Publications by authors named "Shinobu Umemura"

43 Publications

Breast conserving surgery for male noninvasive intracystic papillary carcinoma: a case report.

Tokai J Exp Clin Med 2010 Apr 20;35(1):13-6. Epub 2010 Apr 20.

Department of Surgery, Sougo Oota Hospital, 29-5 Hachimancho, Oota, Gunma 378-0028, Japan.

We report an exceedingly rare case of male breast cancer on two brothers. The patient has family history that his younger brother had breast cancer 5 years ago. The patient was 70-years old man who presented with chief complaint of an indolent tumor mass of the left breast. Mammography demonstrated a well defined mass with microcalcifications. Noninvasive intracystic papillary carcinoma was diagnosed by excisional biopsy. We performed breast conserving surgery (BCS) with sentinel lymph node biopsy for this patient. The histological diagnosis was same as above, with no metastasis of sentinel lymph node. Immunohistochemical study showed estrogen receptor (ER) and progesterone receptor (PgR) were positive respectively, and human epidermal growth factor receptor type 2 (HER2/c-erbB-2) was negative. After surgery, he underwent radiation therapy of 60 Gy for left chest wall include nipple and areolar area. We report the case of BCS for male breast cancer. The preservation of the nipple areolar complex in male patients may also have a positive psychological impact as is the case in women treated for breast cancer. Our patients report an outstanding cosmetic result. As for the man, breast conserving therapy should be enforced without overt nipple and areolar involvement like a woman.
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April 2010

Alteration of immunohistochemical biomarkers between pre- and post-chemotherapy: hormone receptors, HER2 and Ki-67.

Breast Cancer 2011 Apr 3;18(2):98-102. Epub 2011 Feb 3.

Department of Pathology, Tokai University School of Medicine, 143 Shimokasuya, Isehara, Kanagawa, Japan.

The immunohistochemical (IHC) biomarkers of breast cancer, especially hormone receptors and HER2, are very important because the pharmacological therapeutic strategy is generally decided by biomarker expression patterns. Biomarkers are examined on pre-chemotherapeutic biopsy materials from patients in whom neoadjuvant chemotherapy is planned. Statistically significant changes between pre- and post-chemotherapeutic markers have been reported; however, the alterations in biomarkers are poorly understood. Fluctuation of the Ki-67 labeling index (LI) between pre- and post-neoadjuvant therapy is associated with chemotherapeutic effects and with the prognosis of patients. It has been shown that IHC evaluation of Ki-67 LI is useful as a predictive and a prognostic factor. There are issues to be considered surrounding the use of the IHC Ki-67 LI in routine practice, including the standardization of staining procedures and a cutoff point for Ki-67 LI detection. The current understanding of IHC evaluation of biomarkers for breast cancer under neoadjuvant chemotherapy is reviewed based on the literature.
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http://dx.doi.org/10.1007/s12282-010-0238-1DOI Listing
April 2011

A case report of pigmented mammary Paget's disease mimicking nevus of the nipple.

Breast Cancer 2014 May 7;21(3):370-4. Epub 2011 Jan 7.

Department of Pathology, Tokai University School of Medicine, 143 Shimokasuya, Isehara, Kanagawa, 259-1193, Japan,

A 43-year-old Japanese woman consulted our hospital for a pigmented lesion on her right nipple. Two years later, the lesion became enlarged, measuring 5 × 5 mm. It was dark brown, had an irregular shape and relatively clear borders. Incisional biopsy yielded a pathological diagnosis of junctional nevus of the skin. An additional 2 years later, a small mass developed under the right nipple area and core needle biopsy yielded a pathologic diagnosis of invasive ductal carcinoma. Partial resection of the right EC areas included the skin of the nipple and sentinel lymph node biopsy was performed. Histologically, the skin of the nipple demonstrated small clusters of pigmented carcinoma cells that were low molecular weight cytokeratin (CAM5.2) positive. Most of the carcinoma cells were small and did not have abundant cytoplasm, but nuclear enlargement and prominent nucleoli indicated malignancy, and the cytoplasm was pale compared with that of the surrounding squamous epithelial cells. Scattered dendritic melanocytes were identified by S-100 protein and HMB-45 immunohistochemically. In the upper dermis, carcinoma cells also involved the lactiferous ducts. A small focus of carcinoma cells that invaded the fat tissues did not contain melanin pigment. The final diagnosis was pigmented mammary Paget's disease. Pigmented lesions on the nipple should be carefully examined, because pigmented mammary Paget's disease sometimes mimics malignant melanoma or junctional nevus.
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http://dx.doi.org/10.1007/s12282-010-0249-yDOI Listing
May 2014

Fine needle aspiration cytology of ductal adenoma of the breast with intracellular mucin: a report of three cases.

Acta Cytol 2010 Sep-Oct;54(5 Suppl):753-8

Division of Diagnostic Pathology, Tokai University Hospital, Shimokasuya 143, Isehara City, Kanagawa 259-1193, Japan.

Background: Ductal adenoma of the breast is a benign lesion that can mimic both the clinical and cytopathologic features of carcinoma. Benign breast lesions with intracellular mucin are extremely rare, and ductal adenoma with intracellular mucin has not previously been reported. Here we present three cases of ductal adenoma of the breast with foci of intracellular mucin.

Cases: Three patients were admitted to Tokai University School of Medicine Hospital and underwent fine needle aspiration cytology and histologic examination by excisional biopsy or partial resection. Fine needle aspiration cytology was performed using a 23-gauge needle, and smears were immediately fixed in ethanol and stained as Papanicolaou preparations. Epithelial cells formed cohesive clusters, consisting of biphasic luminal and myoepithelial cells accompanied by apocrine metaplasia with occasional high nuclear atypia. All three cases showed intracellular mucin, in varying amounts, which led to their being overdiagnosed as malignant lesions.

Conclusion: To avoid overdiagnosis of ductal adenomas as malignant lesions, it is important to recognize that both intracytoplasmic mucin and atypical apocrine features can be usual cytologic findings of this disease.
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December 2010

HER2 testing on core needle biopsy specimens from primary breast cancers: interobserver reproducibility and concordance with surgically resected specimens.

BMC Cancer 2010 Oct 7;10:534. Epub 2010 Oct 7.

Diagnostic Pathology Section, Clinical Laboratory Division, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan.

Background: Accurate evaluation of human epidermal growth factor receptor type-2 (HER2) status based on core needle biopsy (CNB) specimens is mandatory for identification of patients with primary breast cancer who will benefit from primary systemic therapy with trastuzumab. The aim of the present study was to validate the application of HER2 testing with CNB specimens from primary breast cancers in terms of interobserver reproducibility and comparison with surgically resected specimens.

Methods: A total of 100 pairs of archival formalin-fixed paraffin-embedded CNB and surgically resected specimens of invasive breast carcinomas were cut into sections. All 100 paired sections were subjected to HER2 testing by immunohistochemistry (IHC) and 27 paired sections were subjected to that by fluorescence in situ hybridization (FISH), the results being evaluated by three and two observers, respectively. Interobserver agreement levels in terms of judgment and the concordance of consensus scores between CNB samples and the corresponding surgically resected specimens were estimated as the percentage agreement and κ statistic.

Results: In CNB specimens, the percentage interobserver agreement of HER2 scoring by IHC was 76% (κ = 0.71) for 3 × 3 categories (0-1+ versus 2+ versus 3+) and 90% (κ = 0.80) for 2 × 2 categories (0-2+ versus 3+). These levels were close to the corresponding ones for the surgically resected specimens: 80% (κ = 0.77) for 3 × 3 categories and 92% (κ = 0.88) for 2 × 2 categories. Concordance of consensus for HER2 scores determined by IHC between CNB and the corresponding surgical specimens was 87% (κ = 0.77) for 3 × 3 categories, and 94% (κ = 0.83) for 2 × 2 categories. Among the 13 tumors showing discordance in the mean IHC scores between the CNB and surgical specimens, the results of consensus for FISH results were concordant in 11. The rate of successful FISH analysis and the FISH positivity rate in cases with a HER2 IHC score of 2+ differed among specimens processed at different institutions.

Conclusion: It is mandatory to study HER2 on breast cancers, and either CNB or surgical specimen can be used.
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http://dx.doi.org/10.1186/1471-2407-10-534DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2958945PMC
October 2010

Somatostatin analogue inhibits the mobility of prostate carcinoma cells: a new therapeutic method for advanced prostate carcinoma.

Int J Oncol 2010 Nov;37(5):1077-83

Department of Pathology, Tokai University School of Medicine, Isehara, Kanagawa 259-1193, Japan.

The somatostatin analogue (SA) Octreotide has been used as a therapeutic reagent for somatostatin receptor type 2a (SSTR2a)-positive cancers. The purpose of this study is to detect SSTR2a in human prostate carcinomas and to elucidate the effects of SA on SSTR2a-positive prostate carcinoma cells to determine the potential of this drug as a new therapeutic method for advanced prostate carcinoma. Immunohistochemical study of SSTR2a was performed on 95 prostate carcinoma cases, and the results showed expression of SSTR2a in 14 of the 95 cases (14.74%); the histological grade (Gleason) and capsular invasion of the prostate carcinoma were directly related to SSTR2a expression. Among the ten cases of lymph node metastasis, SSTR2a expression was markedly higher. In vitro studies were performed using SSTR2a-positive prostate cancer cells, DU145 and PC3. Migration and invasion abilities of DU145 and PC3 cells were inhibited by SA in a dose-dependent manner. This inhibition was reversed by Rho-kinase inhibitor Y-27632. Morphological changes of the prostate cancer cells treated with SA and Y27632 corroborate the migration and invasion assays, although SA had no effect on proliferation of DU145 and PC3 cells. In conclusion, the somatostatin analogue may be beneficial for patients with advanced prostate carcinoma or to protect from distal metastasis if they are positive for SSTR2a.
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http://dx.doi.org/10.3892/ijo_00000759DOI Listing
November 2010

Recommendations for 'adequate evaluation of hormone receptors' a report of the task force of the Japanese Breast Cancer Society.

Oncol Rep 2010 Aug;24(2):299-304

Department of Pathology, Tokai University School of Medicine, Isehara 259-1193, Japan.

The task force of the Japanese Breast Cancer Society was assembled to examine variable factors related to the immunohistochemical evaluation of hormone receptors in breast cancer, and to provide recommendations for adequate handling of specimens and accurate evaluations for hormone receptors. The various factors examined were: i) the adequate handling of breast cancer tissue for IHC, ii) the concordant rate between EIA and IHC assays using 5 different staining methods, iii) the inter-observer diversity for evaluation, and iv) the threshold for the predictive value of endocrine therapy of primary and recurrent/metastatic breast cancers. The conducted studies found that a 10% threshold was stable and reliable in spite of different validations including the concordance between IHC and EIA assays, inter-observer diversity and disease-free survival rates for patients who received tamoxifen for primary breast cancers. It was also found that 1% of threshold was useful in limited situations including the predictive value of endocrine therapy for recurrent/metastatic breast cancers. Based on these results for technical, pathological and clinical validation studies, a recommendation was proposed. Herein, we summarize the evidence, on which the recommendations were made, and customize the recommendations suitable for the current status.
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http://dx.doi.org/10.3892/or_00000859DOI Listing
August 2010

Evaluation of HER2 gene amplification in invasive breast cancer using a dual-color chromogenic in situ hybridization (dual CISH).

Pathol Int 2010 Jul;60(7):510-5

Division of Diagnostic Pathology, Tokai University Hospital, 143 Shimokasuya, Isehara, Kanagawa, Japan.

Fluorescence in situ hybridization (FISH) assay is considered the 'gold standard' for evaluation of HER2/neu (HER2) gene status, however, it is difficult to recognize morphologic features of tumors using fluorescence microscopy. Thus, chromogenic in situ hybridization (CISH) has been proposed as an alternative method to evaluate HER2 gene amplification. Here, we examined the dual color CISH (dual CISH) method which provides information regarding the copy number of the HER2 gene and chromosome 17 centromere from a single slide. We examined 40 cases of invasive ductal carcinomas of the breast that were resected surgically. HER2 gene status was assessed with FISH (Abbott) and dual CISH (Dako). HER2 gene amplification status was classified according to the guidelines of the American Society of Clinical Oncology and College of American Pathologists (ASCO/CAP). Comparison of the cut-off values for HER2/chromosome 17 centromere copy number ratio obtained by dual CISH and FISH showed that there was almost perfect agreement between two methods (Kappa coefficient 0.96). The results of the two commercial products were almost consistent for evaluation of HER2 gene counts on the sections. The current study proved that dual CISH is comparable with FISH for evaluating HER2 gene status.
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http://dx.doi.org/10.1111/j.1440-1827.2010.02553.xDOI Listing
July 2010

High expression of thymidine phosphorylase in basal-like breast cancers: Stromal expression in EGFR- and/or CK5/6-positive breast cancers.

Oncol Lett 2010 Mar 1;1(2):261-266. Epub 2010 Mar 1.

Department of Pathology, Tokai University School of Medicine, Kanagawa 259-1193.

Expression of the estrogen receptor (ER), the progesterone receptor (PgR) or the human epidermal growth factor receptor-2 (HER2) in tumors is a good prognostic marker for breast cancer patients. However, approximately 15-20% of breast cancer patients have triple-negative breast cancer (TNBC; negative for ER, PgR and HER2), and efficient therapeutic modalities for these patients are under investigation. We focused on thymidine phosphorylase (TP), an enzyme metabolizing 5'-DFUR, an intermediate of capecitabine, to 5-fluorouracil in order to investigate the application of well-known therapeutics for TNBC. Results of a gene expression analysis showed that TP expression in TNBC and basal-like breast cancer (BLBC) was higher than that of other subtypes. Immunohistochemically, the high expression of TP in TNBC and BLBC reflected expression in stromal but not tumor cells. Notably, a high TP expression was observed in the stromal cells of EGFR- and/or CK5/6-positive breast tumors. Our present results showing a high expression of TP in BLBC indicate that capecitabine-based chemotherapy would be of benefit for patients with TNBC.
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http://dx.doi.org/10.3892/ol_00000046DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3436479PMC
March 2010

The role of trastuzumab in the management of HER2-positive metastatic breast cancer: an updated review.

Breast Cancer 2009 17;16(4):295-300. Epub 2009 Jul 17.

Department of Breast and Endocrine Surgery, Tokai University School of Medicine, 143 Shimokasuya, Isehara, Kanagawa 259-1193, Japan.

Currently, trastuzumab is one of the key drugs in the treatment strategy for HER2-positive breast cancer. Although metastatic breast cancer is unlikely to be cured, some HER2-positive patients have survived for a long time with complete response to trastuzumab therapy. In HER2-positive metastatic breast cancer, single agent trastuzumab is effective and less toxic. Combination of trastuzumab with cytotoxic drugs is also effective. Therefore, major guidelines recommend using trastuzumab as a key drug in the management of HER2-positive metastatic breast cancer. However, many clinical questions still need to be solved. In this article, recent evidence was reviewed to find some answers about these issues.
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http://dx.doi.org/10.1007/s12282-009-0142-8DOI Listing
December 2009

Overexpression of fatty acid binding protein-7 correlates with basal-like subtype of breast cancer.

Pathol Res Pract 2010 Feb 15;206(2):98-101. Epub 2009 Jul 15.

Department of Pathology, Tokai University School of Medicine, 143 Shimokasuya, Isehara-City, Kanagawa 259-1193, Japan.

Fatty acid binding protein-7 (FABP-7) is normally expressed in the mammary gland. The aim of this study was to clarify the phenotype of breast cancers with respect to the overexpression of FABP-7. Reverse transcription PCR (RT-PCR) analysis was carried out on 16 cases, including 4 ER(+)/HER2(-), 2 ER(+)/HER2(+), 3 ER(-)/HER2(+), and 5 ER(-)/HER2(-) samples, and 2 non-neoplastic mammary glands as control tissue. Breast cancers categorized as ER(-)/HER2(-) revealed a high cDNA level of FABP-7 as compared to other groups of breast cancer (p=0.004). An immunohistochemical study carried out on 88 cases showed that FABP-7 overexpression had a strong relationship with triple-negative cases (45.8%, p=0.001) and the basal-like subtype (37.5%, p=0.001). Estrogen receptor (ER) and progesterone receptor (PgR) expressions had reverse correlation with FABP-7 overexpression (p=0.003, p<0.0001), but no significant associations can be identified between human epidermal growth factor receptor-2 (HER2) and FABP-7 (p=0.219). In conclusion, this study is the first to demonstrate overexpression of FABP-7 in triple-negative breast cancers [ER(-), PgR(-)/HER2(-)], especially in basal-like breast cancer, and to give a probable interpretation of the high histological grade and poor prognosis of basal-like breast cancer.
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http://dx.doi.org/10.1016/j.prp.2009.06.010DOI Listing
February 2010

A new reporting form for breast cytology.

Breast Cancer 2009 30;16(3):202-6. Epub 2009 May 30.

Cytology and Core Needle Biopsy Subcommittee of the Japanese Breast Cancer Society, Tokyo, Japan.

The Cytology and Core Needle Biopsy Subcommittee, organized under the Rules Committee of the Japanese Breast Cancer Society, has prepared a new form for breast cytology reports. This reporting form consists of "diagnostic categories" and "recommendations." The "diagnostic category" is either "specimen inadequacy" or "specimen adequacy." The judgment on "specimen adequacy" is subdivided into four categories: "normal or benign," "indeterminate," "suspicious for malignancy," and "malignant." The "recommendation" indicates descriptions of cytological features and estimated histological type of tumor (these descriptions should be as detailed as possible). On the basis of an analysis of cytological data from 3,439 cases performed before preparing this form, the subcommittee has attached the following recommended goals to this form: (1) the percentage of "specimen inadequacy" should be 10% or less of all samples, (2) the percentage of "indeterminate" samples should be 10% or less of all "specimen adequacy" cases, and (3) 90% or more of "suspicious for malignancy" cases should be diagnosed as "malignant" in a subsequent histological examination. We hope that modification of this form, if it requires revision in the future, will be evidence-based, as was the process for compiling this set of rules.
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http://dx.doi.org/10.1007/s12282-009-0128-6DOI Listing
October 2009

Ten cases of sebaceous carcinoma arising in nevus sebaceus.

J Dermatol 2008 Nov;35(11):704-11

Department of Diagnostic Pathology, Tokyo Medical University, Tokyo, Japan.

Although nevus sebaceus is known to develop various types of secondary neoplasms, it rarely causes carcinoma and only 14 cases of secondary sebaceous carcinoma have been reported. In this study, 10 cases of sebaceous carcinoma arising in nevus sebaceus were collected. The clinicopathological features and results of immunohistochemical examinations with adipophilin, perilipin and p53 were summarized. Sebaceous carcinoma arising in nevus sebaceous predominantly occurred on the scalp (8/10) of elderly women (mean age, 67.7 years). No case was associated with Muir-Torre syndrome. We found several pathological features of sebaceous carcinoma; that is, made up mainly of germinative cells, moderate nuclear atypia without pleomorphism and many mitoses (4-28/10 high-power field). Adipophilin and perilipin antibodies highlighted lipid drops in the cytoplasm of the malignant cells in all cases. Overexpression of p53 was seen in all cases. In two cases there were coexisting benign-looking sebaceous lesions at the periphery of the main cancer nodule, and in these lesions p53 showed low positivity compared with the clearly malignant area. There was co-occurrence of another neoplasm in three cases with trichoblastoma, sebaceoma and syringocystadenoma papilliferum, respectively. All cases were treated by excision of the malignant lesion, with or without inclusion of the nevus sebaceus. In a follow-up period of 1-7 years, there was no case of recurrence, lymph node metastases or distant metastases. With these specific pathological and immunohistochemical findings using adipophilin, perilipin and p53, we have to consider the possibility that there is a tendency to underdiagnose secondary sebaceous carcinomas in nevus sebaceus. These clinicopathological features of sebaceous carcinomas developing in the nevus sebaceus seem to indicate different biological entities from de novo sebaceous carcinoma.
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http://dx.doi.org/10.1111/j.1346-8138.2008.00550.xDOI Listing
November 2008

What causes discrepancies in HER2 testing for breast cancer? A Japanese ring study in conjunction with the global standard.

Am J Clin Pathol 2008 Dec;130(6):883-91

Department of Pathology, Tokai University School of Medicine, Isehara, Japan.

We assessed interinstitutional and interobserver consistency of human epidermal growth factor receptor type-2 (HER2) testing using immunohistochemical analysis and fluorescence in situ hybridization (FISH) in a set of 20 breast cancer samples among 10 institutions in Japan and a Herceptin adjuvant study participating laboratory in Germany and identified factors that may lead to discordant results.We found a good agreement in immunohistochemical HER2 scoring between the coordinating institution and 10 participating laboratories (kappa = 0.718) and excellent agreement for FISH (kappa = 0.900). The results of a comparison between 10 Japanese laboratories and the German laboratory was good for immunohistochemical studies (kappa = 0.713) and excellent for FISH (kappa = 0.887). FISH retesting of equivocal samples (2+ immunohistochemically) improved agreement. Discrepancies between results were attributed to the evaluation process in 33.0% of the samples, staining procedures in 25.0%, and a combination of the two in 41.7%. Evaluation of samples according to the American Society of Clinical Oncology/College of American Pathologists guideline increased the number of 2+ immunohistochemical scores. By performing FISH retesting for these samples, consistency among multiple institutions could be archived. The quality of the staining procedures performed and the consistency of evaluations require regular assessment.
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http://dx.doi.org/10.1309/AJCP5UUMFMA5ZKIIDOI Listing
December 2008

Metastin inhibits migration and invasion of renal cell carcinoma with overexpression of metastin receptor.

Eur Urol 2009 Feb 11;55(2):441-9. Epub 2008 Mar 11.

Department of Urology, Tokai University School of Medicine, Isehara city, Kanagawa, Japan.

Background: Metastin, the final peptide of the KiSS-1 gene, has been proposed to suppress cell motility.

Objective: This study investigated whether renal cell carcinoma (RCC) tissue expresses metastin or its receptor, and clarified whether metastin can suppress migration and/or invasion and/or proliferation of RCC cells in vitro.

Design, Setting, And Participants: Twenty-five RCC samples were submitted. Fresh RCC tissues were prepared for real-time RT-PCR, and formalin-fixed and paraffin-embedded tissues blocks were examined by immunohistochemistry. RCC cell lines Caki-1 and ACHN were supplied for cell migration, invasion, and proliferation assays.

Measurements: Real-time RT-PCR was performed by using Taq Man gene expression system. ENVISION system was used in immunohistochemistry. Wound-healing assay and matrigel assays were used to identify migration and invasion abilities of RCC cell lines. Cell Counting Kit-8 was applied to measure the cell proliferation. Cell morphology was examined under a META system. Statistical analysis was performed with SPSS15.0J.

Results And Limitations: In twenty-five RCC samples, the mRNA level of metastin receptor was identified to be significantly higher than non-neoplastic renal cortex by real-time RT-PCR (p=0.011). Immunohistochemical study also detected metastin receptor protein in all RCC tumors. In vitro, this study showed that metastin inhibited migration and invasion of Caki-1 and ACHN cells. In contrast, it had no effects on cell proliferation. Metastin (10 micromol/l) induced excessive formation of focal adhesions and stress fibers in Caki-1 and ACHN cells; this phenomenon was inhibited by pretreating pharmacological Rho-kinase inhibitor (Y-27632) to those cells.

Conclusion: This is the first report regarding overexpression of the metastin receptor hOT7T175 in human RCC. We demonstrate that metastin can inhibit migration and invasion of the RCC cell line, which is regulated by a Rho-kinase inhibitor. Metastin and its receptor are therefore probable targets for suppressing RCC.
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http://dx.doi.org/10.1016/j.eururo.2008.02.048DOI Listing
February 2009

Cytological features of the cystic fluid of pancreatic schwannoma with cystic degeneration. A case report.

JOP 2008 Mar 8;9(2):203-8. Epub 2008 Mar 8.

Department of Pathology, Tokai University School of Medicine. Kanagawa, Japan.

Context: Schwannomas are benign neoplasms arising from peripheral nerve tissue. Pancreatic schwannoma is a very rare condition. We present the histological and cytological features of a pancreatic schwannoma with cystic degeneration.

Case Report: A 51-year-old male was diagnosed with a cystic tumor measuring approximately 6 cm in the tail of the pancreas. Distal pancreatectomy and splenectomy were performed. Cystic fluid from the tumor was obtained intraoperatively by fine-needle aspiration, and it showed scattered spindle tumor cells against a background of hemosiderin-laden histiocytes. During the operation, we informed the surgeon that the tumor consisted of "atypical spindle cells". Histologically, the tumor was diagnosed as a schwannoma with cystic degeneration which had originated in the pancreas. The diagnosis was confirmed by positive immunostaining of the tumor cells in both histological and cytological materials for S-100 protein.

Conclusion: Problems occasionally arise with the use of fine-needle aspiration in the diagnosis of cystic diseases of the pancreas because of the difficulty in obtaining adequate specimens. Nevertheless, it should be emphasized that intraoperative fine-needle aspiration is as informative as a frozen section diagnosis, when appropriately performed.
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March 2008

Lower HER-2/chromosome enumeration probe 17 ratio in cytologic HER-2 fluorescence in situ hybridization for breast cancers: three-dimensional analysis of intranuclear localization of centromere 17 and HER-2 signals.

Cancer 2008 Apr;114(2):134-40

Division of Diagnostic Pathology, Department of Pathology, Tokai, University School of Medicine, Kanagawa, Japan.

Background: Fluorescence in situ hybridization (FISH) is the gold standard for assessing HER-2 status for breast cancers, and paraffin-embedded tissue sections are used routinely for HER-2 FISH. Cytologic samples also are used, but to the authors' knowledge, little is known regarding the reliability of these samples. The objective of this study was to elucidate the usefulness of cytologic specimens for HER-2 FISH testing.

Methods: Histologic and cytologic specimens from 32 patients with invasive ductal carcinoma of the breast were subjected to comparative analysis of HER-2 status by FISH. FISH was performed by using a PathVysion HER-2 DNA Probe Kit according the manufacturer's instructions. The signal ratios of chromosome enumeration probe 17 (CEP17) and HER-2 were estimated and compared. In 15 cytologic specimens, the distance between signals (HER-2 and CEP17) and the nearest nuclear membrane were measured by using 3-dimensional image analysis and confocal microscopy.

Results: Cytologic and histologic FISH results were compared. Signal ratios of HER-2/CEP17 were lower in cytologic specimens from 26 of 32 patients compared with the histologic material. Three-dimensional image analysis demonstrated that the distance between the CEP17 signal and the nuclear membrane was shorter than the distance between the HER-2 gene and the nuclear membrane.

Conclusions: The current results demonstrated that CEP17 could be lost more easily through histologic sectioning compared with the cytology results, because CEP17 is closer to the nuclear membrane. FISH analysis in cytologic specimens produced more accurate HER-2/CEP17 ratios, because the whole nucleus was subjected to FISH testing, compared with matched histologic specimens.
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http://dx.doi.org/10.1002/cncr.23367DOI Listing
April 2008

Immunohistochemical analysis of neuroendocrine (NE) differentiation in testicular germ cell tumors (GCTs): use of confocal laser scanning microscopy (CLSM) to demonstrate direct NE differentiation from GCTs.

Acta Histochem Cytochem 2007 Dec;40(6):143-51

Department of Pathology, Tokai University School of Medicine, Shimokasuya 143, Isehara, Kanagawa 259-1193, Japan.

Neuroendocrine (NE) differentiation is infrequent in testicular tumors and its histogenesis is not well understood. The present study is aimed at elucidating the pathway of neuroendocrine differentiation in germ cell tumors (GCTs) of the testis. In the analysis of 46 germ cell tumor components from 23 testicular tumors, we focused on GCTs with neuroendocrine differentiation, 7 teratoma, 1 embryonal carcinoma and 1 neuroendocrine carcinoma by immunohistochemical study and confocal laser scanning microscopy (CLSM) analysis. NE marker positive cells were noted in the tumor with collision of teratoma and embryonal carcinoma (E&T tumor), in the immature columnar cells of transitional form of embryonal carcinoma to teratoma (E-T cells) and neuroendocrine carcinoma cells, in addition to the well known mature intestinal mucosa in teratoma. Double staining for a NE marker (CGA) and a germ cell marker (PLAP) demonstrated the localization of both proteins in the same E-T cells confirmed by CLSM. Another finding, indicating the intimate relation between embryonal carcinoma and neuroendocrine differentiation, is that neuroendocrine carcinoma expressed a marker of embryonal carcinoma, CD30. The present results indicated that the NE cells might be differentiated from embryonal carcinoma, a view that has not been proposed before, but that is made in the present study using CLSM.
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http://dx.doi.org/10.1267/ahc.07025DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2156079PMC
December 2007

Assessment of a new anti-HER2 monoclonal antibody, SV2-61gamma: a best concordance with HER2 FISH.

Appl Immunohistochem Mol Morphol 2007 Dec;15(4):389-93

Research and Development Center, Nichirei Biosciences Inc., Higashimurayama, Tokyo, Japan.

It is critical to evaluate the overexpression of human epidermal growth factor receptor 2 (HER2) adequately in breast cancer cases. The aim of the present study is to assess the characteristics and usefulness of a novel monoclonal antibody, clone SV2-61gamma. The overexpression of HER2 was studied on paraffin sections of 50 breast cancers using a polyclonal antibody assay (HercepTest) and monoclonal antibodies (clones SV2-61gamma and CB11). Gene amplification of HER2 was determined by fluorescent in situ hybridization (FISH) using a HER2/CEP17DNA probe kit. Fifty tumors were scored as 0 (50.0%), 1+ (26.0%), 2+ (4.0%), or 3+ (20.0%) by immunohistochemistry using a monoclonal antibody, clone SV2-61gamma. The specificities of immunohistochemistry were 72.0% for the polyclonal antibody, 97.0% for SV2-61gamma, and 92.0% for CB11. The concordances with FISH were 78.0% for the polyclonal antibody, 98.0% for SV2-61gamma, and 94.0% for CB11. The positive predictive value of SV2-61gamma (92.0%) was higher than those of the polyclonal antibody (50.0%) and CB11 (79.0%). A monoclonal antibody clone SV2-61gamma showed very specific staining, with the best concordance with FISH, and it is useful for the evaluation of HER2 overexpression.
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http://dx.doi.org/10.1097/PAI.0b013e31802f411cDOI Listing
December 2007

Increased phosphorylation of Akt in triple-negative breast cancers.

Cancer Sci 2007 Dec 24;98(12):1889-92. Epub 2007 Sep 24.

Department of Pathology, Tokai University School of Medicine, Isehara, Kanagawa 259-1193, Japan.

Cells from breast cancers lacking hormone receptors (estrogen receptor [ER], progesterone receptor [PgR]) and human epidermal growth factor receptor (HER) 2 strongly express the cell proliferation marker Ki-67. However, the mechanisms of and stimulus signals involved in cell proliferation of this type of breast cancer are not well understood. The aim of the present study was to examine the characteristics of signal transduction in triple-negative (ER-, PgR-, and HER2-negative) breast cancers. For 44 tumor samples, western blotting analysis was conducted to examine the phosphorylation of HER2, external signal-regulated kinase (ERK)1 and -2 and Akt, and the immunohistochemical phenotypes of the samples with respect to ER and HER2 were also assessed. Phosphorylation of HER2 was detected in 4 of 15 immunohistochemically HER2-positive tumor samples (26.7%). ERK1/2 was more highly phosphorylated in triple-negative breast cancers. Phosphorylation of Akt kinase was significantly higher in triple-negative breast cancers. Triple-negative breast cancers are characterized by increased phosphorylation of Akt kinase. In the present study, we found for the first time that there is a population with a significantly activated Akt pathway in this type of breast cancer.
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http://dx.doi.org/10.1111/j.1349-7006.2007.00622.xDOI Listing
December 2007

[Evaluation of hormone receptors for diagnosis of breast neoplasms].

Authors:
Shinobu Umemura

Nihon Rinsho 2007 Jun;65 Suppl 6:269-74

Department of Pathology, Tokai University School of Medicine.

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June 2007

Impaired tight junction sealing and precocious involution in mammary glands of PKN1 transgenic mice.

J Cell Sci 2007 Jul;120(Pt 13):2272-83

Institute of Pharmacology, Center for Cardiovascular Research, Charité University Medicine, 10115 Berlin, Germany.

The mammary gland undergoes a complex set of changes to establish copious milk secretion at parturition. To test the hypothesis that signaling through the Rho pathway plays a role in secretory activation, transgenic mice expressing a constitutively activated form of the Rho effector protein PKN1 in the mammary epithelium were generated. PKN1 activation had no effect in late pregnancy but inhibited milk secretion after parturition, diminishing the ability of transgenic dams to support a litter. Mammary gland morphology as well as increased apoptosis and expression of IFGBP5 and TGFbeta3 suggest precocious involution in these animals. Furthermore, tight junction sealing at parturition was impaired in transgenic mammary glands as demonstrated by intraductal injection of [14C]sucrose. Consistent with this finding, tight junction sealing in response to glucocorticoid stimulation was highly impaired in EpH4 mammary epithelial cells expressing constitutively activated PKN1, whereas expression of a dominant-negative PKN1 mutant resulted in accelerated tight junction sealing in vitro. Tight junction formation was not impaired as demonstrated by the correct localization of occludin and ZO1 at the apical cell borders. Our results provide evidence that PKN1 participates in the regulation of tight junction sealing in the mammary gland by interfering with glucocorticoid signaling.
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http://dx.doi.org/10.1242/jcs.03467DOI Listing
July 2007

Renal cell carcinoma arising in a long pre-existing angiomyolipoma.

Pathol Int 2007 Mar;57(3):162-6

Department of Pathology, Tokai University School of Medicine, Bohseidai, Isehara, Kanagawa 259-1193, Japan.

Angiomyolipoma (AML) is a mixed mesenchymal tumor belonging to the family of perivascular epithelioid cell tumors. Concurrent development of AML and adult renal cell carcinoma (RCC) is very rare. Herein is presented a unique case in which RCC arose within a previously detected AML tumor mass. A 40-year-old woman had been diagnosed with AML of the right kidney. Fifteen years later, during a regular radiographic examination, a new lesion was detected at the lower pole of the right kidney adjacent to the previously described AML. Because RCC was clinically suspected, the patient underwent right nephrectomy. Macroscopically, the tumor had a yellowish, transparent, fatty area and an opaque yellowish area with cystic features. Microscopically, the former tumor, consisting of an admixture of mature adipose tissue with smooth muscle and vascular tissue, was diagnosed as AML. The latter tumor was diagnosed as RCC (clear cell type). RCC was not completely enclosed within the AML, but overlapped it. No fibrous capsule was found between these tumors. Although this situation is very rare, from a clinical and pathological point of view it is important to consider the possibility that RCC might arise within AML. The relationship between the two lesions is discussed with a review of the literature.
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http://dx.doi.org/10.1111/j.1440-1827.2006.02075.xDOI Listing
March 2007

Comparison of evaluations for hormone receptors in breast carcinoma using two manual and three automated immunohistochemical assays.

Am J Clin Pathol 2007 Mar;127(3):356-65

Department of Anatomical Pathology, Hiroshima University Hospital, Hiroshima, Japan.

The aims of this study were to compare the quality of immunohistochemical assays of estrogen receptor (ER) and progesterone receptor (PR) and to compare the intermethod variability of assays from different manufacturers. immunohistochemical staining was entrusted to the following laboratories in Japan: Kyowa Medex, dealing with the products of BioGenex (Mishima, Shizuoka), DAKO Japan (Kyoto) and Ventana Japan (Yokohama). All slides were semiquantitatively evaluated according to the Allred score. Intermethod variability showed fair to moderate multirater kappa values for ER and PR (for total score, ER, kappa = 0.34; PR, kappa = 0.45). Another scoring system was also applied in which, irrespective of the intensity of nuclear staining, the proportion of cells stained in each specimen was recorded as 0; less than 1%; 1% or more and less than 10%; or 10% or more. Intermethod variability showed substantial multirater kappa values for ER and PR (according to percentage of positive cells, ER, kappa = 0.67; PR, kappa = 0.72). Concerning intermethod consistency, the scoring system based on the percentage of positive cells was advantageous over other scoring systems.
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http://dx.doi.org/10.1309/4D1A04NCDK96WFY7DOI Listing
March 2007

Granulogenesis in non-neuroendocrine COS-7 cells induced by EGFP-tagged chromogranin A gene transfection: identical and distinct distribution of CgA and EGFP.

J Histochem Cytochem 2007 May 22;55(5):487-93. Epub 2007 Jan 22.

Dept of Pathology, Tokai University School of Medicine, Bohseidai, Isehara, Kanagawa, Japan.

We examined whether an enhanced green fluorescent protein (EGFP)-tagged chromogranin A (CgA) gene construct could serve as a marker protein to follow the synthesis of CgA and the process of granulogenesis in non-neuroendocrine (NE) cells. We transfected a CgA-EGFP expression vector into non-NE COS-7 cells and investigated the localization of a chimeric CgA-EGFP protein using confocal laser scanning microscopy (CLSM). The fluorescent signal of CgA-EGFP was distributed granularly in the cytoplasm. An immunocytochemical study using anti-CgA antibody with a quantum dot (Qd)525 shows colocalization of fluorescent signal of chimeric CgA-EGFP and CgA-Qd525 signals in granular structures, particularly at the periphery of the cytoplasm. We interpreted granules that were immunoreactive to CgA in electron micrographs as secretory. Spectral analysis of EGFP fluorescence revealed distinct EGFP signals without CgA colocalization. This is the first report to show that a granular structure can be induced by transfecting the EGFP-tagged human CgA gene into non-NE cells. The EGFP-tagged CgA gene could be a useful tool to investigate processes of the regulatory pathway. A more precise analysis of the fluorescence signal of EGFP by combination with the Qd system or by spectral analysis with CLSM can provide insight into biological phenomena.
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http://dx.doi.org/10.1369/jhc.6A7110.2007DOI Listing
May 2007

Three-dimensional CT and histopathological findings of airway malacia in Hunter syndrome.

Tokai J Exp Clin Med 2007 Jul 20;32(2):59-61. Epub 2007 Jul 20.

Division of Neurology, Department of Internal Medicine, Tokai University School of Medicine, Isehara, Kanagawa, Japan.

A 19-year-old man with known Hunter syndrome presented with dyspnea, and was admitted to our hospital. Bronchoscopy revealed tracheal narrowing with excessive granulation tissue formation in the trachea. Three-dimensional CT clearly demonstrated severe stenosis in the trachea and both main bronchi. Autopsy showed granulomatous tissue proliferation and deposition of mucopolysaccharide in the tracheal wall. We demonstrated the clinico-radiological-pathological correlation of bronchial lesions in Hunter syndrome, and emphasized that three-dimensional CT is helpful in deciding upon therapeutic strategy to treat stenosis in the large airway.
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July 2007

Two cases of ductal adenoma of the breast.

Breast Cancer 2006 ;13(4):354-9

Department of Surgery, Tokai University School of Meidicine, Bohseidai, Isehara, Kanagawa, Japan.

We encountered two cases of ductal adenoma of the breast. In the first case, a 32-year-old woman presented with a two-year history of a left breast lump. Previous ultrasonography had demonstrated three tumors which were thought to be most likely fibroadenoma. On excisional biopsy of the largest , intraoperative pathological examination of frozen sections was suspicious for ductal carcinoma with a differential diagnosis of intraductal papilloma or intraductal papillary carcinoma. Ductal adenoma was diagnosed after pathological examination of the permanent sections. The second case was a 64-year-old woman who presented with a hard lump in her left breast. Mammography and ultrasonography demonstrated images typical of carcinoma. Aspiration biopsy cytology (ABC) repeated twice was reported as " indeterminate". Excisional biopsy was later done. Ductal adenoma (sclerosing papilloma) with hemorrhagic infarction was diagnosed. It is noteworthy that ductal adenoma have clinical and histopathological features that should be differentiated from carcinoma, especially when the tumor is accompanied by secondary changes such as hemorrhage or infarction.
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http://dx.doi.org/10.2325/jbcs.13.354DOI Listing
April 2007

Immunohistochemical evaluation for hormone receptors in breast cancer: a practically useful evaluation system and handling protocol.

Breast Cancer 2006 ;13(3):232

Department of Pathology, Cancer Institute Ariake Hospital, Japan.

This article reviews the current status of hormone receptor evaluation in and out of Japan, and introduces the proposed working protocol of the task force for Adequate immunohistochemical evaluation in routine practice for breast cancer by the Japanese Breast Cancer Society. Understanding the principles and the developmental process of immunohistochemistry helps us to utilize a scoring system adequately. Methodologies of hormone receptor examination and immunohistochemical procedures are briefly introduced. Each scoring system is based on different principles. The proposed working protocol takes into account the reproducibility of results among observers, institutions and staining procedures, which is justified based on the current situation in Japan. Future directions for the standardization of immunohistochemical hormone receptor evaluation are also described.
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http://dx.doi.org/10.2325/jbcs.13.232DOI Listing
December 2006

Gefitinib-induced lung injury successfully treated with high-dose corticosteroids.

Respirology 2006 Jan;11(1):113-6

Division of Pulmonary Medicine, Tokai University School of Medicine, Kanagawa, Japan.

A 55-year-old man was treated with gefitinib for disseminated pleural lesions, 1 year after resection of the left lower lobe for non-small cell lung cancer. After 6 weeks of continuous daily treatment with oral gefitinib, he developed dyspnoea on exertion and a non-productive cough. CXR and CT revealed focal areas of ground-glass opacity (GGO) in the right upper lobe. Despite gefitinib being discontinued, high-resolution CT revealed extension of GGO and restructuring of lung parenchyma, suggesting acute interstitial pneumonia. Transbronchial biopsy revealed acute-phase diffuse alveolar damage. After administration of methylprednisolone pulse therapy (1 g/day intravenously) for three consecutive days, the areas of GGO shrank on high-resolution CT and symptoms resolved. Diffuse alveolar damage caused by gefitinib can be successfully treated in the early phase with high-dose corticosteroids. Patients receiving gefitinib should be carefully examined for symptoms and undergo CT if their condition deteriorates.
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http://dx.doi.org/10.1111/j.1440-1843.2006.00794.xDOI Listing
January 2006

Clinicopathological correlation between expression of PTHrP receptor and various prognostic factors in breast cancer without axillary lymph node metastasis.

Tokai J Exp Clin Med 2005 Jul;30(2):127-32

Department of Surgery, Tokai University School of Medicine, Kanagawa, Japan.

Purpose: Expression of PTHrP is immunohistologically found in mammary tissues of all the normal cell, hyperplasia and malignant cell. In patients of breast cancer, positive ratio of PTHrP is reportedly 60-69%. Higher positive ratios of PTHrP are found in breast cancer showing bone metastasis than those without bone metastasis. And, breast cancer patients with PTHrP positive show poor prognosis suggesting a relationship to histological grade. Regarding PTHrP receptor, there is few report on its physiological role and relationship to other prognostic factors. The aim of this study was to determine the correlation between PTHrP receptor and various prognostic parameters of breast cancer patients with no axillary node metastasis.

Material And Methods: We employed 26 breast cancer patients, who showed negative axillary node metastasis and did not receive postoperative therapy. We examined relationship between PTHrP receptor and various prognostic factors such as hormone receptors, MIB-1 index, proliferation of cell nuclear antigen (PCNA), DNA ploidy, S-phase fraction, age, tumor diameter, c-erbB-2, and Cathepsin D.

Results: No relationship between expression of PTHrP receptor and the cancer recurrence. PTHrP receptor correlated MIB-1 index alone (p < 0.044).

Conclusions: This findings suggest PTHrP receptor is related to the tumor proliferation of breast cancer.
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July 2005
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