Cholangiocarcinoma (CCA) is a heterogeneous group of tumours, derived from cells of the biliary tree, which represent the second most frequent primary liver tumour. According to the most recent ...classifications, CCA can be subdivided into intrahepatic (iCCA) and extrahepatic (eCCA) which include perihilar (pCCA) and distal (dCCA) CCA. CCA are usually identified at advanced stages, when the primary tumour grows enough to produce a large liver mass or when jaundice has developed because of biliary tree obstruction. The ongoing challenges in the identification of risk factors and definition of a specific population at higher risk of developing CCA are the main challenges for the development of screening programs. Therefore, late diagnosis remains an unresolved issue in CCA. Imaging plays an important role in the detection and characterization of CCA, helping with radiological diagnosis, guiding biopsy procedures and allowing staging of the tumour. This review focuses on clinical presentations and diagnosis and staging techniques of CCA.
Noninvasive criteria for the diagnosis of hepatocellular carcinoma (HCC) in cirrhosis, recommended by the European Association for the Study of Liver (EASL) in 2001 and by the American Association ...for the Study of Liver Diseases (AASLD) in 2005, have left a number of small liver neoplastic nodules undefined. We designed this prospective study in 2003 with the aims of assessing the diagnostic contribution of vascular contrast-enhanced techniques and investigating the possible additional contribution of superparamagnetic iron oxide magnetic resonance (SPIO-MR) in this setting.
Between 2003 and 2005, 75 consecutive small (10-30 mm) liver nodules detected at ultrasonography in 60 patients with cirrhosis were prospectively submitted to contrast-enhanced ultrasound (CEUS), helical-computed tomography (helical-CT), and gadolinium magnetic resonance (gad-MR), each blinded to the other. A total of 68 nodules were also studied with SPIO-MR at the same time as gad-MR.
Using the EASL noninvasive criteria, the diagnosis of HCC was established in 44 of 55 (80%) nodules with a final diagnosis of HCC. Gad-MR was the most sensitive technique for detecting the typical vascular pattern. SPIO-MR showed a pattern consistent with HCC in 5 of 10 HCCs, not satisfying the EASL noninvasive criteria, and was negative in 17 of 18 (94.4%) nonmalignant nodules. The review of the present case series according to the AASLD criteria for the noninvasive diagnosis of HCC yielded a sensitivity rate of 81.8%.
This study shows that both EASL and AASLD noninvasive recall strategies for nodules of 10-30 mm in the cirrhotic liver, based on the vascular pattern of nodules, have a false-negative rate of approximately 20%. SPIO-MR may increase the diagnostic potential of noninvasive techniques, contributing to the diagnosis of HCC lacking a typical vascular pattern.
Amplification and/or activation of the c‐Myc proto‐oncogene is one of the leading genetic events along hepatocarcinogenesis. The oncogenic potential of c‐Myc has been proven experimentally by the ...finding that its overexpression in the mouse liver triggers tumor formation. However, the molecular mechanism whereby c‐Myc exerts its oncogenic activity in the liver remains poorly understood. Here, we demonstrate that the mammalian target of rapamycin complex 1 (mTORC1) cascade is activated and necessary for c‐Myc‐dependent hepatocarcinogenesis. Specifically, we found that ablation of Raptor, the unique member of mTORC1, strongly inhibits c‐Myc liver tumor formation. Also, the p70 ribosomal S6 kinase/ribosomal protein S6 and eukaryotic translation initiation factor 4E‐binding protein 1/eukaryotic translation initiation factor 4E signaling cascades downstream of mTORC1 are required for c‐Myc‐driven tumorigenesis. Intriguingly, microarray expression analysis revealed up‐regulation of multiple amino acid transporters, including solute carrier family 1 member A5 (SLC1A5) and SLC7A6, leading to robust uptake of amino acids, including glutamine, into c‐Myc tumor cells. Subsequent functional studies showed that amino acids are critical for activation of mTORC1 as their inhibition suppressed mTORC1 in c‐Myc tumor cells. In human hepatocellular carcinoma specimens, levels of c‐Myc directly correlate with those of mTORC1 activation as well as of SLC1A5 and SLC7A6. Conclusion: Our current study indicates that an intact mTORC1 axis is required for c‐Myc‐driven hepatocarcinogenesis; thus, targeting the mTOR pathway or amino acid transporters may be an effective and novel therapeutic option for the treatment of hepatocellular carcinoma with activated c‐Myc signaling. (Hepatology 2017;66:167–181).
Ultrasonography is a fundamental diagnostic imaging tool in everyday clinical practice. Here, we are unique in describing the use of functionalized multiwalled carbon nanotubes (MWCNTs) as ...hyperechogenic material, suggesting their potential application as ultrasound contrast agents. Initially, we carried out a thorough investigation to assess the echogenic property of the nanotubes in vitro. We demonstrated their long-lasting ultrasound contrast properties. We also showed that ultrasound signal of functionalized MWCNTs is higher than graphene oxide, pristine MWCNTs, and functionalized single-walled CNTs. Qualitatively, the ultrasound signal of CNTs was equal to that of sulfur hexafluoride (SonoVue), a commercially available contrast agent. Then, we found that MWCNTs were highly echogenic in liver and heart through ex vivo experiments using pig as an animal model. In contrast to the majority of ultrasound contrast agents, we observed in a phantom bladder that the tubes can be visualized within a wide variety of frequencies (i.e., 5.5–10 MHz) and 12.5 MHz using tissue harmonic imaging modality. Finally, we demonstrated in vivo in the pig bladder that MWCNTs can be observed at low frequencies, which are appropriate for abdominal organs. Importantly, we did not report any toxicity of CNTs after 7 d from the injection by animal autopsy, organ histology and immunostaining, blood count, and chemical profile. Our results reveal the enormous potential of CNTs as ultrasound contrast agents, giving support for their future applications as theranostic nanoparticles, combining diagnostic and therapeutic modalities.
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•A novel mouse model of intrahepatic cholangiocarcinoma (ICC) was established.•Hydrodynamic transfection of activated forms of AKT and Yap was used to induce ICC.•This model ...recapitulates many morphological and molecular features of human ICC.•MLN0128 may be superior to gemcitabine/oxaliplatin based chemotherapy to treat ICC.•The efficacy of MLN0128 is mainly attributed to induction of apoptosis of ICC cells.
Intrahepatic cholangiocarcinoma (ICC) is a lethal malignancy without effective treatment options. MLN0128, a second generation pan-mTOR inhibitor, shows efficacy for multiple tumor types. We evaluated the therapeutic potential of MLN0128 vs. gemcitabine/oxaliplatin in a novel ICC mouse model.
We established a novel ICC mouse model via hydrodynamic transfection of activated forms of AKT (myr-AKT) and Yap (YapS127A) protooncogenes (that will be referred to as AKT/YapS127A). Genetic approaches were applied to study the requirement of mTORC1 and mTORC2 in mediating AKT/YapS127A driven tumorigenesis. Gemcitabine/oxaliplatin and MLN0128 were administered in AKT/YapS127A tumor-bearing mice to study their anti-tumor efficacy in vivo. Multiple human ICC cell lines were used for in vitro experiments. Hematoxylin and eosin staining, immunohistochemistry and immunoblotting were applied for the characterization and mechanistic study.
Co-expression of myr-AKT and YapS127A promoted ICC development in mice. Both mTORC1 and mTORC2 complexes were required for AKT/YapS127A ICC development. Gemcitabine/oxaliplatin had limited efficacy in treating late stage AKT/YapS127A ICC. In contrast, partial tumor regression was achieved when MLN0128 was applied in the late stage of AKT/YapS127A cholangiocarcinogenesis. Furthermore, when MLN0128 was administered in the early stage of AKT/YapS127A carcinogenesis, it led to disease stabilization. Mechanistically, MLN0128 efficiently inhibited AKT/mTOR signaling both in vivo and in vitro, inducing strong ICC cell apoptosis and only marginally affecting proliferation.
This study suggests that mTOR kinase inhibitors may be beneficial for the treatment of ICC, even in tumors that are resistant to standard of care chemotherapeutics, such as gemcitabine/oxaliplatin-based regimens, especially in the subset of tumors exhibiting activated AKT/mTOR cascade.
Lay summary: We established a novel mouse model of intrahepatic cholangiocarcinoma (ICC). Using this new preclinical model, we evaluated the therapeutic potential of mTOR inhibitor MLN0128 vs. gemcitabine/oxaliplatin (the standard chemotherapy for ICC treatment). Our study shows the anti-neoplastic potential of MLN0128, suggesting that it may be superior to gemcitabine/oxaliplatin-based chemotherapy for the treatment of ICC, especially in the tumors exhibiting activated AKT/mTOR cascade.
Cholangiocarcinoma (CCA) is a highly-aggressive malignancy arising from the biliary tree, characterized by a steady increase in incidence globally and a high mortality rate. Most CCAs are diagnosed ...in the advanced and metastatic phases of the disease, due to the paucity of signs and symptoms in the early stages. This fact, along with the poor results of the local and systemic therapies currently employed, is responsible for the poor outcome of CCA patients and strongly supports the need for novel therapeutic agents and strategies. In recent years, the introduction of next-generation sequencing technologies has opened new horizons for a better understanding of the genetic pathophysiology of CCA and, consequently, for the identification and evaluation of new treatments tailored to the molecular features or alterations progressively elucidated. In this review article, we describe the potential targets under investigation and the current molecular therapies employed in biliary tract cancers. In addition, we summarize the main drugs against CCA under evaluation in ongoing trials and describe the preliminary data coming from these pioneering studies.
Background: Transient Elastography (TE) is widely regarded as the most reliable non-invasive method for evaluating liver fibrosis. Recently, new techniques such as 2D Shear Wave Elastography (2D-SWE) ...have been developed. This study aimed to evaluate the correlation between TE and 2D-SWE in patients with HCV-related chronic liver disease and to redefine the cut-off values of 2D-SWE for predicting different stages of fibrosis based on our results. Methods: Both TE (Fibroscan, Echosens, Paris, France) and 2D-SWE (SuperSonic Imagine) were performed simultaneously in 170 patients, including those with active and eradicated HCV infection. Spearman’s rank correlation coefficient was used to assess the correlation between the two measurements, and the concordance between the assigned METAVIR classes was calculated using Cohen’s kappa coefficient. ROC curves were constructed to determine the optimal cut-off values for 2D-SWE. Results: Ten patients were excluded for invalid measurements. In the remaining 160 patients, TE and 2D-SWE demonstrated a high correlation (ρ = 0.83, p < 0.0001) and good agreement in METAVIR classification (k = 0.74). The optimal cut-off values identified for 2D-SWE were as follows: ≥ 7 kPa for F ≥ 2, ≥ 8.3 kPa for F ≥ 3, and ≥ 9.4 kPa for F4. Conclusions: 2D-SWE is a viable alternative to TE for patients with HCV-related chronic liver disease. Our data suggest that the currently accepted 2D-SWE cut-off values for cirrhosis (F4) should be reconsidered and potentially lowered.
Hepatocellular carcinoma (HCC) and the intrahepatic biliary tract cancers are estimated to rank sixth for incidence among solid cancers worldwide, and third for mortality rates. A critical issue ...remains the need for accurate biomarkers for risk stratification and overall prognosis. The aim of this study was to investigate the ability of a biomarker of heterogeneity of the size of red blood cells, the red cell distribution width (RDW), to predict survival in patients with HCC.
A consecutive series of patients with a histologic diagnosis of HCC were included into this study irrespective of their age, stage of the disease, and treatment administered, and followed-up for a period of three years. Demographic, anthropometric age, sex, body mass index (BMI), and clinical data (Charlson Comorbidity Index, Child-Pugh score, etc.), along with laboratory tests were retrieved from clinical records.
One-hundred and four patients were included in this study. Among them, 54 (69%) were deceased at the end of the follow-up. Higher RDW values, but not other hematological and biochemical parameters, were significantly associated with mortality in both univariate and multivariate analysis. The optimal RDW cut-off value identified with the Youden test for survival was 14.7%, with 65% sensitivity and 74% specificity (AUC = 0.718, 95% CI 0.622-0.802,
< 0.001). Kaplan-Meier survival curves showed significantly lower survival with higher RDW values (HR = 3.5204; 95% CI 1.9680-6.2975,
< 0.0001) with a mean survival of 30.9 ± 9.67 months for patients with RDW ≤ 14.7% and 22.3 ± 11.4 months for patients with RDW > 14.7%.
The results of our study showed that RDW can perform better than other blood-based biomarkers in independently predicting prognosis in patients with HCC.
Background:
The independent association between hepatic steatosis and rheumatoid arthritis is poorly defined.
Methods:
The presence of moderate to severe steatosis was assessed, using liver ...ultrasonography, in 364 consecutive non-diabetic subjects (223 patients with rheumatoid arthritis and 141 age- and sex-matched healthy controls). Adjusted multiple regression analysis was performed to explore the association between rheumatoid arthritis and moderate to severe steatosis in the overall sample and identify independent risk factors in the rheumatoid arthritis subgroup.
Results:
The prevalence of moderate to severe steatosis in the overall sample was 31.3%, with a significantly higher prevalence in patients with rheumatoid arthritis than healthy controls (38.7% versus 19.7%, p < 0.0001). After adjustment for sex, age, cholesterol, triglycerides, body mass index, waist, hypertension and smoke, rheumatoid arthritis remained significantly associated with moderate to severe steatosis odds ratio (95% confidence interval) = 2.24 (1.31, 3.84); p = 0.003. In the rheumatoid arthritis group, male sex, higher body mass index, higher triglycerides concentrations and higher cumulative dosage of methotrexate odds ratio (95% confidence interval) = 1.11 (1.01, 1.23); p = 0.026 were significantly associated with moderate to severe steatosis, while systemic inflammation, disease activity, use of steroids and biologics were not.
Conclusion:
Rheumatoid arthritis is independently associated with moderate to severe steatosis, with male sex, higher body mass index and cumulative dose of methotrexate being predisposing factors. Further prospective studies are warranted to confirm our findings and to investigate the effect of steatosis on liver outcomes in the rheumatoid arthritis population.
Abstract Background Intrahepatic cholangiocarcinoma (iCCA) is a lethal primary liver tumor characterized by clinical aggressiveness, poor prognosis, and scarce therapeutic possibilities. Therefore, ...new treatments are urgently needed to render this disease curable. Since cumulating evidence supports the oncogenic properties of the Heat Shock Factor 1 (HSF1) transcription factor in various cancer types, we investigated its pathogenetic and therapeutic relevance in iCCA. Methods Levels of HSF1 were evaluated in a vast collection of iCCA specimens. The effects of HSF1 inactivation on iCCA development in vivo were investigated using three established oncogene-driven iCCA mouse models. In addition, the impact of HSF1 suppression on tumor cells and tumor stroma was assessed in iCCA cell lines, human iCCA cancer-associated fibroblasts (hCAFs), and patient-derived organoids. Results Human preinvasive, invasive, and metastatic iCCAs displayed widespread HSF1 upregulation, which was associated with a dismal prognosis of the patients. In addition, hydrodynamic injection of a dominant-negative form of HSF1 (HSF1dn), which suppresses HSF1 activity, significantly delayed cholangiocarcinogenesis in AKT/NICD, AKT/YAP, and AKT/TAZ mice. In iCCA cell lines, iCCA hCAFs, and patient-derived organoids, administration of the HSF1 inhibitor KRIBB-11 significantly reduced proliferation and induced apoptosis. Cell death was profoundly augmented by concomitant administration of the Bcl-xL/Bcl2/Bcl-w inhibitor ABT-263. Furthermore, KRIBB-11 reduced mitochondrial bioenergetics and glycolysis of iCCA cells. Conclusions The present data underscore the critical pathogenetic, prognostic, and therapeutic role of HSF1 in cholangiocarcinogenesis.
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