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Magnetic resonance imaging biomarkers in hepatocellular carcinoma: association with response and circulating biomarkers after sunitinib therapy.

ABSTRACT: To investigate the hypothesis that MRI derived diffusion-weighted imaging (DWI) and perfusion (MRP) parameters are sensitive image biomarkers for monitoring early antiangiogenic effects and predicting progression free survival (PFS) in advanced hepatocellular carcinoma (HCC).In this phase II clinical trial, 23 of 34 patients were included in the imaging and circulating biomarker study. DWI and MRP were performed at the baseline and at 2-weeks after initiation of sunitinib. The imaging protocol included an axial DWI sequence using b values of 50, 400 and 800 sec/mm2, and MRP using a series of coronal 3D-VIBE following 20 ml of Gd-DTPA at 2 ml/sec. These parameters were compared with clinical outcome and PFS at 6-months. Correlation between changes in MRI parameters and plasma biomarkers was also evaluated.After 2-week of sunitinib, substantial Ktrans changes in HCC were observed from median baseline value 2.15 min?¹ to 0.94 min?¹ (P = 0.0001) with increases in median apparent diffusion coefficient (ADC) from 0.88 × 10?³ mm²/s to 0.98 × 10?³ mm²/s (P = 0.0001). Tumor size remained unchanged by RECIST and mRECIST (both P > 0.05). Patients who showed larger drop in Ktrans and Kep at 2 weeks correlated with favorable clinical outcome, and higher baseline Ktrans and larger drop in EVF correlated with longer PFS (all P < 0.05). There was a significant association between a decrease in sVEGFR2 and the drop in Ktrans and Kep (P = 0.044, P = 0.030), and a significant and borderline association between decrease in TNF-? and the drop in Ktrans and Kep, respectively (P = 0.051, P = 0.035).In HCC, MRP may be a more sensitive biomarker in predicting early response and PFS following sunitinib than RECIST and mRECIST.ClinicalTrials.gov: NCT00361309.

SUBMITTER: Sahani DV

PROVIDER: S-EPMC3722053 | biostudies-literature | 2013 Jul

REPOSITORIES: biostudies-literature

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Magnetic resonance imaging biomarkers in hepatocellular carcinoma: association with response and circulating biomarkers after sunitinib therapy.

Sahani Dushyant V DV Jiang Tao T Hayano Koichi K Duda Dan G DG Catalano Onofrio A OA Ancukiewicz Marek M Jain Rakesh K RK Zhu Andrew X AX

Journal of hematology & oncology 20130710

<h4>Background</h4>To investigate the hypothesis that MRI derived diffusion-weighted imaging (DWI) and perfusion (MRP) parameters are sensitive image biomarkers for monitoring early antiangiogenic effects and predicting progression free survival (PFS) in advanced hepatocellular carcinoma (HCC).<h4>Methods</h4>In this phase II clinical trial, 23 of 34 patients were included in the imaging and circulating biomarker study. DWI and MRP were performed at the baseline and at 2-weeks after initiation o ...[more]

PMID: 23842041

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Project description:PURPOSE:To determine the natural history of imaging findings seen on magnetic resonance imaging (MRI) of hepatocellular carcinoma (HCC) treated with stereotactic body radiation therapy (SBRT). Although arterial hyperenhancement is a key feature of untreated HCC, our clinical experience suggested that tumors that never progressed could still show hyperenhancement. Therefore, we undertook a systematic study to test the hypothesis that persistent arterial phase hyperenhancement (APHE) after SBRT is an expected finding that does not suggest failure of treatment. METHODS AND MATERIALS:One hundred forty-six patients undergoing SBRT for HCC between January 1, 2007, and December 31, 2015, were screened retrospectively using an institutional review board-approved prospectively maintained registry. Inclusion criteria were (1) HCC treated with SBRT, (2) multiphasic MRI ?3 months before SBRT, (3) up to 1 year of follow-up MRI post-SBRT, and (4) cirrhosis. The exclusion criterion was ?3 months of locoregional therapy to the liver segment containing the SBRT-treated HCC. Pre- and post-SBRT MRI from up to 3 years were analyzed in consensus by independent pairs of subspecialty-trained radiologists to determine the temporal evolution of major features for HCC and imaging findings in off-target parenchyma. RESULTS:Sixty-two patients with 67 HCCs (Organ Procurement and Transplantation Network imaging criteria [OPTN] 5a [n = 26], OPTN 5b [n = 28], OPTN 5x [n = 7]; Liver Imaging Reporting Data System [LI-RAD]-M [n = 4] and LiRADs-4 [n = 2]) were studied. Tumor size either decreased (66% [44 of 67]) or remained unchanged (34% [23 of 67]) within the first 12 months. Post-SBRT APHE was common (58% [39 of 67]). When graded using modified Response Evaluation Criteria in Solid Tumors at 3 to 6 months, 25% (17 of 67) met criteria for complete response and 75% (50 of 67) met criteria for stable disease. CONCLUSIONS:SBRT is an effective locoregional treatment option for HCC. Persistent APHE is common and does not necessarily indicate viable neoplasm; thus, standard response assessment such as modified Response Evaluation Criteria should be used with caution, particularly in the early phases after SBRT therapy.

Project description:Several proteins that promote angiogenesis are overexpressed in hepatocellular carcinoma (HCC) and have been implicated in disease pathogenesis. Sunitinib has antiangiogenic activity and is an oral multitargeted inhibitor of vascular endothelial growth factor receptors (VEGFRs)-1, -2, and -3, platelet-derived growth factor receptors (PDGFRs)-? and -?, stem-cell factor receptor (KIT), and other tyrosine kinases. In a phase II study of sunitinib in advanced HCC, we evaluated the plasma pharmacodynamics of five proteins related to the mechanism of action of sunitinib and explored potential correlations with clinical outcome.Patients with advanced HCC received a starting dose of sunitinib 50 mg/day administered orally for 4 weeks on treatment, followed by 2 weeks off treatment. Plasma samples from 37 patients were obtained at baseline and during treatment and were analyzed for vascular endothelial growth factor (VEGF)-A, VEGF-C, soluble VEGFR-2 (sVEGFR-2), soluble VEGFR-3 (sVEGFR-3), and soluble KIT (sKIT).At the end of the first sunitinib treatment cycle, plasma VEGF-A levels were significantly increased relative to baseline, while levels of plasma VEGF-C, sVEGFR-2, sVEGFR-3, and sKIT were significantly decreased. Changes from baseline in VEGF-A, sVEGFR-2, and sVEGFR-3, but not VEGF-C or sKIT, were partially or completely reversed during the first 2-week off-treatment period. High levels of VEGF-C at baseline were significantly associated with Response Evaluation Criteria in Solid Tumors (RECIST)-defined disease control, prolonged time to tumor progression (TTP), and prolonged overall survival (OS). Baseline VEGF-C levels were an independent predictor of TTP by multivariate analysis. Changes from baseline in VEGF-A and sKIT at cycle 1 day 14 or cycle 2 day 28, and change in VEGF-C at the end of the first off-treatment period, were significantly associated with both TTP and OS, while change in sVEGFR-2 at cycle 1 day 28 was an independent predictor of OS.Baseline plasma VEGF-C levels predicted disease control (based on RECIST) and were positively associated with both TTP and OS in this exploratory analysis, suggesting that this VEGF family member may have utility in predicting clinical outcome in patients with HCC who receive sunitinib.ClinicalTrials.gov: NCT00247676.

Project description:Background:With the development of new magnetic resonance imaging (MRI) techniques, an increasing number of articles have been published regarding hepatocellular carcinoma magnetic resonance imaging (HCCMRI) in the past decade. However, few studies have statistically analyzed these published articles. In this study, we aim to systematically evaluate the scientific outcomes of HCCMRI research and explore the research hotspots from 2008 to 2017. Methods:The included articles regarding HCCMRI research from 2008 to 2017 were downloaded from the Web of Science Core Collection and verified by two experienced radiologists. Excel 2016 was used to analyze the literature data, including the publication years and journals. CiteSpace V was used to perform co-occurrence analyses for authors, countries/regions and institutions and to generate the related collaboration network maps. Reference co-citation analysis (RCA) and burst keyword detection were also performed using CiteSpace V to explore the research hotspots in the past decade. Results:A total of 835 HCCMRI articles published from 2008 to 2017 were identified. Journal of Magnetic Resonance Imaging published the most articles (79 publications, 9.46%). Extensive cooperating relationship were observed among countries/regions and among authors. South Korea had the most publications (199 publications, 21.82%), followed by the United States of America (USA) (190 publications, 20.83%), Japan (162 publications, 17.76%), and the People's Republic of China (148 publications, 16.23%). Among the top 10 co-cited authors, Bruix J (398 citations) was ranked first, followed by Llovet JM (235 citations), Kim YK (170 citations) and Forner A (152 citations). According to the RCA, ten major clusters were explored over the last decade; "LI-RADS data system" and "microvascular invasion" (MVI) were the two most recent clusters. Forty-seven burst keywords with the highest citation strength were detected over time. Of these keywords, "microvascular invasion" had the highest strength in the last 3 years. The LI-RADS has been constantly updated with the latest edition released in July 2018. However, the LI-RADS still has limitations in identifying certain categories of lesions by conceptual and non-quantitative probabilistic methods. Plenty of questions still need to be further answered such as the difference of diagnostic efficiency of each major/ancillary imaging features. Preoperative prediction of MVI of HCC is very important to therapeutic decision-making. Some parameters of Gd-EOB-DTPA-enhanced MRI were found to be useful in prediction of MVI, however, with a high specificity but a very low sensitivity. Comprehensive predictive model incorporating both imaging and clinical variables may be the more preferable in prediction of MVI of HCC. Conclusions:HCCMRI-related publications displayed a gradually increasing trend from 2008 to 2017. The USA has a central position in collaboration with other countries/regions, while South Korea contributed the most in the number of publications. Of the ten major clusters identified in the RCA, the two most recent clusters were "LI-RADS data system" and "microvascular invasion", indicative of the current HCCMRI research hotspots.

Project description:ProposeThe early diagnosis of hepatocellular carcinoma (HCC) with ferritin heavy chain (Fth) modified by alpha-fetoprotein (AFP) promoter has been studied. However, no study has focused on the considerable upregulation and specific targeting effects of transferrin receptors (TfR) caused by the transfection of plasmids encoded with the AFP promoter. Thus, the objective of our study was to investigate whether the transfection of Fth gene modified with AFP promoter (AFP@Fth) could be used for early diagnosis and enhanced treatment of HCC.MethodsThe AFP@Fth plasmid was transfected into AFP positive cells. The expression of intracellular Ferritin was verified by Western blot, and the upregulation of TfR was confirmed by immunofluorescence and flow cytometry analysis. Cellular iron accumulation resulting in decreased imaging signals was examined by magnetic resonance imagining. Doxorubicin liposome modified with transferrin (Tf-LPD) was prepared to investigate the efficiency of the subsequent treatment after transfection. The enhanced drug distribution and effects were investigated both in vitro and in vivo.ResultsBoth Ferritin and TfR were overexpressed after transfection. The transfected cells showed higher intracellular iron accumulation and resulted in a lower MR T2-weighted imaging (T2WI) intensity, suggesting that the transfection of AFP@Fth could be a potential strategy for early diagnosis of liver cancer. The following treatment efficacy was revealed by Tf-LPD. As compared with un-transfected cells, transfected cells exhibited higher uptake of transferrin-modified liposomes (Tf-LP), which was due to the specific interaction between Tf and TfR overexpressed on the transfected cells. This is also the reason why Tf-LPD showed better in vitro and in vivo anticancer ability than doxorubicin loaded liposome (LPD). These results suggested that transfection of AFP@Fth could result in enhanced therapy of liver cancer.ConclusionTransfection of AFP@Fth could be used for early diagnosis and for enhanced treatment of live cancers.

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Magnetic resonance imaging biomarkers in hepatocellular carcinoma: association with response and circulating biomarkers after sunitinib therapy.

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Magnetic resonance imaging biomarkers in hepatocellular carcinoma: association with response and circulating biomarkers after sunitinib therapy.

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