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Yamaguchi R.,Kurume University | Tanaka M.,Kurume Daiichi Social Insurance Hospital | Mizushima Y.,Kurume University | Hirai Y.,Kurume Daiichi Social Insurance Hospital | And 6 more authors.
Medical Molecular Morphology | Year: 2011

High-grade carcinoma with a large central acellular zone (central acellular carcinoma, CAC) and matrixproducing carcinoma (MPC) are aggressive tumors that both have a central myxomatous acellular zone. Their characteristic morphology may be useful in diagnostic imaging. Ultrasonographic findings based on the Breast Imaging Recording and Data System (BI-RADS) and detailed histological features were evaluated in 11 cases of CAC and 2 cases of MPC to characterize their features. Safranin-O staining was undertaken for the evaluation of central acellular zones in these tumors. Overall, ultrasonography demonstrated heterogeneous hyperechoic lesions in the center of the hypoechoic mass. Posterior echo enhancement was observed in all but 1 case. One case was classified as malignant and the others as "borderline." Histologically, cancer tissue was located in the periphery of the tumor with a ring-like structure and fewer cellular central areas comprising hyaline cartilage myxoid material such as those stained by safranin-O. The present study showed that the pathological findings of CACs and MPCs accurately reflect the ultrasonographic findings. Tumors that showed hyperechoic areas in the center of the hypoechoic mass, with posterior echo enhancement indicating acellular zones composed by myxochondroid material, and that were also relatively round on ultrasonography may be benign, but evaluation is required to exclude CAC and MPC. © The Japanese Society for Clinical Molecular Morphology 2011.


Yamaguchi R.,Kurume University | Tanaka M.,Kurume Daiichi Social Insurance Hospital | Yamaguchi M.,Kurume Daiichi Social Insurance Hospital | Fukushima T.,Kurume Daiichi Social Insurance Hospital | And 7 more authors.
Medical Molecular Morphology | Year: 2010

We report a 17-year-old woman with refractory high-grade breast cancer who died early after surgery, with reference to the histogenesis of the cancer. Macroscopically, the tumor was cystic, composed of a mixture of solid and myxomatous areas. Histologically, the tumor exhibited ductal structures and areas with squamoid features. Cancer cells were markedly atypical and polymorphic, and included a mixture of bizarre and eosinophilic cells with rhabdoid feature-like free cells. Immunohistochemically, cytokeratin (CK) 8, CK 18, 34betaE12, CD10, involucrin, CK14, and vimentin were partially positive, whereas estrogen and progesterone receptors and HER-2 were negative. These findings suggest an undifferentiated cancer whose cells have multilineage potential to differentiate into mesenchymal, basal, and squamoid cells, and it was diagnosed as pleomorphic carcinoma, which is a histological type hitherto unreported in young girls. The cancer was refractory to treatment, and the patient died 1 year and 5 months after surgery despite chemotherapy and radiotherapy. © The Japanese Society for Clinical Molecular Morphology 2010.


Ogata Y.,Kurume University | Matono K.,Kurume University | Tsuda H.,Kurume Daiichi Social Insurance Hospital | Ushijima M.,Kurume University | And 3 more authors.
PLoS ONE | Year: 2015

Background: Antineoplastons are naturally occurring peptides and amino acid derivatives found in human blood and urine. Antineoplaston A10 and AS2-1 reportedly control neoplastic growth and do not significantly inhibit normal cell growth. Antineoplastons contain 3-phenylacetyla-mino-2, 6-piperidinedione (A10), phenylacetylglutamine plus phenylacetylisoglutamine (A10-I), and phenylacetylglutamine plus phenylacetate (AS2-1). This open label, nonblinded randomized phase II study compared the efficacy of hepatic arterial infusion (HAI) with 5-fluorouracil,with or without antineoplastons as a postoperative therapy for colorectal metastasis to the liver. Methods: Sixty-five patients with histologically confirmed metastatic colon adenocarcinoma in liver, who had undergone hepatectomy, and/or thermal ablation for liver metastases were enrolled between 1998- 2004 in Kurume University Hospital. Patients were randomly assigned to receive systemic antineoplastons (A10-I infusion followed by per-oral AS2-1) plus HAI (AN arm) or HAI alone (control arm) based on the number of metastases and presence/ absence of extra-hepatic metastasis at the time of surgery. Primary endpoint was cancer-specific survival (CSS); secondary endpoints were relapse-free survival (RFS), status and extent of recurrence, salvage surgery (rate) and toxicity. Findings: Overall survival was not statistically improved (p=0.105) in the AN arm (n=32). RFS was not significant (p=0.343). Nevertheless, the CSS rate was significantly higher in the AN arm versus the control arm (n=33) with a median survival time 67 months (95%CI 43-not calculated) versus 39 months (95%CI 28-47) (p=0.037) and 5 year CSS rate 60% versus 32% respectively. Cancer recurred more often in a single organ than in multiple organs in the AN arm versus the control arm. The limited extent of recurrent tumours in the AN arm meant more patients remained eligible for salvage surgery. Major adverse effects of antineoplastons were fullness of the stomach and phlebitis. No serious toxicity, including bone marrow suppression, liver or renal dysfunction, were found in the AN arm. Interpretation: Antineoplastons (A10 Injection and AS2-1) might be useful as adjunctive therapy in addition to HAI after hepatectomy in colorectal metastases to the liver. © 2015 Ogata et al.


Yamaguchi R.,Kurume University | Tanaka M.,Kurume Daiichi Social Insurance Hospital | Kondo K.,Kurume University | Yokoyama T.,Kurume University | And 11 more authors.
Medical Molecular Morphology | Year: 2012

Metaplastic breast cancers (MBCs) [spindle cell carcinoma (SpCC), squamous cell carcinoma (SCC), and matrix-producing carcinoma (MPC)] and invasive carcinomas with central acellular zones (CACs) were analyzed with respect to biological potential by immunohistochemical analyses. Specimens from 40 patients [20 with MBCs (7 with SCC, 6 with SpCC, 5 with MPC, and 2 with mixed type)] and 20 with CACs were analyzed using antibodies to cytokeratin (CK) 8, 5/6, 14, AE1/AE3, 34αE12, involucrin, c-kit, vimentin (VIM), alpha-smooth muscle actin, p63, epidermal growth factor receptor, epithelial cell adhesion molecule, and estrogen receptor (ER)/progesterone receptor (PR)/HER2. Expression of CK5/6, 34βE12, VIM, nuclear p63, and cytoplasmic p63 was significantly higher with MBCs than CACs (38%/13%, 70%/43%, 85%/33%, 68%/40%, and 48%/18%, respectively). Other markers were expressed at various levels in these tumors, but the difference between them was not significant. Eighteen MBC and 8 CAC cases were triple (ER/PR/HER2) negative; 17 MBCs and 7 CACs were basal-like tumors. Several differences were seen in MBCs and CACs, but they were heterogeneous, differentiating multipotentially into mesenchymal, myoepithelial, basal-like phenotypes with "stem cell-like" features. Thus, CACs are related to MBCs by immunohistochemical analyses as well as according to morphological findings. © 2012 The Japanese Society for Clinical Molecular Morphology.


Yamaguchi R.,Kurume University | Tanaka M.,Kurume Daiichi Social Insurance Hospital | Kondo K.,Kurume University | Yokoyama T.,Kurume University | And 6 more authors.
Japanese Journal of Clinical Oncology | Year: 2010

Objective: Invasive micropapillary carcinoma of the breast is a distinct variant of breast cancer. In the present study, we analyzed potential immunophenotypic changes in invasive micropapillary carcinoma. Methods: Specimens from 15 patients with invasive micropapillary carcinoma were analyzed using clinicopathological and immunohistochemical methods. We also examined the relationship between clinicopathological factors using the Ki-67 labeling index. Results: Immunohistochemical staining for cytoplasmic p63 expression was seen in four (27%) tumors, and p63 nuclear expression was also observed in four (27%) tumors. Involucrin and 34betaE12 were expressed in the invasive micropapillary carcinoma component of nine (60%) and four (27%) tumors, respectively. Cytokeratin 5/6 was expressed in three (20%) tumors and cytokeratin 14 staining was negative in all tumors. In one tumor (case 3), vimentin, epithelial membrane antigen and cytokeratin 8/18 were co-expressed. Four tumors (27%) were negative for the estrogen receptor/progesterone receptor/HER2. However, 11 out of 15 (73%) tumors were positive for the estrogen receptor. The Ki-67 labeling index was significantly higher in cases with p63 tumor expression than in those without (P < 0.0001), and also higher in cases with lymph node metastasis than in cases without (P = 0.0029). Conclusions: Nuclear expression of p63, involucrin and 34betaE12 were detected indicating squamous differentiation. Cytoplasmic p63 expression was also identified. The fact that the Ki-67 labeling index was significantly higher in such cases may have been associated with the aggressive behavior of these tumors. Our findings suggest that the characteristic morphology of invasive micropapillary carcinomas may be due to immunophenotypical and oncogenic changes. © The Author (2010). Published by Oxford University Press. All rights reserved.


Ushijima M.,Kurume University | Ogata Y.,Kurume University | Tsuda H.,Kurume Daiichi Social Insurance Hospital | Akagi Y.,Kurume University | And 2 more authors.
Oncology Reports | Year: 2014

Antineoplastons are naturally occurring peptides and amino acid derivatives found in human blood and urine. Antineoplastons have been shown to control neoplastic growth. In the present study, we investigated demethylation effect of the antineoplaston AS2-1 (a mixture of phenylacetylglutamine and phenylacetate in the ratio of 1:4) on various genes in colon cancer cells. An HpaII-MspI methylation microarray was used to investigate the methylation status of 51 genes at the promoter region in HCT116 and KM12SM human colon cancer cells before and after treatment of AS2-1. The expression of protein and mRNA of the demethylated genes by AS2-1 in HCT116 cells was evaluated. In 19 of the 34 methylated genes in HCT116 and in 7 of the 8 methylated genes in KM12SM, the methylation status was downregulated after treatment with 2 mg/ml of AS2-1 for 24 h. AS2-1 dramatically downregulated the methylation status of p15 and ESR1 in HCT116 cells and of MTHFR and MUC2 in KM12SM cells. Both mRNA and protein expression of p15 increased in a dose- and time-dependent manner after treatment with AS2-1. The antineoplaston AS2-1 may normalize the hypermethylation status at the promoter region in various genes including tumor suppressor genes, resulting in activation of the transcription and translation in colon cancer.


Terasaki H.,Kurume Daiichi Social Insurance Hospital | Terasaki H.,Kurume University | Kato S.,University of Ryukyus | Matsuno Y.,Clinical Laboratory Division | And 6 more authors.
Journal of Thoracic Imaging | Year: 2011

"Adenocarcinoma, mixed subtype" is the most common histologic subtype of lung adenocarcinomas in the World Health Organization classification of 2004. For small peripheral adenocarcinomas, for example, those measuring 2 cm or less in greatest diameter, invasive areas can present various histologic patterns. The purpose of this study is to present the radiologic features of small peripheral lung adenocarcinomas with or without a bronchioloalveolar component and with or without invasive areas, in comparison with histopathologic findings. For this purpose, a detailed evaluation of the characteristics of solid regions in ground-glass opacity on high-resolution computerized tomographic images of lung adenocarcinoma is useful. Copyright © 2011 by Lippincott Williams & Wilkins.


Yamaguchi R.,Kurume University | Tanaka M.,Kurume Daiichi Social Insurance Hospital | Yokoyama T.,Kurume University | Nonaka Y.,Kurume Daiichi Social Insurance Hospital | And 7 more authors.
Diagnostic Cytopathology | Year: 2012

Fibroadenoma (FA) is a benign tumor that must be differentiated from carcinomas. FAs often exhibit myxedematous changes (myxomatous FA, M-FA). We previously reported on the clinical significance of M-FA. M-FA and (mucinous) carcinoma share clinical findings, rapid growth and a relatively large size, a high-depth/width (D/W) ratio, a relatively round shape, and posterior echo enhancement with internal hyperechogenicity on ultrasonography (US). Next, a biopsy is required for differential diagnosis. In this study, we evaluated the diagnostic significance of the cytological findings of M-FA with US findings. Among 13 FAs that were diagnosed by cytology, we compared (i) a group of six mucinous carcinomas with acellular mucin and a D/W ratio ≥ 0.7 (a suspicious factor for malignancy) with a group with a D/W ratio of <0.7, and (ii) the frequency of metachromasia on Giemsa stain between M-FAs and non-M-FAs among eight FA cases confirmed by histology. (i) FA lesions (7 of 13) showed metachromasia with Giemsa staining significantly more frequently than did mucinous carcinoma (0/6) (Fisher's exact test, P < 0.044). FA lesions with a D/W ratio ≥ 0.7 (6/7) showed metachromasia significantly more frequently than did FA with a D/W ratio <0.7 (1/6) (Fisher's exact test, P < 0.029). Among eight FA cases confirmed by histology, M-FA cases (6/6) demonstrated metachromasia significantly more frequently than non-M-FA cases (0/2) (P < 0.036). M-FA cytologically exhibits marked metachromasia on Giemsa staining. Combining cytological examination and understanding the clinical features of M-FA may allow us to choose cytological examination as a first-line diagnostic method for tumor-forming lesions. Diagn. Cytopathol. 2011. © 2011 Wiley-Liss, Inc.


Yamaguchi R.,Kurume University | Tanaka M.,Kurume Daiichi Social Insurance Hospital | Mizushima Y.,Kurume University | Hirai Y.,Kurume Daiichi Social Insurance Hospital | And 6 more authors.
Human Pathology | Year: 2011

Fibroadenoma is a frequently encountered benign tumor that must be differentiated from carcinoma. Fibroadenomas often exhibit myxedematous changes (myxomatous fibroadenoma). We focused on myxomatous fibroadenomas and evaluated their diagnostic imaging and clinicopathologic findings. We examined the (1) clinicopathologic findings of myxomatous fibroadenomas out of 113 fibroadenomas among 592 needle biopsy cases and (2) clinical findings of 27 patients with fibroadenoma who underwent surgical resection. One hundred thirteen (19%) of 592 cases were fibroadenoma, of which 45 cases (40%) were myxomatous fibroadenoma. Based on ultrasonography findings, the depth to width ratio was significantly higher in the myxomatous fibroadenoma group (0.79 ± 0.26) compared with the non-myxomatous fibroadenoma group (0.64 ± 0.26) (P < .01). Forty-two patients were subjected to needle biopsy to differentiate fibroadenoma from carcinomas based on ultrasonography and clinical findings, of which 13 cases (31%) were myxomatous fibroadenoma. These lesions showed a relatively round shape and increased posterior echo enhancement with internal hyperechogenicity on ultrasonography. Among 17 resected cases suspected of malignancy that showed rapid growth and/or size greater than 3 cm, 16 cases were myxomatous fibroadenoma. Tumors showing rapid growth and a relatively large size, a high depth to width ratio, a relatively round shape, and posterior echo enhancement with internal hyperechogenicity on ultrasonography require differentiation from (mucinous) carcinoma but are histologically more likely to be myxomatous fibroadenoma. Understanding the histologic features and combining the ultrasonography findings of myxomatous fibroadenomas may permit reduction in the number of unnecessary needle biopsies for tumor-forming lesions. © 2011 Elsevier Inc.


PubMed | Kurume University and Kurume Daiichi Social Insurance Hospital
Type: Clinical Trial, Phase II | Journal: PloS one | Year: 2015

Antineoplastons are naturally occurring peptides and amino acid derivatives found in human blood and urine. Antineoplaston A10 and AS2-1 reportedly control neoplastic growth and do not significantly inhibit normal cell growth. Antineoplastons contain 3-phenylacetylamino-2, 6-piperidinedione (A10), phenylacetylglutamine plus phenylacetylisoglutamine (A10-I), and phenylacetylglutamine plus phenylacetate (AS2-1). This open label, non- blinded randomized phase II study compared the efficacy of hepatic arterial infusion (HAI) with 5-fluorouracil,with or without antineoplastons as a postoperative therapy for colorectal metastasis to the liver.Sixty-five patients with histologically confirmed metastatic colon adenocarcinoma in liver, who had undergone hepatectomy, and/or thermal ablation for liver metastases were enrolled between 1998- 2004 in Kurume University Hospital. Patients were randomly assigned to receive systemic antineoplastons (A10-I infusion followed by per-oral AS2-1) plus HAI (AN arm) or HAI alone (control arm) based on the number of metastases and presence/ absence of extra-hepatic metastasis at the time of surgery. Primary endpoint was cancer-specific survival (CSS); secondary endpoints were relapse-free survival (RFS), status and extent of recurrence, salvage surgery (rate) and toxicity.Overall survival was not statistically improved (p=0.105) in the AN arm (n=32). RFS was not significant (p=0.343). Nevertheless, the CSS rate was significantly higher in the AN arm versus the control arm (n=33) with a median survival time 67 months (95%CI 43-not calculated) versus 39 months (95%CI 28-47) (p=0.037) and 5 year CSS rate 60% versus 32% respectively. Cancer recurred more often in a single organ than in multiple organs in the AN arm versus the control arm. The limited extent of recurrent tumours in the AN arm meant more patients remained eligible for salvage surgery. Major adverse effects of antineoplastons were fullness of the stomach and phlebitis. No serious toxicity, including bone marrow suppression, liver or renal dysfunction, were found in the AN arm.Antineoplastons (A10 Injection and AS2-1) might be useful as adjunctive therapy in addition to HAI after hepatectomy in colorectal metastases to the liver.ClinicalTrials.gov UMIN000012099.

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