Predictors of Long-Term Outcomes After Liver Transplantation for Unresectable Metastatic Neuroendocrine Tumors.

BACKGROUND Malignant and benign neuroendocrine tumors (NET) share many histopathological features. Liver transplantation (LT) is one of the liver-directed therapies for neuroendocrine liver metastases (NELM). The aim of this study was to determine the outcomes of patients undergoing LT for NELM. MATERIAL AND METHODS This was a retrospective study that included 19 patients who underwent LT for unresectable NELM between December 1989 and December 2022 in the Department of General, Transplant, and Liver Surgery of the Medical University of Warsaw. Kaplan-Meier estimator and Cox proportional hazards regression were used for statistical analyses. RESULTS The primary tumor was located most frequently in the pancreas. The median follow-up was 72.5 months. The overall survival (OS) was 94.7%, 88.0%, 88.0%, 70.4%, and 49.3% after 1, 3, 5, 10, and 15 years, respectively. Accordingly, the recurrence-free survival (RFS) rates were 93.8%, 72.9%, 64.8%, 27.8%, and 27.8% after 1, 3, 5, 10, and 15 years, respectively. Ki-67 index ≥5% was found as a risk factor for both worse OS (hazard ratio (HR) 7.13, 95% confidence intervals (95% CI) 1.32-38.63, P=0.023) and RFS (HR 13.68, 95% CI 1.54-121.52, P=0.019). Recipient age ≥55 years was a risk factor for worse RFS (P=0.046, HR 5.47, 95% CI 1.03-29.08). Multivariable analysis revealed Ki-67 ≥5% as the sole independent factor for worse OS (HR 13.78, 95% CI 1.48-128.56, P=0.021). CONCLUSIONS Patients with unresectable NELM achieve great OS and satisfying RFS after LT. The risk factors associated with worse outcomes are attributed to primary tumor aggressiveness.

Biomarkers of the Complement System Activation (C3a, C5a, sC5b-9) in Serum of Patients before and after Liver Transplantation.

The liver has a huge impact on the functioning of our body and the preservation of homeostasis. It is exposed to many serious diseases, which may lead to the chronic failure of this organ, which is becoming a global health problem today. Currently, the final form of treatment in patients with end-stage (acute and chronic) organ failure is transplantation. The proper function of transplanted organs depends on many cellular processes and immune and individual factors. An enormous role in the process of acceptance or rejection of a transplanted organ is attributed to, among others, the activation of the complement system. The aim of this study was the evaluation of the concentration of selected biomarkers' complement system activation (C3a, C5a, and sC5b-9 (terminal complement complex)) in the serum of patients before and after liver transplantation (24 h, two weeks). The study was conducted on a group of 100 patients undergoing liver transplantation. There were no complications during surgery and no transplant rejection in any of the patients. All patients were discharged home 2-3 weeks after the surgery. The levels of all analyzed components of the complement system were measured using the ELISA method. Additionally, the correlations of the basic laboratory parameters-C-reactive protein (CRP), hemoglobin (Hb), total bilirubin, alkaline phosphatase (ALP), alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma-glutamyl transpeptidase (GGTP), and albumin-with the parameters of the complement system (C3a, C5a, and sC5b-9) were determined. In our study, changes in the concentrations of all examined complement system components before and after liver transplantation were observed, with the lowest values before liver transplantation and the highest concentration two weeks after. The direct increase in components of the complement system (C3a, C5a, and sC5b-9) 24 h after transplantation likely affects liver damage after ischemia-reperfusion injury (IRI), while their increase two weeks after transplantation may contribute to transplant tolerance. Increasingly, attention is being paid to the role of C3a and CRP as biomarkers of damage and failure of various organs. From the point of view of liver transplantation, the most interesting correlation in our own research was found exactly between CRP and C3a, 24 h after the transplantation. This study shows that changes in complement activation biomarkers and the correlation with CRP in blood could be a prognostic signature of liver allograft survival or rejection.

Routine End-ischemic Hypothermic Oxygenated Machine Perfusion in Liver Transplantation From Donors After Brain Death: A Randomized Controlled Trial.

OBJECTIVE: To assess whether end-ischemic hypothermic oxygenated machine perfusion (HOPE) is superior to static cold storage (SCS) in preserving livers procured from donors after brain death (DBD). BACKGROUND: There is increasing evidence of the benefits of HOPE in liver transplantation, but predominantly in the setting of high-risk donors. METHODS: In this randomized clinical trial, livers procured from DBDs were randomly assigned to either end-ischemic dual HOPE for at least 2 hours or SCS (1:3 allocation ratio). The Model for Early Allograft Function (MEAF) was the primary outcome measure. The secondary outcome measure was 90-day morbidity (ClinicalTrials. gov, NCT04812054). RESULTS: Of the 104 liver transplantations included in the study, 26 were assigned to HOPE and 78 to SCS. Mean MEAF was 4.94 and 5.49 in the HOPE and SCS groups ( P =0.24), respectively, with the corresponding rates of MEAF >8 of 3.8% (1/26) and 15.4% (12/78; P =0.18). Median Comprehensive Complication Index was 20.9 after transplantations with HOPE and 21.8 after transplantations with SCS ( P =0.19). Transaminase activity, bilirubin concentration, and international normalized ratio were similar in both groups. In the case of donor risk index >1.70, HOPE was associated with significantly lower mean MEAF (4.92 vs 6.31; P =0.037) and lower median Comprehensive Complication Index (4.35 vs 22.6; P =0.050). No significant differences between HOPE and SCS were observed for lower donor risk index values. CONCLUSION: Routine use of HOPE in DBD liver transplantations does not seem justified as the clinical benefits are limited to high-risk donors.

Predictors of Long-Term Outcomes After Liver Transplantation Depending on the Length of Cold Ischemia Time.

BACKGROUND: Cold ischemia time (CIT) is one of the most significant variables affecting graft survival after liver transplantation. The aim of this study was to identify other predictors of worse graft survival depending on the duration of cold ischemia. METHODS: This retrospective cohort study included data of liver transplant recipients and donors in the period from 2014 to 2019. A total of 724 patients were analyzed after excluding retransplatations and urgent operations. Using receiver operating characteristic analysis, we identified CIT value which divides into 2 clinically different subgroups with respect to 5-year graft loss. Within those 2 subgroups, we performed Cox proportional hazard analysis with time to graft loss as endpoint. RESULTS: The optimal cut-off point for CIT was identified as 496 minutes. Model of end-stage liver disease score, recipient body mass index, and donor sodium concentration showed no significant effect on time to graft loss in either subgroup. For 3 factors we observed a significant effect on time to graft loss in subgroup CIT ≥496 min: transfused red cell concentrate units (hazard ratio [HR] 1.05; 95% confidence interval [CI] 1.00-1.09; P = .02), transfused fresh frozen plasma units (HR 1.04; 95% CI 1.00-1.08; P = .08), and a recipient age of >60 years (HR 1.81; 95% CI 1.10-2.98; P = .02). CONCLUSIONS: Predictive ability of well-known risk factors for worse outcomes after liver transplantation depend on the length of cold ischemia.

The Effect of Early Retransplantation on Early and Late Survival After Liver Transplantation.

BACKGROUND: Early liver retransplantation after liver transplantation (LT) is the ultimate salvage procedure for irreversible graft failure. The aim of this study was to assess the impact of early retransplantation on 90-day and 5-year patient survival. METHODS: This retrospective cohort study included 2185 patients after LT in the period between 1997 and 2019. First, the patients undergoing first retransplantation within 6 months after initial LT were compared with naïve LT patients for early mortality (within 90 days). Second, to assess late survival, the patients who had retransplantation and survived at least 90 days post LT were compared with naïve LT patients for 5-year overall survival. The patients undergoing late retransplantation (>6 months) were excluded from analyses. Fisher's exact test was used to compare groups for early survival and log-rank test for late survival. RESULTS: The cumulative 1-, 3-, and 5-year overall survival was 87.0%, 79.9%, 75.0%, respectively, and did not differ significantly between the groups. The patients undergoing early retransplantation had lower 90-day survival rate of 89.2% as compared to 95.7% for naïve LT patients (P < .001). CONCLUSIONS: The early liver retransplantation has profound impact on post-LT 90-day survival; however, patients who survive that period can achieve long overall survival comparable with naïve LT patients.

Liver Transplantation for Unresectable Calcifying Nested Stromal Epithelial Tumor: Case Report With a 1-Year Follow-Up and Review of Literature.

Introduction: Calcifying nested stromal epithelial tumor (CNSET) is an extremely rare diagnosis among patients treated for primary hepatic neoplasms. There are only 45 cases reported worldwide. Histopathological characteristics are well-demarcated nests of spindle and epithelioid cells in a dense desmoplastic stroma with variable calcification and ossification. It is mostly diagnosed in children and young females. Treatment strategies implemented for the management of CNSET include radiofrequency ablation, transarterial chemoembolization, surgical resection, adjuvant and neoadjuvant chemotherapy, and liver transplantation. Given the small number of available cases, there are still no established standards of treatment for this neoplasm. Case Presentation: A 28-year-old female diagnosed with CNSET presented mild abdominal pain, with normal laboratory values. The tumor was initially deemed unresectable, therefore, the patient was disqualified from liver resection. Further deterioration of the patient's clinical condition and local tumor progression led to qualification for liver transplantation. The patient underwent liver transplantation 1 year following initial diagnosis and a 12 months recurrence-free period was observed. During the course of treatment, she did not receive systemic chemotherapy, radiotherapy, or loco-regional treatment. Conclusion: Multiple strategies have been implemented for the treatment of CNSET, with liver resection providing the best outcomes. Transarterial chemoembolization, radiofrequency ablation, and radiotherapy are reported to be insufficient in the management of this tumor. Various chemotherapy regimens turned out to be ineffective as well. There have been only eight reported cases of patients undergoing liver transplantation for CNSET, with tumor recurrence in two cases. CNSET appears to be a neoplasm with low malignancy potential, although an aggressive progression has subsequently been reported. Further investigation is still required in this field.

The Utility of Early Allograft Dysfunction Components in Determining 90-Day Liver Graft Survival.

BACKGROUND: Early allograft dysfunction (EAD) had been established as a useful tool to asses graft and patient survival after liver transplant. We wanted to evaluate effect of EAD components on early graft survival. METHODS: This retrospective study included 264 patients with EAD after liver transplant in the period between 2015 and 2019. The patients with retransplants were excluded from analyses. The EAD was determined with Olthoff criteria. The logistic regression model was used for analyses. The 90-day graft survival was set as a primary outcome measure. RESULTS: The main indications for transplant in the analyzed group were hepatitis C virus infection (53 patients, 20.1%), hepatitis B infection (22, 8.3%), primary sclerosing cholangitis (28, 10.1%), and alcoholic liver disease (62, 23.5%), with a median model for end-stage liver disease score of 13.5 points. The 90-day graft loss occurred in 51 patients (19.3%). Each of the components used in EAD diagnosis was found to be correlated with 90-day graft loss. The bilirubin concentration on day 7 (odds ratio [OR], 3.1; 95% CI, 1.4-6.7; P < .001), international normalized ratio on day 7 (OR, 179; 95% CI, 39-815; P < .001), and the natural logarithm of alanine aminotransferase (OR, 3.1; 95% CI, 1.6-6.4) and aspartate aminotransferase (OR, 1.4; 95% CI, 0.4-4.9) predicted 90-day graft loss. CONCLUSIONS: In patients with EAD, international normalized ratio ≥ 1.6 on day 7 was the strongest predictor of early graft-loss among all EAD components.

Early Postoperative Transaminase Activities Affecting Early and Late Liver Graft Survival.

BACKGROUND: This study aimed to examine the effect of transaminases' activities in the first posttransplant day on early (90-day) and late (5-year) graft survival. METHODS: This retrospective cohort study included 612 patients after liver transplantation (LT) in the period between 2015 and 2019. Patients with acute liver failure and with vascular complications after LT were excluded. The natural logarithms of alanine transaminase (ALT) and aspartate transaminase (AST) were used for analyses using the logistic regression and Cox proportional hazards regression models. The optimal cut-off point for transaminases was determined using receiver operating characteristic curves. The 5-year graft survival was calculated after previously excluding the patients with 90-day graft loss. RESULTS: The ALT and AST were risk factors for 90-day graft loss (odds ratio 2.16; 95% CI 1.45-3.23; P < .001 and 2.23; 95% CI 1.55-3.19; P < .001, respectively). The optimal cut-off for ALT and AST in prediction of 90-day graft loss was ≥1030 and ≥3899 U/L; area under the curve 0.694 (95% CI 0.602-0.786; P < .001), with 11.3% and 97.1% positive predictive value (PPV) and negative predictive (NPV) value, and 0.673 (95% CI 0.575-0.772; P < .001), with 18.4% PPV and 95.6% NPV, respectively. The activities of AST and ALT on first posttransplant day were not identified as risk factors for late graft loss (P = .924 and P = .629, respectively). CONCLUSIONS: Early post-transplant transaminase activities can be used to determine early liver graft loss; however, their utility is lost for assessing the late graft survival.

Early results of the implementation of laparoscopic major liver resection program.

BACKGROUND: Laparoscopic liver resections offer potential benefits but may require advanced laparoscopic skills and are volume dependent. METHODS: This retrospective study included 12 patients who underwent major laparoscopic resection and 24 patients after open major liver resection for liver malignancy in the time period between September 2020 and May 2021. The primary outcomes were complications according to Clavien-Dindo classification and duration of hospital stay. RESULTS: Median duration of hospital stay in laparoscopic resection group (6 days) was significantly shorter than in open resection group (8 days) (p = 0.046). Complications classified as grade II or higher were significantly less frequent in the laparoscopic resection group (2 patients) versus open resection group (13 patients) (p = 0.031). CONCLUSIONS: Although laparoscopic major liver resections should be limited to expert hepatobiliary centers and are characterized by long learning curve, this approach may offer favorable short-term outcomes even during launching a new program.

Adrenocorticotropin/cortisol ratio - a marker of psoriasis severity.

INTRODUCTION: The hypothalamic-pituitary-adrenal (HPA) axis plays a crucial role in systemic homeostasis and hormonal regulation of metabolic and immune functions. A similar HPA axis analog exists in the skin, where it regulates inflammation, cell proliferation and differentiation. Data regarding central HPA axis dysregulation in psoriasis are interesting but so far inconclusive. AIM: In the study we attempted to determine whether central HPA axis serum components correlate with psoriasis severity. MATERIAL AND METHODS: Forty-two patients (10 women and 32 men) hospitalized at the Department of Dermatology participated in the study. None of our patients received any systemic treatment. Venous blood samples were collected at 6.00 AM. The relationship between quantitative variables and psoriasis severity based on the Psoriasis Area and Severity Index (PASI) was assessed with proc logistic in SAS 9.4. RESULTS: The effect of adrenocorticotropin/cortisol ratio on the PASI group was OR 3.621 (95% confidence limits 1.217-10.775) for a 0.1 change in ratio (p = 0.02), meaning ACTH/cortisol ratio positively correlates with psoriasis severity. The effect of ACTH and cortisol on the PASI group was not statistically significant, with p-values of 0.30 and 0.23 respectively. Other inflammatory markers such as high-sensitivity C-reactive protein, neutrophils level, LDL, and total cholesterol did not show a significant correlation with PASI score. CONCLUSIONS: Our results support the role of HPA axis dysfunction in the complex pathogenesis of psoriasis, showing a positive correlation between morning ACTH/cortisol ratio and disease severity. ACTH/cortisol ratio can be regarded as a new biochemical marker of psoriasis severity worth further studies.

Pregnancy Weight Gain as a Predictor of Fetal Wellbeing in Liver Transplant Recipients.

BACKGROUND Gestational weight gain (GWG) is an important index influencing perinatal outcomes. Inappropriate weight gain during pregnancy is strongly associated with multiple pregnancy complications. In pregnant liver transplant recipients whose risk of adverse pregnancy outcomes is already high, this aspect may be even more significant. The present study analyzed the gestational weight gain in female liver transplant recipients and its effect on neonatal complications. MATERIAL AND METHODS A cohort study of retrospective data was performed in the 1st Department of Obstetrics and Gynecology, Medical University of Warsaw. There were 23 patients who fulfilled all inclusion criteria. The gestational weight gain was analyzed in the context of pre-pregnancy BMI, immunosuppression, and perinatal outcomes. RESULTS The preterm delivery rate was 39.13% and GWG increased according to the duration of pregnancy. The model adjusted to week of delivery revealed no association between weight gain and the length of pregnancy (p=0.82). GWG in liver transplant recipients did not affect hypotrophy incidence, adverse perinatal outcomes, or caesarian delivery rate. A positive correlation between GWG and neonatal birth weight was observed (p=0.06). One patient, with coexisting PIH, had a stillbirth at 23 weeks. In all other cases, the 5-min Apgar score was 10 points. CONCLUSIONS Current obstetrical recommendations do not consider patients with chronic diseases undergoing immunosuppressive treatment. Proper counselling and preparing liver transplant recipients for pregnancy, especially optimizing maternal pre-pregnancy BMI, may be an important element in improving perinatal outcomes by lowering the risk of maternal complications. GWG itself is not relevant as a predictor of term gestation, but it might be important in achieving eutrophic fetus growth.

Is there a rationale for aggressive breast cancer liver metastases resections in Polish female patients? Analysis of overall survival following hepatic resection at a single centre in Poland.

INTRODUCTION: Breast cancer (BC) makes up nearly 26% of malignant tumours worldwide and is the leading cause of cancer-related deaths in European women. With approximately 18,000 new cases of BC diagnosed in Polish women annually, breast cancer liver metastasis (BCLM) is respectively an increasing issue. Recent data found in literature indicates improved survival following liver resection with systemic therapy. OBJECTIVE: The aim of study was to evaluate surgical treatment in patients with isolated BCLM. MATERIALS AND METHOD: During 2009-2013, a retrospective study was undertaken and 30 cases analysed. From nearly 2,000 liver resections performed, 11 female patients at the mean age of 59.18 years with BCLM were qualified for surgery. RESULTS: The median time between primary and secondary treatment was 3.5 years (1-7). One patient (9.1%) presented an extrahepatic lesion - bone metastasis. The left lobe, right lobe and both lobes of the liver were affected, respectively, in 3 (27.3%), 4 (36.4%) and 4 (36.4%) patients. 5 patients (45.5%) presented single hepatic lesion, in contrast to the maximum number of lesions which equalled 6 in the right lobe. Average hospitalisation period was 13.27 days and discharge on the 11.3 postoperative day. One-year survival was 72.7% (8 patients); therefore, three-year survival was 36.4% (4 patients). CONCLUSIONS: Oncological centres should assess BCLM patients more openly and qualify them for hepatic resection along with adjuvant systemic treatment in order to improve overall survival. This, however, needs to be studied in a multicentre randomized trial.