Radioembolization of liver cancers using ⁹⁰Y-loaded microspheres is experiencing more widespread use. However, few data are available concerning the doses delivered to the tumors and the healthy liver. This retrospective study was conducted to calculate the tumor dosimetry (planned tumor dose [T_plan D]) and nontumor dosimetry in patients treated by ⁹⁰Y-loaded glass microspheres and determine whether tumor dosimetry could predict response and survival. Methods: Thirty-six patients with hepatocellular carcinoma (HCC), including 16 with portal vein thrombosis (PVT), were treated with ⁹⁰Y-loaded glass microspheres. The T_plan D and the dose delivered to the injected healthy liver were calculated using a quantitative analysis of the ^99mTc-macroaggregated albumin (^99mTc-MAA) SPECT/CT exam. Responses were assessed after 3 mo, using the criteria of the European Association for the Study of the Liver. Progression-free survival (PFS) and overall survival (OS) were evaluated using Kaplan–Meier tests. Results: The response rate was 69% for the overall population and 75% for the PVT patients. The dose delivered to the tumor was the only parameter associated with response with multivariate analysis (P = 0.019). A threshold T_plan D value of 205 Gy was predictive of response, with a sensitivity of 100% and an accuracy of 91%. Quantitative ^99mTc-MAA SPECT/CT allowed us to increase the injected activity for 4 patients with large lesions. PFS was only 5.2 mo and OS 9 mo when using a T_plan D of less than 205 Gy versus 14 mo (P = 0.0003) and 18 mo (P = 0.0322), respectively, with a T_plan D of 205 Gy or more. Conclusion: Quantitative ^99mTc-MAA SPECT/CT is predictive of response, PFS, and OS. Dosimetry based on ^99mTc-MAA SPECT/CT can be used for the selection of patients and for an adaptation of treatment planning, especially in selected patients (particularly in the case of large tumors). These results also confirm the efficacy and safety of ⁹⁰Y-loaded microspheres in treating HCC, even in the presence of PVT (and especially when ^99mTc-MAA uptake is seen inside the PVT).

Three collagen types (I, III and IV) and fibronectin were localized in normal and alcoholic human liver by light and electron microscopy using the indirect immunoperoxidase technique. In normal liver, most of the bundles of collagen fibers stained for type pro–III collagen while only a few reacted for type I. Basement membranes stainedfor type IV collagen which formed discontinuous discrete deposits in sinusoids. Only fibronectin appeared as an almost continuous layer in the space of Disse. At the intracellular level, hepatocytes were found to contain little type I collagen and large amountsof fibronectin. Fat–storing cells strongly stained for type IV collagen and expressed low amounts of types I and III collagen and fibronectin. Endothelial cells contained low amounts of all the components. Alcoholic livers were studied at three stages: steatosis, fibrosis and cirrhosis. Qualitative and quantitative differences were observed in extracellular and intracellulardistributions of matrix proteins. Increased amounts of all components were usually found in fibrotic and cirrhotic livers compared to normal liver. In two fibrotic livers which contained numerous bundles of collagen in the sinusoids, fat–storing cells stained more intensely for type III collagen. In a cryptogenic fibrotic liver, abundant type IV collagen was observed in hepatocytes. These results suggest that hepatocytes, fat–storing cells and endothelial cells are engaged in production of extracellular matrix components in normal human liver. In fibrosis, hepatocytes which normally did not synthesize types III and IV collagen mayproduce these collagens.

Many solid malignant tumors arise on a background of inflamed and/or fibrotic tissues, features that are found in more than 80% hepatocellular carcinomas (HCC). Activated hepatic stellate cells (HSC) play a critical role in fibrogenesis associated with HCC onset and progression, yet their functional impact on hepatocyte fate remains largely unexplored. Here, we used a coculture model to investigate the cross-talk between hepatocytes (human hepatoma cells) and activated human HSCs. Unsupervised genome-wide expression profiling showed that hepatocyte–HSC cross-talk is bidirectional and results in the deregulation of functionally relevant gene networks. Notably, coculturing increased the expression of proinflammatory cytokines and modified the phenotype of hepatocytes toward motile cells. Hepatocyte–HSC cross-talk also generated a permissive proangiogenic microenvironment, particularly by inducing VEGFA and matrix metalloproteinase (MMP)9 expression in HSCs. An integrative genomic analysis revealed that the expression of genes associated with hepatocyte–HSC cross-talk correlated with HCC progression in mice and was predictive of a poor prognosis and metastasis propensity in human HCCs. Interestingly, the effects of cross-talk on migration and angiogenesis were reversed by the histone deacetylase inhibitor trichostatin A. Our findings, therefore, indicate that the cross-talk between hepatoma cells and activated HSCs is an important feature of HCC progression, which may be targeted by epigenetic modulation. Cancer Res; 72(10); 2533–42. ©2012 AACR.

“A disintegrin and metalloproteinases” (ADAMs) form a family of cell–surface glycoproteins with potential protease and cell–adhesion activities. We have investigated ADAM expression in human liver cancers and their regulation by several cytokines involved in liver injury. Using degenerative RT–PCR, cDNA encoding sequences for ADAM9 and ADAM12 were identified in human activated hepatic stellate cells (HSCs). Northern blot analyses showed that HSCs, but not hepatocytes, expressed transcripts for ADAM9 messenger RNA (mRNA) and both the long and short forms of ADAM12. This expression was associated with the transition from quiescent to activated state of rat HSCs and markedly increased in human livers with cirrhosis. ADAM12 but not ADAM9 expression was up–regulated by transforming growth factor β (TGF–β) in human activated HSCs. The PI3K inhibitor LY294002 and the mitogen–activated protein kinase kinase (MEK) inhibitor UO126 prevented ADAM12 induction by TGF–β, suggesting the involvement of PI3K and MEK activities. In vivo, the steady–state of both ADAM9 and ADAM12 mRNA levels was nearly undetectable in both normal livers and benign tumors and increased in hepatocellular carcinomas (up to 3– and 6–fold, respectively) and liver metastases from colonic carcinomas (up to 40– and 60–fold, respectively). The up–regulation of both ADAM9 and ADAM12 was correlated with an increase in matrix metalloproteinase 2 expression and activity. In conclusion, in liver cancers ADAM9 and ADAM12 expression is associated with tumor aggressiveness and progression.