Influence of donor age on liver transplantation outcomes: A multivariate analysis and comparative study.

BACKGROUND: The growing disparity between the rising demand for liver transplantation (LT) and the limited availability of donor organs has prompted a greater reliance on older liver grafts. Traditionally, utilizing livers from elderly donors has been associated with outcomes inferior to those achieved with grafts from younger donors. By accounting for additional risk factors, we hypothesize that the utilization of older liver grafts has a relatively minor impact on both patient survival and graft viability. AIM: To evaluate the impact of donor age on LT outcomes using multivariate analysis and comparing young and elderly donor groups. METHODS: In the period from April 2013 to December 2018, 656 adult liver transplants were performed at the University Hospital Merkur. Several multivariate Cox proportional hazards models were developed to independently assess the significance of donor age. Donor age was treated as a continuous variable. The approach involved univariate and multivariate analysis, including variable selection and assessment of interactions and transformations. Additionally, to exemplify the similarity of using young and old donor liver grafts, the group of 87 recipients of elderly donor liver grafts (≥ 75 years) was compared to a group of 124 recipients of young liver grafts (≤ 45 years) from the dataset. Survival rates of the two groups were estimated using the Kaplan-Meier method and the log-rank test was used to test the differences between groups. RESULTS: Using multivariate Cox analysis, we found no statistical significance in the role of donor age within the constructed models. Even when retained during the entire model development, the donor age's impact on survival remained insignificant and transformations and interactions yielded no substantial effects on survival. Consistent insignificance and low coefficient values suggest that donor age does not impact patient survival in our dataset. Notably, there was no statistical evidence that the five developed models did not adhere to the proportional hazards assumption. When comparing donor age groups, transplantation using elderly grafts showed similar early graft function, similar graft (P = 0.92), and patient survival rates (P = 0.86), and no significant difference in the incidence of postoperative complications. CONCLUSION: Our center's experience indicates that donor age does not play a significant role in patient survival, with elderly livers performing comparably to younger grafts when accounting for other risk factors.

SPRTN is involved in hepatocellular carcinoma development through the ER stress response.

Endoplasmic reticulum (ER) stress, prompted by the accumulation of misfolded or unfolded proteins, triggers the activation of the unfolded protein response (UPR) pathway to restore ER homeostasis. This stress response is implicated in the development of hepatocellular carcinoma (HCC). A biallelic mutation in SPRTN is currently the only known single-gene mutation implicated in the early onset of HCC. However, the exact mechanism linking SPRTN mutations to HCC remains unclear. In our study, we analyzed SPRTN and UPR in 21 human HCC tissue samples using RT-qPCR, immunoblot, and immunohistochemistry. We found alterations in the expression levels of SPRTN and UPR-related genes and proteins in HCC samples. The impact of SPRTN on the ER stress response was assessed in SPRTN-depleted HepG2 cells through RNA sequencing, pull-down assay, comet assay, and mitotic index calculation. We demonstrated that SPRTN interacts with the UPR sensor GRP78. Furthermore, we observed a decrease in SPRTN levels during ER stress, and increased sensitivity to ER stress in SPRTN-depleted cells. These findings suggest an essential role for SPRTN in the ER stress response and provide new insights into HCC pathogenesis. This newly discovered function of SPRTN could significantly enhance our understanding and treatment of HCC.

Use of machine learning models for identification of predictors of survival and tumour recurrence in liver transplant recipients with hepatocellular carcinoma.

Background: Hepatocellular carcinoma (HCC) is one of the leading indications for liver transplantation (LT) however, selection criteria remain controversial. We aimed to identify survival factors and predictors for tumour recurrence using machine learning (ML) methods. We also compared ML models to the Cox regression model. Methods: Thirty pretransplant donor and recipient general and tumour specific parameters were analysed from 170 patients who underwent orthotopic liver transplantation for HCC between March 2013 and December 2019 at the University Hospital Merkur, Zagreb. Survival rates were calculated using the Kaplan-Meier method and multivariate analysis was performed using the Cox proportional hazards regression model. Data was also processed through Coxnet (a regularized Cox regression model), Random Survival Forest (RSF), Survival Support Vector Machine (SVM) and Survival Gradient Boosting models, which included pre-processing, variable selection, imputation of missing data, training and cross-validation of the models. The cross-validated concordance index (CI) was used as an evaluation metric and to determine the best performing model. Results: Kaplan-Meier curves for 5-year survival time showed survival probability of 80% for recipient survival and 82% for graft survival. The 5-year HCC recurrence was observed in 19% of patients. The best predictive accuracy was observed in the RSF model with CI of 0.72, followed by the Survival SVM model (CI 0.70). Overall ML models outperform the Cox regression model with respect to their limitations. Random Forest analysis provided several relevant outcome predictors: alpha fetoprotein (AFP), donor C-reactive protein (CRP), recipient age and neutrophil to lymphocyte ratio (NLR). Cox multivariate analysis showed similarities with RSF models in identifying detrimental variables. Some variables such as donor age and number of transarterial chemoembolization treatments (TACE) were pointed out, but these were not influential in our RSF model. Conclusions: Using ML methods in addition to classical statistical analysis, it is possible to develop sufficient prognostic models, which, compared to established risk scores, could help us quantify survival probability and make changes in organ utilization.

Emergence of Echinococcus multilocularis in Central Continental Croatia: A Human Case Series and Update on Prevalence in Foxes.

Human alveolar echinococcosis (HAE), caused by the metacestode stage of Echinococcus multilocularis, has emerged in many European countries over the last two decades. Here, we report the first data on the new HAE focus with increasing incidence in central Croatia, describe its clinical presentation and outcomes in diagnosed patients, and provide an update on the prevalence and geographic distribution of Echinococcus multilocuaris in red foxes. After the initial case in 2017 from the eastern state border, from 2019 to 2022, five new autochthonous HAE cases were diagnosed, all concentrated in the Bjelovar-Bilogora County (the county incidence in 2019 and 2021: 0.98/105, in 2022: 2.94/105/year; prevalence for 2019-2022: 4.91/105). The age range among four female and two male patients was 37-67 years. The patients' liver lesions varied in size from 3.1 to 15.5 cm (classification range: P2N0M0-P4N1M0), and one patient had dissemination to the lungs. While there were no fatalities, postoperative complications in one patient resulted in liver transplantation. In 2018, the overall prevalence of red foxes was 11.24% (28/249). A new focus on HAE has emerged in central continental Croatia, with the highest regional incidence in Europe. Screening projects among residents and the implementation of veterinary preventive measures following the One Health approach are warranted.

The Quality of Life After Liver Transplantation-The First Experience from Serbia.

Background: Liver transplantation (LT) is the most effective treatment for patients with end-stage liver disease, which dramatically effects patient's quality of life (QoL). The aim of this study was to evaluate the impact of socio-demographic and clinical factors on different QoL domains of patients who underwent orthotopic LT. Methods: A cross-sectional study included a total of 43 patients who underwent a LT from 2013 to 2018. Socio-demographic and clinical data were recorded in each patient. The QoL was estimated using two validated questionnaires: 36-Item Short Form Health Survey (SF-36) and Chronic Liver Disease Questionnaire (CLDQ). Results: Male patients obtained significantly higher scores than women, in the domains of general health perception (83.2 ± 16.3 vs. 71.0 ± 18.4; t = 2.229, p = .031) and physical component summary (69.0 ± 7.2 vs. 62.0 ± 11.4; t = 2.451, p = .019). There were no significant differences in other domains of SF-36 and CLDQ. Etiology of the underlying liver disease and the presence of post-transplant complications showed no effect on score values of SF-36 and CDLQ domains (p < .05). Time from LT showed negative medium correlation with role limitations due to physical health problems (S = -0.417, p = .005), while no other significant correlations were noted in other items of SF-36 and CLDQ. Conclusions: Men had higher scores in the domain of general health perception and physical component summary following LT than women. With the increase in time from LT, patients experience a decrease in limitations due to physical health problems. The audit and improvement of QoL is an essential part of the individualized long-term health-care approach to LT patients.

Liver graft harbouring hydatid disease: how far can we extend our donor pool?

As the current demand for liver transplantation exceeds our donor pool, the donor search is shifted towards the extended donor criteria. The livers harbouring hydatid disease are a controversial source of grafts. We report the use of a liver graft harbouring hydatid disease in urgent liver transplantation in a patient with autoimmune hepatitis. Corroborated with previous experiences, we show that the liver grafts harbouring hydatid cysts provide a rare but valuable source of organs.

Adrenalectomy for Bilateral Metachronous Adrenal Recurrence of Hepatocellular Carcinoma After Liver Transplant: A Case Report.

Hepatocellular carcinoma is the fifth most common cancer in the world and the third leading cause of cancer-related death. It is currently one of the leading indications for liver transplant, with selected 5-year survival rates after liver transplant of about 70%. Despite excellent results of liver transplant for hepatocellular carcinoma, a number of patients develop metastases after transplant, and multifocal metastatic disease is the most frequent cause of death. In a large autopsy series of patients with hepatocellular carcinoma, adrenal glands were the third most common site of extrahepatic metastasis after lungs and bones. However, isolated metastatic disease in the adrenal glands is rare, and isolated metachronous bilateral metastasis is an even rarer occurrence. Only few reports have been published of metachronous bilateral metastasis of hepatocellular carinoma after liver transplant treated with bilateral adrenalectomy. We describe a case of a 56-year-old man who underwent liver transplant for hepatocellular carcinoma in a cirrhotic liver. Two years after liver tranplant, regular follow-up revealed metastatic disease in the left adrenal gland. Preoperative imaging showed no other metastasis, and he underwent an uneventful left adrenalectomy. A year after surgery, he presented with right flank pain and tenderness. Imaging showed hemorrhage and tumor involvement of the right adrenal gland, and he underwent right adrenalectomy. Two years after surgery, he is alive and well with no signs of disease recurrence. Apparently, in the absence of intrahepatic or other metastases, bilateral metachronous recurrence of hepatocellular carcinoma after liver tranplant can be a good surgical indication with acceptable long-term survival.

Constrictive pericarditis as a cause of refractory ascites after liver transplantation: A case report.

BACKGROUND: Refractory ascites is a rare complication following orthotopic liver transplantation (OLT). The broad spectrum of differential diagnosis often leads to delay in diagnosis. Therapy depends on recognition and treatment of the underlying cause. Constrictive pericarditis is a condition characterized by clinical signs of right-sided heart failure. In the advanced stages of the disease, hepatic congestion leads to formation of ascites. In patients after OLT, cardiac etiology of ascites is easily overlooked and it requires a high degree of clinical suspicion. CASE SUMMARY: We report a case of a 55-year-old man who presented with a refractory ascites three months after liver transplantation for alcoholic cirrhosis. Prior to transplantation the patient had a minimal amount of ascites. The transplant procedure and the early postoperative course were uneventful. Standard post-transplant work up failed to reveal any typical cause of refractory post-transplant ascites. The function of the graft was good. Apart from atrial fibrillation, cardiac status was normal. Eighteen months post transplantation the patient developed dyspnea and severe fatigue with peripheral edema. Ascites was still prominent. The presenting signs of right-sided heart failure were highly suggestive of cardiac etiology. Diagnostic paracentesis was suggestive of cardiac ascites, and further cardiac evaluation showed typical signs of constrictive pericarditis. Pericardiectomy was performed followed by complete resolution of ascites. On the follow-up the patient remained symptom-free with no signs of recurrent ascites and with normal function of the liver graft. CONCLUSION: Refractory ascites following liver transplantation is a rare complication with many possible causes. Broad differential diagnosis needs to be considered.

Role of total pancreatectomy in the treatment of paraduodenal pancreatitis: A case report.

BACKGROUND: Paraduodenal pancreatitis (PP) is a rare form of chronic pancreatitis presenting with symptoms of duodenal obstruction. Conservative treatment is often unsuccessful and pancreaticoduodenectomy is the preferred surgical approach. A mini review of the outcomes of surgical therapy for PP shows that the results of pancreaticoduodenectomy are predominantly favorable. CASE SUMMARY: In our case report of PP, we describe an unusual course first presenting with the symptoms of chronic pancreatitis and a pseudocyst of the pancreatic tail. A pseudocystojejunostomy was performed and the late postoperative course was complicated with the symptoms of duodenal obstruction. At laparotomy, PP was found and the patient was treated with a total pancreatectomy. The postoperative course was uneventful and good weight gain with resolution of pain was demonstrated at follow up visits. CONCLUSION: Surgery is currently the optimal treatment option for PP. It is also the best diagnostic tool in distinguishing between pancreatitis and pancreatic adenocarcinoma.

Right hepatectomy due to portal vein thrombosis in vasculobiliary injury following laparoscopic cholecystectomy: a case report.

INTRODUCTION: Vasculobiliary injury composed of bile duct, portal vein and hepatic artery injury is a rare, but the most severe, complication after cholecystectomy that may require hepatectomy or even urgent liver transplantation. CASE PRESENTATION: We present a case of a 36-year-old Caucasian woman with a biliary sepsis and a large right liver lobe abscess due to an extreme vasculobiliary injury after laparoscopic cholecystectomy. Bismuth type IV biliary duct injury, portal vein thrombosis and injury of right hepatic artery were identified, resulting in life-threatening septic episodes. Right hepatectomy with Roux-en-Y hepaticojejunostomy and reconstruction of her portal vein with a vein allograft were performed. She fully recovered and remained well during 3 years of follow-up. CONCLUSIONS: Although rare, the impact of vasculobiliary injuries after cholecystectomy highlights the need for constant alertness and prompt management in order to minimize the risk of the routine operative procedure. Hepatectomy with biliary and vascular reconstruction should be considered early in the management of vasculobiliary injury to avoid the development of life-threatening consequences.

[Needle tract seeding of hepatocellular carcinoma after liver transplantation]. / Presadba hepatocelularnog karcinoma uzduz bioptickog kanala igle nakon transplantacije jetre.

Ultrasound guided fine needle aspiration cytology (FNAC) and core needle biopsy (CNB) are effective methods for the diagnosis of focal hepatic lesions. In case of neoplastic lesions, however, this may be followed by the seeding of malignant cells along the needle tract. We report a case of subcutaneous needle tract seeding of hepatocellular carcinoma (HCC) 25 months after liver transplantation. A 57-year-old man with compensated hepatitis-B-related liver cirrhosis was diagnosed with HCC by CNB, and the lesion was resected. Ten months after the procedure, FNAC of a small hepatic lesion confirmed tumor recurrence. The patient was successfully transplanted and 25 months later, a subcutaneous tumor appeared on the abdominal wall over the previous site of puncture without further dissemination of the disease. Total resection of the lesion confirmed HCC. It remains undetermined whether the seeding appeared after FNAC or CNB. After 18-month follow-up the patient was uneventful. The objectives of this report are to present clinical aspects and outcome of HCC needle tract seeding in a transplanted patient, discussing the problems and pitfalls of diagnostic workup and management of HCC.

Orthotopic liver retransplantation--case report.

We report a case of orthotopic liver retransplantation (OLRT) in a patient who was suffering from rejection and graft failure after orthotopic liver transplantation (OLT). The patient was a 32-year old female who had diagnosed liver lesion--hepatic cirrhosis. Within two months, with presented condition as a terminal stage of her disease, she underwent the OLT and immunosuppressive postoperative management. Two months after the OLT, in the one-week period, the patient underwent two new operations because of obstructive icterus due to fulminant cholangitis and subhepatic abscess. In spite of this operative and conservative treatment the patient's condition did not improve. Because of graft failure due to bile duct necrosis, she underwent an ORLT operation and her condition is satisfactory, till now. We confirmed that the overall impact of retransplatation persists because patients undergoing elective retransplatation have significantly better prognosis than those requiring an emergency operation.