Hepatocellular carcinoma (HCC) is a morbid condition for which surgical and ablative therapy are the only options for cure. Nonetheless, over half of patients treated with an R0 resection will ...develop recurrence. Early recurrences within 2 years after resection are thought to be due to the presence of residual microscopic disease, while late recurrences > 2 years after resection are thought to be de novo metachronous HCCs arising in chronically injured liver tissue. Microvascular invasion (MVI) is defined as the presence of micrometastatic HCC emboli within the vessels of the liver, and is a critical determinant of early recurrence and survival. In this review, we summarize the pathogenesis and clinical relevance of MVI, which correlates with adverse biological features, including high grade, large tumor size, and epithelial–mesenchymal transition. Multiple classification schemas have been proposed to capture the heterogeneous features of MVI that are associated with prognosis. However, currently, MVI can only be determined based on surgical specimens, limiting its clinical applicability. Going forward, advances in axial imaging technologies, molecular characterization of biopsy tissue, and novel serum biomarkers hold promise as future methods for non-invasive MVI detection. Ultimately, MVI status may be used to help clinicians determine treatment plans, particularly with respect to surgical intervention, and to provide more accurate prognostication.
Background
New insights into molecular pathogenesis of hepatocellular adenomas (HCA) have allowed sub-classification based on distinct genetic alterations and a fresh look at characterizations of ...natural history. Clinically, this is important in understanding risk factors for two feared complications: malignant transformation and hemorrhage.
Methods
PubMed literature search for hepatocellular adenoma over all years, excluding case reports and articles focusing on multiple adenomas or adenomatosis.
Results
The β-catenin exon 3 mutated HCA accounts for about 10% of all HCAs and is associated with the highest risk of malignant transformation. The HF1α subtype accounts for 30–40% of all HCAs and has the lowest risk of malignant transformation. Gender has also emerged as an increasingly important risk factor and males with HCA are at considerably higher risk of malignant transformation, regardless of tumor size. The increasing use of gadoxetic-enhanced MRI has allowed for improved differentiation of HCAs from focal nodular hyperplasia, as well as the identification of specific radiologic features of some subtypes, particularly the inflammatory and HF1α HCAs.
Conclusions
Classification of HCA by subtype has important implications for patient counseling and treatment given variable risks of malignant transformation and hemorrhage. Males and those with β-catenin exon 3 mutated HCAs are two groups who should always be counselled to undergo surgical resection. On the other hand, in the lower risk HF1α subtype observation is appropriate in lesions < 5 cm and may even be considered in larger lesions as longer follow-up data is aggregated and tumorigenesis is better understood.
Background
The incidence of cholangiocarcinoma has doubled over the last 15 years with a similar rise in mortality, which provides the impetus for standardization of evidence-based care through the ...establishment of guidelines.
Methods
We compared available guidelines on the clinical management of cholangiocarcinoma in the United States and Europe, which included the National Comprehensive Cancer Network (NCCN), European Society for Medical Oncology (ESMO), British Society of Gastroenterology (BSG) and the International Liver Cancer Association (ILCA) guidelines.
Results
There is discordance in the recommendation for biopsy in patients with potentially resectable cholangiocarcinoma and in the recommendation for use of fluorodeoxyglucose positron emission tomography scans. Similarly, the recommendation for preoperative biliary drainage for extrahepatic and perihilar cholangiocarcinoma in the setting of jaundice is inconsistent across all four guidelines. The BILCAP (capecitabine) and ABC-02 trials (gemcitabine with cisplatin) have provided the strongest evidence for systemic therapy in the adjuvant and palliative settings, respectively, but all guidelines have refrained from setting them as standard of care, given heterogeneity in the study cohorts and ABC-02’s negative intention-to-treat results.
Conclusions
Future progress in enhancing survivorship of patients with cholangiocarcinoma would likely entail improvements in diagnostic biomarkers and novel systemic therapies. Based on recent results from studies of targeted therapy, future iterations of the guidelines will likely incorporate molecular profiling.
Cancers of origin in the gallbladder and bile ducts are rarely curable with current modalities of cancer treatment. Our clinical application of broad‐based mutational profiling for patients diagnosed ...with a gastrointestinal malignancy has led to the novel discovery of mutations in the gene encoding isocitrate dehydrogenase 1 (IDH1) in tumors from a subset of patients with cholangiocarcinoma. A total of 287 tumors from gastrointestinal cancer patients (biliary tract, colorectal, gastroesophageal, liver, pancreatic, and small intestine carcinoma) were tested during routine clinical evaluation for 130 site‐specific mutations within 15 cancer genes. Mutations were identified within a number of genes, including KRAS (35%), TP53 (22%), PIK3CA (10%), BRAF (7%), APC (6%), NRAS (3%), AKT1 (1%), CTNNB1 (1%), and PTEN (1%). Although mutations in the metabolic enzyme IDH1 were rare in the other common gastrointestinal malignancies in this series (2%), they were found in three tumors (25%) of an initial series of 12 biliary tract carcinomas. To better define IDH1 and IDH2 mutational status, an additional 75 gallbladder and bile duct cancers were examined. Combining these cohorts of biliary cancers, mutations in IDH1 and IDH2 were found only in cholangiocarcinomas of intrahepatic origin (nine of 40, 23%) and in none of the 22 extrahepatic cholangiocarcinomas and none of the 25 gallbladder carcinomas. In an analysis of frozen tissue specimens, IDH1 mutation was associated with highly elevated tissue levels of the enzymatic product 2‐hydroxyglutarate. Thus, IDH1 mutation is a molecular feature of cholangiocarcinomas of intrahepatic origin. These findings define a specific metabolic abnormality in this largely incurable type of gastrointestinal cancer and present a potentially new target for therapy.
摘要
胆囊和胆管起源的肿瘤目前尚难治愈。通过对胃肠恶性肿瘤标本采用广谱突变谱基因分型技术，我们在一种亚群的胆管癌患者中新发现了基因编码异柠檬酸脱氢酶1（ IDH1）突变。本研究对15个癌基因内130个定点突变进行常规临床评估，共检测了胃肠癌患者的287个肿瘤样本（胆道、结直肠、胃食管、肝脏、胰腺和小肠癌）。在部分基因中发现突变，包括 KRAS （35%）、 TP53 （22%）、 PIK3CA（10%）、BRAF（7%）、 APC （6%）、 NRAS （3%）、 AKT1（1%）、CTNNB1（1%）和 PTEN （1%）。尽管代谢酶IDH1突变在该系列其他常见胃肠道恶性肿瘤中十分罕见（2%），但在该系列最初12个胆道癌中却占3个（25%）。为更好地确定 IDH1 和 IDH2 突变状态，我们追加探寻了75个胆囊和胆管癌。结合这些胆管癌队列来看， IDH1 和 IDH2 突变仅见于肝内起源的胆管癌（9/40例，23%），未见于22例肝外胆管癌和25例胆囊癌。冰冻组织样本分析显示， IDH1 突变与酶产物2‐羟基戊二酸组织水平高度升高关联。因此， IDH1 突变是肝内胆管癌的分子特征。这些结果提示，在此类基本无法治愈的胃肠肿瘤中存在一种可能成为治疗新靶点的特异性代谢异常。
The results of mutational profiling of 287 patients with gastrointestinal cancer are presented, identifying for the first time IDH1 mutations in a significant subset of patients with intrahepatic cholangiocarcinoma.
Hepatocellular carcinoma (HCC) is the most rapidly increasing cause of cancer‐related mortality in the United States. Because of the lack of viable treatment options for HCC, prevention in high‐risk ...patients has been proposed as an alternative strategy. The main risk factor for HCC is cirrhosis and several lines of evidence implicate epidermal growth factor (EGF) in the progression of cirrhosis and development of HCC. We therefore examined the effects of the EGF receptor (EGFR) inhibitor erlotinib on liver fibrogenesis and hepatocellular transformation in three different animal models of progressive cirrhosis: a rat model induced by repeated, low‐dose injections of diethylnitrosamine (DEN), a mouse model induced by carbon tetrachloride (CCl4), and a rat model induced by bile duct ligation (BDL). Erlotinib reduced EGFR phosphorylation in hepatic stellate cells (HSC) and reduced the total number of activated HSC. Erlotinib also decreased hepatocyte proliferation and liver injury. Consistent with all these findings, pharmacological inhibition of EGFR signaling effectively prevented the progression of cirrhosis and regressed fibrosis in some animals. Moreover, by alleviating the underlying liver disease, erlotinib blocked the development of HCC and its therapeutic efficacy could be monitored with a previously reported gene expression signature predictive of HCC risk in human cirrhosis patients. Conclusion: These data suggest that EGFR inhibition using Food and Drug Administration‐approved inhibitors provides a promising therapeutic approach for reduction of fibrogenesis and prevention of HCC in high‐risk cirrhosis patients who can be identified and monitored by gene expression signatures. (Hepatology 2014;59:1577‐1590)
We introduce a redox-active iron complex, Fe-PyC3A, as a biochemically responsive MRI contrast agent. Switching between Fe3+-PyC3A and Fe2+-PyC3A yields a full order of magnitude relaxivity change ...that is field-independent between 1.4 and 11.7 T. The oxidation of Fe2+-PyC3A to Fe3+-PyC3A by hydrogen peroxide is very rapid, and we capitalized on this behavior for the molecular imaging of acute inflammation, which is characterized by elevated levels of reactive oxygen species. Injection of Fe2+-PyC3A generates strong, selective contrast enhancement of inflamed pancreatic tissue in a mouse model (caerulein/LPS model). No significant signal enhancement is observed in normal pancreatic tissue (saline-treated mice). Importantly, signal enhancement of the inflamed pancreas correlates strongly and significantly with ex vivo quantitation of the pro-inflammatory biomarker myeloperoxidase. This is the first example of using metal ion redox for the MR imaging of pathologic change in vivo. Redox-active Fe3+/2+ complexes represent a new design paradigm for biochemically responsive MRI contrast agents.
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