H Tsuda

National Defense Medical College, Tokorozawa, Saitama, Japan

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Publications (648)1971.33 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: Chondrosarcoma is the second most frequent malignant bone tumor. However, the etiological background of chondrosarcomagenesis remains largely unknown, along with detailed information on molecular alterations, including potential therapeutic targets. Massively parallel paired-end sequencing of whole genomes of ten primary chondrosarcomas revealed that the process of accumulation of somatic mutations is homogeneous irrespective of pathological subtype or the presence of IDH1 mutation and unique among a range of cancer types, and shares significant commonalities with that of prostate cancer. Clusters of structural alterations localized within a single chromosome were observed in four cases. Combined with targeted resequencing of additional cartilaginous tumor cohort, we identified somatic alterations of the COL2A1 gene, which encodes an essential extracellular matrix protein in chondro-skeletal development, in 19.3% of chondrosarcoma and 31.7% of enchondroma cases. Epigenetic regulators (IDH1 and YEATS2) and an activin/BMP signal component (ACVR2A) were recurrently altered. Furthermore, a novel FN1-ACVR2A fusion transcript was observed in both chondrosarcoma and osteochondromatosis cases. Under the characteristic accumulative process of somatic changes as a background, molecular defects in chondrogenesis and aberrant epigenetic control are primarily causative of both benign and malignant cartilaginous tumors.
    Genome research. 07/2014;
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    ABSTRACT: Triple-negative breast cancer (TNBC) patients are a poor prognostic subgroup, and currently there is no biomarker for targeted therapy.
    Annals of oncology : official journal of the European Society for Medical Oncology / ESMO. 07/2014;
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    ABSTRACT: Involvement of Ras in cancer initiation is known but recent evidence indicates a role in cancer progression including metastasis and invasion; however, the mechanism is still unknown. In this study, it was determined that human lung cancer cells with Ras mutations, among other popular mutations, showed significantly higher expression of CUB domain containing protein 1 (CDCP1) than those without. Furthermore, activated-Ras clearly induced CDCP1, while CDCP1 knockdown or inhibition of CDCP1 phosphorylation by Src-directed therapy abrogated anoikis resistance, migration and invasion induced by activated-Ras. Activation of MMP-2 and secretion of MMP-9, in a model of Ras-induced invasion, was found to be regulated through induction of phosphorylated CDCP1. Thus, CDCP1 is required for the functional link between Ras and Src signaling during the multi-stage development of human malignant tumors, highlighting CDCP1 as a potent target for treatment in the broad spectrum of human cancers associated with these oncogenes. Implications: CDCP1 protein induced by oncogenic Ras/Erk signaling is essential for Ras-mediated metastatic potential of cancer cells.
    Molecular cancer research : MCR. 06/2014;
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    ABSTRACT: HER2 protein overexpression and gene amplification are important biomarkers for identifying gastric cancer patients who may respond to HER2-targeted therapy using trastuzumab. The aim of this study was to evaluate the concordance between HER2 protein expression and gene amplification in both surgically resected tumors and matched biopsy specimens of gastric cancer. Formalin-fixed, paraffin-embedded sections of 207 surgically resected tumors and 158 biopsy specimens from 207 cases of invasive intestinal-type gastric cancer were analyzed. Protein expression was assessed using immunohistochemistry and graded by the modified scoring criteria for gastric cancer. Gene amplification was evaluated by fluorescence in situ hybridization (FISH). HER2 overexpression was observed in 17 % of both surgically resected tumors (35/207) and biopsy specimens (26/158). HER2 gene amplification was detected in 31 % (61/200) of surgically resected tumors and 32 % (47/147) of biopsy specimens. Except for immunohistochemistry (IHC) equivocal (2+) cases, the concordance rates between IHC and FISH was 90.9 % in surgically resected tumors and 90.2 % in biopsy specimens. In IHC 2+ cases, the rate of HER2 gene amplification was 56 and 38 % in surgically resected tumors and biopsy specimens, respectively. IHC-FISH discordance was mainly due to intratumoral heterogeneity and low-level gene amplification. The concordance rate of IHC results between surgically resected specimens and the corresponding biopsy specimen was 57.0 % (κ = 0.224), and in discordant cases, HER2 positivity in biopsies and HER2 negativity in surgically resected tumors were most common. The concordance rate of FISH results between surgically resected tumors and biopsy specimens was 72.7 % (κ = 0.313). Polysomy 17 was detected in 5.5 and 7.5 % of surgically resected tumors and biopsy specimens and significantly correlated with IHC score, but polysomy 17 could explain one IHC score 3+ and FISH-negative tumor only. Although high concordance rates between HER2-protein expression and gene amplification were observed in both surgically resected tumors and biopsy specimens, the agreement levels were evaluated to be fair. Polysomy 17 was infrequent and seemed to have limited impact on gastric HER2 testing. Further investigations are required for an appropriate biopsy method to reduce false results of HER2 testing and to clarify the clinical significance of intratumoral heterogeneity in HER2 status.
    Archiv für Pathologische Anatomie und Physiologie und für Klinische Medicin 06/2014; · 2.68 Impact Factor
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    ABSTRACT: Aim: To assess the clinicopathological significance of the histological growth pattern (HGP) and α-actinin-4 (ACTN4) expression in thyroid cancer. Patients and Methods: We classified 83 thyroid cancer cases into infiltrative margin (IM) and pushing margin (PM) groups according to peripheral tumor margin contour and immunohistochemically determined ACTN4 expression. Correlations between clinical stage and clinicopathological characteristics were analyzed. Results: IM and high ACTN4 expression were observed in 39% and 49% of cancer cases, respectively. Higher clinical stage was significantly correlated with older age, higher T and N factor, preoperative recurrent laryngeal nerve paralysis (pre-RLNP), IM, and poor prognosis. Patients with stage IV disease had significantly poorer prognosis than those with stages I-III. On multivariate analysis, older age, pre-RLNP, and IM correlated with higher clinical stages. IM was significantly correlated with high ACTN4 expression. Conclusion: IM, pre-RLNP, and ACTN4 expression could be novel indicators of tumor aggression and prognostic factors of thyroid cancer.
    Anticancer research 06/2014; 34(6):3157-63. · 1.71 Impact Factor
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    ABSTRACT: We investigated whether some mucinous carcinomas (MUCs) are associated with lobular neoplasia (LN) components, and if so, whether this subset has any distinct biological properties. MUC specimens from 41 patients were stratified into pure and mixed types. The LN components adjacent to MUC lesions were examined histopathologically. We also tested immunohistochemically for E-cadherin, β-catenin, and the neuroendocrine markers chromogranin A and synaptophysin; and compared results between MUCs with and without LN. Of 41 patients with MUC, LN was detected in 12 patients (29%); LN alone was the noninvasive component in 8 patients (20%). Decreased E-cadherin and β-catenin expression in the MUC component was detected in 2 (17%) and 7 (58%) cases, respectively, of MUC with LN, compared with 0% (P = 0.080) and 21% (P = 0.018) in MUCs without LN. Neuroendocrine factors were frequently detected in MUCs with LN (42%) and without LN (52%), but tended to be less frequent in MUCs with only LN components (25%) than in other MUCs (55%; P = 0.133). MUCs associated with LN components appear to be a biologically characteristic subset that frequently shows decreased cell–cell adhesion, cell polarity molecules and lack of neuroendocrine differentiation.
    Pathology International 05/2014; 64(5). · 1.72 Impact Factor
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    ABSTRACT: Pseudomonas aeruginosa is a common pathogen in nosocomial and/or healthcare-associated pneumonia, but is rare in community-acquired pneumonia. A 50-year-old previously healthy woman was taken to the emergency department because of rapidly progressing dyspnea. Chest radiograph showed consolidation of the entire right upper lobe, a finding suggestive of lobar pneumonia. The patient died of respiratory failure with bronchial bleeding, on the same day of admission. Autopsy revealed that the alveoli throughout the upper right lobe were filled with dense inflammatory cells mainly consisting of macrophages and neutrophils. Immunoreactive bacilli by using an anti-P. aeruginosa antibody were localized within macrophages accumulated in the alveoli as well in the vessel walls. Lobar pneumonia composed of dense neutrophils and bacteria-laden macrophages with total lung congestion and edema may be characteristic for community-acquired P. aeruginosa pneumonia in a healthy adult.
    Pathology International 05/2014; 64(5). · 1.72 Impact Factor
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    ABSTRACT: Connective tissue growth factor (CTGF) has been reported to play critical roles in the tumorigenesis of several human malignancies. This study was performed to evaluate CTGF protein expression in head and neck squamous cell carcinoma (HNSCC). Surgical specimens from 76 primary HNSCC were obtained with written informed consents and the expression level of CTGF was immunohistochemically evaluated. The cytoplasmic immunoreactivity of CTGF in cancer cells was semiquantitatively classified into low and high expression. Among all 76 cases with or without neoadjuvant therapy, low CTGF showed significantly longer (P = 0.0282) overall survival (OS), but not disease-free survival (DFS) than high CTGF. Although low CTGF in patients with stage I, II and III did not result in any significant difference of the OS and DFS, stage IV HNSCC patients with low CTGF showed significantly longer OS (P = 0.032) and DFS (P = 0.0107) than those with high CTGF. These differences in stage IV cases were also confirmed using multivariate analyses. These results suggest that low CTGF in stage IV HNSCC is an independent prognostic factor, despite with or without neoadjuvant therapy.
    Human Cell 04/2014; · 1.41 Impact Factor
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    ABSTRACT: Recently, the cancer stem cell hypothesis has become widely accepted. Cancer stem cells are thought to possess the ability to undergo self-renewal and differentiation, similar to normal stem cells. Nucleostemin (NS), initially cloned from rat neural stem cells, binds to various proteins, including p53, in the nucleus and is thought to be a key molecule for stemness. NS is expressed in various types of cancers; therefore, its role in cancer pathogenesis is thought to be important. This study was conducted to clarify the clinicopathological and prognostic impact of NS in invasive breast cancers. The correlation between NS immunoreactivity and clinicopathological parameters was examined in 220 consecutive surgically resected invasive breast cancer tissue samples by using tissue microarrays. The presence of nuclear NS and p53 immunoreactivity in 10% or more of cancer cells was considered as a positive result. Among the 220 patients, 154 were hormone-receptor (HR)-positive, 22 HER2-positive/HR-negative, and 44 HR-negative/HER2-negative. One hundred and forty-two tumors (64.5%) showed NS positivity, and this positivity was significantly correlated with estrogen receptor (ER) (P = 0.050), human epidermal growth factor receptor 2 (HER2) (P = 0.021), and p53 (P = 0.031) positivity. The patients with NS-positive tumors showed significantly shorter disease-free survival than those with NS-negative tumors. Furthermore, the patient group with NS- and p53-positive tumors showed significantly poorer prognosis than other patient groups. Multivariate analysis showed that NS status was an independent prognostic indicator. NS may play a significant role in the determination of breast cancer progression in association with p53 alterations. The NS status of patients with luminal and HER2 type breast cancers may be a useful prognostic marker.
    BMC Cancer 03/2014; 14(1):215. · 3.33 Impact Factor
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    ABSTRACT: Accurate testing for human epidermal growth factor 2 (HER2)-positive status is now mandatory to identify gastric cancer patients that will respond to trastuzumab treatment. Immunohistochemistry testing is the primary method used in hospitals. We performed a study of diagnostic accuracy by assessing interobserver variability in immunohistochemistry scoring of HER2 and determined the effectiveness of an educational program for general pathologists that used full sections of gastric cancer specimens. A first ring study (Japanese gastric cancer [JGC] ring study) was performed by five expert pathologists, using 50 whole surgical sections selected by a coordinator, to confirm interobserver discrepancies. A second study (quality assurance/quality control program) involved administration of an educational program to 49 general pathologists that consisted of (i) comments and explanation for a set of pre-educational program cases, (ii) a lecture, and (iii) presentation of typical and special cases for discussion. Effectiveness was measured by comparing indices of the difference between scores before and after the program. The JGC ring study demonstrated good agreement in the interpretation of HER2-immunohistochemistry. Kappa coefficients among the five observers were 0.73 (substantial) and 0.84 (almost perfect) in 4 × 4 and 3 × 3 cross tests, respectively. In the second study, the concordance rate and kappa coefficients improved from pre-educational program levels of 78.6 % and 0.68, respectively, to post-educational program levels of 87.1 % and 0.79, respectively. The present results suggest that effective educational programs reduce interobserver differences between pathologists and provide optimal information regarding patient selection for treatment.
    Archiv für Pathologische Anatomie und Physiologie und für Klinische Medicin 03/2014; · 2.68 Impact Factor
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    ABSTRACT: Neoadjuvant chemotherapy (NAC) has been accepted as one of the standard treatments for operable breast cancer. However, the term pathologic complete response (pCR) has not been consistently defined. This study was a pooled analysis of three prospective studies of NAC conducted by JBCRG and was performed to compare the prognostic significance of different definitions of pCR. pCRs were defined as follows: QpCR, few or no remaining invasive cancer cells in the breast; CpCR, ypT0/is; CpCRbn, ypT0/isypN0; SpCR, ypT0; SpCRbn, ypT0ypN0; Grade 2b, only a few remaining cancer cells in the breast. A total of 353 patients were included. A Cox proportional hazards model revealed that hazard ratios (HRs) of each pCR were lower than 1; however, pCR was significant for disease-free survival (DFS) and overall survival (OS) only when QpCR, CpCR, and CpCRbn were used (DFS; QpCR, 0.27; CpCR, 0.39; CpCRbn, 0.42, SpCR, 0.57, SpCRbn, 0.68: OS; QpCR, 0.12; CpCR, 0.17; CpCRbn, 0.16; SpCR, 0.30, SpCRbn, 0.45). Grade 2b was also a significant prognostic variable for DFS and OS (HR: DFS, 0.19; OS, 0.15). Neither bone nor brain was the first site of recurrence in patients who achieved pCR, irrespective of the definition of pCR. Triple-negative and Her2-positive tumors tended to recur in soft tissue more frequently than the other subtypes, and luminal tumors had the lowest rate of recurrence in the brain. Prognostic significance of pCR varied according to the definition of pCR, and the pattern of recurrence might be different according to pathologic response and subtype.
    Breast Cancer 02/2014; · 1.33 Impact Factor
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    ABSTRACT: Y-box binding protein-1 (YB-1) is a member of the cold shock protein family and functions in transcription and translation. Many studies indicate that YB-1 is strongly expressed in tumor cells and is considered a marker of tumor aggressiveness and clinical prognosis. Overexpression of epidermal growth factor receptor (EGFR) has been associated with poor outcomes in cervical cancer. Clinical trials of EGFR family-base therapy are currently being initiated in cervical cancer. Nuclear YB-1 expression correlates with EGFR expression in various types of cancer. However, the clinical significance of nuclear YB-1 expression in different settings, the correlation with EGFR, and the prognostic implications of YB-1 expression in cervical cancer remain elusive. Nuclear YB-1 expression was immunohistochemically analyzed in tissue specimens obtained from 204 patients with cervical cancer who underwent surgery. Associations of nuclear YB-1 expression with clinicopathological factors such as survival, EGFR expression, and human epidermal growth factor receptor 2 (HER2) expression were investigated. Nuclear YB-1 expression was found in 41 (20.2%) of 204 cases of cervical cancer and correlated with disease stage, tumor diameter, stromal invasion, and lymph-node metastasis. Nuclear YB-1 expression also correlated with EGFR expression (P=0.0114) as well as HER2 expression (P=0.0053). Kaplan-Meier survival analysis showed that nuclear YB-1 expression was significantly associated with poor progression-free survival (P=0.0033) and overall survival (P=0.0003), respectively. Nuclear YB-1 expression is a prognostic marker and correlates with EGFR expression in cervical cancer.
    Gynecologic Oncology 01/2014; · 3.93 Impact Factor
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    ABSTRACT: Breast cancer patients often develop metastatic disease years after resection of the primary tumor. The patients are asymptomatic because the disseminated cells appear to become dormant and are undetectable. Because the proliferation of these cells is slowed, dormant cells are often unresponsive to traditional chemotherapies that exploit the rapid cell cycling of most cancer cells. We generated a bone marrow-metastatic human breast cancer cell line (BM2) by tracking and isolating fluorescent-labeled MDA-MB-231 cells that disseminated to the bone marrow in mice. Coculturing BM2 cells with bone marrow mesenchymal stem cells (BM-MSCs) isolated from human donors revealed that BM-MSCs suppressed the proliferation of BM2 cells, decreased the abundance of stem cell-like surface markers, inhibited their invasion through Matrigel Transwells, and decreased their sensitivity to docetaxel, a common chemotherapy agent. Acquisition of these dormant phenotypes in BM2 cells was also observed by culturing the cells in BM-MSC-conditioned medium or with exosomes isolated from BM-MSC cultures, which were taken up by BM2 cells. Among various microRNAs (miRNAs) increased in BM-MSC-derived exosomes compared with those from adult fibroblasts, overexpression of miR-23b in BM2 cells induced dormant phenotypes through the suppression of a target gene, MARCKS, which encodes a protein that promotes cell cycling and motility. Metastatic breast cancer cells in patient bone marrow had increased miR-23b and decreased MARCKS expression. Together, these findings suggest that exosomal transfer of miRNAs from the bone marrow may promote breast cancer cell dormancy in a metastatic niche.
    Science Signaling 01/2014; 7(332):ra63. · 7.65 Impact Factor
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    ABSTRACT: To understand the pathogenesis of high-grade neuroendocrine carcinoma (HGNEC), we examined the histopathology and immunoreactivity against adenocarcinoma (AD), squamous cell carcinoma (SQ), and neuroendocrine markers in 34 cases with combined HGNEC. The 5 year overall survival rates of patients with combined small cell carcinoma (SCC) (n = 9) and combined large cell neuroendocrine carcinoma (LCNEC) (n = 25) were 33% and 75%, respectively (P = 0.011). Most of the patients were male (94%), smokers (94%), and had tumors located in the peripheral (94%) and upper lobe (65%) of the lung. Histopathologically, non-HGNEC components were predominantly ADs (65%) followed by SQs (26%). In combined HGNEC and AD, a lepidic AD component was found in 12 cases (48%). For the HGNEC components of combined HGNEC and AD, the incidence of positivity of thyroid transcription factor-1 (TTF-1) (8G7G3/1) and TTF1 (SPT24) were 64% and 91%, respectively. For HGNEC components of combined HGNEC and SQ, the incidence of positivity of 34βE12 and p63 were 22% and 11%, respectively. In conclusion, 48% of combined HGNEC and AD cases had a lepidic AD component, suggesting that HGNEC can develop in association with pre-existing AD. AD markers, but not SQ markers, were frequently retained through development of the HGNEC component.
    Pathology International 01/2014; 64(1):28-33. · 1.72 Impact Factor
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    ABSTRACT: Lobular neoplasias (LNs) are typically small, clinically undetectable breast lesions, but some LNs are of clinical significance. The aim of this study was to clarify the histopathological characteristics of clinically overt (symptomatic) LNs and early invading LNs. Sixty-two surgically resected LNs including 8 with early invasion (≤10 mm) were classified into the following groups: (1) symptomatic and occult and (2) early invasive and non-invasive. Six histopathological factors including Ki-67 labeling index (LI) were assessed and analyzed by logistic regression models. By multivariate analyses, tumor size (p = 0.008), mitotic counts (p = 0.006), and Ki-67 (p = 0.035) were risk factors for symptomatic features, and tumor size (p = 0.009) and Ki-67 (p = 0.015) were risk factors for early invasive lesions. In 8 LNs with invasion, the symptomatic and occult subgroups showed opposite nuclear atypia and structural pattern, but both lesions extended widely (22-96 mm). Wide extension and higher proliferation activity were characteristic features of symptomatic LNs and LNs with early invasion. This article is protected by copyright. All rights reserved.
    Histopathology 12/2013; · 2.86 Impact Factor
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    ABSTRACT: Overexpression of fatty acid synthase (FASN), which is a key enzyme responsible for the endogenous synthesis of fatty acids, and its association with multistep progression have been demonstrated in various human malignant tumors. We aimed to clarify the potential role of FASN overexpression in the development and progression of adult testicular germ cell tumors (TGCTs). From the primary sites of a cohort of 113 TGCT cases, we obtained 221 histological components: 53 intratubular germ cell neoplasias, unclassified (IGCNUs), 84 seminomas, 32 embryonal carcinomas, seven choriocarcinomas, 21 yolk sac tumors, and 24 teratomas. Samples were analyzed for overexpression of FASN by immunohistochemistry. Intensities of immunoreactivity and the fraction of positive cells were classified into each four categories (intensity, 0 to 3; fraction, 0-10 % = 1, 11-50 % = 2, 51-80 % = 3, and >80 % = 4). The overall score was determined by multiplication of both scores and overall scores greater than 6 were considered FASN overexpression. On a component basis, FASN overexpression was detected in 8 % of seminomas but not in IGCNUs (0 %) and was detected frequently in non-seminomatous germ cell tumors (NSGCTs) (88 % of embryonal carcinomas, all choriocarcinomas, 81 % of yolk sac tumors, and 54 % of teratomas). There were no cases of a mixed tumor (i.e., a tumor with multiple histological components) that overexpressed FASN in seminoma components but not in co-existing NSGCT components, suggesting sequential progression. Our immunohistochemical data suggest that FASN overexpression occurs as a late event during the progression from IGCNUs/seminomas to NSGCTs.
    Archiv für Pathologische Anatomie und Physiologie und für Klinische Medicin 12/2013; · 2.68 Impact Factor
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    ABSTRACT: In the past decade, JBCRG has conducted three studies of neoadjuvant chemotherapy which have examined sequential combination of fluorouracil, epirubicin and cyclophosphamide, and docetaxel. The present study is a pooled analysis of these studies performed to determine the prognostic significance of pathologic complete response (pCR) and predictive variables for pCR. A total of 353 patients were included. pCR was defined as the absence of invasive cancer or only a few remaining isolated cancer cells in the breast (quasi-pCR, QpCR). Disease-free survival (DFS) and overall survival (OS) were not significantly different among studies, and patients who achieved a QpCR had significantly better prognosis (DFS, p < 0.001; OS, p = 0.002). Patients with triple-negative (TN) tumors had worse prognosis than patients with the other subtypes (DFS, p = 0.03; OS, p = 0.10). A Cox proportional hazards model showed node-positive, TN, and QpCR were the significant predictors for DFS and OS among study, age, tumor size, nuclear grade, nodal status, subtype, clinical response, and pathologic response (DFS; node-positive, HR = 2.29, p = 0.001; TN, HR = 3.39, p < 0.001; QpCR, HR = 0.27, p < 0.001: OS; node-positive, HR = 3.05, p = 0.003; TN, HR = 4.92, p < 0.001; QpCR, HR = 0.12, p < 0.001). In a logistic regression analysis, subtype and clinical response before surgery were the significant predictive variables for QpCR (luminal/Her2-positive, odds ratio (OR) = 4.15, p = 0.002; Her2-positive, OR = 6.24, p < 0.001; TN, OR = 4.24, p < 0.001; clinical response before surgery, OR = 2.41, p = 0.019). This study confirmed the prognostic significance of QpCR and nodal status and the predictive and prognostic significance of subtype in neoadjuvant chemotherapy.
    Breast Cancer 12/2013; · 1.33 Impact Factor
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    ABSTRACT: Objective: To explore the possibility of nonsurgical treatment of primary breast cancers by a sequential treatment of chemotherapy and radiotherapy. Methods: We conducted a safety and efficacy trial of chemotherapy and radiation therapy sequentially as primary therapy in patients with stage I-IIIA breast cancer. All patients underwent mastectomy or lumpectomy 12-16 weeks after the completion of radiation therapy to maximize the effect of radiation therapy. The primary endpoint was the pathological complete response (pCR) rate. Results: Between June 2004 and April 2005, one hundred eight patients were enrolled. Thirty six percent of the entire population achieved a pCR, which could not reject the null hypothesis. The pCR rate was 57% in patients with hormone receptor (HR)-negative/HER-2-positive tumors and 52% in patients with triple-negative tumors. While 7% of the HR-negative/HER2-positive patients recurred, a higher incidence of recurrence (24%) was observed in triple-negative tumors in a follow-up of 4.5 years. The rate of breast-conserving surgery was 88.9% (96/108). Conclusion: The pCR rate was not high enough, even though preoperative sequential chemoradiation therapy did not increase the risk of operative complications and could achieve a high rate of breast-conserving surgery. © 2013 S. Karger AG, Basel.
    Oncology 11/2013; 85(6):336-341. · 2.17 Impact Factor
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    ABSTRACT: Brain metastases usually present late during the course of breast cancer and are associated with an unfavorable prognosis. It was previously demonstrated that the status of estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor type 2 (HER2) may be altered in the time window between the emergence of the primary breast tumor and the development of metastases. The aim of this study was to compare the expression of ER, PR and HER2 in pathology samples of primary breast cancer and brain metastases in order to evaluate whether previously administered therapy was able to modify this status and determine whether biomarker alterations affect prognosis after the development of brain metastases. Data were collected from 62 patients who were initially diagnosed with breast cancer that had metastasized to the brain. The ER, PR and HER2 status of the samples from the primary tumors and the brain metastases was determined. Differences in the immunohistochemical profiles of ER, PR or HER2 between the primary tumors and the brain metastases in 17 patients (29.3%) were identified. The patients with HER2-positive brain metastases who received trastuzumab had no leptomeningeal metastases and exhibited a longer survival time after brain metastases compared to the HER2-positive patients who did not receive trastuzumab and the patients with HER2-negative brain metastases (P=0.0005). Our results suggested that the patients treated with trastuzumab following surgery and radiotherapy for brain metastases exhibited a better prognosis. Thus, the HER2 status in brain metastases requires re-evaluation and extended trastuzumab therapy is recommended after brain metastases.
    Molecular and clinical oncology. 11/2013; 1(6):995-1001.
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    ABSTRACT: Head and neck squamous cell carcinoma (HNSCC) includes both morphological and functional cellular heterogeneity, as would be expected if it arose from dysregulated stem or progenitor cells as opposed to the simple clonal expansion of a mutated cell; however, stemness molecule expression levels and distribution in HNSCC remain unclear. To clarify this, stemness molecule expressions were determined in HNSCC, as well as their properties and prognosis. Two proto-oncogenic chromatin regulators, Bmi-1 and high-mobility-group A2 (Hmga2), were identified in 12 pair cases of HNSCC tumor regions by comparison with their non-cancerous background tissues using cDNA microarray. Both Bmi-1 and Hmga2 are known to promote stem cell self-renewal by negatively regulating the expressions of Ink4a and Arf tumor suppressors. Despite similar targets, Bmi-1 protein was expressed in an early cancerous region and HMGA2 protein was expressed in a region showing more progression. Similarly, Bmi1 expression had no significance with regard to overall survival (P=0.67), whereas HMGA2 expression was associated with decreased overall survival (P=0.05). Quantitative real-time reverse transcription polymerase chain reaction analyses also correlated with protein levels. These findings suggest that Bmi-1 is an early detection marker to distinguish cancerous from non-cancerous regions, whereas HMGA2 is presumed to be a tumor prognosis marker. Among our HNSCC analyses, these stemness molecules expressed fewer primitive rare cells in the tumor than all other cells in the tumor. HNSCC cells with high expression of stemness molecules partly behave like stem cells.Laboratory Investigation advance online publication, 21 October 2013; doi:10.1038/labinvest.2013.120.
    Laboratory Investigation 10/2013; · 3.96 Impact Factor

Publication Stats

11k Citations
1,971.33 Total Impact Points


  • 2001–2014
    • National Defense Medical College
      • • Department of Surgery
      • • Division of Obstetrics and Gynecology
      • • Division of Pathology
      Tokorozawa, Saitama, Japan
    • University at Buffalo, The State University of New York
      Buffalo, New York, United States
  • 1994–2014
    • National Hospital Organization Kyushu Cancer Center
      Hukuoka, Fukuoka, Japan
  • 2013
    • Juntendo University
      Edo, Tōkyō, Japan
    • Tokai University
      • Department of Oral Surgery
      Hiratuka, Kanagawa, Japan
    • Okayama University
      • Department of Breast and Endocrine Surgery
      Okayama, Okayama, Japan
  • 1987–2013
    • National Cancer Center
      • • Center for Cancer Control and Information Services
      • • Endoscopy Division
      Edo, Tōkyō, Japan
  • 2012
    • Hokkaido University
      • Department of General Surgery
      Sapporo-shi, Hokkaido, Japan
    • Aichi Cancer Center
      Ōsaka, Ōsaka, Japan
  • 2010–2012
    • Keio University
      • Department of Obstetrics and Gynecology
      Tokyo, Tokyo-to, Japan
    • The University of Tokyo
      • Department of Internal Medicine
      Tokyo, Tokyo-to, Japan
  • 2006–2012
    • Saitama Medical University
      • • Research Center for Genomic Medicine
      • • Department of Obstetrics and Gynecology
      Saitama, Saitama-ken, Japan
    • Japan Research Institute
    • Showa University
      • Department of Surgery
      Shinagawa, Tōkyō, Japan
  • 2001–2012
    • Tokyo Medical and Dental University
      • • Department of Molecular Cytogenetics
      • • Department of Oral Restitution
      Edo, Tōkyō, Japan
  • 2000–2012
    • Osaka City University
      Ōsaka, Ōsaka, Japan
    • National Research Institute for Child Health and Development, Tokyo
      Edo, Tōkyō, Japan
    • Korea Institute of Toxicology
      Sŏul, Seoul, South Korea
  • 2010–2011
    • Tokorozawa Central Hospital
      Tokorozawa, Saitama, Japan
  • 2006–2011
    • Osaka City General Hospital
      Ōsaka, Ōsaka, Japan
  • 2009
    • Aichi Medical University
      • Division of Surgery
      Masaki-chō, Ehime, Japan
  • 2008
    • Saitama Cancer Center
      Saitama, Saitama, Japan
  • 2007–2008
    • Kurume University
      • Department of Obstetrics and Gynecology
      Куруме, Fukuoka, Japan
    • Osaka National Hospital
      Ōsaka, Ōsaka, Japan
  • 2006–2007
    • Japan Science and Technology Agency (JST)
      Edo, Tōkyō, Japan
  • 2005
    • Tokyo Metropolitan Komagome Hospital
      Edo, Tōkyō, Japan
  • 2004
    • Dana-Farber Cancer Institute
      • Breast Cancer Treatment Center
      Boston, MA, United States
  • 1996–1999
    • National Cancer Research Institute
      Londinium, England, United Kingdom
  • 1997
    • Clinical Research Hospital, Tokyo
      Edo, Tōkyō, Japan
  • 1993
    • Japan Tobacco Inc.
      Edo, Tōkyō, Japan
  • 1976–1992
    • Nagoya City University
      • • Department of Pathology
      • • Medical School
      Nagoya, Aichi, Japan
  • 1990
    • São Paulo State University
      • Departamento de Patologia
      São Paulo, Estado de Sao Paulo, Brazil
  • 1988–1989
    • National Cancer Institute (USA)
      • Cancer Etiology Branch (CEB)
      Maryland, United States
    • Osaka University
      • School of Medicine
      Suika, Ōsaka, Japan
  • 1986
    • Hirosaki University
      Khirosaki, Aomori Prefecture, Japan