• Angiogenesis
• Colony stimulating factor 1
• Differentiation
• Endothelial cells
• Hepatic progenitor cells
• Paracrine

• Humans
• Paracrine Communication
• Endothelial Cells
• Liver/metabolism
• Hepatocytes/metabolism
• Stem Cells
• Liver Neoplasms/pathology
• Disease Progression

• P30 DK078392 NIDDK NIH HHS
• R37 CA225807 NCI NIH HHS

Radioembolization of hepatic tumors is performed by injecting ⁹⁰Y or ¹⁶⁶Ho loaded spheres into the hepatic artery. A twofold tumor to normal liver absorbed dose ratio is commonly obtained. In order to improve tumoral cell killing while preserving lobule function, co-injection of arterial vasoconstrictor has been proposed, but without success: the hepatic arterial buffer response quickly inhibits the arterioles vasoconstriction. The aim of the study is to investigate whether it is possible to take benefit from this buffer response, by co-infusing a mesenteric arterial vasodilator in order to dump the hepatic lobules arterial flow. Animal studies evidencing such mechanism are reviewed. Some potential mesenteric vasodilators are identified and their safety profile discussed. A four to sixfold improvement of the tumoral to normal tissue dose ratio is expected, pushing the therapy towards a real curative intention, especially in hepatocellular carcinoma (HCC), more frequent in obese subjects, and where ultra-selective spheres delivery is often not possible.

Liver radioembolization is a treatment option for unresectable liver cancers, performed by infusion of ⁹⁰Y or ¹⁶⁶Ho loaded spheres in the hepatic artery. As tumoral cells are mainly perfused via the liver artery unlike hepatic lobules, a twofold tumor to normal liver dose ratio is commonly obtained. To improve tumoral cell killing while preserving lobules, co-infusion of arterial vasoconstrictor has been proposed but with limited success: the hepatic arterial buffer response (HABR) and hepatic vascular escape mechanism hamper the arterioles vasoconstriction. The proposed project aims to take benefit from the HABR by co-infusing a mesenteric arterial vasodilator: the portal flow enhancement inducing the vasoconstriction of the intra sinusoids arterioles barely impacts liver tumors that are mainly fed by novel and anarchic external arterioles. Animal studies were reviewed and dopexamine was identified as a promising safe candidate, reducing by four the hepatic lobules arterial flow. A clinical trial design is proposed. A four to sixfold improvement of the tumoral to normal tissue dose ratio is expected, pushing the therapy towards a real curative intention, especially in HCC where ultra-selective spheres delivery is often not possible.

• SIRT
• TARE
• cancer therapy
• dose optimization
• liver radioembolization

• acetate
• fluoro-d-glucose
• hepatoma
• positron emission tomography/computed tomography
• prognosis
• transarterial chemoembolization

• Acetates
• Adult
• Aged
• Aged, 80 and over
• Carbon
• Carcinoma, Hepatocellular/diagnostic imaging
• Carcinoma, Hepatocellular/mortality
• Carcinoma, Hepatocellular/therapy
• Chemoembolization, Therapeutic/mortality
• Female
• Fluorodeoxyglucose F18
• Humans
• Liver/diagnostic imaging
• Liver Neoplasms/diagnostic imaging
• Liver Neoplasms/mortality
• Liver Neoplasms/therapy
• Male
• Middle Aged
• Positron Emission Tomography Computed Tomography/methods
• Positron Emission Tomography Computed Tomography/statistics & numerical data
• Predictive Value of Tests
• Prognosis
• Proportional Hazards Models
• Radiopharmaceuticals
• Regression Analysis
• Retrospective Studies
• Treatment Outcome

• Advanced hepatocellular carcinoma
• Liver cancer
• Nanomedicine
• Targeted drug delivery systems

• Antigens, CD34/metabolism
• Biomarkers, Tumor/metabolism
• Carcinoma, Hepatocellular/blood supply
• Carcinoma, Hepatocellular/diagnosis
• Humans
• Liver Neoplasms/blood supply
• Liver Neoplasms/diagnosis
• Neovascularization, Pathologic/metabolism
• Platelet Endothelial Cell Adhesion Molecule-1/metabolism
• Prognosis
• von Willebrand Factor/metabolism

• computed tomography
• contrast agents
• hepatocellular carcinoma
• liver cirrhosis
• magnetic resonance imaging
• ultrasound

Previously we observed that dual phase ¹¹C-acetate positron emission tomography (AC-PET) could be employed for differential diagnosis of liver malignancies. In this study, we prospectively evaluated the effect of dual phase AC-PET on differential diagnosis of primary hepatic lesions of 1–3 cm in size.

33 patients having primary hepatic lesions with size of 1–3 cm in diameter undertook dual phase AC-PET scans. Procedure included an early upper-abdomen scan immediately after tracer injection and a conventional scan in 11–18 min. The standardized uptake value (SUV) was calculated for tumor (SUVT) and normal tissue (SUVB), from which ¹¹C-acetate uptake ratio (as lesion against normal liver tissue, SUVT/SUVB) in early imaging (R1), conventional imaging (R2), and variance between R2 and R1 (ΔR) were derived. Diagnoses based on AC-PET data and histology were compared. Statistical analysis was performed with SPSS 19.0.

20 patients were found to have HCC and 13 patients had benign tumors. Using ΔR>0 as criterion for malignancy, the accuracy and specificity were significantly increased comparing with conventional method. The area under ROC curve (AUC) for R1, R2, and ΔR were 0.417, 0.683 and 0.831 respectively. Differential diagnosis between well-differentiated HCCs and benign lesions of FNHs and hemangiomas achieved 100% correct. Strong positive correlation was also found between R1 and R2 in HCC (r² = 0.55, P<0.001).

Dual phase AC-PET scan is a useful procedure for differential diagnosis of well-differentiated hepatocellular carcinoma and benign lesions. The dynamic changes of ¹¹C-acetate uptake in dual phase imaging provided key information for final diagnosis.

AIM: To study the difference of microvessel density (MVD) between malignant and benign hepatic lesions and study the relationship between MVD and dynamic enhanced magnetic resonance imaging (MRI) for evaluation of microvessels within malignant and benign hepatic lesions.

METHODS: A total of 265 specimens of hepatocellular carcinoma (HCC), 122 cirrhosis tissues and 22 hepatic benign lesions were enrolled for MVD by immunohistochemistry on tissue microarray, of which 49 underwent MRI examination before surgery, then contrast-to-noise ratios (CNR) and enhancement index (EI) in all the phases were calculated. Pearson correlation was performed for correlation analysis between CNR, EI and MVD.

RESULTS: MVD of HCC was 22.7 ± 15.8 (mean ± SD), which was obviously higher than that of cirrhosis tissue (8.3 ± 7.6, P < 0.01), but was not statistically different from that of benign lesions (31.3 ± 22.7, P>0.05). Among HCC, MVD of gradesI-II was 29.9 ± 18.6, which was much higher than those of grade III (22.2 ± 18.2, P < 0.01) and gradeIV (22.9 ± 19.0, P < 0.01). MVD of HCC (P = 0.018) and of benign lesions (P = 0.014) were both correlative with CNR in arterial phase.

CONCLUSION: Neoangiogenesis is an important feature for malignant tumor, and MVD may act as a biological marker in differentiating malignant from benign hepatic lesions. Dynamic enhanced MRI, especially image in arterial phase, may act as an MVD evaluation criterion for malignant and benign hepatic lesions.

• Carcinoma, Hepatocellular/blood supply
• Carcinoma, Hepatocellular/pathology
• Diagnosis, Differential
• Humans
• Immunohistochemistry
• Liver Circulation
• Liver Cirrhosis/pathology
• Liver Neoplasms/blood supply
• Liver Neoplasms/pathology
• Magnetic Resonance Imaging
• Microcirculation
• Neovascularization, Pathologic/pathology

AIM: To clarify the location and distribution of Kupffer cells in hepatocellular carcinoma (HCC), and to investigate their role in hepatocarcinogenesis.

METHODS: Kupffer cells were immunohistochemically stained by streptavadin-peroxidase conjugated method (S-P). The numbers of Kupffer cells in cancerous, para-cancerous and adjacent normal liver tissues of 48 HCCs were comparatively examined.

RESULTS: The mean number of Kupffer cells in cancerous, para-cancerous and adjacent normal liver tissues was 12.7 ± 6.8, 18.1 ± 8.2 and 18.9 ± 7.9 respectively. The number of Kuppfer cells in cancerous tissues was significantly lower than that in para-cancerous tissues (t = 2.423, P < 0.05) and adjacent normal liver tissues (t = 2.521, P < 0.05). As tumor size increased, the number of Kupffer cells in cancerous tissues significantly decreased (F = 4.61, P < 0.05). Moreover, there was also a significant difference in the number of Kupffer cells among well-differentiated, moderately-differentiated and poorly-differentiated cases(F = 4.49, P < 0.05).

CONCLUSION: This study suggests that decrease of Kupffer cells in HCCs may play an important role in the carcinogenesis of HCC, the number of Kupffer cells in HCC is closely related to the size and differentiation grade of the tumor.

• Carcinoma, Hepatocellular/pathology
• Cell Count
• Humans
• Immunohistochemistry
• Kupffer Cells/pathology
• Liver/pathology
• Liver Neoplasms/pathology