Background: Lenvatinib has been approved in Italy since October 2019 as a first-line therapy for advanced hepatocellular carcinoma (HCC) and to date data on effectiveness and safety of lenvatinib are not available in our region. To fill this gap, we performed a multicentric analysis of the real-world treatment outcomes with the propensity score matching in a cohort of Italian patients with unresectable HCC who were treated with either sorafenib or lenvatinib. Aims and Methods: To evaluate the effectiveness of sorafenib and lenvatinib as primary treatment of advanced HCC in clinical practice we performed a multicentric analysis of the treatment outcomes of 288 such patients recruited in 11 centers in Italy. A propensity score was used to mitigate confounding due to referral biases in the assessment of mortality and progression-free survival. Results: Over a follow-up period of 11 months the Cox regression model showed 48% reduction of death risk for patients treated with lenvatinib (95% CI: 0.34– 0.81; p = 0.0034), compared with those treated with sorafenib. The median PFS was 9.0 and 4.9 months for lenvatinib and sorafenib arm, respectively. Patients treated with lenvatinib showed a higher percentage of response rate (29.4% vs 2.8%; p < 0.00001) compared with patients treated with sorafenib. Sorafenib was shown to be correlated with more HFSR, diarrhea and fatigue, while lenvatinib with more hypertension and fatigue. Conclusion: Our study highlighted for the first time the efficacy and safety of lenvatinib in an Italian cohort of patients.

Background: Whether the etiology of underlying liver disease represents a prognostic factor in patients with hepatocellular carcinoma (HCC) treated with lenvatinib is still a matter of debate. This study investigates whether the viral etiology of HCC plays a prognostic role in overall survival (OS). Methods: Data derived from a multicenter series of 313 HCC patients treated with lenvatinib between 2019 and 2022 were analyzed. Actuarial survival estimates were computed using the Kaplan–Meier method and compared with the log-rank test. We performed an event-based counterfactual mediation analysis to estimate direct (chronic inflammation and immunosuppression), indirect (tobacco smoking, alcohol use, illicit drug abuse with injections), and the total effect of viral etiology on OS. Results were expressed as hazard ratio (HR) and 95% CI. Results: Median OS was 21 months (95% CI: 20–23) in the group with other etiologies and 15 months (14–16) in the group with viral etiology (p < 0.0001). The total effect of viral etiology was associated with OS (HR 2.76, 1.32–5.21), and it was mainly explained by the pure direct effect of viral etiology (HR 2.74, 1.15–4.45). By contrast, its total indirect effect was not associated with poorer survival (HR 1.05, 0.82–2.13). These results were confirmed when considering tobacco, alcohol consumption, or injection drug abuse as potential mediators. Median progression-free survival was 9 months (8–10) in patients with other etiologies and 6 months (5–7) in patients with viral etiology (p < 0.0001). No difference in terms of adverse event rate was observed between the two groups. Conclusions: Patients affected by HCC with nonviral etiology treated with lenvatinib exhibit longer survival than those with viral etiology. This finding may have relevance in the treatment decision-making process.

Therapeutic endoscopy permits many and various treatments for cancer palliation in patients with bilio-pancreatic cancers, enabling different options, supporting patients during their route to oncologic treatments, and trying to improve their quality of life. Therefore, both endoscopic and endoscopic ultrasound (EUS)-guided techniques are performed in this scenario. We performed a literature review focusing on the role of endoscopy in the palliation of those advanced pancreatic and biliary cancers developing malignant biliary obstruction (MBO), gastric outlet obstruction (GOO), and pain unresponsive to medical therapies. Therefore, we explored and focused on the clinical outcomes of endoscopic procedures in this scenario. In fact, the endoscopic treatment is based on achieving biliary drainage in the case of MBO through endoscopic retrograde cholangiopancreatography (ERCP) or EUS-guided biliary drainage (EUS-BD), while GOO is endoscopically treated through the deployment of an enteral stent or the creation of EUS-guided gastro-entero-anastomosis (EUS-GEA). Furthermore, untreatable chronic abdominal pain is a major issue in patients unresponsive to high doses of painkillers, so EUS-guided celiac plexus neurolysis (CPN) or celiac ganglia neurolysis (CGN) helps to reduce dosage and have better pain control. Therefore, therapeutic endoscopy in the palliative setting is an effective and safe approach for managing most of the clinical manifestations of advanced biliopancreatic tumors.

Hepatocellular carcinoma (HCC) is a challenging malignancy characterised by clinical and biological heterogeneity, independent of the stage. Despite the application of surveillance programs, a substantial proportion of patients are diagnosed at advanced stages when curative treatments are no longer available. The landscape of systemic therapies has been rapidly growing over the last decade, and the advent of immune-checkpoint inhibitors (ICIs) has changed the paradigm of systemic treatments. The coexistence of the tumour with underlying cirrhosis exposes patients with HCC to competing events related to tumour progression and/or hepatic decompensation. Therefore, it is relevant to adopt proper clinical endpoints to assess the extent of treatment benefit. While overall survival (OS) is the most accepted endpoint for phase III randomised controlled trials (RCTs) and drug approval, it is affected by many limitations. To overcome these limits, several clinical and radiological outcomes have been used. For instance, progression-free survival (PFS) is a useful endpoint to evaluate the benefit of sequential treatments, since it is not influenced by post-progression treatments, unlike OS. Moreover, radiological endpoints such as time to progression (TTP) and objective response rate (ORR) are frequently adopted. Nevertheless, the surrogacy between these endpoints and OS in the setting of unresectable HCC (uHCC) remains uncertain. Since most of the surrogate endpoints are radiology-based (e.g., PFS, TTP, ORR), the use of standardised tools is crucial for the evaluation of radiological response. The optimal way to assess the radiological response has been widely debated, and many criteria have been proposed over the years. Furthermore, none of the criteria have been validated for immunotherapy in advanced HCC. The coexistence of the underlying chronic liver disease and the access to several lines of treatments highlight the urgent need to capture early clinical benefit and the need for standardised radiological criteria to assess cancer response when using ICIs in mono- or combination therapies. Here, we review the most commonly used clinical and radiological endpoints for trial design, as well as their surrogacy with OS. We also review the criteria for radiological response to treatments for HCC, analysing the major issues and the potential future perspectives.

Gastric outlet obstruction for benign indications (bGOO) is an uncommon condition, typically treated with surgery when medical therapy or endoscopic treatments fail. At present, endoscopic ultrasound (EUS)-guided gastrojejunostomy (GJ) may prove to be an effective alternative. We performed a systematic review with meta-analysis evaluating outcomes of EUS-GJ for bGOO. A comprehensive search was conducted up to February 2025. Pooled estimates were obtained using a random-effects model. Study quality was evaluated using the Newcastle-Ottawa quality scale. Heterogeneity was evaluated with I² statistic. Technical success, clinical success, recurrence rate, and adverse events (AE) rate were the main outcomes. Fifteen (15) studies, including a total of 376 patients, were identified. Pooled technical success was 95.8 % (CI 95 %, 93.8 %-97.8 %, I² =0 %), while clinical success was 93.4 % (CI 95 %, 90.4 %-96.5 %, I²= 31.83 %). Pooled recurrence rate was 11.6 % (CI 95 %, 5.5 %-17.7 %, I2=32.36 %). The pooled rate of AE was 11.6 % (CI 95 %, 6.8-16.5 %, I² = 57.18 %). Subgroup analyses found differences in safety when AE classification was used (17 % use vs. 6 % no use, p = 0.02) and based on quality of studies (low 22 % vs. moderate 10 % vs. high 3 %, p = 0.04). In conclusion, our findings show that EUS-GJ is effective and safe in those patients with bGOO in whom other endoscopic treatments fail, and surgery is not an option or could be performed as bridge-to-surgery. Our results suggest that safety is influenced by the use of AE classification and the quality of studies.

The number of effective systemic therapies for the treatment of unresectable hepatocellular carcinoma (uHCC) is rapidly increasing and the advent of immunotherapy changed the treatment paradigm for these patients, leading to a significant improvement in survival outcomes. While sorafenib, a tyrosine‐kinase inhibitor monotherapy, remained the only effective treatment for almost a decade, the combination of atezolizumab, an immune checkpoint inhibitor (ICI) targeting programmed death‐ligand 1, plus bevacizumab, an antiangiogenic agent targeting vascular endothelial growth factor, now represents the new standard of care for patients with uHCC. Moreover, several further clinical trials are ongoing to evaluate novel combinations between ICIs with other drugs, belonging to the same class or to other classes. As HCC occurs in most cases in the setting of cirrhosis, the evaluation of the risk/benefit ratio of systemic treatments represents a critical point. The underlying liver disease significantly influences the safety and the effectiveness of current and future systemic treatments for uHCC. For this reason, the hepatotoxicity profile and impact on liver function of these molecules should be carefully assessed in both clinical trials and in the real‐world setting. Here, we review hepatotoxicity data on systemic treatments for uHCC and offer suggestions on monitoring and managing liver‐related adverse events occurring during the treatment.