"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.

Prediction models of donor arrest and graft utilization in liver transplantation from maastricht-3 donors after circulatory death.

Shortage of organs for transplantation has led to the renewed interest in donation after circulatory-determination of death (DCDD). We conducted a retrospective analysis (2001-2009) and a subsequent prospective validation (2010) of liver Maastricht-Category-3-DCDD and donation-after-brain-death (DBD) offers to our program. Accepted and declined offers were compared. Accepted DCDD offers were divided into donors who went on to cardiac arrest and those who did not. Donors who arrested were divided into those producing grafts that were transplanted or remained unused. Descriptive comparisons and regression analyses were performed to assess predictor models of donor cardiac arrest and graft utilization. Variables from the multivariate analysis were prospectively validated. Of 1579 DCDD offers, 621 were accepted, and of these, 400 experienced cardiac arrest after withdrawal of support. Of these, 173 livers were transplanted. In the DCDD group, donor age < 40 years, use of inotropes and absence of gag/cough reflexes were predictors of cardiac arrest. Donor age >50 years, BMI >30, warm ischemia time >25 minutes, ITU stay >7 days and ALT ≥ 4× normal rates were risk factors for not using the graft. These variables had excellent sensitivity and specificity for the prediction of cardiac arrest (AUROC = 0.835) and graft use (AUROC = 0.748) in the 2010 prospective validation. These models can feasibly predict cardiac arrest in potential DCDDs and graft usability, helping to avoid unnecessary recoveries and healthcare expenditure.

GeConT 2: gene context analysis for orthologous proteins, conserved domains and metabolic pathways.

The Gene Context Tool (GeConT) allows users to visualize the genomic context of a gene or a group of genes and their orthologous relationships within fully sequenced bacterial genomes. The new version of the server incorporates information from the COG, Pfam and KEGG databases, allowing users to have an integrated graphical representation of the function of genes at multiple levels, their phylogenetic distribution and their genomic context. The sequence of any of the genes can be easily retrieved, as well as the 5' or 3' regulatory regions, greatly facilitating further types of analysis. GeConT 2 is available at: http://bioinfo.ibt.unam.mx/gecont.

Planning Generational Change in a Liver Transplant Team.

Liver transplantation (LT) is a demanding and stressful practice. It requires full dedication and great personal sacrifice. It carries with it a long, difficult learning curve. We present the current situation with one LT team and carried out a critical analysis on the current problems in LT units with regard to access to leadership the future generational changes. An LT team has several similarities with a family-owned company. A generation change planning in liver transplantation may address 3 important aspects: the succession of the leader; establishment and reinforcement of the talent pool; and accessibility to the working group. An LT team is manned by highly qualified personnel. The ideal scenario is when the successor surgeon is accepted by every member in a joint agreement; all the surgeons on the team have the potential to be the next team leader; and the working group presents a high level of personal effort and a motivated attitude. There is an ongoing problem in LT units, however-the growing lack of interest from young surgeons to be part of a transplant team. There are many reasons for this, but it primarily involves the high level of dedication required. The formation of a good transplant team, with a pool of high-quality young surgeons and the realization of a proper generational change, could improve its operation and its results in the future.

Laparoscopic Living Donor Hepatectomy for Pediatric Liver Transplantation: the First 7 Cases in Spain.

Herein we report on laparoscopic donor hepatectomy (left lateral sectionectomy) for pediatric living donor liver transplantation by using a pure laparoscopic approach. Seven laparoscopic living donor procedures were performed during the period March 2016 to February 2017 at our institution. The average age of donors was 33.3 years. Preoperative liver function was normal in all donors. Four donors required 1 or more Pringle maneuver(s). The etiology was biliary atresia (n = 3), metabolic disorders (n = 2) (OTC deficiency), Alagille syndrome (n = 1), and neonatal ductopenia (n = 1). The graft was implanted orthotopically in 6 patients; we performed an auxilliary transplantation in a patient with an OTC deficiency. The time of donor surgery was 363 minutes. Dindo-Clavien complications among donors were type I (n = 1), type IIa (n = 1), and type IIb (n = 2). The mean hospital stay for the recipients was 14 days. The mean donor stay was 3.7 days. Perioperative donor and recipient mortality was 0%. Graft survival was 87.5% with 1 graft loss secondary to inadequate venous outflow. In conclusion, we can propose the laparoscopic approach in experienced centers as a "standard of practice" due to its minimal complication rate and short hospital stay.

Use of Peritoneovenous Shunt for the Management of Refractory Ascites.

BACKGROUND: Guidelines for the management of refractory ascites (RA) recommend transjugular intrahepatic portosystemic shunting (TIPS), diuretics, and paracentesis as the main strategies, discouraging use of surgical peritoneovenous shunts (PVSs). However, PVSs, including both Denver (DS) or saphenoperitoneal (SPS) modalities, may still have indications. Herein we report our experience with PVSs in the context of modern surgical and anesthetic management. METHODS: In our unit, PVSs are offered to patients with ascites refractory to diuretics in which TIPS are contraindicated. Heart function and spontaneous bacterial peritonitis must be assessed before surgical indication. RESULTS: Seven procedures were performed on 5 patients (6-DS, 1-SPS) in 2013. Their mean age was 61 (range, 54-68) years. In 3 patients, the indication was RA without options for liver transplant; 2 patients were on the waiting list for liver transplantation, which were performed to improve renal function and quality of life (QOL). The median hospital stay was 6.5 (range, 3-12) days. All patients were alive after 12 months. One patient died 2 years after the first DS and another later died due to liver insufficiency with patency of the DS. The ascites was well-controlled in 4 of 5 patients at up to 48 months of follow-up. Decreases in diuretics doses, proper weight maintenance, and a dramatic improvement in QOL (measured by a modified Ascites Symptom Inventory-7 [ASI-7] test) were observed after the procedures. CONCLUSION: PVSs are useful for the treatment of patients with RA who develop resistance to common therapies, leading to a major improvement in QOL. These surgical procedures should be included in the armamentarium of experienced liver surgeons.

Rescue of Discarded Grafts for Liver Transplantation by Ex Vivo Subnormothermic and Normothermic Oxygenated Machine Perfusion: First Experience in Spain.

BACKGROUND: Ex vivo machine perfusion (MP) has been reported as a possibly method to rescue discarded organs. The main aim of this study was to report an initial experience in Spain using MP for the rescue of severely marginal discarded liver grafts, and to, secondarily, define markers of viability to test the potential applicability of these devices for the real increase in the organ donor pool. METHODS: The study began in January 2016. Discarded grafts were included in a research protocol that consisted of standard retrieval followed by 10 hours of cold ischemia. Next, either normothermic (NMP) or controlled subnormothermic (subNMP) rewarming was chosen randomly. Continuous measurements of portal-arterial pressure and resistance were screened. Lactate, pH, and bicarbonate were measured every 30 minutes. The perfusion period was 6 hours, after which the graft was discarded and evaluated as potentially usable, but never implanted. Biopsies of the donor and at 2, 4, and 6 hours after ex vivo MP were obtained. RESULTS: A total of 4 grafts were included in the protocol. The first 2 grafts were perfused by NMP and grafts 3 and 4 by subNMP. The second and third grafts showed a clear trend toward optimal recovery and may have been used. Lactate dropped to levels below 2.5 mmol/L with stable arterial and portal pressure and resistance. Clear biliary output started during MP. Biopsies showed an improvement of liver architecture with reduced inflammation at the end of the perfusion. CONCLUSION: This preliminary experience has demonstrated the potential of MP devices for the rescue of severely marginal liver grafts. Lactate and biliary output were useful for viability testing of the grafts. The utility of NMP or subNMP protocols requires further research.

Model for end-stage liver disease can predict very early outcome after liver transplantation.

Postoperative Model for End-stage Liver Disease (MELD) values have never been assessed to predict very early (<1 week) death after liver transplantation (OLT). We retrospectively reviewed 275 consecutive OLTs performed in 252 recipients reported in a prospective database. We calculated the MELD score (pre-MELD) and consecutive postoperative MELD (post-MELD) scores computed daily during the first postoperative week and on days 15 and 30 after OLT. Post-MELD scores from nonsurviving recipients displayed on a scatterplot of immediate probability of death were adjusted to the best goodness-of-fit curve, and, finally, depicted graphically as a receiver operating characteristic (ROC) curve. Nonsurviving recipients showed higher post-MELD scores: day 1: 23.5 versus 16.6 (P = .05); day 3: 25.1 versus 12.5 (P = .000); day 5: 25.7 versus 11.8 (P = .000); and day 7: 22.1 versus 10.2 (P = .000). Overall comparisons were performed using a time-dependent general linear regression model, revealing higher post-MELD scores for nonsurviving recipients, irrespective of postoperative time (P = .002). The best goodness-of-fit curve was displayed when adjusting to a theoretical exponential regression curve calculated as follows: Probability of dying within the first week (%) = 3.36 x e(0.079 x (post-MELD)) (r = .89; P = .000). The area under the ROC curve was 0.783 (95% confidence interval, 0.630-0.935; P = .001). The model had a positive predictive value of 82.3%, a negative predictive value of 33.1%, and an accuracy of 79.2%. In conclusion, this study corroborated the suggestion that the MELD score may serve as a reliable tool to assess very early death after OLT.

Factors affecting survival and tumor recurrence in patients transplanted for hepatocellular carcinoma and coexistent hepatitis C virus.

A better understanding of tumor factors influencing patient and graft survival and recurrence of hepatocellular carcinoma (HCC) associated with hepatitis C virus (HCV) cirrhosis may be useful to maximize the benefits of liver transplantation (OLT). Sixty-three adults underwent OLT for end-stage liver disease secondary to HCV with concomitant HCC. The outcome measures were patient and graft survival, as well as recurrence-free survival, computed using a stepwise Cox proportional hazards regression analysis. Kaplan-Meier 1-, 3-, and 5-year patient survival rates were 82%, 80%, and 69%, respectively, they were better for incidentally discovered HCC compared with preoperatively diagnosed HCC (P = .04). The overall recurrence-free survival rates were 81%, 76%, and 61% at 1, 3, and 5 years, respectively. Univariate analysis showed that nonincidental HCC (P = .04), pTNM stage (P = .012) and vascular invasion (P = .003) correlated with recipient mortality. Vascular invasion (odds ratio [OR] = 2.12; P = .001) and pTNM (OR = 1.50; P = .008) were independent predictors of overall survival. A combination of tumor vascular invasion with advanced pTNM was associated with a dismal prognosis (log-rank = 21.89; P = .0001). Tumor grading (OR = 1.2; P = .04), pTNM (OR = 3.7; P = .001) and vascular invasion (OR = 1.6; P = .002) were independent predictors of recurrence. In conclusion, advanced pTNM and the presence of vascular invasion are strong predictors of poor survival and tumor recurrence.

Contribution of marginal donors to liver transplantation for hepatitis C virus infection.

The use of marginal liver donors can affect the outcomes of liver transplantation in patients with hepatitis C virus (HCV) infection. There are no firm conclusions about which donor criteria are important for allocation of high-risk grafts to recipients with HCV cirrhosis. We performed 120 consecutive liver transplantations for HCV infection between 1995 and 2005. Marginal donor criteria were considered to be: age >70 years, macrovesicular steatosis >30%, moderate-to-severe liver preservation injury, high inotropic drug dose (dopamine >15 microg/kg/min; epinephrine, norepinephrine, or dobutamine at any doses), peak serum sodium >155 mEq/L, any hypotensive episode <60 mm Hg and >1 hour, cold ischemia time >12 hours, ICU hospitalization >4 days, bilirubin >2 mg/dL, AST and/or ALT >200 UI/dL. Graft survival with donors showing these marginal criteria was compared with optimal donors using Kaplan-Meier analysis and the log-rank test. Independent predictors of survival were computed with the Cox proportional hazards model. Fifty-six grafts (46%) were lost during follow-up irrespective of the Model for End-Stage Liver Disease (MELD) scores of the recipients in each category. Upon univariate analysis, grafts with moderate-to-severe steatosis (P = .012), those with severe liver preservation injury (P = .007) and prolonged cold ischemia time (P = .0001) showed a dismal prognosis at 1, 3, and 5 years. Upon multivariate analysis, fat content (P = .0076; OR = 4.2) and cold ischemia time >12 hours (P = .034; OR = 7.001) were independent predictors of graft survival. Among HCV recipients, marginal liver donors worked similar to those from "good" donors, except for those with fatty livers >30%, especially when combined with a prolonged cold ischemia time.

Treatment of peritoneal carcinomatosis from ovarian cancer. Present, future directions and proposals.

Peritoneal carcinomatosis, considered years ago as a final stage of unresectable cancer, can now be managed with curative intention by means of a radical cytoreductive surgical procedure with associated peritonectomy and intraperitoneal chemotherapy, as described by Sugarbaker. Malignant neoplasms such as mesothelioma and pseudomyxoma peritonei, ovarian and colon cancer nowadays are experiencing some new therapeutical approaches. Higher survival rates can be reached in ovarian cancer, which is commonly diagnosed in the presence of peritoneal carcinomatosis, using an optimal cytoreductive radical surgery with intraperitoneal chemotherapy. An actualised review of the treatment of advanced ovarian cancer and a proposal of a national multicentre protocol for the treatment of peritoneal carcinomatosis from ovarian cancer has been performed by a group of Spanish surgeons and oncologists dedicated to a therapeutical approach to this pathology.

Optimizing the management of patients with BCLC stage-B hepatocellular carcinoma: Modern surgical resection as a feasible alternative to transarterial chemoemolization.

OBJECTIVE: To analyse the impact of liver resection (LR) in patients with Hepatocellular Carcinoma (HCC) within the Barcelona-Clinic-Liver-Cancer (BCLC)-B stage. METHODS: Analysis of patients with BCLC-B HCC treated with LR or transarterial chemoembolization (TACE) between 2007 and 2012 in our hospital. Survival/recurrence analyses were performed by log-rank tests and Cox multivariate models. Further analyses were specifically obtained for the HCC subclassification (B1-2-3-4) proposed recently. RESULTS: Eighty patients were treated (44-TACE/36-LR). Number of nodules was [1.8(1.1)], being multinodular in 50% of cases. Although resected patients had a higher hospital stay than those who underwent TACE (14 ± 13 vs 7 ± 6; P = 0.004), the rate and severity of complications was lower measured by Dindo-Clavien scale (P < 0.05). Overall survival was 40% with a median follow-up of 29.5 months (0.07-96.9). Five-years survival rates were 62.9%, 28.1% and 15.4%, respectively (P = 0.004) for B1, B2 and B3-4 stages. Cox model showed that only total bilirubin [OR = 2.055(1.23-3.44)] and BCLC subclassification B3-4 [OR = 2.439(1.04-5.7)] and B2 [OR = 2.79(1.35-5.77)] vs B1 were independent predictors of 5-years-survival. In B1 patients, surgical approach led a significant decrease in 5-years recurrence-rate (25% vs 60%; P = 0.018). In the surgical subgroup analysis, better results were observed if well/moderate differentiation combined with no microvascular-invasion (VI) in 5-years-survival (84.6%; P = 0.001) and -recurrence (23.1%; P = 0.041), respectively. These survival and recurrence trends were remarkable in B1 stages. CONCLUSIONS: Management of Intermediate BCLC-B HCC stage should be more complex and include updated criteria regarding B-stage subclassifications, VI and tumour differentiation. Modern surgical resection would offer improved survival benefit with acceptable safety in selected BCLC-B stage patients.

Limits for adult liver donation in Spain.

BACKGROUND: Liver donation is the cornerstone for the expansion of liver transplantation. Although big efforts have been performed to release alternatives for increasing the donor pool, only extended-criteria donors have become a feasible option. METHODS: The success of the Spanish Model for organ transplantation is well known. Approximately 5.4% of all the liver transplants (LT) are performed in Spain, with a rate of 22.9 LT per million people (pmp). RESULTS: Approximately 70 papers on extended-criteria donors have been reported from Spanish LT teams. Pioneering works in donor steatosis, non-heart-beating donors, donor age-hepatitis C virus, ischemia/reperfusion injury, normothermic extracorporeal membrane oxygenation, and donor steatosis-hepatitis C virus are among the main contributions in the field. Considering data from the Spanish National Registry, it can be observed that an accumulation of donor and recipient factors leads to a continuum of risk for liver transplantation. Donors are not "bad" enough to decline a liver offer per se. CONCLUSIONS: In Spain, clear efforts should be made to work on more stable and homogeneous criteria for donor acceptance. In this sense, defining a specific Spanish donor risk index would be helpful.

Donation after cardiac death: where, when, and how?

The continuing shortage of donors has led to the increasing use of marginal grafts. Surgical techniques such as split, domino, and living donations have not been able to decrease waiting list mortality. Donation after cardiac death (DCD) was the only source of grafts prior to the establishment of brain death criteria in 1968. Thereafter, donation after brain death emerged as the leading source of grafts. The context in which irreversible cessation of circulatory and respiratory functions happens was the cornerstone to definite the four categories of DCD by the First International Workshop on DCD held in Maastricht in 1995. Controlled (CDCD) and uncontrolled (UDCD) categories now account for 10%-20% of the donor pool in several countries. Despite initial high rates of primary nonfunction and ischemic-type biliary lesions, refinements in protocols and surgical techniques have led to excellent 1- and 3-year graft survivals of 80% and 70%, respectively with PNF and ITBL rates below 3%. The institution of UDCD and CDCD depends on legal considerations of presumed consent and withdrawal of maneuvers, respectively. The potential for DCD programs is huge; it may be the only real, effective way to increase the grafts pool, both in adult and pediatric populations. Recent advances in perfusion machines will surely optimize this donor pool and allow new therapies for graft resuscitation.

Early graft dysfunction after liver transplantation.

Liver transplantation has become the treatment of choice for fulminant hepatic failure and end-stage liver diseases. Several factors have been described to be predictors of graft function. Since early graft dysfunction dramatically influences graft and patient outcomes after liver transplantation, prevention of this event is mandatory. Donor-, procurement-, operative- and recipient-related factors influence the development of graft dysfunction. We have presented herein a review of the impact of these factors on graft dysfunction.

Establishment of a pediatric liver transplantation program: experience with 100 transplantation procedures.

OBJECTIVE: To analyze the primary factors that influence the development and consolidation of a pediatric liver transplantation program. PATIENTS AND METHODS: This was a retrospective study of 100 liver transplantation procedures performed in 84 pediatric patients between May 1990 and November 2007. The male-female ratio was 40:60. Mean (SD) age was 5 years (40 patients were younger than 2 years); cold ischemia time was 7.10 (3.1) hours; surgery time was 5.2 (2.2) hours; and time on the waiting list for transplantation was 75 (range, 1-1012) days. Indications for transplantation included cholestatic disease (43%), acute hepatic failure (AHF; 34%), metabolic disorders (14%), and cirrhosis (9%). Transplanted organs included 3 split grafts, 29 partial grafts, and 8 living-donor grafts. RESULTS: Mean graft survival was 70.4%, 59.2%, and 58.1% at 1, 3, and 5 years, respectively. Factors that influenced graft outcome were age younger than 2 years; surgery time more than 6 hours; and AHF vs cholestatic disease, metabolic disorders, and cirrhosis. There were no significant differences in long-term (51% vs 59%) and short-term (71% vs 70%) graft survival between procedures performed in 1990-1998 compared with those performed in 1999-2007; however, there was a higher percentage (P = .005) of recipients at high risk (age younger than 2 years or with AHF) in the later period. All data were consistent with those of the European Liver Transplant Registry 2007. CONCLUSIONS: A pediatric liver transplantation program can be established by a group experienced in liver transplantation.

GeConT: gene context analysis.

SUMMARY: The fact that adjacent genes in bacteria are often functionally related is widely known. GeConT (Gene Context Tool) is a web interface designed to visualize genome context of a gene or a group of genes and their orthologs in all the completely sequenced genomes. The graphical information of GeConT can be used to analyze genome annotation, functional ortholog identification or to verify the genomic context congruence of any set of genes that share a common property. AVAILABILITY: http://www.ibt.unam.mx/biocomputo/gecont.html