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.

Retroperitoneal Paraganglioma Treated With Tumor Resection and Replacement of the Inferior Vena Cava.

Retroperitoneal paragangliomas are tumors of neuroectodermal origin rarely appearing in the pediatric population. We report a case of a large paraganglioma infiltrating the right kidney and inferior vena cava in a 16-year-old boy who initially presented with a right-sided varicocele. Right retroperitoneal paraganglioma was embolized preoperatively, followed by total tumor excision, right nephrectomy, inferior vena cava resection, and reconstruction using a prosthetic vascular graft. Retroperitoneal tumors requiring surgery can successfully be treated by radical resection and replacement of the inferior vena cava in experienced centers.

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.

Dinutuximab Beta in Children with High-Risk Neuroblastoma: Experience from a Single Center in Croatia.

To determine the potential benefits and feasibility of administering maintenance therapy with dinutuximab beta for high-risk neuroblastoma (HRNB) in clinical practice, a retrospective review of charts of patients with HRNB treated at a single center in Croatia (2012-2021) was undertaken. Of 23 patients with HRNB, 11 received up to five cycles of dinutuximab beta as part of multimodal therapy; 12 patients did not (i.e., no immunotherapy). In the no immunotherapy group, one patient had complete remission (8%), and 11 patients died of tumor progression (92%). In the dinutuximab beta group, eight patients had complete remission (73%; median duration of response 5 years and 2 months), one had stable disease (9%), and two died of disease (18%). Patients who received dinutuximab beta had a higher median event-free survival (40.0 months [range: 12.5-83.0]) and median overall survival (56.0 months [range: 16.2-101.0]) than those who did not (12.9 months [range: 3.3-126.0] and 20.7 months [3.3-126.0], respectively). Dinutuximab beta was generally well tolerated; adverse events were manageable and as reported in clinical studies. These results confirm the benefits and feasibility of maintenance therapy with dinutuximab beta as part of multimodal therapy for patients with HRNB in real-world clinical practice.

Liver transplantation for benign liver tumors.

Benign liver tumors are common lesions that are usually asymptomatic and are often found incidentally due to recent advances in imaging techniques and their widespread use. Although most of these tumors can be managed conservatively or treated by surgical resection, liver transplantation (LT) is the only treatment option in selected patients. LT is usually indicated in patients that present with life-threatening complications, when the lesions are diffuse in the hepatic parenchyma or when malignant transformation cannot be ruled out. However, due to the significant postoperative morbidity of the procedure, scarcity of available donor liver grafts, and the benign course of the disease, the indications for LT are still not standardized. Hepatic adenoma and adenomatosis, hepatic hemangioma, and hepatic epithelioid hemangioendothelioma are among the most common benign liver tumors treated by LT. This article reviews the role of LT in patients with benign liver tumors. The indications for LT and long-term outcomes of LT are presented.

Seroprevalence of SARS-CoV-2 in Croatian solid-organ transplant recipients.

INTRODUCTION: The data on the coronavirus disease (COVID-19) in solid-organ transplant recipients (SOTRs) in Croatia is unknown. The aim of this study was to analyze the seroprevalence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in Croatian SOTRs. MATERIALS AND METHODS: From 7 September to 27 November 2020 (beginning of the second COVID-19 pandemic wave), a cross-sectional screening for COVID-19 was performed in the adult outpatient liver (LTRs; N = 280) and kidney transplant recipients (KTRs; N = 232). Serum samples were initially tested for SARS-CoV-2 IgG antibodies using a commercial enzyme-linked immunosorbent assay (ELISA; Vircell Microbiologists, Granada, Spain). All positive samples were confirmed using a virus neutralization test (VNT). Data on risk exposure and COVID-19 related symptoms were collected using a questionnaire. RESULTS: The transplanted cohort's seroprevalence detected by ELISA and VNT was 20.1% and 3.1%, respectively. Neutralizing (NT) antibodies developed in 15.6% of anti-SARS-CoV-2 ELISA IgG positive SOTRs. The difference in seropositivity rates between LTRs and KTRs was not statistically significant (ELISA 21.1% vs. 19.0%, P = 0.554; VNT 3.6% vs. 2.6%, P = 0.082). Overall VNT positivity rates were higher in patients who reported participation in large community events (5.9% vs. 1.0%; P = 0.027) as well as in patients who reported COVID-19 related symptoms in the past six months. In addition, symptomatic VNT positive patients showed significantly higher (P = 0.031) NT antibody titers (median 128, interquartile range (IQR) = 32-128) compared to asymptomatic patients (median 16, IQR = 16-48). CONCLUSIONS: This study showed that 15.6% of anti-SARS-CoV-2 ELISA positive Croatian SOTRs developed NT antibodies indicating protective immunity. Further studies are needed to determine the dynamic of NT antibodies and COVID-19 immunity duration in immunocompromised populations such as LTRs and KTRs.

Borderline resectable pancreatic cancer and vascular resections in the era of neoadjuvant therapy.

While pancreatic cancer is still characterized by early systemic spread and poor outcomes, the treatment of this disease has changed significantly in recent years due to major advancements in systemic therapy and advanced surgical techniques. Broader use of effective neoadjuvant approaches combined with aggressive surgical operations within a multidisciplinary setting has improved outcomes. Borderline resectable pancreatic cancer is characterized by tumor vascular invasion, and is a setting where the combination of potent neoadjuvant chemotherapy and aggressive surgical methods, including vascular resections and reconstructions, shows its full potential. Hopefully, this will lead to improved local control and curative treatment in a number of patients with this aggressive malignancy.

Hepatitis E Virus in Croatia in the "One-Health" Context.

Hepatitis E virus (HEV) is the most common cause of viral hepatitis globally. The first human case of autochthonous HEV infection in Croatia was reported in 2012, with the undefined zoonotic transmission of HEV genotype 3. This narrative review comprehensively addresses the current knowledge on the HEV epidemiology in humans and animals in Croatia. Published studies showed the presence of HEV antibodies in different population groups, such as chronic patients, healthcare professionals, voluntary blood donors and professionally exposed and pregnant women. The highest seroprevalence in humans was found in patients on hemodialysis in a study conducted in 2018 (27.9%). Apart from humans, different studies have confirmed the infection in pigs, wild boars and a mouse, indicating the interspecies transmission of HEV due to direct or indirect contact or as a foodborne infection. Continued periodical surveys in humans and animals are needed to identify the possible changes in the epidemiology of HEV infections.

How far along are we in revealing the connection between metformin and colorectal cancer?

Colorectal cancer (CRC) is among the most prevalent cancers worldwide, and its prevention and reduction of incidence is imperative. The presence of diabetes has been associated with a 30% increased risk of CRC, likely through the mechanism of hyperinsulinemia, which promotes tumorigenesis via the insulin receptor in the epithelium or by insulin-like growth factor pathways, inflammation, or adipokines, inducing cancer cell proliferation and cancer spread. Metformin, the first-line agent in treating type 2 diabetes, has a chemopreventive role in CRC development. Additionally, preclinical studies suggest synergistic effects of metformin with oxaliplatin in inhibiting in vitro models of colon cancer. Although preclinical studies on the post diagnostic use of metformin were promising and suggested its synergistic effects with chemotherapy, the data on the possible effects of metformin after surgery and other CRC treatment in the clinical setting are less conclusive, and randomized controlled trials are still lacking.

Publication Activity on Liver Transplantation from Southeastern European Countries: A Bibliometric Analysis.

Background: Liver transplantation (LT) has become a field with rich publication activity; however, there is a paucity of research regarding LT publications from southeastern European (SEE) countries. Understanding the factors that influence the publication output is essential to direct the research and to promote the publication of high-quality papers. Methods: A bibliometric analysis was performed in PubMed for articles published on LT-related clinical experience from 11 countries from the SEE region before 2020. Data included the number of publications, citations, journal (cumulative) impact factors (IFs) and first/senior author gender and profession. Results: 188 publications fitted the inclusion criteria. 25.5% of papers were published in journals without IFs. Most papers came from Greece (43.6%, 199.663 IFs), Romania (29.3%, 60.695 IFs) and Croatia (16%, 45.645 IFs). In the top three countries, first authors were dominantly male physicians. Senior authors were also mostly male (63.3-88%), with varying professions depending on the country (p=0.008). Conclusions: The overall LT publication activity from the SEE countries is modest. The authors of Greece are the most productive in the region. The high liver LT activity does not necessarily translate into high publication output. LT communities in the SEE countries should find solutions on how to increase research and publication output.

Pre- and intraoperative predictors of acute kidney injury after liver transplantation.

BACKGROUND: Acute kidney injury (AKI) after liver transplantation (LT) is a frequent and multifactorial event related to increased morbidity and mortality. Risk factors for AKI after LT still need to be clarified. AIM: To identify the predictors of acute kidney injury after liver transplantation. METHODS: The frequency and pre- and intraoperative predictors of AKI within the first 7 d after LT were evaluated in adult liver transplant candidates in a single LT center in Croatia. AKI was defined according to the Kidney Disease: Improving Global Outcomes criteria. RESULTS: Out of 205 patients (mean age 57 ± 10 years; 73.7% males, 52.7% with alcohol-related liver disease) 93 (45.36%) developed AKI, and the majority of them (58.06%) had stage 1. Only 5.38% of patients required renal replacement therapy after LT. The majority of patients (82.8%) developed AKI within the first two days after the procedure. Multivariate logistic regression identified pre-LT body mass index (OR = 1.1, 95%CI: 1.05-1.24) and red blood cell transfusion (OR = 1.66, 95%CI: 1.09-2.53) as independent predictors of early post-LT AKI occurrence. 30-d survival after LT was significantly better for patients without AKI (P = 0.01). CONCLUSION: Early AKI after LT is a frequent event that negatively impacts short-term survival. The pathogenesis of AKI is multifactorial, but pre-LT BMI and intraoperative volume shifts are major contributors.

Liver transplantation and aging.

An increase in the average life expectancy, paralleled by a demographic shift in the population with end-stage liver disease lies behind the rising demand for liver transplantation (LT) among the elderly. Some of the most common indications for LT including hepatocellular carcinoma, alcohol-related liver disease, chronic hepatitis C and non-alcoholic fatty liver disease tend to affect older patients. Transplant professionals are faced with an increasing demand for LT among elderly patients in an age of organ shortage and it is important that risk and benefits are carefully weighed in order to achieve the optimum use of precious liver grafts.

Emerging and neglected zoonoses in transplant population.

Zoonoses represent a problem of rising importance in the transplant population. A close relationship and changes between human, animal and environmental health ("One Health" concept) significantly influence the transmission and distribution of zoonotic diseases. The aim of this manuscript is to perform a narrative review of the published literature on emerging and neglected zoonoses in the transplant population. Many reports on donor-derived or naturally acquired (re-)emerging arboviral infections such as dengue, chikungunya, West Nile, tick-borne encephalitis and Zika virus infection have demonstrated atypical or more complicated clinical course in immunocompromised hosts. Hepatitis E virus has emerged as a serious problem after solid organ transplantation (SOT), leading to diverse extrahepatic manifestations and chronic hepatitis with unfavorable outcomes. Some neglected pathogens such as lymphocytic choriomeningitis virus can cause severe infection with multi-organ failure and high mortality. In addition, ehrlichiosis may be more severe with higher case-fatality rates in SOT recipients. Some unusual or severe presentations of borreliosis, anaplasmosis and rickettsioses were also reported among transplant patients. Moreover, toxoplasmosis as infectious complication is a well-recognized zoonosis in this population. Although rabies transmission through SOT transplantation has rarely been reported, it has become a notable problem in some countries. Since the spreading trends of zoonoses are likely to continue, the awareness, recognition and treatment of zoonotic infections among transplant professionals should be imperative.

Liver Graft Failure and Bile Cast Nephropathy.

The consequences of graft failure after liver transplantation (LT) range far beyond the liver. The kidneys are often affected, where persistent and progressive cholestasis can result in acute kidney injury (AKI) leading to the development of bile cast nephropathy (BCN). BCN is an often unrecognized condition that is characterized by proximal tubulopathy and the formation of bile casts in the distal tubules, which is almost diagnosed exclusively on a kidney biopsy or autopsy. This condition is potentially reversible, provided the bilirubin levels can be reduced early. LT may represent a treatment option in the case of irreversible liver (or liver graft) failure, which is beneficial for both the liver and the kidney. This paper reports a case of BCN in a patient with idiopathic graft failure after LT. Despite his chronic kidney disease, liver re-transplantation led to the successful improvement of his AKI.

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.

The Role of Emerging and Neglected Viruses in the Etiology of Hepatitis.

PURPOSE OF REVIEW: In this review, we present the overview of emerging and neglected viruses associated with liver involvement. RECENT FINDINGS: Hepatitis E virus (HEV) emerged in the last two decades, causing hepatitis in many parts of the world. Moreover, liver involvement was also described in some emerging arboviral infections. Many reports showed dengue-associated liver injury; however, chikungunya, West Nile, tick-borne encephalitis, and Zika virus are rarely associated with clinically manifest liver disease. In addition, some neglected highly prevalent viruses such as adenoviruses and parvovirus B19 are capable of causing hepatitis in specific population groups. Anelloviruses (torque teno virus/torque teno mini virus/torque teno midi virus, SEN virus), human bocavirus, pegiviruses, and lymphocytic choriomeningitis virus have shown a little potential for causing hepatitis, but their role in the etiology of liver disease remains to be determined. In addition to the well-known hepatotropic viruses, many emerging and neglected viruses have been associated with liver diseases. The number of emerging zoonotic viruses has been increasingly recognized. While zoonotic potential of HEV is well documented, the recent identification of new hepatitis-related animal viruses such as HEV strains from rabbits and camels, non-primate hepaciviruses in domestic dogs and horses, as well as equine and porcine pegivirus highlights the possible zoonotic transmission in the context of "One Health." However, zoonotic potential and hepatotropism of animal hepatitis viruses remain to be determined.

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.