Cholangiopathies include a group of chronic progressive disorders, affecting the cholangiocytes, the epithelial cells that line the biliary tree, leading to liver parenchymal fibrosis and eventually end-stage liver disease necessitating transplantation. Experimental modeling of these multifactorial cholestatic diseases faces challenges due to the lack of adequate experimental in vitro and in vivo models. A novel approach employs three-dimensional organoid systems that offer several advantages for modeling disease and testing drug response in vitro. Organoids mimic intercellular communication, replicate the architecture of organs, and maintain the cell’s original phenotype. Cholangiocyte organoids provide an in vitro model to study the pathogenesis and pharmacotherapeutic treatment of cholangiopathies and show great promise for regenerative therapies. In particular, patient-derived organoids allow personalized medicine approaches and the study of individual disease characteristics. This review highlights the significance of cholangiocyte organoid models in advancing our understanding of cholangiopathies and driving advancements in regenerative medicine strategies.

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.

Background: The role of tailored immunosuppression (IS) in the development of the humoral response (HR) to SARS-CoV-2 mRNA-based vaccination in liver transplant (LT) recipients is unknown. Methods: This is a single-centre prospective study of patients who underwent LT between January 2015 and December 2021 and who have received three doses of mRNA-based SARS-CoV-2 vaccination. Patients undergoing Tacrolimus-based immunosuppression (TAC-IS) were compared with those undergoing Everolimus-based immunosuppression (EVR-IS). Patients receiving the TAC-EVR combination were divided into two groups based on trough TAC concentrations, i.e., above or below 5 ng/mL. HR (analysed with ECLIA) was assessed at 30 to 135 days after vaccination. The primary outcome was the presence of a positive antibody titre ($\ge$0.8 U/mL). Secondary outcomes were the presence of a highly protective antibody titre ($\ge$142 U/mL), median antibody titre, and incidence of COVID-19. Results: Sixty-one participants were included. Twenty-four (40%) were receiving TAC-IS and thirty-seven (60%) were receiving EVR-IS. At the median follow-up of 116 (range: 89–154) days, there were no significant differences in positive antibody titre (95.8% vs. 94.6%; p = 0.8269), highly-protective antibody titre (83.3% vs. 81.1%; p = 0.8231), median antibody titre (2410 [IQ range 350–2500] vs. 1670 [IQ range 380–2500]; p = 0.9450), and COVID-19 incidence (0% vs. 5.4%; p = 0.5148). High serum creatinine and low estimated glomerular filtration rate were risk factors for a weak or absent HR. Conclusions: Three doses of mRNA-based SARS-CoV-2 vaccination yielded a highly protective HR in LT recipients. The use of TAC or EVR-based IS does not appear to influence HR or antibody titre, while renal disease is a risk factor for a weak or null HR.

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.

Background: Liver transplantation (LT) continues to evolve with techniques aimed at minimizing perioperative complications associated with caval and portal vein clamping. Caval-sparing approaches, such as the piggyback technique, preserve hemodynamic stability; however, portal clamping remains necessary and may trigger postreperfusion syndrome, endotoxemia, and hepatic microcirculatory disturbances. Temporary portocaval shunts (PCSs) have been developed to maintain portal flow during LT, mitigating these adverse effects and allowing for hemodynamic stability and a reduced intraoperative bleeding. Portocaval Shunts: Various PCS techniques—including end-to-side, right-branch, portosaphenous, mesenterico-saphenous, iliac-venous conduit interposition, portoumbilical, and Rex-saphenous shunts—allow an individualized approach based on patient anatomy and surgical complexity. Review of Evidence: Available evidence demonstrates that PCS improves intraoperative hemodynamic stability, reduces blood transfusion requirements, and preserves renal function, particularly in patients with high portal flow or severe portal hypertension. PCS may also shorten warm ischemia time, facilitate hepatectomy, and enhance outcomes in extended criteria donor grafts or marginal organs. Meta-analyses and randomized studies support its role in reducing intraoperative blood loss, improving early graft function, and accelerating postoperative recovery. However, the effect of PCS on long-term survival and major postoperative morbidity remains variable, likely due to heterogeneity in patient populations, donor types, and perioperative management. Conclusions: Overall, PCS represents a safe and feasible adjunct in LT, offering significant hemodynamic and technical advantages. Its use should be individualized based on patient risk factors, intraoperative hemodynamics, and anticipated intraoperative challenges. PCS provides a practical strategy to preserve portal flow, minimizing intraoperative complications and facilitating the hepatectomy. However, the decision to create a PCS during LT still depends on the surgeon’s preference. Postoperative outcomes and impact on long-term survival require further investigation.

Background: Lymphadenectomy in the operative management of hepatocellular carcinoma (HCC) remains controversial, with no recommendation for routine practice. Our study aimed to assess the effects of lymphadenectomy in addition to hepatic resection (HR) compared to HR alone for adults with HCC. Methods: This systematic review was conducted according to PRISMA guidelines until March 2023, searching and selecting the relevant literature comparing lymph node dissection or sampling, combined with HR, and with no lymph node removal. Critical appraisal of the included studies was performed using the ROBINS-I tool. Fixed- or random-effect meta-analysis models were carried out, and inter-studies were assessed for heterogeneity. Results: Fourteen studies were selected during the screening process. Data from eight studies containing 32,041 HCC patients were included in the quantitative synthesis. In total, 12,694 patients underwent lymph node dissection (LND), either selectively for preoperatively diagnosed or intraoperatively suspected lymph node metastasis (LNM) or unselectively (i.e., regardless of suspected LNM). According to LN status, 1-, 3- and 5-year mortality rates were higher in the LNM group with respect to both clinically negative LN (OR 3.25, 95% CI 2.52–4.21; p < 0.001; OR 3.79, 95% CI 2.74–5.24; p < 0.001; OR 3.92, 95% CI 2.61–5.88; p < 0.001) and proven LN0 (OR 1.75, 95% CI 1.0–3.04; p = 0.05; OR 2.88, 95% CI 1.79–4.63; p < 0.001; OR 2.54, 95% CI 1.33–4.84; p < 0.001). Moreover, the summary estimates of two controlled trials showed no significant difference in overall survival between LND groups and those without LND for negative LN patients. Conclusions: Lymph node dissection does not appear to improve overall survival, according to the available literature; thus, this does not support its routine adoption as part of standard liver resection for HCC. A case-by-case decision remains advisable.