Touko Inao

Kumamoto University, Kumamoto, Kumamoto, Japan

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Publications (15)61.42 Total impact

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    ABSTRACT: Recently, research into the development of new targeted therapies has focused on specific genetic alterations to create advanced, more personalized treatment. One of the target genes, Fibroblast growth factor receptor-1 (FGFR1), has been reported to be amplified in estrogen receptor (ER)-positive subtype breast cancer, and is considered one possible mechanism of endocrine resistance through cross-talk between ER and growth factor receptor signaling. We performed a comprehensive analysis of FGFR1 at the levels of gene copy number, transcript and protein expression, and examined the relationships between FGFR1 status and clinicopathological parameters including prognosis in 307 ER-positive/HER2-negative primary breast cancer patients treated with standard care at our institute. Most notably, a high level of FGFR1 protein expression was observed in 85 patients (27.7%), and was positively associated with invasive tumor size (P=0.039). Furthermore, univariate analysis revealed that high FGFR1 protein expression was significantly correlated with poor relapse-free survival rate (P=0.0019, HR: 2.63, 95%CI: 1.17-5.98), and showed a tendency towards an increase in recurrent events if the observation period extended beyond the 5 years of the standard endocrine treatment term. FGFR1 gain/amplification was found in 43 (14.0%) patients, which was only associated with higher nuclear grade (P=0.010). No correlation was found between FGFR1 mRNA expression levels and any clinicopathological factors. Overall, the level of FGFR1 protein expression may be a biomarker of ER-positive/HER2-negative primary breast cancer with possible resistance to standard treatment, and may be a useful tool to identify more specific patients who would benefit from FGFR-1 targeted therapy. This article is protected by copyright. All rights reserved.
    No preview · Article · Jan 2016 · Cancer Science
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    ABSTRACT: Single-photon emission computed tomography (SPECT)/computed tomography (CT) improves the anatomical identification of sentinel lymph nodes (SNs). We aimed to evaluate the possibility of predicting the SN status using SPECT/CT. SN mapping using a SPECT/CT system was performed in 381 cases of clinically node-negative, operable invasive breast cancer. We evaluated and compared the values of SN mapping on SPECT/CT, the findings of other modalities and clinicopathological factors in predicting the SN status. Patients with SNs located in the Level I area were evaluated. Of the 355 lesions (94.8 %) assessed, six cases (1.6 %) were not detected using any imaging method. According to the final histological diagnosis, 298 lesions (78.2 %) were node negative and 83 lesions (21.7 %) were node positive. The univariate analysis showed that SN status was significantly correlated with the number of SNs detected on SPECT/CT in the Level I area (P = 0.0048), total number of SNs detected on SPECT/CT (P = 0.011), findings of planar lymphoscintigraphy (P = 0.011) and findings of a handheld gamma probe during surgery (P = 0.012). According to the multivariate analysis, the detection of multiple SNs on SPECT/CT imaging helped to predict SN metastasis. The number of SNs located in the Level I area detected using the SPECT/CT system may be a predictive factor for SN metastasis.
    Full-text · Article · Apr 2015 · Surgery Today

  • No preview · Article · Mar 2014 · Cancer Research

  • No preview · Article · Mar 2014 · Cancer Research
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    ABSTRACT: The patient was 77-year-old woman whose breast cancer had metastasized to the bone and soft tissue 5 years after surgery. Although she had been sequentially treated with endocrine therapies following chemotherapies, new metastatic lesions in the pleura and skin appeared 8 years after recurrence. The biopsied skin tissue showed high positivity for estrogen receptor(ER), was negative for human epidermal growth factor receptor 2(HER2), and had a low Ki-67 labeling index. Following the treatment with exemestane(EXE)for 3months, ethinyl estradiol(EE2)was administered at 3mg/day. After 4 months of treatment, the lymph nodes shrunk to 35% of their size and pleural effusion disappeared. The efficacy of EE2 was observed for 10 months. Subsequently, fulvestrant was administered because the skin lesions showed progressive disease. Adverse events such as nausea and general fatigue were observed at the beginning of EE2 therapy. Pigmentation of the nipple and areola and cystic swelling of the cervical canal were observed after a few months. This therapy can be considered to be effective in patients with ER-positive metastatic breast cancer who have been heavily treated with endocrine therapies and chemotherapies.
    No preview · Article · Dec 2013 · Gan to kagaku ryoho. Cancer & chemotherapy
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    ABSTRACT: Background: Oestrogens usually stimulate the progression of oestrogen receptor (ER)-positive breast cancer. Paradoxically, high-dose oestrogens suppress the growth of these tumours in certain circumstances. Methods: We prospectively examined the efficacy and safety of ethinylestradiol treatment (3 mg per day oral) in postmenopausal patients with advanced or recurrent ER-positive breast cancer who had previously received endocrine therapies, especially those with resistance to aromatase inhibitors. Results: Eighteen patients were enrolled with the median age of 63 years and the mean observation time of 9.2 months. Three cases withdrew within 1 week due to oestrogen flare reactions with nausea, fatigue and muscle-skeletal pain. The response rate was 50% (9 out of 18), and the clinical benefit rate was 56% (10 out of 18). The stable disease (<6 months) was 17% (3 out of 18) and another 2 cases were judged as progressive disease. Time-to-treatment failure including 2 on treatment was a median of 5.6 months (range 0.1 to 14.5+). Although vaginal bleeding or endometrial thickening was observed in patients receiving long-term treatment, there were no severe adverse events, such as deep venous thrombosis or other malignancies. Conclusion: Although the mechanism of this treatment has not been fully understood, our data may contribute to change the common view of late-stage endocrine therapy.
    Full-text · Article · Sep 2013 · British Journal of Cancer
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    ABSTRACT: Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) and agonistic death receptor-specific antibodies can induce apoptosis in cancer cells with little cytotoxicity to normal cells. To improve TRAIL-induced antitumor effects, we tested its effectiveness in combination with pifithrin-μ, which has the potential to inhibit HSP70 function and autophagy, both of which participate in TRAIL resistance in cancer cells. Among the four human pancreatic cancer cell lines tested, MiaPaca-2, Panc-1, and BxPC-3 cells showed varying sensitivities to TRAIL. In MiaPaca-2 and Panc-1 cells, knockdown of HSP70 or Beclin-1, the latter an autophagy-related molecule, by RNA interference augmented TRAIL-induced antitumor effects, decreasing cell viability and increasing apoptosis. Based on these findings, we next determined whether the TRAIL-induced antitumor effects could be augmented by its combination with pifithrin-μ. The combination of TRAIL plus pifithrin-μ significantly decreased the viability and colony-forming ability of MiaPaca-2 and Panc-1 cells compared to cells treated with either agent alone. When applied alone, pifithrin-μ increased Annexin V+ cells in both caspase-dependent and caspase-independent manners. It also promoted TRAIL-induced apoptosis and arrested cancer cell growth. Furthermore, pifithrin-μ antagonized TRAIL-associated NF-κB activation in cancer cells. In a xenograft mouse model, combination therapy significantly inhibited MiaPaca-2 tumor growth compared to treatment with either agent alone. The results of this study suggest protective roles for HSP70 and autophagy in TRAIL resistance in pancreatic cancer cells and suggest that pifithrin-μ is a promising agent for use in therapies intended to enhance the antitumor effects of TRAIL.
    Preview · Article · Jan 2013 · Molecular Cancer Therapeutics
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    ABSTRACT: Several chemotherapeutic drugs have immune-modulating effects. For example, cyclophosphamide (CP) and gemcitabine (GEM) diminish immunosuppression by regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs), respectively. Here, we show that intermittent (metronomic) chemotherapy with low-dose CP plus GEM can induce anti-tumor T cell immunity in CT26 colon carcinoma-bearing mice. Although no significant growth suppression was observed by injections of CP (100 mg/kg) at 8-day intervals or those of CP (50 mg/kg) at 4-day intervals, CP injection (100 mg/kg) increased the frequency of tumor peptide-specific T lymphocytes in draining lymph nodes, which was abolished by two injections of CP (50 mg/kg) at a 4-day interval. Alternatively, injection of GEM (50 mg/kg) was superior to that of GEM (100 mg/kg) in suppressing tumor growth in vivo, despite the smaller dose. When CT26-bearing mice were treated with low-dose (50 mg/kg) CP plus (50 mg/kg) GEM at 8-day intervals, tumor growth was suppressed without impairing T cell function; the effect was mainly T cell dependent. The metronomic combination chemotherapy cured one-third of CT26-bearing mice that acquired tumor-specific T cell immunity. The combination therapy decreased Foxp3 and arginase-1 mRNA levels but increased IFN-γ mRNA expression in tumor tissues. The percentages of tumor-infiltrating CD45(+) cells, especially Gr-1(high) CD11b(+) MDSCs, were decreased. These results indicate that metronomic chemotherapy with low-dose CP plus GEM is a promising protocol to mitigate totally Treg- and MDSC-mediated immunosuppression and elicit anti-tumor T cell immunity in vivo.
    No preview · Article · Aug 2012 · Cancer Immunology and Immunotherapy
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    ABSTRACT: Innate adjuvant receptors are expressed in immune cells and some types of cancers. If antitumor therapies targeting these receptors are established, it is likely that they will be therapeutically beneficial because antitumor effects and immune-cell activation can be induced simultaneously. In this study, we tested this possibility of using an innate adjuvant receptor ligand, polyinosinic-polycytidylic acid [poly(I:C)], to treat human breast cancer cell lines. Three breast cancer cell lines (MCF-7, MDA-MB-231, and BT-549) were used in this study. Poly(I:C) was transfected into these cancer cells to stimulate melanoma differentiation-associated gene (MDA) 5, which is a cytoplasmic adjuvant receptor. Poly(I:C) transfection significantly reduced the viability of all cell lines in a manner partially dependent on MDA5. Flow cytometeric analyses and immunoblot assays revealed that the antitumor effect depended on both caspase-dependent apoptosis and c-Myc- and cyclinD1-dependent growth arrest. Interestingly, poly(I:C) transfection was accompanied by autophagy, which is thought to protect cancer cells from apoptosis after poly(I:C) transfection. In a xenograft mouse model, local transfection of poly(I:C) significantly inhibited the growth of xenografted MDA-MB-231 cells. Our findings indicate that cytoplasmic delivery of poly(I:C) can induce apoptosis and growth arrest of human breast cancer cells, and that therapy-associated autophagy prevents apoptosis. The results of this study suggest that the innate adjuvant receptors are promising targets and that their ligands could serve as antitumor reagents, which have the potential to simultaneously induce antitumor effects and activate immune cells.
    No preview · Article · Dec 2011 · Breast Cancer Research and Treatment
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    ABSTRACT: We assessed the expression of cytokeratin (CK) and apomucin (MUC) in ampullary carcinoma (AC) to develop a system for the classification of ACs on the basis of their clinical significance. We studied the expressions of CK7, CK20, MUC1, MUC2, MUC5AC, and MUC6 in 43 patients with ACs. Clinical data were obtained retrospectively by examining surgically resected ACs of the patients. We classified the cases into 3 groups: tumors expressing CK20 and lacking MUC1 (intestinal type [I-type], 26%), tumors expressing MUC1 and lacking CK20 (pancreatobiliary type [PB-type], 35%), and those expressing or lacking both CK20 and MUC1 (other type [O-type], 39%). Eight (73%) of 11 I-type carcinomas, 3 (20%) of 15 PB-type carcinomas, and 4 (24%) of 17 O-type carcinomas were classified as pT1. The number of I-type carcinomas in the early tumor stages was significantly higher than the number of PB- and O-type carcinomas (p = 0.014 and p = 0.018, respectively). The 5-year survival rates for pT1, pT2, and pT3 tumors were 76%, 33%, and 22%, respectively (p < 0.001). Rates of MUC5AC and MUC6 coexpression for I-type, PB-type, and O-type tumors were 18%, 13%, and 53%, respectively. There was a significant correlation between MUC5AC and MUC6 coexpression and O-type characteristics (p = 0.031). The five-year survival rates for O-type ACs with and without MUC5AC and MUC6 coexpression were 71% and 17%, respectively (p = 0.048). The immunohistochemical subtypes based on CK and MUC expression correlated with tumor progression. Gastric MUC5AC and MUC6 coexpression correlated with better prognosis for O-type ACs.
    Full-text · Article · Nov 2010 · Diagnostic Pathology
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    ABSTRACT: Intraductal papillary mucinous neoplasm (IPMN) is reported to complicate malignancies disease in 30% of cases and complicate invasive ductal carcinoma of the pancreas too, but is rare in multiple cancers. We report a patient with IPMN accompanied by triple cancers. The 60-year-old woman had been followed for IPMN for 7 years, during which time she underwent a hysterectomy due to uterine corpus cancer at age 56 and bilateral breast-preserving surgery due to bilateral breast cancer at age 60. During radiation therapy after breast cancer surgery, a tumor was found in the pancreas body in abdominal computed tomography. Magnetic resonance cholangiopancreatography and endoscopic retrograde cholangiopancreatography showed the main pancreas duct to be occluded at the body and at the tail to be delated. Cytology of the pancreatic juice was class IV. We diagnosed pancreatic cancer with IPMN and conducted subtotal distal pancreatectomy, without resecting the IPMN, which was considered benign. Physicians should look for malignant disease in patients with IPMN because cancer complications may adversely affect their prognosis.
    No preview · Article · Jun 2008 · Nippon Shokaki Geka Gakkai zasshi

  • No preview · Article · Apr 2008 · Gastroenterology
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    ABSTRACT: A 67-year-old man admitted for sudden severe upper abdominal pain was found in abdominal computed tomography to have ruptured hepatocellular carcinoma (HCC) in the left caudate (Spiegel) lobe protruding caudally with hematoma into the lesser omentum. After hemostasis, stabilization of his general condition, and liver function evaluation, we conducted T2-weighted imaging that showed a low-intensity mass occupying the entire Spiegel lobe and involving the proper hepatic artery and portal vein. We conducted partial hepatectomy after his general condition improved. Macroscopically, the tumor was attached by a stalk to the surface of the Spiegel lobe. Histological examination showed moderately differenciated hepatocellular carcinoma and hemorrhagic change in the stalk. The postoperative course was uneventful. Twelve case reports of HCC rupture of HCC of the caudate lobe have been made, to the best of our knowledge, and a case of spontaneous HCC rupture of the Spiegel's lobe with a stalk is very rare.
    No preview · Article · Sep 2007 · Nippon Shokaki Geka Gakkai zasshi
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    ABSTRACT: A 55-year-old man admitted for fever, right lower abdominal pain and skin redness was found in laboratory data examination to have marked leukocytosis (13,900/μl) and high C- reactive protein (27.7mg/dl). Abdominal computed tomography (CT) showed a 10 x 6 x 5cm cystic lesion in the right lower abdominal cavity. The abdominal abscess ruptured the day after hospitalization, and the man was treated with antibiotics and drainage. The drainage wound was closed and he was discharged 8 days after admission. The abscess ruptured again, however, and fistelography showed an enterocutaneous fisutula. Intraabdominal findings during laparotomy showed mucious ascites and multiple small size white indurations in the abdominal cavity. Histological examination of the small indurations showed epitheloid granuloma with caseous necrosis, suggesting tubercular peritonitis. Colonoscopy showed ileocecal erosion leading to a diagnosis of histologically tuberculous peritonitis. Antituberculous agents were administered and abdominal symptoms disappeared. Tuberculous peritonitis should thus be taken into consideration in differentitial diagnosis.
    No preview · Article · Aug 2007

  • No preview · Article · Jan 2007 · Nihon Rinsho Geka Gakkai Zasshi (Journal of Japan Surgical Association)

Publication Stats

91 Citations
61.42 Total Impact Points

Institutions

  • 2013-2016
    • Kumamoto University
      • Department of Breast and Endocrine Surgery
      Kumamoto, Kumamoto, Japan
  • 2007-2013
    • Shimane University
      • • Department of Surgery
      • • Department of Immunology
      • • Department of Digestive and General Surgery
      Matsu, Shimane, Japan