Liver transplantation is a treatment option for nonresectable patients with early-stage HCC, with more significant advantages when Milan criteria are fulfilled. An immunosuppressive regimen is required to reduce the risk of graft rejection after transplantation, and CNIs represent the drugs of choice in this setting. However, their inhibitory effect on T-cell activity accounts for a higher risk of tumour regrowth. mTOR inhibitors (mTORi) have been introduced as an alternative immunosuppressive approach to conventional CNI-based regimens to address both immunosuppression and cancer control. The PI3K-AKT-mTOR signalling pathway regulates protein translation, cell growth, and metabolism, and the pathway is frequently deregulated in human tumours. Several studies have suggested the role of mTORi in reducing HCC progression after LT, accounting for a lower recurrence rate. Furthermore, mTOR immunosuppression controls the renal damage associated with CNI exposure. Conversion to mTOR inhibitors is associated with stabilizing and recovering renal dysfunction, suggesting an essential renoprotective effect. Limitations in this therapeutic approach are related to their negative impact on lipid and glucose metabolism as well as on proteinuria development and wound healing. This review aims to summarize the roles of mTORi in managing patients with HCC undergoing LT. Strategies to overcome common adverse effects are also proposed.

Diabetic and obese patients have a high prevalence of non-alcoholic fatty liver disease (NAFLD). This condition groups a spectrum of conditions varying from simple steatosis to non-alcoholic steatohepatitis (NASH), with or without fibrosis. Multiple factors are involved in the development of NAFLD. However, details about its pathogenesis and factors that promote the progression to NASH are still missing. Growth hormone (GH) and insulin-like growth factor 1 (IGF-1) regulate metabolic, immune, and hepatic stellate cell functions. Increasing evidence suggests they may have roles in the progression from NAFLD to NASH. Following the PRISMA reporting guidelines, we conducted a systematic review to evaluate all clinical and experimental studies published in the literature correlating GH and IGF-1 to inflammation and fibrosis in NAFLD and NASH. Our results showed that GH and IGF-1 have a fundamental role in the pathogenesis of NASH, acting in slightly different ways to produce a synergic effect. Indeed, GH may mediate its protective effect in the pathogenesis of NASH by regulating lipogenesis pathways, while IGF-1 has the same effect by regulating cholesterol transport. Therefore, they could be used as therapeutic strategies in preventing NAFLD progression to NASH.

Background: The role of surgical resection of liver metastases in patients with breast cancer liver metastasis (BCLM) remains controversial. A systematic review and meta-analysis of prognostic factors related to survival after BCLM resection was performed. Methods: An electronic search of relevant publications was performed. Pooled outcome measures were expressed as hazard ratios (HRs), including 95% confidence interval values (95% CIs), and calculated through a random-effects model. Heterogeneity was tested through the I² index. Results: Thirty-five publications reported analyses on prognostic factors and survival. A total of 2782 patients who underwent liver resection for BCLM were included. Positive axillary lymph nodes at breast cancer diagnosis were an unfavorable survival factor (HR 1.74, 95% CI 1.25 to 2.41, I² = 0%). Cumulative predictive factor HRs (multiple liver metastases, size of the metastases, short interval between primary tumor and onset of liver disease) related to the BCLM pattern were 1.32 (95% CI 1.17 to 1.48, I² = 71%) and 1.51 (95% CI 1.15 to 1.98, I² = 76%) for surgical and pathological features (resection margin and presence of extrahepatic disease), respectively. Conclusion: Resection of BCLM may provide a survival benefit for selected patients. For better long-term results, surgical selection should consider both primary tumor and BCLM features such as negative axillary lymph nodes at breast resection, a single hepatic lesion, a time longer than 24 months between breast and hepatic diagnosis, and a realizable R0 liver resection. However, the high heterogeneity among studies suggests the need for an RCT to validate the present findings.

Cholangiocarcinoma (CCA) encompasses all malignant neoplasms arising from the epithelial cells of the biliary tree. About 40% of CCAs are perihilar, involving the bile ducts distal to the second-order biliary branches and proximal to the cystic duct implant. About two-thirds of pCCAs are considered unresectable at the time of diagnosis or exploration. When resective surgery is deemed unfeasible, liver transplantation (LT) could be an effective alternative. The overall survival rates after LT at 1 and 3 years are 91% and 81%, respectively. The overall five-year survival rate after transplantation is 73% (79% for patients with underlying PSC and 63% for de novo pCCA). Multicenter case series reported a 5-year disease-free survival rate of ~65%. However, different protocols, including neoadjuvant therapy, have been proposed. The scarcity of organ availability represents a crucial limiting factor in recommending LT preferentially in treating pCCA. Living donor transplantations and marginal cadaveric allografts have proven to be exciting options to overcome organ shortage. Management of jaundice and cholangitis is still challenging for these patients and could impact LT listing. Whether to adopt surgical resection or LT as standard-of-care in pCCA is still a matter of debate, and more prospective studies are needed.

Hepatocellular carcinoma is the most common primary liver tumor. Orthotopic liver transplant is one of the best treatment options, but its waiting list has to be considered. Bridge therapies have been introduced in order to limit this issue. The aim of this study is to evaluate if bridge therapies in advanced hepatocellular carcinoma can improve overall survival and reduce de-listing. We selected 185 articles. The search was limited to English articles involving only adult patients. These were deduplicated and articles with incomplete text or irrelevant conclusions were excluded. Sorafenib is the standard of care for advanced hepatocellular carcinoma and increases overall survival without any significant drug toxicity. However, its survival benefit is limited. The combination of transarterial chemoembolization + sorafenib, instead, delays tumor progression, although its survival benefit is still uncertain. A few studies have shown that patients undergoing transarterial chemoembolization + radiation therapy have similar or even better outcomes than those undergoing transarterial chemoembolization or sorafenib alone for rates of histopathologic complete response (89% had no residual in the explant). Also, the combined therapy of transarterial chemoembolization + radiotherapy + sorafenib was compared to the association of transarterial chemoembolization + radiotherapy and was associated with a better survival rate (24 vs. 17 months). Moreover, immunotherapy revealed new encouraging perspectives. Combination therapies showed the most encouraging results and could become the gold standard as a bridge to transplant for patients with advanced hepatocellular carcinoma.

Background: Liver transplantation (LT) is regarded as a curative approach for patients with hepatocellular carcinoma (HCC), especially those with underlying advanced liver disease. However, the recurrence of HCC post-LT poses significant challenges, with reported rates of 15–20% within the first two years following surgery. Effective management of single-nodule recurrence is critical to improving patient outcomes. Methods: This meta-analysis evaluates the efficacy of surgical resection versus locoregional therapies (LRT) in patients with localized HCC recurrence after LT. We adhered to the PRISMA Statement in conducting a thorough search of relevant studies published from 2009 to 2024, ultimately including ten studies that met our eligibility criteria. Results: The results indicate that patients undergoing surgical treatment displayed superior one-year overall survival (OS) rates compared to those receiving LRT (71% vs. 62%, p = 0.038), as well as higher one-year disease-free survival (DFS) rates (60% vs. 54%, p = 0.042). Notably, patients in the LRT group presented with more advanced HCC characteristics prior to transplantation, including higher rates of microvascular invasion and elevated alpha-fetoprotein levels. Conclusions: Our findings suggest that while surgical resection is associated with better survival outcomes, the choice between surgical and locoregional approaches must be individualized based on tumor characteristics and liver function. The ongoing development of standardized guidelines with the inclusion of immunotherapy or targeted agents will be essential in refining treatment pathways and improving outcomes for patients experiencing HCC recurrence following LT.