Non-cirrhotic Liver Research Articles

A pro-tumorigenic function of S100A8/A9 in carcinogen-induced hepatocellular carcinoma

Human hepatocellular carcinoma (HCC) is a heterogeneous disease, driven by different risk factors and presenting diverse clinicopathological features and outcomes. Epidemiological and experimental data indicate that the damage-associated molecular pattern molecules S100A8 and S100A9, forming a heterodimer called calprotectin, might be critically involved in HCC development. However, deletion of S100a9 in an inflammation- and cirrhosis-driven mouse model did not show any impairment in liver tumorigenesis, most likely due to functional compensation by other inflammatory cytokines. Here, we investigated the effect of calprotectin ablation in mice treated with diethylnitrosamine, a carcinogen-driven HCC model mimicking cancer development caused by acute liver damage in the absence of prominent chronic inflammation and tissue damage. We found that tumor cell proliferation was diminished in the absence of S100A8/A9, leading to significant reduction of tumor size.Our results demonstrate that calprotectin is required for the progression of non-inflammation driven liver tumor and might represent a therapeutic target for the treatment of HCC formed in non-cirrhotic liver.

Real‐time Tissue Elastography for Assessment of Liver Stiffness in Adults Without Known Liver Disease

To investigate normal liver stiffness and its influential factors in adults without liver disease using real-time tissue elastography. The liver stiffness threshold value for identifying patients with chronic liver disease was also determined. One hundred twenty healthy volunteers were examined with real-time tissue elastography. An integrated quantitative elastographic parameter, defined as the liver fibrosis index, was obtained by tissue dispersion quantitative analysis. Correlations between the liver fibrosis index and age, sex, and body mass index (BMI) were studied. To determine the threshold value for identifying chronic liver disease, 29 patients with chronic hepatitis B who underwent liver biopsy, including patients without fibrosis (fibrosis stage F0; n = 9) and patients with substantial fibrosis (F1-F2; n = 20) were also investigated. A receiver operating characteristic curve analysis for differentiating the F0 from the F1-F2 group was performed. There were no significant differences in the mean liver fibrosis index between sexes or among different age groups. There was a positive correlation between BMI and the liver fibrosis index. The mean liver fibrosis index ± SD in healthy participants with a normal BMI was 1.31 ± 0.25. The mean liver fibrosis index values for F0 and F1-F2 patients with a normal BMI were 1.47 ± 0.24 and 2.44 ± 0.49, respectively (P < .001). The optimal liver fibrosis index threshold value for discriminating normal liver from noncirrhotic chronic liver disease was 2.12 in participants with a normal BMI. Liver stiffness determined by real-time tissue elastography in healthy Chinese adults is not affected by age and sex but has a positive correlation with BMI. Real-time tissue elastography for assessment of liver stiffness can also be used for identification of substantial fibrosis in patients with chronic liver disease.

Obliterative portal venopathy without portal hypertension: an underestimated condition

Obliterative portal venopathy without portal hypertension has been described by a single study in a limited number of patients, thus very little is known about this clinical condition. This study aimed to investigate the prevalence of obliterative portal venopathy and its clinical-pathological correlations in patients with cryptogenic chronic liver test abnormalities without clinical signs of portal hypertension. We analysed 482 liver biopsies from adults with non-cirrhotic cryptogenic chronic liver disorders and without any clinical signs of portal hypertension, consecutively enrolled in a 5-year period. Twenty cases of idiopathic non-cirrhotic portal hypertension diagnosed in the same period, were included for comparison. Histological findings were matched with clinical and laboratory features. Obliterative portal venopathy was identified in 94 (19.5%) of 482 subjects and in all 20 cases of idiopathic non-cirrhotic portal hypertension: both groups shared the entire spectrum of histological changes described in the latter condition. The prevalence of incomplete fibrous septa and nodular regenerative hyperplasia was higher in the biopsies of idiopathic non-cirrhotic portal hypertension (P = 0.006 and P = 0.002), a possible hint of a more advanced stage of the disease. The two groups also shared several clinical laboratory features, including a similar liver function test profile, concomitant prothrombotic conditions and extrahepatic autoimmune disorders. Obliterative portal venopathy occurs in a substantial proportion of patients with unexplained chronic abnormal liver function tests without portal hypertension. The clinical-pathological profile of these subjects suggests that they may be in an early (non-symptomatic) stage of idiopathic non-cirrhotic portal hypertension.

Preoperative Sequential Portal and Hepatic Vein Embolization in Patients with Hepatobiliary Malignancy.

Preoperative portal vein embolization (PVE) induces shrinkage of the embolized lobe and compensatory regeneration in the non-embolized lobe, but does not always induce sufficient regeneration of the future remnant liver (FRL). We previously developed preoperative sequential PVE-hepatic vein embolization (HVE), and here we present our experience of treating 42 patients with sequential PVE-HVE. During 8-year study period, preoperative PVE-HVE was performed on 42 patients with hepatobiliary malignancies. Primary diseases were bile duct cancers [perihilar cholangiocarcinoma (n = 33) and diffuse bile duct cancer (n = 1)], hepatocellular carcinomas (n = 4), and intrahepatic tumors [intrahepatic cholangiocarcinoma (n = 3) and gallbladder cancer liver invasion (n = 1)]. These patients demonstrated insufficient FRL regeneration following PVE, thus HVE was performed to induce further regeneration. No PVE-HVE procedure-associated complications occurred. In the bile duct cancer group, FRL volume was 33.9 ± 2.2 % before PVE, 38.4 ± 1.5 % before HVE, 43.7 ± 2.1 % at surgery, and 73.6 ± 8.3 % at 2 weeks after right hepatectomy. The degree of FRL hypertrophy was 13.3 % after PVE, 28.9 % after PHV-HVE, and 117.1 % at 2 weeks after right hepatectomy. All patients except one recovered uneventfully after surgery, and the 3-year patient survival rate was 45.1 %. In the HCC group, transarterial chemoembolization was initially performed and FRL regeneration following PVE-HVE occurred very slowly. Active FRL regeneration occurred in the liver tumor group, but rapid tumor growth was observed in 1 of 4 patients. The sequential application of HVE following PVE safely and effectively induces further FRL regeneration in non-cirrhotic livers. Further validation using larger patient population and multicenter studies is needed to reliably widen the indications.

Recurrent AAV2-related insertional mutagenesis in human hepatocellular carcinomas.

Hepatocellular carcinomas (HCCs) are liver tumors related to various etiologies, including alcohol intake and infection with hepatitis B (HBV) or C (HCV) virus. Additional risk factors remain to be identified, particularly in patients who develop HCC without cirrhosis. We found clonal integration of adeno-associated virus type 2 (AAV2) in 11 of 193 HCCs. These AAV2 integrations occurred in known cancer driver genes, namely CCNA2 (cyclin A2; four cases), TERT (telomerase reverse transcriptase; one case), CCNE1 (cyclin E1; three cases), TNFSF10 (tumor necrosis factor superfamily member 10; two cases) and KMT2B (lysine-specific methyltransferase 2B; one case), leading to overexpression of the target genes. Tumors with viral integration mainly developed in non-cirrhotic liver (9 of 11 cases) and without known risk factors (6 of 11 cases), suggesting a pathogenic role for AAV2 in these patients. In conclusion, AAV2 is a DNA virus associated with oncogenic insertional mutagenesis in human HCC.

Endovascular treatment of acute and chronic portal vein thrombosis in patients with cirrhotic and non-cirrhotic liver.

Treatment of patients with portal vein thrombosis (PVT) differs due to different etiology and wide range of symptoms but certain patients seems to benefit from endovascular intervention. To assess the safety and efficiency of endovascular treatment of acute and chronic PVT in patients with cirrhotic and non-cirrhotic liver. Twenty-one patients with PVT treated with an endovascular procedure in 2002-2013 were studied retrospectively. Data on etiology, onset and extension of thrombus, presenting symptoms, methods of intervention, portal pressure gradients, complications, recurrence of symptoms, re-interventions, clinical status at latest follow-up, and survival were collected. Four non-cirrhotic patients with acute extensive PVT and bowel ischemia were treated with local thrombolysis, in three combined with placement of a transjugular intrahepatic portosystemic shunt (TIPS) placement. Three recovered and have survived more than 6 years. In six non-cirrhotic patients with chronic PVT and acute or threatening variceal bleeding recanalization and TIPS were successful in three and failed in three. Eleven cirrhotic patients with PVT and variceal bleeding or refractory ascites were successfully treated with recanalization and TIPS. Re-intervention was performed in five of these patients and five patients died, three within 12 months of intervention. Four cirrhotic patients had episodes of shunt-related encephalopathy and three had variceal re-bleeding. TIPS was found to be effective in reducing portal hypertension in patients with PVT. In patients with extensive PVT and bowel ischemia treatment with TIPS combined with thrombolysis should be considered.

Hepatocellular Carcinoma in the Setting of Non-cirrhotic Nonalcoholic Fatty Liver Disease and the Metabolic Syndrome: US Experience.

Type 2 diabetes mellitus, obesity, and the metabolic syndrome (MS) have been growing in prevalence in the USA and are independent risk factors for the development of hepatocellular carcinoma (HCC). Nonalcoholic fatty liver disease (NAFLD), the hepatic manifestation of the MS, with or without nonalcoholic steatohepatitis (NASH) can predispose to HCC in the absence of cirrhosis or advanced fibrosis. Nevertheless, the US literature investigating non-cirrhotic HCC in the setting of NAFLD/NASH and MS is lacking. To describe a retrospective case series of patients who developed HCC without cirrhosis in the setting of NAFLD/NASH or features of the MS. We identified NAFLD/NASH-associated HCC cases arising in the absence of cirrhosis between January 2010 and September 2012 from a tumor board database at Brooke Army Medical Center (BAMC). Of 44 cases of HCC reviewed, six cases of non-cirrhotic HCC associated with NAFLD/NASH and/or MS were identified. Only one patient underwent partial hepatectomy with curative intent. The other five might have been candidates for potential curative partial hepatectomy or liver transplantation had they been diagnosed earlier. Our case series highlights the development of NAFLD/NASH and MS-associated HCC in the absence of cirrhosis in the US population and raises the important question of HCC screening for this at-risk group.

Facing the enigma of the vascular network in hepatocellular carcinomas in cirrhotic and non-cirrhotic livers

AimsIn this paper we aimed to analyse the typology and the phenotype of the different vascular modifications in human hepatocellular carcinomas (HCCs) with a new immunomorphological and gene expression approach....

Development of a Support Vector Machine - Based Image Analysis System for Focal Liver Lesions Classification in Magnetic Resonance Images

Purpose: The design and implementation of a computer-based image analysis system employing the support vector machine (SVM) classifier system for the classification of Focal Liver Lesions (FLLs) on routine non-enhanced, T2-weighted Magnetic Resonance (MR) images. Materials and Methods: The study comprised 92 patients; each one of them has undergone MRI performed on a Magnetom Concerto (Siemens). Typical signs on dynamic contrast-enhanced MRI and biopsies were employed towards a three class categorization of the 92 cases: 40-benign FLLs, 25-Hepatocellular Carcinomas (HCC) within Cirrhotic liver parenchyma and 27-liver metastases from Non-Cirrhotic liver. Prior to FLLs classification an automated lesion segmentation algorithm based on Marcov Random Fields was employed in order to acquire each FLL Region of Interest. 42 texture features derived from the gray-level histogram, co-occurrence and run-length matrices and 12 morphological features were obtained from each lesion. Stepwise multi-linear regression analysis was utilized to avoid feature redundancy leading to a feature subset that fed the multiclass SVM classifier designed for lesion classification. SVM System evaluation was performed by means of leave-one-out method and ROC analysis. Results: Maximum accuracy for all three classes (90.0%) was obtained by means of the Radial Basis Kernel Function and three textural features (Inverse- Different-Moment, Sum-Variance and Long-Run-Emphasis) that describe lesion's contrast, variability and shape complexity. Sensitivity values for the three classes were 92.5%, 81.5% and 96.2% respectively, whereas specificity values were 94.2%, 95.3% and 95.5%. The AUC value achieved for the selected subset was 0.89 with 0.81 - 0.94 confidence interval. Conclusion: The proposed SVM system exhibit promising results that could be utilized as a second opinion tool to the radiologist in order to decrease the time/cost of diagnosis and the need for patients to undergo invasive examination.

Increased Autophagy Markers Are Associated with Ductular Reaction during the Development of Cirrhosis

Autophagy is a regulatory pathway in liver fibrosis. We investigated the roles of autophagy in human cirrhotic livers. Cirrhotic and noncirrhotic liver tissues were obtained from patients with hepatocellular carcinoma, and liver tissues from live donors served as control. Patients with cirrhotic livers had significantly increased levels of various essential autophagy-related genes compared with noncirrhotic livers. In addition, colocalization of autophagy marker microtubule-associated protein 1 light chain 3B (LC3B) with lysosome-associated membrane protein-1, increased levels of lysosome-associated membrane protein-2, and increased maturation of lysosomal cathepsin D were observed in cirrhotic livers. By using dual-immunofluorescence staining, we demonstrated that increased LC3B was located mainly in the cytokeratin 19-labeled ductular reaction (DR) in human cirrhotic livers and in an experimental cirrhosis induced by 2-acetylaminofluorene (AAF) with carbon tetrachloride (CCl4), indicating a conserved response to chronic liver damage. Furthermore, an AAF/CCl4-mediated increase in DR and fibrosis were attenuated after chloroquine treatment, suggesting that the autophagy-lysosome pathway was essential for AAF/CCl4-induced DR-fibrosis. In conclusion, we demonstrated that increased autophagy marker positively correlated with DR during the development of cirrhosis. Therefore, targeting autophagy may hold therapeutic value for liver cirrhosis.

MR imaging features for improved diagnosis of hepatocellular carcinoma in the non-cirrhotic liver: Multi-center evaluation

PurposeTo determine MR-imaging features for the differentiation between hepatocellular carcinoma (HCC) and benign hepatocellular tumors in the non-cirrhotic liver. Material and Methods107 consecutive patients without liver cirrhosis (46 male; 45±14 years) who underwent liver resection due to suspicion of HCC were included in this multi-center study. The following imaging features were assessed: lesion diameter and demarcation, satellite-lesions, central-scar, capsule, fat-content, hemorrhage, vein-infiltration and signal-intensity (SI) on native T1-, T2- and dynamic-enhanced T1-weighted images (center versus periphery). In addition, contrast-media (CM) uptake in the liver specific phase was analyzed in a sub-group of 42 patients. ResultsSignificant differences between HCC (n=55) and benign lesions (n=52) were shown for native T1-, T2- and dynamic-enhanced T1-SI, fat-content, and satellite-lesions (all, P<.05). Independent predictors for HCC were T1-hypointensity (odds-ratio, 4.81), T2-hypo-/hyperintensity (5.07), lack of central tumor-enhancement (3.36), and satellite-lesions (5.78; all P<0.05). Sensitivity and specificity of HCC was 91% and 75% respectively for two out-of four independent predictors, whereas specificity reached 98% for all four predictors. Sub-analysis, showed significant differences in liver specific CM uptake between HCC (n=18) and benign lesions (n=24; P<0.001) and revealed lack of liver specific CM uptake (odds-ratio, 2.7) as additional independent feature for diagnosis of HCC. ConclusionIndependent MRI features indicating HCC are T1-hypointensity, T2-hypo- or hyperintensity, lack of central tumor-enhancement, presence of satellite-lesions and lack of liver specific CM-uptake. These features may have the potential to improve the diagnosis of HCC in the non-cirrhotic liver.

Differential reactivation of fetal/neonatal genes in mouse liver tumors induced in cirrhotic and non-cirrhotic conditions.

Hepatocellular carcinoma develops in either chronically injured or seemingly intact livers. To explore the tumorigenic mechanisms underlying these different conditions, we compared the mRNA expression profiles of mouse hepatocellular tumors induced by the repeated injection of CCl4 or a single diethylnitrosamine (DEN) injection using a cDNA microarray. We identified tumor-associated genes that were expressed differentially in the cirrhotic CCl4 model (H19, Igf2, Cbr3, and Krt20) and the non-cirrhotic DEN model (Tff3, Akr1c18, Gpc3, Afp, and Abcd2) as well as genes that were expressed comparably in both models (Ly6d, Slpi, Spink3, Scd2, and Cpe). The levels and patterns of mRNA expression of these genes were validated by quantitative RT-PCR analyses. Most of these genes were highly expressed in mouse livers during the fetal/neonatal periods. We also examined the mRNA expression of these genes in mouse tumors induced by thioacetamide, another cirrhotic inducer, and those that developed spontaneously in non-cirrhotic livers and found that they shared a similar expression profile as that observed in CCl4-induced and DEN-induced tumors, respectively. There was a close relationship between the expression levels of Igf2 and H19 mRNA, which were activated in the cirrhotic models. Our results show that mouse liver tumors reactivate fetal/neonatal genes, some of which are specific to cirrhotic or non-cirrhotic modes of pathogenesis.

Bile duct thrombi in hepatocellular carcinoma: is aggressive surgery worthwhile?

IntroductionObstructive jaundice as a result of bile duct tumour thrombus (BDTT) is an unusual clinical entity and an uncommon presenting feature of hepatocellular carcinoma (HCC). This study evaluates the outcome of hepatectomy for HCC with obstructive jaundice as a result of BDTT in non-cirrhotic livers. MethodsBetween 1997 and 2012, out of 426 patients with HCC in non-cirrhotic livers, 39 patients with BDTT (Group I n = 39), who underwent a hepatectomy, were analysed and compared with the non-BDTT group (Group II n = 387). ResultsThe demographic profile and biochemical parameters between Group I and Group II were compared; apart from the presence of jaundice at presentation and an elevated serum bilirubin, there were no significant differences. Post-operative morbidity and mortality were 11 (28.2%) and 2 (5.1%), respectively, in Group I. There were no differences between the groups with regards to the operative variables and short-term outcomes. The 1-, 3- and 5-year survival rates in Group I were 82%, 48% and 10%, respectively, with a median survival of 28.6 months and were significantly poorer than Group II (90%, 55% and 38%, respectively, with a median survival of 39.2 months). ConclusionThe mere presence of BDTT in HCC does not indicate an advanced or inoperable lesion. When technically feasible, a formal hepatic resection is the preferred first-line treatment option in these patients.

Hepatocellular adenoma with malignant transformation in male patients with non-cirrhotic livers.

IntroductionHepatocellular adenomas (HCAs), with a risk of malignant transformation into hepatocellular carcinoma (HCC), classically develop in young women who are taking oral contraceptives. It is now clear that HCAs may also occur in men. However, it is rarely reported that HCAs with malignant transformation occur in male patients with non-cirrhotic livers. This study aimed to characterize the malignancy of HCAs occurring in male patients.MethodsAll patients with HCAs with malignant transformation who underwent hepatectomy at the Cancer Institute and Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College between January 1, 1999 and December 31, 2011 were enrolled in the study. The clinical characteristics as well as radiologic and pathologic data were reviewed.ResultsHCAs with malignant transformation were observed in 5 male patients with non-cirrhotic livers, but not in female patients. The alpha-fetoprotein (AFP) levels were higher in patients with HCAs with malignant transformation than in patients with HCAs without malignant transformation. The diameters of the tumors with malignant transformation were larger than 5 cm in 3 cases and smaller than 5 cm in 2 cases. The 5 patients were all alive without recurrence by the end of the study period. The disease-free survival times of the 5 patients were 26, 48, 69, 69, and 92 months.ConclusionOur results indicate that resection would be advised even if the presumptive diagnosis is adenoma smaller than 5 cm in diameter, especially in male patients.

Focal masses in a non-cirrhotic liver: The additional benefit of CEUS over baseline imaging

Incidentally detected focal liver lesions are commonly encountered in clinical practice presenting a challenge in the daily department work flow. Guidelines for the management of incidental focal liver lesions have been published but comments, illustrations and recommendations regarding practical issues are crucial. The unique features of contrast-enhanced ultrasound in non-invasive assessment of focal liver lesion enhancement throughout the vascular phases in real-time has allowed an impressive improvement in the diagnostic accuracy of ultrasound.We highlight the additional benefit of contrast-enhanced ultrasound over conventional B-mode ultrasound imaging in detection, characterization, differential and final diagnosis of focal liver lesions, as well as for liver metastases screening. The current roles of cross-sectional imaging are explained in detail, with indications and limitations for each procedure. The advantages of CEUS, such as non-ionizing radiation exposure, cost benefits, non-iodinate contrast agents, and repeatability are also described ultimately improving patient management.

Hepatocellular Carcinoma Without Cirrhosis Presenting With Hypercalcemia: Case Report and Literature Review

Hepatocellular carcinoma (HCC) in non-cirrhotic livers is an uncommon finding and can present insidiously in patients. Another uncommon finding in HCC, and one of poor prognosis, is the presence of paraneoplastic diseases such as hypercalcemia. We report a case of a 66-year-old previous healthy Filipina woman who after routine laboratory evaluation was discovered to have hypercalcemia as the first sign of an advanced HCC without underlying cirrhosis. Because of the patient's relative lack of symptoms, healthy liver function, lack of classical HCC risk factors, and unexpected hypercalcemia, the diagnosis of a paraneoplastic syndrome caused by a noncirrhotic HCC was unanticipated. Case Analysis with Pubmed literature review. It is unknown how often hypercalcemia is found in association with HCC in a non-cirrhotic liver. However, paraneoplastic manifestations of HCC, particularly hypercalcemia, can be correlated with poor prognosis. For this patient, initial management included attempts to lower calcium levels via zoledronate, which wasn't completely effective. Tumor resection was then attempted however the patient expired due to complications from advanced tumor size. Hypercalcemia of malignancy can be found in association with non-cirrhotic HCC and should be considered on the differential diagnosis during clinical work-up.

Tu2027 Endoscopic Versus Percutaneous Drainage for Management of Hilar Cholangiocarcinoma

Background: The incidence of hepatocellular carcinoma (HCC) has increased significantly in United States over the last few decades in parallel with the epidemic of nonalcoholic fatty liver disease (NAFLD). Limited data suggest that HCC could arise in steatotic livers without the presence of cirrhosis. The aim of the current study was to characterize patients with NAFLD presenting with HCC in non-cirrhotic liver (NCL) compared to those with HCC in association with liver cirrhosis (LC). Methods: A retrospective analysis was performed on all patients with HCC and NAFLD diagnosis seen at our institution between 2003 and 2012. We characterized the patients with respect to demographic, clinical, histological and tumor features. Comparisons between the NCL and LC groups were done using t-test, Mann Whitney U test, and Chi square test as appropriate. P value 5 cm) (77.8% vs. 23 %), and receive hepatic resection as the modality for HCC treatment (66.7% vs. 17%); and were less likely to receive loco-regional therapy (16.7% vs. 51.1%) or liver transplant (0% vs. 72.3%), p value < 0.001 for all. Furthermore, 62% of patients without cirrhosis had HCC recurrence compared to only 12.5% in patients with cirrhosis (p < 0.001) and had worse survival with mortality rate of 41.7% at last follow up for the HCC-NCL group compared to 27.7% in the cirrhotic group (p = 0.008). Conclusion: Patients with HCC in the absence of liver cirrhosis are more likely to present at an older age with larger tumor and have higher rates of tumor recurrence. Studies to assess the cost-effectiveness of HCC surveillance in this group should be conducted.

Tu2026 Characterization of Hepatocellular Carcinoma (HCC) in NAFLD Patients Without Cirrhosis

Background: The incidence of hepatocellular carcinoma (HCC) has increased significantly in United States over the last few decades in parallel with the epidemic of nonalcoholic fatty liver disease (NAFLD). Limited data suggest that HCC could arise in steatotic livers without the presence of cirrhosis. The aim of the current study was to characterize patients with NAFLD presenting with HCC in non-cirrhotic liver (NCL) compared to those with HCC in association with liver cirrhosis (LC). Methods: A retrospective analysis was performed on all patients with HCC and NAFLD diagnosis seen at our institution between 2003 and 2012. We characterized the patients with respect to demographic, clinical, histological and tumor features. Comparisons between the NCL and LC groups were done using t-test, Mann Whitney U test, and Chi square test as appropriate. P value 5 cm) (77.8% vs. 23 %), and receive hepatic resection as the modality for HCC treatment (66.7% vs. 17%); and were less likely to receive loco-regional therapy (16.7% vs. 51.1%) or liver transplant (0% vs. 72.3%), p value < 0.001 for all. Furthermore, 62% of patients without cirrhosis had HCC recurrence compared to only 12.5% in patients with cirrhosis (p < 0.001) and had worse survival with mortality rate of 41.7% at last follow up for the HCC-NCL group compared to 27.7% in the cirrhotic group (p = 0.008). Conclusion: Patients with HCC in the absence of liver cirrhosis are more likely to present at an older age with larger tumor and have higher rates of tumor recurrence. Studies to assess the cost-effectiveness of HCC surveillance in this group should be conducted.

Therapeutic strategies for hepatocellular carcinoma: new advances and challenges.

Hepatocellular carcinoma (HCC) is the fastest growing malignancy in the USA, and its prognosis remains poor with a 5-year survival around 12%. Clinical data demonstrate that 85% of cases occur in individuals with underlying cirrhosis and only 15% develop in non-cirrhotic livers. Therefore, American and European guidelines recommend routine HCC screening for high-risk individuals (patients with cirrhosis) with abdominal ultrasound every 6months. Once a lesion is identified or suspected on ultrasound, dynamic imaging is then indicated. The diagnosis of HCC is established in a patient with cirrhosis when a lesion measures at least 1cm in diameter and demonstrates arterial enhancement and portal venous washout on contrast-enhanced computerized tomography or magnetic resonance imaging. Indeterminate lesions should be followed with surveillance imaging or further investigated with biopsy according to the level of suspicion for malignancy. Given the clinical, pathological, and molecular heterogeneity of HCC, there are multiple therapeutic modalities available. These may be curative, such as surgical resection, liver transplantation, and local ablation, or palliative, such as catheter-directed therapies (transarterial chemo, radio, or bland embolization), and systemic therapy (sorafenib). Patients with a single lesion, good performance status, and preserved liver synthetic function should be offered curative surgical resection or ablation therapy. Patients with HCC and decompensated liver disease should be evaluated and listed for liver transplantation. For unresectable disease or tumor burden precluding transplantation or curative ablation, palliative therapeutic modalities should be offered. Sorafenib is indicated for patients with vascular invasion and/or extra-hepatic metastasis if the estimated life expectancy is more than 3months. Systemic internal radiation therapy using yttrium-90 microspheres in cases of multifocal bi-lobar disease and/or portal vein occlusion is an emerging therapy. Best supportive care is recommended for patients who lack the hepatic reserve to tolerate therapy.

Intra-arterial yttrium-90 radioembolization combined with systemic chemotherapy is a promising method for downstaging unresectable huge intrahepatic cholangiocarcinoma to surgical treatment.

To evaluate the downstaging efficacy of yttrium-90 radioembolization (Ytt-90)-associated with chemotherapy and the results of surgery for initially unresectable huge intrahepatic cholangiocarcinoma (ICC). Between January 2008 and October 2013, unresectable ICC were treated with chemotherapy and Ytt-90. Patients with unique tumors localized to noncirrhotic livers and without extrahepatic metastasis were considered to be potentially resectable and were evaluated every 2 months for possible secondary resection. Forty-five patients were treated for unresectable ICCs; ten had potentially resectable tumors, and eight underwent surgery. Initial unresectability was due to the involvement of the hepatic veins or portal vein of the future liver remnant in seven and one cases, respectively. Preoperative treatment induced significant decreases in tumor volume (295 vs. 168 ml, p = 0.02) and allowed for R0 resection in all cases. Three patients (37.5 %) had Clavien-Dindo grade three or higher complications, including two postoperative deaths. The median follow-ups were 15.6 [range 4-40.7] months after medical treatment initiation and 7.2 [0.13-36.4] months after surgery. At the end of the study period, five patients were still alive, with one patient still alive 40 months after medical treatment initiation (36.4 months after surgery); two patients experienced recurrences. For initially unresectable huge ICCs, chemotherapy with Ytt-90 radioembolization is an effective downstaging method that allows for secondary resectability.