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Hepatocellular carcinoma (HCC) is the fourth leading cause of cancer death worldwide and its prognosis is highly heterogeneous, being related not only to tumour burden but also to the severity of underlying chronic liver disease. Moreover, advances in systemic therapies for HCC have increased the complexity of patient management. Randomised-controlled trials represent the gold standard for evidence generation across all areas of medicine and especially in the oncology field, as they allow for unbiased estimates of treatment effect without confounders. Observational studies have many problems that could reduce their internal and external validity. However, large prospective (well-conducted) observational real-world studies can detect rare adverse events or monitor the occurrence of long-term adverse events. How best to harness real world data, which refers to data generated from the routine care of patients, and real-world 'evidence', which is the evidence generated from real-world data, represents an open challenge. In this review article, we aim to provide an overview of the benefits and limitations of different study designs, particularly focusing on randomised-controlled trials and observational studies, to address important and not fully resolved questions in HCC research., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background & Aims: Recognition of non-characterized liver nodules (NCLN) prior to direct-acting antivirals (DAAs) is associated with increased hepatocellular carcinoma (HCC) risk in patients with HCV. The risk of HCC has not been defined in F3/F4 patients in whom NCLN have been ruled-out before starting DAAs and at sustained virological response (SVR). This study aimed to estimate HCC incidence in this population., Methods: We performed a prospective study including HCV-infected patients with F3/F4 fibrosis, without a history of HCC, and who achieved SVR after DAAs. Patients were only included if they had undergone ultrasound imaging that excluded the presence of HCC/NCLN within 30 days after SVR. All patients were evaluated every 6 months until developing primary liver cancer, death or withdrawal of informed consent. HCC incidence was expressed per 100 patient-years (/100PY). Adherence to screening program was calculated every 6 months for the first 48 months., Results: A total of 185 patients (63/122, F3/F4) were included. Among those with cirrhosis, 92% were Child-Pugh A and 42.7% had clinically significant portal hypertension (CSPH). Albumin-bilirubin score was 1 in 84.9% and 2 in 15.1% of patients, respectively. The median clinical and radiologic follow-up was 52.4 months and 48 months, respectively. Ten patients developed HCC: HCC incidence was 1.46/100PY (95% CI 0.79-2.71) in the whole cohort, 2.24/100PY (95% CI 1.21-4.17) in F4 only and 3.63/100PY (95% CI 1.95-6.74) in patients with CSPH. No HCC was registered in patients with F3. Median time between SVR and HCC occurrence was 28.1 months; 12 non-primary liver cancers were also identified., Conclusions: Patients with cirrhosis without NCLN at SVR remain at risk of HCC development. The absence of HCC in patients with F3 reinforces their marginal cancer risk, but prospective studies are needed to exclude them from screening programs., Lay Summary: Patients with HCV-related cirrhosis, without non-characterized liver nodules at sustained virologic response, remain at risk of hepatocellular carcinoma despite viral cure. However, the cancer risk after successful direct-acting antiviral treatment is marginal in patients with F3 fibrosis without non-characterized liver nodules. If confirmed in larger prospective studies, current screening recommendations may need to be revisited in this group of patients., Competing Interests: Conflict of interest MSZ: received speaker fees from Bayer and travel grants from Bayer, BTG and Eisai; ZM: received consultancy fees from Gilead, Abbvie, Alexion, Orphalan and Deep Genomics; speaker fees from Gilead and Abbvie and research grants from Gilead; SL: received consultancy and speaker fees from Gilead and Abbvie and grants from Gilead, VS: received travel grants from Bayer; GI: received ravel grants from Bayer; NG: congress inscriptions: Eisai; NLL: Bayer, AstraZeneca, Travel funding: Bayer Congress inscriptions: Eisai; AD: speaker fees and travel grants from Bayer; AGC: Speaker fees from BTG and Terumo; AD: speaker fees from Bayer and travel grants from Bayer; SMM: received speaker fees from Bayer and travel grants from Bayer and Eisai; CA: Speaker fees, travel and research grants from Bayer, BTG and Terumo. Consultancy from ROCHE; JR: has consulted for Roche and received speaker fees from Bayer and Roche and travel grants from Bayer; AF: Lecture fees from Bayer, Gilead and MSD; consultancy fees from Bayer, AstraZeneca, Roche and Guerbert; FT: DSMB fees from Archivel Farma, S.L., Daiichi-Sankyo Pharma Development, ArQule and Rovi; speaker fees from Bayer; lecture fees from Janssen; JB: has consulted for Arqule, Bayer-Shering Pharma, Novartis, BMS, BTG- Biocompatibles, Eisai, Kowa, Terumo, Gilead, Bio-Alliance, Roche, AbbVie, MSD, Sirtex, Ipsen, Astra-Medimmune, Incyte, Quirem, Adaptimmune, Lilly, Basilea, Nerviano, Sanofi; and received research/educational grants from Bayer, and lecture fees from Bayer-Shering Pharma, BTG-Biocompatibles, Eisai, Terumo, Sirtex, Ipsen; XF: acted as advisor for Gilead and Abbvie; MR: received consultancy fees and/or travel support from Bayer, BMS, Roche, Ipsen, AstraZeneca, UniversalDX, Boston Scientific and Lilly, lecture fees from Bayer, BMS, Gilead, and Lilly and research grants from Bayer and Ipsen. Please refer to the accompanying ICMJE disclosure forms for further details., (Copyright © 2021. Published by Elsevier B.V.)

There have been major advances in the armamentarium for hepatocellular carcinoma (HCC) since the last official update of the Barcelona Clinic Liver Cancer prognosis and treatment strategy published in 2018. Whilst there have been advances in all areas, we will focus on those that have led to a change in strategy and we will discuss why, despite being encouraging, data for select interventions are still too immature for them to be incorporated into an evidence-based model for clinicians and researchers. Finally, we describe the critical insight and expert knowledge that are required to make clinical decisions for individual patients, considering all of the parameters that must be considered to deliver personalised clinical management., Competing Interests: Conflict of interest MR: reports consultancy from Bayer, BMS, Roche, Ipsen, Astra Zeneca, Boston Science and Lilly; lecture fees from Bayer, BMS, Gilead, Lilly,Roche and UniversalDX and travel support from Bayer, BMS, Lilly and Astra Zeneca. Received research funding (to institution) from Bayer and Ipsen. AF: reports lecture fees from Bayer, Boston Science, Gilead, and MSD, consultancy fees from Bayer, Astra Zeneca, Roche, SIRTEX, AB Exact Science and Guerbert. JR: reports lectures and travel grants from Bayer and Roche. JFF: reports lecture fees from Bayer. MB: reports lectures and/or travel support from Boston Science, Terumo, Guerbet and Bayer. AGC: reports lectures fee from Boston Science, Terumo. KRK: reports consultancy fees (to self) from Exact Sciences, Genentech/Roche, Gilead. Received travel support from Ipsen. Received research funding (to institution) from Agios, Astra Zeneca, Bayer, BMS, Eli Lilly, EMD Serono, Exelixis, Genentech/Roche, Merck, Novartis, Partner Therapeutics, QED, Relay Therapeutics, Surface Oncology, Taiho. PRG: consultancy fees and/or travel support from Bayer, Boston Scientific, AstraZeneca, Adaptimmune, BMS, MSD, Sirtex, Lilly, Roche, Guerbet, Ipsen, Eisai. VM: Nothing to disclose. RS: reports consultancy fees from Boston Scientific, Cook, Bard, Genentech, Astrazeneca, Eisai, Sirtex, Siemens, research support from Boston Scientific. BS: reports consultancy fees from Adaptimmune, Astra Zeneca, Bayer, BMS, Boston Scientific, BTG, Eisai, Eli Lilly, H3 Biomedicine, Ipsen, Novartis, Merck, Roche, Sirtex Medical, Terumo; speaker fees from Astra Zeneca, Bayer, BMS, BTG, Eli Lilly, Ipsen, Novartis, Merck, Roche, Sirtex Medical, Terumo; research grants (to Institution) from BMS and Sirtex Medical. AS: has served on advisory boards or consulted for Genentech, Bayer, Eisai, AstraZeneca, BMS, and Exelixis. AV: Speaker, consultancy and advisory role: Amgen, Roche, Bayer, Sanofi, BMS, Lilly, Novartis, EISAI, AstraZeneca, Merck, Incyte, Ipsen, PierreFabre, MSD, Sirtex, BTG, Servier, Terumo, GSK. JFu: Nothing to disclose. CA: reports lectures fee from Bayer. JB: has consulted for Arqule, Bayer-Shering Pharma, Novartis, BMS, BTG- Biocompatibles, Eisai, Kowa, Terumo, Gilead, Bio-Alliance, Roche, AbbVie, MSD, Sirtex, Ipsen, Astra-Medimmune, Incyte, Quirem, Adaptimmune, Lilly, Basilea, Nerviano, Sanofi and UniversalDX; and received research/educational grants from Bayer, and lecture fees from Bayer-Shering Pharma, BTG-Biocompatibles, Eisai, Terumo, Sirtex, Ipsen. Please refer to the accompanying ICMJE disclosure forms for further details., (Copyright © 2021 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Background: the assessment of fibrosis in Crohn's disease (CD) bowel lesions helps to guide therapeutic decisions. Real-time elastography (RTE) and delayed-enhancement magnetic resonance enterography (DE-MRE) have demonstrated good accuracy in quantifying CD-related ileal fibrosis as compared with histological examination. To date no study has compared DE-MRE and RTE., Aims: we aimed to evaluate the agreement between RTE and DE-MRE on quantifying CD-related ileal fibrosis., Methods: consecutive patients with ileal or ileocolonic CD underwent RTE and DE-MRE. Ileal fibrosis was quantified by calculating the strain ratio (SR) at RTE and the 70s-7 min percentage of enhancement gain (%EG) of both mucosa and submucosa at DE-MRE. A SR ≥2 was applied to define severe fibrosis. Clinically relevant outcomes occurring at follow-up were recorded., Results: 40 CD patients were enrolled. A significant linear correlation was observed between SR and submucosal %EG (r = 0.594, p < 0.001). Patients with severe fibrosis (SR ≥2) had significantly higher submucosal %EG values than patients with low/moderate fibrosis (median values 26.4% vs. 9.5%, p < 0.001). During a median 43.8-month follow-up relevant disease outcomes occurred more frequently in the severe-fibrosis group (75% vs. 36%, HR 5.4, 95% CI 1.2-24.6, p = 0.029)., Conclusions: the study demonstrates an excellent agreement between RTE and DE-MRE in assessing ileal fibrosis in CD., Competing Interests: Declaration of Competing Interest The authors declare no conflict of interest., (Copyright © 2021. Published by Elsevier Ltd.)

Background and Aims: Hepatic epithelioid hemangioendothelioma is an ultra-rare hepatic vascular tumor, diagnosed more frequently in females. The knowledge about this tumor derives mainly from small case series with sub-optimal treatment outcomes. The aim of this study is to identify the clinical and radiological issues helpful to develop an international prospective registry., Methods: We conducted an international multicentric and retrospective study of patients with hepatic hemangioendothelioma. The clinical, pathological and radiological images collected during follow-up were reviewed. Central radiological revision was performed and 3 patterns of contrast were defined., Results: Between 1994 and 2016, 27 patients with hepatic hemangioendothelioma were identified in three institutions but the final diagnosis was hepatic angiosarcoma in one. The majority were females, median age was 38.7-years and 17 patients were asymptomatic at diagnosis. No patient had Two out of ten (20%) patients had surgical specimens with positive macro-vascular invasion and 50% had extrahepatic disease, and the most frequent pattern was the progressive-central-contrast-uptake. After a median follow-up of 6.7-years, the 5- and 10-year survival rates are 91.5% and 51.9%, respectively., Conclusions: This multicentric study shows the heterogeneous profile of patients with hepatic hemangioendothelioma, reflecting the need to establish a reference network in order to better characterize these patients and ultimately develop a personalized treatment strategy., Competing Interests: Declaration of Competing Interest None., (Copyright © 2020 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.)

Background: In APPRECIA trial, Crohn's disease (CD) patients undergoing intestinal resection were randomized to postoperative adalimumab (ADA) or azathioprine (AZA)., Aims: To evaluate health-related quality of life (HRQoL) in APPRECIA trial., Methods: HRQoL was evaluated using disease-specific shortened Spanish version of the IBDQ (SIBDQ-9) and generic European Quality of Life-5 Dimensions (EQ-5D) questionnaires, completed at baseline and at weeks 24 and 52., Results: Sixty-one patients (37 ADA and 24 AZA) had evaluable data for HRQoL. Patients treated with ADA or AZA had significant improvement from baseline to weeks 24 and 52 in SIBDQ-9 and EQ-5D (p < 0.001 and p ≤ 0.006 for all comparisons, respectively). There were no differences between treatment arms in mean change in SIBDQ-9 and EQ-5D at weeks 24 and 52 vs baseline. Only patients without endoscopic recurrence had significant improvement in SIBDQ-9 (p < 0.001) and EQ-5D (p < 0.001) at week 52. At week 52, there was a high to moderate negative correlation between CDAI score with SIBDQ-9 score (Pearson's r: -0.768) and with EQ-5D index (r: -0.644)., Conclusion: HRQoL improved after intestinal resection in CD, irrespective of the postoperative therapy used (ADA or AZA). Outcomes in HRQoL were associated with prevention of endoscopic recurrence, since improvements in HRQoL were only significant in patients with endoscopic remission at 1 year., (Copyright © 2019 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.)

Background & Aims: Current guidelines recommend diagnostic work-up for nodules >1cm detected during screening for hepatocellular carcinoma (HCC). This implies that patients with benign conditions may undergo unnecessary evaluation and those with small nodules may be intervened too early, leading to overdiagnosis. Since increased arterial vascularization is the hallmark of malignancy, its detection by contrast-enhanced ultrasound (CEUS) could become the signal to proceed with diagnosis confirmation. The aim was to assess if HCCs <2 cm without arterial hyperenhancement by baseline CEUS have a benign evolutionary profile, suggesting that diagnosis and invasive treatment could be delayed until detection of an overt malignant profile, associated with increased vascularization., Methods: We prospectively included 168 cirrhotic patients with a newly detected solitary nodule of 5-20mm by screening ultrasonography. MRI, CEUS and fine needle biopsy (FNB) were performed and if no confident diagnosis was obtained, patients were closely followed to rule out HCC. Final diagnosis was: HCC (n = 119), cholangiocarcinoma (n = 3), neuroendocrine tumour (n = 1) and benign lesions (n = 45)., Results: CEUS did not detect contrast hyperenhancement in the arterial phase in 55 cases (34%). Eighteen out of these 55 nodules were diagnosed as HCC. Non-CEUS hyperenhanced HCCs were more frequently well-differentiated than CEUS-hyperenhanced HCCs (p < 0.004). Fourteen patients were treated with ablation and 4 with resection. Ten (55.6%) patients experienced tumour recurrence after treatment, mostly distant, confirming their overt malignant profile., Conclusions: Absence of contrast hyperenhancement on CEUS during the arterial phase in nodules <2 cm in a cirrhotic liver does not predict a less malignant profile. Accordingly, priority for diagnostic work-up and treatment should not differ according to contrast profiles on CEUS., (Copyright © 2014 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Background & Aims: There are no clinical data/markers to predict improved survival in patients with hepatocellular carcinoma treated with sorafenib. Majority of sorafenib adverse events appear within the first 60 days of treatment and studies correlating them with outcome are needed., Methods: We prospectively studied 147 hepatocellular carcinoma patients (97% cirrhotic, 82% Child-Pugh A, BCLC-B 77, BCLC-C 69) treated with sorafenib. Follow-up included monthly clinical and laboratory monitoring and tumor staging at week 4 and every 8 weeks., Results: After a median follow up of 11.6 months (treatment duration 6.7 months), time to progression and overall survival were 5.1 and 12.7 months. All but one patient presented at least one adverse event (median time to appearance 56 days). Time dependent covariate analysis (HR [95% CI]) identified baseline performance status (2.86 [1.75 to 4.55], p<0.001), BCLC (1.69 [1.18 to 2.50], p = 0.005), and dermatologic adverse event requiring dose adjustment within the first 60 days (0.58 [0.36 to 0.92], p = 0.022) as independent predictors of better outcome. Other early adverse events did not have an impact in outcome. The predictive value of dermatologic adverse events for survival was confirmed by the landmark analysis (p = 0.0270)., Conclusions: Development of dermatologic adverse events within 60 days of sorafenib initiation is associated with better survival. Therefore, this should not to be taken as a negative event and discourage treatment maintenance. Likewise, second line clinical trials should be designed and/or evaluated considering this information to avoid significant bias., (Copyright © 2014 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Background & Aims: To prospectively assess the diagnostic accuracy of the incorporation of additional magnetic resonance imaging (MRI) parameters in those based on contrast enhancement pattern for the diagnosis of solitary nodules between 5 and 20mm, detected during surveillance in patients with cirrhosis., Methods: Between November 2003 and January 2010, we prospectively included 159 cirrhotic patients with a newly detected solitary nodule between 5 and 20mm in diameter by screening ultrasonography (US). Hepatic MRI and fine-needle biopsy were performed in all patients., Results: Final diagnoses were hepatocellular carcinoma (HCC) (n=103), other malignant lesions (intrahepatic cholangiocarcinoma/metastases) (n=4), and benign lesions (n=52). The specific enhancement pattern (arterial enhancement followed by washout) yielded a sensitivity and specificity of 58.3% and 96.4%, respectively. Peritumoral capsule was present in 43 HCC and in 2 non-HCC lesions. Intralesional fat was detected in 24 nodules; 5 nodules were non-HCC. Finally, the presence of both capsule and fat was observed in 10 cases, all of them HCC (100% specificity), but all of them also displayed the specific enhancement pattern, thus adding no sensitivity or specificity., Conclusions: Conclusive non-invasive diagnosis of HCC in cirrhosis should be based only on the contrast enhancement pattern, while other characteristics at MRI do not increase the diagnostic accuracy., (Copyright © 2012 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)