Citations

The persistent shortage of allogenic donor organs has driven the exploration of xenotransplantation as a viable alternative for patients with end-stage liver disease. This review investigates the progress and challenges in liver xenotransplantation, focusing on the use of genetically engineered animals, particularly pigs, as potential organ donors. This narrative review discusses various sources of xenografts, highlighting their advantages and limitations, and provides a historical overview of liver xenotransplantation, encompassing both clinical and experimental experiences. Key obstacles, such as immunological rejection, coagulation dysfunction, and the risk of zoonotic infections, are analyzed, with emphasis on how these challenges have been addressed through genetic modifications and adjunctive therapies. Recent clinical trials are also reviewed, offering insights into the outcomes and lessons learned from these pioneering efforts. We also explored the regulatory, legal, and ethical considerations critical to advancing liver xenotransplantation into clinical practice, along with future perspectives on the field’s evolution. This comprehensive overview aims to provide a clear understanding of the current state of liver xenotransplantation and the strategies being developed to overcome existing barriers, paving the way for future clinical applications.

Abstract Background Some centres advocate preoperative radiotherapy in patients with pancreatic cancer and arterial involvement despite a lack of Level 1 evidence on survival benefit. Although it has been suggested that preoperative radiotherapy may increase the risk of postpancreatectomy haemorrhage (PPH) and morbidity, evidence is again lacking. This study investigated the association between preoperative radiotherapy and both PPH and major morbidity following arterial divestment/resection during pancreatic adenocarcinoma resection after chemotherapy. Methods Consecutive patients diagnosed with pancreatic adenocarcinoma and > 180° arterial involvement who were treated with preoperative chemotherapy with or without radiotherapy followed by pancreatic resection with arterial divestment/resection were included in the study. Logistic regression analyses including propensity score-based overlap weighting were performed to investigate associations between radiotherapy and in-hospital PPH grade B/C and major morbidity, expressed as adjusted risk differences (aRDs). Results Overall, 246 patients undergoing pancreatic resection with arterial resection (169, 69%) or divestment (77, 31%) were included. Radiotherapy was not associated with PPH (aRD 6%; 95% confidence interval (c.i.) −3 to 14), regardless of arterial divestment (aRD 3%; 95% c.i. −5 to 11) or arterial resection (aRD 12%; 95% c.i. 1 to 23; Pinteraction = 0.189). Radiotherapy was associated with a 14% (95% c.i. 2 to 25) higher risk of major morbidity, especially after arterial resection (aRD 27%; 95% c.i. 11 to 43) compared with arterial divestment (aRD −12%; 95% c.i. −35 to 11; Pinteraction = 0.006) and after external beam radiotherapy (aRD 21%; 95% c.i. 8 to 32) compared with stereotactic body radiotherapy (aRD −12%; 95% c.i. −27 to 6; Pinteraction = 0.0001). Ninety-day mortality was increased, albeit not significantly, after preoperative radiotherapy (10 (8%) versus 3 (3%) deaths with versus without preoperative radiotherapy, respectively; P = 0.067). Conclusions Radiotherapy before resection of pancreatic cancer with > 180° arterial involvement was associated with an increased risk of postoperative major morbidity when arterial resection, but not arterial divestment, was performed. This risk should be taken into account when considering preoperative radiotherapy in patients who may require arterial resection.

Metabolic dysfunction-associated steatohepatitis (MASH) is a global health care burden. Appropriate large animal models mimicking the main MASH characteristics of steatosis, inflammation, and hepatocyte damage alongside progression of fibrosis are imperative for robust preclinical studies, especially in the field of hepatobiliary surgery. The present study aimed to characterize a novel model of steatohepatitis in fumarylacetoacetate hydroxylase-deficient ( FAH -/- ) pigs. FAH -/- pigs were generated using a CRISPR/Cas9 system. The animals received a choline-deficient, L-amino acid-defined high-fat diet and subtherapeutic doses of nitisinone and were followed for 3 months. Liver biopsies were obtained at baseline and every month during treatment. Steatosis, inflammation, and fibrosis were assessed by conventional histological scoring systems and by an artificial intelligence (AI) model. Serum liver parameters were analyzed every 2 weeks. Steatosis increased significantly throughout the study, with severe steatosis observed as early as 2 months into treatment. The inflammation score was increased in all animals after 3 months of treatment, whereas the AI-based CD45+ cell count showed region-specific trends in the portal and lobular areas. Collagen content and the corresponding fibrosis stage showed an increase over the 3-month period; however, the difference was not significant. Serum liver parameters did not show any relevant elevations during the study. In summary, we successfully developed and characterized a novel model of steatohepatitis in the FAH -/- pig within 3 months. Further studies with prolonged observation time and/or cycling of nitisinone administration are needed to evaluate whether progressive fibrosis and cirrhosis could be achieved with this model.

Background Short-term outcomes after pancreatoduodenectomy (PD) are well-studied, but long-term reoperation rates and their indications remain poorly characterized. Methods A single-center retrospective chart review was performed on patients who underwent PD for pancreatic adenocarcinoma between 1/2011 and 12/2021. Reoperations occurring >90 days after PD were dichotomized to being related or unrelated to the index PD or pancreatic adenocarcinoma. The Kaplan-Meier analysis estimated the incidence of long-term reoperation at 1 and 5 years postoperatively. Results Six-hundred twenty-eight patients were included. The 5-year incidence of any additional operation >90 days after PD was 30.0% (95% CI 23.2-36.2%), and the 5-year incidence of any long-term related reoperation was 21.2% (95% CI 15.0-26.8%). The most common indications for reoperations by 5-year incidence were cancer recurrence (12.8%, 95% CI 7.6-17.7%), incisional hernia (6.2%, 95% CI 2.6-9.7%), small bowel obstruction (1.3%, 95% CI 0.2-2.4%), and leak, fistula, or infection (1.0%, 95% CI 0.1-2.0%). Of the examined risk factors, only 90-day reoperation was found to be predictive of long-term related reoperations ( P = 0.02). Additionally, the 5-year incidence of endoscopic or interventional radiology procedures was 20.2% (95% CI 14.5-25.4%). However, 40.9% (95% CI 33.6-47.3%) of patients required additional surgery or procedures of any kind between 90 days and 5 years after PD. Discussion Within 5 years of PD, one in three patients required additional surgery, and one in five had operations for related indications. Related reoperative indications included recurrence, hernia, PD-specific complications, and small bowel obstruction. However, the rates of each of these reoperations were relatively low.

ABSTRACT Background and Objectives Hepatic epithelioid hemangioendothelioma (HEHE) is an uncommon vascular neoplasm characterized by variable clinical behavior. Our aim was to describe the therapeutic approach for HEHE at diagnosis and define clinicopathological characteristics associated with tumor progression and long‐term survival. Methods This is a retrospective study that includes patients with HEHE who received treatment at Mayo Clinic Rochester between 1984 and 2023. Results Eighty patients were included in the study (median age: 44 years; 62.5% female), 24 underwent liver transplantation, 26 underwent liver resection, and 30 were managed medically. The 3‐year overall survival rates were 86.7%, 80.9%, and 51.1%, respectively. Notably, 26 patients had extrahepatic metastases at the time of diagnosis, four (16.7%) in the transplantation group, four (15.4%) in the resection group, and 18 (69.2%) in the nonsurgical group. On multivariable modeling, bone metastasis was independently associated with long‐term mortality (HR 6.3, p < 0.001) while lung metastasis and surgical intervention were not associated with long‐term mortality (HR 0.8, p = 0.8; HR 1.1, p = 0.9, respectively). Conclusion Bone metastasis emerged as a strong predictor of poor survival. Hence, aggressive surgical intervention may not be advantageous in patients with skeletal metastases but can still be offered for those with other extrahepatic metastases.

AbstractBackgroundProton pump inhibitors (PPIs) negatively impact fluoropyrimidine‐based chemotherapy efficacy in colorectal cancer. This study assessed PPI impact on major pathologic response (mPR) rates of pancreatic adenocarcinoma (PDAC) patients receiving fluoropyrimidine‐based chemotherapy.MethodsAn institutional retrospective review of resected PDAC patients receiving neoadjuvant fluoropyrimidine‐based chemotherapy (98% FOLFIRINOX) from 2011 to 2021 was conducted. Outcomes were stratified by use or nonuse of PPIs within 6 months of neoadjuvant chemotherapy initiation. Primary outcome was mPR defined as complete or near complete response.ResultsAmong 540 patients included, the median age was 64 (IQR: 60–70) years, 297 (55%) were male, and 202 (37%) were PPI users. 170 (31%) patients had mPR with similar rates among PPI users and nonusers (29% vs. 33%, p = 0.38). No difference in mPR was seen between PPI users and nonusers receiving chemoradiation (35% vs. 36%, p = 0.89) or ≥8 cycles of NAC (33% vs. 36%, p = 0.55). Median OS for PPI users was 30.9 versus 31.7 months for nonusers (p = 0.62). On multivariable analysis, PPI therapy was not associated with decreased survival.ConclusionPPI usage did not significantly influence mPR or OS following neoadjuvant fluoropyrimidine‐based chemotherapy in resected PDAC patients. Further analysis of all patients, not just those who underwent resection, is required.