Portal hypertension has no role in perioperative bleeding during liver transplantation with systematic porto-caval shunt.

BACKGROUND: More than a half of patients undergoing liver transplantation (LT) receive intraoperative transfusion. Portal hypertension (PHT) may contribute to perioperative blood loss. We study the relationship between preoperative hepatic venous pressure gradient (HVPG) values and intraoperative transfusion requirements in adult patients undergoing LT. METHODS: 160 cirrhotic patients undergoing first elective LT (2009-2019) with an HVPG measurement within the previous 6 months were included. Surgical technique was piggyback with portocaval shunt (PCS). The association of HVPG and other variables with transfusion requirements and blood loss were studied. RESULTS: Blood loss (ml/kg) was positively correlated with HVPG, among other variables, but at multivariable analysis it only remained associated with MELD-Na and HCC indication. Regarding RBC transfusion, MELD-Na and hemoglobin were independently associated with the need and magnitude of RBC transfusion. Subanalysis by surgical stage (hepatectomy, anhepatic, neohepatic) and by serial HVPG cut-offs found no clear associations with either bleeding or transfusion. DISCUSSION: The severity of PHT plays a minor role on bleeding and transfusion during LT in a contemporary cohort with systematic PCS. Main determinants of transfusion are liver function and baseline hemoglobin, which would seem the suitable goal to optimize transfusion in LT.

STARD1 promotes NASH-driven HCC by sustaining the generation of bile acids through the alternative mitochondrial pathway.

BACKGROUND & AIMS: Besides their physiological role in bile formation and fat digestion, bile acids (BAs) synthesised from cholesterol in hepatocytes act as signalling molecules that modulate hepatocellular carcinoma (HCC). Trafficking of cholesterol to mitochondria through steroidogenic acute regulatory protein 1 (STARD1) is the rate-limiting step in the alternative pathway of BA generation, the physiological relevance of which is not well understood. Moreover, the specific contribution of the STARD1-dependent BA synthesis pathway to HCC has not been previously explored. METHODS: STARD1 expression was analyzed in a cohort of human non-alcoholic steatohepatitis (NASH)-derived HCC specimens. Experimental NASH-driven HCC models included MUP-uPA mice fed a high-fat high-cholesterol (HFHC) diet and diethylnitrosamine (DEN) treatment in wild-type (WT) mice fed a HFHC diet. Molecular species of BAs and oxysterols were analyzed by mass spectrometry. Effects of NASH-derived BA profiles were investigated in tumour-initiated stem-like cells (TICs) and primary mouse hepatocytes (PMHs). RESULTS: Patients with NASH-associated HCC exhibited increased hepatic expression of STARD1 and an enhanced BA pool. Using NASH-driven HCC models, STARD1 overexpression in WT mice increased liver tumour multiplicity, whereas hepatocyte-specific STARD1 deletion (Stard1ΔHep) in WT or MUP-uPA mice reduced tumour burden. These findings mirrored the levels of unconjugated primary BAs, ß-muricholic acid and cholic acid, and their tauroconjugates in STARD1-overexpressing and Stard1ΔHep mice. Incubation of TICs or PMHs with a mix of BAs mimicking this profile stimulated expression of genes involved in pluripotency, stemness and inflammation. CONCLUSIONS: The study reveals a previously unrecognised role of STARD1 in HCC pathogenesis, wherein it promotes the synthesis of primary BAs through the mitochondrial pathway, the products of which act in TICs to stimulate self-renewal, stemness and inflammation. LAY SUMMARY: Effective therapy for hepatocellular carcinoma (HCC) is limited because of our incomplete understanding of its pathogenesis. The contribution of the alternative pathway of bile acid (BA) synthesis to HCC development is unknown. We uncover a key role for steroidogenic acute regulatory protein 1 (STARD1) in non-alcoholic steatohepatitis-driven HCC, wherein it stimulates the generation of BAs in the mitochondrial acidic pathway, the products of which stimulate hepatocyte pluripotency and self-renewal, as well as inflammation.

Vascular invasion and survival after liver transplantation for hepatocellular carcinoma: a study from the European Liver Transplant Registry.

BACKGROUND: Studies suggest that vascular invasion may be a superior prognostic marker compared with traditional selection criteria, e.g. Milan criteria. This study aimed to investigate the prognostic value of micro and macrovascular invasion in a large database material. METHODS: Patients liver transplanted for HCC and cirrhosis registered in the European Liver Transplant Registry (ELTR) database were included. The association between the Milan criteria, Up-to-seven criteria and vascular invasion with overall survival and HCC specific survival was investigated with univariate and multivariate Cox regression analyses. RESULTS: Of 23,124 patients transplanted for HCC, 9324 had cirrhosis and data on explant pathology. Patients without microvascular invasion, regardless of number and size of HCC nodules, had a five-year overall survival of 73.2%, which was comparable with patients inside both Milan and Up-to-seven criteria. Patients without macrovascular invasion had an only marginally reduced survival of 70.7% after five years. Patients outside both Milan and Up-to-seven criteria without micro or macrovascular invasion still had a five-year overall survival of 65.8%. CONCLUSION: Vascular invasion as a prognostic indicator remains superior to criteria based on size and number of nodules. With continuously improving imaging studies, microvascular invasion may be used for selecting patients for transplantation in the future.

Can we prevent ischemic-type biliary lesions in donation after circulatory determination of death liver transplantation?

The pool of livers for transplantation consists of an increasingly greater proportion of marginal grafts, in particular those arising through donation after circulatory determination of death (DCD). However, a primary factor limiting the use of marginal livers, and, thereby, the applicability of liver transplantation in general, is concern over the subsequent development of ischemic-type biliary lesion (ITBL). ITBL is a devastating complication of liver transplantation; in its most severe forms, recipients suffer frequent infectious complications that require repeated invasive biliary procedures and ultimately result in either retransplantation or death. In the present review article, we discuss our current understanding of ITBL pathogenesis as it pertains to DCD, in particular. We discuss the most relevant theories regarding its development and provide a comprehensive overview of the most promising strategies we have available today to prevent the appearance of ITBL, strategies that may, furthermore, allow us to transplant a greater proportion of marginal livers in the future. Liver Transplantation 22 1025-1033 2016 AASLD.

Abdominal regional in-situ perfusion in donation after circulatory determination of death donors.

PURPOSE OF REVIEW: Provide an overview regarding the current state of abdominal regional perfusion (ARP) in donation after circulatory determination of death (DCD) organ transplantation, including the principles behind how ARP functions and the most recent results of its clinical application. RECENT FINDINGS: ARP has been applied clinically in DCD at both hypothermic and normothermic temperatures. The use of hypothermic perfusion has primarily been limited to DCD kidney transplantation, whereas normothermic regional perfusion has been used to improve and assess the quality of DCD kidneys, livers, and even a handful of pancreata for transplantation. Results of recent single-center series reflect acceptable rates of early graft function and survival using grafts that might have otherwise been discarded. SUMMARY: ARP is an important form of donor maintenance that helps improve DCD organ viability and may help expand the applicability of transplantation using organs arising through this process.

European approach to increasing organ donation: European Union donor card, presumed consent, and other innovations.

KEY POINTS: 1. Liver transplantation has become the standard of care for terminal liver disease. 2. Unfortunately, liver transplantation has become the victim of its own success because the number of available donors is not meeting the growing demand for organs.

Single-incision transperitoneal laparoscopic left adrenalectomy.

BACKGROUND: Laparoscopic adrenalectomy via three or four trocars is a well-established procedure. This report describes the initial experience with single-incision laparoscopic surgery (SILS) using the transperitoneal approach for left adrenalectomy. METHODS: Between April 2010 and August 2011, all consecutive patients with adrenal masses, including Conn's syndrome, Cushing's adenoma, and nonfunctional adrenal tumors, who agreed to undergo SILS adrenalectomy were included in a prospective study. The left 2.5-cm subcostal incision was the sole point of entry. Data of patients who underwent SILS adrenalectomy were compared with those from an uncontrolled group of patients who underwent conventional laparoscopic adrenalectomy during the same study period. RESULTS: There were 20 patients in each study group (20 men, 20 women; mean age [SD] = 50 [6.5] years). SILS was successfully performed and none of the patients required conversion to an open procedure. In one case of SILS procedure, an additional lateral 5-mm port was needed for retraction of the kidney. The mean (SD) duration of the operation was 95 (20) min in the SILS group and 80 (8) min in the conventional laparoscopic adrenalectomy group (p = 0.052). There were no intraoperative or postoperative complications. There were no differences between the two study groups with respect to postoperative pain, number of patients who resumed oral intake within the first 24 h, final pathologic diagnosis, and length of hospital stay. CONCLUSION: SILS left adrenalectomy is a technically feasible and safe procedure in carefully selected patients. The definitive clinical, aesthetic and functional advantages of this technique require further analysis.

Extracorporeal machine liver perfusion: are we warming up?

PURPOSE OF REVIEW: Recently, considerable focus has been placed on the use of hypothermic perfusion ex vivo in abdominal organ transplant. Herein, we discuss the appropriateness of using this modality to preserve livers, in particular those of suboptimal quality, and whether perfusing at warmer temperatures in this context may, in fact, be better. RECENT FINDINGS: Hypothermic perfusion (0-4°C) appears to improve the hepatocellular energy charge and achieve adequate results in normal livers. However, its use for the preservation of suboptimal grafts may lead to significant endothelial and Kupffer cell injury that is incompatible with survival. Studies on the perfusion of suboptimal livers at higher temperatures, on the contrary, indicate that results improve as temperatures approach 37°C, provided that the oxygen supply during perfusion is adequate. SUMMARY: Normothermic perfusion provides oxygen and other metabolic substrates under physiological conditions; in liver transplant, it appears to be the best option to improve the viability of suboptimal organs.

Superior preservation of DCD livers with continuous normothermic perfusion.

OBJECTIVE: Unexpected donation after cardiac death (DCD) donors suffer cardiac arrest suddenly and are maintained with normothermic extracorporeal membrane oxygenation (NECMO) while consent for donation is obtained. The objective of this study was to determine whether ex vivo normothermic machine perfusion (NMP) improves upon the benefits of NECMO in a large-animal model of unexpected DCD liver transplant. METHODS: Donor pigs underwent 90-minute cardiac arrest and were divided in to 3 groups. In the first, livers were preserved immediately with cold storage (CS, n = 6). In the other 2 groups, donors underwent 60-minute NECMO followed by CS (NECMO+CS, n = 6) or NMP (NECMO+NMP, n = 6). After 4-hour preservation, livers were transplanted into recipient pigs. RESULTS: Five-day survival was 0 in CS, 83% in NECMO+CS, and 100% in NECMO+NMP. After reperfusion, injury, and inflammatory markers rose significantly among CS grafts, all of which developed primary nonfunction. Sixty minutes of NECMO, however, resulted in only 1 death, whereas NECMO followed by NMP led to no deaths and significant improvements in injury, inflammation, and synthetic function in comparison to NECMO and CS. CONCLUSION: Although 60 minutes recuperative NECMO is better than CS alone, NMP improves further on NECMO and may have a role in preserving DCD livers in the clinical setting.

Step-by-step guide for a simplified model of porcine orthotopic liver transplant.

BACKGROUND: Based on similar anatomy, physiology, and size to humans, pigs provide an excellent means for studying new therapies related to orthotopic liver transplant (OLT). Techniques that have been described to date, however, are unnecessarily complex and increase the likelihood of morbidity and adverse outcome. MATERIALS AND METHODS: Male outbred weanling pigs underwent OLT according to our procedure, with a short anhepatic time (<20 min) and without veno-venous bypass or vasoactive substances during the anhepatic phase. Vascular anastomoses were performed identical to the clinical setting, and a simple stented choledochocholedochostomy was created. RESULTS: The authors have performed this procedure 130 times using four transplant models: standard, whole-liver (n = 10), small-for-size (n = 48), donor after cardiac death (n = 44), and donor adenoviral gene transfection (n = 28). The average cold ischemic and anhepatic times were 302 ± 43 and 17 ± 3 min, respectively. Hypotension was successfully treated with intravenous fluids. In all cases, the recipient survived the operation and was extubated. Survival to the end follow-up varied according to the model and was 56% (73/130) for all cases. At autopsy or euthanasia, no vascular thrombosis or outflow obstruction was found. Survival was 100% for pigs transplanted with standard, whole-liver grafts (n = 10). In this group, AST and bilirubin rose during the first 24 h after graft reperfusion, while the Quick prothrombin time (QPT) fell. By the fifth postoperative day, these parameters had returned to baseline. CONCLUSIONS: This model is straightforward and reproducible and offers surgeons and researchers the opportunity to perform OLT studies under clinically relevant conditions.

Suprapubic single-incision laparoscopic appendectomy: a nonvisible-scar surgical option.

BACKGROUND: At the present time, and given the increasing concern about body image, laparoscopic surgeons are faced with an increasing number of patients who want to conserve the umbilicus free of scars for cosmetic reasons. Single-incision laparoscopic surgery (SILS) using the suprapubic approach for appendectomy, while keeping the advantages of SILS through an umbilical incision, leaves the visible abdomen without scars. Moreover, insertion of an additional port in patients with retrocecal or purulent or gangrenous acute appendicitis requiring intra-abdominal drainage is avoided. This report describes the initial experience with suprapubic SILS appendectomy. METHODS: Between September 2009 and December 2010, patients with acute appendicitis admitted to the General Surgery and Emergency Unit of the authors' institution and who agreed to undergo SILS appendectomy through the suprapubic approach were included in a prospective study. Demographics, clinical characteristics, and surgical outcome were recorded. RESULTS: A total of 20 patients (12 men and 8 women) with a mean age of 30 ± 3 years underwent suprapubic SILS appendectomy. The mean duration of the operation was 40 ± 7 min. Placement of a suction drain was necessary in four patients. The mean length of hospital stay was 2 ± 0.5 days. The operation was completed successfully in all patients, and conversion to either multiport or open surgery was not required. No intraoperative or postoperative complications occurred. In all patients, the appearance of the suprapubic wound was good at 7 days after surgery. CONCLUSION: Suprapubic SILS appendectomy offers better, cosmetically appealing results than the standard umbilical access. In case of retrocecal or purulent or gangrenous acute appendicitis, the view provided via the suprapubic approach makes access to and dissection of the appendix easy, and it also enables exteriorization of a drain without adding new lateral incisions.

Hepatitis C virus superinfection of liver grafts: a detailed analysis of early exclusion of non-dominant virus strains.

Liver transplantation (LT) of hepatitis C virus (HCV)-infected grafts into HCV-infected recipients leads to superinfection with two different virus strains. To characterize the virological outcomes of HCV superinfection immediately after LT, we performed phylogenetic analysis of a fragment of the NS5B gene in donor and recipient serum samples prospectively collected before and after LT, starting on day 1. In four of six cases, the donor strain finally prevailed, while in the remaining two cases, the native recipient strain overtook the donor quasispecies. Clonal sequence analysis showed that, in three cases, the expelled strain was undetectable 1 day after LT. Our study shows that superinfection with a different HCV strain can lead to the exclusion of one strain by the other as soon as the first day after LT. This would suggest that competition might not be limited to the replication level, but could also take place during virus entry.

Portal hyperperfusion: mechanism of injury and stimulus for regeneration in porcine small-for-size transplantation.

Understanding the pathogenesis of small-for-size (SFS) syndrome is critical to expanding the applicability of partial liver transplantation. We aimed to characterize its acute presentation and association with alterations in hepatic hemodynamics, microstructure, and regeneration in a porcine model. Eighteen SFS liver transplants were performed. Donors underwent 70% hepatectomy. Partial grafts were implanted into larger recipients. Whole liver transplants were also performed (n = 6). Recipients were followed until death or for 5 days. Hemodynamics were measured, and tissue was sampled intraoperatively and at the study end. Serum was sampled regularly during follow-up. Seventeen SFS transplants and 6 whole liver transplants were included. SFS grafts represented 23.2% (19.3%-25.3%) of the recipients' standard liver volume. The survival rate was 29% and 100% in the SFS and whole liver groups, respectively. The portal venous flow, pressure gradient, and resistance were significantly higher in recipients of SFS grafts versus whole livers after portal and arterial reperfusion. Arterial flow as a percentage of the total liver blood flow was significantly lower after reperfusion in SFS grafts and remained so when measured again after 5 days. Markers of endothelial cell injury increased soon after reperfusion, and those of hepatocellular injury increased later; both predicted the appearance of either graft failure or histological recovery. Proliferative activity peaked earlier and higher among nonsurvivors in the SFS group. Surviving grafts demonstrated a slower but maintained rise in regenerative activity, although metabolic activity failed to improve. In SFS transplantation in the acute setting, portal hyperperfusion is a stimulus for regeneration but may simultaneously cause irreparable endothelial injury. This porcine model not only helps to elucidate the inciting factors in SFS pathogenesis but also offers a clinically relevant means to study its prevention.

Laparoendoscopic single-site surgery appendectomy.

BACKGROUND: Laparoscopic appendectomy via the three-trocar technique is widely used for appendectomy. This report describes the initial experience with laparoendoscopic single-site surgery (LESS) appendectomy. METHODS: Between December 2008 and March 2009, patients with acute appendicitis admitted to the General Surgery and Emergency Unit of the authors' institution who agreed to undergo LESS appendectomy were included in a prospective study. All operations were performed by the same surgical team specially trained in this type of emergency surgery. The umbilicus was the sole point of entry for all patients, and the same operative technique was used in all cases. The data for patients undergoing LESS appendectomy were compared with the data from an uncontrolled group of patients undergoing standard laparoscopic appendectomy during the same study period. RESULTS: The LESS and standard appendectomy groups included 15 patients each. The LESS procedure was performed successfully for all the patients, and none required conversion to an open procedure or a conventional laparoscopic appendectomy by the addition of more entry ports. The mean operating time of 51 min in the LESS group was not significantly different from the 46 min in the standard laparoscopic appendectomy group. CONCLUSIONS: In this study, LESS appendectomy was technically feasible and safe, representing a reproducible alternative to standard laparoscopic appendectomy.

Surgical outcomes of total thyroidectomy using the LigaSure™ Small Jaw versus LigaSure Precise™: A retrospective study of 2000 consecutive patients.

BACKGROUND: We compared surgical outcomes of LigaSure™ Small Jaw, which is a multifunctional thermal device that incorporates a tissue divider versus LigaSure Precise™ in thyroid surgery. METHODS: A retrospective, single-center study was carried out in an acute-care teaching hospital in Barcelona, Spain. Between January 2008 and June 2015, consecutive patients scheduled for total thyroidectomy were included in the study. Surgical outcomes were operative time, length of skin incision, use of a suction drain, intraoperative bleeding, postoperative complications and length of hospital stay. RESULTS: A total of 2000 patients were included (LigaSure™ Small Jaw, n = 1000; LigaSure Precise™, n = 1000). Demographics and indication for surgery were similar in both groups. A significant and independent shorter operative time (median 40 vs. 65 min, P = 0.002), smaller length of the skin incision (mean [SD] 4 [2] vs. 7 [3] cm, P = 0.031), lower percentages of patients with suction drain (15% vs. 66%, P = 0.012) and intraoperative bleeding (4% vs. 9%, P = 0.045) and reduced length of stay (median 1 vs. 3 days, P = 0.039) were found in the LigaSure™ Small Jaw than in the LigaSure Precise™. Postoperative complications including haematoma, hypoparathyroidism and recurrent laryngeal nerve injury were similar. CONCLUSIONS: The LigaSure™ Small Jaw in thyroid surgery results in significant less blood loss and operative time as well as shorter hospital stay compared to LigaSure Precise™. These findings could have direct application in daily practice.

Time-related improvement of survival in resectable gastric cancer: the role of Japanese-style gastrectomy with D2 lymphadenectomy and adjuvant chemotherapy.

BACKGROUND: We investigated the change of prognosis in resected gastric cancer (RGC) patients and the role of radical surgery and adjuvant chemotherapy. METHODS: We retrospectively analyze the outcome of 426 consecutive patients from 1975 to 2002, divided into 2 time-periods (TP) cohort: Before 1990 (TP1, n = 207) and 1990 or after (TP2; n= 219). Partial gastrectomy and D1-lymphadenectomy was predominant in TP1 and total gastrectomy with D2-lymphadenectomy it was in TP2. Adjuvant chemotherapy consisted of mitomycin C (MMC), 10-20 mg/m2 i.v. 4 courses or MMC plus Tegafur 500 mg/m2 for 6 months. RESULTS: Positive nodes were similar in TP2/TP1 patients with 56%/59% respectively. Total gastrectomy was done in 56%/45% of TP2/TP1 respectively. Two-drug adjuvant chemotherapy was administered in 65%/18% of TP2/TP1 respectively. Survival at 5 years was 66% for TP2 versus 42% for TP1 patients (p < 0.0001). Survival by stages II, IIIA and IIIB for TP2 versus TP1 patients was 70 vs. 51% (p = 0.0132); 57 vs. 22% (p = 0.0008) and 30 vs. 15% (p = 0.2315) respectively. Multivariate analysis showed that age, stage of disease and period of treatment were independent variables. CONCLUSION: The global prognosis and that of some stages have improved in recent years with case RGC patients treated with surgery and adjuvant chemotherapy.

Hepatic preconditioning after prolonged warm ischemia by means of S-adenosyl-L-methionine administration in pig liver transplantation from non-heart-beating donors.

BACKGROUND: This study ascertained the effect of S-adenosyl-L-methionine (SAMe) administration on the ischemia-reperfusion injury associated with pig liver transplantation from non-heart-beating donors (NHBDs) after prolonged warm ischemia. METHOD: Twenty-five animals underwent transplantation with an allograft from an NHBD. After donor cardiac arrest, cardiopulmonary bypass and normothermic recirculation (NR) were performed for 30 min. Ten animals were given SAMe during NR. Donors were cooled to 15 degrees C, and liver procurement was performed. RESULTS: SAMe reduced histologic liver damage 5 days after transplantation. The necrotic area affected 15.9%+/-14.5% of the liver biopsies in controls and 7.4%+/-9% in SAMe livers. Six of eight controls and only one of eight survivors in the SAMe group developed ischemic cholangitis. SAMe reduced apoptosis of hepatocytes 5 days after transplantation and apoptosis of sinusoidal endothelial cells at reperfusion and at 5 days. SAMe increased energy charge at the end of NR and favored the balance between adenosine and xanthine. It was also associated with higher portal blood flow (740+/-59.2 vs. 475.2+/-65.0 mL/min-1/m-2), hepatic hyaluronic acid extraction (132+/-72.2 vs. -205.8+/-64.6 microg/L), and lower levels of alpha-glutathione-S-transferase after reperfusion (2,601%+/-581% with respect to baseline vs. 6,488%+/-5,612%). CONCLUSION: SAMe administration during liver procurement from NHBDs prevents liver endothelial, parenchymal, and biliary tract damage. The protective role of SAMe may be partially mediated by the effect of adenosine during liver procurement.

Abdominal drainage after liver resection for hepatocellular carcinoma in cirrhotic patients: a randomized controlled study.

BACKGROUND/AIMS: The use of drainage after liver resection remains controversial. Data of the usefulness of drains in cirrhotic patients undergoing surgical resection are scarce. The objective of our study is to assess the usefulness of intra-abdominal drainage after liver resection for hepatocellular carcinoma in cirrhotic patients. METHODOLOGY: We performed a randomized controlled trial to assess the benefits of abdominal drainage after resection of hepatocellular carcinoma in cirrhotic patients. The main end point was to compare postoperative complications and hospital stay in both groups. RESULTS: Abdominal drainage decreased ascites leakage and significantly reduced hospital stay in comparison to the non-drainage group. In addition, local complications were less frequent in the drainage group. Postoperative ascites leakage significantly complicated patients with clinically relevant portal hypertension. CONCLUSIONS: Intra-abdominal closed drainage is advisable in cirrhotic patients undergoing liver resection for hepatocellular carcinoma, mainly if presenting preoperative portal hypertension.