Role of Epigenetic Factors in Determining the Biological Behavior and Prognosis of Hepatocellular Carcinoma.

BACKGROUND: The current study's objective is to evaluate the molecular genetic mechanisms influencing the biological behavior of hepatocellular carcinoma (HCC) by analyzing the transcriptomic and epigenetic signatures of the tumors. METHODS: Transcriptomic data were downloaded from the NCBI GEO database. We investigated the expression differences between the GSE46444 (48 cirrhotic tissues versus 88 HCC tissues) and GSE63898 (168 cirrhotic tissues versus 228 HCC tissues) data sets using GEO2R. Differentially expressed genes were evaluated using GO and KEGG metabolic pathway analysis websites. Whole genome bisulfite sequencing (WGBS) and Methylated DNA Immunoprecipitation Sequencing (MeDIP-Seq) data sets (26 HCC tissues versus 26 adjacent non-tumoral tissues) were also downloaded from the NCBI SRA database. These data sets were analyzed using Bismark and QSEA, respectively. The methylation differences between the groups were assessed using functional enrichment analysis. RESULTS: In the GSE46444 data set, 80 genes were upregulated, and 315 genes were downregulated in the tumor tissue (HCC tissue) compared to the non-tumor cirrhotic tissue. In the GSE63898 data set, 1261 genes were upregulated, and 458 genes were downregulated in the cirrhotic tissue compared to the tumor tissues. WGBS revealed that 20 protein-coding loci were hypermethylated. while the hypomethylated regions were non-protein-coding. The methylated residues of the tumor tissue, non-tumorous cirrhotic tissue, and healthy tissue were comparable. MeDIP-Seq, conducted on tumoral and non-tumoral tissues, identified hypermethylated or hypomethylated areas as protein-coding regions. The functional enrichment analysis indicated that these genes were related to pathways including peroxisome, focal adhesion, mTOR, RAP1, Phospholipase D, Ras, and PI3K/AKT signal transduction. CONCLUSIONS: The investigation of transcriptomic and epigenetic mechanisms identified several genes significant in the biological behavior of HCC. These genes present potential targets for the development of targeted therapy.

The impact of subdermal adipose derived stem cell injections and early excision on systemic oxidative stress and wound healing in rats with severe scald burns.

AIM: This study aims to develop an experimental treatment model effective against oxidative stress in the acute period of severe burns and to analyze the mechanisms of healing large wound defects. METHODS: Five rats, including 2 females and 3 males, were used as donors to obtain adipose-derived stem cells (ADSC) from the inguinal fat pad. The stem cells were labeled with green fluorescent protein. The study included four groups of 17 rats, each with grade 3 scalding burns on 30 % of their body surface, and a control group of 10 rats with an equal number of males and females. After early excision, 106 ADSC-derived stem cells were administered subdermally to the burned wound and autografted to the stem cell group (n = 17). The early excision group (n = 17) received early excision and autograft, with 2 ml of normal saline injected subdermally into the burn wound edge. The PLM group (n = 17) was treated with a polylactic membrane (PLM) dressing after the burn. No treatment was given to the burn group (n = 17). Ten rats from all groups were sacrificed on the 4th day post-burn for oxidative stress evaluation. The control group (n = 10) was sacrificed on day 4. Blood and tissue samples were collected post-sacrifice. Oxidative stress and inflammation in the blood, as well as cell damage in the skin, liver, kidneys, and lungs, were investigated histopathologically and biochemically on the 4th day post-burn. On the 70th day after burn, wound healing was examined macroscopically and histopathologically. RESULTS: On the 4th day, oxidative stress results showed that the levels of Total Oxidative Capacity (TOC) in the blood were lowest in the stem cell (7.4 [6-8.8]), control (6.7 [5.9-7.6]), and early excision (7.5 [6.6-8.5]) groups, with no significant difference between them. The burn group (14.7 [12.5-16.9]) had the highest TOC levels. The PLM group (9.7 [8.6-10.7]) had lower TOC levels than the burn group but higher levels than the other groups. Histopathological examination on the 4th day revealed low liver caspase-3 immunoreactivity in the stem cell and early excision groups among the burn groups. Caspase-3 immunoreactivity levels were as follows: stem cell group (20 [10-30]), early excision group (25 [15-50]), PLM group (70 [50-100]), control group (0), and burn group (80 [60-120]). Other oxidative stress and end-organ damage outcomes were consistent with these results. All rats in the stem cell group had burn wounds that healed completely by the 70th day. Examination of the skin and its appendages from the stem cell group with an immunofluorescence microscope demonstrated green coloration, indicating incorporation of stem cells. CONCLUSION: Stem cells may have the potential to form new skin and its appendages, providing better healing for large skin defects. Early excision treatment, by removing local necrotic tissues after extensive and deep burns, can prevent end-organ damage due to systemic oxidative stress and inflammation. We also believe that when these two treatments are used together, they can achieve the best results.

Peripheral blood platelet counts identify prognostically diverse clinical phenotypes in hepatocellular carcinoma.

Background: The factors responsible for hepatocellular carcinoma (HCC) growth are not precisely known. Aims: To study the clinical parameters associated with increases in maximum tumor diameter (MTD). Methods: A new cohort of 944 prospectively accrued HCC patients was analyzed for large size associations. Results: Patients were ordered into MTD terciles. Blood platelets, GGT and AST levels significantly increased and total bilirubin decreased with increase in MTD. Similar results were found only for platelets, in patients with low alpha-fetoprotein (AFP) levels, for whom biomarkers are scanty. Survival significantly decreased for patients with high platelet or GGT levels, even when AFP levels were low.Comparison of patients with low and high platelet levels showed that in the ≤6cm MTD group, patients with higher platelet numbers had lower total bilirubin and AST, and higher albumin, hemoglobin and percent patients with portal vein thrombosis (PVT) than those with lower platelets. Univariable logistic analysis on HCCs >6cm versus ≤6cm revealed significantly higher odds ratios for elevated blood platelet, AFP, GGT and ALKP levels. Cox regression analysis on death showed that in ≤6cm MTD patients, significant hazard ratios were for platelets, GGT, AFP, ALKP and PVT; but not for >6cm MTD patients, suggesting different mechanisms. Given the association of higher platelets with larger tumors and good liver function, their precursors are suggested to be small tumors with higher platelets and endogenous tumor factors. However, patients with low platelets and larger HCCs might have a different HCC lineage, likely associated with liver inflammation factors. Conclusions: Blood platelet levels are a potential marker for HCC phenotype and prognosis, including in patients with low AFP. They may also be a therapeutic target.

An Elbow Patch Reconstruction Technique for Narrowed Remnant Portal Veins during Right Lobe Living Donor Hepatectomy: A Rescue Surgery.

Background: Treatment of established portal vein narrowing after living donor hepatectomy is challenging. We aimed to present a new approach termed the "elbow patch reconstruction technique" to correct the narrowed remnant portal vein just or late after right lobe living donor hepatectomy. Methods: Demographic and clinical data of 12 living liver donors with narrowed remnant portal veins and treated with the "elbow patch reconstruction technique" were prospectively collected and retrospectively evaluated. Anatomic variation of the portal vein was defined in accordance with the Nakamura classification; six of the living liver donors had type A, three had type B, and the remaining three had type C. In eight of the living liver donors with a narrowed remnant portal vein, diagnosis was detected by intraoperative Doppler ultrasonography and visual inspection by experienced transplant surgeons in the living donor hepatectomy procedure. In the remaining four living liver donors, diagnosis was performed postoperatively when elevation of liver enzymes was noticed during the routine liver function test and Doppler US. The diagnosis was confirmed by multidetector computed tomography. Results: Data from nine males and three females aged 18 to 54 years were analyzed. All of the living liver donors were followed up for a median of 1710 days (min-max: 1178-4447 days; IQR: 1516 days), and none of the living liver donors had any structural or functional complications in the portal vein. Conclusions: Narrowing remnant portal veins are rare, but they are a life-threatening complication in living liver donors, and this condition requires urgent management. Image guided interventions and narrowed segment resection with end-to-end anastomosis using a vascular graft carried a potential risk for thrombosis and restenosis. To avoid these complications, we shared a technique named "elbow patch reconstruction technique". This technique can be very effective in relieving the narrowing of the remnant portal vein after right lobe living donor hepatectomy.

The Effect of Pringle Maneuver Applied during Living Donor Hepatectomy on the Ischemia-Reperfusion Injury Observed in the Donors and Recipients.

Background and Objectives: The aim of this study is to evaluate the clinical and laboratory changes of ischemia and reperfusion injury in the remnant livers of donors with and without Pringle maneuver. Furthermore, we evaluated the recipients who have been transplanted with liver grafts from these donors. Methods and Materials: A total of 108 patients (54 living liver donors and 54 liver recipients) who underwent donor hepatectomy and recipients who living donor liver transplantation, were included in this randomized double-blind study between February 2021 and June 2021. The donors were divided into two groups: Pringle maneuver applied (n = 27) and Pringle maneuver not applied (n = 27). Similarly, recipients with implanted liver obtained from these donors were divided into two groups as the Pringle maneuver was performed (n = 27) and not performed (n = 27). Blood samples from donors and recipients were obtained on pre-operative, post-operative 0 h day (day of surgery), post-operative 1st day, post-operative 2nd day, post-operative 3rd day, post-operative 4th day, post-operative 5th day, and liver tissue was taken from the graft during the back table procedures. Liver function tests and complete blood count, coagulation tests, IL-1, IL-2, IL-6, TNF-α, and ß-galactosidase measurements, and histopathological findings were examined. Results: There was no statistically significant difference in the parameters of biochemical analyses for ischemia-reperfusion injury at all periods in the donors with and without the Pringle maneuver. Similarly, there was no statistically significant difference between in the recipients in who received liver grafts harvested with and without the Pringle maneuver. There was no statistically significant difference between the two recipient groups in terms of perioperative bleeding and early bile duct complications (p = 0.685). In the histopathological examinations, hepatocyte damage was significantly higher in the Pringle maneuver group (p = 0.001). Conclusions: Although the histological scoring of hepatocyte damage was found to be higher in the Pringle maneuver group, the Pringle maneuver did not augment ischemia-reperfusion injury in donors and recipients that was evaluated by clinical and laboratory analyses.

Microvascular Invasion in Hepatocellular Carcinoma: Some Puzzling Facets.

BACKGROUND/AIMS: Hepatocellular carcinoma is the main type of primary liver cancer. Macroscopic vascular invasion is usually identified during imaging, whereas microvascular invasion is usually determined by histopathological evaluation. We aim to identify the association between microvascular invasion and other markers of tumor aggressiveness and to identify the role of microvascular invasion in the prognosis of patients who were treated by liver transplantation for hepatocellular carcinoma. MATERIALS AND METHODS: This is a single-center retrospective analysis of prospectively collected data. Patients who received liver transplantation for hepatocellular carcinoma were included in the study. Data were collected regarding sociodemographic variables, criteria of selection for liver transplantation, pretransplant alpha-fetoprotein, presence or absence of microvascular invasion, presence or absence of recurrence, overall survival, and disease-free survival. Data were analyzed using Statistical Package for the Social Sciences. RESULTS: Sociodemographic laboratory values and radiologic tumor characteristics were found to be similar in patients with or without microvascular invasion. Our study revealed that microvascular invasion is associated with increased recurrence, decreased diseasedfree survival, and decreased overall survival, only for patients with hepatocellular carcinoma beyond Milan criteria at the time of liver transplantation. CONCLUSION: For patients beyond Milan criteria, but not within Milan criteria, microvascular invasion plays a significant role in predicting recurrence and shorter survival after liver transplantation.

Transplant and non-transplant HCC patients at a single institution.

Background and Aim: Patients with hepatocellular carcinoma (HCC) are managed in various hospital departments, which complicates the assessment of the overall picture. In our large liver transplant institute, we evaluate all HCC patients in a weekly multi-disciplinary liver tumor board, and their data are prospectively collected in an institutional HCC database to evaluate HCC causes, tumor features, treatments, and survival. Materials and Methods: Baseline data for patients (n=1322) were prospectively recorded, including hepatitis status, routine clinical serum parameters, radiological assessment of maximum tumor diameter (MTD), tumor number, presence of macroscopic portal vein thrombosis (PVT), and serum alpha-fetoprotein (AFP) levels. Results: Cirrhosis was found in 81.1% of patients; 58.5% had hepatitis B virus (HBV), 14.9% hepatitis C virus (HCV), 8.9% cryptogenic cirrhosis, and less than 2% had alcoholism. MTD was <5 cm in 61.95% of patients, and 31.9% had PVT. The median overall survival was more than six-fold greater for the 444 liver transplant patients than for those without surgery. Transplanted patients had smaller tumors, whereas larger tumors (MTD >10 cm) were primarily in the no-surgery group. Parallel differences were found for AFP levels (highest in the no-surgery group). PVT was present in similar proportions (25.0% for transplant, 28.0% for no-surgery). The presence of cirrhosis was higher in the transplant group. MTD and levels of serum AFP, gamma-glutamyl transferase (GGT), and blood platelets were prognostic parameters for transplant. Furthermore, AFP and GGT levels were prognostic for transplanted PVT patients. Only albumin was prognostic in the no-surgery patients. Conclusion: Transplanted HCC patients have longer survival, smaller tumors, and more severe liver damage than no-surgery patients. Prognostic subsets were identified within the surgery and the PVT groups.

HBV viral load and tumor and non-tumor factors in patients with HBV-associated HCC.

Background and Aim: Several tumor and non-tumor factors affect the prognosis of hepatocellular carcinoma (HCC) patients. This study aimed to investigate the effects of hepatitis B virus (HBV) viral load on tumor and non-tumor factors in patients with HBV-associated HCC. Materials and Methods: Patients with hepatitis B and HCC who presented to the HCC council at the Faculty of Medicine, Marmara University Liver Transplantation Institute, were included in our study. Patients were divided into two groups according to the presence or absence of HBV-DNA, and it was determined whether there were differences between these two groups with respect to tumor and non-tumor parameters. Results: Comparison of serum alanine aminotransferase (ALT), gamma-glutamyl transferase (GGT), hepatitis B surface antigen (HBsAg), and C-reactive protein (CRP) levels between HBV-DNA negative and positive patients showed significant differences (respectively p<0.01, p<0.01, p<0.05, and p<0.05). A major finding was a very significant difference between the two patient groups in terms of portal vein invasion (PVI) and venous invasion (p<0.001 and p<0.01, respectively). However, there was no significant difference in metastasis or lymph node involvement between HBV-DNA negative and positive patients. Conclusion: Our findings suggest that HBV viral load plays an important role in PVI in HCC patients, and there is a significant relationship between HBV viral load and inflammation.

Recent outcomes of liver transplantation for Budd-Chiari syndrome: A study of the European Liver Transplant Registry (ELTR) and affiliated centers.

BACKGROUND AND AIMS: Management of Budd-Chiari syndrome (BCS) has improved over the last decades. The main aim was to evaluate the contemporary post-liver transplant (post-LT) outcomes in Europe. APPROACH AND RESULTS: Data from all patients who underwent transplantation from 1976 to 2020 was obtained from the European Liver Transplant Registry (ELTR). Patients < 16 years, with secondary BCS or HCC were excluded. Patient survival (PS) and graft survival (GS) before and after 2000 were compared. Multivariate Cox regression analysis identified predictors of PS and GS after 2000. Supplemental data was requested from all ELTR-affiliated centers and received from 44. In all, 808 patients underwent transplantation between 2000 and 2020. One-, 5- and 10-year PS was 84%, 77%, and 68%, and GS was 79%, 70%, and 62%, respectively. Both significantly improved compared to outcomes before 2000 ( p < 0.001). Median follow-up was 50 months and retransplantation rate was 12%. Recipient age (aHR:1.04,95%CI:1.02-1.06) and MELD score (aHR:1.04,95%CI:1.01-1.06), especially above 30, were associated with worse PS, while male sex had better outcomes (aHR:0.63,95%CI:0.41-0.96). Donor age was associated with worse PS (aHR:1.01,95%CI:1.00-1.03) and GS (aHR:1.02,95%CI:1.01-1.03). In 353 patients (44%) with supplemental data, 33% had myeloproliferative neoplasm, 20% underwent TIPS pre-LT, and 85% used anticoagulation post-LT. Post-LT anticoagulation was associated with improved PS (aHR:0.29,95%CI:0.16-0.54) and GS (aHR:0.48,95%CI:0.29-0.81). Hepatic artery thrombosis and portal vein thrombosis (PVT) occurred in 9% and 7%, while recurrent BCS was rare (3%). CONCLUSIONS: LT for BCS results in excellent patient- and graft-survival. Older recipient or donor age and higher MELD are associated with poorer outcomes, while long-term anticoagulation improves both patient and graft outcomes.

Alpha-fetoprotein and albumin inversely relate to each other and to tumor parameters in patients with hepatocellular carcinoma.

Background and Aim: Alpha-fetoprotein (AFP), an oncofetal protein and biomarker in hepatocellular carcinoma (HCC), has unclear roles and actions.To evaluate the relationships between AFP, liver function tests, and HCC aggressiveness. Materials and Methods: A retrospective analysis of an HCC patient database was conducted to examine the relationships between baseline serum AFP values, liver function tests, and tumor characteristics. Results: Statistically significant positive trends were observed between AFP levels and both AST and bilirubin, along with negative trends between AFP and albumin. Significant correlations were also found between AFP and MTD, multifocality, and PVT. Increases in MTD, multifocality, and PVT were noted even at low AFP levels, indicating both AFP-independent and AFP-dependent processes. However, these parameter changes were minimal compared to the substantial changes in AFP levels. Relationships between AFP-related liver and tumor characteristics were found to be similar but inverse to those for albumin, with normal albumin levels associated with more favorable tumor characteristics. Additionally, serum levels of albumin and AFP were inversely related. Conclusion: AFP and albumin levels significantly, but inversely, correlate with tumor parameters, suggesting that albumin may suppress HCC functions and could serve as a potential prognostic marker.

Discordance among aggressiveness characteristics of hepatocellular carcinoma: Portal vein thrombosis and multifocality, related to tumor size, but not to serum alpha-fetoprotein level.

Background and aims: Hepatocellular carcinoma (HCC) is characterized by several clinically important prognostic parameters, including portal vein thrombosis (PVT), tumor multifocality, and serum alpha-fetoprotein (AFP) levels, in addition to maximum tumor diameter (MTD). However, associations among these parameters have not been thoroughly examined. Thus, the study aimed to investigate the correlations among these HCC characteristics in a prospectively collected database. Methods: An 8080 HCC patient database derived from our weekly HCC council meeting was examined with respect to the correlations at baseline patient presentation between increases in MTD and changes in the percentage of patients with PVT, multifocality, or AFP levels. Results: The percentage of patients with PVT and with multifocality (tumor nodule numbers ≥3) significantly increased with enlarging MTD, regardless of the serum AFP level, showing the independence of PVT and multifocality on AFP. The percentage of patients with multifocality increased with enlarging MTD, in the presence or absence of PVT, showing the independence of multifocality from PVT. Therefore, discordance was found between different tumor parameters. Conclusions: A statistically significant association was found between PVT and MTD and between multifocality and MTD, all three of which are independent of AFP. PVT and multifocality appeared to be independent of each other. Although PVT and multifocality were independent of AFP, they were also augmented with high serum AFP levels. The results suggest the possibility of multiple pathways of tumor progression in the later stages of HCC development.

Liver Transplantation for Hepatocellular Carcinoma in Patients with Inherited Metabolic Liver Diseases: A Single-Center Analysis.

BACKGROUND/AIMS: Liver transplantation is an acceptable treatment for some selected hepatocellular carcinoma. We report our experience of 6 patients with liver transplantation for hepatocellular carcinoma with background inherited metabolic disease. MATERIALS AND METHODS: This is a single-center retrospective, descriptive study. Consecutive patients who underwent liver transplantation for hepatocellular carcinoma with background inherited metabolic disease were included in the study. The record of the patients was accessed, and the following data were extracted: sociodemographic variables, type of metabolic disease, date of liver transplantation, tumor characteristics, laboratory parameters, Model for End-Stage Liver Disease score, immediate- and long-term outcome after transplantation, disease-free survival, and overall survival. Data were analyzed using Statistical Package for the Social Sciences version 25.0. RESULTS: Six patients received liver transplantation for hepatocellular carcinoma with background inherited metabolic liver disease. The median age was 4.5 years. The median Model for End-Stage Liver Disease score was 29.30. The median maximum tumor diameter was 2.15 cm. Three patients had multiple tumor nodules. Half of the patients had microvascular invasion. Four of the patients had a moderately differentiated tumor. Progressive familial intrahepatic cholestasis type II is the commonest inherited metabolic disease seen in 3 patients. Median follow-up is 46.1 months. Half of the patients are currently more than 5 years post liver transplantation with no features of recurrence. The estimated survival rates at 1, 3, and 5 years are 100%, 83.3%, and 83.3%, respectively. CONCLUSION: Liver transplant for these categories of patients is associated with good disease-free and overall survival, even in the presence of some seemingly poor prognostic features.

Parameters Predicting Microvascular Invasion and Poor Differentiation in Hepatocellular Carcinoma Patients with Normal Alpha-fetoprotein Level Before Liver Transplantation.

BACKGROUND/AIMS: The aim of this study is to evaluate the parameters that might be associated with pathologically diagnosed microvascular invasion and poor differentiation, using complete blood count and routine clinical biochemistry test results, in hepatocellular carcinoma patients before liver transplantation. MATERIALS AND METHODS: The data of patients who underwent liver transplantation for hepatocellular carcinoma at our institute, between March 2006 and November 2021, was researched retrospectively. RESULTS: The incidence of microvascular invasion was 28.6%, poor differentiation rate was 9.3%, hepatocellular carcinoma recurrence rate after liver transplantation was 12.1%, and median time to recurrence was 13 months, in the patients with normal alpha-fetoprotein levels. After univariate and multivariate analysis, maximum tumor diameter >4.5 cm and the number of nodules (n > 5) were found to be independent risk factors for microvascular invasion, and number of nodules >4 and mean platelet volume ≤8.6 fL were found to be independent risk factors for poor differentiation. Serum alpha-fetoprotein levels were still within the normal range at the recurrence time, in 53% of the patients who had recurrence after liver transplantation, but surprisingly were elevated in 47% of the patients at time of hepatocellular carcinoma recurrence. CONCLUSIONS: In hepatocellular carcinoma patients with normal alpha-fetoprotein levels before liver transplantation, independent risk factors of the presence of microvascular invasion were maximum tumor diameter and number of nodules, and independent risk factors of poor differentiation were mean platelet volume and number of nodules. Furthermore, serum alpha-fetoprotein levels were still normal at time of recurrence in 53% of hepatocellular carcinoma patients whose alpha-fetoprotein levels were normal before liver transplantation but were elevated in 47% of the patients at recurrence time, despite having normal levels before liver transplantation.

Comparison of liver resection and living donor liver transplantation in patients with hepatocellular carcinoma within Milan criteria and well-preserved liver function.

Background and Aim: Liver resection (LR) and liver transplantation (LT) are curative treatments for hepatocellular carcinoma (HCC). The main purpose of this study was to compare the survival of LR and LDLT in patients with HCC within the Milan criteria. Materials and Methods: The results of the LR (n=67) and LDLT (n=391) groups were compared for overall survival (OS) and disease-free survival (DFS). Twenty-six of the HCCs in the LRs met the Milan and Child A criteria. Also, 200 of the HCC patients in the LDLTs met the Milan criteria, of which 70 also met the Child A criteria. Results: Early mortality was higher in the LDLT group (13.9% vs 1.47%; p=0.003). The 5-year OS was higher in the LDLTs than the LRs, but not statistically significant (84.6% vs 74.2%; p=0.287). However, 5-year DFS was better in the LDLT group (96.8% vs 64.3%; p<0.001). When the LRs (n=26) and the LDLTs (n=70) that met both Milan and Child A criteria were compared, 5-year OS was similar (81.4% vs 74.2%; p=0.512), but DFS was better in the LDLTs (98.6% vs 64.3%; p<0.001). Conclusion: LR can be justified as the first-line treatment for HCC patients who meet Milan and Child A criteria in terms of early mortality and OS.

Effect of the COVID-19 Pandemic on the Psychological Health of Patients Who Underwent Liver Transplantation Due to Hepatocellular Carcinoma.

BACKGROUND: The primary aim of this study was to compare liver transplant (LT) recipients with and without hepatocellular carcinoma (HCC) in terms of COVID-19-related depression, anxiety, and stress. METHOD: A total of 504 LT recipients with (HCC group; n = 252) and without HCC (non-HCC group; n = 252) were included in the present case-control study. Depression Anxiety Stress Scales (DASS-21) and Coronavirus Anxiety Scale (CAS) were used to evaluate the depression, stress, and anxiety levels of LT patients. DASS-21 total and CAS-SF scores were determined as the primary outcomes of the study. Poisson regression and negative binomial regression models were used to predict the DASS and CAS scores. The incidence rate ratio (IRR) was used as a coefficient. Both groups were also compared in terms of awareness of the COVID-19 vaccine. RESULTS: Poisson regression and negative binomial regression analyses for DASS-21 total and CAS-SF scales showed that the negative binomial regression method was the appropriate model for both scales. According to this model, it was determined that the following independent variables increased the DASS-21 total score: non-HCC (IRR: 1.26; p = 0.031), female gender (IRR: 1.29; p = 0.036), presence of chronic disease (IRR: 1.65; p < 0.001), exposure to COVID-19 (IRR: 1.63; p < 0.001), and nonvaccination (IRR: 1.50; p = 0.002). On the other hand, it was determined that the following independent variables increased the CAS score: female gender (IRR:1.75; p = 0.014) and exposure to COVID-19 (IRR: 1.51; p = 0.048). Significant differences were found between the HCC and non-HCC groups in terms of median DASS-21 total (p < 0.001) and CAS-SF (p = 0.002) scores. Cronbach's alpha internal consistency coefficients of DASS-21 total and CAS-SF scales were calculated to be 0.823 and 0.783, respectively. CONCLUSION: This study showed that the variables including patients without HCC, female gender, having a chronic disease, being exposed to COVID-19, and not being vaccinated against COVID-19 increased anxiety, depression, and stress. High internal consistency coefficients obtained from both scales indicate that these results are reliable.

Evaluation of Bone Mineral Metabolism After Liver Transplantation by Bone Mineral Densitometry and Biochemical Markers.

AIM: This study aimed to evaluate the course of bone and mineral metabolism after liver transplantation (LT) in patients with chronic liver disease. METHODS: One hundred four patients who had undergone LT and had a minimum of 6 months of follow-up after LT were included in this prospective cohort study. The following parameters were evaluated for each patient: preoperative and postoperative (postoperative day [POD]30, POD90, POD180) osteocalcin, bone-specific alkaline phosphatase (BALP), type 1 collagen, beta-C-terminal end telopeptide (ß-CTx), vitamin D, parathyroid hormone (PTH), ALP, calcium, phosphate, sedimentation, and bone mineral densitometer scores (L2, L4, L total, and F total). The parameters were compared in terms of sex, presence of liver tumor (hepatocellular carcinoma [HCC; n = 19] vs non-HCC [n = 85]), and presence of autoimmune liver disease (autoimmune liver disease [ALD; n = 8] vs non-ALD [n = 96]). RESULTS: The median age of the patients (n = 81 men and n = 23 women) was 52 years (95% CI, 50-56). There was a significant change in the defined time intervals in parameters such as osteocalcin (P < .001), BALP (P < .001), ß-CTx (P < .001), vitamin D (P < .001), PTH (P < .001), ALP (P = .001), calcium (P < .001), phosphate (P = .001), L2 (P = .038), L total (P = .026), and F total (P < .001) scores. There was a significant difference in POD90 ALP (P = .033), POD180 calcium (P = .011), POD180 phosphate (P = .011), preoperative sedimentation (P = .032), and POD180 F total (P = .013) scores between both sexes. There was a significant difference in POD180 osteocalcin (P = .023), POD180 ß-CTx (P = .017), and preOP calcium (P = .003) among the HCC and non-HCC groups. Furthermore, we found significant differences in preoperative ALP (P = .008), preoperative sedimentation (P = .019), POD90 (P = .037) and POD180 L2 (P = .005) scores, preoperative (P = .049) and POD180 L4 (P = .017), and POD180 L total (P = .010) and F total (P = .022) scores between the patients with and without ALD. CONCLUSION: This study shows that the bone and mineral metabolism of the LT recipients was negatively affected after LT. In addition, we showed that bone and mineral metabolism was more prominent in patients with HCC, and bone mineral density scores were higher in patients with ALD.

Effect of COVID-19 Pandemic on Patients Who Have Undergone Liver Transplantation Because of Hepatocellular Carcinoma.

BACKGROUND AND AIM: Many clinical studies have shown that the COVID-19 case fatality rate is higher in older patients, those with comorbidities, those with immunosuppressive conditions, and those who stay in the intensive care unit. This study aims to evaluate the clinical outcomes of 66 liver transplant (LT) patients with primary liver cancer who were exposed to COVID-19 infection. METHODS: Demographic and clinical data of 66 patients with primary liver cancer (hepatocellular carcinoma = 64, hepatoblastoma = 1, cholangiocarcinoma = 1) who underwent LT in our institute and were exposed to COVID-19 infection between March 2020 and November 2021 were analyzed in this cross-sectional study. The following data of the patients were recorded: age, sex, body mass index (kg/m2), blood group, underlying primary liver disease, smoking, tumor characteristics, post-transplant immunosuppressive agents, COVID-19 symptoms, hospitalization, intensive care unit stay, intubation, and other clinical features. RESULTS: There were 55 (83.3%) male and 11 (16.7%) female patients, with a median age of 58 years. Sixty-four patients were exposed to COVID-19 only once, whereas the remaining 2 patients were exposed 2 and 4 times, respectively. After exposure to COVID-19, it was determined that 37 patients used antiviral drugs, 25 were hospitalized, 9 were followed in the intensive care unit, and 3 were intubated. One intubated patient was under hospital follow-up because of biliary complications before exposure to COVID-19, and this patient died from sepsis. CONCLUSION: The low mortality rate of LT patients with primary liver cancer exposed to COVID-19 infection can be attributed to background immunosuppression that prevents cytokine storm. However, it is appropriate to support this study with multicenter studies to make strong comments on this issue.

Immunosuppressive Medication Adherence in Patients With Hepatocellular Cancer Who Have Undergo Liver Transplantation: A Case Control Study.

BACKGROUND: We aimed to compare the adherence to immunosuppressive medication use in patients who underwent liver transplantation (LT) due to hepatocellular carcinoma (HCC) and non-HCC reasons. METHODS: The study population was determined as 242 patients with HCC and 1290 patients with non-HCC who had LT performed in our institute between March 2002 and November 2021; all these patients were contacted by phone in March 2022. The sample size was calculated using the MedCalc software program, and the number of patients required in each group was determined as 111 patients. Furthermore, we used the sample.int function, a random integer generator in the R (version 4.1.2) software program. Whereas demographic and clinical parameters were determined as independent variables, the immunosuppressive medication adherence scale (IMAS) score was determined as a dependent variable. Patients were evaluated by the IMAS. This 11-item IMAS scale evaluates the lowest compliance score as 11 and the highest as 55. RESULTS: Out of a total number of 221 patients, 161 (72%) were men and 60 (27.1%) were women, with a median age of 58 years (IQR: 14); one patient in the non-HCC group was excluded due to lack of data. Among the HCC and non-HCC groups, significant differences were found in terms of the variables of age (P = .003), IMAS score (P < .001), sex (P = .001), working status (P = .004), chronic diseases (P = .008), tacrolimus alone (P < .001), tacrolimus plus everolimus (P < .001), and often medication changes (P < .001). A statistically significant correlation was found between the IMAS score and whether the patients had HCC (P < .001) and frequently changing immunosuppressive drugs (P = .023). CONCLUSION: This study showed that patients with frequent drug changes or non-HCC etiology had better adherence to immunosuppressive drug use.

Histopathological Evaluation of Gallbladder Specimens Obtained From Living Liver Donors.

BACKGROUND: Cholecystectomy is routinely performed during living donor hepatectomy both to see the structure of the biliary tract and to determine the demarcation line based on the biliary tract junction. This study aims to present the general histopathological features of the gallbladder specimen obtained from living liver donors (LLD). METHODS: Data from 2577 LLDs who underwent living donor hepatectomy (n = 2511) or aborted living donor hepatectomy (n = 66) in our Liver Transplantation Institute between September 2005 and June 2021 were analyzed retrospectively. Age, gender, macroscopic (length, diameter, and wall thickness), and microscopic (histopathological) features of the gallbladder of the LLDs were recorded for use in this study. RESULTS: A total of 2493 LLDs (men: 1486, women: 1007) with a median age of 29 years (interquartile range [IQR]: 13) met the inclusion criteria in this study. The median length, width and wall thickness of the gallbladder specimens were measured as 70 mm (IQR: 20), 50 mm (IQR: 20), and 2 mm (IQR: 1), respectively. The most common histopathological findings are normal structure (2026; 81.3%), chronic cholecystitis (n = 446; 17.9%), adenomyomatosis (n = 9), and papillary hyperplasia (n = 6), respectively. The most common pathologic findings in the gallbladder lumen are cholesterolosis (n = 207; 0.4%), cholelithiasis (n = 53), cholesterol polyp (n = 31), and noncholesterol polyp (n = 19), respectively. Significant differences were detected between the male and female genders in terms of age (P < .001), height (P < .001), weight (P < .001), body mass index (P < .001), gallbladder width (P = .001), gallbladder length (P < .001), histopathological finding (content) (P < .001), and lymph node around the gallbladder (P = .015). CONCLUSIONS: The results we obtained in this study are true gallbladder pathologies that can be detected in healthy people. In this study, it was shown that the diameter and size of the gallbladder were larger in men, whereas the incidence of cholesterolosis and cholelithiasis was higher in women.

Measurement of Heavy Metal and Antioxidant-Oxidant Levels in Tissues Obtained From Three Different Localizations of Explant Hepatectomy of Patients With Hepatocellular Carcinoma.

BACKGROUND: To reveal any difference in terms of heavy metal and antioxidant/oxidant levels of liver tissues obtained from 3 different locations of hepatectomy specimens of patients with hepatocellular carcinoma (HCC). METHODS: Total hepatectomy materials of patients who underwent liver transplantation for HCC were objects of this study. Three liver tissue samples were obtained from each material, one from HCC tissue, one adjacent from the border of HCC, and one at least 3 cm distant from HCC, each 10 × 10 mm in diameter. Samples are preserved at -70°C. Levels of heavy metals (As, Cd, Cu, Mn, Pb, Se, and Zn) and oxidant-antioxidant parameters (catalase, glutathione peroxidase [GSHPx], superoxide dismutase [SOD], nitric oxide, prolidase, glutathione, malondialdehyde, total oxidant status, antioxidant status, oxidative stress index, total-thiol, native thiol, and disulphid) are measured. RESULTS: This study included 22 patients (18 men, 4 women with an age range of 3 to 66 years. There were significant differences in terms of Cd, Pb, Zn, GSHPx, SOD, nitric oxide, and native thiol levels between liver tissues derived from 3 different locations. Cd, Pb, and Zn levels were significantly different in tumor tissues, whereas GSHPx and SOD levels were significantly different in tumor and neighboring tissues. Nitric oxide levels were relatively different in tumor tissues compared with tumor-neighboring tissues. Native thiol levels differed significantly in tumor tissues compared with tissues distant from tumor. CONCLUSIONS: The aim of this study is unique in medical literature, which reveals that the amount of heavy metals and antioxidant/oxidant accumulation are variable in the same liver tissue in different locations because of multiple and yet unknown factors.