Differences in the incidence and clinical evolution of early neurotoxicity after liver transplantation based on tacrolimus formulation used in the immunosuppressive induction protocol.

INTRODUCTION: Posttransplant early calcineurin inhibitor (CNI)-induced neurotoxicity (ECIIN) was related to high CNI levels, among other factors. Minimizing exposure could modify its incidence or clinical evolution. OBJECTIVE: To compare the incidence, predisposing factors, and clinical evolution of ECIIN after immunosuppressive induction with low-dose tacrolimus-MR (Advagraf) or conventional dose tacrolimus (Prograf). PATIENTS AND METHODS: We matched 71 patients treated with an immunosuppression induction schedule with basiliximab and low doses of Advagraf (cases group) 1:1 by recipient age and indication for liver transplantation (OLT) with patients treated with a conventional tacrolimus regimen (control group). Baseline characteristics, liver and kidney function, operative technical characteristics, kidney function, and C0 tacrolimus levels at several time points after liver OLT were analyzed. RESULTS: There were 31 cases of ECIIN (21%), 14 in the cases group (20%) and 17 in the control group (24%; P < .001). The incidence of ECIIN was higher in alcoholic liver disease (odds ratio [OR], 8.2; 95% CI, 2.3-28.6; P < .001) and past history of encephalopathy (OR, 2.6; 95% CI, 1.16-5.9; P < .02). Among cases, the incidence of ECIIN was higher when encephalopathy signs were present at time of transplantation (36% vs 12%; P < .001). Control of ECIIN required a switch to cyclosporine therapy in all those in the cases group, whereas this was only needed for 9 cases in the control group (47%; P < .001). CONCLUSION: In this study, although the incidence rate of neurotoxicity induced by Advagraf was lower than the induced by Prograf, it did not respond to routine treatment and required a significantly higher rate of switch to cyclosporine for its control.

"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.

Late recurrence of hepatocellular carcinoma after liver transplantation: is an active surveillance for recurrence needed?

INTRODUCTION: Liver transplantation (OLT) is considered the most efficient therapeutic option for patients with liver cirrhosis and early stage hepatocellular carcinoma (HCC) in terms of overall survival and recurrence rates, when restrictive selection criteria are applied. Nevertheless, tumor recurrence may occur in 3.5% to 21% of recipients. It usually occurs within 2 years following OLT, having a major negative impact on prognosis. The efficacy of active posttransplantation surveillance for recurrence has not been demonstrated, due to the poor prognosis of recipients with recurrences. AIM: To analyze the clinical, pathological, and prognostic consequences of late recurrence (>5 years after OLT). METHOD: We analyzed the clinical records of 165 HCC patients including 142 males of overall mean age of 58 ± 6.9 years who underwent OLT between July 1994 and August 2011. RESULTS: Overall survival was 84%, 76%, 66.8%, and 57% at 1, 3, 5, and 10 years, respectively. Tumor recurrence, which was observed in 18 (10.9%) recipients, was a major predictive factor for survival: its rates were 72.2%, 53.3%, 26.7%, and 10% at 1, 3, 5, and 10 years, respectively. HCC recurrence was detected in 77.8% of patients within the first 3 years after OLT. Three recipients (100% males, aged 54-60 years) showed late recurrences after 7, 9, and 10 years. In only one case were Milan criteria surpassed after the examination of explanted liver; no vascular invasion was detected in any case. Recurrence sites were peritoneal, intrahepatic, and subcutaneous abdominal wall tissue. In all cases, immunosuppression was switched from a calcineurin-inhibitor to a mammalian target of rapamycin inhibitor. We surgically resected the extrahepatic recurrences. The remaining recipient was treated with transarterial chemoembolization with doxorubicin-eluting beads and sorafenib. Prognosis after diagnosis of recurrence was poor with median a survival of 278 days (range, 114-704). CONCLUSIONS: Global survival, recurrence rate, and pattern of recurrence were similar to previously reported data. Nevertheless, in three patients recurrence was diagnosed >5 years after OLT. Although recurrence was limited and surgically removed in two cases, disease-free survival was poor. Thus, prolonged active surveillance for HCC recurrence beyond 5 years after OLT may be not useful to provide a survival benefit for these patients.

Calcineurin inhibitors in liver transplantation: to be or not to be.

Orthotopic liver transplantation is currently the procedure of choice for patients with end-stage liver disease, with survival rates greater than 90% and 80% at 1 and 5 years, respectively. These excellent results are largely due to knowledge of the natural history of liver diseases, improved surgical techniques and postoperative management of recipients, and availability of active antibacterial, antiviral, and antifungal drugs, as well as the development and application of potent immunosuppressive drugs. The introduction of calcineurin inhibitors (CNI)-cyclosporine and tacrolimus-has been one of the most important advances in solid-organ transplantation. Nevertheless, the survivals have been impaired by an increasing prevalence and long-term consequences of drug-related cardiovascular diseases, de novo neoplasias, recurrence of both viral and tumor diseases, and posttransplant renal dysfunction. Strategies for immunosuppression include the design of individualized protocols with the objective to increase immunologic efficacy with a reduced number and severity of secondary effects, according to the clinical status and the posttransplant complications: renal failure, de novo neoplasia, recurrent hepatocellular carcinoma. In this setting, new immnunosuppressive protocols have been investigated to include reduction in or withdrawal of CNI.

Strategies of immunosuppression for liver transplant recipients with hepatocellular carcinoma.

Liver transplantation is considered to be the most efficient therapeutic option for patients with liver cirrhosis and early stage hepatocellular carcinoma (HCC) in terms of overall survival and recurrence rate. The application of restrictive selection criteria based on tumor size and number of nodules is advised to obtain optimal results. Nevertheless, tumor recurrence occurs in 3.5% to 21% of recipients, despite careful pretransplant staging and patient selection. Post transplant recurrence of hepatocarcinoma clearly has a major negative impact on prognosis. Intuitively, an immunosupressed state is undesirable in cancer patients. Inversely, modulation or minimization of immunosuppressive therapy could influence tumor progression and reduce the negative impact of recurrence on posttransplant survival. Experimental evidence shows that mammalian target of rapamycin (mTOR) inhibitors have antiangiogenic and antiproliferative effects. Thus, their application has been proposed as antineoplastic agents for immunosuppressive protocols in liver transplant recipients with HCC and may reduce the rate or the impact of tumor recurrence. Clinical data about efficacy and safety of mTOR-based immunosuppressant protocols in liver transplant recipients with HCC show promising results, namely low recurrence and higher survival rates compared with standard calcineurin inhibitor-based immunosuppressive protocols, even among patients with extended morphological criteria. The safety profile is regarded generally as adequate.

Viral and host factors related with histopathologic activity in patients with chronic hepatitis B and moderate or intermittently elevated alanine aminotransferase levels.

OBJECTIVE: viral and host factors are related with progression of pathological lesion in chronic hepatitis B. We analyzed these factors in patients with moderate or intermittently elevated ALT levels, and its threshold that determinate significant histological activity. PATIENTS AND METHODS: retrospective analyses of viral and host parameters in 89 consecutive chronic hepatitis B patients biopsied because of moderate or intermittently elevated ALT levels [1-2 x ULN (ULN = 39 IU/ml)] and/or DNA-HBV > 2 x 10³ IU/ml in AntiHBe+ patients. It was analyzed age, gender, ALT levels, HBeAg, viral load and genotype. It was considered advanced histological lesion a Knodell Score (KS) > 7 and histological lesion indicating treatment, lobular inflammation ≥2 or fibrosis ≥2 according to Scheuer Classification. RESULTS: KS > 7 and histological lesion indicating treatment was found in 47.8 and 60.7% respectively. It was observed relationship between age, male gender, ALT levels and viral load with histological damage (p < 0.05). Frequency of advanced lesion indicating treatment was upper in patients with ALT levels > ULN (69.1 vs. 47.1%, p = 0.04). There were not significant upper frequencies of advanced lesion when a cut-off of 40 years or DNA-HBV > 2 x 10³ IU/ml viral load or serological status HBeAg was considerate. Histological activity was lesser in genotype D patients than those infected with others genotypes (p < 0.05). CONCLUSION: upper frequency of advanced histological lesion in chronic hepatitis B patients with moderate or intermittently elevated ALT levels make recommended liver biopsy, independent of viral load and serological status HBeAg. Other factors like age, gender or genotype can help to indicate biopsy in individual cases.

Influencia de factores virales y del huésped en la actividad histológica en pacientes con hepatitis crónica por virus de la hepatitis B y elevación moderada o intermitente de alanina aminotransferasa / No disponible

Objetivo: analizar factores virales y del huésped relacionados con actividad histológica en un subgrupo de pacientes con hepatitis crónica B y elevación intermitente o moderada de alanina aminotransferasa (ALT), y el umbral que determine daño histológico indicativo de tratamiento. Pacientes y métodos: análisis retrospectivo de parámetros virales y del huésped en 89 pacientes con hepatitis crónica B biopsiados consecutivamente por elevación intermitente o moderada de ALT [1-2 x USN (USN = 39 UI/ml)]. Fueron analizados edad, sexo, ALT, HBeAg, carga viral y genotipo. Se consideró como lesion histológica avanzada un Índice de Knodell (IK) > 7, e indicativa de tratamiento la inflamación lobulillar ≥ 2 o fibrosis ≥ 2 según la clasificación de Scheuer. Resultados: existió un IK > 7 y lesión indicativa de tratamiento en 47,8 y 60,7%, respectivamente. La edad, sexo varón, ALT y carga viral se relacionaron con lesión avanzada (p < 0,05). La frecuencia de lesión indicativa de tratamiento fue mayor en pacientes con ALT > USN (69,1 vs. 47,1%, p = 0,04). La frecuencia de lesión avanzada no fue significativamente mayor cuando se consideraron como puntos de corte la edad de 40 años o ADNVHB > 2 x 103 UI/ml o positividad de HBeAg. Se observó menor actividad histológica en pacientes con genotipo D respecto a aquellos infectados con otros genotipos (p < 0,05). Conclusión: una mayor frecuencia de lesión avanzada en pacientes con hepatitis crónica B y elevación intermitente o moderada de ALT hacen recomendable la biopsia hepática independientemente de la carga viral y positividad de HBeAg. Factores como la edad, sexo o genotipo pueden ayudar de forma individual a dicha indicación(AU)

Objective: viral and host factors are related with progression of pathological lesion in chronic hepatitis B. We analyzed these factors in patients with moderate or intermittently elevated ALT levels, and its threshold that determinate significant histological activity. Patients and methods: retrospective analyses of viral and host parameters in 89 consecutive chronic hepatitis B patients biopsied because of moderate or intermittently elevated ALT levels [1-2 x ULN (ULN = 39 IU/ml)] and/or DNA-HBV > 2 x 103 IU/ml in AntiHBe+ patients. It was analyzed age, gender, ALT levels, HBeAg, viral load and genotype. It was considered advanced histological lesion a Knodell Score (KS) > 7 and histological lesion indicating treatment, lobular inflammation ≥ 2 or fibrosis ≥ 2 according to Scheuer Classification. Results: KS > 7 and histological lesion indicating treatment was found in 47.8 and 60.7% respectively. It was observed relationship between age, male gender, ALT levels and viral load with histological damage (p < 0.05). Frequency of advanced lesion indicating treatment was upper in patients with ALT levels > ULN (69.1 vs. 47.1%, p = 0.04). There were not significant upper frequencies of advanced lesion when a cut-off of 40 years or DNAHBV > 2 x 103 IU/ml viral load or serological status HBeAg was considerate. Histological activity was lesser in genotype D patients than those infected with others genotypes (p < 0.05). Conclusion: upper frequency of advanced histological lesion in chronic hepatitis B patients with moderate or intermittently elevated ALT levels make recommended liver biopsy, independent of viral load and serological status HBeAg. Other factors like age, gender or genotype can help to indicate biopsy in individual cases(AU)

The future of liver transplantation.

Liver transplantation has been a positive impact on both the survival and the quality of life of patients with advanced liver diseases. Progressive, spectacular improvements in the results of liver transplantation have been observed since the preliminary studies by Thomas Starzl in the United States and Roy Calne in Europe. This improvement is related to better knowledge of the natural history of liver diseases, allowing more adequate recipient selection, improvement of surgical techniques, progress in postoperative management, availability of potent antibacterial, antiviral, and antifungal drugs, as well as introduction of new immunosuppressive agents and protocols. These advances have occurred in the short interval of 45 years, suggesting future improvements in the liver transplantation field. The main investigative efforts in liver transplantation have been directed as follows: First attenuation of disproprortion between the numbers of available liver grafts versus waiting list recipients, by increasing the donor pool applying bioartificial support systems, or rendering grafts compatible by the use of stem cells. Second, improved knowledge about the biology of primary liver tumors establishes indications for and optimal moments of transplantation. Third, application of individualized immunosuppressive protocols, adapted to clinical status of the recipient, as well as the development of more selective, less toxic new immunosuppressive agents.

Improvement of renal function after conversion to mycophenolate mofetil combined with low-level calcineurin inhibitor in liver transplant recipients with chronic renal dysfunction.

INTRODUCTION: Calcineurin inhibitors (CNI) are the main pathogenic factors for renal dysfunction in solid organ transplant recipients. Introduction of non-nephrotoxic immunosuppressive drugs, such as mycophenolate mofetil (MMF), may allow discontinuation or reduction of CNI treatment, thereby improving renal function. The aim of this study was to assess the feasibility, efficacy and safety of MMF introduction and CNI dosage reduction in the maintenance immunosuppressive protocol to improve renal function in liver transplant recipients with chronic renal dysfunction. PATIENTS AND METHODS: We prospectively included 88 liver transplant recipients including 74 men and an overall mean age of 58.8 +/- 10.3 years who all displayed chronic renal dysfunction (creatinine >1.4 mg/dL) and proteinuria <1 g/d. They were subdivided into 3 groups according to the basal creatinine value 1.4-1.7 mg/dL (group I; n = 41); 1.8-2.0 mg/dL (group II; n = 28); and >2 mg/dL (group III; n = 19). MMF was initiated at 1.5-2.0 g/d. Reduction of tacrolimus or cyclosporine dosage was performed to achieve respective target trough levels of <5 ng/mL or <50 ng/mL. We performed periodic determinations of arterial pressure, liver function tests, serum creatinine, blood cells count, CNI levels, and proteinuria. RESULTS: Creatinine values after conversion were 1.4 +/- 0.5 mg/dL in the overall group. Improvement of renal function was more frequent among groups I (80.4%) and II (92.8%) versus III (73.6%). Normalization of creatinine values was more frequent in group I (68.2%) with respect to cohorts II (21.4%) and III (10.5%). Rejection was not detected. CONCLUSION: Application of an immunosuppressive protocol with MMF and low-level CNI in liver transplant recipients with chronic renal dysfunction was associated with improvement or normalization of creatinine, without an increased risk of rejection. Early conversion is needed to achieve the best results.

Safety of an immunosuppressant protocol based on sirolimus in liver transplant recipients with malignancies or high risk of tumor recurrence.

BACKGROUND: The mammalian target of rapamycin inhibitors are immunosuppressive agents with antiproliferative effects and consequent potential application as anticancer agents. The safety and tolerance of calcineurin inhibitor (CNI)-free sirolimus-based immunosuppressant protocols in liver transplant recipients with malignancies or high risk of tumor recurrence has been scarcely evaluated. PATIENTS AND METHODS: Fourteen liver transplant recipients, including 12 men, of overall mean age of 57.4 +/- 12.4 years were distributed into two groups: group I, corresponding to 11 patients with malignant neoplasia, eight de novo neoplasia, and three recurrent hepatocarcinoma and; group II, three patients with high risk of tumor recurrence due to cholangiocarcinoma. Sirolimus was initiated at 2 mg od, with target levels of 3 to 9 ng/mL. Withdrawal of CNI was performed after reaching target levels of sirolimus. Periodic examinations of weight, arterial pressure, liver function tests, serum creatinine, triglycerides, cholesterol, sirolimus blood levels, and creatinine clearance were performed at 30, 60, 90, 180, and 360 days. RESULTS: After a median follow-up of 221.5 days, eight group I patients (72.7%) were alive, including six with stable disease. All group II patients were alive without evidence of tumor recurrence after a median follow-up of 560 days. CNI was withdrawn in 11 patients (78.6%). Sirolimus was withdrawn in only one case due to severe symptomatic oral ulcers. No vascular complications or rejection episodes were observed. CONCLUSIONS: A sirolimus-based immunosuppressant protocol was well tolerated and safe in liver transplant recipients with malignancies or a high risk of recurrence of neoplastic disease.

Orthotopic liver transplantation for hepatocellular carcinoma: a thirteen-year single-center experience.

BACKGROUND: When restrictive selection criteria are applied orthotopic liver transplantation (OLT) is the most efficient option for the treatment of hepatocellular carcinoma (HCC) in terms of survival and recurrence rate. Nevertheless, tumor recurrence may occur in 3.5%-21% of recipients, with a consequent negative impact on prognosis. The aim of this study was to analyze the long-term survival and tumor recurrence rate among a cohort of liver transplant recipients with HCC. METHODS: During the period 1994-2007, 130 HCC patients, including 111 males with a mean overall age of 57.8 +/- 7.1 years (range, 38-70), underwent cadaveric donor-OLT. The etiology of liver disease was alcoholic cirrhosis in 66 patients (50.8%) and viral infection in 52 patients (40%). Baseline alpha fetoprotein values were 53.4 +/- 280.9 ng/mL (range, 1-2593). Median interval between inclusion date and transplantation was 179.5 days. RESULTS: After a median follow-up of 40.8 months, 93 recipients (71.5%) were alive. Tumor recurrence was detected in 11 patients (8.5%). Neoplasm recurrence sites were as follows: liver graft (45.4%), bone (36.4%), lymphoadenopathies (27.3%), adrenal glands (27.3%), and lung (27.3%). Overall survival rates at 1, 3, 5, and 10 years were 85.1%, 78.3%, 70.1%, and 57%, respectively. After examination of the explanted liver, Milan criteria were surpassed in 32 recipients (24.6%). Nevertheless, no differences in survival were observed according to fulfilment or not of Milan criteria (log-rank test, P > .05). Hepatitis C virus (HCV) infection, female gender, and tumor recurrence were associated with a worse survival rate (log-rank test, < .05). CONCLUSIONS: OLT is an effective option for the treatment of HCC with good long-term survival and low recurrence rates. In this series, survival was not affected by findings of poor prognostic factors in the explanted liver.

Gastrointestinal complications in liver transplant recipients: MITOS study.

INTRODUCTION: Liver transplant recipients frequently suffer gastrointestinal (GI) complications but their prevalence and their influence on quality of life remain unknown. OBJECTIVE: The objective of this study was to asses the prevalence, impact on quality of life, and management of GI complications in liver transplant recipients. PATIENTS AND METHODS: This was an epidemiologic, cross-sectional, multicenter study. Four hundred seventeen liver recipients were recruited in 14 centers. A questionnaire was filled for every patient. RESULTS: The median age of the patients was 55 years. The median time since transplantation was 4.1 +/- 4 years. Whereas 19.2% presented some GI disease before transplantation, 49.4% showed this type of complication after transplantation. Diarrhea was the most prevalent GI complication, and anorexia was the GI disorder that affected patients daily activities the most frequently. GI complications were more frequent among female patients, subjects with pretransplantation hiatal hernia, and those readmitted after transplantation. Of the patients with GI complications, 70.9% received pharmacological treatment (89.7% with gastric protectors). Immunosuppressive therapy was also modified because of GI complications. Immunosuppressive drug dose was reduced in 18.1%, transiently stopped in 3.4%, and definitively stopped in 3.4% of cases. The drug most frequently changed was mycophenolate mofetil: dose reduction, 23.6%; transient withdrawal, 5.7%; and definitive withdrawal, 6.6%. CONCLUSIONS: The prevalence of GI complications in the liver transplant population was approximately 50%. GI complications showed a significant impact on the quality of life of the patients. They were related to female gender, to pretransplantation GI pathology, and posttransplantation hospital admission. These complications were frequently managed with pharmacological therapy or with changes in immunosuppressive therapy.

Absceso subfrénico con extensión pleural y subcutánea como complicación de un cálculo vertido al peritoneo durante la colecistectomía laparoscópica: implicaciones terapéuticas / Subfrenic abscess with pleural and subcutaneous involvement as complication of peritoneal gallstone dropped during laparoscopic cholecystectomy: therapeutic implications

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Prospective histopathological analysis of hepatocellular carcinoma treated with percutaneous ethanol injection in patients on the waiting list for liver transplantation.

INTRODUCTION: Liver transplantation (LT) improves survival in selected patients suffering from hepatocellular carcinoma (HCC). Unfortunately, the long time lapse between indication and LT may cause tumor progression. Thus, percutaneous ethanol injection (PEI) has been proposed as adjuvant therapy of HCC in patients awaiting LT. The efficacy of PEI assessed using histopathological analysis of hepatectomy specimens has not been adequately evaluated. PATIENTS AND METHODS: Twenty-nine nodules of HCC in 27 patients (21 men; mean age, 58.1 +/- 7.3 years) listed for LT were treated with PEI. Pretreatment mean serum alpha-fetoprotein (AFP) was 11 +/- 13.4 ng/mL. Mean tumor diameter was 30.8 +/- 12.9 mm. Data from the explanted livers after transplantation included percentage tumor necrosis, presence of satellite and distant nodules, vascular invasion, tumor capsule, and grade of differentiation. RESULTS: Nineteen patients with 20 treated lesions underwent transplantation. The median interval PEI-LT was 3 months. Complete necrosis was observed in 13 nodules (65%). Satellite nodules were present in 10% of lesions. Previously unrecognized distant lesions were seen in 15.8% of patients. Only 1 nodule presented microscopic vascular invasion. Most HCC were well differentiated (90%), and completely encapsulated (80%). No tumor-related deaths occurred. Seventeen patients are alive and recurrence-free after a median follow-up of 15 months. CONCLUSIONS: PEI may achieve significant necrosis in cases of HCC awaiting LT. Nevertheless, previously unrecognized satellite and distant lesions may be observed. Further studies are needed to evaluate the influence of tumor necrosis on overall survival of these patients.

Doppler ultrasonography for the assessment of tumor necrosis after percutaneous ethanol injection prior to liver transplantation as adjuvant therapy of hepatocellular carcinoma.

INTRODUCTION: Percutaneous ethanol injection (PEI) is considered to be a curative treatment for hepatocellular carcinoma (HCC). The imaging technique of choice for the assessment of local response after PEI has not been well defined, but helical computerized tomography (hCT) has been recommended. The aim of this study was to assess the accuracy of Doppler ultrasonography (US) for evaluation of tumor necrosis after PEI. PATIENTS AND METHODS: Twenty-one patients with single HCC listed for liver transplantation underwent multisession US-guided PEI. Liver Doppler US was done at the 4th week after PEI. Complete response was defined as the absence of any intratumoral Doppler signal. The liver was analyzed in transplant recipients during the follow-up. Complete pathological response was defined as necrosis > or = 90% of total tumor volume. Histological and sonographic findings were compared. RESULTS: Twelve patients underwent transplantation (9 men, mean age 60 +/- 5.2 years). Nine of these (75%) showed a complete ultrasonographic response. In the explanted liver, complete necrosis was present in 6 nodules, and incomplete necrosis was seen in the remaining 6 cases. In comparison with histology, Doppler US showed values of sensitivity, specificity, positive predictive values, and negative predictive values of 50%, 100%, 100%, and 60%, respectively. Overall accuracy was 75%. CONCLUSIONS: In our series, Doppler US showed low sensitivity but high specificity in the assessment of HCC necrosis after PEI. The ultrasonographic finding of complete response requires hCT for confirmation, but the presence in Doppler US of neoplastic viable tissue is enough to indicate a further cycle of PEI.

Safety of percutaneous ethanol injection as neoadjuvant therapy for hepatocellular carcinoma in waiting list liver transplant candidates.

UNLABELLED: Orthotopic liver transplantation (OLT) as therapy of hepatocellular carcinoma (HCC) improves the survival of a selected group of patients. Unfortunately, the progressive increase in waiting time for OLT may allow tumor progression. Percutaneous ethanol injection (PEI) has been proposed as neoadjuvant therapy for HCC in patients awaiting OLT, but its safety has not been defined. PATIENTS AND METHODS: During a 60-month period, 34 patients (27 men, overall mean age of 58.5 years, range 41-67) with HCC, were listed for OLT. Ultrasonography-guided PEI was delivered into 39 nodules at 117 sessions on an inpatient basis. Written informed consent was obtained from all patients before PEI. Doppler-ultrasonography was done before PEI, immediately after, and 4 weeks later. Noninvasive monitoring of arterial pressure, cardiac rate, and temperature was performed during the procedure and during a 24-hour period after each session. Pain was considered significant if analgesia was required or discontinuation of PEI necessary. Fever was defined as a temperature > or =37.5 degrees C after PEI. RESULTS: Minor complications included pain in 45 sessions (38.5%), fever in 17 (14.5%), arterial hypertension in 14 (12%), hypotension in 7 (7%), and vomiting in 2 (1.7%). The major complications were segmental liver infarction (n = 3), portal branch venous thrombosis (n = 2), ascites (n = 2), and one case each of subcapsular hematoma, duodenal ulcer, pneumonia, hepatic encephalopathy, and hepatic artery thrombosis. In all cases, clinical outcomes were favorable with conservative treatment. No evidence of tumor seeding in the needle track was reported and no PEI-related mortality observed. CONCLUSIONS: PEI is a safe neoadjuvant therapy for HCC on waiting list liver transplant candidates. In our series, pain and self-limited fever were the most frequent complications. Clinically significant severe complications were uncommon, and nonconservative treatments were not required.

Prospective interventional study to evaluate the efficacy and safety of liposomal amphotericin B as prophylaxis of fungal infections in high-risk liver transplant recipients.

INTRODUCTION: Invasive fungal infections are a life-threatening complication in transplant recipients. The prevalence of fungal infection after orthotopic liver transplantation (OLT) is 5% to 42%. The most common isolated pathogens are Candida and Aspergillus species. High-risk liver transplant recipients are more susceptible to the development of invasive fungal infections, with prevalence >40% and mortality rates of 78% to 100%. The strategy for fungal prophylaxis in this population has not been defined. PATIENTS AND METHODS: Among 100 consecutive OLT followed for 28 months, 21 recipients (15 men, overall mean age of 48.5 years, range 23-65 years) were considered to be high risk for the development of fungal infections when they presented at least one of the following criteria: acute liver failure, assisted ventilation >7 days, retransplantation, relaparotomy, antibiotic therapy >14 days, transfusion requirements >20 red blood cells units, and/or biliary leakage. This group received intravenous liposomal amphotericin B (1 mg/kg/d for 7-10 days). RESULTS: One-year survival in the high-risk group was 80%. Prevalence of invasive fungal infection was 9.5%. No Candida infection was observed. Two patients developed Aspergillus infection: an abdominal aspergillosis treated with percutaneous drainage and liposomal amphotericin B (5 mg/kg/d) showed a favorable clinical outcome. The other patient who developed brain aspergillosis died 25 days after OLT. Adverse events related to the drug were hypokalemia (n = 2), back pain (n = 3), and renal dysfunction (n = 2). None of these events required withdrawal of the prophylaxis regimen. CONCLUSION: In our series, prophylaxis with liposomal amphotericin B in high-risk liver graft recipients showed a low rate of severe fungal infections. More studies are needed in order to determine the highest risk population and the best drug dosage.