Restoring mir122 in human stem-like hepatocarcinoma cells, prompts tumor dormancy through smad-independent TGF-β pathway.

miR122 is the prevalent miRNA in adult healthy liver and it is responsible for liver stem cell differentiation towards hepatocyte lineage. Its expression is frequently lost in hepatocellular carcinoma (HCC). We studied the effects of restoring miR122 expression in a distinctive cell line derived from human HCC-BCLC9 cells-with a solid stem-like cell profile, high tumor initiating ability and undetectable miR122 expression. We generated a stable BCLC9 cell line that expresses miR122 (BCLC9-miR122). Restitution of miR122 in BCLC9 cells, decreases cell proliferation rate and reduces significantly tumor size in vivo. BCLC9-miR122 cells down-regulate expression of MYC, KLF4, FOXM1, AKT2 and AKT3 genes and up-regulate FOXO1 and FOXO3A gene expression. In addition, miR122 transfected cells decreased AKT2 kinase activation while decreased FOXO1 and FOXO3A protein inactivation. Reduction in tumor size in BCLC9-miR122 associated with an increase in p38MAPK protein expression and activation leading to a low phospho-ERK1/2 to phospho-p38 ratio. Treatment of miR122 positive cells with an inhibitor of TGFBR1 activation, abolished tumor dormancy program and recovered cell proliferation rate through a Smad-independent TGF-β response.HCC stem-like cells can be directed towards cell differentiation and tumor dormancy by restoring miR122 expression. We demonstrate, for the first time, that dormancy program is achieved through a Smad-independent TGF-β pathway. Restablishing miR122 expression is a promising therapeutic strategy that would work concurrently reducing tumor aggressiveness and decreasing disease recurrence

Cost-effectiveness of adjuvant therapy for hepatocellular carcinoma during the waiting list for liver transplantation.

Background: Survival after liver transplantation for early hepatocellular carcinoma (HCC) is worsened by the increasing dropout rate while waiting for a donor. Aims: To assess the cost effectiveness of adjuvant therapy while waiting for liver transplantation in HCC patients. Method: Using a Markov model, a hypothetical cohort of cirrhotic patients with early HCC was considered for: (1) adjuvant treatment—resection was limited to Child-Pugh's A patients with single tumours, and percutaneous treatment was considered for Child-Pugh's A and B patients with single tumours unsuitable for resection or with up to three nodules < 3 cm; and (2) standard management. Length of waiting time ranged from six to 24 months. Results: Surgical resection increased the transplantation rate (>10%) and provided gains in life expectancy of 4.8–6.1 months with an acceptable cost ($40 000/ year of life gained) for waiting lists ≥1 year whereas it was not cost effective ($74 000/life of year gained) for shorter waiting times or high dropout rate scenarios. Percutaneous treatment increased life expectancy by 5.2–6.7 months with a marginal cost of approximately $20 000/year of life gained in all cases, remaining cost effective for all waiting times. Conclusions: Adjuvant therapies for HCC while waiting for liver transplantation provide moderate gains in life expectancy and are cost effective for waiting lists of one year or more. For shorter waiting times, only percutaneous treatment confers a relevant survival advantage

Diagnosis and treatment of hepatocellular carcinoma. Update of the consensus document of the AEEH, AEC, SEOM, SERAM, SERVEI, and SETH

tHepatocellular carcinoma (HCC) is the most common primary liver neoplasm and one of the most com-mon causes of death in patients with cirrhosis of the liver. In parallel, with recognition of the clinicalrelevance of this cancer, major new developments have recently appeared in its diagnosis, prognosticassessment and in particular, in its treatment. Therefore, the Spanish Association for the Study of theLiver (AEEH) has driven the need to update the clinical practice guidelines, once again inviting all thesocieties involved in the diagnosis and treatment of this disease to participate in the drafting and appro-val of the document: Spanish Society for Liver Transplantation (SETH), Spanish Society of DiagnosticRadiology (SERAM), Spanish Society of Vascular and Interventional Radiology (SERVEI), Spanish Associa-tion of Surgeons (AEC) and Spanish Society of Medical Oncology (SEOM). The clinical practice guidelinespublished in 2016 and accepted as National Health System Clinical Practice Guidelines were taken as thereference documents, incorporating the most important recent advances. The scientific evidence and thestrength of the recommendation is based on the GRADE system.nEl carcinoma hepatocelular (CHC) es la neoplasia primaria de hígado más frecuente y una de las causasde muerte más común en los pacientes afectos de cirrosis hepática. Simultáneamente al reconocimientode la relevancia clínica de esta neoplasia, en los últimos a˜nos han aparecido novedades importantes enel diagnóstico, evaluación pronóstica y, especialmente, en el tratamiento del CHC. Por tal motivo, desdela Asociación Espa˜nola para el Estudio del Hígado (AEEH) se ha impulsado la necesidad de actualizarlas guías de práctica clínica, invitando de nuevo a todas las sociedades involucradas en el diagnósticoy tratamiento de esta enfermedad a participar en la redacción y aprobación del documento: SociedadEspa˜nola de Trasplante Hepático (SETH), Sociedad Espa˜nola de Radiología Médica (SERAM), SociedadEspa˜nola de Radiología Vascular e Intervencionista (SERVEI), Asociación Espa˜nola de Cirujanos (AEC) ySociedad Espa˜nola de Oncología Médica (SEOM). Se han tomado como documentos de referencia las guíasde práctica clínica publicadas en 2016, aceptadas como Guía de Práctica Clínica del Sistema Nacional deSalud, incorporando los avances más importantes que se han obtenido en los últimos a˜nos. La evidenciacientífica y la fuerza de la recomendación se basa en el sistema GRADE

Chronic intestinal pseudoobstruction and ophthalmoplegia in a patient with mitochondrial myopathy

A 38 year old woman having chronic intestinal pseudoobstruction associated with mitochondrial myopathy is reported. The clinical and radiographic features suggested the diagnosis of chronic intestinal pseudoobstruction. Muscular atrophy and ophthalmoplegia led to muscle biopsy, which disclosed accumulation of normal and abnormal mitochondria ('ragged red fibres'), characteristic of mitochondrial myopathy

Early diarrhoea under sorafenib as a marker to consider the early migration to second-line drugs

Background: Despite atezolizumab and bevacizumab (A + B) is currently the first-line treatment for hepatocellular carcinoma (HCC) patients, some patients will not be adequate for this combination. In the setting of sorafenib some adverse events have been proposed as prognostic factors. Objective: To characterize the early diarrhoea development as prognostic factor in 344 HCC patients. Methods: The development of early diarrhoea in sorafenib treatment defined as patients who developed diarrhoea and needed dose modification within the first 60 days of treatment (e-diarrhoea) and 3-grouping variables were analysed: Patients with e-diarrhoea, patients who developed diarrhoea after the first 60 days of treatment (L-diarrhoea) and patients that never developed diarrhoea (never diarrhoea). Results: The median overall survival in sorafenib treated patients was significantly different across groups (6.8 months for e-diarrhoea, 26.7 months for L-diarrhoea and 13.3 months for never-diarrhoea). The emergence of e-diarrhoea was associated with poor outcomes (hazard ratio [HR] 1.84 [95%CI 1.15-2.95]), while there was no increased/decreased risk of dismal evolution in patients with L-diarrhoea (HR 0.66 [95%CI 0.42-1.03]). Conclusion: The emergence of e-diarrhoea in HCC patients treated with sorafenib is an early predictor of dismal evolution under this therapy. Thus, prompt identification of these non-responders may be useful for an early switch to second-line therapies

Complete response under sorafenib in patients with hepatocellular carcinoma: Relationship with dermatologic adverse events.

The clinical benefit of sorafenib in patients with hepatocellular carcinoma (HCC) has been undervalued due to the absence of complete responses, even though patients who develop early dermatologic reactions have shown to have a positive outcome. In addition, sorafenib is described as an antiangiogenic drug, but it also acts on immunological cells. Thus, the goal of this study was to assess the complete response rate in a retrospective cohort of HCC patients treated with sorafenib and to describe the profile of the patients who achieve complete response for identifying factors related to this event and their connection with the immunological profile of sorafenib. Ten Spanish centers submitted cases of complete response under sorafenib. The baseline characteristics, development of early dermatologic reactions, and cause of treatment discontinuation were annotated. Radiological images taken before starting sorafenib, at first control, after starting sorafenib, at the time of complete response, and at least 1 month after treatment were centrally reviewed. Of the 1119 patients studied, 20 had been classified as complete responders by the centers, but eight of these patients were excluded after central review. Ten patients had complete disappearance of all tumor sites, and two had just a small residual fibrotic scar. Thus, 12 patients were classified as complete responders (58% HCV, median age 59.7 years, 83.4% Child-Pugh class A, Eastern Cooperative Oncology Group performance status 0 91.7%, and Barcelona Clinic Liver Cancer stage C 83.3%). The median overall survival and treatment duration were 85.8 and 40.1 months, respectively. All but one patient developed early dermatologic reactions, and seven patients discontinued sorafenib after achieving complete response due to adverse events, patient decision, or liver decompensation. CONCLUSION: Complete response affects 1% of patients with HCC who are treated with sorafenib. The association of complete response with early dermatologic reactions supports the role of a specific immune/inflammatory patient profile in the improved response to sorafenib

Antiapoptotic BCL-2 proteins determine Sorafenib/regorafenib resistance and BH3-mimetic efficacy in hepatocellular carcinoma

Sorafenib, systemic treatment for advanced hepatocellular carcinoma (HCC), and regorafenib, novel second line treatment after sorafenib failure, have efficacy limited by evasive mechanisms of acquired-drug resistance. BCL-2 proteins participate in the response to tyrosine kinase inhibitors; however, their role in HCC therapy with sorafenib/regorafenib remains uncertain. BH3-mimetic ABT-263 (navitoclax) enhanced sorafenib activity, inducing cell death via a mitochondrial caspase-dependent mechanism, after BCL-xL/BCL-2 inhibition. Sorafenib-resistant hepatoma cells (HepG2R and Hep3BR) exhibited altered mRNA expression of BCL-2 and other anti-apoptotic family members, such as MCL-1, priming drug-resistant cancer cells to death by BH3-mimetics. ABT-263 restored sorafenib efficacy in sorafenib-resistant cell lines and HCC mouse models. Moreover, in mice xenografts from patient-derived BCLC9 cells, better tumor response to sorafenib was associated to higher changes in the BCL-2 mRNA pattern. HCC non-treated patients displayed altered BCL-2, MCL-1 and BCL-xL mRNA levels respect to adjacent non-tumoral biopsies and an increased BCL-2/MCL-1 ratio, predictive of navitoclax efficacy. Moreover, regorafenib administration also modified the BCL-2/MCL-1 ratio and navitoclax sensitized hepatoma cells to regorafenib by a mitochondrial caspase-dependent mechanism. In conclusion, sorafenib/regorafenib response is determined by BCL-2 proteins, while increased BCL-2/MCL-1 ratio in HCC sensitizes drug resistant-tumors against ABT-263 co-administration. Thus, changes in the BCL-2 profile, altered in HCC patients, could help to follow-up sorafenib efficacy, allowing patient selection for combined therapy with BH3-mimetics or early switch them to second line therapy

Pilot study of living donor liver transplantation for patients with HCC exceeding Milan criteria

BACKGROUND & AIMS: A subset of patients with hepatocellular carcinoma (HCC) beyond Milan criteria might obtain acceptable survival outcomes after liver transplantation. Living donor liver transplantation (LDLT) has emerged as a feasible alternative to overcome the paucity of donors. METHODS: In 2001 we started a protocol for LDLT in Child A-B patients with HCC fulfilling a set of criteria - the BCLC expanded criteria- that expanded the conventional indications of transplantation: 1 tumor ≤ 7cm, 5 tumors ≤ 3cm, 3 tumors ≤ 5cm without macrovascular invasion or down-staging to Milan after loco-regional therapies. RESULTS: We present a prospective cohort of 22 patients with BCLC extended indications based on size/number (17) or down-staging (5) treated with LDLT between 2001 and 2014. Characteristics of the patients were as follows: median age: 57yr old; males/female: 20/2, Child-Pugh A/B: 16/6, AFP <100ng/mL: 21. Twelve patients received neo-adjuvant loco-regional therapies. At the time of transplantation, 12 patients had HCC staging beyond Milan criteria and 10 within. Pathological reports showed that 50% exceeded BCLC expanded criteria. Perioperative mortality was 0%. After a median follow up of 81 months, the 1-, 3-, 5- and 10-year survival was 95.5%, 86.4%, 80.2% and 66.8%, respectively. Overall, seven patients recurred (range 9-108 mo), and the 5-y and 10-yr actuarial recurrence rate was of 23.8% and 44,4%, respectively. CONCLUSION: A proper selection of candidates for extended indications of living donor liver transplantation for HCC patients provide survival outcomes comparable

Search: A phase III, randomized, double-blind, placebo-controlled trial of sorafenib plus erlotinib in patients with advanced hepatocellular carcinoma

PURPOSE: To compare the clinical outcomes of sorafenib plus either erlotinib or placebo in patients with advanced hepatocellular carcinoma (HCC) in a multicenter, multinational, randomized, phase III trial. PATIENTS AND METHODS: Patients with advanced HCC and underlying Child-Pugh class A cirrhosis, who were naive to systemic treatment (N = 720), were randomly assigned to sorafenib plus either erlotinib (n = 362) or placebo (n = 358). The primary end point was overall survival (OS). RESULTS: Median OS was similar in the sorafenib plus erlotinib and sorafenib plus placebo groups (9.5 v 8.5 months, respectively; hazard ratio [HR], 0.929; P = .408), as was median time to progression (3.2 v 4.0 months, respectively; HR, 1.135; P = .18). In the sorafenib/erlotinib arm versus the sorafenib/placebo arm, the overall response rate trended higher (6.6% v 3.9%, respectively; P = .102), whereas the disease control rate was significantly lower (43.9% v 52.5%, respectively; P = .021). The median durations of treatment with sorafenib were 86 days in the sorafenib/erlotinib arm and 123 days in the sorafenib/placebo arm. In the sorafenib/erlotinib and sorafenib/placebo arms, the rates of treatment-emergent serious AEs (58.0% v 54.6%, respectively) and drug-related serious AEs (21.0% v 22.8%, respectively) were similar. AEs matched the known safety profiles of both agents, but rates of rash/desquamation, anorexia, and diarrhea were higher in the sorafenib/erlotinib arm, whereas rates of alopecia and hand-foot skin reaction were higher in the sorafenib/placebo arm. Withdrawal rates for AEs during cycles 1 to 3 were higher in the sorafenib/erlotinib arm. CONCLUSION: Adding erlotinib to sorafenib did not improve survival in patients with advanced HCC

Hepatitis G virus infection in chronic liver disease

Background¿The hepatitis G virus (HGV), a recently identified member of the Flaviviridae family, can cause chronic infection in man but the role of this agent in chronic liver disease is poorly understood. Aims¿To evaluate the prevalence and meaning of HGV infection in a large series of patients with chronic liver disease. Subjects¿Two hundred volunteer blood donors, 179 patients with chronic hepatitis C, 111 with chronic hepatitis B, 104 with alcoholic liver disease, 136 with hepatocellular carcinoma, and 24 with cryptogenic chronic liver disease were studied. Methods¿HGV RNA was investigated in serum samples by reverse transcription and polymerase chain reaction amplification of the 5¿ non-coding region of HCV and hybridisation to a specific probe. The main features of HGV RNA seropositive and seronegative patients were compared. Results¿The prevalence of HGV infection was 3% in blood donors, 7% in chronic hepatitis C, 8% in chronic hepatitis B, 2% in alcoholic liver disease, 4% in hepatocellular carcinoma, and 8% in cryptogenic chronic liver disease. HGV infected patients tended to be younger than non-infected patients but no differences concerning sex, possible source of infection, clinical manifestations, biochemical and virological parameters, or severity of liver lesions were found. Conclusions¿The prevalence of HGV infection in chronic liver disease seems to be relatively low in our area. Infection with HGV does not seem to play a significant pathogenic role in patients with chronic liver disease related to chronic HBV or HCV infection or to increased alcohol consumption, or in those with cryptogenic chronic liver disease