Noboru Oriuchi

Osaka University, Suika, Ōsaka, Japan

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Publications (244)563.94 Total impact

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    ABSTRACT: CD98 has been described to play a crucial role in tumor progression and survival. However, the role of CD98 in biliary tract cancer remains unclear. We found that 36.7% of all patients with biliary tract cancer had a high CD98 expression. Statistical analysis using Spearman's rank correlation showed that CD98 was significantly correlated with L-type amino acid transporter 1 (LAT1, r=0.562, P<0.001), Ki-67 (r=0.230, P=0.006) and CD34 (r=0.290, P=0.005). Multivariate analysis confirmed that a high CD98 expression was an independent prognostic factor for predicting poor outcome. CD98 is closely associated with tumor growth, biological aggressiveness, and survival of patients. With these data we proposed that CD98 expression is necessary for the development and pathogenesis of biliary tract cancer.
    Hepatobiliary & pancreatic diseases international: HBPD INT 12/2014; 13(6):654-7. · 1.26 Impact Factor
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    ABSTRACT: PurposeAmino acid transporters play an important role in the tumor progression and survival of cancer cells. But, it remains unclear about the prognostic significance of L-type amino acid transporter 1 (LAT1), system ASC amino acid transporter-2 (ASCT2) and xCT expression in patients with hepatocellular carcinoma (HCC). The aim of this study is to investigate the clinicopathological significance of these amino acid transporters in patients with HCC.Material and Methods We examined 84 patients with surgically resected HCC. Tumor sections were stained by immunohistochemistry for LAT1, ASCT2, xCT, 4F2hc/CD98hc (4F2hc), Ki-67, and microvessel density (MVD) determined by CD34.ResultsLAT1, 4F2hc, ASCT2 and xCT were positively expressed in 61% (50/84), 77% (65/84), 63% (53/84) and 65% (55/84), respectively. Positive LAT1 expression was significantly associated with 4F2hc expression, Ki-67 and the serum albumin. By univariate analysis, LAT1 expression, disease stage and albumin had a significant relationship with overall survival. Tumor size, disease stage, portal vein invasion, albumin and α-fetoprotein had a significant relationship with progression-free survival. Multivariate analysis confirmed that LAT1 expression is an independent and significant prognostic factor for predicting worse outcome after surgery.ConclusionLAT1 can serve as a significant prognostic marker for predicting negative prognosis after surgery.
    Hepatology Research 10/2014; · 2.07 Impact Factor
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    ABSTRACT: Effective treatments for malignant neuroendocrine tumors are under development. While iodine-131 metaiodobenzylguanidine ((131)I-MIBG) radiotherapy has been used in the treatment of malignant neuroendocrine tumors, there are few studies evaluating its therapeutic effects and safety in a multicenter cohort. In the current study, we sought to evaluate the effects and safety of (131)I-MIBG therapy for conditions including malignant pheochromocytoma and paraganglioma within a multicenter cohort. Forty-eight malignant neuroendocrine tumors (37 pheochromocytoma and 11 paraganglioma) from four centers underwent clinical (131)I-MIBG radiotherapy. The tumor responses were observed before and 3 to 6 months after the (131)I-MIBG radiotherapy in accordance with RECIST criteria. We also evaluated the data for any adverse effects. The four centers performed a total of 87 (131)I-MIBG treatments on 48 patients between January 2000 and March 2009. Of the treatments, 65 were evaluable using RECIST criteria. One partial response (PR), 40 stable disease (SD), and 9 progressive disease (PD) in malignant pheochromocytoma were observed after each treatment. Fourteen SD and one PD were observed in paraganglioma. Patients with normal hypertension (systolic blood pressure (BP) > 130 mmHg) showed significantly reduced systolic BP after the initial follow-up (n=10, 138.1±8.2 to 129.5±13.5 mmHg, P=0.03). In adult neuroendocrine tumors with a treatment-basis analysis, there were side effects following 41 treatments (47.1%) and most of them (90.2%) were minor. In this multicenter registry, PR or SD was achieved in 84.6% of the treatment occasions in adult neuroendocrine tumors through (131)I-MIBG radiotherapy. This indicated that most of the (131)I-MIBG radiotherapy was performed safely without significant side effects.
    Endocrine Journal 09/2014; · 2.23 Impact Factor
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    ABSTRACT: L-type amino-acid transporter 1 (LAT1) plays a key role in cell growth and survival. To determine the prognostic significance of LAT1 in multiple myeloma (MM), we investigated the expression of LAT1 and its functional subunit, 4Fc heavy chain (CD98), on myeloma cells by immunohistochemistry in 100 newly diagnosed MM patients. High expression (moderate or strong staining intensity) of LAT1 and CD98 was detected in 56% and 45% of patients, respectively. The LAT1 expression score was positively correlated with Ki-67 index (r=0.631, p<0.001), and there was a statistically significant difference in Durie-Salmon stage between patients with high and low LAT1 expression (p=0.03). In 43 patients treated with melphalan and prednisolone, overall response rate was significantly higher in the high LAT1 expression group (60.0%) than in the low LAT1 expression group (17.6%) (p=0.03). Multivariate analysis confirmed that high expression of LAT1 was a significant prognostic factor for predicting poor overall survival independently from the International staging system (both p=0.01). Here, we show that the overexpression of LAT1 is significantly associated with high proliferation and poor prognosis in newly diagnosed MM patients. Thus, LAT1 may be a promising pathological marker for identifying high-risk MM.This article is protected by copyright. All rights reserved.
    Cancer Science 09/2014; · 3.48 Impact Factor
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    ABSTRACT: Purpose: Both L-type amino acid transporter 1 (LAT1) and CD98 are strongly expressed in primary human cancer and play essential roles in tumor growth. We studied the clinicopathological significance of LAT1 and CD98 expression in hypopharyngeal squamous cell carcinoma (HSCC). Materials and Methods: A total of 70 patients with stage III/IV disease were retrospectively reviewed. Immunohistochemical staining of tumor sections was used to examine LAT1 and CD98, Ki-67, CD34 and p53. Results: High LAT1 and CD98 expressionwere noted in 60.0% and 47.1%, respectively (p=0.174). A statistically significant correlation was recognized between LAT1 and CD98 expression and both, expression were closely associated with tumor cell proliferation. Although LAT1 expression was not significantly associated with poor survival, multivariate analysis revealed high CD98 expression to be an independent prognostic factor for predicting a poor outcome. Conclusions: CD98 is a promising prognostic marker for predicting outcomes after surgical treatment in patients with advanced HSCC. Head Neck, 2014.
    Head & Neck 06/2014; · 2.83 Impact Factor
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    ABSTRACT: ASCT2 is highly expressed in cancer cells. However, the clinicopathological significance of ASCT2 expression in pancreatic cancer remains unclear. The aim of this study was to investigate the clinical significance of ASCT2 expression in pancreatic cancer.
    Histopathology 05/2014; · 2.86 Impact Factor
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    ABSTRACT: Background:Amino-acid transporters are necessary for the tumour cell growth and survival, and have a crucial role in the development and invasiveness of cancer cells. But, it remains unclear about the prognostic significance of L-type amino-acid transporter 1 (LAT1), system ASC amino-acid transporter-2 (ASCT2), and xCT expression in patients with tongue cancer. We conducted the clinicopathological study to investigate the protein expression of these amino-acid transporters in tongue cancer.Methods:Eighty-five patients with surgically resected tongue cancer were evaluated. Tumour sections were stained by immunohistochemistry for LAT1, ASCT2, xCT, 4F2hc/CD98hc (4F2hc), Ki-67, and microvessel density (MVD) determined by CD34, and p53.Results:L-type amino-acid transporter 1 and 4F2hc were highly expressed in 61% (52 out of 85) and 45% (38 out of 47), respectively. ASC amino-acid transporter-2 and xCT were positively expressed in 59% (50 out of 85) and 21% (18 out of 85), respectively. The expression of both LAT1 and ASCT2 was significantly associated with disease staging, lymph-node metastasis, lymphatic permeation, 4F2hc expression and cell proliferation (Ki-67). xCT expression indicated a significant association with advanced stage and tumour factor. By univariate analysis, disease staging, lymphatic permeation, vascular invasion, LAT1, ASCT2, 4F2hc, and Ki-67 had a significant relationship with overall survival. Multivariate analysis confirmed that LAT1 was an independent prognostic factor for predicting poor prognosis.Conclusions:L-type amino-acid transporter 1 and ASCT2 can serve as a significant prognostic factor for predicting worse outcome after surgical treatment and may have an important role in the development and aggressiveness of tongue cancer.British Journal of Cancer advance online publication, 24 April 2014; doi:10.1038/bjc.2014.178 www.bjcancer.com.
    British Journal of Cancer 04/2014; · 5.08 Impact Factor
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    ABSTRACT: Purpose:(18)F-FAMT as an amino-acid tracer for positron emission tomography (PET) is useful for detecting human neoplasms. (18)F-FAMT is accumulated in tumour cells solely via L-type amino-acid transporter 1 (LAT1). This study was conducted to investigate the biological significance of (18)F-FAMT uptake in patients with oesophageal cancer.Methods:From April 2008 to December 2011, 42 patients with oesophageal cancer underwent both (18)F-FAMT PET/CT and (18)F-FDG PET/CT before surgical treatment. The immunohistochemical analysis of LAT1, CD98, Ki-67, CD34, p53, p-Akt and p-mTOR was performed on the primary lesions. In vitro experiments were performed to examine the mechanism of (18)F-FAMT uptake.Results:High uptake of (18)F-FAMT was significantly associated with advanced stage, lymph node metastasis and the expression of LAT1, CD98, Ki-67 and CD34. LAT1 expression yielded a statistically significant correlation with CD98 expression, cell proliferation, angiogenesis and glucose metabolism. In vitro experiments revealed that (18)F-FAMT was specifically transported by LAT1.Conclusions:The uptake of (18)F-FAMT within tumour cells is determined by the LAT1 expression and correlated with cell proliferation and angiogenesis in oesophageal cancer. The present experiments also confirmed the presence of LAT1 as an underlying mechanism of (18)F-FAMT accumulation.British Journal of Cancer advance online publication, 25 March 2014; doi:10.1038/bjc.2014.142 www.bjcancer.com.
    British Journal of Cancer 03/2014; · 5.08 Impact Factor
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    ABSTRACT: Background:ASC amino-acid transporter 2 (ASCT2) is a major glutamine transporter that has an essential role in tumour growth and progression. Although ASCT2 is highly expressed in various cancer cells, the clinicopathological significance of its expression in non-small cell lung cancer (NSCLC) remains unclear.Methods:One hundred and four patients with surgically resected NSCLC were evaluated as one institutional cohort. Tumour sections were stained by immunohistochemistry (IHC) for ASCT2, Ki-67, phospho-mTOR (mammalian target of rapamycin), and CD34 to assess the microvessel density. Two hundred and four patients with NSCLC were also validated by IHC from an independent cohort.Results:ASC amino-acid transporter 2 was expressed in 66% of patients, and was closely correlated with disease stage, lymphatic permeation, vascular invasion, CD98, cell proliferation, angiogenesis, and mTOR phosphorylation, particularly in patients with adenocarcinoma (AC). Moreover, two independent cohorts confirmed that ASCT2 was an independent marker for poor outcome in AC patients.Conclusions:ASC amino-acid transporter 2 expression has a crucial role in the metastasis of pulmonary AC, and is a potential molecular marker for predicting poor prognosis after surgery.British Journal of Cancer advance online publication, 6 March 2014; doi:10.1038/bjc.2014.88 www.bjcancer.com.
    British Journal of Cancer 03/2014; · 5.08 Impact Factor
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    ABSTRACT: The aim of this study is to investigate the underlying biologic mechanisms of 2-[(18)F]-fluoro-2-deoxy-d-glucose ((18)F-FDG) uptake on positron emission tomography (PET) in non-small cell lung cancer (NSCLC). One-hundred forty patients with NSCLC who underwent (18)F-FDG PET were included in the study. Tumor sections were stained by immunohistochemistry for glucose transporter 1 (GLUT1), GLUT3, hypoxia-inducible factor-1 alpha (HIF-1α), hexokinase I, vascular endothelial growth factor (VEGF), microvessels (CD34), epidermal growth factor receptor (EGFR), and molecules relevant to PI3K/Akt/mTOR signaling pathway (PTEN, p-Akt, p-mTOR and p-S6). We also conducted in vitro studies of (18)F-FDG uptake and mTOR inhibition in NSCLC cells. High (18)F-FDG uptake was significantly associated with poor prognosis in NSCLC patients. (18)F-FDG uptake was significantly correlated with GLUT1, hexokinase I, HIF-1α, VEGF, CD34, p-Akt, p-mTOR and EGFR. PTEN expression showed inverse correlation with (18)F-FDG uptake. In in vitro study, (18)F-FDG uptake was markedly decreased by the inhibition of GLUT1 and GLUT1 upregulation by the induction of HIF-1α increased the (18)F-FDG uptake. Inhibition of both mTOR complex1 (mTORC1) and mTORC2 suppressed cell growth, but activity of mTORC1 regulated the (18)F-FDG uptake. NCI-H1650 cells with PTEN loss showed the highest (18)F-FDG uptake and the least sensitivity to mTOR inhibitors. The amount of (18)F-FDG accumulation is associated with molecules relevant to glucose metabolism, hypoxia, angiogenesis and mTOR signaling pathway. Especially, PTEN status may affect not only (18)F-FDG uptake but also effect of mTOR inhibitors on the growth of NSCLC.
    Lung cancer (Amsterdam, Netherlands) 12/2013; · 3.14 Impact Factor
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    ABSTRACT: Abstract Carcinoembryonic antigen (CEA) is an attractive target molecule of radioimmunotherapy (RIT). To enhance RIT's therapeutic efficacy, the fractionation of radiolabeled antibody doses is an attractive strategy. In this study, a fully human anti-CEA monoclonal antibody (mAb) C2-45 was selected by virtue of its lack of immunogenicity, and the effectiveness of fractionated RIT with yttrium-90 ((90)Y)-labeled mAb C2-45 was evaluated. In LS180 tumor-bearing mice, indium-111 ((111)In)-labeled mAb C2-45 showed high and persistent tumor accumulation. Therapeutic studies were performed with single doses of (90)Y-mAb C2-45 (100 or 200 μCi) or double doses of 100 μCi (90)Y-mAb C2-45 at different intervals (5, 10, and 15 days). All (90)Y-mAb C2-45-treated mice showed inhibition of tumor progression, while the time to tumor progression was much longer in both the 200-μCi-treated group and the double 100-μCi-treated group than in the single 100-μCi-treated group. The therapeutic effect of the double 100 μCi administration at days 0 and 15 lasted significantly longer than that in the other treatment groups. These findings indicate that (90)Y-mAb C2-45 may be a promising agent for the treatment of CEA-positive cancer and that the fractionation of (90)Y-labeled antibody doses could enhance the therapeutic effect if performed according to an appropriate protocol.
    Cancer Biotherapy & Radiopharmaceuticals 12/2013; · 1.44 Impact Factor
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    ABSTRACT: The expression of L-type amino acid transporter 1 (LAT1) has been described to play essential roles in tumor cell growth and survival. However, it remains unclear about the clinicopathological significance of LAT1 expression in biliary tract cancer. This study was conducted to determine biological significance of LAT1 expression and investigate whether LAT1 could be a prognostic biomarker for biliary tract cancer. A total of 139 consecutive patients with resected pathologic stage I-IV biliary tract adenocarcinoma were retrospectively reviewed. Tumor specimens were stained by immunohistochemistry for LAT1, Ki-67, microvessel density determined by CD34, and p53; and prognosis of patients was correlated. Biological significance of LAT1 expression was investigated by in vitro and in vivo experiments with LAT inhibitor, 2-aminobicyclo-(2,2,1)-heptane-2-carboxylic acid (BCH) using cholangiocarcinoma cell line. In total patients, high LAT1 expressions were recognized in 64.0%. The expression of LAT1 was closely correlated with lymphatic metastases, cell proliferation and angiogenesis, and was a significant indicator for predicting poor outcome after surgery. LAT1 expression was a significant independent predictor by multivariate analysis. Both in vitro and in vivo preliminary experiments indicated that BCH significantly suppressed growth of the tumor and yielded an additive therapeutic efficacy to gemcitabine and 5-FU. High expression of LAT1 is a promising pathological marker to predict the outcome in patients with biliary tract adenocarcinoma. Inhibition of LAT1 may be an effective targeted therapy for this distressing disease.
    BMC Cancer 10/2013; 13(1):482. · 3.33 Impact Factor
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    ABSTRACT: L-[3-(18)F]-α-Methyltyrosine ((18)F-FAMT) was developed as an amino acid tracer for PET imaging to provide better specificity than 2-[(18)F]fluoro-2-deoxy-D-glucose ((18)F-FDG) PET for cancer diagnosis. We investigated the diagnostic usefulness of (18)F-FAMT in oral squamous cell carcinoma (OSCC). The correlation between tumour uptake of (18)F-FAMT and L-type amino acid transporter 1 (LAT1) expression was determined. The study group comprised 68 OSCC patients who underwent both (18)F-FAMT and (18)F-FDG PET. Resected tumour sections were stained by immunohistochemistry for LAT1, CD98 and Ki-67, and microvessel density was determined in terms of CD34 and p53 expression. The sensitivity of primary tumour detection by (18)F-FAMT and (18)F-FDG PET was 98 % and 100 %, respectively. The sensitivity, specificity and accuracy of (18)F-FAMT PET for detecting malignant lymph nodes were 68 %, 99 % and 97 %, respectively, and equivalent values for (18)F-FDG PET were 84 %, 94 % and 94 %, respectively. The specificity and accuracy of (18)F-FAMT were significantly higher than those of (18)F-FDG. The uptake of (18)F-FAMT was significantly correlated with LAT1 expression, cell proliferation and advanced stage. The expression of LAT1 in OSCC cells was closely correlated with CD98 levels, cell proliferation and angiogenesis. (18)F-FAMT PET showed higher specificity for detecting malignant lesions than (18)F-FDG PET. The uptake of (18)F-FAMT by OSCC cells can be determined by the presence of LAT1 expression and tumour cell proliferation.
    European Journal of Nuclear Medicine 06/2013; · 4.53 Impact Factor
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    ABSTRACT: The expression of L-type amino acid transporter 1 (LAT1) is correlated with tumor cell growth and survival. However, the clinicopathological significance of LAT1 expression in adenoid cystic carcinoma (ACC) remains to be elucidated. The aim of this study is to investigate the clinicopathological significance of LAT1 expression in ACC. A total of 30 patients with ACC were retrospectively reviewed. Tumor sections were stained by immunohistochemistry for LAT1, p53, and CD98, and cell proliferation and microvessel density (MVD) were determined by Ki-67 and CD34, respectively. High LAT1 and CD98 expression were observed in 27 % (8/30) and 23 % (7/30) of samples, respectively (p > 0.999). The high expression of LAT1 was significantly correlated with cell proliferation (Ki-67) and the cell cycle regulator p53. By univariate analysis, solid histological pattern, maxillary tumor site, LAT1, CD98, Ki-67 and p53 were significantly associated with poor prognosis. Multivariate analysis demonstrated that the high expression of LAT1 was an independent prognostic factor for predicting poor prognosis after surgical resection. LAT1 is a promising clinical marker to predict the outcome after surgery in patients with ACC.
    Pathology & Oncology Research 03/2013; · 1.56 Impact Factor
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    ABSTRACT: OBJECTIVE: 3-[(18)F]Fluoro-α-methyl-L-tyrosine (L-[(18)F]FAMT) is a useful amino acid tracer for positron emission tomography (PET) imaging of malignant tumors. Because D-amino acids are not well distributed in non-target organs and are rapidly excreted in urine, the D-isomer of [(18)F]FAMT could allow clear PET imaging of tumors early after administration. In this study, we prepared 3-[(18)F]fluoro-α-methyl-D-tyrosine (D-[(18)F]FAMT) and evaluated its usefulness. METHODS: D-[(18)F]FAMT was synthesized according to the method for preparation of L-[(18)F]FAMT. The in vitro and in vivo stability of [(18)F]FAMT were evaluated by high-performance liquid chromatography. Cellular uptake of [(18)F]FAMT was evaluated using LS180 colon adenocarcinoma cells. Biodistribution studies were performed in LS180 tumor-bearing mice, and the tumors were imaged using a small-animal PET scanner. RESULTS: The radiolabeling yield of D-[(18)F]FAMT was approximately 10 %, similar to that of L-[(18)F]FAMT. Over 95 % of D-[(18)F]FAMT remained intact in mice until 60 min after administration. D-[(18)F]FAMT was gradually taken up by the LS180 cells. Tumor uptake of D-[(18)F]FAMT was competitively inhibited by pretreatment with α-methyl-L-tyrosine, a selective substrate for the system L-amino acid transporter 1 (LAT1), suggesting the involvement of LAT1 in tumor uptake of D-[(18)F]FAMT. In biodistribution studies, D-[(18)F]FAMT showed rapid clearance from the blood, marked accumulation and retention in the tumor, and lower accumulation in non-target organs, especially kidney and pancreas, compared to L-[(18)F]FAMT. The amount of D-[(18)F]FAMT in the tumor was also reduced, and tumor-to-blood ratio and tumor-to-muscle ratio of D-[(18)F]FAMT were similar to those of L-[(18)F]FAMT at every time point. PET imaging with D-[(18)F]FAMT did not provide a clear image of the tumor early after administration. However, D-[(18)F]FAMT provided higher tumor-to-background contrast than L-[(18)F]FAMT. CONCLUSIONS: D-[(18)F]FAMT showed rapid blood clearance, low accumulation in non-target organs, and tumor-selective imaging compared with L-[(18)F]FAMT. Thus, D-[(18)F]FAMT could potentially serve as a novel PET tracer for imaging malignant tumors.
    Annals of Nuclear Medicine 01/2013; · 1.41 Impact Factor
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    ABSTRACT: The purpose of our study is the establishment of normal database (NDB) from persons (aged 50-80 years) for 3D-SSP analysis of 123I-IMP brain perfusion SPECT image, and we analyzed whether the presence or absence of image correction methods, scatter correction (SC) and attenuation correction (AC), affects the created NDB and 3D-SSP analysis. We created NDB from 63 healthy volunteers (32 males and 31 females, aged 50-80 years), and calculated the coefficient of variation for each pixel from the mean value and standard deviation. Next, we compared the visual assessments of the standard deviation images by each image correction method, and the coefficient of variation of SEE analysis in each part of the brain. Furthermore, we examined frontotemporal dementia and healthy volunteers by 3D-SSP analysis, and evaluated the differences of Z-score in the presence or absence of image correction methods. In NDB, the coefficient of variation was the minimum when SC and AC were not applied and the maximum in periventricular and cerebellum when SC and AC were applied. In Z-score image of 3D-SSP analysis, Z-score of the low value was the maximum when SC and AC were not applied. It was shown that the results from NDB coefficient of variation and 3D-SSP analysis were affected by the differences of image correction methods. It is important to understand the feature of imaging reconstruction conditions in your own facilities, and evaluate 3D-SSP analysis.
    Kaku igaku. The Japanese journal of nuclear medicine 11/2012; 49(4):341-9.
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    ABSTRACT: The expression of L-type amino-acid transporter 1 (LAT1) is tumour-specific and has been shown to have essential roles in cell growth and survival. However, little is known regarding the clinical significance of LAT1 expression in pancreatic cancer. This study was conducted to determine the prognostic significance of LAT1 expression. A total of 97 consecutive patients with surgically resected pathological stage I-IV pancreatic ductal adenocarcinoma were retrospectively reviewed. Tumour sections were stained by immunohistochemistry for LAT1, CD98, Ki-67 and vascular endothelial growth factor (VEGF), and microvessel density was determined by CD34 and p53. L-type amino-acid transporter 1 and CD98 were highly expressed in 52.6% (51/97) and 56.7% (55/97) of cases, respectively (P=0.568). The expression of LAT1 within pancreatic cancer cells was significantly associated with disease stage, tumour size, Ki-67, VEGF, CD34, p53 and CD98. L-type amino-acid transporter 1 expression was confirmed to be a significant prognostic factor for predicting poor outcome by multivariate analysis. L-type amino-acid transporter 1 expression is a promising pathological marker for the prediction of outcome in patients with pancreatic cancer.
    British Journal of Cancer 07/2012; 107(4):632-8. · 5.08 Impact Factor
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    ABSTRACT: l-3-(18)F-α-methyl tyrosine ((18)F-FAMT) has been developed as a PET radiotracer for tumor imaging. Clinical studies have demonstrated the usefulness of (18)F-FAMT PET for the prediction of prognosis and the differentiation of malignant tumors and benign lesions. (18)F-FAMT exhibits higher cancer specificity in peripheral organs than other amino acid PET tracers and (18)F-FDG. The accumulation of (18)F-FAMT is strongly correlated with the expression of L-type amino acid transporter 1 (LAT1), an isoform of system L highly upregulated in cancers. In this study, we examined the interaction of 3-fluoro-l-α-methyl-tyrosine (FAMT) with amino acid transporters to assess the mechanisms of (18)F-FAMT uptake in PET. We applied in vitro assays using established mammalian cell lines stably expressing LAT1 or a non-cancer-type system L isoform LAT2. The inhibitory effect on l-(14)C-leucine uptake and the induction effect on efflux of preloaded l-(14)C-leucine were examined for FAMT and other amino acid tracers. FAMT transport was compared among cell lines with varied LAT1 expression level. FAMT prominently inhibited LAT1-mediated l-(14)C-leucine uptake in a competitive manner but had less of an effect on LAT2. In the efflux experiments, FAMT induced the efflux of preloaded l-(14)C-leucine through LAT1, indicating that FAMT is transported by LAT1 and not by LAT2. Among amino acid-related compounds examined in this study, including those used for PET tracers, the compounds with an α-methyl group such as FAMT, 2-fluoro-l-α-methyl-tyrosine, 3-iodo-l-α-methyl-tyrosine, and l-α-methyl-tyrosine were well transported by LAT1 but not by LAT2. However, l-methionine, l-tyrosine, 3-fluoro-l-tyrosine, 2-fluoro-l-tyrosine, and O-(2-fluoroethyl)-l-tyrosine were transported by both LAT1 and LAT2, suggesting that the α-methyl moiety is responsible for the LAT1 selectivity of FAMT. FAMT transport rate and LAT1 protein level were well correlated, supporting the importance of LAT1 for the cellular uptake of FAMT. Distinct from other amino acid PET tracers, because of its α-methyl moiety, FAMT is selective to LAT1 and not transported by LAT2. This property of FAMT is proposed to contribute to highly tumor-specific accumulation of (18)F-FAMT in PET.
    Journal of Nuclear Medicine 06/2012; 53(8):1253-61. · 5.77 Impact Factor
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    ABSTRACT: To evaluate whether there is a correlation between the differences in joint uptake of 2-[18F]-fluoro-2-deoxy-d-glucose ((18)F-FDG) and the improvement of clinical findings in RA patients undergoing anti-TNF therapies. Twenty-two patients who received anti-TNF therapies, including infliximab for 16 patients and etanercept for 6 patients, were assessed. PET with (18)F-FDG studies and clinical assessments were performed at baseline and 6 months after the initiation of therapy. The maximal standardized uptake value (SUV(max)) was used as a representative value for the assessment of the FDG uptake in the bilateral shoulder, elbow, wrist, hip, knee and ankle joints. Spearman's rank correlation test was applied to assess the correlation between the SUV and the clinical parameters. The ΔSUV (12 joints), the difference in the SUV(max) of the affected 12 joints before and after treatment, was positively correlated with the ΔDAS28 (r = 0.609, P = 0.003), ΔDAS28-CRP (r = 0.656, P = 0.001) and Δtender joint count (TJC) (r = 0.609, P = 0.003). There were also significantly positive correlations between ΔSUV (8 joints); the difference in the SUV(max) of the bilateral shoulder, elbow, wrist and knee joints before and after treatment and the ΔDAS28 (r = 0.642, P = 0.001), ΔDAS28-CRP (r = 0.712, P < 0.001) and ΔTJC (r = 0.608, P = 0.003), respectively. The FDG uptake observed in the inflamed RA joints may reflect disease activity. The FDG-PET response was correlated with the clinical response to the biologic treatment of RA.
    Rheumatology (Oxford, England) 04/2012; 51(8):1484-91. · 4.24 Impact Factor
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    ABSTRACT: The purpose of this study was to investigate the detectability of small hot lesions with the 3-dimensional transmission/emission (3D T/E) acquisition mode in FDG-PET scan. The correlation of target detectability, target size, target to non-target uptake ratio (T/N ratio) and standardized uptake value (SUV) were studied. Small hot lesions ranged from 4.4 mm to 36.9 mm in diameter were located in cylindrical phantom. The images of phantoms with a T/N ratio of 2.0, 4.0, 6.0, 8.0, 9.6, 13.2, 17.5, 23.8 and 30.3 were obtained with 2-dimensional transmission/emission (2D T/E) scan and 3D T/E scans. Targets in diameter more than 10.6 mm in diameter with an actual T/N ratio ranged from 6.0 to 30.3 could be identified on the images obtained with all the 2D T/E and 3D T/E acquisition modes. The detectability efficiency of small hot target in 2D T/E and 3D T/E scans was as same (77.8%). The T/N ratio of targets from 2D T/E images was 30% to 48.4% different to that from 3D T/E image, and the SUV of the target from the 2D T/E images was almost the same as that from 3D T/E images. This study revealed that 3D T/E scanning had similar hot spot detectability to 2D T/E scanning; 3D T/E and 2D T/E scanning had the same faculty for semiquantitative analysis using SUV. These findings may be helpful for the diagnosis and understanding of 3D T/E FDG-PET in hot lesion detection.
    Annals of Nuclear Medicine 04/2012; 14(4):279-284. · 1.41 Impact Factor

Publication Stats

3k Citations
563.94 Total Impact Points

Institutions

  • 2014
    • Osaka University
      • Division of Otorhinolaryngology-Head and Neck Surgery
      Suika, Ōsaka, Japan
  • 1992–2014
    • Gunma University
      • • Department of Orthopaedic Surgery
      • • Department of General Surgical Science
      • • Graduate School of Medicine
      • • Department of Surgery
      • • School of Medicine
      Maebashi, Gunma Prefecture, Japan
  • 2012
    • OncoTherapy Science
      Kawasaki Si, Kanagawa, Japan
  • 2010–2012
    • Shizuoka Cancer Center
      • Division of Drug Discovery and Development
      Sizuoka, Shizuoka, Japan
  • 2011
    • St. Luke's Medical Center (Philippines)
      Alfonso XIII, Mimaropa, Philippines
  • 2002
    • Yokohama City University
      • Department of Radiology (YCUH)
      Yokohama, Kanagawa, Japan
  • 2001
    • Department of Nuclear Medicine
      Nyitra, Nitriansky, Slovakia
    • Nippon Medical School
      • Department of Pathology
      Edo, Tōkyō, Japan
  • 2000
    • National Institute of Radiological Sciences
      Tiba, Chiba, Japan
  • 1996–2000
    • University of Texas MD Anderson Cancer Center
      • Department of Nuclear Medicine
      Houston, Texas, United States
  • 1990
    • Niigata Teishin Hospital
      Niahi-niigata, Niigata, Japan