Hironobu Sasano

Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia

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Publications (936)3308.04 Total impact

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    ABSTRACT: Background Triple-negative breast cancer (TNBC) is associated with an aggressive clinical course due to the lack of therapeutic targets. Therefore, identifying reliable prognostic biomarkers and novel therapeutic targets for patients with TNBC is required. Proline, glutamic acid, leucine rich protein 1 (PELP1) is a novel steroidal receptor co-regulator, functioning as an oncogene and its expression is maintained in estrogen receptor (ER) negative breast cancers. PELP1 has been proposed as a prognostic biomarker in hormone-related cancers, including luminal-type breast cancers, but its significance in TNBC has not been studied. Methods PELP1 immunoreactivity was evaluated using immunohistochemistry in 129 patients with TNBC. Results were correlated with clinicopathological variables including patient’s age, tumor size, lymph node stage, tumor grade, clinical stage, histological type, Ki-67 LI, as well as clinical outcome of the patients, including disease-free survival (DFS) and overall survival (OS). Results PELP1 was localized predominantly in the nuclei of carcinoma cells in TNBC. With the exception of a positive correlation between PELP1 protein expression and lymph node stage (p = 0.027), no significant associations between PELP1 protein expression and other clinicopathological variables, including DFS and OS, were found. However, when PELP1 and Ki-67 LI were grouped together, we found that patients in the PELP1/Ki-67 double high group (n = 48) demonstrated significantly reduced DFS (p = 0.005, log rank test) and OS (p = 0.002, log rank test) than others (n = 81). Multivariable analysis supported PELP1/Ki-67 double high expression as an independent prognostic factor in patients with TNBC, with an adjusted hazard ratio of 2.020 for recurrence (95 % CL, 1.022–3.990; p = 0.043) and of 2.380 for death (95 % CL, 1.138–4.978; p = 0.021). Conclusions We found that evaluating both PELP1 and Ki-67 expression in TNBC could enhance the prognostic sensitivity of the two biomarkers. Therefore, we propose that PELP1/Ki-67 double high expression in tumors is an independent prognostic factor for predicting a poor outcome for patients with TNBC.
    BMC Cancer 12/2015; 15(1). DOI:10.1186/s12885-015-1694-y · 3.36 Impact Factor
  • Fouzia Guestini · Keely May McNamara · Takanori Ishida · Hironobu Sasano ·
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    ABSTRACT: Introduction: Triple negative breast cancer (TNBC) is a heterogeneous clinicopathological entity constituting approximately 15-20% of all breast cancer (BC) patients. It shows high recurrence rate and poor prognosis. At this juncture, because of the lack of specific targeted therapies available and the development in patients of resistance to some therapeutic agents, clinical and translational settings have gained importance over the past decades. Areas covered: The development of novel, safe and effective alternatives for the treatment of TNBC are in high demand. Therefore, this review aims to summarize the state of the art of TNBC, its current therapies and potential therapeutic targets. In particular, focus is put on recent advances regarding the identification of emerging biomarkers as prognostic and/or predictive markers, including surrogate markers for molecular tumor subtyping and identifying potential responders to new therapies. Expert opinion: Effective development of informative markers could constitute an important armamentarium tool for identifying appropriate therapies to challenge the aggressiveness of TNBC.
    Expert Opinion on Therapeutic Targets 11/2015; DOI:10.1517/14728222.2016.1125469 · 5.14 Impact Factor
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    ABSTRACT: Object: This comparative study clarified the clinical characteristics and in vitro steroidogenic activities of aldosterone-producing adenomas (APAs) harboring ATPase or CACNA1D gene mutations. Design and patients: Genetic testing was performed on 159 unilateral APAs. Somatic ATPase and CACNA1D gene mutations were analyzed in 42 APA tissues without KCNJ5 gene mutations. Results: ATP1A1, ATP2B3, and CACNA1D mutations were detected in 1, 4, and 4 patients, respectively. Compared with patients without KCNJ5, ATPase, or CACNA1D mutations (wild type), ATPase mutations tended to have more severe hyperaldosteronism and smaller tumors; those with CACNA1D mutations had clinical characteristics and tumor sizes similar to those with wild-type genes. APAs with ATPase mutations were composed mainly of compact eosinophilic tumor cells, whereas CACNA1D mutations resulted in predominantly clear tumor cells. Aldosterone production in APA cells with ATP2B3 mutations were more responsive to (Bt)2cAMP, whereas those with CACNA1D mutations were more responsive to adrenocorticotropic hormone than the wild-type cells. Conclusion: APAs with ATPase mutations demonstrated a potentially severe primary aldosteronism phenotype, whereas those with CACNA1D mutations displayed characteristics similar to wild-type APAs. The status of stimulated aldosterone production was also different according to the cell types, suggesting that the regulatory effects of adrenocorticotropic hormone on aldosterone synthesis could possibly vary according to the intracellular signaling involved in hormone production.
    The Journal of Clinical Endocrinology and Metabolism 11/2015; DOI:10.1210/jc.2015-3284 · 6.21 Impact Factor
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    ABSTRACT: A 43-yr-old hypertensive male was admitted due to hypokalemia (1.8 mEq/L) and renal dysfunction (eGFR, 20.0 mL/min/1.73 m(2)). His plasma aldosterone was 901.0 ng/dL, plasma renin activity 5.7 ng/mL/hr, and aldosterone/renin activity ratio 158. Angiotensin II (AII) was 0.7 pg/mL, ACTH <1.0 pg/mL, and cortisol 21.6 μg/dL. Liquid chromatography-tandem mass spectrometry analysis showed that aldosterone (104 times the control) as well as its precursors were significantly elevated in the patient's plasma. A left adrenal (4-cm-diameter) tumor with (131)I-Adosterol(®) uptake was found and removed. Four days later, plasma aldosterone and renin activity had dropped to 7.73 ng/dL and 1.6 ng/mL/hr, respectively. However, they rose to 24.0 ng/dL and 10.9 ng/mL/hr, respectively, by Day 102. Nevertheless, magnetic resonance angiography found no evidence of a renovascular lesion. The tumor was a benign adrenocortical adenoma composed predominantly of clear cells positive for 17α-hydroxylase, [hydroxy-delta-5-steroid dehydrogenase, 3 beta- and steroid delta-isomerases], and aldosterone synthase. A quantitative real-time polymerase chain reaction analysis of the tumor cells revealed that expression of the gene encoding aldosterone synthase was 85 times the control level. In addition, the tumor cells harbored G151R mutation of the inward rectifying potassium channel subfamily j, member 5 gene. The striking overexpression of aldosterone synthase by the tumor cells was considered the primary mechanism for the extravagant overproduction of aldosterone in this case. This overexpression may have resulted from integration of signals from AII and forced membrane depolarization due to the potassium channel mutation.
    Endocrine Journal 11/2015; DOI:10.1507/endocrj.EJ15-0398 · 2.00 Impact Factor
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    ABSTRACT: Primary aldosteronism due to unilateral aldosterone-producing adenoma (APA) is a surgically curable form of hypertension. Bilateral APA can also be surgically curable in theory but few successful cases can be found in the literature. It has been reported that even using successful adrenal venous sampling (AVS) via bilateral adrenal central veins, it is extremely difficult to differentiate bilateral APA from bilateral idiopathic hyperaldosteronism (IHA) harbouring computed tomography (CT)-detectable bilateral adrenocortical nodules. We report a case of bilateral APA diagnosed by segmental AVS (S-AVS) and blood sampling via intra-adrenal first-degree tributary veins to localize the sites of intra-adrenal hormone production. A 36-year-old man with marked long-standing hypertension was referred to us with a clinical diagnosis of bilateral APA. He had typical clinical and laboratory profiles of marked hypertension, hypokalaemia, elevated plasma aldosterone concentration (PAC) of 45.1 ng dl(-1) and aldosterone renin activity ratio of 90.2 (ng dl(-1) per ng ml(-1 )h(-1)), which was still high after 50 mg-captopril loading. CT revealed bilateral adrenocortical tumours of 10 and 12 mm in diameter on the right and left sides, respectively. S-AVS confirmed excess aldosterone secretion from a tumour segment vein and suppressed secretion from a non-tumour segment vein bilaterally, leading to the diagnosis of bilateral APA. The patient underwent simultaneous bilateral sparing adrenalectomy. Histopathological analysis of the resected adrenals together with decreased blood pressure and PAC of 5.2 ng dl(-1) confirmed the removal of bilateral APA. S-AVS was reliable to differentiate bilateral APA from IHA by direct evaluation of intra-adrenal hormone production.Journal of Human Hypertension advance online publication, 5 November 2015; doi:10.1038/jhh.2015.100.
    Journal of human hypertension 11/2015; DOI:10.1038/jhh.2015.100 · 2.70 Impact Factor
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    ABSTRACT: Introduction: Cytochrome P450 11B2 (CYP11B2) plays a pivotal role in aldosterone synthesis, while cytochrome P450 11B1 (CYP11B1) and cytochrome P450 17A1 (CYP17) are involved in cortisol synthesis in normal human adrenal glands. However, their detailed distribution in aldosterone-producing adenoma (APA) remains incompletely settled. Materials and methods: We examined the status of CYP11B1/CYP11B2 and CYP11B2/CYP17A1 expressions in 27 APA (double staining) cases and 21 APA (triple staining) cases by using immunofluorescence staining and semi-quantitative evaluation. Results: Tumor cells co-expressing CYP11B1/B2 (hybrid cell type A), CYP11B2/17 (hybrid cell type B), CYP11B1/17 (hybrid cell type C), and CYP11B1/B2/17 (triple-positive cells) were identified. The area and cell number of these cells were relatively small, but size of individual hybrid cells were different between three hybrid cell types (A/B/C) and triple-positive cells. Conclusion: The presence of hybrid cells indicated the marked intratumoral heterogeneity of steroidogenesis in APAs, particularly in those producing glucocorticoids and mineralocorticoids.
    Molecular and Cellular Endocrinology 11/2015; DOI:10.1016/j.mce.2015.11.014 · 4.41 Impact Factor
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    The Journal of steroid biochemistry and molecular biology 10/2015; 155(Pt A). DOI:10.1016/j.jsbmb.2015.09.028 · 3.63 Impact Factor
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    ABSTRACT: Extramammary Paget disease (EMPD) has been known to frequently express androgen receptor (AR). Therefore, androgens could play roles in the biological behavior of Paget cells. 5α-Reductase (5α-red) types 1 and 2 and 17β-hydroxysteroid dehydrogenase type 5 (17β-HSD5) are pivotal in situ regulators of androgen production in androgen-responsive tissues including androgen-dependent neoplasms. Therefore, in this study, we immunolocalized AR, androgen-producing enzymes, and their transcription factors to assess the state of in situ androgen production and actions and its correlation of invasiveness in EMPD. We studied 51 cases of EMPD with known clinicopathological status. AR, 5α-red1, 17β-HSD5, and β-catenin immunoreactivity was evaluated by using the modified H-score method while cyclin D1, p53, forkhead box protein P1, and a proliferation marker, Ki-67, were quantified using labeling index. The mean scores of AR, 5α-red1, and 17β-HSD5 in invasive EMPD were all significantly higher than noninvasive EMPD (P < .0001). Ki-67 labeling index as well as the cyclin D1 score was also significantly higher in invasive than noninvasive lesions of EMPD. These results demonstrated that androgen receptor and androgen-producing enzymes were both associated with cell cycle regulation and subsequently the invasiveness of EMPD lesions and could also indicate those above as potential markers of invasive potentials in EMPD.
    Human pathology 09/2015; 46(11). DOI:10.1016/j.humpath.2015.07.007 · 2.77 Impact Factor
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    ABSTRACT: Introduction: The status of tumor-infiltrating lymphocytes (TILs) has been recently proposed to predict clinical outcome of patients with breast cancer. We therefore studied the prognostic significance of CD8(+) TILs and FOXP3(+) TILs in residual tumors after neoadjuvant chemotherapy (NAC) and the alterations in these parameters before and after NAC in patients with triple-negative breast cancer (TNBC). Methods: One hundred thirty-one TNBC patients who received NAC at three institutions were examined. CD8(+) TIL and FOXP3(+) TIL in residual tumors and biopsy specimens were evaluated by double-staining immunohistochemistry. The CD8(+) TIL and FOXP3(+) TIL status of the residual tumors was assessed, and the rates of their changes before and after NAC were calculated. Results: TNBC patients with high CD8(+) TIL levels or a high CD8/FOXP3 ratio in residual tumors had significantly better recurrence-free survival (RFS) and breast cancer-specific survival (BCSS) than patients with low values of these parameters. In multivariate analyses, CD8(+) TIL exhibited strong prognostic significance for RFS, with a hazard ratio (HR) of 3.09 (95 % confidence interval (CI) 1.537-6.614, P=0.0013). The CD8/FOXP3 ratio was also significantly correlated with RFS (HR=2.07, 95 % CI 1.029-4.436, P=0.0412). TNBC with larger residual tumor size and positive lymph node status, which are known prognostic factors, was independently associated with worse RFS (P=0.0064 and P=0.0015, respectively). High CD8(+) TIL levels were a markedly powerful indicator of improved BCSS, with an HR of 3.59 (95 % CI 1.499-9.581, P=0.0036). Nodal status was also associated with BCSS (P=0.0024). TNBC with a high rate of CD8(+) TIL changes was associated with significantly better RFS compared with the low group (P=0.011). Higher rates of changes in the CD8/FOXP3 ratio were significantly correlated with both better RFS and BCSS compared with lower rates (P=0.011 and P=0.023, respectively). Conclusions: This is the first study to demonstrate that high CD8(+) TIL and a high CD8/FOXP3 ratio in residual tumors and increment of these parameters following NAC and accurately predict improved prognosis in TNBC patients with non-pathological complete response following NAC. These parameters could serve as a surrogate one for adjuvant treatment in patients with residual disease in the neoadjuvant setting.
    Breast cancer research: BCR 09/2015; 17(1):124. DOI:10.1186/s13058-015-0632-x · 5.49 Impact Factor
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    ABSTRACT: Metastatic breast cancer still remains a highly lethal disease, and it is very important to evaluate biomarkers associated with the distant metastasis. MicroRNAs (miRNAs) are small non-protein coding RNAs and regulate various cellular functions. Recent investigations have demonstrated importance of some miRNAs in breast cancer, but the significance has still remained largely unclear in a great majority of miRNAs in breast cancer metastasis. Therefore, in this study, we first examined expression profiles of miRNAs in stage IV breast carcinoma tissues comparing stages I-III cases by miRNA PCR array, and identified miR-1 as a miRNA which was the most associated with the distant metastasis. However, miR-1 has not yet been examined in breast carcinoma tissue, and its significance remains unknown. Therefore, we further examined miR-1 expression in breast carcinoma using in situ hybridization (ISH). miR-1 was localized in carcinoma cells in 20% of breast carcinoma cases, but it was negligible in non-neoplastic mammary glands or stroma. miR-1 ISH status was significantly associated with stage, pathological T factor, lymph node metastasis, distant metastasis, histological grade, estrogen receptor, progesterone receptor and Ki-67 in breast carcinoma. Moreover, the miR-1 status was demonstrated an independent worse prognostic factor for both disease-free and breast cancer-specific survival by multivariate analysis. These findings suggest that abnormal miR-1 expression is associated with an aggressive phenotype of breast carcinoma and miR-1 status is a potent prognostic factor in human breast cancer patients. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
    Cancer Science 09/2015; DOI:10.1111/cas.12808 · 3.52 Impact Factor
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    ABSTRACT: Lymphangioleiomyomatosis (LAM) is a rare, potentially fatal disease primarily affecting young women. Estrogens enhance cell proliferation and progression of the tumor. Clinical trials using molecularly targeted agents such as endocrine manipulation and mammalian target of rapamycin (mTOR) inhibitors are in progress, but the status of these molecules, including aromatase and mTOR, has not been explored in LAM tissue. We first examined immunoreactivity for sex steroid receptors (estrogen receptor [ER] α, ERβ, progesterone receptor, androgen receptor), sex steroid-synthesizing enzymes (aromatase, steroid sulfatase, 17β-hydroxysteroid dehydrogenase 1, 5α-reductases), apoptotic suppression factor (Bcl-2), and factors involved in the mTOR signaling pathway in 30 pulmonary LAM tissues. Immunoreactivity for ERα, ERβ, progesterone receptor, aromatase, and Bcl-2 was significantly more abundant in epithelioid cells, whereas the status of androgen receptor, 5α-reductases, and phospho-mTOR signaling was not different in epithelioid and spindle-shaped LAM cells. We further examined the correlation among H scores of these markers using hierarchical clustering analysis. The results indicated that LAM tumors can be further classified into "aromatase" and "mTOR" groups on the basis of the patterns of immunoreactivity, and the 2 types could benefit from different modes of therapy. Copyright © 2015. Published by Elsevier Inc.
    Human pathology 07/2015; 46(11). DOI:10.1016/j.humpath.2015.02.019 · 2.77 Impact Factor
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    ABSTRACT: Adrenal venous sampling (AVS) is critical to determine the subtype of primary aldosteronism (PA). "Central" AVS, that is, the collection of effluents from bilateral adrenal central veins, sometimes does not allow differentiation between bilateral aldosterone-producing adenomas (APA) and idiopathic hyperaldosteronism (IHA). To establish the best treatment course, we have developed "segmental AVS"; that is, we collect effluents from the tributaries of central veins to determine the intra-adrenal sources of aldosterone overproduction. We then evaluated the clinical utility of this novel approach in the diagnosis and treatment of PA. We performed central and/or segmental AVS in 297 PA patients, and assessed the accuracy of diagnosis based on the results of central (n=138, 46.5%) and segmental AVS (n=159, 53.5%) by comparison with those of clinicopathological evaluation of resected specimens. Segmental AVS demonstrated both elevated and attenuated secretion of aldosterone from APA and non-tumorous segments, respectively, in patients with bilateral APA and recurrent APA. These findings were completely confirmed by detailed histopathological examination after surgery. Segmental AVS, but not central AVS, also served to identify APA located distal from the central vein. Compared to central AVS, segmental AVS served to identify APA in some patients and its use should expand the pool of patients eligible for adrenal sparing surgery through the identification of unaffected segments, despite the fact that segmental AVS requires more expertise and time. Especially, this new technique could enormously benefit patients with bilateral or recurrent APA because of the preservation of non-tumorous glandular tissue.
    European Journal of Endocrinology 07/2015; 173(4). DOI:10.1530/EJE-14-1161 · 4.07 Impact Factor
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    ABSTRACT: The androgen receptor plays a pivotal role in the sebaceous glands. Its primary function is to stimulate cell proliferation and differentiation in the sebaceous and is association with acne. Previous studies have demonstrated expression of AR and steroidogenic enzymes in normal sebaceous glands and in all sebaceous disorders present evidence that androgen receptor may be a sensitive marker of sebaceous differentiation. It has been previously suggested that AR and steroidogenic enzymes immunohistochemistry may be useful particularly in identifying poorly sebaceous carcinoma. This review will provide an overview of the AR functions in the sebaceous glands and discussion of the therapeutic targets in acne and carcinoma.
    Current Molecular Pharmacology 07/2015;
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    ABSTRACT: Prostaglandins are a group of lipid compounds involved in inflammation and cancer. We focused on PGF2α and its stereoisomer 11β-PGF2α and examined the expression and functions of their cognate receptor (FP receptor) and metabolizing enzymes (AKR1B1 and AKR1C3 respectively) in breast cancer. In immunohistochemical analysis FP receptor status associated with adverse clinical outcome only in the AKR1C3 positive cases. Therefore, we studied FP receptor-mediated functions of 11β-PGF2α using FP receptor expressed MCF-7 cell line (MCF-FP). 11β-PGF2α treatment phosphorylated ERK and CREB and induced Slug expression through FP receptor in MCF-FP, and MCF-FP cells demonstrated decreased chemosensitivity compared to parental controls. Finally, the correlation between FP receptor and Slug was also confirmed immunohistochemically in breast cancer cases. Overall these results indicated that the actions of AKR1C3 can produce FP receptor ligands whose activation results in carcinoma cell survival in breast cancer. Copyright © 2015. Published by Elsevier Ireland Ltd.
    Molecular and Cellular Endocrinology 07/2015; 413. DOI:10.1016/j.mce.2015.07.008 · 4.41 Impact Factor
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    ABSTRACT: Adrenocortical carcinoma (ACC) is a malignant neoplasm often associated with an aggressive biological behavior. The histologic differentiation between ACC and adrenocortical adenoma (ACA) is largely determined by employing the Weiss criteria, although this classification may not apply to all the cases. Additionally, various genomic features of ACC could be an auxiliary mode to establish the diagnosis of ACC. Most ACC cases are hormonally functional, and immunohistochemical analysis of steroidogenic enzymes has provided pivotal information as to the analysis of intratumoral production of corticosteroids. This article summarizes the current status of the histopathological diagnosis, molecular pathogenesis, and hormonal features of ACC. Copyright © 2015 Elsevier Inc. All rights reserved.
    Endocrinology & Metabolism Clinics of North America 06/2015; 44(2):399-410. DOI:10.1016/j.ecl.2015.02.007 · 3.40 Impact Factor
  • Keely May McNamara · Hironobu Sasano ·
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    ABSTRACT: Breast cancer's hormonal dependence is well known and has been so for a long time. However in the last two decades great advances have been made in understanding the local metabolism of steroids within tissue. In the form of aromatase inhibition this is already one of the mainstays of breast cancer therapy. This review aims to summarise briefly what is known in terms of the metabolism of C18 steroids but perhaps more importantly to touch on the new developments regarding the importance of the metabolism of androgens and glucocorticoids in breast tissue. It is our hope that this review should provide the reader with a "birds eye view" of the current state of knowledge regarding localised steroid metabolism in the breast. Copyright © 2015. Published by Elsevier Inc.
    Steroids 06/2015; 93. DOI:10.1016/j.steroids.2015.05.008 · 2.64 Impact Factor
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    ABSTRACT: Aldosterone is one of the mineralocorticoids synthesized and secreted by the adrenal glands, and it plays pivotal roles in regulating extracellular fluid volume and blood pressure. Autonomous excessive aldosterone secretion resulting from adrenocortical diseases is known as primary aldosteronism, and it constitutes one of the most frequent causes of secondary hypertension. Therefore, it is important to understand the molecular mechanisms of aldosterone synthesis in both normal and pathological adrenal tissues. Various factors have been suggested to be involved in regulation of aldosterone biosynthesis, and several adrenocortical cell lines have been developed for use as in vitro models of adrenal aldosterone-producing cells, for analysis of the underlying molecular mechanisms. In this review, we summarize the available reports on the regulation of aldosterone biosynthesis in the normal adrenal cortex, in associated disorders, and in in vitro models. Copyright © 2015 Elsevier Ltd. All rights reserved.
    The Journal of steroid biochemistry and molecular biology 06/2015; 153. DOI:10.1016/j.jsbmb.2015.05.008 · 3.63 Impact Factor
  • Article: 8D.02
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    ABSTRACT: Objective: Definitive diagnosis of primary aldosteronism requires a long process, including adrenal venous sampling, which currently represents the only reliable method to distinguish unilateral from bilateral diseases. In this study, we attempted to determine whether peripheral plasma levels of 18-oxocortisol and 18-hydroxycortisol could contribute to the clinical differentiation between aldosteronoma and bilateral hyperaldosteronism. Design and method: This study included 234 primary aldosteronism patients including CT-detectable aldosteronoma (APA) (n = 113) and bilateral hyperaldosteronism (BHA) (n = 121), all of whom underwent adrenal venous sampling. All aldosteronomas were surgically resected and their diagnosis was both clinically and histopathologically confirmed. Both 18-oxocortisol and 18-hydroxycortisol were measured using liquid chromatography tandem mass spectrometry. Results: ROC analysis of 18-oxocortisol discrimination of adenoma from hyperplasia demonstrated sensitivity/specificity of 0.83/0.99 at a cutoff value of 4.7 (ng/dL), compared to that based upon 18-hydroxycortisol (sensitivity/specificity: 0.62/0.96). 18-oxocortisol levels above 6.1 ng/dL and/or of aldosterone above 32.7 ng/dL were found in 95 of 113 aldosteronoma patients (84%) but in none of 121 bilateral hyperaldosteronism, 30 of whom harbored CT-detectable unilateral nonfunctioning nodules in their adrenals. In addition, 18-oxocortisol levels below 1.2 ng/dL, the lowest in aldosteronoma, were found 52 out of the 121 (43%) patients with bilateral hyperaldosteronism. Further analysis of 27 patients with CT-undetectable micro aldosteronomas revealed that eight of these 27 patients had CT-detectable contralateral adrenal nodules, the highest values of peripheral 18-oxocortisol and aldosterone were 4.8 and 24.5 ng/dL, respectively, both below their cutoff levels indicated above. Conclusions: The peripheral plasma 18-oxocortisol concentrations served not only to differentiate aldosteronoma, but also could serve to avoid unnecessary surgery for nonfunctioning adrenocortical nodules concurrent with hyperplasia or microadenoma. Copyright
    Journal of Hypertension 06/2015; 33:e113. DOI:10.1097/01.hjh.0000467656.46285.fb · 4.72 Impact Factor
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    ABSTRACT: BACKGROUND: c-Met is widely known as a poor prognostic factor in various human malignancies. Previous studies have suggested the involvement of c-Met and/or its ligand, hepatocyte growth factor (HGF), in esophageal squamous cell carcinoma (ESCC), but the correlation between c-Met status and clinical outcome remains unclear. Furthermore, the identification of a novel molecular therapeutic target might potentially help improve the clinical outcome of ESCC patients. METHODS: The expression of c-Met and HGF was immunohistochemically assessed in 104 surgically obtained tissue specimens. The correlation between c-Met/HGF expression and patients' clinicopathological features, including survival, was evaluated. We also investigated changes in cell functions and protein expression of c-Met and its downstream signaling pathway components under treatments with HGF and/or c-Met inhibitor in ESCC cell lines. RESULTS: Elevated expression of c-Met was significantly correlated with tumor depth and pathological stage. Patients with high c-Met expression had significantly worse survival. In addition, multivariate analysis identified the high expression of c-Met as an independent prognostic factor. Treatment with c-Met inhibitor under HGF stimulation significantly inhibited the invasive capacity of an ESCC cell line with elevated c-Met mRNA expression. Moreover, c-Met and its downstream signaling inactivation was also detected after treatment with c-Met inhibitor. CONCLUSIONS: The results of our study identified c-Met expression as an independent prognostic factor in ESCC patients and demonstrated that c-Met could be a potential molecular therapeutic target for the treatment of ESCC with elevated c-Met expression.
    BMC Cancer 06/2015; 15(1):451. DOI:10.1186/s12885-015-1450-3 · 3.36 Impact Factor
  • F Satoh · R Morimoto · Y Ono · Y Iwakura · K Omata · M Kudo · N Satani · H Ota · K Seiji · K Takase · Y Nakamura · H Sasano · S Ito ·
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    ABSTRACT: Objective: Adrenal venous sampling (AVS) has been well known to play pivotal roles in clinical differential diagnosis of unilateral aldosterone producing adenoma (APA) from bilateral idiopathic hyperaldosteronism (IHA). However, it is also true that a central vein AVS or c-AVS which collects the blood from right and left central adrenal veins can by no means discriminate bilateral APA from BHA. There have been no published studies reporting the reliable clinical differential diagnosis between bilateral APA and IHA, especially IHA cases with bilateral non-functioning adenomas (NFA), which has been considered practically impossible in clinical differential diagnosis. As an attempt to this clinical dilemma, segmental AVS (S-AVS), which could evaluate segmental effluents from adrenal tributary veins, has been recently developed. Design and method: We have performed S-AVS in these patients above following C-AVS, via the insertion of a microcatheter in up to three intra-adrenal first-degree tributary veins on bilateral adrenals. Results: S-AVS did enable us to evaluate the intra-adrenal localization of corticosteroidogenesis. These data did indicate that S-AVS should be performed in the PA patients who had increased aldosterone levels in bilateral central vein and demonstrated space occupying lesions in the bilateral adrenals in order to avoid bilateral adrenalectomy or long lasting medical treatment toward persistent PA. In addition to the situations above, we have administere S-AVS to the following patients; those who had clinically suspected APA but not sufficiently high lateralization indexes according to the results of C-AVS, very young ones with higher clinical probability of recurrence and those who could benefit from partial adrenalectomy by demonstrating the sites of specific steroidogenesis. However, it is also entirely true that S-AVS is more expensive, time-consuming and labor-intensive compared to C-AVS. Copyright
    Journal of Hypertension 06/2015; 33 Suppl 1 - ESH 2015 Abstract Book:e114. DOI:10.1097/01.hjh.0000467658.23414.b0 · 4.72 Impact Factor

Publication Stats

22k Citations
3,308.04 Total Impact Points


  • 2015
    • Peter MacCallum Cancer Centre
      Melbourne, Victoria, Australia
  • 1994-2015
    • Tohoku University
      • • Department of Pathology
      • • Division of Internal Medicine
      Miyagi, Japan
    • Yokohama Rosai Hospital
      Yokohama, Kanagawa, Japan
  • 2012-2014
    • St. Luke's International Hospital
      • Department of Radiology
      Edo, Tōkyō, Japan
  • 2013
    • Sendai National College of Technology
      Sendai, Kagoshima, Japan
    • Kyoto University
      • Division of Pharmaceutical Sciences
      Kioto, Kyōto, Japan
  • 1989-2013
    • University of Texas Southwestern Medical Center
      • • Department of Obstetrics and Gynecology
      • • Department of Biochemistry
      Dallas, Texas, United States
  • 2010
    • Fudan University
      Shanghai, Shanghai Shi, China
  • 2004-2007
    • Sendai University
      Sendai, Kagoshima, Japan
  • 2005
    • The Jikei University School of Medicine
      • Department of Pathology
      Edo, Tōkyō, Japan
  • 2000-2003
    • University of Illinois at Chicago
      • • Department of Obstetrics and Gynecology (Chicago)
      • • Department of Obstetrics and Gynecology (Peoria)
      Chicago, Illinois, United States
    • Fujita Health University
      Nagoya, Aichi, Japan
  • 2002
    • Matsunami General Hospital
      Gihu, Gifu, Japan
    • Aomori Prefectural Central Hospital
      Aomori, Aomori Prefecture, Japan
  • 2001
    • Hokkaido University of Education
      Sapporo, Hokkaidō, Japan
    • Hyogo Prefectural Amagasaki Hospital
      Amagasaki, Hyōgo, Japan
  • 1998
    • Hamamatsu University School Of Medicine
      Hamamatu, Shizuoka, Japan
  • 1997
    • Sendai City Hospital
      Sendai, Kagoshima, Japan
  • 1995
    • Kyushu University
      • Department of Molecular Biology
      Hukuoka, Fukuoka, Japan
  • 1993
    • Kitasato University
      • Graduate School of Fisheries Sciences
      Edo, Tōkyō, Japan
  • 1988-1991
    • George Washington University
      • Department of Pathology
      Washington, Washington, D.C., United States
  • 1985-1988
    • Cornell University
      • Department of Pediatrics
      Итак, New York, United States