Keon Wook Kang

A Prospective Evaluation of 18F-FDG and 11C-Acetate PET/CT for Detection of Primary and Metastatic Hepatocellular Carcinoma

Because 18F-FDG PET has insufficient sensitivity for the detection of hepatocellular carcinoma (HCC), 11C-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. Methods: One hundred twelve patients (99 with HCC, 13 with cholangiocellular carcinoma) underwent biopsy and 18F-FDG and 11C-acetate PET/CT. Results: The overall sensitivities of 18F-FDG, 11C-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 α-fetoprotein levels, an advanced tumor stage, portal vein tumor thrombosis, large tumors, and multiple tumors were significantly associated with positive 18F-FDG PET/CT results. Uptake of 11C-acetate was associated with large and multiple tumors. For 18F-FDG, the sensitivities according to tumor size (1–2, 2–5, and ≥5 cm) were 27.2%, 47.8%, and 92.8%, respectively; for 11C-acetate, these respective values were 31.8%, 78.2%, and 95.2%. 18F-FDG was more sensitive in the detection of poorly differentiated HCC. Overall survival was lower in patients with 18F-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 18F-FDG PET/CT was 64.4% for primary HCC and 84.4% for 11C-acetate PET/CT. The overall sensitivities of 18F-FDG, 11C-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. Conclusion: The addition of 11C-acetate to 18F-FDG PET/CT increases the overall sensitivity for the detection of primary HCC but not for the detection of extrahepatic metastases. 18F-FDG, 11C-acetate, and dual-tracer PET/CT have a low sensitivity for the detection of small primary HCC, but 18F-FDG PET/CT has a relatively high sensitivity for the detection of extrahepatic metastases of HCC.

Assessment of lymph node metastases using 18F-FDG PET in patients with advanced gastric cancer

PurposeThe aim of this study was to assess the diagnostic accuracy of 18F-fluoro-2-deoxyglucose (FDG) positron emission tomography (PET) with respect to lymph node (LN) metastasis in patients with advanced gastric cancer, and to ascertain the factors that affect this accuracy.MethodsSeventy-three patients with advanced gastric cancer, verified in all cases by endoscopic biopsy, were enrolled in this prospective study. We conducted FDG PET and other routine preoperative studies, including abdominal computed tomography (CT). Patients underwent either curative-intent gastrectomy and lymphadenectomy (n=67) or exploratory laparotomy. The Japanese system for the classification of gastric cancer was used for LN assessment.ResultsFDG PET was able to detect primary lesions in 70 of the 73 cases. The sensitivity, specificity, positive predictive value (PPV) and negative predictive value of FDG PET for LN metastasis were 40%, 95%, 91% and 56%, respectively. Signet-ring cell carcinoma was associated with the lowest sensitivity (15%), whereas other cell types could be detected with moderate sensitivity (30–71%) and high specificity (93–100%). According to multiple logistic regression, the standardised uptake value for primary tumours was the only independent variable to be significantly related to sensitivity for LN metastasis (p=0.02, odds ratio=1.14). CT was superior to PET in terms of sensitivity (p<0.0001), and PET was superior to CT in terms of specificity (p<0.0001) and PPV (p=0.05).ConclusionFDG PET exhibits good specificity for LN staging of gastric cancer, and FDG uptake in the primary tumour is significantly related to the accuracy of FDG PET. Despite some clear limitations, FDG PET proved useful in the LN staging of FDG-avid gastric cancer.

Prediction of Tumor Recurrence by 18F-FDG PET in Liver Transplantation for Hepatocellular Carcinoma

Although several prognostic factors are used to predict recurrence and to select adequate candidates for liver transplantation for hepatocellular carcinoma (HCC), these prognostic factors have some clinical limitations. The purpose of this study was to evaluate 18F-FDG PET as a prognostic factor and to optimize its ability to predict tumor recurrence in liver transplantation for HCC. Methods: The study included a total of 59 HCC patients (45 men and 15 women; mean age ± SD, 56 ± 8 y) who underwent 18F-FDG PET and subsequent orthotopic liver transplantation. All patients were followed up for more than 1 y (mean, 29 ± 17 mo), and recurrence of tumor was monitored. Three PET parameters—maximal standardized uptake value (SUVmax), ratio of tumor SUVmax to normal-liver SUVmax (TSUVmax/LSUVmax), and ratio of tumor SUVmax to normal-liver mean SUV (TSUVmax/LSUVmean)—were tested as prognostic factors and compared with conventional prognostic factors. Results: Among the 3 parameters tested, TSUVmax/LSUVmax was the most significant in the prediction of tumor recurrence, with a cutoff value of 1.15. In a multivariate analysis of various prognostic factors including TSUVmax/LSUVmax, serum α-fetoprotein, T stage, size of tumor, and vascular invasion of tumor, TSUVmax/LSUVmax was the most significant, and only vascular invasion of tumor had additional significance. According to TSUVmax/LSUVmax, the 1-y recurrence-free survival rate above the cutoff was markedly different from the rate below the cutoff (97% vs. 57%, P < 0.001). Conclusion: In this study, 18F-FDG PET was an independent and significant predictor of tumor recurrence. In liver transplantation for HCC, 18F-FDG PET can provide effective information on the prognosis for tumor recurrence and the selection of adequate candidates for liver transplantation.

Tumor Targeting and Imaging Using Cyclic RGD‐PEGylated Gold Nanoparticle Probes with Directly Conjugated Iodine‐125

Radioactive iodine-labeled, cyclic RGD-PEGylated gold nanoparticle (AuNP) probes are designed and synthesized for targeting cancer cells and imaging tumor sites. These iodine-125-labeled cRGD-PEG-AuNP probes are stable in various conditions including a range of pHs and high salt and temperature conditions. These probes can target selectively and be taken up by tumor cells via integrin αvβ3-receptor-mediated endocytosis with no cytotoxicity. The probes show a significant increase in the avidity of αvβ3 integrin compared to the corresponding free cRGD peptides. In-vivo SPECT/CT imaging results show that the iodine-125-labeled cRGD-PEG-AuNP probes can target the tumor site as soon as 10 min after injection, and also that cyclic RGD peptides are needed for efficient and long-term in-vivo monitoring. The results suggest that the probes circulate through the whole body, including renal filtration, and are excretable. These promising results show that radioactive-iodine-labeled gold nanoprobes have potential for highly specific and sensitive tumor imaging or for use as angiogenesis-targeted SPECT/CT imaging probes.

Procyanidins in crataegus extract evoke endothelium-dependent vasorelaxation in rat aorta.

The extract of Crataegus, a mixture of flavonoids and procyanidins extracted from hawthorn, Crataegus oxyacantha, L. and C. monogyna Jacq., relaxed vascular tone or increased production of cyclic GMP in the rat aorta, but flavonoid components of Crataegus extract, hyperoside, rutin and vitexin, did not affect the vascular tone. The aim of the present study was to characterize the endothelium-dependent relaxation elicited by procyanidins fractionated from Crataegus extract in isolated rat aorta. Procyanidins caused endothelium-dependent relaxation which was associated with the production of cyclic GMP. Both responses to these procyanidins were inhibited by methylene blue or N(G)-nitro-L-arginine, but not by indomethacin. Relaxation in response to procyanidins was not affected by atropine, diphenhydramine, [D-Pro2,D-Trp7,9]substance P, propranolol, nifedipine, verapamil and glibenclamide, but were markedly reduced by tetraethylammonium. These findings showed that procyanidins in Crataegus extract may be responsible for the endothelium-dependent nitric oxide-mediated relaxation in isolated rat aorta, possibly via activation of tetraethylammonium-sensitive K+ channels.

Prognostic Value of Metabolic Tumor Volume and Total Lesion Glycolysis in Head and Neck Cancer: A Systematic Review and Meta-Analysis

We conducted a comprehensive systematic review of the literature on volumetric parameters and a meta-analysis of the prognostic value of metabolic tumor volume (MTV) and total lesion glycolysis (TLG) in patients with head and neck cancer (HNC). Methods: A systematic search of MEDLINE and EMBASE was performed using the key words PET, head and neck, and volume. Inclusion criteria were 18F-FDG PET used as an initial imaging tool; studies limited to HNC; patients who had not undergone surgery, chemotherapy, or radiotherapy before PET scans; and studies reporting survival data. Event-free survival and overall survival were considered markers of outcome. The impact of MTV or TLG on survival was measured by the effect size hazard ratio (HR). Data from each study were analyzed using Review Manager. Results: Thirteen studies comprising 1,180 patients were included in this study. The combined HR for adverse events was 3.06 (2.33–4.01, P < 0.00001) with MTV and 3.10 (2.27–4.24, P < 0.00001) with TLG, meaning that tumors with high volumetric parameters were associated with progression or recurrence. Regarding overall survival, the pooled HR was 3.51 (2.62–4.72, P < 0.00001) with MTV and 3.14 (2.24–4.40, P < 0.00001) with TLG. There was no evidence of significant statistical heterogeneity at an I2 of 0%. Conclusion: MTV and TLG are prognostic predictors of outcome in patients with HNC. Despite clinically heterogeneous HNC and the various methods adopted between studies, we can confirm that patients with a high MTV or TLG have a higher risk of adverse events or death.

Ginsenoside Rg3 inhibits phenylephrine‐induced vascular contraction through induction of nitric oxide synthase

Ginsenoside Rg3 (Rg3) isolated from Panax ginseng relaxes vessels and exerts a cytoprotective effect. In view of the fact that nitric oxide (NO) is involved in vascular hyporeactivity and immunostimulation, the effects of total ginsenosides (GS) and Rg3 on the vascular responses and the expression of inducible nitric oxide synthase (iNOS) were investigated. Vasocontraction of endothelium‐denuded aortic ring was induced by phenylephrine with or without GS or Rg3. The expression of iNOS was assessed by Western blot and RT–PCR analyses. NF‐κB activation was monitored by gel shift, immunoblot and immunocytochemical analyses. Incubation of the endothelium‐denuded aortic ring with GS or Rg3 inhibited phenylephrine‐induced vasocontraction, which was abrogated by NOS inhibition. GS or Rg3 increased NO production in aortic rings, but Rb1, Rc, Re and Rg1 had no effect. Aortic rings obtained from rats treated with GS or Rg3 responded to phenylnephrine to a lesser extent, while producing NO to a larger extent, than those from control animals. GS or Rg3 induced iNOS in vascular smooth muscle. Rg3 induced iNOS with increase in NO production in Raw264.7 cells. Rg3 increased NF‐κB DNA binding, whose band was supershifted with anti‐p65 and anti‐p50 antibodies, and elicited p65 nuclear translocation, which was accompanied by phosphorylation and degradation of I‐κBα. PKC regulated iNOS induction by Rg3. In conclusion, Rg3 relaxes vessels as a consequence of NO production, to which iNOS induction contributes, and iNOS induction by Rg3 accompanied NF‐κB activation, which involves phosphorylation and degradation of I‐κBα and nuclear translocation of p65.

Differentiating radiation necrosis from tumor recurrence in high-grade gliomas: assessing the efficacy of 18F-FDG PET, 11C-methionine PET and perfusion MRI.

PURPOSE The authors analyzed the characteristics of perfusion magnetic resonance imaging (MRI), (18)F-fluorodeoxyglucose (FDG) positron emission tomography (PET) and (11)C-methionine (MET) PET to compare the efficacies of these modalities in making the distinction between radiation necrosis and tumor recurrence of high-grade glioma. PATIENTS AND METHODS Ten patients were evaluated with dynamic susceptibility contrast perfusion MRI, (11)C-MET PET and (18)F-FDG PET to visualize gadolinium-enhanced lesions during the post-radiation follow-up period. In the perfusion MRI, four regions of interest (ROIs) were identified and average values were calculated. A reference ROI of the same size was defined in the contralateral white matter to obtain the relative cerebral blood volume (rCBV). After coregistering the PET images with the MRI, we measured the maximum uptake values of the lesion and of the contralateral cerebral white matter as reference area to calculate the L(max)/R(max) ratio. RESULTS The rCBV was higher in the recurrence group than in the necrosis group (p=0.010). There was no difference between groups in terms of the L(max)/R(max) ratio as derived from the (18)F-FDG and (11)C-MET PET. CONCLUSION A quantitative rCBV as calculated from a perfusion MRI scan might be superior to the L(max)/R(max) ratio as derived from (18)F-FDG and (11)C-MET PET in order to distinguish a recurrence of high-grade glioma from radiation necrosis.

Peroxynitrite activates NF-E2-related factor 2/antioxidant response element through the pathway of phosphatidylinositol 3-kinase: the role of nitric oxide synthase in rat glutathione S-transferase A2 induction.

The protective adaptive response to electrophiles and reactive oxygen species is mediated by the induction of phase II detoxifying genes through antioxidant response elements (AREs). Our previous study showed that sulfur amino acid deprivation (SAAD) produces peroxides and induces rat glutathione S-transferase A2 (rGSTA2) through NF-E2-related factor 2 (Nrf2)/ARE activation via the pathway of phosphatidylinositol 3-kinase (PI3-kinase). The current study was designed to investigate the role of peroxynitrite in Nrf2/ARE activation and rGSTA2 induction. L-Arginine deficiency or N(G)-nitro-L-arginine methyl ester (L-NAME) reduced peroxide production induced by SAAD in H4IIE cells. Northern and Western blot analyses revealed that the levels of rGSTA2 mRNA and protein were significantly increased 24h after incubation of the cells in SAAD medium, which was inhibited by L-arginine deficiency or L-NAME. Subcellular fractionation and gel shift analyses revealed that SAAD increased the level of nuclear Nrf2 and activated ARE, which were also blocked by L-arginine deficiency or L-NAME. Whereas the exogenous NO donor S-nitroso-N-acetyl-penicillamine (SNAP) alone failed to significantly induce rGSTA2, SNAP enhanced SAAD-inducible rGSTA2 expression, verifying the notion that peroxynitrite derived from NO contributes to rGSTA2 induction. 3-Morpholinosydnonimine (SIN-1), which decomposes and yields peroxynitrite, increased the rGSTA2 mRNA and protein levels in a dose-dependent manner. SIN-1 increased the level of nuclear Nrf2 and activated Nrf2/ARE, which was supershifted by anti-Nrf2 and anti-Maf antibodies. SIN-1 increased the activity of PI3-kinase, as monitored by phosphorylation of Akt. SIN-1-inducible rGSTA2 expression was inhibited by PI3-kinase inhibitors. These results provide evidence that peroxynitrite plays an essential role in nuclear translocation of Nrf2 and ARE activation through the pathway of PI3-kinase and that nitric oxide synthase is involved in the induction of rGSTA2.

Prognostic value of metabolic tumor volume measured by FDG-PET/CT in patients with cervical cancer

OBJECTIVE To determine if preoperative metabolic tumor volume (MTV) measured by integrated (18)F-fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (FDG-PET/CT) imaging has prognostic value in patients with cervical cancer treated primarily with radical hysterectomy. METHODS Patients with FIGO stage IB to IIA cervical cancer were imaged with FDG-PET/CT before radical surgery. MTV was measured from attenuation-corrected FDG-PET/CT images using a standard uptake value (SUV)-based automated contouring program. We evaluated the relationship of MTV to disease-free survival (DFS). RESULTS A total of 63 patients were included in the study. The cut-off value for predicting recurrence was determined using a receiver operating characteristic (ROC) curve. MTV in this study was found to be correlated with lymph node (LN) metastasis, parametrium (PM) involvement, FIGO stage, and SUV(max). In univariate analysis, MTV≥23.4 mL (HR 1.017, 95% confidence interval (CI) 1.005-1.029, P=0.004), SUV(max)≥9.5 (HR 5.198, 95% CI 1.076-25.118, P=0.04), LN metastasis (HR 12.338, 95% CI 1.541-98.813, P=0.018), PM involvement (HR 14.274, 95% CI 1.785-114.149, P=0.012), and lymphovascular space invasion (HR 8.871, 95% CI 1.104-71.261, P=0.04), were related to DFS. In multivariate analyses, age (HR 0.748, 95% CI 0.587-0.952, P=0.018) and MTV≥23.4 mL (HR 49.559, 95% CI 1.257-1953.399, P=0.037) were determined to be independent prognostic factors of DFS. CONCLUSION Preoperative MTV is an independent prognostic factor for DFS in patients with cervical cancer treated by radical surgery.