Red Cell Distribution Width as a Predictor of Survival in Patients with Hepatocellular Carcinoma.

Background and Objectives. Hepatocellular carcinoma (HCC) and the intrahepatic biliary tract cancers are estimated to rank sixth for incidence among solid cancers worldwide, and third for mortality rates. A critical issue remains the need for accurate biomarkers for risk stratification and overall prognosis. The aim of this study was to investigate the ability of a biomarker of heterogeneity of the size of red blood cells, the red cell distribution width (RDW), to predict survival in patients with HCC. Materials and Methods. A consecutive series of patients with a histologic diagnosis of HCC were included into this study irrespective of their age, stage of the disease, and treatment administered, and followed-up for a period of three years. Demographic, anthropometric [age, sex, body mass index (BMI)], and clinical data (Charlson Comorbidity Index, Child-Pugh score, etc.), along with laboratory tests were retrieved from clinical records. Results. One-hundred and four patients were included in this study. Among them, 54 (69%) were deceased at the end of the follow-up. Higher RDW values, but not other hematological and biochemical parameters, were significantly associated with mortality in both univariate and multivariate analysis. The optimal RDW cut-off value identified with the Youden test for survival was 14.7%, with 65% sensitivity and 74% specificity (AUC = 0.718, 95% CI 0.622-0.802, p < 0.001). Kaplan-Meier survival curves showed significantly lower survival with higher RDW values (HR = 3.5204; 95% CI 1.9680-6.2975, p < 0.0001) with a mean survival of 30.9 ± 9.67 months for patients with RDW ≤ 14.7% and 22.3 ± 11.4 months for patients with RDW > 14.7%. Conclusions. The results of our study showed that RDW can perform better than other blood-based biomarkers in independently predicting prognosis in patients with HCC.

Characteristics and outcome of anti-hepatitis D virus positive patients with hepatocellular carcinoma.

BACKGROUND & AIMS: Chronic hepatitis D virus (HDV) often leads to end-stage liver disease and hepatocellular carcinoma (HCC). Comprehensive data pertaining to large populations with HDV and HCC are missing, therefore we sought to assess the characteristics, management, and outcome of these patients, comparing them to patients with hepatitis B virus (HBV) infection. METHODS: We analysed the Italian Liver Cancer database focusing on patients with positivity for HBV surface antigen and anti-HDV antibodies (HBV/HDV, n = 107) and patients with HBV infection alone (n = 588). Clinical and oncological characteristics, treatment, and survival were compared in the two groups. RESULTS: Patients with HBV/HDV had worse liver function [Model for End-stage Liver Disease score: 11 vs. 9, p < .0001; Child-Turcotte-Pugh score: 7 vs. 5, p < .0001] than patients with HBV. HCC was more frequently diagnosed during surveillance (72.9% vs. 52.4%, p = .0002), and the oncological stage was more frequently Milan-in (67.3% vs. 52.7%, p = .005) in patients with HBV/HDV. Liver transplantation was more frequently performed in HBV/HDV than in HBV patients (36.4% vs. 9.5%), while the opposite was observed for resection (8.4% vs. 20.1%, p < .0001), and in a competing risk analysis, HBV/HDV patients had a higher probability of receiving transplantation, independently of liver function and oncological stage. A trend towards longer survival was observed in patients with HBV/HDV (50.4 vs. 44.4 months, p = .106). CONCLUSIONS: In patients with HBV/HDV, HCC is diagnosed more frequently during surveillance, resulting in a less advanced cancer stage in patients with more deranged liver function than HBV alone. Patients with HBV/HDV have a heightened benefit from liver transplantation, positively influencing survival.

Sorafenib and Metronomic Capecitabine in Child-Pugh B patients with advanced HCC: A real-life comparison with best supportive care.

BACKGROUND AND AIMS: The efficacy of systemic therapy for unresectable advanced hepatocellular carcinoma (aHCC) has not been proven in patients with Child-Pugh (C-P) B cirrhosis. Nevertheless, in real-world these patients are treated both with tyrosine kinase inhibitors (TKIs) and with metronomic capecitabine (MC). This study aimed to compare sorafenib and MC outcomes versus best supportive care (BSC) in C-P B patients. METHOD: Between 2008 and 2020, among 774 C-P B patients with aHCC not amenable/responsive to locoregional treatments, 410 underwent sorafenib, 62 MC, and 302 BSC. The propensity score matching method was used to correct the baseline unbalanced prognostic factors. RESULTS: In the unmatched population, median OS was 9.7 months in patients treated with sorafenib, 8.0 with MC, and 3.9 months with BSC. In sorafenib vs. BSC-matched patients (135 couples), median OS was 7.3 (4.9-9.6) vs. 3.9 (2.6-5.2) months (p<0.001). ECOG-Performance Status, tumor size, macrovascular invasion, AFP, treatment-naive, and sorafenib were independent predictors of survival. In MC vs. BSC-matched patients (40 couples), median OS was 9.0 (0.2-17.8) vs.3.0 (2.2-3.8) months (p<0.001). Median OS did not differ (p = 0.283) in sorafenib vs. MC-matched patients (55 couples). CONCLUSION: C-P B patients with aHCC undergoing BSC have poor survival. Both Sorafenib and MC treatment improve their prognosis.

Predictors of non-transplantable recurrence in hepatocellular carcinoma patients treated with frontline liver resection.

BACKGROUND AND AIMS: Hepatocellular carcinoma (HCC) recurrence is common in patients treated with liver resection (LR). In this study, we aimed to evaluate the incidence and preoperative predictors of non-transplantable recurrence in patients with single HCC ≤5 cm treated with frontline LR. METHODS: From the Italian Liver Cancer (ITA.LI.CA) database, 512 patients receiving frontline LR for single HCC ≤5 cm were retrieved. Incidence and predictors of recurrence beyond Milan criteria (MC) and up-to-seven criteria were compared between patients with HCC <4 and ≥4 cm. RESULTS: During a median follow-up of 4.2 years, the overall recurrence rate was 55.9%. In the ≥4 cm group, a significantly higher proportion of patients recurred beyond MC at first recurrence (28.9% vs. 14.1%; p < 0.001) and overall (44.4% vs. 25.2%; p < 0.001). Similar results were found considering recurrence beyond up-to-seven criteria. Compared to those with larger tumours, patients with HCC <4 cm had a longer recurrence-free survival and overall survival. HCC size ≥4 cm and high alpha-fetoprotein (AFP) level at the time of LR were independent predictors of recurrence beyond MC (and up-to-seven criteria). In the subgroup of patients with available histologic information (n = 354), microvascular invasion and microsatellite lesions were identified as additional independent risk factors for non-transplantable recurrence. CONCLUSIONS: Despite the high recurrence rate, LR for single HCC ≤5 cm offers excellent long-term survival. Non-transplantable recurrence is predicted by HCC size and AFP levels, among pre-operatively available variables. High-risk patients could be considered for frontline LT or listed for transplantation even before recurrence.

Landscape of alcohol-related hepatocellular carcinoma in the last 15 years highlights the need to expand surveillance programs.

Background & Aims: Alcohol abuse and metabolic disorders are leading causes of hepatocellular carcinoma (HCC) worldwide. Alcohol-related aetiology is associated with a worse prognosis compared with viral agents, because of the lower percentage of patients diagnosed with HCC under routine surveillance and a higher burden of comorbidity in alcohol abusers. This study aimed to describe the evolving clinical scenario of alcohol-related HCC over 15 years (2006-2020) in Italy. Methods: Data from the Italian Liver Cancer (ITA.LI.CA) registry were used: 1,391 patients were allocated to three groups based on the year of HCC diagnosis (2006-2010; 2011-2015; 2016-2020). Patient characteristics, HCC treatment, and overall survival were compared among groups. Survival predictors were also investigated. Results: Approximately 80% of alcohol-related HCCs were classified as cases of metabolic dysfunction-associated fatty liver disease. Throughout the quinquennia, <50% of HCCs were detected by surveillance programmes. The tumour burden at diagnosis was slightly reduced but not enough to change the distribution of the ITA.LI.CA cancer stages. Intra-arterial and targeted systemic therapies increased across quinquennia. A modest improvement in survival was observed in the last quinquennia, particularly after 12 months of patient observation. Cancer stage, HCC treatment, and presence of oesophageal varices were independent predictors of survival. Conclusions: In the past 15 years, modest improvements have been obtained in outcomes of alcohol-related HCC, attributed mainly to underuse of surveillance programmes and the consequent low amenability to curative treatments. Metabolic dysfunction-associated fatty liver disease is a widespread condition in alcohol abusers, but its presence did not show a pivotal prognostic role once HCC had developed. Instead, the presence of oesophageal varices, an independent poor prognosticator, should be considered in patient management and refining of prognostic systems. Impact and Implications: Alcohol abuse is a leading and growing cause of hepatocellular carcinoma (HCC) worldwide and is associated with a worse prognosis compared with other aetiologies. We assessed the evolutionary landscape of alcohol-related HCC over 15 years in Italy. A high cumulative prevalence (78%) of metabolic dysfunction-associated fatty liver disease, with signs of metabolic dysfunction, was observed in HCC patients with unhealthy excessive alcohol consumption. The alcohol + metabolic dysfunction-associated fatty liver disease condition tended to progressively increase over time. A modest improvement in survival occurred over the study period, likely because of the persistent underuse of surveillance programmes and, consequently, the lack of improvement in the cancer stage at diagnosis and the patients' eligibility for curative treatments. Alongside the known prognostic factors for HCC (cancer stage and treatment), the presence of oesophageal varices was an independent predictor of poor survival, suggesting that this clinical feature should be carefully considered in patient management and should be included in prognostic systems/scores for HCC to improve their performance.

SIUMB recommendations on the use of ultrasound in neoplastic lesions of the gallbladder and extrahepatic biliary tract.

Extrahepatic biliary tract and gallbladder neoplastic lesions are relatively rare and hence are often underrepresented in the general clinical recommendations for the routine use of ultrasound (US). Dictated by the necessity of updated summarized review of current literature to guide clinicians, this paper represents an updated position of the Italian Society of Ultrasound in Medicine and Biology (SIUMB) on the use of US and contrast-enhanced ultrasound (CEUS) in extrahepatic biliary tract and gallbladder neoplastic lesions such as extrahepatic cholangiocarcinoma, gallbladder adenocarcinoma, gallbladder adenomyomatosis, dense bile with polypoid-like appearance and gallbladder polyps.

Infectious Pneumonia and Lung Ultrasound: A Review.

The application of thoracic ultrasound examination has not long been developed because ultrasound's interaction with the lung does not generate an anatomical image but an artifactual one. Subsequently, the evaluation of pulmonary artifacts and their correlation to specific diseases allowed the development of ultrasound semantics. Currently, pneumonia still represents one of the main causes of hospitalization and mortality. Several studies in the literature have demonstrated the ultrasound features of pneumonia. Although ultrasound cannot be considered the diagnostic gold standard for the study of all lung diseases, it has experienced an extraordinary development and growth of interest due to the SARS-CoV-2 pandemic. This review aims to provide essential information on the application of lung ultrasound to the study of infectious pneumonia and to discuss the differential diagnosis.

Gastrointestinal Ultrasound in Emergency Setting.

Acute bowel diseases are responsible for more than one third of subjects who were referred to the emergency department for acute abdominal pain and gastrointestinal evaluation. Gastrointestinal ultrasound (GIUS) is often employed as the first imaging method, with a good diagnostic accuracy in the setting of acute abdomen, and it can be an optimal diagnostic strategy in young females due to the radiation exposure related to X-ray and computed tomography methods. The physician can examine the gastrointestinal system in the area with the greatest tenderness by ultrasound, thus obtaining more information and data on the pathology than the standard physical examination. In this comprehensive review, we have reported the most relevant indications and advantages to using ultrasound in the investigation of abdominal acute pain.

Epidemiological trends and trajectories of MAFLD-associated hepatocellular carcinoma 2002-2033: the ITA.LI.CA database.

BACKGROUND: Metabolic 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. METHODS: We 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. RESULTS: MAFLD 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). CONCLUSIONS: The 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.

Asymptomatic and symptomatic deep venous thrombosis in hospitalized acutely ill medical patients: risk factors and therapeutic implications.

BACKGROUND: Acutely ill medical patients experience deep venous thrombosis (DVT) during the hospitalization, however the time course of DVT is still unclear. OBJECTIVES: To evaluate risk factors in acutely ill hospitalized medical patients for proximal asymptomatic DVT (ADVT) and symptomatic DVT (SDVT) at admission and discharge. PATIENTS/METHODS: In this prospective observational study, consecutive acutely ill medical patients (hospitalized mainly for acute medical disease as infections, neoplasm, anemia, heart failure) underwent compression ultrasonography (CUS) of proximal lower limb veins within 48 h from admission and at discharge to diagnose ADVT and SDVT. Covid-19 patients, anticoagulant therapy, surgical procedures, acute SDVT, and acute pulmonary embolism, were exclusion criteria. Biographical characteristics at hospitalization, D-Dimer (assessed by ELISA)) and DD-improve score. RESULTS: Of 2,100 patients (1002 females, 998 males, age 71 ± 16 years) 58 (2.7%) had proximal ADVT at admission. Logistic regression analysis showed that age, and active cancer were independently associated with ADVT at admission. The median length of hospitalization was 10 days [interquartile range: 6-15]. During the hospital stay, 6 patients (0.3%) with a negative CUS at admission experienced DVT (2 SDVT and 4 ADVT). In the subgroup of patients (n = 1118), in whom D-dimer was measured at admission, D-Dimer and IMPROVE-DD score were associated with ADVT at admission (n = 37) and with all DVT (n = 42) at discharge. ROC curve defined an IMPROVE-DD score of 2.5 as the optimal cut-off for discriminating patients with and without thrombotic events. CONCLUSIONS: We provide evidence of early development of ADVT in unselected acutely ill medical patients suggesting the need of investigating patients by CUS immediately after hospital admission (within 48 h). Advanced age, active cancer, known thrombophilia and increased IMPROVE-DD score may identify patients at risk. The benefit of anticoagulation needs to be investigated in patients with these specific risk factors and negative CUS at admission. TRIAL REGISTRATION: NCT03157843.

Contrast-enhanced ultrasound Liver Imaging Reporting and Data System: Lights and shadows in hepatocellular carcinoma and cholangiocellular carcinoma diagnosis.

BACKGROUND: Contrast-enhanced ultrasound (CEUS) is considered a secondary examination compared to computed tomography (CT) and magnetic resonance imaging (MRI) in the diagnosis of hepatocellular carcinoma (HCC), due to the risk of misdiagnosing intrahepatic cholangiocarcinoma (ICC). The introduction of CEUS Liver Imaging Reporting and Data System (CEUS LI-RADS) might overcome this limitation. Even though data from the literature seems promising, its reliability in real-life context has not been well-established yet. AIM: To test the accuracy of CEUS LI-RADS for correctly diagnosing HCC and ICC in cirrhosis. METHODS: CEUS LI-RADS class was retrospectively assigned to 511 nodules identified in 269 patients suffering from liver cirrhosis. The diagnostic standard for all nodules was either biopsy (102 nodules) or CT/MRI (409 nodules). Common diagnostic accuracy indexes such as sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were assessed for the following associations: CEUS LR-5 and HCC; CEUS LR-4 and 5 merged class and HCC; CEUS LR-M and ICC; and CEUS LR-3 and malignancy. The frequency of malignant lesions in CEUS LR-3 subgroups with different CEUS patterns was also determined. Inter-rater agreement for CEUS LI-RADS class assignment and for major CEUS pattern identification was evaluated. RESULTS: CEUS LR-5 predicted HCC with a 67.6% sensitivity, 97.7% specificity, and 99.3% PPV (P < 0.001). The merging of LR-4 and 5 offered an improved 93.9% sensitivity in HCC diagnosis with a 94.3% specificity and 98.8% PPV (P < 0.001). CEUS LR-M predicted ICC with a 91.3% sensitivity, 96.7% specificity, and 99.6% NPV (P < 0.001). CEUS LR-3 predominantly included benign lesions (only 28.8% of malignancies). In this class, the hypo-hypo pattern showed a much higher rate of malignant lesions (73.3%) than the iso-iso pattern (2.6%). Inter-rater agreement between internal raters for CEUS-LR class assignment was almost perfect (n = 511, k = 0.94, P < 0.001), while the agreement among raters from separate centres was substantial (n = 50, k = 0.67, P < 0.001). Agreement was stronger for arterial phase hyperenhancement (internal k = 0.86, P < 2.7 × 10-214; external k = 0.8, P < 0.001) than washout (internal k = 0.79, P < 1.6 × 10-202; external k = 0.71, P < 0.001). CONCLUSION: CEUS LI-RADS is effective but can be improved by merging LR-4 and 5 to diagnose HCC and by splitting LR-3 into two subgroups to differentiate iso-iso nodules from other patterns.

Potential feasibility of atezolizumab-bevacizumab therapy in patients with hepatocellular carcinoma treated with tyrosine-kinase inhibitors.

BACKGROUND: The combination of atezolizumab-bevacizumab has been proven to be superior to sorafenib for the treatment of unresectable hepatocellular carcinoma not amenable to locoregional treatments, becoming the standard of care of systemic therapy. AIM: This study aimed at assessing real-world feasibility of atezolizumab-bevacizumab in patients treated with tyrosine-kinase inhibitors. METHODS: Among 1447 patients treated with tyrosine-kinase inhibitors from January 2010 to December 2020, we assessed the percentage of those potentially eligible to atezolizumab-bevacizumab (according to IMbrave-150 trial criteria), and the overall survival of eligible and non-eligible patients. RESULTS: 422 (29%) patients were qualified for atezolizumab-bevacizumab therapy. The main exclusion causes were Child-Pugh class and Performance Status. Adopting the more permissive inclusion criteria of SHARP trial, 535 patients became eligible. The median overall survival of tyrosine-kinase inhibitors patients was 14.9 months, longer in eligible patients than in their counterpart due to better baseline liver function and oncological features. CONCLUSION: Real-world data indicate that less than one-third of hepatocellular carcinoma patients treated with tyrosine-kinase inhibitors are potentially eligible to atezolizumab-bevacizumab according to the registration trial criteria. These patients have a longer survival than the non-eligible ones. If the selection criteria of atezolizumab-bevacizumab trial are maintained in clinical practice, tyrosine-kinase inhibitors will remain the most used systemic therapy for hepatocellular carcinoma patients.

Role of Lung Ultrasound in the Management of Patients with Suspected SARS-CoV-2 Infection in the Emergency Department.

Background: The lung ultrasound (LUS) score has been proposed as an optimal scheme for the ultrasound study of patients with suspected/confirmed COVID-19 pneumonia. The aims of our study were to evaluate the use of lung ultrasound as a diagnostic tool for diagnosing SARS-CoV-2 pneumonia, to examine the validity of the LUS score for the diagnosis of COVID-19 pneumonia, and to correlate this score with hospitalization rate and 30-day mortality. Materials and Methods: A retrospective analysis was performed on 1460 patients who were referred to the General Emergency Department of the S. Orsola-Malpighi Hospital from April 2020 to May 2020 for symptoms suspected to indicate SARS-CoV-2 infection. The ultrasound examination was based on a common execution scheme called the LUS score, as previously described. Results and Conclusions: The LUS score was found to correlate with the degree of clinical severity and respiratory failure (paO2/FiO2 ratio and the alveolar−arterial gradient increase than expected for age). It was shown that COVID-19 patients with an LUS score of >7 require the use of oxygen support, and a value of >10 is associated with an increased risk of oro-tracheal intubation. The LUS score was found to present higher values in hospitalized patients, increasing according to the degree of care intensity. Patients who died from COVID-19 were characterized by a mean LUS score of 11 at presentation to the emergency department. An LUS score of >7.5 was found to indicate a sensitivity of 83% and a specificity of 89% for 30-day mortality in COVID-19 patients. The use of LUS seems to be an optimal first level method for pneumonia detection and risk stratification in patients with suspected SARS-CoV-2 infection.

Characteristics and survival of patients with primary biliary cholangitis and hepatocellular carcinoma.

BACKGROUND: Comprehensive and contemporary data pertaining large populations of patients with Primary Biliary Cholangitis (PBC) and hepatocellular carcinoma (HCC) are missing. AIM: To describe main characteristics and outcome of PBC patients with HCC diagnosed in the new millennium. METHODS: Analysing the Italian Liver Cancer registry we identified 80 PBC patients with HCC diagnosed after the year 2000, and described their clinical characteristics, access to treatment and survival. RESULTS: Median age of patients was 71 years and 50.0% were males. Cirrhosis was present in 86.3% of patients, being well-compensated in 58.0%. Median HCC diameter was smaller in patients under surveillance (2.6 vs 4.0 cm, P = 0.007). Curative treatment, feasible in 50.0% of patients, was associated with improved survival compared to palliative and supportive care (42 vs 33 vs 6 months, P<0.0001). Surveillance was associated with a non-significant improved survival (36 vs 23 months), likely due to similar rate of curative treatment in patients under (51.4%) and outside surveillance (42.6%). CONCLUSIONS: PBC patients with HCC are often elderly males with well-preserved liver function. Feasibility of curative treatment is high and associated with improved prognosis. Description of these patients may help focus surveillance to identify earlier tumours, increase their curability, and improve prognosis.

Cholangiocarcinoma landscape in Europe: Diagnostic, prognostic and therapeutic insights from the ENSCCA Registry.

BACKGROUND & AIMS: Cholangiocarcinoma (CCA) is a rare and heterogeneous biliary cancer, whose incidence and related mortality is increasing. This study investigates the clinical course of CCA and subtypes (intrahepatic [iCCA], perihilar [pCCA], and distal [dCCA]) in a pan-European cohort. METHODS: The ENSCCA Registry is a multicenter observational study. Patients were included if they had a histologically proven diagnosis of CCA between 2010-2019. Demographic, histomorphological, biochemical, and clinical studies were performed. RESULTS: Overall, 2,234 patients were enrolled (male/female=1.29). iCCA (n = 1,243) was associated with overweight/obesity and chronic liver diseases involving cirrhosis and/or viral hepatitis; pCCA (n = 592) with primary sclerosing cholangitis; and dCCA (n = 399) with choledocholithiasis. At diagnosis, 42.2% of patients had local disease, 29.4% locally advanced disease (LAD), and 28.4% metastatic disease (MD). Serum CEA and CA19-9 showed low diagnostic sensitivity, but their concomitant elevation was associated with increased risk of presenting with LAD (odds ratio 2.16; 95% CI 1.43-3.27) or MD (odds ratio 5.88; 95% CI 3.69-9.25). Patients undergoing resection (50.3%) had the best outcomes, particularly with negative-resection margin (R0) (median overall survival [mOS] = 45.1 months); however, margin involvement (R1) (hazard ratio 1.92; 95% CI 1.53-2.41; mOS = 24.7 months) and lymph node invasion (hazard ratio 2.13; 95% CI 1.55-2.94; mOS = 23.3 months) compromised prognosis. Among patients with unresectable disease (49.6%), the mOS was 10.6 months for those receiving active palliative therapies, mostly chemotherapy (26.2%), and 4.0 months for those receiving best supportive care (20.6%). iCCAs were associated with worse outcomes than p/dCCAs. ECOG performance status, MD and CA19-9 were independent prognostic factors. CONCLUSION: CCA is frequently diagnosed at an advanced stage, a proportion of patients fail to receive cancer-specific therapies, and prognosis remains dismal. Identification of preventable risk factors and implementation of surveillance in high-risk populations are required to decrease cancer-related mortality. LAY SUMMARY: This is, to date, the largest international (pan-European: 26 hospitals and 11 countries) observational study, in which the course of cholangiocarcinoma has been investigated, comparing the 3 subtypes based on the latest International Classification of Diseases 11th Edition (ICD-11) (i.e., intrahepatic [2C12], perihilar [2C18], or distal [2C15] affected bile ducts), which come into effect in 2022. General and tumor-type specific features at diagnosis, risk factors, biomarker accuracy, as well as patient management and outcomes, are presented and compared, outlining the current clinical state of cholangiocarcinoma in Europe.

Transarterial Chemoembolization for Hepatocellular Carcinoma in Clinical Practice: Temporal Trends and Survival Outcomes of an Iterative Treatment.

BACKGROUND: Transarterial chemoembolization (TACE) is one of the most frequently applied treatments for hepatocellular carcinoma (HCC) worldwide. In this study, we aimed at evaluating whether and how TACE application and repetition, as well as the related outcome, have changed over the last three decades in Italy. METHODS: Data of 7,184 patients with HCC were retrieved from the Italian Liver Cancer (ITA.LI.CA) database. Patients were divided according to the period of diagnosis in six cohorts: P1 (1988-1993), P2 (1994-1998), P3 (1999-2004), P4 (2005-2009), P5 (2010-2014), and P6 (2015-2019). All the analyses were repeated in the overall patient population and in Barcelona Clinic Liver Cancer (BCLC) B patients, who are the subgroup of HCC patients originally supposed to receive TACE according to guidelines. TACE was defined as either the first or the main (more effective) treatment. RESULTS: The proportion of patients receiving TACE as first or main therapy declined over time, and less than 50% of BCLC B patients were treated with chemoembolization from P3 onward. Conversely, TACE was widely used even outside the intermediate stage. Survival of TACE-treated patients progressively increased from P1 to P6. Although TACE was performed only once in the majority of patients, there was an increasing proportion of those receiving 2 or ≥3 treatments sessions over time. The overall survival (OS) of patients undergoing repeated treatments was significantly higher compared to those managed with a single TACE (median OS 40.0 vs. 65.0 vs. 71.8 months in 1, 2, and ≥3 TACE groups, respectively; p < 0.0001). However, after a first-line TACE, the adoption of curative therapies provided longer survival than repeating TACE (83.0 vs. 42.0 months; p < 0.0001), which in turn was associated with better outcomes compared to systemic therapies or best supportive care (BSC). CONCLUSIONS: Despite a decline in the percentage of treated patients over time, TACE has still an important role in the management of HCC patients. The survival of TACE-treated patients gradually improved over time, probably due to a better patient selection. Iterative TACE is effective, but an upward shift to curative therapies provides better outcomes while transition to systemic therapies and BSC leads to a worse prognosis.

Surveillance for hepatocellular carcinoma with a 3-months interval in "extremely high-risk" patients does not further improve survival.

BACKGROUND: An enhanced surveillance schedule has been proposed for cirrhotics with viral etiology, who are considered at extremely high-risk of hepatocellular carcinoma (HCC). AIMS: We compared the 3- and 6-months surveillance interval, evaluating cancer stage at diagnosis and patient survival. METHODS: Data of 777 HBV and HCV cirrhotic patients with HCC diagnosed under a 3-months (n = 109, 3MS group) or a 6-months (n = 668, 6MS group) surveillance were retrieved from the Italian Liver Cancer database. Survival in the 3MS group was considered as observed and adjusted for lead-time bias, and survival analysis was repeated after a propensity score matching. RESULTS: The 3-months surveillance interval neither reduced the share of patients diagnosed outside the Milano criteria, nor increased their probability to receive curative treatments. The median survival of 6MS patients (55.0 months [45.9-64.0]) was not significantly different from the observed (47.0 months [35.0-58.9]; p = 0.43) and adjusted (44.9 months [33.4-56.4]; p = 0.30) survival of 3MS patients. A propensity score analysis confirmed the absence of a survival advantage for 3MS patients. CONCLUSIONS: A tightening of surveillance schedule does not increase the diagnosis of early-stage tumors, the feasibility of curative treatments and the survival. Therefore, we should maintain the 6-months interval in the surveillance of viral cirrhotics.

Prevalence and risk factors of moderate to severe hepatic steatosis in patients with rheumatoid arthritis: an ultrasonography cross-sectional case-control study.

BACKGROUND: The independent association between hepatic steatosis and rheumatoid arthritis is poorly defined. METHODS: The presence of moderate to severe steatosis was assessed, using liver ultrasonography, in 364 consecutive non-diabetic subjects (223 patients with rheumatoid arthritis and 141 age- and sex-matched healthy controls). Adjusted multiple regression analysis was performed to explore the association between rheumatoid arthritis and moderate to severe steatosis in the overall sample and identify independent risk factors in the rheumatoid arthritis subgroup. RESULTS: The prevalence of moderate to severe steatosis in the overall sample was 31.3%, with a significantly higher prevalence in patients with rheumatoid arthritis than healthy controls (38.7% versus 19.7%, p < 0.0001). After adjustment for sex, age, cholesterol, triglycerides, body mass index, waist, hypertension and smoke, rheumatoid arthritis remained significantly associated with moderate to severe steatosis [odds ratio (95% confidence interval) = 2.24 (1.31, 3.84); p = 0.003]. In the rheumatoid arthritis group, male sex, higher body mass index, higher triglycerides concentrations and higher cumulative dosage of methotrexate [odds ratio (95% confidence interval) = 1.11 (1.01, 1.23); p = 0.026] were significantly associated with moderate to severe steatosis, while systemic inflammation, disease activity, use of steroids and biologics were not. CONCLUSION: Rheumatoid arthritis is independently associated with moderate to severe steatosis, with male sex, higher body mass index and cumulative dose of methotrexate being predisposing factors. Further prospective studies are warranted to confirm our findings and to investigate the effect of steatosis on liver outcomes in the rheumatoid arthritis population.