Faculty Profiles - YAMAMOTO HIDETAKA

Papers - YAMAMOTO HIDETAKA

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Utility of adaptive control processing for the interpretation of digital mammograms. Reviewed International journal

Mikako Jinnouchi, Hidetake Yabuuchi, Makoto Kubo, Eriko Tokunaga, Hidetaka Yamamoto, Hiroshi Honda

Acta radiologica (Stockholm, Sweden : 1987) 57 ( 11 ) 1297 - 1303 2016.11

Language：English Publishing type：Research paper (scientific journal)

Background Adaptive control processing for mammography (ACM) is a novel program that automatically sets up appropriate image-processing parameters for individual mammograms (MMGs) by analyzing the focal and whole breast histogram. Purpose To investigate whether ACM improves the image contrast of digital MMGs and whether it improves radiologists' diagnostic performance in reading of MMGs. Material and Methods One hundred normal cases for image quality assessment and another 100 cases (50 normal and 50 cancers) for observer performance assessment were enrolled. All mammograms were examined with and without ACM. Five radiologists assessed the intra- and extra-mammary contrast of 100 normal MMGs, and the mean scores of the intra- and extra-mammary contrast were compared between MMGs with and without ACM in both the dense and non-dense group. They classified 100 MMGs into BI-RADS categories 1-5, and were asked to rate the images on a scale of 0 to 100 for the likelihood of the presence of category 3-5 lesions in each breast. Detectability of breast cancer, reading time, and frequency of window adjustment were compared between MMGs with and without ACM. Results ACM improved the intra-mammary contrast in both the dense and non-dense group but degraded extra-mammary contrast in the dense group. There was no significant difference in detectability of breast cancer between MMGs with and without ACM. Frequency of window adjustment without ACM was significantly higher than that with ACM. Reading time without ACM was significantly longer than that with ACM. Conclusion ACM improves the image contrast of MMGs and shortens reading time.

DOI： 10.1177/0284185115586022

Lymphomatoid Granulomatosis: Two Different Phenotypes of Computed Tomography Findings. Reviewed International journal

Torahiko Yamanouchi, Satoshi Kawanami, Takeshi Kamitani, Koji Sagiyama, Yuzo Yamasaki, Yuko Tanaka, Michinobu Nagao, Hidetake Yabuuchi, Naoki Hamada, Tatsuro Okamoto, Hidetaka Yamamoto, Hiroshi Honda

Journal of thoracic imaging 31 ( 6 ) W80-W82 2016.11

Reclassification of rhabdoid tumor and pediatric undifferentiated/unclassified sarcoma with complete loss of SMARCB1/INI1 protein expression: three subtypes of rhabdoid tumor according to their histological features. Reviewed International journal

Kenichi Kohashi, Yukichi Tanaka, Hiroshi Kishimoto, Hidetaka Yamamoto, Yuichi Yamada, Tomoaki Taguchi, Yukihide Iwamoto, Yoshinao Oda

Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc 29 ( 10 ) 1232 - 42 2016.10

Language：English Publishing type：Research paper (scientific journal)

Rhabdoid tumor is characterized by rhabdoid cells and shows complete loss of SMARCB1/INI1 protein expression. In existing classifications, the diagnostic synonyms vary depending on the anatomic site: rhabdoid tumors in the central nervous system or extra-central nervous system are, respectively, classified as atypical teratoid/rhabdoid tumor or malignant rhabdoid tumor. In this study, we analyzed the histological, immunohistochemical, microRNA, and clinicopathological statuses of tumors initially diagnosed as malignant rhabdoid tumor (n=33), atypical teratoid/rhabdoid tumor (n=11), and pediatric undifferentiated/unclassified sarcoma (n=8) with complete loss of SMARCB1/INI1 expression, and considered the possibility of their histological reclassification. Our analysis indicated that the tumors could be histologically reclassified into three groups: conventional-type tumors resembling malignant rhabdoid tumor, atypical teratoid/rhabdoid-type tumors resembling atypical teratoid/rhabdoid tumor, and small cell-type tumors resembling malignant lymphoma. The reclassified conventional type was composed of 27 malignant rhabdoid tumors and 9 atypical teratoid/rhabdoid tumors (36 cases). The atypical teratoid/rhabdoid type consisted of six malignant rhabdoid tumors, two atypical teratoid/rhabdoid tumors, and two undifferentiated/unclassified sarcomas (10 cases). The six cases of small cell type were made up of six undifferentiated/unclassified sarcomas. All of the available tumor specimens were positive for vimentin and epithelial marker (EMA, CAM5.2, or AE1/AE3). MicroRNA profiles were not significantly different between the conventional- and small cell-type tumors (Pearson's correlation coefficient: 0.888300 or 0.891388). There was no significant difference in overall survival between atypical teratoid/rhabdoid tumor and malignant rhabdoid tumor (P=0.16). In addition, there were no significant differences in survival between any of the reclassified combinations. In conclusion, we could classify eight tumors initially diagnosed as undifferentiated/unclassified sarcomas into two cases of atypical teratoid/rhabdoid type and six cases of small cell type. We suggest that reclassification of malignant rhabdoid tumors into three groups according to their histologic features rather than the traditional classification by sites of origin would be favorable for their histopathological diagnosis.

DOI： 10.1038/modpathol.2016.106

Mucoepidermoid carcinoma of the breast found during treatment of lymphoma

Minoru Fujino, Daisuke Mori, Michiaki Akashi, Hidetaka Yamamoto, Hitoshi Aibe, Kunishige Matake, Kengo Shirahane

Case Reports in Oncology 9 ( 3 ) 806 - 814 2016.9

Histological spectrum of angiofibroma of soft tissue: histological and genetic analysis of 13 cases. Reviewed International journal

Yuichi Yamada, Hidetaka Yamamoto, Kenichi Kohashi, Takeaki Ishii, Kunio Iura, Akira Maekawa, Hirofumi Bekki, Hiroshi Otsuka, Kyoko Yamashita, Hiroyuki Tanaka, Tsubasa Hiraki, Munenori Mukai, Atsuko Shirakawa, Yoko Shinnou, Mari Jinno, Hiroyuki Yanai, Kenichi Taguchi, Yoshihiko Maehara, Yukihide Iwamoto, Yosinao Oda

Histopathology 69 ( 3 ) 459 - 69 2016.9

Language：English Publishing type：Research paper (scientific journal)

AIMS: Angiofibroma of soft tissue (AFST) is a rare soft tissue neoplasm characterized by a fibroblastic cytomorphology and a prominent vascular structure. AFSTs possess a novel fusion gene, i.e. NCOA2-AHRR/AHRR-NCOA2 or GTF2I-NCOA2, providing a useful approach to diagnosing AFST. Morphologically, AFSTs span a wide spectrum, making diagnosis a challenge. The aim of this study was to review AFST cases and to report previously unknown histological features, which we confirmed by genetic analysis. METHODS AND RESULTS: We reviewed 276 cases diagnosed as solitary fibrous tumours/haemangiopericytomas (232 cases), unclassified tumours of fibroblastic differentiation (36 cases), and recently diagnosed AFSTs (eight cases), and retrieved 13 cases compatible with AFST. Immunohistochemical staining was performed for these cases, all 13 of which were analysed by reverse transcription polymerase chain reaction and fluorescence in-situ hybridization. The histological findings were as follows: amianthoid fibres, extravasation of red blood cells, haemosiderin deposition, aggregates of foamy histiocytes, cystic change, necrosis, and haemorrhage. Immunohistochemically, the tumour cells were positive for epithelial membrane antigen (four of 13 cases), desmin (six of 13 cases), CD163 (13 of 13 cases), CD68 (seven of 13 cases), oestrogen receptor (13 of 13 cases), progesterone receptor (three of 13 cases), and STAT6 (one of 13 cases, weak nuclear staining), but they were negative for CD34, α-smooth muscle actin, muscle-specific actin, S100, pan-cytokeratin, MDM2, and CDK4. The AHRR-NCOA2 fusion gene was detected in eight cases, and NCOA2 gene rearrangement in nine cases. CONCLUSION: We revealed the previously unreported histological variation and immunohistochemical findings of AFST, and confirmed them by using genetic methods. The results suggested that AFST should be considered in the diagnosis of fibrous or fibrohistiocytic tumours with the above histological features.

DOI： 10.1111/his.12943

Insulin-like growth factor II messenger RNA-binding protein-3 is an indicator of malignant phyllodes tumor of the breast. Reviewed International journal

Katsumi Takizawa, Hidetaka Yamamoto, Kenichi Taguchi, Shinji Ohno, Eriko Tokunaga, Nami Yamashita, Makoto Kubo, Masafumi Nakamura, Yoshinao Oda

Human pathology 55 30 - 8 2016.9

Language：English Publishing type：Research paper (scientific journal)

The aim of this study was to elucidate the clinicopathological and prognostic significance of the expressions of insulin-like growth factor II mRNA-binding protein-3 (IMP3) and epidermal growth factor receptor (EGFR) in phyllodes tumors (PTs). Immunohistochemical staining for IMP3 and EGFR was performed in 130 cases of primary PTs (83 benign, 28 borderline, 19 malignant), 34 recurrent/metastatic PTs, and 26 fibroadenomas (FAs). Among the primary tumors, a high expression of IMP3 was significantly more frequently present in malignant PTs (17/19, 89%) than in the FAs (0/26, 0%), benign PTs (0/83, 0%) and borderline PTs (3/28, 11%). The recurrent and metastatic lesions of malignant PTs also showed high IMP3 expression (3/5 [60%] and 6/6 [100%], respectively). Most malignant PTs showed strong IMP3 expression at the interductal area or more diffusely, whereas weak and focal (low) expression of IMP3 was limited to the periductal area in FAs and benign PTs. EGFR overexpression was significantly correlated with tumor grade and high IMP3 expression. Overexpressions of IMP3 and EGFR were significantly associated with shorter periods of metastasis-free and disease-free survival. The results suggest that high expressions of IMP3 and EGFR with a characteristic staining pattern may be helpful for both identifying malignant PT and predicting the prognosis of these tumors.

DOI： 10.1016/j.humpath.2016.04.007

ALK, ROS1 and NTRK3 gene rearrangements in inflammatory myofibroblastic tumours. Reviewed International journal

Hidetaka Yamamoto, Akihiko Yoshida, Kenichi Taguchi, Kenichi Kohashi, Yui Hatanaka, Atsushi Yamashita, Daisuke Mori, Yoshinao Oda

Histopathology 69 ( 1 ) 72 - 83 2016.7

Language：English Publishing type：Research paper (scientific journal)

AIMS: The aim of this study was to elucidate the pathological features of inflammatory myofibroblastic tumour (IMT) with gene rearrangement other than ALK. METHODS AND RESULTS: We investigated anaplastic lymphoma kinase (ALK), ROS1, ETV6, NTRK3 and RET in 36 cases of IMT by using immunohistochemical (IHC) staining, fluorescence in-situ hybridization, and reverse transcription polymerase chain reaction (RT-PCR). IHC staining showed ALK and ROS1 to be positive in 22 of 36 (61.1%) and two of 36 (5.6%) cases, respectively. In one case with ROS1 positivity, IHC staining showed cytoplasmic and dot-like ROS1 expression, and RT-PCR showed the presence of the TFG-ROS1 fusion transcript. Two cases of pulmonary IMT, in a 7-year-old patient and a 23-year-old patient, had ETV6 rearrangement, and the presence of the ETV6-NTRK3 fusion transcript was confirmed in one case. These tumours were composed of hypocellular myxoid areas and highly cellular areas with rich plasmacytic infiltration; the histological features were different from those of infantile fibrosarcoma. RET rearrangement was not detected. CONCLUSIONS: These results suggest that a subset of ALK-negative IMTs have rearrangement of ROS1, ETV6 or NTRK3 as a possible oncogenic mechanism, and that the detection of these alterations may be of diagnostic value and helpful for determining promising therapeutic strategies.

DOI： 10.1111/his.12910

Bi-cytopenia possibly induced by anti-PD-1 antibody for primary malignant melanoma of the esophagus: A case report. Reviewed International journal

Kyoko Inadomi, Hozumi Kumagai, Shuji Arita, Nobuhiro Tsuruta, Kotoe Takayoshi, Koji Mishima, Shun-Ichiro Ota, Mamoru Tanaka, Yuta Okumura, Kosuke Sagara, Kenta Nio, Michitaka Nakano, Hiroshi Uchi, Hidetaka Yamamoto, Hiroshi Ariyama, Hitoshi Kusaba, Hiroaki Niiro, Yoshinao Oda, Koichi Akashi, Eishi Baba

Medicine 95 ( 29 ) e4283 2016.7

Language：English Publishing type：Research paper (scientific journal)

BACKGROUND: Anti-programmed cell death 1 antibody nivolumab is a promising agent for various cancers. Immune-related adverse events are recognized; however, bi-cytopenia with nivolumab has not been reported. CASE PRESENTATION: A 73-year-old man was diagnosed with advanced primary malignant melanoma of the esophagus with liver, lung, and lymph node metastases. Previous therapies including dacarbazine and radiation of 39 Gy to the esophageal region were performed, but the liver metastases deteriorated. The patient was then administered nivolumab (2 mg/kg, every 3 weeks). After 3 cycles, the esophageal tumor and lymph nodes showed marked reductions in size, the lung metastases disappeared, and the liver metastases shrank partially. The treatment continued with 7 cycles for 4 months. However, severe anemia and thrombocytopenia appeared in the 6th cycle, and intermittent blood transfusions were required. The patient received high-dose intravenous methylprednisolone therapy for bi-cytopenia, but it was ineffective. Seven months after the initiation of nivolumab, the patient died of tumor. Although the mechanisms of bi-cytopenia were unclear, it could have been induced by nivolumab. CONCLUSION: The present case shows a rare but serious life-threatening bi-cytopenia possibly associated with nivolumab and suggests the importance of awareness of hematological adverse events during nivolumab therapy.

DOI： 10.1097/MD.0000000000004283

Reduced MUTYH, MTH1, and OGG1 expression and TP53 mutation in diffuse-type adenocarcinoma of gastric cardia. Reviewed International journal

Yukiko Kohno, Hidetaka Yamamoto, Minako Hirahashi, Yoshiteru Kumagae, Masafumi Nakamura, Eiji Oki, Yoshinao Oda

Human pathology 52 145 - 52 2016.6

Language：English Publishing type：Research paper (scientific journal)

The effects of oxidative stress in adenocarcinomas of gastric cardia (AGCs) have not been fully elucidated. With a strict definition of AGC, we examined the immunohistochemical expressions of inducible nitric oxide synthase; 8-hydroxy-deoxyguanosine; and the base excision repair enzymes such as MUTYH, MTH1, and OGG1, and TP53 mutational status. Sixty-three cases of AGC were characterized by younger patient age (P = .0227) and more frequent venous invasion (P = .0106) compared with the adenocarcinomas of pylorus (APs). 8-hydroxy-deoxyguanosine was accumulated (P = .0011), whereas MUTYH (P = .0325) and OGG1 (P = .0007) were decreased, in the AGCs compared with the adjacent mucosa, but these differences were not detected in the APs. Among the AGCs, lower expressions of MUTYH (P = .0013) and MTH1 (P = .0059) were each significantly associated with diffuse-type histology. A lower expression of OGG1 was correlated with higher T-stage (P = .0011), lymphatic invasion (P = .004), and lymph node metastasis (P = .0094). In addition, the presence of TP53 mutation was associated with diffuse-type histology (P = .0153) and a lower level of MUTYH (P = .0221). The AGCs also showed a relatively high rate of a transversion-type mutation of TP53 (50%), whereas all TP53 mutations in the APs were transition type. Age 62years or older (P = .0073), diffuse-type histology (P = .0020), and TP53 mutation (P = .0066) were each associated with worse survival in the AGC patients. Our results indicate that oxidative stress accumulation and a downregulation of base excision repair enzymes may play an important role in the pathogenesis of AGC, in particular diffuse-type AGCs. Diffuse-type AGC might involve molecular pathways different from those of other subsets of gastric cancer.

DOI： 10.1016/j.humpath.2016.01.006

Primary Cardiac T-Cell Lymphoma Localized in the Mitral Valve. Reviewed International journal

Yuma Motomatsu, Yasuhisa Oishi, Shogo Matsunaga, Hirofumi Onitsuka, Hidetaka Yamamoto, Eiko Zaitsu, Yuichi Yamada, Kenichi Kohashi, Yoshinao Oda, Ryuji Tominaga

The Annals of thoracic surgery 101 ( 6 ) 2363 - 5 2016.6

Language：English Publishing type：Research paper (scientific journal)

Primary cardiac lymphoma is a rare cardiac tumor, and usually originates from B cells and involves the right side of the heart. We present an extremely rare case of primary cardiac T-cell lymphoma involving the mitral valve alone. A 58-year-old woman who was positive for human T-cell leukemia virus 1 underwent mitral valve replacement because of severe mitral regurgitation. The postoperative pathologic diagnosis of the mitral valve was T-cell lymphoma. Further evaluation revealed no malignancy, except for the mitral valve. To the best of our knowledge, this is the first case of primary cardiac T-cell lymphoma localized in the mitral valve.

DOI： 10.1016/j.athoracsur.2015.08.091

Activation of the Akt-mTOR and MAPK pathways in dedifferentiated liposarcomas. Reviewed International journal

Takeaki Ishii, Kenichi Kohashi, Kunio Iura, Akira Maekawa, Hirofumi Bekki, Yuichi Yamada, Hidetaka Yamamoto, Kazuki Nabeshima, Hiroyuki Kawashima, Yukihide Iwamoto, Yoshinao Oda

Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine 37 ( 4 ) 4767 - 76 2016.4

Language：English Publishing type：Research paper (scientific journal)

The Akt/mTOR and MAPK pathways play important roles in modulating cellular function in response to extracellular signals, and they are known to be activated in certain kinds of sarcomas. Few investigations have examined these pathways in dedifferentiated liposarcoma (DDLS), in relation to clinicopathological features. Clinicopathological and immunohistochemical analyses were conducted using 99 DDLS specimens. An in vitro study was also conducted to examine the antitumor effects of an mTOR inhibitor and a MEK inhibitor on two DDLS cell lines. The clinicopathological analyses revealed that the AJCC staging was a significant prognostic factor for overall survival and that the tumor size, depth, and location were significant prognostic factors for event-free survival. Phosphorylated Akt (pAkt), pmTOR, pS6RP, p4E-BP1, pMEK, and pERK expressions were positive in 57.4, 52.4, 71.4, 57.1, 84.1, and 50.8 % of the dedifferentiated component of the 63 primary DDLSs. Positive staining for pmTOR was significantly more frequent in the dedifferentiated component than the well-differentiated component. A univariate prognostic analysis revealed that pmTOR expression was associated with poor prognosis in the tumors in the retroperitoneum/ventral body cavity. The mTOR and MEK inhibitors dose-dependently inhibited the cell proliferation of both DDLS cell lines and decreased the expression of downstream pS6RP and pERK, respectively. The combined use of the two inhibitors enhanced antiproliferative activity. In conclusion, the Akt/mTOR and MAPK pathways were activated in DDLS specimens, and the inhibition of these pathways decreased cell proliferation in DDLS cell lines. Our findings suggest that these pathways could be a therapeutic target for patients with DDLS.

DOI： 10.1007/s13277-015-4232-2

Molecular subclassification determined by human papillomavirus and epidermal growth factor receptor status is associated with the prognosis of oropharyngeal squamous cell carcinoma. Reviewed International journal

Takafumi Nakano, Hidetaka Yamamoto, Torahiko Nakashima, Toshimitsu Nishijima, Masanobu Satoh, Yui Hatanaka, Hideki Shiratsuchi, Ryuji Yasumatsu, Satoshi Toh, Shizuo Komune, Yoshinao Oda

Human pathology 50 51 - 61 2016.4

Language：English Publishing type：Research paper (scientific journal)

Human papillomavirus (HPV) infection is an indicator of good response to chemoradiotherapy in oropharyngeal squamous cell carcinoma (OPSCC), and epidermal growth factor receptor (EGFR) is a molecular-therapeutic target in head and neck squamous cell carcinoma. Here we investigated the prevalence and prognostic significance of HPV infection and EGFR alteration in OPSCC. We analyzed the presence of high-risk HPV using in situ hybridization, protein expressions of p16 and EGFR using immunohistochemistry, and the EGFR gene copy number gain using chromogenic in situ hybridization (CISH) in 105 cases of OPSCC. The biopsy specimens before chemoradiotherapy were used for these analyses. HPV infection and p16 protein overexpression were detected in 53.3% and 52.4% of the OPSCCs, and each factor was associated with better overall survival (P = .0026 and P = .0026) and nonkeratinizing histology (P = .0002 and P = .0004), respectively. EGFR gene copy number gain (high polysomy or amplification) was detected in 12.4% of the OPSCCs and was correlated with EGFR protein overexpression (P = .0667) and worse overall survival (P < .0001). HPV infection and EGFR gene copy number gain (EGFR CISH positive) were mutually exclusive. The HPV-negative/EGFR CISH-positive OPSCCs had significantly worse overall survival than did the HPV-positive/EGFR CISH-negative OPSCCs and HPV-negative/EGFR CISH-negative OPSCCs (P < .0001 and P < .0001, respectively). The EGFR CISH-negative OPSCCs had favorable prognosis irrespective of HPV infection. Our results suggest that EGFR gene copy number gain-positive tumors represent an HPV-negative, aggressive subgroup of OPSCCs. The molecular subclassification of OPSCCs based on HPV infection and EGFR status may serve as important information for appropriate therapeutic strategy.

DOI： 10.1016/j.humpath.2015.11.001

Intraluminal superior vena cava metastasis from adenosquamous carcinoma of the duodenum: A case report. Reviewed International journal

Kotoe Takayoshi, Hiroshi Ariyama, Shingo Tamura, Shunsuke Yoda, Takeshi Arita, Toshihiro Yamaguchi, Keigo Ozono, Hidetaka Yamamoto, Kyoko Inadomi, Hozumi Kumagai, Mamoru Tanaka, Yuta Okumura, Kosuke Sagara, Kenta Nio, Michitaka Nakano, Shuji Arita, Hitoshi Kusaba, Keita Odashiro, Yoshinao Oda, Koichi Akashi, Eishi Baba

Oncology letters 11 ( 1 ) 605 - 609 2016.1

Language：English Publishing type：Research paper (scientific journal)

In 2013, a 76-year-old male with a cardiac pacemaker was diagnosed with adenosquamous carcinoma of the duodenum. Subsequently, a pancreatoduodenectomy and lymph node dissection were performed, and 12 cycles of adjuvant chemotherapy (modified FOLFOX6 regimen), which consisted of fluorouracil, leucovorin and oxaliplatin, were administered via a central venous catheter. At 5 months after the completion of adjuvant chemotherapy, the patient experienced the sudden onset of severe pain at the back right of the ear, edema of the right side of the face and right jugular vein dilatation. Computed tomography (CT) revealed filling defects in the superior vena cava (SVC) and right brachiocephalic vein, indicating catheter-induced venous thrombosis. Although the catheter was removed and anti-coagulation therapy, aspiration of the thrombosis and ballooning dilatation were performed immediately, the patient's symptoms were not ameliorated. Notably, histological examination following thrombus aspiration revealed metastatic cancer cells, and fluorodeoxyglucose-positron emission tomography/CT identified metabolically active nodules in the SVC at locations consistent with the initial duodenal tumors detected by CT and in the first thoracic vertebrae. The tumor thrombus rapidly increased in size and resulted in worsening dyspnea. Subsequently, radiotherapy was performed, followed by chemotherapy, which relieved the systemic symptoms and suppressed the tumor growth. Adenosquamous carcinoma of the duodenum is extremely rare, and to the best of our knowledge, intraluminal SVC metastasis as a result of adenosquamous carcinoma of the duodenum has not been reported previously. The placement of a cardiac pacemaker, central venous catheter and tumor cells possessing high metastatic potential are hypothesized to have contributed to this rare case of metastasis.

Dual gain of HER2 and EGFR gene copy numbers impacts the prognosis of carcinoma ex pleomorphic adenoma. Reviewed International journal

Toshimitsu Nishijima, Hidetaka Yamamoto, Takafumi Nakano, Torahiko Nakashima, Ken-ichi Taguchi, Muneyuki Masuda, Jun-ichi Motoshita, Shizuo Komune, Yoshinao Oda

Human pathology 46 ( 11 ) 1730 - 43 2015.11

Language：English Publishing type：Research paper (scientific journal)

We investigated the potential roles of HER2 and EGFR and evaluated their prognostic significance in carcinoma ex pleomorphic adenoma (CXPA). We analyzed HER2 and EGFR overexpression status using immunohistochemistry (IHC) and gene copy number gain by chromogenic in situ hybridization (CISH) in 50 cases of CXPA (40 ductal-type and 10 myoepithelial-type CXPAs). Salivary duct carcinoma was the most common histologic subtype of malignant component (n = 21). Immunohistochemistry positivity and chromogenic in situ hybridization positivity were closely correlated in both HER2 and EGFR. HER2 CISH positivity (mostly gene amplification) and EGFR CISH positivity (mostly gene high polysomy) were present in 19 (40%) and 21 (44%) cases, respectively, and were each significantly correlated with poor outcome (P = .0009 and P = .0032, respectively). Dual gain of HER2 and EGFR gene copy numbers was present in 11 cases (23%) and was the most aggressive genotype. HER2 CISH positivity was more frequently present in ductal-type CXPAs (47%) than in myoepithelial-type CXPAs (10%), whereas the prevalence of EGFR CISH positivity was similar in both histologic subtypes (42% and 50%, respectively). Our results suggest that HER2 and EGFR gene copy number gains may play an important role in the progression of CXPA, in particular ductal-type CXPAs. HER2 CISH-positive/EGFR CISH-positive tumors may be the most aggressive subgroup in CXPA. The molecular subclassification of CXPA based on the HER2 and EGFR status may be helpful for prognostic prediction and decisions regarding the choice of therapeutic strategy.

DOI： 10.1016/j.humpath.2015.07.014

Successful combination chemotherapy for metastatic inflammatory myofibroblastic tumor: A case report. Reviewed International journal

Kyoko Inadomi, Hozumi Kumagai, Kotoe Takayoshi, Hiroshi Ariyama, Hitoshi Kusaba, Akihiro Nishie, Hidetaka Yamamoto, Ken Takase, Mamoru Tanaka, Kosuke Sagara, Yuta Okumura, Kenta Nio, Michitaka Nakano, Shuji Arita, Yoshinao Oda, Koichi Akashi, Eishi Baba

Oncology letters 10 ( 5 ) 2981 - 2985 2015.11

Language：English Publishing type：Research paper (scientific journal)

A 64-year-old male presented with increased abdo-minal fullness and fever. Radiological examination revealed moderate ascites, a tumor with a diameter of 12.5 cm in the mesenteric region, as well as multiple tumors in the thoracic and abdominal para-aortic regions and in the left supraclavicular regions. Pathohistological findings of the biopsy specimen revealed atypical spindle cells accompanied by infiltration of lymphocytes. The plasmacytes were positive for CD68, murine double minute 2 and S-100, while they were negative for α-smooth muscle actin, cyclin-dependent kinase 4 and anaplastic lymphoma kinase. Clinically, the patient presented systemic symptoms and laboratory results indicated an elevation in the inflammatory response, while the CT and MRI findings were consistent with an inflammatory myofibroblastic tumor (IMT). Based on the clinical and histological findings, the patient was diagnosed with IMT. In total, 4 cycles of combination chemotherapy with doxorubicin and ifosfamide were administered. Tumor size reduction by 50% was achieved subsequent to the 4th chemotherapy cycle. In conclusion, successful control of this rare metastatic IMT was achieved by systemic chemotherapy.

Elevated expression of HSP90 and the antitumor effect of an HSP90 inhibitor via inactivation of the Akt/mTOR pathway in undifferentiated pleomorphic sarcoma. Reviewed International journal

Hirofumi Bekki, Kenichi Kohashi, Akira Maekawa, Yuichi Yamada, Hidetaka Yamamoto, Katsumi Harimaya, Michiyuki Hakozaki, Kazuki Nabeshima, Yukihide Iwamoto, Yoshinao Oda

BMC cancer 15 804 - 804 2015.10

Language：English Publishing type：Research paper (scientific journal)

BACKGROUND: Undifferentiated pleomorphic sarcoma (UPS) is a heterogeneous tumor group, and little is known about molecular target therapy for UPS. Heat shock protein 90 (HSP90) is an expressed chaperone that refolds certain denatured proteins under stress conditions. One of these proteins is Akt. The disruption of Akt signaling plays an important role in tumor progression. The present study's purpose was to analyze the HSP90 expression, Akt/mTOR pathway activation and the correlation between HSP90 expression and its pathway activation in UPS. METHODS: The status of HSP90 and the profiles of the Akt/ mTOR pathway were assessed by immunohistochemistry in 79 samples of UPS, and these data were compared with clinicopathological and histopathological findings. The expressions of indicated proteins were assessed by Western blotting in five frozen samples. After treating UPS cells with the HSP90 inhibitor, we assessed the antitumor effect of the inhibitor. RESULTS: Immunohistochemically, phosphorylated Akt (p-Akt), p-mTOR, p-S6RP and p-4EBP were positive in 57.3, 51.9, 54.5 and 57.1% of the UPS samples, respectively. The expressions of those phosphorylated proteins were correlated with each other. HSP90 expression was elevated in 56.4% of the samples and was correlated with p-Akt, p-mTOR and p-S6RP. The immunohistochemical results were confirmed by Western blotting. The HSP90 inhibitor led to decreased viability and invasiveness of the cells and inactivated the AKT/mTOR pathway in vitro. CONCLUSION: Elevated expression of HSP90 is a poor-prognosis factor and is involved in the activation of the Akt/mTOR pathway in UPS. HSP90 inhibition is a potential treatment option for UPS.

DOI： 10.1186/s12885-015-1830-8

Expression of adhesion molecules and epithelial-mesenchymal transition factors in medullary carcinoma of the colorectum. Reviewed International journal

Shunsuke Takahashi, Kenichi Kohashi, Hidetaka Yamamoto, Minako Hirahashi, Reiko Kumagai, Nobuyoshi Takizawa, Kazuhiko Nakamura, Yoshihiko Maehara, Masao Tanaka, Ryoichi Takayanagi, Yoshinao Oda

Human pathology 46 ( 9 ) 1257 - 66 2015.9

Language：English Publishing type：Research paper (scientific journal)

Medullary carcinoma (MC) of the colorectum is known as a rare variant with favorable prognosis despite its poorly differentiated morphology. The mechanism of its favorable behavior has been unclear. Here, we compared the expressions of adhesion molecules and epithelial-mesenchymal transition (EMT)-related proteins in the central portion and invasive front between 43 MCs and 30 poorly differentiated adenocarcinomas (PDAs). The expressions of membranous E-cadherin (P < .0001), β-catenin (P < .0001) and claudin 1 (P = .0036) were significantly preserved in the invasive front of the MCs compared to those in the invasive front of the PDAs. E-cadherin membranous expression was also significantly preserved in the central portion of the MCs (P = .0178). Nuclear β-catenin expression in both the central portion (P = .0463) and invasive front (P = .0346) of the MCs was significantly less frequent compared to that in the PDAs. Snail (P = .0035) and Twist1 (P = .0463) expressions in the invasive front of the MCs were significantly less frequent compared to the PDAs, suggesting that the EMT phenomenon may occur rarely in colorectal MC. Reduced membranous E-cadherin expression in the MC central portion was significantly correlated with poor clinical outcome (P = .0086). Our immunohistochemical results indicate that preserved adhesion molecule protein and less frequent expression of EMT-related transcription factors in the invasive front contribute to the favorable prognosis of colorectal MCs. We suggest that a reduced expression of E-cadherin in the central portion might be a good biomarker for an unfavorable prognosis in cases of MC.

DOI： 10.1016/j.humpath.2015.05.023

Successful treatment of adult Langerhans cell histiocytosis with intensified chemotherapy. Reviewed

Mariko Minami, Takahiro Shima, Koji Kato, Hidetaka Yamamoto, Kenji Tsuchihashi, Seido Oku, Tomonori Shimokawa, Taro Tochigi, Goichi Yoshimoto, Kenjiro Kamezaki, Katsuto Takenaka, Hiromi Iwasaki, Yoshinao Oda, Toshihiro Miyamoto, Koichi Akashi

International journal of hematology 102 ( 2 ) 244 - 8 2015.8

Language：English Publishing type：Research paper (scientific journal)

Langerhans cell histiocytosis (LCH) is a rare disease in adults. The treatment strategy for this condition remains controversial. Intensified systemic chemotherapy is required in pediatric patients with the multiple system form of LCH (MS-LCH) for aggressive forms of the disease. Recent clinical trials have shown that intensified chemotherapy for pediatric patients diagnosed with MS-LCH results in improved outcomes. However, whether the feasibility and efficacy of an intensified systemic chemotherapy regimen are also beneficial for adult patients with MS-LCH remains unclear. Here, we report two cases of adult MS-LCH that were successfully treated with an intensified treatment protocol as used in pediatric patients. One patient fully completed the protocol, and has since maintained a complete response (CR) for 2 years following completion of the treatment. The other patient also achieved CR after induction therapy, and is now undergoing maintenance therapy in an outpatient clinic. The cases presented in this study suggest that intensified systemic chemotherapy as used for pediatric patients with MS-LCH is well tolerated and effective for adult patients as well.

DOI： 10.1007/s12185-015-1778-0

Cancer-testis antigens PRAME and NY-ESO-1 correlate with tumour grade and poor prognosis in myxoid liposarcoma. Reviewed International journal

Kunio Iura, Kenichi Kohashi, Yuka Hotokebuchi, Takeaki Ishii, Akira Maekawa, Yuichi Yamada, Hidetaka Yamamoto, Yukihide Iwamoto, Yoshinao Oda

The journal of pathology. Clinical research 1 ( 3 ) 144 - 59 2015.7

Language：English Publishing type：Research paper (scientific journal)

Myxoid liposarcoma is the second most common liposarcoma. Although myxoid liposarcoma is relatively chemosensitive and thus a good candidate for chemotherapy, cases with relapsed or metastatic disease still have poor outcome. Here, we performed a gene microarray analysis to compare the gene expression profiles in six clinical myxoid liposarcoma samples and three normal adipose tissue samples, and to identify molecular biomarkers that would be useful as diagnostic markers or treatment targets in myxoid liposarcoma. This showed that the cancer-testis antigen PRAME was up-regulated in myxoid liposarcoma. We then performed immunohistochemical, western blotting and real-time polymerase chain reaction analyses to quantify the expression of PRAME and another cancer-testis antigen, NY-ESO-1, in clinical samples of myxoid liposarcoma (n = 93), dedifferentiated (n = 46), well-differentiated (n = 32) and pleomorphic liposarcomas (n = 14). Immunohistochemically, positivity for PRAME and NY-ESO-1 was observed in 84/93 (90%) and 83/93 (89%) of the myxoid liposarcomas, and in 20/46 (43%) and 3/46 (7%) of the dedifferentiated, 3/32 (9%) and 1/32 (3%) of the well-differentiated and 7/14 (50%) and 3/21 (21%) of the pleomorphic liposarcomas, respectively. High immunohistochemical expression of PRAME and/or NY-ESO-1 was significantly correlated with tumour diameter, the existence of tumour necrosis, a round-cell component of >5%, higher histological grade and advanced clinical stage. High PRAME and NY-ESO-1 expression correlated significantly with poor prognosis in a univariate analysis. The myxoid liposarcomas showed significantly higher protein and mRNA expression levels of PRAME and NY-ESO-1 (CTAG1B) than the other liposarcomas. In conclusion, PRAME and NY-ESO-1 (CTAG1B) were expressed in the vast majority of myxoid liposarcomas, and their high-level expression correlated with tumour grade and poor prognosis. Our results support the potential use of PRAME and NY-ESO-1 as ancillary parameters for differential diagnosis and as prognostic biomarkers, and indicate that the development of immunotherapy against these cancer-testis antigens in myxoid liposarcoma would be warranted.

DOI： 10.1002/cjp2.16

Mucinous phenotype and CD10 expression of primary adenocarcinoma of the small intestine. Reviewed International journal

Reiko Kumagai, Kenichi Kohashi, Shunsuke Takahashi, Hidetaka Yamamoto, Minako Hirahashi, Kenichi Taguchi, Kenichi Nishiyama, Yoshinao Oda

World journal of gastroenterology 21 ( 9 ) 2700 - 10 2015.3

Language：English Publishing type：Research paper (scientific journal)

AIM: To clarify the correlation with phenotypic expression, clinicopathological features, genetic alteration and microsatellite-instability status in small intestinal adenocarcinoma (SIA). METHODS: The cases of 47 patients diagnosed with primary SIAs that were surgically resected at our institution in 1975-2005 were studied. We reviewed clinicopathological findings (age, gender, tumor size, gross appearance, histological morphologic type, invasion depth, lymphatic permeation, venous invasion, and lymph node metastasis), and the immunohistochemical expression of MUC5AC, MUC6, MUC2, CD10, and mismatch-repair (MMR) proteins (MLH1 and MSH2). We analyzed KRAS and BRAF gene mutations, and the microsatellite instability (MSI) status. The immunohistochemical staining of CD10, MUC2, MUC5AC and MUC6 was considered positive when distinct staining in > 5% of the adenocarcinoma cells was recorded. To evaluate of MMR protein expression, we used adjacent normal tissue including lymphoid follicles, inflammatory cells, and stromal cells as an internal positive control. Sections without nuclear staining in the tumor cells were considered to have lost the expression of the respective MMR protein. RESULTS: There were 29 males and 18 females patients (mean age 59.9 years, range: 23-87 years). Tumors were located in the duodenum in 14 cases (30%), the jejunum in 21 cases (45%), and the ileum in 12 cases (25%). A phenotypic expression analysis revealed 20 MUC2-positive tumors (42.6%), 11 MUC5AC-positive (23.4%), 4 MUC6-positive (8.5%), and 7 CD10-positive (14.9%). The tumor sizes of the MUC2(+) tumors were significantly larger than those of the MUC2(-) tumors (mean, 5.7 ± 1.4 cm vs 4.7 ± 2.1 cm, P < 0.05). All three tumors with adenomatous component were positive for MUC2 (P < 0.05). Polypoid appearance was seen significantly more frequently in the CD10(+) group than in the CD10(-) group (P < 0.05). The tumor size was significantly larger in the CD10 (+) group than in the CD10(-) group (mean, 5.9 ± 1.4 cm vs 5.0 ± 2.1 cm, P < 0.05). Of 34 SIAs with successfully obtained MSI data, 4 were MSI-high. Of the 4 SIAs positive for both MUC5AC and MUC2, 3 showed MSI-H (75%) and 3 were mucinous adenocarcinoma (75%). KRAS mutations were detected in 4 SIAs. SIAs had KRAS mutation expressed only MUC2, but were negative for MUC5AC, MUC6 and CD10. CONCLUSION: These findings suggest that the phenotypic expression of SIAs is correlated with their biological behavior, genetic alteration, and MSI status.

DOI： 10.3748/wjg.v21.i9.2700

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