Teresa Serrano

Resection or transplantation for hepatocellular carcinoma in cirrhotic patients: outcomes based on indicated treatment strategy

BACKGROUND Surgical resection has been the treatment of choice for hepatocellular carcinoma (HCC), but the resection rate remains low in cirrhotic patients and recurrence is common. Unfavorable results compared with benign disease and the shortage of organ donors have led to a restricted indication for orthotopic liver transplantation (OLT) for HCC. STUDY DESIGN The aim of this study was to analyze the results of our surgical approach to HCC in patients with cirrhosis. The first treatment strategy indicated in these patients was OLT. From January 1990 to May 1999, 85 patients underwent OLT and the remaining 35 had surgical resection. RESULTS One-, 3-, and 5-year survival rates were 84%, 74%, and 60% versus 83%, 57%, and 51%, respectively, in the OLT and resection groups (p = 0.34). Hepatic tumor recurrence was much less frequent in the OLT group than in the resection group. The 1-, 3-, and 5-year disease-free survival rates were 83%, 72%, and 60% versus 70%, 44%, and 31%, respectively (p = 0.027). In the multivariate Cox regression analysis, macroscopic vascular invasion was the only factor independently associated with death or recurrence after OLT (p = 0.006). After partial liver resection, the tumors significantly associated with mortality and recurrence in the multivariate analysis were solitary or multiple tumors greater than 2cm with microscopic vascular invasion (pathologic pT3) (p = 0.01). CONCLUSIONS Our results confirm that in cirrhotic patients, OLT may provide better outcomes than liver resection in carefully selected HCC and that longterm survival is similar to the results of OLT in cirrhotic patients without tumors.

Application of fibrin glue sealant after hepatectomy does not seem justified: results of a randomized study in 300 patients.

Objective:To evaluate the efficacy, amount of hemorrhage, biliary leakage, complications, and postoperative evolution after fibrin glue sealant application in patients undergoing liver resection. Summary Background Data:Fibrin sealants have become popular as a means of improving perioperative hemostasis and reducing biliary leakage after liver surgery. However, trials regarding its use in liver surgery remain limited and of poor methodologic quality. Patients and Methods:A total of 300 patients undergoing hepatic resection were randomly assigned to fibrin glue application or control groups. Characteristics and debit of drainage and postoperative complications were evaluated. The amount of blood loss, measurements of hematologic parameters liver test, and postoperative evolution (particularly involving biliary fistula and morbidity) was also recorded. Results:Postoperatively, no differences were observed in the amount of transfusion (0.15 ± 0.66 vs. 0.17 ± 0.63 PRCU; P = 0.7234) or in the patients that required transfusion (18% vs. 12%; P = 0.2), respectively, for the fibrin glue or control group. There were no differences in overall drainage volumes (1180 ± 2528 vs. 960 ± 1253 mL) or in days of postoperative drainage (7.9 ± 5 vs. 7.1 ± 4.7). Incidence of biliary fistula was similar in the fibrin glue and control groups, (10% vs. 11%). There were no differences regarding postoperative morbidity between groups (23% vs. 23%; P = 1). Conclusions:Application of fibrin sealant in the raw surface of the liver does not seem justified. Blood loss, transfusion, incidence of biliary fistula, and outcome are comparable to patients without fibrin glue. Therefore, discontinuation of routine use of fibrin sealant would result in significant cost saving.

Efficacy of interferon for chronic hepatitis C virus–related hepatitis in kidney transplant candidates on hemodialysis: results after transplantation

OBJECTIVES:Interferon-α (IFN) may have undesirable effects on a functioning graft. The aim of this study was to evaluate IFN treatment in kidney transplant candidates during the hemodialysis period as well as the results after transplantation.METHODS:A total of 29 noncirrhotic hemodialysis patients with chronic hepatitis C virus (HCV) infection (based on long-term rise in ALT, HCV serology, HCV RNA by polymerase chain reaction methods, and histological evidence) were included. Tolerability to IFN treatment, pre- and posttransplantation therapeutic results, and long-term outcome were recorded. IFN regimen consisted of 3 million units (MU) times per week after hemodialysis sessions for 6 months, followed by 1.5 MU after each hemodialysis session for an additional 6 months. All patients gave informed consent for participation.RESULTS:IFN therapy was fairly well tolerated. Adverse effects due to IFN toxicity, renal disease, or causes related to the immunological properties of IFN were observed in 24% of patients. At the end of treatment, ALT had normalized in 23/28 patients (82.1%), and HCV RNA had cleared in 23/28 patients (82.1%). During follow-up, HCV RNA was persistently negative in 18 patients (64%, including transplant recipients). A total of 14 patients (nine HCV RNA–negative) received a kidney transplant. Mean follow-up after the procedure was 41 ± 28 months. In all, 12 patients had a functioning graft, one had acute vascular rejection, and one died of carcinoma. All transplanted patients maintained normal ALT levels, and eight remained HCV RNA–negative.CONCLUSIONS:Treatment results in our study population were better than those observed in the general population. The long-term response achieved, which was maintained after transplantation, supports the use of IFN for HCV hepatitis in kidney transplant candidates under hemodialysis.

Overactivation of the TGF‐β pathway confers a mesenchymal‐like phenotype and CXCR4‐dependent migratory properties to liver tumor cells

Transforming growth factor‐beta (TGF‐β) is an important regulatory suppressor factor in hepatocytes. However, liver tumor cells develop mechanisms to overcome its suppressor effects and respond to this cytokine by inducing other processes, such as the epithelial‐mesenchymal transition (EMT), which contributes to tumor progression and dissemination. Recent studies have placed chemokines and their receptors at the center not only of physiological cell migration but also of pathological processes, such as metastasis in cancer. In particular, CXCR4 and its ligand, stromal cell‐derived factor 1α (SDF‐1α) / chemokine (C‐X‐C motif) ligand 12 (CXCL12) have been revealed as regulatory molecules involved in the spreading and progression of a variety of tumors. Here we show that autocrine stimulation of TGF‐β in human liver tumor cells correlates with a mesenchymal‐like phenotype, resistance to TGF‐β‐induced suppressor effects, and high expression of CXCR4, which is required for TGF‐β‐induced cell migration. Silencing of the TGF‐β receptor1 (TGFBR1), or its specific inhibition, recovered the epithelial phenotype and attenuated CXCR4 expression, inhibiting cell migratory capacity. In an experimental mouse model of hepatocarcinogenesis (diethylnitrosamine‐induced), tumors showed increased activation of the TGF‐β pathway and enhanced CXCR4 levels. In human hepatocellular carcinoma tumors, high levels of CXCR4 always correlated with activation of the TGF‐β pathway, a less differentiated phenotype, and a cirrhotic background. CXCR4 concentrated at the tumor border and perivascular areas, suggesting its potential involvement in tumor cell dissemination. Conclusion: A crosstalk exists among the TGF‐β and CXCR4 pathways in liver tumors, reflecting a novel molecular mechanism that explains the protumorigenic effects of TGF‐β and opens new perspectives for tumor therapy. (Hepatology 2013; 58:2032–2044)

Impact of immunosuppression without steroids on rejection and hepatitis C virus evolution after liver transplantation: Results of a prospective randomized study

The purpose of this study was to evaluate the influence of a steroid‐free immunosuppression on hepatitis C virus (HCV) recurrence. A total of 198 liver transplantation (LT) patients were randomized to receive immunosuppression with basiliximab and cyclosporine, either with prednisone (steroid [St] group) or without prednisone (no steroids [NoSt] group). The group of 89 HCV‐infected patients was followed up with protocol biopsies for 2 years after LT. This group of HCV patients are the patients evaluated in the present study. The rejection rate was 19% (St: 21% versus NoSt: 17%; P = 0.67). Patients in the St group had a slightly higher rate of bacterial infections (59% versus 38%; P = 0.05). Almost all patients had histological HCV‐recurrence (St: 39/40 (97%) versus NoSt: 40/41 (97%); P = 1). The percentage of accumulated biopsies with grade 4 portal inflammation at 6 months, 1 year, and 2 years were, 23%, 49%, and 49% in the NoSt group, compared to 33%, 55%, and 69% in the St group, respectively (P = 0.04 at 2 years). The percentage of accumulated biopsies with grade 3 or 4 fibrosis at 6 months, 1 year, and 2 years were 0%, 8%, and 22% in the NoSt group, compared to 8%, 19%, and 31% in the St group, respectively. Immunosuppression without steroids in HCV patients is safe, reduces bacterial infections and metabolic complications, and improves histological short‐term evolution of HCV recurrence. Liver Transpl 14:1752–1760, 2008.

Transcatheter Arterial Chemoembolization in Patients with Hepatocellular Carcinoma on the Waiting List for Orthotopic Liver Transplantation

OBJECTIVE The objective of this study was to perform a retrospective analysis of patients with hepatocellular carcinoma (HCC) who underwent transcatheter arterial chemoembolization (TACE) before undergoing liver transplantation at our institution. SUBJECTS AND METHODS From January 2000 to August 2005, 56 patients with HCC underwent TACE before orthotopic liver transplantation (OLT). Radiologic findings before and after TACE were assessed and correlated with histologic findings after OLT. The area of induced necrosis was pathologically evaluated in each HCC nodule. RESULTS One hundred thirty-one HCC nodules were detected at histologic study. One hundred seventeen HCC nodules (91.4%) were hyperenhancing in the arterial phase on the preoperative imaging studies. The percentage of tumor necrosis was greater than 90% in 48 nodules (38%), between 50% and 90% in 19 nodules (15%), and less than 50% in 61 nodules (48%); tumor necrosis data were not recorded for the remaining three nodules. The size of the preoperatively detected lesions ranged from 0.2 to 9 cm (mean, 2.58 cm). The mean percentage of tumor necrosis was 67.8% in this group, but it rose to 79.2% in the hypervascular lesions. The size of the nodules that were not detected preoperatively ranged from 0.1 to 1.9 cm (mean, 0.68 cm), and the mean percentage of tumor necrosis was only 1.57%. CONCLUSION TACE is a safe treatment in well-selected patients. Its antitumoral effect is high in hypervascular lesions (mean necrosis, 79.2%). It provides good local control in preoperatively diagnosed HCC (mean necrosis, 67.8%), but its impact is limited in lesions not detected preoperatively (mean necrosis, 1.57%).

Metronomic chemotherapy following the maximum tolerated dose is an effective anti-tumour therapy affecting angiogenesis, tumour dissemination and cancer stem cells.

In this article, the effectiveness of a multi‐targeted chemo‐switch (C‐S) schedule that combines metronomic chemotherapy (MET) after treatment with the maximum tolerated dose (MTD) is reported. This schedule was tested with gemcitabine in two distinct human pancreatic adenocarcinoma orthotopic models and with cyclophosphamide in an orthotopic ovarian cancer model. In both models, the C‐S schedule had the most favourable effect, achieving at least 80% tumour growth inhibition without increased toxicity. Moreover, in the pancreatic cancer model, although peritoneal metastases were observed in control and MTD groups, no dissemination was observed in the MET and C‐S groups. C‐S treatment caused a decrease in angiogenesis, and its effect on tumour growth was similar to that produced by the MTD followed by anti‐angiogenic DC101 treatment. C‐S treatment combined an increase in thrombospondin‐1 expression with a decrease in the number of CD133+ cancer cells and triple‐positive CD133+/CD44+/CD24+ cancer stem cells (CSCs). These findings confirm that the C‐S schedule is a challenging clinical strategy with demonstrable inhibitory effects on tumour dissemination, angiogenesis and CSCs.

Equipamiento, experiencia mínima y estándares en la cirugía hepatobiliopancreática (HBP)

Resumen En la cirugia del higado, pancreas y vias biliares hay ciertos tipos de procedimientos quirurgicos como la hepatectomia y duodenopancreatectomia que se asocian a gran morbilidad y mortalidad. Es importante establecer equipamientos, experiencia y unos estandares minimos aceptables La optimizacion de la tecnica radiologica (tomografia computarizada y resonancia magnetica) con adquisicion multifasica e inyeccion de dosis adecuadas de contraste es basica para obtener exploraciones de calidad que permitan un diagnostico certero La ecografia intraoperatoria se ha convertido en una pieza imprescindible en la cirugia del higado. El uso del bisturi ultrasonico en la transeccion hepatica ha demostrado que disminuye significativamente la hemorragia. Para la hemostasia parenquimatosa es muy util el coagulador de argon. Cuando los pacientes con tumores del higado no son candidatos a exeresis quirurgica, la destruccion por radiofrecuencia o crioterapia es otra alternativa de la que se debe disponer La mortalidad de la hepatectomia mayor debe ser inferior al 5% y la morbilidad inferior al 30%. En el hepatocarcinoma sobre higado cirrotico la supervivencia a los 5 anos debe ser superior al 50%, en las metastasis hepaticas superior al 30% y en el colangiocarcinoma hiliar superior al 20% En cirugia pancreatica se debe aceptar en general una mortalidad inferior al 10%. La morbilidad debe ser inferior al 50%. La supervivencia a los 5 anos es mejor para los ampulomas e inferior para el carcinoma de pancreas, pero como media debe ser superior al 30% Un centro de referencia deberia realizar como minimo 50 hepatectomias anuales y 24 duodenopancreatectomias anuales

Análisis de 500 trasplantes hepáticos en el Hospital de Bellvitge

Fundamento Se presenta la experiencia del programa de trasplante hepatico del Hospital de Bellvitge en 500 trasplantes realizados durante 15 anos, con el objetivo de poner de manifiesto los cambios que se han producido y exponer los resultados a largo plazo de esta terapeutica. Pacientes y metodo Se consideraron y compararon 5 grupos de 100 trasplantes consecutivos (I-V). Resultados Las indicaciones mas frecuentes fueron el hepatocarcinoma (23%), la cirrosis alcoholica (22,8%) y la hepatopatia cronica por virus C (18,8%). En 59 pacientes se llevaron a cabo 65 retrasplantes (13%), cuyas indicaciones mas frecuentes fueron la trombosis arterial (13 pacientes) y el fallo primario del injerto (10 pacientes). En 19 enfermos se realizo un trasplante combinado hepatorrenal. La causa mas frecuente de muerte del donante en el grupo I fueron los traumatismos craneales (80%), mientras que en el grupo V fue la enfermedad vascular (52%). Otras diferencias significativas entre estos grupos se observan en la proporcion de pacientes en estadio 2 y 3 de la clasificacion UNOS (el 45 frente al 19%), en el consumo de hemoderivados (29,6 [26] frente a 4,6 [5,3] concentrados de hematies), en la frecuencia de reintervenciones por hemoperitoneo (el 22 frente al 5%), en la estancia en UCI (13 [13] frente a 7,4 [11] dias) y en el hospital 40 [52] frente a 23,7 [17] dias), y en la incidencia de rechazo (el 46 frente al 20%) y de fallo primario del injerto (el 9 frente al 3%). Sin embargo, la prevalencia de infeccion (el 48 frente al 54,5%) y la incidencia de complicaciones biliares (el 26 frente al 20%) no han presentado variaciones significativas. La supervivencia actuarial de los pacientes trasplantados desde 1990 es del 83 y del 70% al ano y a los 5 anos, respectivamente. Conclusiones Se observa una mejoria notable y progresiva de los resultados del trasplante hepatico. Sin embargo, los tumores de novo, la recidiva de la hepatitis por virus C y el rechazo cronico pueden limitar los resultados a largo plazo.

Liver transplantation without steroid induction in HIV-infected patients.

Until recently, human immunodeficiency virus (HIV) infection was considered an absolute contraindication for liver transplantation in Spain. We present the first 4 cases of liver transplantation (LT) carried out in our center in patients infected with HIV and coinfected by the hepatitis C virus (HCV), immunosuppressed with cyclosporine A (CyA) and basiliximab, but without steroids. The 4 patients were male, with a mean age of 38.25 ± 4.5 years. Mean time of HIV infection was 114 ± 62.3 months and all patients were receiving highly active antiretroviral therapy (HAART). HCV genotypes of the 4 patients were 4, 1b, 1b, and 1a. Two patients were classified as Child‐Turcotte‐Pugh C (10 and 11 points), 1 was B (8 points), and the patient with hepatocellular carcinoma was A (5 points). Immunosuppression consisted of basiliximab and monotherapy with CyA. There were no postoperative infections. With a follow‐up of 17 ± 8 months, all patients are alive. There was only 1 acute rejection episode, and this was solved with steroid pulses. Three patients showed HCV recurrence with enzymatic and histological changes and were treated with interferon and ribavirin. One patient had negative HCV–ribonucleic acid after 6 months of treatment. In conclusion, HIV infection should not be considered an absolute contraindication for liver transplantation. The evolution of this type of patients will probably depend on the HCV infection. Immunosuppression without steroids may reduce opportunistic infection. (Liver Transpl 2004;10:1320–1323.)