María Varela

Diagnosis of hepatic nodules 20 mm or smaller in cirrhosis: Prospective validation of the noninvasive diagnostic criteria for hepatocellular carcinoma†

This study prospectively evaluates the accuracy of contrast‐enhanced ultrasound (CEUS) and dynamic magnetic resonance imaging (MRI) for the diagnosis of nodules 20 mm or smaller detected during ultrasound (US) surveillance. We included 89 patients with cirrhosis [median age, 65 years; male 53, hepatitis C virus 68, Child‐Pugh A 80] without prior hepatocellular carcinoma (HCC) in whom US detected a small solitary nodule (mean diameter, 14 mm). Hepatic MRI, CEUS, and fine‐needle biopsy (gold standard) (FNB) were performed at baseline. Non‐HCC cases were followed (median 23 months) by CEUS/3 months and MRI/6 months. FNB was repeated up to 3 times and on detection of change in aspect/size. Intense arterial contrast uptake followed by washout in the delayed/venous phase was registered as conclusive for HCC. Final diagnoses were: HCC (n = 60), cholangiocarcinoma (n = 1), and benign lesions (regenerative/dysplastic nodule, hemangioma, focal nodular hyperplasia) (n = 28). Sex, cirrhosis cause, liver function, and alpha‐fetoprotein (AFP) levels were similar between HCC and non‐HCC groups. HCC patients were older and their nodules significantly larger (P < 0.0001). First biopsy was positive in 42 of 60 HCC patients. Sensitivity, specificity, and positive and negative predictive values of conclusive profile were 61.7%, 96.6%, 97.4%, and 54.9%, for MRI, 51.7%, 93.1%, 93.9%, and 50.9%, for CEUS. Values for coincidental conclusive findings in both techniques were 33.3%, 100%, 100%, and 42%. Thus, diagnosis of HCC 20 mm or smaller can be established without a positive biopsy if both CEUS and MRI are conclusive. However, sensitivity of these noninvasive criteria is 33% and, as occurs with biopsy, absence of a conclusive pattern does not rule out malignancy. These results validate the American Association for the Study of Liver Disease (AASLD) guidelines. (HEPATOLOGY 2007.)

Unexpected high rate of early tumor recurrence in patients with HCV-related HCC undergoing interferon-free therapy

BACKGROUND & AIMSnThe success of direct-acting antivirals (DAA) against hepatitis C is a major breakthrough in hepatology. Until now, however, there are very few data on the effect of hepatitis C virus (HCV) eradication in patients who have already developed hepatocellular carcinoma.nnnMETHODSnThe study included patients with HCV infection and prior history of treated hepatocellular carcinoma who achieved complete response and lacked non-characterized nodules at the time they underwent anti-HCV treatment with all-oral DAAs in 4 hospitals. Patients receiving interferon as part of the antiviral regimen were excluded. The baseline characteristics, laboratory and radiologic tumor response were registered in all patients before starting antiviral therapy and during the follow-up according to the clinical practice policy.nnnRESULTSnBetween 2014 and 2015, 103 patients with prior hepatocellular carcinoma received DAA, 58 of them met the inclusion criteria. After a median follow-up of 5.7months, 3 patients died and 16 developed radiologic tumor recurrence (27.6%). The pattern of recurrence was: intrahepatic growth (3 patients), new intrahepatic lesion (1 nodule in 5 patients, up to 3 nodules less or equal to 3cm in 4 cases and multifocal in one patient) and infiltrative ill-defined hepatocellular carcinoma and/or extra-hepatic lesions in 3 patients.nnnCONCLUSIONSnOur data show an unexpected high rate and pattern of tumor recurrence coinciding with HCV clearance and, although based in a very small cohort of patients, should be taken as a note of caution and prime a large scale assessment that exceeds the individual investigators capacity.nnnLAY SUMMARYnHigh rate of cancer recurrence after DAA treatment in patients with prior hepatocellular carcinoma. Disruption of immune surveillance may facilitate the emergence of metastatic clones.

Evaluation of tumor response after locoregional therapies in hepatocellular carcinoma: are response evaluation criteria in solid tumors reliable?

Evaluation of response to treatment is a key aspect in cancer therapy. Response Evaluation Criteria in Solid Tumors (RECIST) are used in most oncology trials, but those criteria evaluate only unidimensional tumor measurements and disregard the extent of necrosis, which is the target of all effective locoregional therapies. Therefore, the European Association for the Study of the Liver (EASL) guidelines recommended that assessment of tumor response should incorporate the reduction in viable tumor burden. The current report provides an assessment of the agreement/concordance between both RECIST and the EASL guidelines for the evaluation of response to therapy.

High pathological risk of recurrence after surgical resection for hepatocellular carcinoma: An indication for salvage liver transplantation

Surgical resection and liver transplantation offer a 5‐year survival greater than 70% in patients with hepatocellular carcinoma, but the high recurrence rate impairs long‐term outcome after resection. Pathological data such as vascular invasion and detection of additional nodules predict recurrence and divide patients into high and low risk profile. Based on this, we proposed salvage liver transplant to resected patients in whom pathology evidenced high recurrence risk even in the absence of proven residual disease. From January 1995 to August 2003 we have evaluated 1,638 patients. Resection was indicated in 77 patients, but only 17 (22%) (all cirrhotics, 14 hepatitis C virus+) were optimal candidates for both resection and transplantation. Of them, 8 exhibited a high risk profile at pathology and were offered transplantation. Among the 8 high risk patients, 7 presented recurrence, compared with only 2 of the 9 at low risk (P = .012). Two of the high risk patients refused transplant and developed multifocal disease during follow‐up. The other 6 were enlisted and all but 1 had tumor foci in the explant. Only 1 presented extrahepatic dissemination early after transplant and died 4 months later. The others are free of disease after a median follow‐up of 45 months. Two recurrences were detected in low risk patients, 1 of them being transplanted 18 months after surgery. These data in a small series of patients confirm that pathological parameters identify patients at higher risk of recurrence, which allow them to be listed for liver transplantation without proven malignant disease. In conclusion, this policy is clinically effective and could further improve the outcome of resected patients. (Liver Transpl 2004;10:1294–1300.)

Electric-field control of exchange bias in multiferroic epitaxial heterostructures.

The magnetic exchange between epitaxial thin films of the multiferroic (antiferromagnetic and ferroelectric) hexagonal YMnO3 oxide and a soft ferromagnetic (FM) layer is used to couple the magnetic response of the FM layer to the magnetic state of the antiferromagnetic one. We will show that biasing the ferroelectric YMnO3 layer by an electric field allows control of the magnetic exchange bias and subsequently the magnetotransport properties of the FM layer. This finding may contribute to paving the way towards a new generation of electric-field controlled spintronic devices.

Staging systems in hepatocellular carcinoma

Staging systems are key to predict the prognosis of patients with cancer, to stratify the patients according to prognostic variables in the setting of clinical trials, to allow the exchange of information among researchers, and finally to guide the therapeutic approach. The current knowledge of the disease, however, prevents recommendation of a staging system that can be used world-wide. The conventional staging systems for hepatocellular carcinoma (HCC), such as the Okuda stage or the TNM stage have shown important limitations in classifying patients. Several new systems have been proposed recently, and only three of them have been validated at this point. The BCLC staging classification links the stage of the disease to a specific treatment strategy. The JIS score has been proposed and used in Japan, although it needs Western validation. The CLIP score is used in patients with advanced tumors. Several reasons explain the difficulty in identifying a world-wide system. First, HCC is a complex neoplasm inserted on a pre-neoplastic cirrhotic liver, and thus variables of both diseases leading to death should be taken into account. Second, the disease is very heterogeneous around the world, and this reflects different underlying epidemiological backgrounds and risk factors. Third, HCC is the sole cancer treated by transplantation in a small proportion of patients. Fourth, only around 20% of the cases are currently treated by surgery, thus precluding the wide use of pathology-based systems, such as TNM. Finally, the potential relevance of a molecular signature identified in terms of outcome prediction is unknown, and further research is needed to obtain this valuable biological information that may aid in classifying the patients.

Is microbubble-enhanced ultrasonography sufficient for assessment of response to percutaneous treatment in patients with early hepatocellular carcinoma?

The objective of this study was to assess the efficacy of contrast-enhanced ultrasonography (CEUS) with SonoVue R to evaluate the response to percutaneous treatment (ethanol injection/radiofrequency) of hepatocellular carcinoma in comparison with spiral computed tomography (CT) immediately and 1 month after treatment. Forty-one consecutive cirrhotic patients with early stage tumor (not suitable for resection) were included. Spiral CT and CEUS were performed in all patients before treatment, in the following 24xa0h, and 1 month later. The results of each examination were compared with the 1-month spiral CT, considered the gold standard technique. The 24-h CEUS and the 24-h spiral CT sensitivity to detect residual disease were 27% and 20%, respectively. The 24-h CEUS and the 24-h spiral CT positive predictive value of persistent vascularization detection were 75% and 66%, respectively. The 1-month CEUS detected partial responses in ten out of 11 cases (91% sensitivity, 97% specificity, 95% accuracy). Spiral CT and CEUS performed in the 24xa0h following treatment are slightly useful to evaluate therapeutic efficacy. The 1-month CEUS has a high diagnostic accuracy compared with spiral -CT in the usual assessment of percutaneous treatment response.

Annual incidence of hepatocellular carcinoma among patients with alcoholic cirrhosis and identification of risk groups.

BACKGROUND & AIMSnThe incidence of hepatocellular carcinoma (HCC) and associated risk factors in patients with alcoholic cirrhosis are not well defined. Surveillance for HCC among patients with cirrhosis who do not have hepatitis B is cost effective only if the expected risk of HCC exceeds 1.5% per year. We performed a prospective study to determine the incidence of HCC among patients with alcoholic cirrhosis and to identify risk factors.nnnMETHODSnWe analyzed data from a surveillance program of 450 patients, aged 40 to 75 years, with alcoholic cirrhosis of Child-Pugh class A or B; patients were enrolled at the liver unit of a tertiary center from September 1992 through March 2010. Data were collected on 20 demographic, clinical, and laboratory variables at the start of the study. Patients were examined every 3 to 6 months for 5 years to identify risk factors for HCC; incidence was determined from a median follow-up time of 42 months.nnnRESULTSnOver the follow-up period, 62 patients developed HCC (43 in the first 5 y of follow-up evaluation), with an annual incidence of 2.6%. By using multivariate analysis, age 55 years and older (hazard ratio, 2.39; 95% confidence interval, 1.27-4.51) and platelet counts less than 125 × 10(3)/mm(3) (hazard ratio, 3.29; 95% confidence interval, 1.39-7.85) were associated independently with the development of HCC. These variables were used to define 3 risk groups. The annual incidence of HCC in the group without either of these factors was 0.3% (n = 93), the annual incidence with 1 factor was 2.6% (n = 228), and the annual incidence with both factors was 4.8% (n = 129) (P < .0001).nnnCONCLUSIONSnThe annual incidence of HCC among patients with alcoholic cirrhosis of Child-Pugh class A or B is around 2.5%. Age and platelet count can be used to classify the patients in 3 different risk groups for HCC development within the next 5 years.

Treatment of hepatocellular carcinoma: is there an optimal strategy?

The incidence of hepatocellular carcinoma is increasing worldwide and now it accounts for as many as 1 million deaths annually, representing the third cause of cancer-related death. Surveillance programmes in the population at risk, namely cirrhotic patients, aim to detect tumours at an early stage when benefit from effective therapy may be provided. Patients with early tumours (single tumours measuring less than 5 cm or with less than 3 nodules measuring less than 3 cm in size) constitute the early stage category. These patients may be treated with surgical resection, transplantation, or percutaneous ablation, and the 5-year survival rate will exceed 50%. Patients with more advanced disease constitute the intermediate-advanced stage. Intermediate stage includes individuals without cancer-related symptoms and absence of vascular invasion and/or extrahepatic spread. They may achieve a 50% survival rate at 3 years that can be expanded by transarterial chemoembolization. Symptomatic patients with more advanced disease have a survival rate of less than 20% at 3 years. In this group of patients the efficacy of new agents should be assessed in phase II trials or randomized controlled trials versus no treatment to determine the impact of any therapy on survival. Finally, patients with end-stage disease with heavily impaired liver function (Child-Pugh class C) or severe physical impairment (performance status 3-4) die within 6 months and should receive only symptomatic treatment.

Selection of candidates with HCC for transplantation in the MELD era

Key Points 1 Liver transplantation is the main option for patients with early HCC who are not optimal candidates for surgical resection. 2 Shortage of donors is its main limitation, as waiting for a liver allows the tumor to progress and induce exclusion from the waiting list and death. 3 The absence of randomized controlled trials hinders the establishment of the most effective therapy to prevent tumor progression while waiting. 4 Live donation may be a cost‐effective approach if optimal results are expected and the mortality risk for the donor is kept below .3%. 5 Priority policies have to be developed and refined to provide a fair and effective distribution of cadaveric organs. (Liver Transpl 2004;10:S4–S9.)