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.

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.

Complicated appendicitis with scrotal fistula: case report and review of the literature.

Appendicitis is the most common emergency abdominal surgery today. Although its common complications are well-known, retroperi-toneal abscess and scrotal abscess are rare and less known complications. In this study, we presented our patient who presented with appendicitis complicated with retroperitoneal abscess and scrotal fistula after appendectomy, and the literature review we conducted through PubMed. A 69-year-old man was admitted to the emergency department with complaints of abdominal pain, nausea-vomiting continuing for about 7 days, and fever and mental status change in the last 24 h. He was taken to emergency surgery with the pre-liminary diagnosis of perforation and retroperitoneal abscess. At laparotomy, perforated appendicitis and associated retroperitoneal abscess were seen. An appendectomy was performed, and the abscess was drained. The patient, who stayed in the intensive care unit for 4 days due to sepsis, was discharged on the 15th postoperative day with full recovery. He was admitted 15 days after his discharge because of an abscess from the scrotum. Percutaneous drainage was performed in the patient, whose tomography revealed an abscess extending from the retroperitoneal area to the left scrotum. The patient, whose abscess regressed, was discharged with recovery 17 days after hospitalization. These rare complications associated with appendicitis should be on the minds of surgeons to make an early diagnosis. Delay in treatment may lead to increased morbidity and mortality.

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.

Liver transplantation for hepatocellular carcinoma: Historical evolution of transplantation criteria.

Liver transplantation (LT) for hepatocellular carcinoma is still a hot topic, and the main factor that is associated with the success of treatment is to determine the patients who will benefit from LT. Milan criteria have been defined 25 years ago and still is being used for patient selection for LT. However, in living donor LT, the Milan criteria is being extended. Current criteria for patient selection do not only consider morphologic characteristics such as tumor size and number of tumor nodules but also biologic markers that show tumor aggressiveness is also being considered. In the present review article, we have summarized all the criteria and scoring systems regarding LT for hepatocellular carcinoma. All criteria have 5-year overall survival rates that were comparable to the Milan Criteria and ranged between 60%-85%. On the other hand, it was seen that the recurrence rates had increased as the Milan criteria were exceeded; the 5-year recurrence rates ranged between 4.9% to 39.9%. Treatment of hepatocellular carcinoma needs a multidisciplinary approach. Ideal selection criteria are yet to be discovered. The same is true for treatment modalities. The goal will be achieved by a harmonic interplay between basic science researchers and clinicians.

Impact of COVID-19 pandemic on clinicopathological features of transplant recipients with hepatocellular carcinoma: A case-control study.

BACKGROUND: The coronavirus disease 2019 (COVID-19) pandemic had a significant impact on the management of all diseases. Various diseases such as cancer have a higher risk of COVID-19-related death. Despite this fact, any delay or alteration in treatment of cancer may have fatal consequences. Hepatocellular carcinoma (HCC) is an aggressive liver cancer that requires multimodality treatment to improve survival. AIM: To evaluate the impact of COVID-19 on the management of patients with HCC by determining changes in demographic, clinical and histopathological variables. METHODS: Demographic, clinical and pathological variables of patients with HCC who had undergone liver transplantation between March 2020 and June 2021 (Pandemic group, n = 48) were retrospectively compared with that of the patients with HCC transplanted between November 2018 and March 2020 (Pre-pandemic group, n = 61). RESULTS: The median age of the patients in the study was 56 (interquartile range = 15). Ninety-seven patients (89%) were male and 12 were female (11%). The most common etiology of liver disease was hepatitis B virus (n = 52, 47.7%). According to our results, there was a 21.3% drop in the number of patients transplanted for HCC. There was no difference in the demographic, clinical and pathological characteristics of the patients except blood alkaline phosphatase levels (P = 0.029), lymphovascular invasion (P = 0.019) and type of the liver graft that was transplanted (P = 0.017). CONCLUSION: It is important to develop a surveillance strategy for liver transplant centers. The liver transplantation for HCC is justified and safe provided that strict surveillance protocols are applied.

Adipose-derived stem cells in the treatment of hepatobiliary diseases and sepsis.

Determination of the mesenchymal stem cells is one of the greatest and most exciting achievements that tissue engineering and regenerative medicine have achieved. Adipose-derived mesenchymal stem cells (AD-MSC) are easily isolated and cultured for a long time before losing their stem cell characteristics, which are self-renewal and pluripotency. AD-MSC are mesenchymal stem cells that have pluripotent lineage characteristics. They are easily accessible, and the fraction of stem cells in the adipose tissue lysates is highest among all other sources of mesenchymal stem cells. It is also HLA-DR negative and can be transplanted allogenically without the need for immunosuppression. These advantages have popularized its use in many fields including plastic reconstructive surgery. However, in the field of hepatology and liver transplantation, the progress is slower. AD-MSC have the potential to modulate inflammation, ameliorate ischemia-reperfusion injury, and support liver and biliary tract regeneration. These are very important for the treatment of various hepatobiliary diseases. Furthermore, the anti-inflammatory potential of these cells has paramount importance in the treatment of sepsis. We need alternative therapeutic approaches to treat end-stage liver failure. AD-MSC can provide a means of therapy to bridge to definitive therapeutic alternatives such as liver transplantation. Here we propose to review theoretic applications of AD-MSC in the treatment of hepatobiliary diseases and sepsis.

De Novo Malignancies After Liver Transplantation: Experience of a High-Volume Center.

PURPOSE: Patient care, newer immunosuppressive medications, and advances in surgical technique, have resulted in significant prolongation of survival after liver transplantation in recent years. However, as life expectancy increased and the early mortality rates have decreased, different problems have evolved due to chronic immunosuppressive therapy. The aim of the present study is to evaluate patients who were transplanted and then developed de novo malignancies, in terms of the type of malignancies and the follow-up period. METHODS: The study was conducted on 2814 patients who received liver transplantation between 2008 and 2020 in Inonu University Liver Transplant Institute. In total, the data of 23 patients were evaluated retrospectively. RESULTS: Non-melanoma skin cancer was the most common de novo malignancy (21.7%), followed by gynecological cancers (17.3%). The interval between the time of transplantation until the development of de novo malignancy was 36 (6-75) months. The median follow-up period after the diagnoses of the de novo malignancies was 4.11 years. One, 3-, 5-year survival rates of patients after the diagnoses of de novo malignancies were 69.6%, 56.5%, and 41.9%; respectively. CONCLUSION: Non-melanotic skin cancers were the most common de novo cancers in liver transplant recipients. A strict surveillance program is very important in the follow-up of liver transplant recipients.

High-Level Procalcitonin in Patient with Mixed Fibrolamellar Hepatocellular Carcinoma: A Case Report and Literature Review.

Course of blood procalcitonin levels by days.

Recommendations for the ethical guidelines for publication of scientific studies: The responsibilities of editors, reviewers and the authors.

OBJECTIVE: We aimed to evaluate the role of anesthesiologist in the management of hydatid disease from the perspective of the editors, reviewers and the authors. METHODS: We searched the PubMed/Medline database using the following keywords: (hydatid* OR echinococc*) AND (disease OR cyst) AND (anesthesiology). We have evaluated the authors, their institutions and department, and the aim of the studies. We also evaluated the studies published by anesthesiologists in terms of content. RESULTS: The literature search showed 6344 articles published between February 2010 to 2021. Sixty-three had at least one anesthesiologist in the author list. Anesthesiologists were leading authors in 35 studies; and in 19 of them, all the authors were anesthesiologist. Sixteen (84.2%) of these articles defined the outcomes of surgical therapy and there was no information regarding anesthesia technique. CONCLUSION: The results of our study emphasize an important controversy regarding jurisdiction of different departments in terms of scientific research ethics. We believe that different disciplines can work together to evaluate a scientific problem and can publish a study in collaboration. But collaboration is very important and violating the subject of another field without collaboration is a deontological problem.

Hepatocellular Carcinoma Tumor Microenvironment and Its Implications in Terms of Anti-tumor Immunity: Future Perspectives for New Therapeutics.

PURPOSE: Hepatocellular cancer is an insidious tumor that is often diagnosed in a later stage of life. The tumor microenvironment is the key to tumorigenesis and progression. Many cellular and non-cellular components orchestrate the intricate process of hepatocarcinogenesis. The most important feature of hepatocellular cancer is the immune evasion process. The present review aims to summarize the key components of the tumor microenvironment in the immune evasion process. METHODS: Google Scholar and PubMed databases have been searched for the mesh terms "Hepatocellular carcinoma" or "Liver Cancer" and "microenvironment." The articles were reviewed and the components of the tumor microenvironment were summarized. RESULTS: The tumor microenvironment is composed of tumor cells and non-tumoral stromal and immune cells. HCC tumor microenvironment supports aggressive tumor behavior, provides immune evasion, and is an obstacle for current immunotherapeutic strategies. The components of the tumor microenvironment are intratumoral macrophages (tumor-associated macrophages (TAM)), bone marrow-derived suppressor cells, tumor-associated neutrophils (TAN), fibroblasts in the tumor microenvironment, and the activated hepatic stellate cells. CONCLUSION: There are intricate mechanisms that drive hepatocarcinogenesis. The tumor microenvironment is at the center of all the complex and diverse mechanisms. Effective and multistep immunotherapies should be developed to target different components of the tumor microenvironment.

Management of irreducible giant rectal prolapse: A case report and literature review.

INTRODUCTION AND IMPORTANCE: Rectal prolapse is defined as herniation of mucosa or full-thickness of the rectal wall through the anal canal. It has a negative impact on the quality of life and therefore, it should be treated as soon as diagnosis is confirmed. Definitive treatment is surgical and it depends on the clinical characteristics of the patients. We aimed to present the one of the largest rectal prolapse case in the literature. CASE PRESENTATION: A 32- years- old male patient with a history of severe constipation was admitted to our institution with a giant rectal prolapse. The prolapsed segment was incarcerated, and a semi-emergent procedure was performed though a mid-line laparotomy. The sigmoid colon was redundant and therefore sigmoid colon and the upper two thirds of rectum were resected and end to end anastomosis was performed. The patient was discharged postoperative day 7 without any complication. CLINICAL DISCUSSION: Rectal prolapse has a negative impact on quality of life and should be operated as soon as the diagnosis is reached. The surgical strategy depends on the compliance of the patient as well as the experience of the surgical team. CONCLUSION: Clinicians should know that chronic constipation together with other factors may result in rectal prolapse which may become disproportionately large in size.

Diagnostic and therapeutic management algorithm for biliary complications in living liver donors.

This study aimed to demonstrate the efficacy of our diagnostic and therapeutic management algorithm and catheter-assisted (percutaneous transhepatic biliary tract drainage [PTBD] or transanastomotic feeding tube) hepaticojejunostomy (HJ) procedures in living liver donors (LLDs) with biliary complications. Living donor hepatectomy (LDH) was performed between September 2005 and April 2021 in 2 489 LLDs. Biliary complications developed in 220 LLDs (8.8%), 136 of which were male, and the median age was 29 (interquartile range [IQR]: 12) years. Endoscopic sphincterotomy ± stenting was performed in 132 LLDs, which was unsuccessful in 9 LLDs and required HJ. Overall, 142 LLDs underwent interventional radiologic procedures. Fifteen LLDs with biliary complications underwent HJ (PTBD catheter = 6 and transanastomotic feeding tube = 9) at a median of 44 days (IQR: 82). Following HJ, 14 LLDs did not have any complications throughout the median follow-up period of 1619 days (IQR: 1454). However, percutaneous dilation for HJ anastomotic stricture was performed in one patient. Biliary complications are very common following LDH; therefore, surgeons in the field should have a low threshold to perform HJ for biliary complications that persist after other treatments. Our catheter-assisted HJ techniques demonstrated a high success rate and aided HJ in a hostile abdomen during revisional surgery.