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Sustained virological response (SVR) by direct‐acting antivirals (DAAs) may reverse the hypercoagulable state of HCV cirrhosis and the portal vein thrombosis (PVT) risk. We evaluated the incidence and predictive factors of de novo, non‐tumoral PVT in patients with cirrhosis after HCV eradication. Patients with HCV‐related cirrhosis, consecutively enrolled in the multi‐center ongoing PITER cohort, who achieved the SVR using DAAs, were prospectively evaluated. Kaplan‐Meier and competing risk regression analyses were performed. During a median time of 38.3 months (IQR: 25.1–48.7 months) after the end of treatment (EOT), among 1609 SVR patients, 32 (2.0%) developed de novo PVT. A platelet count ≤120,000/μL, albumin levels ≤3.5 mg/dL, bilirubin >1.1 mg/dL, a previous liver decompensation, ALBI, Baveno, FIB‐4, and RESIST scores were significantly different (p< 0.001), among patients who developed PVT versus those who did not. Considering death and liver transplantation as competing risk events, esophageal varices (subHR: 10.40; CI 95% 4.33–24.99) and pre‐treatment ALBI grade ≥2 (subHR: 4.32; CI 95% 1.36–13.74) were independent predictors of PVT. After HCV eradication, a significant variation in PLT count, albumin, and bilirubin (p< 0.001) versus pre‐treatment values was observed in patients who did not develop PVT, whereas no significant differences were observed in those who developed PVT (p> 0.05). After the EOT, esophageal varices and ALBI grade ≥2, remained associated with de novo PVT (subHR: 9.32; CI 95% 3.16–27.53 and subHR: 5.50; CI 95% 1.67–18.13, respectively). In patients with HCV‐related cirrhosis, a more advanced liver disease and significant portal hypertension are independently associated with the de novo PVT risk after SVR.

Introduction:In REFLECT, lenvatinib was noninferior to sorafenib in terms of overall survival (OS) in patients with unresectable hepatocellular carcinoma (uHCC; median 13.6 vs. 12.3 months; HR 0.92, 95% CI 0.79–1.06). The objective response rate (ORR) with lenvatinib was 18.8% by blinded independent imaging review (IIR) per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1); per modified RECIST (mRECIST), the ORR was 40.6%. We sought to further characterize these tumor responses and explore ORR’s importance among outcomes for patients with HCC. Methods:Efficacy assessments included all patients randomly assigned to receive lenvatinib treatment (if bodyweight ≥60 kg, 12 mg/day; if <60 kg, 8 mg/day). Time to first objective response (TTR) and duration of response (DOR) included patients who achieved a partial or complete tumor response. Tumors were assessed by IIR per RECIST v1.1 or mRECIST. Results:Four hundred seventy-eight patients were randomly assigned to receive lenvatinib. By IIR, 90 patients (18.8%) achieved an objective response per RECIST v1.1, and 194 (40.6%) had an objective response per mRECIST. Median TTR/DOR were 2.8 months/7.4 months in responders per RECIST v1.1, and 1.9 months/7.3 months in responders per mRECIST, respectively. Per baseline disease characteristics, ORRs by Child-Pugh score (A5/A6) were 21.2%/11.2% per RECIST v1.1 and 42.9%/33.6% per mRECIST, respectively. By baseline alpha-fetoprotein level (<400/≥400 ng/mL), ORRs were 21.4%/15.4% per RECIST v1.1 and 45.6%/33.8% per mRECIST, respectively. Incidences of treatment-related treatment-emergent adverse events were 98.9% in responders per RECIST v1.1 and 97.9% in responders per mRECIST. Conclusions:Responses were seen even in those patients with more severe disease at baseline. Tumor responses occurred early and were durable.

The diagnosis of clinically significant portal hypertension is crucial for prognosis and treatment guidance in patients with compensated advanced chronic liver disease (ACLD). Spleen stiffness measurement (SSM) might improve the non-invasive diagnosis of clinically significant portal hypertension, but previous studies have reported heterogeneous SSM cutoffs. We aimed to evaluate the accuracy of SSM and SSM-based algorithms in this setting.

Introduction:Lenvatinib is indicated for the forefront treatment of advanced hepatocellular carcinoma (aHCC), but its use may be limited by the risk of esophagogastric varices (EGV) bleeding. This study assessed the prevalence, predictors, and complications of EGV in aHCC patients treated with lenvatinib. Methods:In this multicenter international retrospective study, cirrhotic patients treated with lenvatinib for aHCC, were enrolled if upper-gastrointestinal endoscopy was available within 6 months before treatment. Primary endpoint was the incidence of EGV bleeding during lenvatinib therapy; secondary endpoints were predictors for EGV bleeding, prevalence, and risk factors for the presence of EGV and high-risk EGV at baseline, as well as impact of EGV bleeding on patients’ survival. Results:535 patients were enrolled in the study (median age: 72 years, 78% male, 63% viral etiology, 89% Child-Pugh A, 16% neoplastic portal vein thrombosis [nPVT], 56% Barcelona Clinic Liver Cancer-C): 234 had EGV (44%), 70 (30%) were at high risk and 59 were on primary prophylaxis. During lenvatinib treatment, 17 patients bled from EGV (3 grade 5), the 12-month cumulative incidence being 3%. The only baseline independent predictor of EGV bleeding was the presence of baseline high-risk EGV (hazard ratio: 6.94, 95% confidence interval [CI]: 2.23–21.57, p= 0.001). In these patients the 12-month risk was 17%. High-risk varices were independently associated with Child-Pugh B score (odds ratio [OR]: 2.12; 95% CI: 1.08–4.17, p= 0.03), nPVT (OR: 2.54; 95% CI: 1.40–4.61, p= 0.002), and platelets 150,000/μL (OR: 2.47; 95% CI: 1.35–4.50, p= 0.003). Conclusion:In hepatocellular carcinoma patients treated with lenvatinib, the risk of EGV bleeding was mostly low but significant only in patients with high-risk EGV at baseline.

IMPORTANCE: Clear indications on how to select retreatments for recurrent hepatocellular carcinoma (HCC) are still lacking. OBJECTIVE: To create a machine learning predictive model of survival after HCC recurrence to allocate patients to their best potential treatment. DESIGN, SETTING, AND PARTICIPANTS: Real-life data were obtained from an Italian registry of hepatocellular carcinoma between January 2008 and December 2019 after a median (IQR) follow-up of 27 (12-51) months. External validation was made on data derived by another Italian cohort and a Japanese cohort. Patients who experienced a recurrent HCC after a first surgical approach were included. Patients were profiled, and factors predicting survival after recurrence under different treatments that acted also as treatment effect modifiers were assessed. The model was then fitted individually to identify the best potential treatment. Analysis took place between January and April 2021. EXPOSURES: Patients were enrolled if treated by reoperative hepatectomy or thermoablation, chemoembolization, or sorafenib. MAIN OUTCOMES AND MEASURES: Survival after recurrence was the end point. RESULTS: A total of 701 patients with recurrent HCC were enrolled (mean [SD] age, 71 [9] years; 151 [21.5%] female). Of those, 293 patients (41.8%) received reoperative hepatectomy or thermoablation, 188 (26.8%) received sorafenib, and 220 (31.4%) received chemoembolization. Treatment, age, cirrhosis, number, size, and lobar localization of the recurrent nodules, extrahepatic spread, and time to recurrence were all treatment effect modifiers and survival after recurrence predictors. The area under the receiver operating characteristic curve of the predictive model was 78.5% (95% CI, 71.7%-85.3%) at 5 years after recurrence. According to the model, 611 patients (87.2%) would have benefited from reoperative hepatectomy or thermoablation, 37 (5.2%) from sorafenib, and 53 (7.6%) from chemoembolization in terms of potential survival after recurrence. Compared with patients for which the best potential treatment was reoperative hepatectomy or thermoablation, sorafenib and chemoembolization would be the best potential treatment for older patients (median [IQR] age, 78.5 [75.2-83.4] years, 77.02 [73.89-80.46] years, and 71.59 [64.76-76.06] years for sorafenib, chemoembolization, and reoperative hepatectomy or thermoablation, respectively), with a lower median (IQR) number of multiple recurrent nodules (1.00 [1.00-2.00] for sorafenib, 1.00 [1.00-2.00] for chemoembolization, and 2.00 [1.00-3.00] for reoperative hepatectomy or thermoablation). Extrahepatic recurrence was observed in 43.2% (n = 16) for sorafenib as the best potential treatment vs 14.6% (n = 89) for reoperative hepatectomy or thermoablation as the best potential treatment and 0% for chemoembolization as the best potential treatment. Those profiles were used to constitute a patient-tailored algorithm for the best potential treatment allocation. CONCLUSIONS AND RELEVANCE: The herein presented algorithm should help in allocating patients with recurrent HCC to the best potential treatment according to their specific characteristics in a treatment hierarchy fashion.

BackgroundMetabolic dysfunction-associated fatty liver disease (MAFLD) represents a new inclusive definition of the whole spectrum of liver diseases associated to metabolic disorders. The main objective of this study was to compare patients with MAFLD and non-MAFLD with hepatocellular carcinoma (HCC) included in a nationally representative cohort.MethodsWe analysed 6882 consecutive patients with HCC enrolled from 2002 to 2019 by 23 Italian Liver Cancer centres to compare epidemiological and future trends in three subgroups: pure, single aetiology MAFLD (S-MAFLD); mixed aetiology MAFLD (metabolic and others, M-MAFLD); and non-MAFLD HCC.ResultsMAFLD was diagnosed in the majority of patients with HCC (68.4%). The proportion of both total MAFLD and S-MAFLD HCC significantly increased over time (from 50.4% and 3.6% in 2002–2003, to 77.3% and 28.9% in 2018–2019, respectively, p<0.001). In Italy S-MAFLD HCC is expected to overcome M-MAFLD HCC in about 6 years. Patients with S-MAFLD HCC were older, more frequently men and less frequently cirrhotic with clinically relevant portal hypertension and a surveillance-related diagnosis. They had more frequently large tumours and extrahepatic metastases. After weighting, and compared with patients with non-MAFLD, S-MAFLD and M-MAFLD HCC showed a significantly lower overall (p=0.026, p=0.004) and HCC-related (p<0.001, for both) risk of death. Patients with S-MAFLD HCC showed a significantly higher risk of non-HCC-related death (p=0.006).ConclusionsThe prevalence of MAFLD HCC in Italy is rapidly increasing to cover the majority of patients with HCC. Despite a less favourable cancer stage at diagnosis, patients with MAFLD HCC have a lower risk of HCC-related death, suggesting reduced cancer aggressiveness.

Hemoperitoneum in cirrhosis is a life‐threatening condition that requires emergent evaluation. Contrast‐enhanced ultrasound (CEUS) permits multiple dynamic characterizations of abdominal structures through all vascular phases, and contrast extravasation or the presence of microbubbles in the ascites could be a sensitive tool. We reviewed 13 patients with cirrhosis that underwent CEUS due to high suspicion for intra‐abdominal bleeding. In 10 cases, CEUS demonstrated extravasation of contrast, including 2 instances where CEUS detected active bleeding despite negative computed tomography. These data support further study of CEUS in direct comparison to other imaging modalities in this clinical context.

Mammalian cells release several membrane-enclosed vesicles called extracellular vesicles. Those vesicles can contain several molecules such as proteins, DNA and various RNA. Therefore, extracellular vesicles can act as a target delivery system and exert multiple biological effects. Several works demonstrated that extracellular vesicles are increased or dysregulated in patients with cirrhosis, and they can be predictive of disease progression, complications and mortality. This review aims to summarize and highlight the role of extracellular vesicles in the cirrhotic patient and how they correlate with the degree of disease and with complications, particularly with the development of portal thrombosis and hepatocellular carcinoma.

Most CT/MRI and CEUS LI-RADS major features had independent associations with hepatocellular carcinoma; arterial phase hyperenhancement and washout had the strongest associations whereas, for CT/MRI, threshold growth had no association.

Supplemental Digital Content is available in the text.

Liver Imaging Reporting and Data System Contrast-Enhanced US Nonradiation Treatment Response Assessment Version 2024 evaluates both intralesional and perilesional tumor viability to assign a single treatment response category: nonviable, equivocal, or viable.

Tocilizumab is a humanised interleukin-6 receptor-inhibiting monoclonal antibody that is currently approved for the treatment of rheumatoid arthritis and other immune-related conditions. Recently, tocilizumab has been investigated as a possible treatment for severe coronavirus-induced disease 2019 (COVID-19). Despite the lack of direct antiviral effects, tocilizumab could reduce the immune-induced organ damage caused by severe acute respiratory syndrome-coronavirus 2 (SARS-CoV2) infection. Until recently, most reports on tocilizumab for COVID-19 included a limited number of patients, preventing an overall evaluation of its efficacy and safety for this specific condition. Therefore, we reviewed the literature regarding the physiopathological rationale of tocilizumab for COVID-19 and its outcomes. We searched the MEDLINE database with the string “(SARS-CoV-2 OR coronavirus OR COVID-19 OR MERS- cov OR SARS-cov) AND (IL-6 OR interleukin 6 OR tocilizumab)”. While the scientific rationale supporting tocilizumab for COVID-19 is solid, the evidence regarding the outcomes remains controversial. Available data and results from ongoing trials will provide useful information in the event of new COVID-19 outbreaks or future pandemics from different coronaviruses.

Background: Hepatocellular carcinoma prognosis depends on both liver and tumor determinants, especially on maximum tumor diameter, multifocality, and presence of portal vein thrombosis, despite apparently complete tumor removal by resection or liver transplantation.Aims: To examine parameters of hepatocellular carcinoma aggressiveness as tumor size increases.Methods: A large hepatocellular carcinoma database was examined for trends in serum alpha-fetoprotein and the percentage of patients with macroscopic portal vein thrombosis or tumor multifocality.Results: A total of 13,016 hepatocellular carcinoma patients were identified having full tumor and survival data. Of these, 76.56% were male and 23.44% were female, with a median age of 64.4 years. We found that as the maximum tumor diameter increased, there was a significant trend for increased alpha-fetoprotein levels (P<0.001) and an increased percentage of patients with either portal vein thrombosis or tumor multifocality, each P<0.0001. Furthermore, the increases of both alpha-fetoprotein and portal vein thrombosis were proportionately greater than the related maximum tumor diameter increases. These trends of increased alpha-fetoprotein, portal vein thrombosis, and multifocality with increasing maximum tumor diameter had non-linear patterns. Within alpha-fetoprotein and multifocality trends, there were identifiable sub-trends associated with specific maximum tumor diameter ranges.Conclusions: The greater fold-increases in alpha-fetoprotein and portal vein thrombosis compared with increases in maximum tumor diameter imply that hepatocellular carcinoma characteristics may change with increasing size to a more aggressive phenotype, suggesting that follow-up tumor sampling might be useful, in addition to baseline tumor sampling, for optimal therapeutic choices to be made.

Introduction:Cabozantinib has been approved by the European Medicine Agency (EMA) for hepatocellular carcinoma (HCC) previously treated with sorafenib. Cabozantinib is also being tested in combination with immune checkpoint inhibitors in the frontline setting. Real-life clinical data of cabozantinib for HCC are still lacking. Moreover, the prognostic factors for HCC treated with cabozantinib have not been investigated. Methods:We evaluated clinical data and outcome of HCC patients who received cabozantinib in the legal context of named patient use in Italy. Results:Ninety-six patients from 15 centres received cabozantinib. All patients had preserved liver function (Child-Pugh A), mostly with an advanced HCC (77.1%) in a third-line setting (75.0%). The prevalence of performance status (PS) > 0, macrovascular invasion (MVI), extrahepatic spread, and alpha-fetoprotein (AFP) >400 ng/mL was 50.0, 30.2, 67.7, and 44.8%, respectively. Median overall survival (OS) and progression-free survival were 12.1 (95% confidence interval 9.4–14.8) and 5.1 (3.3–6.9) months, respectively. Most common treatment-related adverse events (AEs) were fatigue (67.7%), diarrhoea (54.2%), anorexia (45.8%), HFSR (43.8%), weight loss (24.0%), and hypertension (24.0%). Most common treatment-related Grade 3–4 AEs were fatigue (6.3%), HFSR (6.3%), and increased aminotransferases (6.3%). MVI, ECOG-PS > 0, and AFP >400 ng/mL predicted a worse OS. Discontinuation for intolerance and no new extrahepatic lesions at the progression were associated with better outcomes. Conclusions:In a real-life Western scenario (mostly in a third-line setting), cabozantinib efficacy and safety data were comparable with those reported in its registration trial. Data regarding the prognostic factors might help in patient selection and design of clinical trials.

Background:Due to its poor survival, intrahepatic cholangiocarcinoma (ICC) is held to be a much more aggressive cancer than hepatocellular carcinoma (HCC). In most published series, patients were diagnosed when symptomatic. However, ICC is now increasingly being discovered during the surveillance for HCC in cirrhosis. Whether this earlier detection of ICC is associated with an equally dismal prognosis or not is unknown. Methods:This is amulticenter retrospective study of consecutive ICC patients. Patients were stratified into subgroups according to the absence/presence of cirrhosis. A propensity score matching was performed to reduce the potential biases. Cirrhotic patients were further stratified according to their surveillance status. The lead-time bias and its potential effects were also estimated. Results:We gathered 184 patients. Eighty-five patients (46.2%) were cirrhotic. Liver cirrhosis was not related to a worse overall survival (33.0 vs. 32.0 months, p= 0.800) even after the propensity score analysis (43.0 in vs. 44.0 months in 54 pairs of patients, p= 0.878). Among the cirrhotic population, 47 (55.3%) patients had received a diagnosis of ICC during a surveillance programme. The 2 subgroups differed in maximum tumour dimensions (30 vs. 48 mm in surveyed and non-surveyed patients, respectively). Surveyed patients were more likely to receive surgical treatments (59.8 vs. 28.9%, p= 0.003). Overall survival was higher in surveyed patients (51.0 vs. 21.0 months, p< 0.001). These benefits were confirmed after correcting for the lead-time bias. Conclusions:Cirrhotic patients have different clinical presentation and outcomes of ICC according to their surveillance status. In our series, ICC in cirrhosis was not associated with worse OS. Cirrhosis itself should not discourage either surgical or non-surgical treatments.

Background: Non-alcoholic fatty liver disease (NAFLD) is a global epidemic involving 20-40% of the general population. NAFLD is rapidly becoming the leading cause of hepatocellular carcinoma (HCC) worldwide. Knowledge about NAFLD-HCC peculiar features is needed to understand this emerging disease better. Objective: To review the current literature about the epidemiological, pathogenic and clinical features characterising the NAFLD and distinguishing it from HCC of other etiologies. Methods: A systematic review of the literature (PubMed and Medline) using the following string ("Non-alcoholic Fatty Liver Disease"[Mesh] and "Carcinoma, Hepatocellular"[Mesh]). Particular relevance was given to papers published in the last five years as well as previously published manuscript very relevant to this topic according to the experience of the authors. Results: A total of 244 original papers in humans in English literature were analysed. Inherent difficulties in the identification of high-risk subjects and the possibility of occurrence in non-cirrhotic livers are peculiar characteristics of NAFLD-HCC hampering surveillance programs. The consequently delayed diagnosis limits access to surgical procedures and impacts on survival. After correction for tumour burden, however, the survival is not different from that of viral HCC, suggesting that NAFLD-HCC is not intrinsically a more aggressive malignancy. Conclusion: A great deal of effort is needed to improve the clinical outcome of NAFLD-HCC, especially in terms of prevention, surveillance protocols, and identification of drug modifying the natural history of the underlying liver disease. The outcome of these efforts will significantly impact global HCC-related costs and mortality.

Diagnosis of hepatocellular carcinoma can be achieved by imaging in cirrhotic patients. Combined hepatocellular-cholangiocarcinoma is a primary liver tumor and its imaging patterns have been poorly investigated. Misdiagnosis for either hepatocellular carcinoma or benign lesions can occur. We aimed to evaluate the enhancement pattern of combined hepatocellular-cholangiocarcinoma in cirrhosis with imaging techniques and to estimate the risk of misdiagnosis for hepatocellular carcinoma. All histology-confirmed combined hepatocellular-cholangiocarcinoma in cirrhosis seen in two Italian centers between 2003 and 2016, in which at least one imaging technique had been performed, was retrospectively collected. The enhancement pattern was analyzed for all available imaging modalities. A total of 37 combined hepatocellular-cholangiocarcinoma nodules were identified. Contrast-enhanced ultrasound, computed tomography, and magnetic resonance imaging had been performed in 27, 34, and 17 nodules, respectively. Contrast-enhanced ultrasound was at higher risk of misdiagnosis for pure hepatocellular carcinoma than computed tomography (p?=?0.005) or magnetic resonance imaging (p?=?0.040). Only six of 24 combined hepatocellular-cholangiocarcinoma lesions submitted to both contrast-enhanced ultrasound and computed tomography showed coincident patterns; contrast-enhanced ultrasound correctly suggested a condition of malignancy in a higher number of cases than computed tomography (p?

Background Diagnosis of hepatocellular carcinoma can be achieved by imaging in cirrhotic patients. Combined hepatocellular-cholangiocarcinoma is a primary liver tumor and its imaging patterns have been poorly investigated. Misdiagnosis for either hepatocellular carcinoma or benign lesions can occur. We aimed to evaluate the enhancement pattern of combined hepatocellular-cholangiocarcinoma in cirrhosis with imaging techniques and to estimate the risk of misdiagnosis for hepatocellular carcinoma.Methods All histology-confirmed combined hepatocellular-cholangiocarcinoma in cirrhosis seen in two Italian centers between 2003 and 2016, in which at least one imaging technique had been performed, was retrospectively collected. The enhancement pattern was analyzed for all available imaging modalities.Results A total of 37 combined hepatocellular-cholangiocarcinoma nodules were identified. Contrast-enhanced ultrasound, computed tomography, and magnetic resonance imaging had been performed in 27, 34, and 17 nodules, respectively. Contrast-enhanced ultrasound was at higher risk of misdiagnosis for pure hepatocellular carcinoma than computed tomography (p= 0.005) or magnetic resonance imaging (p= 0.040). Only six of 24 combined hepatocellular-cholangiocarcinoma lesions submitted to both contrast-enhanced ultrasound and computed tomography showed coincident patterns; contrast-enhanced ultrasound correctly suggested a condition of malignancy in a higher number of cases than computed tomography (p< 0.001) and magnetic resonance imaging (p= 0.002).Conclusions Contrast-enhanced ultrasound misdiagnosed a higher number of combined hepatocellular-cholangiocarcinoma as hepatocellular carcinoma than computed tomography and magnetic resonance imaging. However, the latter techniques were able to identify features of malignancy less often.

Background:Liver cancer is the second most common cause of cancer-related death, with hepatocellular carcinoma (HCC) accounting for most primary liver cancers and most commonly arising from a history of advanced chronic liver disease. Among the available therapies, transarterial chemoembolization (TACE) is the most widely utilized and is considered the first-line treatment recommended for patients staged as intermediate HCC (Barcelona Clinic Liver Cancer stage B). If applied correctly, TACE can produce survival benefits without adversely affecting hepatic functional reserve. Summary:The aim of this nonsystematic review is to evaluate the evidence supporting TACE, with a special interest in intermediate HCC, for which this treatment is recommended in first line. However, intermediate HCC represents a broad and heterogeneous group of patients, not all of whom will benefit from TACE. This review highlights the importance of appropriate patient selection for initial TACE and for retreatment. It also evaluates evidence for the treatment of patients who become refractory to TACE. Some patients may, in fact, benefit from early switch (i.e., after 1 or 2 TACE treatments) to systemic therapies rather than continuing retreatments with TACE in order to preserve liver function, thus allowing sequential first- and second-line drug therapies. Key Messages:Careful assessment of an individual patient's benefit/risk ratio is recommended before any TACE session is considered to ensure optimal long-term outcomes in intermediate HCC.

This mono-institutional observational study was conducted to determine incidence, severity, risk factors, and outcome of sinusoidal obstruction syndrome/veno-occlusive disease (SOS/VOD) in high-risk Ewing sarcoma (ES) patients treated with intravenous busulfan and melphalan (BU-MEL) followed by autologous stem cell transplantation (ASCT). During the past 10 years, 75 consecutive ES patients resulted evaluable for the analysis. After diagnosis of SOS/VOD, defibrotide therapy was started as soon as the medication was available. The variables analyzed as potential risk factors were: gender, patient's age at diagnosis, primary tumor site, disease stage, and prior radiation therapy (RT) given, focusing on RT liver exposure. The median age at diagnosis was 18.8 years. Five patients developed moderate to severe SOS/VOD (cumulative incidence, 6.67%). None of 32 pediatric patients (≤17 years) developed SOS/VOD (p= 0.0674). In univariate analysis, prior RT liver exposure resulted statistically significant (p= 0.0496). There was one death due to severe SOS/VOD. This study reports the largest series of high-risk ES patients treated with intravenous BU-MEL before ASCT. The incidence of SOS/VOD was lower when compared with other studies that used oral busulfan. Any prior RT liver exposure should be avoided. Earlier defibrotide treatment confirms to be effective.

In a phase 2 trial, lenvatinib, an inhibitor of VEGF receptors 1–3, FGF receptors 1–4, PDGF receptor α, RET, and KIT, showed activity in hepatocellular carcinoma. We aimed to compare overall survival in patients treated with lenvatinib versus sorafenib as a first-line treatment for unresectable hepatocellular carcinoma.

ObjectiveMany improvements have been made in diagnosing hepatocellular carcinoma (HCC), but the radiological hallmarks of HCC have remained the same for many years. We prospectively evaluated the imaging criteria of HCC, early HCC and high-grade dysplastic nodules (HGDNs) in patients under surveillance for chronic liver disease, using gadolinium-ethoxybenzyl-diethylenetriamine pentaacetic acid (Gd-EOB-DTPA) MRI and diffusion-weighted imaging.DesignOur study population included 420 nodules >1 cm in 228 patients. The MRI findings of each nodule were collected in all sequences/phases. The diagnosis of HCC was made according to the American Association for the Study of Liver Diseases (AASLD) criteria; all atypical nodules were diagnosed using histology.ResultsA classification and regression tree was developed using three MRI findings which were independently significant correlated variables for early HCC/HCC, and the best sequence of their application in a new diagnostic algorithm (hepatobiliary hypointensity, arterial hyperintensity and diffusion restriction) was suggested. This algorithm demonstrated, both in the entire study population and for nodules ≤2 cm, higher sensitivity (96% [95% CI 93.5% to 97.6%] and 96.6% [95% CI 93.9% to 98.5%], P<0.001, respectively) and slightly lower specificity (91.8% [95% CI 88.6% to 94.1%], P=0.063, and 92.7% [95% CI 88.9% to 95.4%], P=0.125, respectively) than those of the AASLD criteria. Our new diagnostic algorithm also showed a very high sensitivity (94.7%; 95% CI 92% to 96.6%) and specificity (99.3%; 95% CI 97.7% to 99.8%) in classifying HGDN.ConclusionOur new diagnostic algorithm demonstrated significantly higher sensitivity and comparable specificity than those of the AASLD imaging criteria for HCC in patients with cirrhosis evaluated using Gd-EOB-DTPA MRI, even for lesions ≤2 cm. Moreover, this diagnostic algorithm allowed evaluating other lesions which could arise in a cirrhotic liver, such as early HCC and HGDN.

Aim/Background:After the introduction of sorafenib in the treatment of advanced hepatocellular carcinoma (HCC), different studies tried to evaluate whether other systemic therapies can improve survival. To provide a comprehensive indirect treatment comparison of efficacy and safety of novel drugs, a network meta-analysis (NMA) of phase III randomized controlled trials was performed. Methods:After pertinent literature search up to November 1, 2016, 6 studies were eligible for the analysis including 4,812 individual patients with advanced HCC: 2,454 received sorafenib, 577 received brivanib, 530 received sunitinib, 514 received linifanib, 358 received sorafenib + erlotinib and 379 received placebo. Frequentist NMA was used to compare treatments within a single analytical framework. Results:NMA showed that sorafenib alone, regardless of combination with erlotinib, and linifanib provide a significant survival advantage over placebo (p< 0.05) but without any significant difference between each other. Conversely, all regimens significantly ameliorate progression-free survival versus placebo (p< 0.05). The rank order of efficacy was: sorafenib ± erlotinib, linifanib, brivanib, sunitinib, and placebo. Sorafenib ± erlotinib was the regimen with the fewest number of adverse events that required discontinuation of treatment, whereas linifanib and brivanib resulted in the most adverse events. The risk-benefit summary identified one cluster of therapies with a similar balance between efficacy and safety which included sorafenib alone or in combination with erlotinib, having, at the same time, the highest efficacy and safety. Conclusions:Sorafenib remains the best systemic treatment for advanced HCC; linifanib also resulted in survival advantages over placebo but with a lower safety profile.

Background Although transarterial chemoembolization is considered the standard of care for intermediate hepatocellular carcinoma patients, robust data in favor of a clear superiority of chemoembolization (with chemotherapy injection) over bland embolization are lacking.Objective The objective of this article is to systematically analyze the results provided by randomized controlled trials comparing these two treatments in hepatocarcinoma patients.Methods A computerized bibliographic search on the main databases was performed. Survival rates assessed at one, two, and three years, objective response, one-year progression-free survival, and severe adverse event rate were analyzed. Comparisons were performed by using the Mantel-Haenszel test in cases of low heterogeneity or DerSimonian and Laird test in cases of high heterogeneity.Results Six trials with 676 patients were included. No difference in one-year (risk ratio: 0.93, 0.85–1.03, p= 0.16), two-year (risk ratio: 0.88, 0.74–1.06, p= 0.18) and three-year survival (risk ratio: 0.97, 0.74–1.27, p= 0.81) was observed. Objective response and one-year progression-free survival showed no significant difference between the two treatments (p= 0.36 and p= 0.40, respectively). A statistically significant increase in severe toxicity after chemoembolization was found (risk ratio: 1.44, 1.08–1.92, p= 0.01), although this result could be affected by the heterogeneity of techniques adopted.Conclusions Our meta-analysis demonstrates a non-superiority of transarterial chemoembolization with respect to bland embolization in hepatocarcinoma patients.

Although transarterial chemoembolization is considered the standard of care for intermediate hepatocellular carcinoma patients, robust data in favor of a clear superiority of chemoembolization (with chemotherapy injection) over bland embolization are lacking. The objective of this article is to systematically analyze the results provided by randomized controlled trials comparing these two treatments in hepatocarcinoma patients. A computerized bibliographic search on the main databases was performed. Survival rates assessed at one, two, and three years, objective response, one-year progression-free survival, and severe adverse event rate were analyzed. Comparisons were performed by using the Mantel-Haenszel test in cases of low heterogeneity or DerSimonian and Laird test in cases of high heterogeneity. Six trials with 676 patients were included. No difference in one-year (risk ratio: 0.93, 0.85–1.03, p?=?0.16), two-year (risk ratio: 0.88, 0.74–1.06, p?=?0.18) and three-year survival (risk ratio: 0.97, 0.74–1.27, p?=?0.81) was observed. Objective response and one-year progression-free survival showed no significant difference between the two treatments (p?=?0.36 and p?=?0.40, respectively). A statistically significant increase in severe toxicity after chemoembolization was found (risk ratio: 1.44, 1.08–1.92, p?=?0.01), although this result could be affected by the heterogeneity of techniques adopted. Our meta-analysis demonstrates a non-superiority of transarterial chemoembolization with respect to bland embolization in hepatocarcinoma patients.

AbstractDue to the ability to detect the typical contrast-imaging pattern for hepatocellular carcinoma (HCC), that is hyperenhancement in the arterial phase and hypoenhancement in the late phase on a cirrhotic background, contrast-enhanced ultrasonography (CEUS) was included in the American diagnostic algorithm for HCC in 2005. However, its role has been questioned because of the possibility of misdiagnosis of cholangiocarcinoma. The present review aims to describe the advantages and disadvantages of CEUS applications using Sonovue® for HCC. In particular there is focus on the accuracy of CEUS in detecting the typical HCC pattern, the CEUS patterns of intrahepatic cholangiocarcinoma (ICC), the risk of misdiagnosis with HCC, the diagnostic use of CEUS in cases of locoregional and systemic treatments, and the evaluation of response to antiangiogenic treatment using dedicated software.© 2015 S. Karger AG, Basel

OBJECTIVES:The Barcelona Clinic Liver Cancer (BCLC) intermediate stage (BCLC B) includes a heterogeneous population of patients with hepatocellular carcinoma (HCC). Recently, in order to facilitate treatment decisions, a panel of experts proposed to subclassify BCLC B patients. In this study, we aimed to assess the prognostic capability of the BCLC B stage reclassification in a large cohort of patients with untreated HCC managed by the Italian Liver Cancer Group.METHODS:We assessed the prognosis of 269 untreated HCC patients observed in the period 1987–2012 who were reclassified according to the proposed subclassification of the BCLC B stage from stage B1 to stage B4. We evaluated and compared the survival of the various substages.RESULTS:Median survival progressively decreased from stage B1 (n=65, 24.2%: 25 months) through stages B2 (n=105, 39.0%: 16 months) and B3 (n=22, 8.2%: 9 months), to stage B4 (n=77, 28.6%: 5 months; P<0.0001). Moreover, we observed a significantly different survival between contiguous stages (B1 vs. B2, P=0.0002; B2 vs. B3, P<0.0001; B3 vs. B4, P=0.0219). In multivariate analysis, the BCLC B subclassification (P<0.0001), MELD score (P=0.0013), and platelet count (P=0.0252) were independent predictors of survival.CONCLUSIONS:The subclassification of the intermediate-stage HCC predicts the prognosis of patients with untreated HCC. The prognostic figures identified in this study may be used as a benchmark to assess the efficacy of therapeutic intervention in the various BCLC B substages, whereas it remains to be established whether incorporation of the MELD score might improve the prognosis of treated patients.