incidence of HCC. Recently, published data in the literature suggested an increased risk of HCC after IFN free treatments. The mechanism evoked to explain this trend is the deregulation of antitumor response, following the sudden decrease of HCV viral load, due to immune subversion which could favour the progressive development of pre-existing neoplastic clones. The lack of randomised controlled trials (RCTs) with control groups of patients and the fact that majority of studies are limited by retrospective settings, recruitment bias and lack of clinical goals scheduled at the start of treatment make difficult an adequate analysis of data. Main evidence seems to confirm that DAA therapy has not a carcinogenic effect per se but can lead to the earlier manifestation of latent tumours still present but underestimated. At present patients with HCV infection should be encouraged initiating DAA therapy to prevent cirrhosis and HCC but intensive screening is necessary to exclude HCC before initiating DAA. Curing HCV infection does not eliminate the possibility of ongoing liver disease and HCC, as such an adequate monitoring should continue for an indefinite period after SVR.

LncRNAs as novel players in hepatocellular carcinoma recurrence.

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.

Current guidelines for the management of non-alcoholic fatty liver disease: A systematic review with comparative analysis.

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.

Contrast ultrasound LI-RADS LR-5 identifies hepatocellular carcinoma in cirrhosis in a multicenter restropective study of 1,006 nodules.

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.

Contrast-enhanced ultrasound in liver cancer.

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.

Long-term durable response to lenalidomide in a patient with hepatic epithelioid hemangioendothelioma.

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.

Adherence to AASLD guidelines for the treatment of hepatocellular carcinoma in clinical practice: experience of the Bologna Liver Oncology Group.

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.