Loreto Boix

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.)

Focus on hepatocellular carcinoma

We apologize to the many laboratories whose contribution to this field could not be discussed or cited. Due to space limitations, many primary references were omitted. Loreto Boix has a contract with Fundacion Cientifica de la Asociacion Espanola Contra el Cancer. Josep M. Llovet is a recipient of a contract from programa “Ramon y Cajal”, IDIBAPS, Ministerio de Ciencia y Tecnologia. This work was supported by a grant from Red Tematica del Cancer, Instituto de Salud Carlos III (grant number C03/10). The sponsors had no part in the research or writing of this paper.

K-ras Mutations in DNA Extracted From the Plasma of Patients With Pancreatic Carcinoma: Diagnostic Utility and Prognostic Significance

PURPOSE Previous studies have demonstrated the presence of K-ras mutations in the plasma of patients with pancreatic carcinoma. However, the diagnostic utility and the prognostic significance of this finding have never been addressed. PATIENTS AND METHODS Forty-four consecutive patients with histologically confirmed primary pancreatic ductal adenocarcinoma were included. A control group of 37 patients with chronic pancreatitis, 10 patients with other tumors of the pancreatic area, nine patients with acute pancreatitis, and four healthy volunteers was also included. Plasma DNA was isolated and K-ras codon-12 mutations were analyzed by means of restriction fragment length polymorphism-polymerase chain reaction and single-strand conformation polymorphism techniques. Patients were followed up to establish their clinical outcome. RESULTS The mutant-type K-ras gene was found in plasma DNA samples of 12 (27%) of 44 patients with pancreatic ductal adenocarcinoma; this finding was related to the tumor stage (P = .05), mainly in the presence of distant metastases (P = .02). In addition, K-ras mutations were detected in the plasma DNA of two (5%) of 37 patients with chronic pancreatitis. In the subset of patients with pancreatic masses, the sensitivity and specificity of plasma K-ras analysis for pancreatic adenocarcinoma were 27% and 100%, respectively. Finally, pancreatic carcinoma patients with the mutant-type K-ras gene in plasma DNA exhibited a shorter survival time than patients with the wild-type gene (P<.005), and plasma K-ras mutations were identified as the only independent prognostic factor (odds ratio, 1.51; 95% confidence interval, 1.02 to 2.23). CONCLUSION Plasma K-ras analysis is a highly specific, low-sensitivity approach that has diagnostic and prognostic clinical implications in patients with pancreatic carcinoma.

Treatment of hepatocellular carcinoma with tamoxifen: A double-blind placebo-controlled trial in 120 patients

BACKGROUND & AIMS The progression of hepatocellular carcinoma may be influenced by estrogens. This has offered the rationale for evaluating the therapeutic usefulness of estrogen-receptor blockers; it is being debated whether long-term tamoxifen administration improves survival in patients with this neoplasm. The aim of this study was to assess the efficacy of tamoxifen administration in the treatment of hepatocellular carcinoma. METHODS One hundred twenty patients with this neoplasm who were not suitable for surgery, ethanol injection, or transarterial embolization were included in a placebo-controlled trial and randomized to tamoxifen, 20 mg/day per os, (group A, n = 58) or placebo (group B, n = 62). Patients with terminal diseases were excluded. RESULTS Both groups were similar with regard to sex, age, liver function (Child-Pughs score, 6.5 +/- 1.4 vs. 6.4 +/- 1.4), baseline performance status, and tumor stage. Tamoxifen had no antitumoral effect with no differences in the survival between groups (1- and 2-year actuarial rate: group A, 51% and 27%; and group B, 43% and 29%; P = 0.75), even when stratifying patients according to baseline status. Furthermore, there were no differences in the probability of disease progression (P = 0.46) and baseline performance status maintenance (P = 0.93) during follow-up. CONCLUSIONS Tamoxifen has no efficacy in the treatment of patients with advanced hepatocellular carcinoma.

Prospective validation of an immunohistochemical panel (glypican 3, heat shock protein 70 and glutamine synthetase) in liver biopsies for diagnosis of very early hepatocellular carcinoma

Background and aims Conventional pathological analysis fails to achieve sufficient sensitivity and specificity for the diagnosis of hepatocellular carcinoma (HCC) in small nodules. Immunohistochemical staining for glypican 3 (GPC3), heat shock protein 70 (HSP70) and glutamine synthetase (GS) has been suggested to allow a confident diagnosis but no prospective study has established the diagnostic accuracy of this approach. The aim of this study is to assess prospectively the diagnostic accuracy of a panel of markers (GPC3, HSP70, GS) for the diagnosis of HCC in patients with cirrhosis with a small (5–20 mm) nodule detected by ultrasound screening. Methods Sixty patients with cirrhosis with a single nodule 5–20 mm newly detected by ultrasound were included in the study. Contrast-enhanced ultrasound, magnetic resonance and fine needle biopsy of the nodule (gold standard) were performed; the biopsy was repeated in case of diagnostic failures. Three consecutive sections of the first biopsy sample with meaningful material were stained with antibodies against GPC3, HSP70 and GS. Results Forty patients were diagnosed with HCC. The sensitivity and specificity for HCC diagnosis were: GPC3 57.5% and 95%, HSP70 57.5% and 85%, GS 50% and 90%, respectively. The sensitivity and specificity of the different combinations were: GPC3+HSP70 40% and 100%; GPC3+GS 35% and 100%; HSP70+GS 35% and 100%; GPC3+HSP70+GS 25% and 100%. When at least two of the markers were positive (regardless of which), the sensitivity and specificity were 60% and 100%, respectively. Conventional pathological analysis yielded three false negative results, but the addition of this panel only correctly classified one of these cases as HCC. Conclusion These data within a prospective study establish the clinical usefulness of this panel of markers for the diagnosis of early HCC. However, the panel only slightly increases the diagnostic accuracy in an expert setting.

Transarterial embolization for hepatocellular carcinoma. Antibiotic prophylaxis and clinical meaning of postembolization fever

BACKGROUND/AIMS The aim of this prospective randomized controlled trial was to investigate the need for prophylactic antibiotherapy in patients with cirrhosis and hepatocellular carcinoma who underwent transarterial embolization and to establish the parameters that determine the development of fever > 38 degrees C after this procedure. METHODS Sixty-one consecutive patients with cirrhosis undergoing 75 procedures were randomized into Group I [(n = 37) allocated to receive prophylactic antibiotics (Cefotaxime + Metronidazole)] and Group II [(n = 38) allocated to receive no antibiotic treatment]. RESULTS Twelve of the 37 patients (32%) in Group I and 13 of the 38 patients (34%) in Group II developed fever > 38 degrees C after treatment. However, none of them developed bacterial infection, and all biological fluid cultures were negative. A logistic regression analysis disclosed that the obtention of an extensive tumor necrosis was the unique parameter independently associated with the development of fever. CONCLUSIONS Antibiotic prophylaxis is therefore not necessary in patients with cirrhosis and hepatocellular carcinoma undergoing transarterial embolization. The appearance of fever after this procedure does not indicate bacterial infection; it rather represents a clinical marker of extensive tumor necrosis and thus of a favorable response to treatment.

Gene Expression of Endothelin-1 and ETA and ETB Receptors in Human Cirrhosis: Relationship with Hepatic Hemodynamics

Previous experimental studies have suggested that the paracrine endothelin system may participate in the regulation of hepatic hemodynamics in cirrhosis. The present study assesses the relationship between increased portal pressure and preproET-1, ETA receptor and ETB receptor gene expression in human cirrhosis. PreproET-1, ETA receptor and ETB receptor mRNA abundance was estimated by quantitative PCR in human hepatic tissue from subjects with normal liver and in cirrhotic patients in whom a hepatic hemodynamic study was performed. The expression of the three transcripts was significantly higher in liver samples of cirrhotic patients than in those obtained from subjects without any histological alteration. Moreover, while no significant correlation was found between preproET-1 mRNA abundance and portal pressure, there was a highly significant direct relationship between ETA and ETB receptor gene expression and portal pressure in cirrhotic patients. These results indicate that the liver paracrine endothelin system is overactivated in human cirrhosis and that a direct relationship exists between endothelin receptor mRNA abundance and the degree of portal hypertension in these patients.

Sex hormone receptors in hepatocellular carcinoma: Is there a rationale for hormonal treatment?

The present study assessed the tumor concentration of receptors for estrogens, progesterone and androgens in a series of Western patients with hepatocellular carcinoma. Receptors for estrogens and for progesterone were determined by enzyme immunoassay, while androgen receptors were determined by receptor binding assay. Receptors for progesterone were always absent. Estrogen receptors were detected in only 4 tumors, while in the remaining specimens estrogen receptor concentration was lower than 5 fmol/mg of protein. The concentration of receptors within the tumor was not related to the presence of receptor in the non-tumoral liver, which contained estrogen receptors in 12 cases, ranging between 5 and 27 fmol/mg of protein. In contrast, 14 of the 26 tumors contained androgen receptors at concentrations ranging between 2 and 211 fmol/mg of protein; these were not related to the characteristics of the underlying liver, which contained androgen receptors in 14 cases. The results suggest that the beneficial effects of tamoxifen on the survival of patients with hepatocellular carcinoma cannot be explained by the action of this drug on estrogen receptors and that anti-androgen therapy may have some benefit in patients with androgen-receptor-positive tumors.

Sex hormone receptors in hepatocellular carcinoma

The present study assessed the tumor concentration of receptors for estrogens, progesterone and androgens in a series of Western patients with hepatocellular carcinoma. Receptors for estrogens and for progesterone were determined by enzyme immunoassay, while androgen receptors were determined by receptor binding assay. Receptors for progesterone were always absent. Estrogen receptors were detected in only 4 tumors, while in the remaining specimens estrogen receptor concentration was lower than 5 fmol/mg of protein. The concentration of receptors within the tumor was not related to the presence of receptor in the non-tumoral liver, which contained estrogen receptors in 12 cases, ranging between 5 and 27 fmol/mg of protein. In contrast, 14 of the 26 tumors contained androgen receptors at concentrations ranging between 2 and 211 fmol/mg of protein; these were not related to the characteristics of the underlying liver, which contained androgen receptors in 14 cases. The results suggest that the beneficial effects of tamoxifen on the survival of patients with hepatocellular carcinoma cannot be explained by the action of this drug on estrogen receptors and that anti-androgen therapy may have some benefit in patients with androgen-receptor-positive tumors.

Surgical resection and survival in western patients with hepatocellular carcinoma

In a retrospective study the survival of 28 patients with hepatocellular carcinoma, 25 of them with underlying cirrhosis, submitted to surgical resection was compared with the survival of 28 untreated patients, matched for variables known to bear independent prognostic value and therefore sharing the same baseline prognosis. Diagnosis was made in the same time period for both groups of patients. In addition, to further evaluate the effects of tumor resection on survival, the outcome of operated patients was also compared to their expected survival. This was derived from a mathematical model which takes into account the regression coefficients of the variables previously shown to be independently related to the survival of untreated patients with hepatocellular carcinoma. The median survival for resected patients was 27.1 months, which was significantly better than untreated controls (12.4 months; p less than 0.003). Median survival for patients submitted to resection and with tumors smaller than 5 cm was 35.8 months, while the median survival for untreated cases was 14.6 months p less than 0.0005. The comparison of observed survival (82% at one year and 73% at two years) and statistically expected survival (58% and 34%, respectively) further indicated that surgical resection effectively improves prognosis in Western patients with hepatocellular carcinoma. Thus, early detection of small tumors in the population at risk appears to be justified.