"Very early" intrahepatic cholangiocarcinoma in cirrhotic patients: should liver transplantation be reconsidered in these patients?

A retrospective cohort multicenter study was conducted to analyze the risk factors for tumor recurrence after liver transplantation (LT) in cirrhotic patients found to have an intrahepatic cholangiocarcinoma (iCCA) on pathology examination. We also aimed to ascertain whether there existed a subgroup of patients with single tumors ≤2 cm ("very early") in which results after LT can be acceptable. Twenty-nine patients comprised the study group, eight of whom had a "very early" iCCA (four of them incidentals). The risk of tumor recurrence was significantly associated with larger tumor size as well as larger tumor volume, microscopic vascular invasion and poor degree of differentiation. None of the patients in the "very early" iCCA subgroup presented tumor recurrence compared to 36.4% of those with single tumors >2 cm or multinodular tumors, p = 0.02. The 1-, 3- and 5-year actuarial survival of those in the "very early" iCCA subgroup was 100%, 73% and 73%, respectively. The present is the first multicenter attempt to ascertain the risk factors for tumor recurrence in cirrhotic patients found to have an iCCA on pathology examination. Cirrhotic patients with iCCA ≤2 cm achieved excellent 5-year survival, and validation of these findings by other groups may change the current exclusion of such patients from transplant programs.

Intrahepatic cholangiocarcinoma or mixed hepatocellular-cholangiocarcinoma in patients undergoing liver transplantation: a Spanish matched cohort multicenter study.

OBJECTIVE: To evaluate the outcome of patients with hepatocellular-cholangiocarcinoma (HCC-CC) or intrahepatic cholangiocarcinoma (I-CC) on pathological examination after liver transplantation for HCC. BACKGROUND: Information on the outcome of cirrhotic patients undergoing a transplant for HCC and with a diagnosis of HCC-CC or I-CC by pathological study is limited. METHODS: Multicenter, retrospective, matched cohort 1:2 study. STUDY GROUP: 42 patients undergoing a transplant for HCC and with a diagnosis of HCC-CC or I-CC by pathological study; and control group: 84 patients with a diagnosis of HCC. I-CC subgroup: 27 patients compared with 54 controls; HCC-CC subgroup: 15 patients compared with 30 controls. Patients were also divided according to the preoperative tumor size and number: uninodular tumors 2 cm or smaller and multinodular or uninodular tumors 2 cm or larger. Median follow-up: 51 (range, 3-142) months. RESULTS: The 1-, 3-, and 5-year actuarial survival rate differed between the study and control groups (83%, 70%, and 60% vs 99%, 94%, and 89%, respectively; P < 0.001). Differences were found in 1-, 3-, and 5-year actuarial survival rates between the I-CC subgroup and their controls (78%, 66%, and 51% vs 100%, 98%, and 93%; P < 0.001), but no differences were observed between the HCC-CC subgroup and their controls (93%, 78%, and 78% vs 97%, 86%, and 86%; P = 0.9). Patients with uninodular tumors 2 cm or smaller in the study and control groups had similar 1-, 3-, and 5-year survival rate (92%, 83%, 62% vs 100%, 80%, 80%; P = 0.4). In contrast, patients in the study group with multinodular or uninodular tumors larger than 2 cm had worse 1-, 3-, and 5-year survival rates than their controls (80%, 66%, and 61% vs 99%, 96%, and 90%; P < 0.001). CONCLUSIONS: Patients with HCC-CC have similar survival to patients undergoing a transplant for HCC. Preoperative diagnosis of HCC-CC should not prompt the exclusion of these patients from transplant option.

Acute retroperitoneal bleeding due to inferior mesenteric artery aneurysm: case report.

BACKGROUND: Visceral artery aneurysms (VAA), although uncommon, are increasingly being detected. We describe a case of spontaneous retroperitoneal hemorrhage from a ruptured IMA aneurysm associated with stenosis of the superior mesenteric artery (SMA) and celiac trunk, successfully treated with surgery. METHODS: A 65-year-old man presented with abdominal pain and hypovolemic shock. Abdominal CT scan showed an aneurysm of the inferior mesenteric artery with retroperitoneal hematoma. In addition, an obstructive disease of the superior mesenteric artery and celiac axis was observed. RESULTS: Upon emergency laparotomy a ruptured inferior mesenteric artery aneurysm was detected. The aneurysm was excised and the artery reconstructed by end-to-end anastomosis. CONCLUSIONS: This report discusses the etiology, presentation, diagnosis and case management of inferior mesenteric artery aneurysms.

Gene expression profiling in liver transplant recipients with alcoholic cirrhosis.

The main objective of this study was to identify differences in gene expression profile using microarray technology in liver transplant recipients with alcoholic cirrhosis before and after liver transplantation. The study was performed in liver transplant recipients with alcoholic cirrhosis (n = 10) and in healthy volunteers (n = 10), as a reference group. Peripheral blood samples were obtained before (T0) and 7 days after liver transplantation (T7d) using tubes with an RNA stabilizer. RNA was purified and quality tested. From each participant in the study, microarrays were done in duplicate using 10 mug of cRNA. After reverse transcription, complementary RNAs were labeled with Cy5 Streptavidine and used for hybridization of 20,000 human genes CodeLink bioarrays (Applied Microarrays, United States) overnight at 37 degrees C. Arrays were read with a laser scanner and quantified and normalized with CodeLink Software 4.2. Liver transplant recipients showed a gene expression profile before transplantation (T0) of 4310 overexpressed genes compared with healthy volunteers, with 407 of these genes increased more than 2-fold (P < .05). After transplantation (T7d), the same group of patients showed a profile of 1011 overexpressed genes compared with T0, with 109 of these genes increased more than 2-fold (P < .05). We determined gene expression profiles in peripheral blood samples obtained before and after liver transplantation, giving a report of array gene expression profiles of peripheral blood samples from each of these patients. One implication of these results is that gene profiling of peripheral blood samples using microarray technology could be used to dynamically monitor the impact and adequacy of immunosuppression in individual patients.

Effect of N-acetylcysteine administration on intraoperative plasma levels of interleukin-4 and interleukin-10 in liver transplant recipients.

We investigated whether intraoperative administration of N-acetylcysteine (NAC) in liver transplant recipients ameliorated their inflammatory responses by increasing intraoperative plasma levels of interleukin (IL)-4 and IL-10. This prospective, randomized, double-blind clinical trial included liver transplant recipients randomly assigned to the NAC-treated (n = 25) or the placebo (n = 25) group. The NAC-treated group received 100 mg/kg dissolved in 5% dextrose over 15 minutes during the anhepatic phase, followed by a continuous infusion of 50 mg/kg in 5% dextrose over the next 24 hours, whereas the placebo group received equal amounts of 5% dextrose solution during the same time. Peripheral blood samples were drawn in EDTA-containing tubes after induction of anesthesia (I-1); at 15 minutes into the anhepatic phase (I-2) prior to the administration of NAC or placebo; at 5 minutes before reperfusion (I-3); at 10 minutes after reperfusion (I-4); at 20 minutes after reperfusion (I-5); at 60 minutes after reperfusion (I-6); and at 1 hour after completion of the liver transplantation (I-7). Cytokine levels were determined using a technique which combined enzyme-linked immunosorbent assay (ELISA) and flow cytometry. Plasma IL-4 levels were significantly higher among the NAC-treated group than the placebo group at I-3 (P = .046) and I-4 (P = .041). Plasma IL-10 levels showed significant enhancement in the NAC-treated group at 5 minutes before reperfusion (I-3; P = .007). We concluded that intraoperative NAC administration during the anhepatic phase of liver transplantation significantly increased recipient IL-4 plasma levels before and after reperfusion, and IL-10 plasma values before reperfusion (I-3). These enhancements seemed to be associated with a protective effect against reperfusion injury.

Study of gene expression profile in liver transplant recipients with hepatitis C virus.

The main objective of this study was to identify differences in gene expression profiles by liver transplant recipients with hepatitis C virus (HCV) using microarray technology before versus after liver transplantation. The study was performed in liver transplant recipients with HCV (n = 6) versus a group of healthy volunteers (n = 6). Peripheral blood samples were obtained before (T0) and 7 days after liver transplantation (T7d) using tubes with an RNA stabilizer. The quality of purified RNA was tested (28S/18S ratio >1.5) in a bioanalyzer. Each participant in the study underwent microarrays in duplicate using 10 mug of complementary RNA. After reverse transcription, cRNAs were labeled with Cy5 Streptavidine. Hybridization of 20000 human genes CodeLink bioarrays (Applied Microarrays, United States) was performed overnight at 37 degrees C. Arrays read with a laser scanner were normalized with CodeLink Software 4.2. At T0, liver transplant recipients showed 116 over-expressed genes when compared with healthy volunteers, who had 33 genes increased >2-fold (P < .05). At T7d after transplantation, the same group of patients showed 613 over-expressed genes compared with T0, of which 97 genes were increased >2-fold (P < .05). We determined gene expression profiles in peripheral blood samples obtained before and after liver transplantation, reporting the array of gene expression profiles in peripheral blood samples from each of these patients classes. One implication of these results is that gene profiling of peripheral blood samples could be used to dynamically monitor the impact and adequacy of immunosuppression in individual patients using microarray technology.

Gallbladder tuberculosis: false-positive PET diagnosis of gallbladder cancer.

Gallbladder tuberculosis (GT) is an extremely rare disease, and very few cases have been reported in the literature. The first case of GT was described in 1870 by Gaucher. A correct preoperative diagnosis of GT is unusual, and it is frequently confused with various gallbladder diseases. We present a new case of a patient who underwent surgery with the preoperative diagnosis of gallbladder cancer after a false positive positron emission tomography scan in the diagnostic work-up.

Early postoperative response of cytokines in liver transplant recipients.

We evaluated the early postoperative response of several cytokines (IL-2, IL-4, IL-6, IL-10, TNF-alpha, IFN-gamma) prior to liver transplantation (T(0)) as well as 1, 6, and 12 hours and 1, 2, 3, 5, and 7 days afterward. Cytokine concentrations were correlated with serum levels of bilirubin as a predictor of postoperative complications. Cytokine levels were determined in plasma samples from 16 liver transplant recipients (13 men, 3 women) aged 43 to 61 years. IL-6 and IL-10 reached their maximum concentrations 1 hour after transplantation. Each increase in IL-6 correlated to a rise in IL-10. IL-2, IL-4, TNF-alpha, and IFN-gamma had a particular time-course for each patient studied. Bilirubin fell to almost normal values but not in cases of postoperative complications, where IL-6 showed values four times higher compared to those of liver transplant recipients who did not show postoperative complications. IL-6 and IL-10 plasma concentrations and serum bilirubin level might be useful as a predictive factor of postoperative complications in liver transplant recipients.

Time course of intraoperative cytokine levels in liver transplant recipients.

We evaluated the levels of several cytokines (interleukin [IL]-2, IL-4, IL-6, IL-10, tumor necrosis factor [TNF]-alpha, and interferon [IFN]-gamma) in plasma samples obtained before surgical intervention (T0) and during intraoperative liver transplantation: after induction of anesthesia (I-1), 15 minutes of anhepatic phase (I-2), 5 minutes before reperfusion (I-3), 10 minutes after reperfusion (I-4), 20 minutes after reperfusion (I-5), 60 minutes after reperfusion (I-6), and 1 hour after liver transplantation (I-7). Cytokine levels were determined using a technique which combines ELISA technique and flow cytometry. The study was approved by the local clinical research (ethics) committee. Written informed consent was obtained from patients' relatives. Twenty patients (14 men, 6 women) aged 23 to 61 years, recipients of a liver transplantation were studied. The cytokine IL-2 plasma values were maintained during the whole study period, with a slight increase at 15 minutes of anhepatic phase (I-2). IL-4 showed a peak value 20 minutes after reperfusion (I-5). IL-6 increased its plasma value starting at 15 minutes of anhepatic phase (I-2), maintaining high concentrations during the whole intraoperative period. IL-10 increased progressively, reaching a maximum 1 hour after transplantation (I-7). TNF-alpha reached maximum plasma levels 20 minutes after reperfusion (I-5), whereas IFN-gamma showed a peak at 15 minutes of anhepatic phase (I-2). Our results indicate that the anhepatic phase (I-2) is the earliest phase during which proinflammatory and anti-inflammatory cytokines, such as IL-6 and IL-10, respectively, are involved during liver transplantation. We conclude that IL-6 is the first cytokine involved in the inflammatory response during liver transplantation.

Indications and therapeutical options in hepatolithiasis.

OBJECTIVE: to present our experience with the treatment of hepatolithiasis. EXPERIMENTAL DESIGN: a retrospective study. Every patient operated on during 2002-2004. RESULTS: mean age was 68.2 years. All patients were male. Two patients had been operated on before. The other three suffered from: monolobar Caroli s disease (1), cholangiocarcinoma (1), and hepatolihtiasis without clear etiologic factors (1). All of them had intrahepatic and extrahepatic litihiasis. Clinical signs included: pain in RUQ, fever, and jaundice. Bilirubin was 3.5 mg/dl (min: 1.7, max: 5.9), GGT: 676.2 IU/l (min: 29, max: 2039), and alkaline phosphatase: 400 IU/l (min: 100, max: 1136). Abdominal ultrasounds always correctly diagnosed HL. CT (3 patients) only diagnosed one case. ERCP (3 patients) and cholangio-MRI (2 patients) always diagnosed HL correctly. Surgical procedures were: hepatojejunostomy with lavage of bile duct (2 cases) and hepatectomy (3 cases) -both right (1) and left (2). We always performed an intraoperative ultrasonography and choledoscopy. Morbidity was: biliary fistula (1 case) treated by percutaneous drainage. No mortality occurred. Median stay was 8.8 days. Mean follow-up is 12 months (min: 11, max: 20). No relapse has been observed. CONCLUSIONS: HL is infrequent in Spain. Surgical treatment, usually liver resection, obtains good results with low morbidity and mortality.

Split for two adults: what is the real feasibility?

INTRODUCTION: A split liver for two adults is a good theoretical option but the number of cases is low. We have tried to assess the feasibility of this technique. MATERIALS AND METHODS: From April 2002 to April 2004, we evaluated 81 donors of which only 59 (72.8%) were used for transplantation of which 10 were grafted in other centers (pediatric or emergency code). Among the 49 donors the criteria for splitting were: ages >14 and <50 years, weight >70 and <100 kg, less than 3 days in the intensive care unit (ICU), hemodynamic stability, Na(+) < 160 mg/L, liver enzymes elevated no more than twofold, no macroscopic steatosis, and procurement in our hospital. RESULTS: The mean donor age was 50.7 years (range: 16 to 77) of whom 25 were men (51%). The mean weight was 65.7 kg (range: 50 to 100) and days of ICU stay, 3 (range: 1 to 23). Six grafts (12%) were split. The reasons for not splitting were: age (n = 26 [53%]), weight (n = 17 [34.7%]), UCI >3 days (n = 9 [18.3%]), Na(+) > 160 (n = 1 [2%]), blood liver test elevated (n = 5 [10.2%]), steatosis (n = 6 [12.2%]), and procurement outside our center (n = 20 [40.8%]). The donors not suitable for splitting had: only one criteria (n = 12 [24.4%]; 2 (n = 23 [46.9%], 3 (n = 6 [12.2%]) or 4 (n = 2 [4.1%]). If we had had two suitable recipients, we could performed six more liver transplantations (12.2% increase). CONCLUSIONS: The theoretical feasibility of a split liver for two adults is 12.2%, but the actual probability is lower because of lack of two adequate candidates.

Time course of antioxidant enzyme activities in liver transplant recipients.

Reactive oxygen species (ROS) play a central role in ischemia-reperfusion injury after organ transplantation. They are degraded by endogenous radical scavengers such as antioxidant enzymes. The purpose of this study was to evaluate the temporal variations of antioxidant enzyme activities in liver transplant recipients. The study was performed in 13 liver transplant patients (11 men and 2 women). Blood samples were obtained pre- and postsurgical intervention: before transplant (T(0)), and 1, 6, 12, 24, 48, and 72 hours, as well as 5 and 7 days thereafter. We determined total and specific superoxide dismutase (SOD) activity, catalase (CAT), glutathione peroxidase (GPX), and glutathione reductase (GR) activities as well as malondialdehyde (MDA) and low-density lipoproteins (LDL). The results showed increased SOD and mainly GPX activities after liver transplantation, which correlated with MDA levels. Total SOD activity was mainly represented by Mn-SOD (75%) and Cu,Zn-SOD (25%), whereas Fe-SOD was not detected. In conclusion, the enhanced antioxidant enzyme activities reported in this study indicated a control of oxidative stress generated in liver transplantation. In this sense, although MDA levels showed an enormeous increase at 1 hour after transplantation, the lipid peroxidation was compensated for by GPX activity.

Postlaparoscopic cholecystectomy bile leak secondary to an accessory duct of Luschka.

Complications produced by the sectioning of a nonvisualized duct of Luschka are uncommon during laparoscopic cholecystectomy. From 1999 through 2003, we performed 1351 laparoscopic cholecystectomies in our department and observed 2 cases (0.15%) of bile leakage due to duct of Luschka injury. Injury during laparoscopic cholecystectomy is usually produced by an excessively deep plane of dissection and by the anatomical localization of this accessory duct. Clinical symptoms are scarce after duct of Luschka injury. Numerous diagnostic methods have been used to detect these injuries. Nevertheless, careful clinical examination is still of the utmost importance. Noninvasive treatments are usually effective. In patients who present with acute abdomen, as in our cases, or who are not cured by noninvasive treatments, exploratory laparotomy is the best approach. The surgical treatment consists of a lavage of the abdominal cavity, closure of the duct of Luschka, and intraoperative cholangiography to confirm that the biliary tree is intact.

Immunosuppression Strategies in the Treatment of Hepatocellular Carcinoma in Virgen de las Nieves University Hospital.

BACKGROUND: We describe an observational, retrospective study that included patients who underwent a liver transplantation (LT) for hepatocellular carcinoma (HCC) in our center between 2004 and 2012. METHODS: Clinical variables were recorded for donors and recipients as diagnosis and treatment, immunosuppressive therapy, toxicity, graft dysfunction, recurrence, and exitus. Fifty-eight patients were analyzed. The mean age was 57 ± 8 years. The viral etiology of HCC was 50% (n = 29), alcoholic 26% (n = 15), and others, 24% (n = 14). Regarding initial immunosuppressive strategy (IS), 51 patients (87.9%) were treated with standard regimen with corticosteroids (CS) and tacrolimus (TA), compared with 7 patients with impaired renal function (12.1%) who underwent a delayed therapy with calcineurin inhibitors (CNI) + mycophenolate mophetil (MMF) + CS. Concomitant use of anti-CD25 monoclonal antibodies was less than 10%. Regarding maintenance, 43 patients (74.1%) were treated with MMF + CNI versus 15 treated only with TA (25.9%). RESULTS: Recurrence of HCC was approximately 12%: 7 patients (2 hepatic only, 5 also extra-hepatic). Exitus was established in 19 patients (32.75%); only 3 patients (5.17%) were attributable to HCC. Bivariate studies were conducted according to the initial IS (standard regimen versus delayed therapy) and maintenance therapy (MMF + TA versus TA alone), with no differences in any of them in recurrence, treatment toxicity, graft rejection, and dysfunction. CONCLUSIONS: In our experience with the IS, we found no differences in the development of recurrent disease, treatment toxicity, development of graft dysfunction, or rejection. We believe that individualized immunosuppressive therapy in these patients is safe and effective.

Retroperitoneal actinomycosis due to dropped gallstones.

Dropped bile and gallstones after accidental perforation of the biliary gallbladder is a frequent event during laparoscopic cholecystectomy and is generally of no clinical importance. However, calculi left in the abdominal cavity can produce a series of severe late complications. We present a patient with retroperitoneal actinomycosis produced by dropped gallstones after a laparoscopic cholecystectomy.

[Total intravenous anesthesia with propofol in orthotopic liver transplantation in swine]. / Anestesia intravenosa total con propofol en el trasplante ortotópico de hígado en cerdos.

OBJECTIVE: To study the use of total intravenous anesthesia with propofol as an anesthetic model for orthotopic liver transplantation (OLT) in pigs. ANIMALS AND METHOD: Fifteen OLT were performed in pigs using portacava-jugular veno-venous shunt with an injector pump. Anesthesia was maintained by perfusion of 10 mg/kg/h propofol. Hemodynamic and biochemical measurements were recorded at the following times: AO, baseline; AI, five minutes before removal of the liver; B1, five minutes later but before starting the bypass injector pump; B2, five minutes after starting the injector pump; B3, five minutes before reperfusion; C1, five minutes after starting reperfusion, and C2, after aortic declamping. RESULTS: No cases of malignant hyperthermia appeared. When the liver was removed cardiac output decreased (p < 0.01), as did mean arterial pressure (p < 0.01), mixed venous saturation (p < 0.05), pulmonary capillary pressure and temperature (p < 0.05). Pulmonary vascular resistances increased (p < 0.05). CONCLUSIONS: The use of total intravenous anesthesia with propofol is a satisfactory experimental anesthetic model for OLT in pigs, and it prevents the possible appearance of malignant hyperthermia.

Experience of the transplant unit from Virgen de las Nieves Hospital in using liver grafts from asystolic donors.

Given the shortage of donors, it has become increasingly necessary to use alternative sources to meet the growing demand for organs, and evolution in the use of asystolic donors is proving to be an important resource in helping to meet those needs. The goal of this study is to describe the initial results of our experience with Type II asystolic donation. An observational retrospective study was conducted to analyze the variables of four cases in this type of donation. After the analysis we conclude that, despite the limited number of cases in our series, the results are compatible with larger series and permit us to continue to value this method as a resource for broadening the donor pool.

Liver transplantation using low-weight recipients from a graft split program.

We present our experience with a split liver (SL) program shared with the children's liver transplantation (LT) program from 2 different hospitals in the use of partial grafts from cadaver donors in brain death. We describe an observational, retrospective study, which included patients who underwent a SL transplantation in our center between January 2006 and December 2012. Clinical variables were recorded of both donors and recipients and their data were analyzed using SPSS 19.0 software. Of a total of 204 LT, 4 (2%) patients were treated with a SL. The causes of LT were alcoholic cirrhosis in 2 cases, cryptogenic cirrhosis, and primary biliary cirrhosis (PBC). In all cases there was a temporary portocaval shunt. The confluence of the hepatic veins of the recipient was anastomosed to the donor vena cava and arterial anastomosis was performed. The reconstruction was hepato-choledochal in all cases. There were no cases of postreperfusion syndrome or vascular thrombosis and no retransplantation was necessary. Currently, 3 of the 4 cases are still alive. Death in the other patient was due to mesenteric ischemia. Our center has participated in the development of a protocol that considers the indication of this technique provided expert groups are involved in its development, regardless of hospital level. This will expand the pool of donors and partially solve the current problems with available grafting.

Perioperative levels of glutathione reductase in liver transplant recipients with hepatitis C virus cirrhosis.

Surgical intervention causes oxidative stress leading to an adaptive responses by the body. To evaluate changes in the defense capacity of antioxidant enzymes, we determined the activity of glutathione reductase (GR) levels among liver transplant recipients with due to hepatitis C virus cirrhosis. The study was performed in 22 patients (16 males and 6 females) of average ages 52.63 ± 5.49 years for males and 59.67 ± 5.65 years for females. Blood samples for glutathione reductase activity were drawn on admission before as well as at 1, 6, and 12 h and 1, 2, 3, 5 and 7 days after the liver transplantation. Perioperative glutathione reductase levels were significant (P = .014) over the period using Bonferroni tests. GR activity reached a maximum (15.6112 ± 6.56035 nmol/mg protein) at 3 days after liver transplantation (T3d) (P = .001). The increased GR activity values detected perioperatively indicated scavenging of reactive oxygen species generated after liver transplantation of hepatitis C virus cirrhosis patients.