Comparative RNA-Sequencing Analysis Reveals High Complexity and Heterogeneity of Transcriptomic and Immune Profiles in Hepatocellular Carcinoma Tumors of Viral (HBV, HCV) and Non-Viral Etiology.

Background and Objectives: Hepatocellular carcinoma (HCC), the most common type of primary liver cancer, is the leading cause of cancer-related mortality. It arises and progresses against fibrotic or cirrhotic backgrounds mainly due to infection with hepatitis viruses B (HBV) or C (HCV) or non-viral causes that lead to chronic inflammation and genomic changes. A better understanding of molecular and immune mechanisms in HCC subtypes is needed. Materials and Methods: To identify transcriptional changes in primary HCC tumors with or without hepatitis viral etiology, we analyzed the transcriptomes of 24 patients by next-generation sequencing. Results: We identified common and unique differentially expressed genes for each etiological tumor group and analyzed the expression of SLC, ATP binding cassette, cytochrome 450, cancer testis, and heat shock protein genes. Metascape functional enrichment analysis showed mainly upregulated cell-cycle pathways in HBV and HCV and upregulated cell response to stress in non-viral infection. GeneWalk analysis identified regulator, hub, and moonlighting genes and highlighted CCNB1, ACTN2, BRCA1, IGF1, CDK1, AURKA, AURKB, and TOP2A in the HCV group and HSF1, HSPA1A, HSP90AA1, HSPB1, HSPA5, PTK2, and AURKB in the group without viral infection as hub genes. Immune infiltrate analysis showed that T cell, cytotoxic, and natural killer cell markers were significantly more highly expressed in HCV than in non-viral tumors. Genes associated with monocyte activation had the highest expression levels in HBV, while high expression of genes involved in primary adaptive immune response and complement receptor activity characterized tumors without viral infection. Conclusions: Our comprehensive study underlines the high degree of complexity of immune profiles in the analyzed groups, which adds to the heterogeneous HCC genomic landscape. The biomarkers identified in each HCC group might serve as therapeutic targets.

Resection of a Large Celiac Trunk Aneurysm Followed by Cadaveric Graft Reconstruction - A Case Report.

BACKGROUND/AIM: Celiac artery aneurysms represent rare eventualities which remain symptomatic for a long period of time; however, once diagnosed, it should be carefully monitored due to the high risk of developing life-threatening complications. When it comes to the types of therapeutic strategies, both endovascular and surgical therapies can be taken in consideration. CASE REPORT: Depending on the patency of the collateral network, simple ligation or graft placement should be performed. The aim of the current paper is to report the case of a patient diagnosed with a celiac trunk aneurysm who was successfully submitted to resection in association with iliac graft placement between the abdominal aorta and the common hepatic artery. CONCLUSION: Whenever celiac artery aneurysm is diagnosed, it should be closely monitored and treated, resection and reconstruction being a feasible method in order to avoid the development of a life-threatening complication.

The Complement System, T Cell Response, and Cytokine Shift in Normotensive versus Pre-Eclamptic and Lupus Pregnancy.

Successful pregnancy requires an immunological shift with T helper CD4+ bias based on disbalance Th1/Th17 versus Th2/T regulatory (Tregs) required to induce tolerance against the semi-allogeneic fetus and placenta and to support fetal growth. Considered a pregnancy-specific hypertensive disorder, pre-eclampsia is characterized by multifaceted organ involvement related to impaired maternal immune tolerance to paternal antigens triggered by hypoxic placental injury as well as excessive local and systemic anti-angiogenic and inflammatory factor synthesis. Both systemic and local Th1/Th2 shift further expands to Th17 cells and their cytokines (IL-17) complemented by suppressive Treg and Th2 cytokines (IL-10, IL-4); alterations in Th17 and Tregs cause hypertension during pregnancy throughout vasoactive factors and endothelial dysfunction, providing an explanatory link between immunological and vascular events in the pathobiology of pre-eclamptic pregnancy. Apart from immunological changes representative of normotensive pregnancy, lupus pregnancy is generally defined by higher serum pro-inflammatory cytokines, lower Th2 polarization, defective and lower number of Tregs, potential blockade of complement inhibitors by anti-phospholipid antibodies, and similar immune alterations to those seen in pre-eclampsia. The current review underpins the immune mechanisms of pre-eclampsia focusing on local (placental) and systemic (maternal) aberrant adaptive and innate immune response versus normotensive pregnancy and pregnancy in systemic autoimmune conditions, particularly lupus.

Hypothermic Oxygenated Machine Perfusion of Liver Grafts: Preliminary Experience in a Single Center.

Background: The need to maximize the use of donor organs and the issue of ischemia-reperfusion injury led to the use of thermoregulated oxygenated machine perfusion that improves the function of liver graft prior to transplantation. Among these methods, the HOPE (hypothermic oxygenated perfusion) protocol shows significant benefits. The aim of the paper is to analyze the early experience in using such procedure in a high-volume liver transplantation center. Methods: Normal liver grafts with cold ischemia time â?¥6 hours, marginal grafts and discarded (beyond ECD criteria) grafts were perfused using HOPE. Our selection criteria for dual HOPE (hepatic artery and portal perfusion) were steatosis, at least 3 associated ECD criteria, and discarded grafts. The main criteria to establish graft improvement were the progressive increase of arterial and portal flows, with lactate under 3 mmol/L or, even if over this value, with a decreasing trend during perfusion. Results: Whole liver grafts harvested from 28 donors between February 2016 and June 2021 benefitted from HOPE: 9 otherwise discarded grafts were assessed and considered not fit for transplantation, while the other 19 were ECD or standard grafts that were subsequently transplanted. Dual HOPE was used in 8 out of the 19 procedures (42.1%). We obtained a significant increase of arterial and portal flow (p=0.005 and p=0.001, respectively). In recipients, significant improvement of AST, ALT, INR and lactate values were recorded (p 0.001, p 0.001, p 0.001, and p=0.05, respectively). The rate of major postoperative complications (Dindo-Clavien grade 3) after LT was 26.3%, while the rate of early graft dysfunction was 15.8%. No PRS or acute rejection was recorded. The postoperative mortality rate was 15.8%. After a median follow-up of 9.3 months (range 2-44), the late major complication rate was 15.8%, without mortality. Conclusion: Machine perfusion is nowadays part of current clinical practice. This way, marginal liver grafts (DCD, ECD-DBD) may be safely used for transplantation improving the outcome, thus effectively enhance the use of a persistent scarce pool of donors. For best results, we believe that both techniques of HOPE (mono and dual HOPE) should be used based on specific selection criteria.

Gastrointestinal stromal tumors of the colon and rectum.

Gastrointestinal stromal tumors (GISTs) are rare neoplasms, colorectal location being met in less than 5% of cases. Knowledge about this site related particularities are limited. The aim of this study is to present our experience with colorectal GISTs between 2005 and 2018 from the clinical, morphological, and immunohistochemical perspectives, with emphasis on prognostic factors. From a total of 203 gastrointestinal stromal tumors registered, 12 were colorectal (6%). The number of colonic tumors surpassed that of the rectum (9 : 3) and on the right side were registered more cases than on the left side (6/3). 9 were primary tumors and 3 were recurrences. Men and women were represented equally and the age range was between 22 and 76. Tumor dimensions varied between 0.5 and 14 cm. Microscopically, spindle cell type was dominant. Mitotic rate was variable between 1 and 115/50HPFs. Accordingly, for primary tumors progression risks were assigned (low risk: 2 cases, intermediate risk: 3 cases and high risk: 4 cases). All GISTs were CD117 and DOG1 positive. Four of the patients died of the disease.

Novel diagnosis of mesenteric endometrioma: Case report.

RATIONALE: Mesenteric cysts are benign gastrointestinal cystic lesions, with an incidence of <1/100 000. They usually develop in the small bowel mesentery, mesocolon (24%), retroperitoneum (14.5%), and very rarely originate from the sigmoid mesentery. Endometriomas represent a localized type of endometriosis and are usually within the ovary. Our case is unique because there are no reports in the literature of endometrial mesenteric cysts. PATIENT CONCERNS: We present a case of a 29-year-old woman who underwent a routine gynecologic control. DIAGNOSIS: Clinical examination and imaging identified 2 endometriomas on the left and posterior to the uterus. INTERVENTIONS: The patient underwent exploratory laparoscopy. Unexpectedly, a 10 cm mesenteric cyst was identified; this was associated with adhesions in the left adnexal area and a left ovarian endometrioma. The classic surgical approach which was necessary identified the mesenteric cyst with cranial mesosigmoid and ileal adhesions, as well as distal adhesions which included the uterus, ileum, left ovarian endometrioma, left hydrosalpinx, left ureter, and rectum. The cyst was removed completely and a left adnexectomy was performed because of the presence of the endometrioma and adhesions. OUTCOMES: The patient's outcome was favorable, with discharge at 72 hours after surgery. The histopathological report revealed that both the mesenteric and ovarian cysts were endometriomas. LESSONS: Our case is unusual in that a mesenteric cyst was identified in a patient with no clinical symptoms. Furthermore, the histopathological examination revealed the endometriotic origin of the mesenteric cyst which has not previously been reported in the literature.

An Attempt to Build a National Prospective Electronic Database for Pancreaticoduodenectomies in Romania - Preliminary Results of the First Year Enrollment.

Introduction: National databases for pancreaticoduodenectomies (PD) have contributed to better postoperative outcomes after such complex surgical procedure because the multicentre collection of data allowed more reliable analyses with quality assessment and further improvement of technical issues and perioperative management. The current practice and outcomes after PD are poorly known in Romania because there was no national database for these patients. Thus, in 2016 a national-intent electronic registry for PD was proposed for all Romanian surgical centers. The study aims to present the preliminary results of this national-intent registry for PD after one-year enrollment. Patients Methods: The database was started on October 1st, 2016. Data were prospectively collected with an electronic online form including 102 items for each patient. The registry was opened to all the Departments of Surgery from Romania performing PD, with no restriction. Results: During the first year of enrollment were collected the data of 181 patients with PD performed by 24 surgeons from four surgical centers. The age of patients was 64 years (28 - 81 years), with slightly male predominance (61.3%). Computed tomography was the main preoperative imaging investigation (84.5%). All the PDs were performed by an open approach. The Whipple technique was used in 53% of patients, and a venous resection was required in 14.3% of cases. A posterior approach PD was considered in 16.6% of patients. The stomach was used to treat the distal remnant pancreas in 50.1% of patients. The operative time was 285 min (110 - 615 min), and the estimated blood loss was 400 ml (80 - 3000 ml). The overall morbidity rate was 55.8%, with severe (i.e., grade III-IV Dindo-Clavien) morbidity rate of 10%, and 3.9% in-hospital mortality rate. The overall pancreatic fistula, delayed gastric emptying and hemorrhage rates were 19.9%, 39.8% and 15.5%. Periampullary malignancies were the main indications for PD (78.9%), with pancreatic cancer on the top (48%). Conclusions: To build a prospective electronic online database for PD in Romania appears to be a feasible project and a useful tool to know the current practice and outcomes after PD in our country. However, improvements are still required to encourage a larger number of surgical centers to introduce the data of patients with PD.

The Romanian National Program for Liver Transplantation - 852 Procedures in 815 Patients over 17 Years (2000-2017): A Continuous Evolution to Success.

Background: Liver transplantation (LT) has become an established treatment for end-stage liver disease, with more than 20.000 procedures yearly worldwide. The aim of this study was to analyze the results of Romanian National Program of LT. Methods: Between April 2000 and April 2017, 817 pts received 852 LTs in Romania. Male/female ratio was 487/330, while adult/pediatric ratio was 753/64, with a mean age of 46 years (median 50 yrs; range 7 months - 68 yrs). Main LT indications were HBV cirrhosis (230 pts; 28.2%), HCC (173 pts; 21.2%), and HCV cirrhosis (137 pts; 16.8%). Waiting time and indications for LT, patient and donor demographics, graft features, surgical procedures, and short and long-term outcomes were analyzed. Results: DDLT was performed in 682 pts (83.9%): whole LT in 662 pts (81%), split LT in 16 pts (2.3%), reduced LT in 2 pts (0.2%), and domino LT in 1 pts (0.1%). LDLT was performed in 135 pts (16.5%): right hemiliver in 93 pts (11.4%), left lateral section in 28 pts (3.4%), left hemiliver in 8 pts (1%), left hemiliver with segment 1 in 4 pts (0.5%), and dual graft LDLT in 2 pts (0.2%). Overall major morbidity rate was 31.4% (268 pts), while perioperative mortality was 7.9% (65 pts). Retransplantation rate was 4.3% (35 pts): 27 whole LTs, 3 reduced LTs, 3 split LTs, and 2 LDLT. Long-term overall 1-, 3-, and 5-year estimated survival rates for patients were 87.9%, 81.5%, and 79.1%, respectively. One-, 3-, and 5-year overall mortality on waiting list also decreased significantly over time from 31.4%, 54.1% and 63.5%, to 4.4%, 13.9% and 23.6%, respectively. Conclusions: The Romanian National program for liver transplantation addresses all causes of acute and chronic liver failure or liver tumors in adults and children, using all surgical techniques, with good long-term outcome. The program constantly evolved over time, leading to decreased mortality rate on the waiting list.

Curative Intent Treatment of Hepatocellular Carcinoma - 844 Cases Treated in a General Surgery and Liver Transplantation Center.

Background: The objective of this study is to assess the outcome of the patients treated for hepatocellular carcinoma (HCC) in a General Surgery and Liver Transplantation Center. Methods: This retrospective study includes 844 patients diagnosed with HCC and surgically treated with curative intent methods. Curative intent treatment is mainly based on surgery, consisting of liver resection (LR), liver transplantation (LT). Tumor ablation could become the choice of treatment in HCC cases not manageable for surgery (LT or LR). 518 patients underwent LR, 162 patients benefited from LT and in 164 patients radiofrequency ablation (RFA) was performed. 615 patients (73%) presented liver cirrhosis. Results: Mordidity rates of patient treated for HCC was 30% and mortality was 4,3% for the entire study population. Five year overall survival rate was 39 % with statistically significant differences between transplanted, resected, or ablated patients (p 0.05) with better results in case of LT followed by LR and RFA. Conclusions: In HCC patients without liver cirrhosis, liver resection is the treatment of choice. For early HCC occurred on cirrhosis, LT offers the best outcome in terms of overall and disease free survival. RFA colud be a curative method for HCC patients not amenable for LT of LR.

Ocular posterior pole pathological modifications related to complicated pregnancy. A review.

Ocular posterior pole modification are a pathological manifestation in complicated pregnancies, especially when pregnancy induced hypertension is present (PIH), as well as in preeclampsia (PE) or eclampsia. Nonetheless, as the pregnancy evolves, the possibility for an aggravated evolution with HELLP syndrome, disseminated intravascular coagulation, and idiopathic thrombocytopenic purpura may have an ocular manifestation that, mainly, implies a loss of visual field or acuity, that, left unattended, may constitute a permanent impairment. Pregestational conditions like pituitary adenoma or genetic pedigree for complement factor H gene (1q31.1) single nucleotide mutations could lead to central serous chorioretinopathy or retinal detachment with severe, ischemic, central cilioretinal artery or vein occlusion and optic nerve atrophy. Furthermore, although subtle in many cases, any new visual symptoms during pregnancy should constitute an alarming factor for obstetrical reevaluation and ophthalmological approach in order to preserve the mother's quality of life.

The impact of donor liver graft quality on postoperative outcome in liver transplant recipients. A single centre experience.

INTRODUCTION: The Donor Risk Index (DRI) has become a universal score for organ allocation in liver transplantation (LT) worldwide. The aim of this study was to evaluate the impact of liver graft quality measured by DRI, CIT, WIT and donor age on intraoperative hemodynamics (reperfusion syndrome) and early postoperative outcome, defined as initial graft poor function (within 3 days of LT), of deceased donor liver transplant (DDLT) recipients. Secondary end-points were the assessment of the impact of graft quality on the intraoperative and postoperative day 1 hemostasis (evaluated using ROTEM assay). METHODS: We retrospectively analyzed 135 patients who underwent deceased-donor LT between January 2013 and December 2014. Patient demographic data (age, sex, cause of End-Stage Liver Disease), preoperative paraclinical data (total bilirubin, creatinine, serum sodium), severity of liver disease scores (Model for End-Stage Liver Disease - MELD and MELD-sodium), intraoperative blood loss and blood products transfusion, incidence of post reperfusion syndrome, postoperative biochemical data (including total bilirubin, hepatic transaminases, lactate levels) and outcome (initial graft poor function diagnosis) were noted. Donor characteristics including DRI, CIT, WIT and donor age were noted. Coagulation was assessed by rotational thromboelastometry (ROTEM) after reperfusion of the graft and on postoperative day 1 in order to determine the effects of liver graft quality on hemostasis. RESULTS: Donor age has significantly correlated with decreased derived ROTEM parameters time to the maximum velocity of clot formation - MaxVt (p = 0.000), area under the curve (AUC) (p = 0.008) and maximum clot elasticity (MCE) (p = 0.018) although no difference in transfusion requirements has been observed. A longer CIT was associated with an increase in AST and ALT observed during the early postoperative period: day 1 ALT (p = 0.032) and AST (p = 0.008), day 2 ALT (p = 0.001) and AST (p = 0.001) and day 3 AST (p = 0.010) and ALT (p = 0.001). Higher DRI correlated with higher bilirubin levels measured on postoperative day 1 (p = 0.027) and 2 (p = 0.001). Patients who developed initial graft poor function received liver grafts from older donors (p = 0.05) with a higher DRI (p = 0.002). CONCLUSION: Our results suggest a significant impact of donor age and DRI on perioperative coagulation kinetics that may be a result of initial graft poor function. Although CIT and DRI correlated with a more severe cholestasis and hepatocitolysis during the early postoperative period these seems to be short-lived.