Efficacy and safety of sorafenib in combination with mammalian target of rapamycin inhibitors for recurrent hepatocellular carcinoma after liver transplantation.

There is currently no consensus on the most suitable treatment for the recurrence of hepatocellular carcinoma (HCC) after liver transplantation. This open, multicenter, retrospective, uncontrolled cohort study was designed to evaluate the safety and preliminary efficacy of the combined use of a mammalian target of rapamycin (mTOR) inhibitor and sorafenib in this setting. In 31 patients who suffered from HCC recurrence after liver transplantation, the immunosuppressive therapy was changed to mTOR inhibitors, and systemic treatment with sorafenib was initiated. This combination was maintained until symptomatic tumor progression, death, hepatic decompensation, or unacceptable toxicity occurred. Primary treatment efficacy was determined by overall survival and progression-free survival, and secondary efficacy was determined by the overall response rate. Toxicity parameters associated with the use of sorafenib and mTOR inhibitors were also analyzed. The overall response rate according to the Response Evaluation Criteria in Solid Tumors was 3.8% (1/26), and there was sustained stabilization of the disease in 13 additional cases (50.0%). The median overall survival was 19.3 months [95% confidence interval (CI) = 13.4-25.1 months], and the median time to progression was 6.77 months (95% CI = 2.3-11.1 months). Only 2 grade 3/4 cases of hyperglycemia and 1 case of grade 3/4 mucositis were reported, and they were possibly related to mTOR inhibitors. The most common severe adverse event probably related to sorafenib was diarrhea (12.9%). In conclusion, the coadministration of sorafenib and an mTOR inhibitor could be effective despite notable toxicity in patients with post-liver transplant HCC recurrence not suitable for radical therapy. The toxicity and efficacy need to be further evaluated in randomized controlled studies for this combination to be considered a valid option.

[Basiliximab in the treatment of acute steroid-resistant rejection after liver transplantation]. / Basiliximab en el tratamiento del rechazo celular agudo resistente a los corticoides postrasplante hepático.

We present the case of a liver transplant recipient with alcoholic liver cirrhosis and early-stage hepatocellular carcinoma who developed biopsy-proven acute steroid-resistant rejection 3 months after liver transplantation. After the failure of immunosuppressive therapy with intravenous boluses of 6-methyl-prednisolone and switching of the immunosuppressive regimen to tacrolimus plus mycophenolate mofetil, two doses of intravenous basiliximab were administered four days apart. Clinical, analytical, and biopsy-proven histological response was complete. No basiliximab-related adverse events were detected. Basiliximab may represent an alternative in liver transplantation immunosuppression to treat acute steroid-resistant rejection, without increasing the incidence of infections, neoplasms, or other adverse events, as shown by this case.

Improvement of renal function after the switch from a calcineurin inhibitor to everolimus in liver transplant recipients with chronic renal dysfunction.

Chronic renal dysfunction is a frequent and severe complication in solid-organ transplant recipients. Calcineurin inhibitors (CNIs) are the main pathogenic factors of renal dysfunction. Switching from CNIs to nonnephrotoxic drugs, such as mammalian target of rapamycin inhibitors (everolimus and sirolimus), can improve renal function in these patients, but available data about the efficacy and safety of everolimus in liver transplant recipients are scarce. Twenty-one liver transplant recipients (19 males, mean age = 60.6 +/- 7.8 years) with chronic renal dysfunction (creatinine >or= 1.5 mg/dL) were prospectively included. The basal creatinine values were 1.79 +/- 0.39 mg/dL (range = 1.50-2.90 mg/dL). The basal creatinine clearance, evaluated with the Cockroft-Gault formula, was 54.64 +/- 12.47 mL/minute. Everolimus was initiated at a dosage of 0.75 mg twice daily, with target levels of 3 to 8 ng/mL. The withdrawal of CNIs was initiated after the target levels of everolimus were reached. Periodic controls of the weight, arterial pressure, liver function tests, serum creatinine, everolimus levels, proteinuria, creatinine clearance, and glomerular filtration rate at days 30, 90, 180, and 360 were made. After a median follow-up of 19.8 months, the respective creatinine values at 30, 90, 180, and 360 days were 1.68 +/- 0.40 (P = 0.012 with respect to basal values), 1.67 +/- 0.34 (P = 0.107), 1.70 +/- 0.41 (P = 0.521), and 1.57 +/- 0.30 mg/dL (P = 0.047). The respective creatinine clearance values at 30, 90, 180, and 360 days were 58.64 +/- 16.50 (P = 0.013 with respect to basal values), 59.49 +/- 13.27 (P = 0.028), 59.82 +/- 16.83 (P = 0.124), and 64.46 +/- 16.79 mL/minute (P = 0.025). CNIs were withdrawn in 20 recipients (95.2%). Rejection was not detected in any case. In conclusion, the application in liver transplant recipients with chronic renal dysfunction of an immunosuppressive protocol with everolimus and the withdrawal of CNIs was associated with an initial improvement of renal function tests without an increase in the risk of rejection.

[Chronic nephropathy in non-kidney transplantation: [prevention, early diagnosis and management]. / Nefropatía crónica en trasplante no renal: prevención, diagnóstico precoz y manejo.

Transplant from solid nonrenal organ has experienced an important increase in the last decades. It is due to the increasing improvement of the results obtained with the above mentioned transplants. Parallel, many nonrenal transplanted patients have developed a chronic renal failure that has determined, in some cases, the need of beginning the substitution of renal function by means of dialysis and/or transplant. The origin of the same one is multifactorial and the consequences derived from it are very important so much in morbimortality as of economic nature for the set of the system. The present review tries to help to the identification of risk factors of renal insufficiency in the nonrenal transplanted patient and to determine which might be the basic concepts of prevention, early diagnosis and of derivation to the nephrologist expert in transplants and renal dysfunction. Finally, we check the possibilities of managing of the immunosuppressive treatment and substitution of renal function by means of dialysis and/or simple or double transplant.

Bilateral adrenal metastases from hepatocellular carcinoma after liver transplantation.

Therapeutic management of hepatocellular carcinoma is a controversial issue. Orthotopic liver transplantation is an alternative for the treatment of hepatocellular carcinoma in a selected group of patients, but recurrence is possible. A 51-year-old patient with liver transplantation due to hepatocellular carcinoma presented bilateral adrenal metastases in a successive manner. A left adrenal gland metastasis was diagnosed five months after liver transplantation, and a left adrenalectomy was carried out. Eight months later, a right adrenal gland metastasis was diagnosed, and a right adrenalectomy was performed. Pathological examination confirmed the diagnosis of a well-differentiated hepatocellular carcinoma. At present, there is no evidence of recurrence 35 months after the second adrenalectomy. Bilateral adrenal gland metastases from hepatocellular carcinoma after liver transplantation have not been previously reported in English literature. Surgical resection of metastases may be indicated in similar patients with successful treatment of the primary tumor, absence of additional metastasic disease, and good performance status.

Sonographic features of liver involvement by lymphoma.

OBJECTIVE: The liver is one of the most frequent extranodal locations of non-Hodgkin lymphoma and Hodgkin disease. Nevertheless, lymphoma constitutes only 6% to 8% of focal lesions of the liver. Few studies have evaluated the sonographic patterns of lymphoma with liver involvement. The purpose of this study was to describe the sonographic features and to evaluate the accuracy of sonography for the diagnosis of lymphoma with liver infiltration. METHODS: The abdominal sonographic findings of 23 consecutive patients with histologically proven diagnosis of lymphoma with liver involvement were reviewed. RESULTS: The most prevalent sonographic features were hepatomegaly and splenomegaly. Abdominal lymphoadenopathies were identified in 34.8% of cases. Liver nodules were seen in half of patients, and the most frequent sonographic appearance was as multiple small focal lesions. Differences in sonographic patterns between high- and low-grade non-Hodgkin lymphoma were not seen. None of the patients with Hodgkin disease had liver nodules. Concordance between sonography and computed tomography for the diagnosis of focal liver lesions was observed. CONCLUSIONS: Sonography may contribute to the diagnosis of liver infiltration by lymphoma. The presence of multiple focal liver lesions associated with splenomegaly and lymphoadenopathies should make us consider the diagnosis of lymphoma with liver involvement. Nevertheless, the low specificity of these findings requires histologic confirmation of lymphomatous infiltration of the liver.

Características clínicas del carcinoma hepatocelular en España. Comparación con el período 2008-2009 y análisis de las causas del diagnóstico fuera de cribado. Estudio de 686 casos en 73 centros / Clinical characteristics of hepatocellular carcinoma in Spain. Comparison with the 2008-2009 period and analysis of the causes of diagnosis out of screening programs. Analysis of 686 cases in 73 centers

Antecedentes y objetivo: En 2010 publicamos que en España el 53% de los carcinomas hepatocelulares (CHC) se diagnostican fuera de programas de cribado, lo que conlleva una menor supervivencia. El objetivo del presente estudio es evaluar la situación actual y las causas del diagnóstico fuera de cribado. Material y métodos: Registro prospectivo entre el 1 de octubre de 2014 y el 31 de enero de 2015 en 73 centros asistenciales españoles de segundo/tercer nivel. Se registraron las características basales y el primer tratamiento de los tumores primarios hepáticos incidentales de ese período. Resultados: Se incluyeron 720 pacientes: CHC (n=686), colangiocarcinoma intrahepático (n=29), hepatocolangiocarcinoma (n=2), otros (n=3). Los pacientes con CHC fueron varones en el 82% de los casos; media de 67 años; cirrosis en el 87%; etiología: alcohol 35%, VHC 30%, alcohol y VHC 15%, enfermedad hepática por depósito de grasa 6%; estadio tumoral: BCLC-0 11%, A 43%, B 19%, C 16% y D 11%; tratamiento inicial: quimioembolización transarterial (23%), ablación percutánea (22%), tratamiento sintomático (20%), resección (11%), sorafenib (11%). Se diagnosticaron fuera de cribado 356 pacientes (53%). Los motivos principales fueron la ausencia de diagnóstico previo de hepatopatía (76%) y la mala adherencia al cribado (18%). Estos pacientes eran predominantemente varones (p<0,001), de etiología alcohólica (p<0,001), con consumo activo de alcohol (p<0,001) y se diagnosticaron en estadios más avanzados (p<0,001), recibiendo menos tratamientos radicales (p<0,001). Conclusiones: En España, la principal causa del diagnóstico de CHC fuera del cribado es la ausencia de diagnóstico previo de enfermedad hepática, principalmente en varones con consumo de alcohol. La detección de hepatopatía en población asintomática y la mejora de la adherencia al cribado son los principales aspectos para mejorar la detección precoz (AU)

Background and objective: In 2010 we published that 53% of cases of hepatocellular carcinoma (HCC) detected in Spain were diagnosed outside the context of standard screening programs, which consequently leads to lower survival rates. The aim of this study was to analyze the current situation and the causes of diagnosis out of screening programs. Material and methods: Prospective registry of 73 second- and third-level Spanish healthcare centers carried out between October 1, 2014 and January 31, 2015. The baseline characteristics of the disease and the first treatment administered for the incidental primary liver tumors during such period were recorded. Results: A total of 720 patients were included in the study: HCC (n=686), intrahepatic cholangiocarcinoma (n=29), hepatic cholangiocarcinoma (n=2), other (n=3). HCC characteristics: male 82%; mean age 67 years; cirrhosis 87%; main etiologies: alcohol 35%, HCV 30%, alcohol and HCV 15%, non-alcoholic fatty liver disease 6%; tumor stage: BCLC-0 11%, A 43%, B 19%, C 16% and D 11%; first treatment: transarterial chemoembolization (23%), percutaneous ablation (22%), symptomatic treatment (20%), resection (11%), sorafenib (11%). Three hundred and fifty-six patients (53%) were diagnosed outside of screening programs, mainly owing to the fact that they suffered from an undiagnosed liver disease (76%) and to the poor adherence to the screening program (18%). These patients were mainly male (P<.001), with an alcoholic etiology (P<.001) and active alcohol consumption (P<.001). Moreover, the disease was predominantly diagnosed at more advanced stages (P<.001) and was addressed with less radical treatments (P<.001). Conclusions: In Spain, the main cause of diagnosis of a HCC outside the context of a screening program is the absence of a prior diagnosis of a liver disease, particularly in alcohol-consuming men. Detecting a liver disease in asymptomatic populations and improving adherence to screening programs are the main areas that must be subject to improvement in order to improve the early detection of HCC (AU)

Basiliximab en el tratamiento del rechazo celular agudo resistentea los corticoides postrasplante hepático / Basiliximab in the treatment of acute steroid-resistant rejection after liver transplantation

Se presenta el caso de un receptor de un trasplante hepático con la indicación de cirrosis hepática alcohólica y carcinoma hepatocelular en estadio inicial que presentó un rechazo celular agudo resistente a los corticoides demostrado por biopsia a los 3 meses del trasplante. Tras la ausencia de mejora analítica o histológica con 6-metil-prednisolona intravenosa y la conversión del régimen inmunosupresor a tacrolimus y micofenolato mofetil, se administraron 2 dosis de basiliximab intravenoso separadas por 4 días, asistiendo a la normalización clínica, analítica e histológica. No se detectaron episodios adversos relacionados con el tratamiento con basiliximab. El basiliximab puede representar una opción terapéutica en el rechazo celular agudo resistente a los corticoides tras el trasplante hepático, sin que se hayan observado infecciones, neoplasias ni otros efectos adversos potencialmente relacionados en este caso (AU)

We present the case of a liver transplant recipient with alcoholic liver cirrhosis and early-stage hepatocellular carcinoma who developed biopsy-proven acute steroid-resistant rejection 3 months after liver transplantation. After the failure of immunosuppressive therapy with intravenous boluses of 6-methyl-prednisolone and switching of the immunosuppressive regimen to tacrolimus plus mycophenolate mofetil, two doses of intravenous basiliximab were administered four days apart. Clinical, analytical, and biopsy-proven histological response was complete. No basiliximab-related adverse events were detected. Basiliximab may represent an alternative in liver transplantation immune suppression to treat acute steroid-resistant rejection, without increasing the incidence of infections, neoplasms, or other adverse events, as shown by this case (AU)