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Hepatocellular carcinoma appears frequently in patients with cirrhosis. Surveillance by biannual ultrasound is recommended for such patients because it allows diagnosis at an early stage, when effective therapies are feasible. The best candidates for resection are patients with a solitary tumour and preserved liver function. Liver transplantation benefits patients who are not good candidates for surgical resection, and the best candidates are those within Milan criteria (solitary tumour ≤5 cm or up to three nodules ≤3 cm). Image-guided ablation is the most frequently used therapeutic strategy, but its efficacy is limited by the size of the tumour and its localisation. Chemoembolisation has survival benefit in asymptomatic patients with multifocal disease without vascular invasion or extrahepatic spread. Finally, sorafenib, lenvatinib, which is non-inferior to sorafenib, and regorafenib increase survival and are the standard treatments in advanced hepatocellular carcinoma. This Seminar summarises the scientific evidence that supports the current recommendations for clinical practice, and discusses the areas in which more research is needed.

Systemic treatment for hepatocellular carcinoma (HCC) has been boosted by the incorporation of new agents after many negative phase III trials in the decade since the approval of sorafenib. Sorafenib introduced the concept that targeting specific hallmarks of hepatocarcinogenesis could modify the dismal prognosis of this disease, with the drug remaining a cornerstone in the upfront therapy for advanced HCC. The design of clinical trials in this malignancy is complicated by important obstacles related to patient selection, prognostic assessment and the need for endpoints that correlate with improvement in survival outcomes. In addition, the currently used criteria to determine treatment response or progression might prevent physicians from making appropriate clinical judgements and interpreting evidence arising from trials. In this Review, we discuss the advances in systemic therapy for HCC and critically review trial designs in HCC. Although novel therapies, such as new targeted agents and immunotherapies, are being rapidly incorporated, it is paramount to design future clinical trials based on the lessons learned from past failures and successes.

ObjectiveTo determine the diagnostic accuracy and predictive value of gadoxetic acid liver MRI (Gd-EOB-DTPA MRI) alone or in combination with diffusion-weighted imaging (DWI) as a second-line tool for detecting early hepatocellular carcinoma (HCC) recurrence in cirrhotic patients with previous HCC treated with resection or ablation.MethodsBetween 2014 and 2017, we prospectively included 34 cirrhotic patients with complete response to resection and/or ablation of early HCC in whom a new focal lesion enhancing in the arterial phase without washout was detected during follow-up with EC-MRI. After signing the informed consent, all patients underwent DWI and Gd-EOB-DTPA MRI; two readers analyzed signal intensities on each phase of dynamic study and on DWI. The final diagnosis was established by histology or follow-up EC-MRI. We used cross-tabulation to calculate indices of diagnostic accuracy.ResultsWe evaluated 34 patients (7 women; 73.5% with hepatitis C virus) with a total of 53 new arterial-phase-enhancing foci (median size, 10 [IQR 9–14] mm). The final diagnosis, reached by histopathology in 15 (35.7%) lesions and EC-MR follow-up in 27 (64.3%), was HCC in 42 (79.2%) and benign conditions in 11 (21.8%). Hepatobiliary-phase hypointensity on Gd-EOB-DTPA MRI plus hyperintensity on DWI yielded 54.8% sensitivity, 90.9% specificity, 95.8% positive predictive value, and 34.5% negative predictive value for diagnosing HCC recurrence.ConclusionAmong potential indices, combining hypointensity on hepatobiliary-phase Gd-EOB-DTPA MRI and hyperintensity on DWI has the highest specificity and positive predictive value to optimally detect HCC recurrence prior to confident diagnosis by conventional imaging criteria on EC-MRI in cirrhotic liver.Key Points• In patients at risk of HCC recurrence, the use of gadoxetic acid liver MRI and DWI may improve the differentiation of unspecific new arterial-enhancing foci from early hypervascular HCC recurrence in patients with non-conclusive findings on extracellular liver MRI.• Combined findings on hepatobiliary-phase gadoxetic acid–enhanced liver MRI and DWI had high specificity (90.9%) and positive predictive value (95.8%) for detecting early hypervascular HCC recurrence, but limited sensitivity.• Combining hepatobiliary-phase hypointensity on gadoxetic acid MRI and hyperintensity on diffusion-weighted imaging allows early diagnosis of hypervascular hepatocellular carcinoma and may help select patients for salvage therapy.

Objectives Liver Imaging Reporting and Data System (LI-RADS) for hepatocellular carcinoma (HCC) diagnosis in high-risk patients is a dynamic system, which was lastly updated in 2018. We aimed to evaluate the accuracy for HCC diagnosis of LI-RADS v2018 with magnetic resonance imaging (MRI) with extracellular contrast for solitary nodules ≤ 20 mm detected during ultrasound (US) surveillance in cirrhotic patients, with particular interest in those observations categorized as LI-RADS 3. Methods Between November 2003 and February 2017, we included 262 consecutive cirrhotic patients with a newly US-detected solitary ≤ 20-mm nodule. A LI-RADS (LR) v2018 category was retrospectively assigned. The diagnostic accuracy for each LR category was described, and the main MRI findings associated with HCC diagnosis were analyzed. Results Final diagnoses were as follows: 197 HCC (75.2%), 5 cholangiocarcinoma (1.9%), 2 metastasis (0.8%), and 58 benign lesions (22.1%); 0/15 (0%) LR-1, 6/26 (23.1%) LR-2, 51/74 (68.9%) LR-3, 11/12 (91.7%) LR-4, 126/127 (99.2%) LR-5, and 3/8 (37.5%) LR-M were HCC. LR-5 category displayed a sensitivity and specificity of 64% (95% CI, 56.8–70.7) and 98.5% (95% CI, 91.7–100), respectively. Considering also LR-4 as diagnostic for HCC, the sensitivity slightly increased to 69.5% (95% CI, 62.6–75.9) with minor impact on specificity (96.2%; 95% CI, 89.3–99.6). Regarding LR-3 observations, 51 out of 74 were HCC, 2 were non-HCC malignancies, and 20 out of 21 LR-3 nodules > 15 mm (95.2%) were finally categorized as HCC. Conclusions The high probability of HCC in US-detected LR-3 observations (68.9%) justifies triggering an active diagnostic work-up if intended to diagnose HCC at a very early stage. Key Points • In cirrhotic patients with nodules ≤ 20 mm detected during US surveillance, 51 out of 74 (68.9%) of LR-3 nodules by MRI corresponded to an HCC. • In LR-3 nodules, HCC diagnosis was closely related to baseline tumor size. All 5 nodules smaller than 1 cm were diagnosed as benign. Oppositely, 20 out of 21 LR-3 observations > 15 mm (95.2%) were diagnosed as HCC. • The high probability of HCC in US-detected LR-3 observations justifies triggering an active diagnostic work-up if intended to diagnose HCC at a very early stage.

Background To date, no definitive treatment exists for rosacea. Phototherapies, including intense pulsed light (IPL), have been reported to reduce its characteristic features of erythema and telangiectasias. Methods This multicenter, retrospective study reviewed the charts of 82 patients with vascular and pigmented rosacea who underwent treatment with the Harmony XL Pro VL/PL Cooled Applicator. Lesion coverage was assessed from photographs taken before and 3–4 months after the last treatment session. Physicians assessed aesthetic improvement using the 5‐point Global Aesthetic Improvement Scale. Patients rated pain experienced during the session and satisfaction with outcomes. Treatment safety was monitored throughout. Results A total of 82 patients with rosacea underwent up to four IPL treatment sessions. Mean patient age was 41.9 ± 15.2 years, and most were female (84.1%), with skin type II or III (96.1%) and with facial rosacea (93.9%). Clearance of > 75% was achieved in 69.5% of the patients, and the remaining 30.5% achieved 51%–75% clearance. Physician‐rated aesthetic improvement was optimal (64.6%) or good (34.1%); minimal change was reported for one lesion. Skin type III was associated with 3.59 times higher odds of achieving high clearance compared to skin type I or II (95% CI: 1.2–11.3). Patients were mostly very highly (95.1%) or highly satisfied (3.7%) with treatment outcomes. Most patients reported low (39.0%) to medium (46.3%) pain during treatment. Apart from a blister reported by one patient, no adverse events were reported. Conclusion IPL is a safe, effective, and versatile light‐based modality for the treatment of vascular rosacea lesions in individuals of skin types I–III.

ObjectiveTo develop a domain-specific large language model (LLM) for LI-RADS v2018 categorization of hepatic observations based on free-text descriptions extracted from MRI reports.Material and methodsThis retrospective study included 291 small liver observations, divided into training (n = 141), validation (n = 30), and test (n = 120) datasets. Of these, 120 were fictitious, and 171 were extracted from 175 MRI reports from a single institution. The algorithm’s performance was compared to two independent radiologists and one hepatologist in a human replacement scenario, and considering two combined strategies (double reading with arbitration and triage). Agreement on LI-RADS category and dichotomic malignancy (LR-4, LR-5, and LR-M) were estimated using linear-weighted κ statistics and Cohen’s κ, respectively. Sensitivity and specificity for LR-5 were calculated. The consensus agreement of three other radiologists served as the ground truth.ResultsThe model showed moderate agreement against the ground truth for both LI-RADS categorization (κ = 0.54 [95% CI: 0.42–0.65]) and the dichotomized approach (κ = 0.58 [95% CI: 0.42–0.73]). Sensitivity and specificity for LR-5 were 0.76 (95% CI: 0.69–0.86) and 0.96 (95% CI: 0.91–1.00), respectively. When the chatbot was used as a triage tool, performance improved for LI-RADS categorization (κ = 0.86/0.87 for the two independent radiologists and κ = 0.76 for the hepatologist), dichotomized malignancy (κ = 0.94/0.91 and κ = 0.87) and LR-5 identification (1.00/0.98 and 0.85 sensitivity, 0.96/0.92 and 0.92 specificity), with no statistical significance compared to the human readers’ individual performance. Through this strategy, the workload decreased by 45%.ConclusionLI-RADS v2018 categorization from unlabelled MRI reports is feasible using our LLM, and it enhances the efficiency of data curation.Critical relevance statementOur proof-of-concept study provides novel insights into the potential applications of LLMs, offering a real-world example of how these tools could be integrated into a local workflow to optimize data curation for research purposes.Key PointsAutomatic LI-RADS categorization from free-text reports would be beneficial to workflow and data mining.LiverAI, a GPT-4-based model, supported various strategies improving data curation efficiency by up to 60%.LLMs can integrate into workflows, significantly reducing radiologists’ workload.

The risk of hepatocellular carcinoma recurrence is universal regardless of the treatment modality applied, and secondary prevention is still an unmet issue even though the elimination of hepatitis C (HCV) with direct antiviral agents (DAAs) was expected to be one of the new options. Unfortunately, the impact of DAAs on hepatocellular carcinoma (HCC) development (de novo and recurrence) is still controversial. Since the first publication on the subject in 2016, almost all groups worldwide have carried out research in this field with hundreds of publications now available. This revision is focused on the impact of DAAs on HCC recurrence and aims to discuss the potential underlying mechanisms and host factors pointing out the time association phenomenon between DAA treatment and HCC recurrence. Moreover, we comment on the methodological issues that could affect the different interpretations of the published results. In conclusion, this is an area of research with potential in the understanding of the impact of factors not previously considered, and may also help change hepatocarcinogenesis tenets, such as the belief that the elimination of HCV should be used as a second prevention treatment.

The aim of the study was to analyze the association between the liver uptake of Gadolinium-ethoxybenzyl-diethylenetriamine penta-acetic acid (Gd-EOB-DTPA) in the hepatobiliary phase (HBP) in cirrhotic patients and the presence of clinically significant portal hypertension (CSPH), and how these features impact on hepatocellular carcinoma (HCC) detection in the HBP. Post-hoc analysis of a prospective cohort of 62 cirrhotic patients with newly US-detected nodule between 1-2 cm (study group). Twenty healthy subjects were used as control group. Qualitative and quantitative analysis of the liver contrast uptake in the HBP assessed by Relative Liver-Enhancement (RLE), Liver-Spleen (LSCR), Liver-Muscle (LMCR), and Liver-Kidney Contrast-Ratio (LKCR), Contrast Enhancement Index (CEI), and Hepatic Uptake (HUI), and biliary excretion, were registered. CSPH was confirmed invasively (HVPG > 10 mmHg) or by indirect parameters. The appearance of HCC at the HBP was analyzed. Nineteen patients (30.6%) did not have CSPH. In 41 patients (66.1%) the final diagnosis was HCC. All indices were significantly higher in the control group, indicating a more intense HBP liver signal intensity compared to patients with cirrhosis, even if the comparison was restricted to patients with no CSPH. CSPH was associated to a lower rate of HCC hypointensity in the HBP (51.9% . 85.7% without CSPH, p = 0.004). Liver uptake of Gd-EOB-DTPA at the HBP is decreased in cirrhosis even if the liver function is minimally impaired and it falls down significantly in patients with CSPH compromising the recognition of hypointense lesions. This fact may represent a limitation for the detection of small HCC in patients with cirrhosis and CSPH.

Background The eradication of the Hepatitis C Virus (HCV) reduce the risk of liver cancer (LC), but lifestyle changes after cure may counterbalance its benefit. Our study investigates lifestyle changes that occur in HCV patients with Sustained Virological Response (SVR) after direct-acting antiviral (DAA) treatment. Methods In this prospective, single-center study, HCV patients with advanced liver disease (F3/F4) treated and cured with DAA were invited to fill a lifestyle habits questionnaire in and perform abdominal ultrasound (US), blood extraction and anthropometric measurements within the 1st month after SVR and every 6 months thereafter until 48 months of follow-up, LC development, death, or loss to follow-up. Results This prospective cohort included 182 patients with SVR after DAA in this first analysis through the 4 years of follow-up. At the time of SVR, 65.9% had cirrhosis, median BMI was 27.1 kg/m 2 , 74.2% were overweight or obese and 6.6% had an US with hepatic steatosis. Within a year of SVR, 9% of males and 4% of females progressed from normal weight to overweight/obesity and 19.4% increased alcohol consumption. At 48 months, there were statistically significant increases in BMI (0.75, p  = 0.001) and alcohol consumption (6.4% p  = 0.007). Conclusions In this prospective cohort, successful HCV therapy was followed by significant changes in lifestyle habits translating into increases in BMI and alcohol consumption. These post-SVR changes raise concerns that the chemopreventive benefits of HCV cure may be counterbalanced by increased risks of liver disease progression and LC development from metabolic risk factors and alcohol use. Post-SVR, patients may benefit from intensive counseling and pharmacotherapy to address obesity and alcohol use. Trial registration/ clinical trial number Not applicable.