carbon-11-acetate and Liver-Neoplasms

Topics: Acetates; Adult; Aged; Biomarkers, Tumor; Carbon; Carcinoma, Hepatocellular; Female; Fluorodeoxyglucose F18; Humans; Liver Neoplasms; Male; Middle Aged; Positron Emission Tomography Computed Tomography; Positron-Emission Tomography; Radiopharmaceuticals

It is well known that 40%-50% of hepatocellular carcinoma (HCC) do not show increased 18F-fluorodeoxyglucose (FDG) uptake. Recent research studies have demonstrated that 11C-acetate may be a complementary tracer to FDG in positron emission tomography (PET) imaging of HCC in the liver. Quantitative dynamic modeling is, therefore, conducted to evaluate the kinetic characteristics of this tracer in HCC and nontumor liver tissue. A three-compartment model consisting of four parameters with dual inputs is proposed and compared with that of five parameters. Twelve regions of dynamic datasets of the liver extracted from six patients are used to test the models. Estimation of the adequacy of these models is based on Akaike Information Criteria (AIC) and Schwarz Criteria (SC) by statistical study. The forward clearance K = K1 * k3/(k2 + k3) is estimated and defined as a new parameter called the local hepatic metabolic rate-constant of acetate (LHMRAct) using both the weighted nonlinear least squares (NLS) and the linear Patlak methods. Preliminary results show that the LHMRAct of the HCC is significantly higher than that of the nontumor liver tissue. These model parameters provide quantitative evidence and understanding on the kinetic basis of C-acetate for its potential role in the imaging of HCC using PET.

Topics: Acetates; Algorithms; Carbon; Carcinoma, Hepatocellular; Computer Simulation; Humans; Image Interpretation, Computer-Assisted; Liver; Liver Function Tests; Liver Neoplasms; Models, Biological; Radioisotope Dilution Technique; Radiopharmaceuticals; Reproducibility of Results; Sensitivity and Specificity; Tomography, Emission-Computed

Our recent research has demonstrated that 11C-acetate could be a complementary tracer to 18F-fluorodeoxyglucose (FDG) in positron emission tomography (PET) imaging of hepatocellular carcinoma (HCC). In our previous modeling study, a three-compartment four-parameter model with a fixed contribution ratio of the liver's two blood supplies was proposed to characterize the kinetic behavior of 11C-acetate in liver. However, in real pathology, both tumor and nontumor liver tissue can be heterogeneous in the distribution and proportion of the two blood supplies. To further improve the accuracy of quantitative analysis, the actual proportion of the hepatic artery and portal vein (PV) in different regions of interest (ROIs) was investigated in this study. An extra parameter av was included in the model input function to describe the contribution of PV to the liver. Ten ROIs extracted from six patients were used to test the models with fixed/nonfixed weighted dual-input function. The weighted nonlinear least squares algorithm was used to estimate all of the parameters. Evaluation of the adequacy of the two models was conducted and the computer simulation was performed to test the estimation accuracy of the new model. The forward clearance K was also estimated by the linear Patlak method. The results show that the model with parameter av in the input function was more suitable for mapping the tracer time activity curves. Moreover, the estimated av value fits the practical physiological and pathological conditions well and could be a potential candidate to provide useful additional diagnostic information for the early detection of hepatic metastases.

Topics: Acetates; Blood Flow Velocity; Carbon; Carcinoma, Hepatocellular; Computer Simulation; Feasibility Studies; Hepatic Artery; Hepatitis C; Humans; Image Interpretation, Computer-Assisted; Kinetics; Liver; Liver Circulation; Liver Neoplasms; Metabolic Clearance Rate; Models, Biological; Portal System; Radioisotope Dilution Technique; Radiopharmaceuticals; Reproducibility of Results; Sensitivity and Specificity; Tomography, Emission-Computed

The aim of the present study was to evaluate the clinical significance of dual radiotracer studies, C-acetate and F-fluoro-D-glucose positron emission tomography/computed tomography (F-FDG PET/CT), for the prediction of response and recurrence after transarterial chemoembolization (TACE).This study retrospectively included a total 42 hepatoceullar carcinoma (HCC) patients (median age, 59; range, 34-85 years old) who underwent C-acetate and F-FDG PET/CT concurrently. Tumor uptake normalized by liver uptake (TNR; maximum tumor SUV to mean normal liver SUV ratio) was obtained first. Then, FAratio, which is the ratio of F-FDG TNR (TNR_FDG) to C-acetate TNR, was obtained and correlated with response after TACE and recurrence-free survival (RFS), using a Cox multivariate proportional-hazard model.Among clinical factors, including the Hepatoma Arterial Embolization Prognostic score and positron emission tomography (PET) parameters, multiple regression analysis revealed FAratio and tumor size to be the only significant factors. As a PET parameter, FAratio exhibited the largest area under the curve in the prediction of response after TACE. In the Cox multivariate proportional-hazard model, TNR_FDG was the only significant predictive factor for RFS. In subgroup analysis, TNR_FDG was the only significant predictive factor for recurrence in intermediate stage patients. However, FAratio was the only significant predictive factor for recurrence in advanced stage patients.Dual radiotracer use of C-acetate and F-FDG PET/CT contributed to the prediction of response and recurrence after TACE. Used in addition to F-FDG, C-acetate PET/CT could give additional information in advanced stage patients. Based on the characteristics of tumor metabolism assessed by dual radiotracer PET/CT, treatment plans could be more personalized and optimized.

Topics: Acetates; Adult; Aged; Aged, 80 and over; Carbon; Carcinoma, Hepatocellular; Chemoembolization, Therapeutic; Female; Fluorodeoxyglucose F18; Humans; Liver; Liver Neoplasms; Male; Middle Aged; Positron Emission Tomography Computed Tomography; Predictive Value of Tests; Prognosis; Proportional Hazards Models; Radiopharmaceuticals; Regression Analysis; Retrospective Studies; Treatment Outcome

This prospective study was to investigate the value of [. The patient-related sensitivity of [. Our study suggests that combining [

Topics: Acetates; Aged; Arteries; Bevacizumab; Carbon; Carcinoma, Hepatocellular; Chemoembolization, Therapeutic; Female; Fluorodeoxyglucose F18; Humans; Liver Neoplasms; Male; Middle Aged; Positron-Emission Tomography; Survival Analysis; Treatment Outcome

Hepatocellular carcinoma (HCC) remains a global health problem with unique diagnostic and therapeutic challenges, including difficulties in identifying the highest risk patients. Previous work from our lab has established the murine multidrug resistance-2 mouse (MDR2) model of HCC as a reasonable preclinical model that parallels the changes seen in human inflammatory associated HCC. The purpose of this study is to evaluate modalities of PET/CT in MDR2(-/-) mice in order to facilitate therapeutic translational studies from bench to bedside.. 18F-FDG and 11C-acetate PET/CT was performed on 12 m MDR2(-/-) mice (n = 3/tracer) with HCC and 12 m MDR2(-/+) control mice (n = 3/tracer) without HCC. To compare PET/CT to biological markers of HCC and cellular function, serum alpha-fetoprotein (AFP), lysophosphatidic acid (LPA), cAMP and hepatic tumor necrosis factor α (TNFα) were quantified in 3-12 m MDR2(-/-) (n = 10) mice using commercially available ELISA analysis. To translate results in mice to patients 11C-acetate PET/CT was also performed in 8 patents suspected of HCC recurrence following treatment and currently on the liver transplant wait list.. Hepatic18F-FDG metabolism was not significantly increased in MDR2(-/-) mice. In contrast, hepatic 11C-acetate metabolism was significantly elevated in MDR2(-/-) mice when compared to MDR2(-/+) controls. Serum AFP and LPA levels increased in MDR2(-/-) mice contemporaneous with the emergence of HCC. This was accompanied by a significant decrease in serum cAMP levels and an increase in hepatic TNFα. In patients suspected of HCC recurrence there were 5 true positives, 2 true negatives and 1 suspected false 11C-acetate negative.. Hepatic 11C-acetate PET/CT tracks well with HCC in MDR2(-/-) mice and patients with underlying liver disease. Consequently 11C-acetate PET/CT is well suited to study (1) HCC emergence/progression in patients and (2) reduce animal numbers required to study new chemotherapeutics in murine models of HCC.

Topics: Acetates; Animals; ATP Binding Cassette Transporter, Subfamily B; ATP-Binding Cassette Sub-Family B Member 4; Carbon; Carcinoma, Hepatocellular; Disease Models, Animal; Fluorodeoxyglucose F18; Liver Neoplasms; Mice; Mice, Knockout; Multimodal Imaging; Positron-Emission Tomography; Radiopharmaceuticals; Reproducibility of Results; Sensitivity and Specificity; Tomography, X-Ray Computed

Microvascular invasion is a poor prognostic indicator of the recurrence of hepatocellular carcinoma (HCC) after surgical treatment. Positron emission tomography (PET) with [(18) F]fludeoxyglucose ([(18) F]FDG) as a tracer has been employed to predict the prognosis before surgery for various kinds of tumors, but it has not been found to be sensitive enough for HCC. Thus, [(11) C]acetate has been adopted as an additional tracer. This study was designed to evaluate the ability of dual-tracer PET ([(18) F]FDG and [(11) C]acetate) to predict microvascular invasion before liver resection or transplantation. Fifty-eight HCC patients who were preoperatively examined with whole-body dual-tracer PET were studied. Twenty-five patients were [(18) F]FDG-positive, and 56 were [(11) C]acetate-positive. The sensitivity of [(18) F]FDG in detecting primary HCC was 43%, and the sensitivity of [(11) C]acetate was 93%. Twenty-nine patients had HCC with microvascular invasion according to the final pathological examination. The sensitivity, specificity, positive predictive value, and negative predictive value of [(18) F]FDG PET in predicting microvascular invasion were 55.2%, 69%, 64%, and 60.6%, respectively; the corresponding rates for [(11) C]acetate PET were 93.1%, 0%, 48.2%, and 0%. The factors associated with HCC recurrence, which included multifocal involvement, a large tumor size, microsatellite lesions, poor HCC differentiation, and an advanced stage of disease, were analyzed and compared with positive PET results. A tumor size greater than 5 cm was significantly associated with positive [(18) F]FDG PET results; [(11) C]acetate was not associated with poor prognostic indicators. Preoperative [(18) F]FDG PET may predict microvascular invasion. The addition of [(11) C]acetate improves the overall sensitivity of PET, but it has no incremental value in predicting microvascular invasion.

Topics: Acetates; Adult; Aged; Aged, 80 and over; Carbon; Carcinoma, Hepatocellular; Chi-Square Distribution; Disease-Free Survival; Female; Fluorodeoxyglucose F18; Hepatectomy; Hong Kong; Humans; Liver Neoplasms; Liver Transplantation; Male; Microvessels; Middle Aged; Neoplasm Invasiveness; Positron-Emission Tomography; Predictive Value of Tests; Preoperative Care; Radiopharmaceuticals; Retrospective Studies; Sensitivity and Specificity; Survival Analysis; Survival Rate; Time Factors; Treatment Outcome

We analyzed the pattern of (11)C-acetate and (18)F-FDG uptake on PET/CT in patients with hepatocellular carcinoma (HCC). We also assessed the expression of important regulatory enzymes related to glycolysis and lipid synthesis in relation to (18)F-FDG and (11)C-acetate uptake in human HCC cell lines. The significance of (11)C-acetate uptake regulation was further evaluated with regard to cell viability.. (18)F-FDG and (11)C-acetate uptake patterns in HCC in 11 patients and in 5 HCC cell lines were assessed. We evaluated the gene expression of metabolic enzymes related to glycolysis and lipid synthesis in a cell line with the highest (18)F-FDG uptake and another cell line with the highest (11)C-acetate uptake. They included hexokinase II, adenosine triphosphate citrate lyase, acetyl coenzyme A (CoA) synthetase 1 (ACSS1), acetyl CoA synthetase 2 (ACSS2), acetyl CoA carboxylase, and fatty acid synthase. In a cell line with high (11)C-acetate uptake, the enzymatic activities of ACSS1 and ACSS2 were blocked using respective small, interfering RNAs (siRNAs), and the impact on (11)C-acetate uptake and cell viability was assessed.. In all 11 patients and 4 of the 5 cell lines, the uptake patterns of the 2 radiotracers were complementary. ACSS1 and ACSS2 were highly expressed in a cell line with low (18)F-FDG uptake and high (11)C-acetate uptake, whereas only ACSS2 was expressed in a cell line with high (18)F-FDG uptake and low (11)C-acetate uptake. Fatty acid synthase expression was seen in cells with high (18)F-FDG or (11)C-acetate uptake. These findings indicate the possibility that both glucose and acetate can be a compensatory carbon source for lipid synthesis in cancer. Transient transfection with ACSS1 or ACSS2 siRNA in cells with high (11)C-acetate uptake decreased (11)C-acetate uptake and cell viability.. The patterns of (18)F-FDG and (11)C-acetate uptake seemed to complement each other in both human HCC and HCC cell lines. Fatty acid synthase expression was seen in cells with high (18)F-FDG or (11)C-acetate uptake, suggesting glucose- or acetate-dependent lipid synthesis. Acetyl CoA synthetase appears to be important in (11)C-acetate uptake and acetate-dependent lipid synthesis for the growth of cancer cells with a low-glycolysis phenotype. Inhibition of acetyl CoA synthetase in these cells may be promising for anticancer treatment.

Topics: Acetate-CoA Ligase; Acetates; Adult; Aged; Carbon; Carcinoma, Hepatocellular; Cell Line, Tumor; Cell Survival; Fatty Acid Synthases; Female; Fluorodeoxyglucose F18; Humans; Liver Neoplasms; Male; Metabolic Clearance Rate; Middle Aged; Radionuclide Imaging; Radiopharmaceuticals

We assessed the usefulness of F-18 fluorodeoxyglucose positron emission tomography (FDG PET) and C-11 acetate PET (AC PET) in distinguishing hepatic lesions due to consequential disease (hepatocellular adenoma and malignant lesions) from focal nodular hyperplasia (FNH) in patients at low risk of malignancy.. Thirty-one patients with 43 lesions were prospectively enrolled. The diagnostic work-up included Doppler and contrast-enhanced ultrasonography, contrast-enhanced computed tomography, and/or magnetic resonance imaging. Fine needle biopsy was performed if the imaging study was inconclusive. The work-up revealed 36 FNH and 7 consequential lesions (5 hepatocellular adenoma, 1 hepatoma, and 1 metastasis). All patients underwent FDG and AC PET. FDG PET with target/background ratio (T/Br) greater than 1.2 and AC PET with T/Br of less than 1.2 were considered positive test for consequential disease.. On FDG PET, we had 6 true-positive out of 7 lesions due to consequential diseases, with a sensitivity of 85.7%, and 33 true-negative out of 36 lesions with FNH, with a specificity of 91.7%. Using AC PET, there were 2 true-positive lesions out of 7 caused by neoplasms, with a sensitivity of 28.6%, and 34 true-negative lesions out of 36 FNH, with a specificity of 94.4%.. When the goal is differentiating FNH from liver neoplasms, AC PET offered no additional diagnostic advantage over what is achieved with FDG PET.

Topics: Acetates; Adenoma, Liver Cell; Adolescent; Adult; Aged; Aged, 80 and over; Carbon; Carbon Isotopes; Diagnosis, Differential; Female; Fluorodeoxyglucose F18; Focal Nodular Hyperplasia; Humans; Liver Neoplasms; Male; Middle Aged; Positron-Emission Tomography; Tomography, X-Ray Computed; Young Adult

C-11 acetate positron emission tomography (PET) is known to have high sensitivity in detecting hepatocellular carcinoma. However, one of the shortcomings of C-11 acetate PET in the diagnosis of hepatocellular carcinoma is that C-11 acetate also accumulates in focal nodular hyperplasia, which makes it challenging to distinguish hepatocellular carcinoma form focal nodular hyperplasia when a conventional single time point PET imaging method is used. Two patients with suspected hepatocellular carcinoma and negative fluoro-deoxy-glucose PET scans underwent C-11 acetate PET dual time imaging in which both early and delayed images were acquired. One patient was subsequently confirmed having hepatocellular carcinoma while the other had focal nodular hyperplasia. C-11 acetate imaging was positive in both patients. Interestingly, in hepatocellular carcinoma the C-11 acetate activity in the delayed images is higher than in the early images while in focal nodular hyperplasia, the C-11 acetate activity decreased in the delayed image when compared with early images. Our findings suggest that dual time point imaging has potential to improve the diagnostic accuracy of C-11 acetate PET in the diagnosis of hepatocellular carcinoma.

Topics: Acetates; Carbon; Carcinoma, Hepatocellular; Diagnosis, Differential; Feasibility Studies; Focal Nodular Hyperplasia; Humans; Liver Neoplasms; Male; Middle Aged; Positron-Emission Tomography; Radiopharmaceuticals; Reproducibility of Results; Sensitivity and Specificity

Because (18)F-FDG PET has insufficient sensitivity for the detection of hepatocellular carcinoma (HCC), (11)C-acetate PET has been proposed as another technique for this use. We prospectively evaluated the value of PET/CT using these 2 tracers for the detection of primary and metastatic HCC.. One hundred twelve patients (99 with HCC, 13 with cholangiocellular carcinoma) underwent biopsy and (18)F-FDG and (11)C-acetate PET/CT.. The overall sensitivities of (18)F-FDG, (11)C-acetate, and dual-tracer PET/CT in the detection of 110 lesions in 90 patients with primary HCC were 60.9%, 75.4%, and 82.7%, respectively. Elevated serum alpha-fetoprotein levels, an advanced tumor stage, portal vein tumor thrombosis, large tumors, and multiple tumors were significantly associated with positive (18)F-FDG PET/CT results. Uptake of (11)C-acetate was associated with large and multiple tumors. For (18)F-FDG, the sensitivities according to tumor size (1-2, 2-5, and >/=5 cm) were 27.2%, 47.8%, and 92.8%, respectively; for (11)C-acetate, these respective values were 31.8%, 78.2%, and 95.2%. (18)F-FDG was more sensitive in the detection of poorly differentiated HCC. Overall survival was lower in patients with (18)F-FDG PET/CT positive for all indexed lesions than in those with FDG negative or partially positive through the entire follow-up period. In analysis based on biopsied lesions, the sensitivity of (18)F-FDG PET/CT was 64.4% for primary HCC and 84.4% for (11)C-acetate PET/CT. The overall sensitivities of (18)F-FDG, (11)C-acetate, and dual-tracer PET/CT for 35 metastatic HCCs were 85.7%, 77.0%, and 85.7%, respectively. There was no significant difference in the sensitivity of tracers according to metastatic tumor size, location, or differentiation.. The addition of (11)C-acetate to (18)F-FDG PET/CT increases the overall sensitivity for the detection of primary HCC but not for the detection of extrahepatic metastases. (18)F-FDG, (11)C-acetate, and dual-tracer PET/CT have a low sensitivity for the detection of small primary HCC, but (18)F-FDG PET/CT has a relatively high sensitivity for the detection of extrahepatic metastases of HCC.

Topics: Acetates; Adult; Carbon; Carcinoma, Hepatocellular; Female; Fluorodeoxyglucose F18; Humans; Incidence; Korea; Liver Neoplasms; Male; Middle Aged; Positron-Emission Tomography; Prognosis; Prospective Studies; Radiopharmaceuticals; Reproducibility of Results; Risk Assessment; Risk Factors; Sensitivity and Specificity; Subtraction Technique; Survival Analysis; Survival Rate; Tomography, X-Ray Computed

The successful investigation of 11C-acetate in positron emission tomography (PET) imaging for marking hepatocellular carcinoma (HCC) has been validated by both clinical and quantitative modeling studies. In the previous quantitative studies, all the individual model parameters were estimated by the weighted nonlinear least squares (NLS) algorithm. However, five parameters need to be estimated simultaneously, therefore, the computational time-complexity is high and some estimates are not quite reliable, which limits its application in clinical environment. In addition, liver system modeling with dual-input function is very different from the widespread single-input system modeling. Therefore, most of the currently developed estimation techniques are not applicable. In this paper, two parameter estimation techniques: graphed NLS (GNLS) and graphed dual-input generalized linear least squares (GDGLLS) algorithms were presented for 11C-acetate dual-input liver model. Clinical and simulated data were utilized to test the proposed algorithms by a systematic statistical analysis. Compared to NLS fitting, these two novel methods achieve better estimation reliability and are computationally efficient, and they are extremely powerful for the estimation of the two potential HCC indicators: local hepatic metabolic rate-constant of acetate and relative portal venous contribution to the hepatic blood flow.

Topics: Acetates; Carbon; Carcinoma, Hepatocellular; Computer Simulation; Humans; Image Interpretation, Computer-Assisted; Liver; Liver Circulation; Liver Neoplasms; Models, Biological; Positron-Emission Tomography; Radiopharmaceuticals; Reproducibility of Results; Sensitivity and Specificity

Topics: Acetates; Angiomyolipoma; Carbon; Carcinoma, Hepatocellular; False Positive Reactions; Humans; Liver; Liver Neoplasms; Middle Aged; Positron-Emission Tomography