研究者詳細 - 西原　広史

論文 - 西原　広史

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Pathways of Progression From Intraductal Papillary Mucinous Neoplasm to Pancreatic Ductal Adenocarcinoma Based on Molecular Features

Omori Y., Ono Y., Tanino M., Karasaki H., Yamaguchi H., Furukawa T., Enomoto K., Ueda J., Sumi A., Katayama J., Muraki M., Taniue K., Takahashi K., Ambo Y., Shinohara T., Nishihara H., Sasajima J., Maguchi H., Mizukami Y., Okumura T., Tanaka S.

Gastroenterology （Gastroenterology） 156 （ 3 ） 647 - 661.e2 2019年02月

共著, 査読有り, ISSN 00165085

© 2019 AGA Institute Background & Aims: Intraductal papillary mucinous neoplasms (IPMNs) are regarded as precursors of pancreatic ductal adenocarcinomas (PDAs), but little is known about the mechanism of progression. This makes it challenging to assess cancer risk in patients with IPMNs. We investigated associations of IPMNs with concurrent PDAs by genetic and histologic analyses. Methods: We obtained 30 pancreatic tissues with concurrent PDAs and IPMNs, and 168 lesions, including incipient foci, were mapped, microdissected, and analyzed for mutations in 18 pancreatic cancer-associated genes and expression of tumor suppressors. Results: We determined the clonal relatedness of lesions, based on driver mutations shared by PDAs and concurrent IPMNs, and classified the lesions into 3 subtypes. Twelve PDAs contained driver mutations shared by all concurrent IPMNs, which we called the sequential subtype. This subset was characterized by less diversity in incipient foci with frequent GNAS mutations. Eleven PDAs contained some driver mutations that were shared with concurrent IPMNs, which we called the branch-off subtype. In this subtype, PDAs and IPMNs had identical KRAS mutations but different GNAS mutations, although the lesions were adjacent. Whole-exome sequencing and methylation analysis of these lesions indicated clonal origin with later divergence. Ten PDAs had driver mutations not found in concurrent IPMNs, called the de novo subtype. Expression profiles of TP53 and SMAD4 increased our ability to differentiate these subtypes compared with sequencing data alone. The branch-off and de novo subtypes had substantial heterogeneity among early clones, such as differences in KRAS mutations. Patients with PDAs of the branch-off subtype had a longer times of disease-free survival than patients with PDAs of the de novo or the sequential subtypes. Conclusions: Detailed histologic and genetic analysis of PDAs and concurrent IPMNs identified 3 different pathways by which IPMNs progress to PDAs—we call these the sequential, branch-off, and de novo subtypes. Subtypes might be associated with clinical and pathologic features and be used to select surveillance programs for patients with IPMNs.

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Practical procedures for the integrated diagnosis of astrocytic and oligodendroglial tumors

Sonoda Y., Yokoo H., Tanaka S., Kinoshita M., Nakada M., Nishihara H., Ichimura K., Oka H., Shibahara J., Hashimoto N., Kenemura Y., Natsume A., Nobusawa S., Ueki K., Komori T., Shibuya M., Matsumura A.

Brain Tumor Pathology （Brain Tumor Pathology） 36 （ 2 ） 56 - 62 2019年

共著, 査読有り, ISSN 14337398

© 2019, The Japan Society of Brain Tumor Pathology. The publication of the 2016 World Health Organization Classification of Tumors of the Central Nervous System (2016 WHO CNS) represented a major change in the classification of brain tumors. However, many pathologists in Japan cannot diagnose astrocytic or oligodendroglial tumors according to the 2016 WHO CNS due to financial or technical problems. Therefore, the Japan Society of Brain Tumor Pathology established a committee for molecular diagnosis to facilitate the integrated diagnosis of astrocytic and oligodendroglial tumors in Japan. We created three levels of diagnoses: Level 1 was defined as simple histopathological diagnosis using hematoxylin and eosin staining and routine cell lineage-based immunostaining. Level 2 was defined as immunohistochemical diagnosis using immunohistochemical examinations using R132H mutation-specific IDH1, ATRX, and/or p53 antibodies. Level 3 was defined as molecular diagnosis, such as diagnosis based on 1p/19q status or the mutation status of the IDH1 and IDH2 genes. In principle, astrocytic and oligodendroglial tumors should be diagnosed based on the 2016 WHO CNS and/or cIMPACT-NOW criteria; however, the findings obtained through our diagnostic flowchart can be added to the histological diagnosis in parentheses. This classification system would be helpful for pathologists with limited resources.

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Analysis of DLL3 and ASCL1 in Surgically Resected Small Cell Lung Cancer (HOT1702)

Furuta M., Sakakibara-Konishi J., Kikuchi H., Yokouchi H., Nishihara H., Minemura H., Harada M., Yamazaki S., Akie K., Fujita Y., Takamura K., Kojima T., Harada T., Minami Y., Watanabe N., Oizumi S., Suzuki H., Nishimura M., Dosaka-Akita H., Isobe H.

Oncologist （Oncologist） 24 （ 11 ） e1172 - e1179 2019年

共著, 査読有り, ISSN 10837159

© AlphaMed Press 2019 Background: Delta-like protein 3 (DLL3) is a Notch ligand that has an important role in the tumorigenesis of small cell lung cancer (SCLC). Recently, rovalpituzumab tesirine (Rova-T), a DLL3-targeted antibody-drug conjugate, has been developed for treating SCLC. DLL3 is a transcriptional target of the achaete-scute homolog-1 (ASCL1) transcription factor, which is involved in pulmonary neuroendocrine cell development. However, the relationship between DLL3 and/or ASCL1 expression and the clinical features of SCLC remains unknown, especially for early-stage resected SCLC. This study aimed to investigate the expression of DLL3 and ASCL1 in resected SCLC samples using immunohistochemical analysis. Materials and Methods: We collected 95 surgically resected SCLC samples, which were formalin fixed and paraffin embedded. Immunohistochemistry staining was performed to investigate the correlation between the expression of either DLL3 or ASCL1 and clinicopathological features of study patients. Results: Seventy-seven (83%) of 93 immunohistochemically evaluable samples were positive for DLL3 (expression in ≥1% of tumor cells), and DLL3-high expression (≥75%) was observed in 44 samples (47%). Sixty-one (64%) of 95 samples were positive for ASCL1 (expression in ≥5% of tumor cells). A positive correlation was observed between DLL3 and ASCL1 expression. DLL3 and ASCL1 expression were not associated with survival in SCLC patients. DLL3 was more prevalent in patients with advanced clinical disease. Conclusion: DLL3 and ASCL1 were highly expressed in patients with surgically resected SCLC. DLL3 and ASCL1 may be targets for the treatment of SCLC. Implications for Practice: This article examines the relationship between delta-like protein 3 (DLL3) and achaete-scute homolog-1 (ASCL1) protein expression with the clinical features of 95 surgically resected small cell lung cancer (SCLC). DLL3 is attracting attention because rovalpituzumab tesirine (Rova-T), a DLL3-targeted antibody-drug conjugate, was developed recently. DLL3 and ASCL1 were highly expressed in patients with surgically resected SCLC. DLL3 and ASCL1 may be targets for the treatment of early-stage SCLC, including with Rova-T.

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Olaparib monotherapy for BRIP1-mutated high-grade serous endometrial cancer

Nakamura K., Aimono E., Tanishima S., Imai M., Nagatsuma A.K., Hayashi H., Yoshimura Y., Nakayama K., Kyo S., Nishihara H.

JCO Precision Oncology （JCO Precision Oncology） 3 283 - 290 2019年

研究論文（学術雑誌）, 共著, 査読有り

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Mutations in bassoon in individuals with familial and sporadic progressive supranuclear palsy-like syndrome

Yabe I., Yaguchi H., Kato Y., Miki Y., Takahashi H., Tanikawa S., Shirai S., Takahashi I., Kimura M., Hama Y., Matsushima M., Fujioka S., Kano T., Watanabe M., Nakagawa S., Kunieda Y., Ikeda Y., Hasegawa M., Nishihara H., Ohtsuka T., Tanaka S., Tsuboi Y., Hatakeyama S., Wakabayashi K., Sasaki H.

Scientific Reports （Scientific Reports） 8 （ 1 ） 819 - 819 2018年12月

研究論文（学術雑誌）, 共著

© 2018 The Author(s). Clinical diagnosis of progressive supranuclear palsy (PSP) is sometimes difficult because various phenotypes have been identified. Here, we report a mutation in the bassoon (BSN) gene in a family with PSP-like syndrome. Their clinical features resembled not only those of PSP patients but also those of individuals with multiple system atrophy and Alzheimer's disease. The neuropathological findings showed a novel three + four repeat tauopathy with pallido-luysio-nigral degeneration and hippocampal sclerosis. Whole-exome analysis of this family identified a novel missense mutation in BSN. Within the pedigree, the detected BSN mutation was found only in affected individuals. Further genetic analyses were conducted in probands from four other pedigrees with PSP-like syndrome and in 41 sporadic cases. Three missense mutations in BSN that are very rarely listed in databases of healthy subjects were found in four sporadic cases. Western blot analysis of tau following the overexpression of wild-type or mutated BSN revealed the possibility that wild-type BSN reduced tau accumulation, while mutated BSN lost this function. An association between BSN and neurological diseases has not been previously reported. Our results revealed that the neurodegenerative disorder associated with the original proband's pedigree is a novel tauopathy, differing from known dementia and parkinsonism syndromes, including PSP.

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Targeted next-generation sequencing of cancer-related genes in thyroid carcinoma: A single institution's experience

Bandoh N., Akahane T., Goto T., Kono M., Ichikawa H., Sawada T., Yamaguchi T., Nakano H., Kawase Y., Kato Y., Kamada H., Harabuchi Y., Shimizu K., Nishihara H.

Oncology Letters （Oncology Letters） 16 （ 6 ） 7278 - 7286 2018年12月

共著, 査読有り, ISSN 17921074

© 2018, Spandidos Publications. All rights reserved. Thyroid carcinoma (TC) has characteristic genetic alterations, including point mutations in proto-oncogenes and chromosomal rearrangements that vary by histologic subtype. Recent developments in next-generation sequencing (NGS) technology enable simultaneous analysis of cancer-associated genes of interest, thus improving diagnostic accuracy and allowing precise personalized treatment for human cancer. A total of 50 patients who underwent thyroidectomy between 2014 and 2016 at Hokuto Hospital were enrolled. Total DNA was extracted from formalin-fixed, paraffin-embedded tissue sections and quantified. Targeted regions of 24 cancer-associated genes were amplified by PCR, barcoded and sequenced using an Illumina MiSeq platform. Subjects included 30 patients with papillary carcinoma (PC), two with PC tall cell variant (TVPC), two with PC follicular variant (FVPC), eight with follicular carcinoma, seven with poorly differentiated carcinoma (PDC), and one with anaplastic carcinoma (AC). The BRAF V600E mutation was present in 25 of 30 (83%) patients with PC, 2 of 2 (100%) patients with TVPC, 6 of 7 (86%) patients of PDC, and one patient with AC. PIK3CA mutations were present in 3 of 30 (delPV104P, A1046T and C420R; 10%) patients with PC and 1 of 7 (H1047R; 14%) patients with PDC. The TP53 mutation was present in 1 of 30 (R306*; 3.3%) patients with PC and 1 of 7 (Q152*; 14%) patients with PDC. The NRAS mutation was present in 1 of 2 (Q61K, 50%) patients with FVPC. Statistical analysis showed that patients without the BRAF V600E mutation had advanced pathologic T and N stages compared with those with the mutation (P=0.047 and P=0.019, respectively). The BRAF V600E mutation was not correlated with overall and disease-free survival in patients with PC. A patient with PC with a mutation in EGFR (K852Q) and the PIK3CA mutation had an aggressive course with multiple bone and lung metastases. Detection of mutations in cancer-associated genes using NGS could enhance the understanding of the clinical behavior of TC.

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Genetic mutation analysis of the malignant transformation of sinonasal inverted papilloma by targeted amplicon sequencing

Yasukawa S., Kano S., Hatakeyama H., Nakamaru Y., Takagi D., Mizumachi T., Suzuki M., Suzuki T., Nakazono A., Tanaka S., Nishihara H., Homma A.

International Journal of Clinical Oncology （International Journal of Clinical Oncology） 23 （ 5 ） 835 - 843 2018年10月

研究論文（学術雑誌）, 共著, ISSN 13419625

© 2018, Japan Society of Clinical Oncology. Background: The mechanism underlying the malignant transformation of inverted papilloma (IP) has not yet been elucidated. Methods: To clarify the genes responsible for the malignant transformation, we analyzed 10 cases of IP, 8 of IP with dysplasia, and 11 of squamous cell carcinoma (SCC) by targeted amplicon sequencing. Results: The number of mutant genes increased in the order of IP < dysplasia < SCC. Significant differences were observed in the mutation rates of three genes (KRAS, APC and STK11) in particular. TP53 was altered frequently in each group and might be involved in malignant transformation based on to the site of the mutation. A comparison of the genetic variants by region of IP tissue among patients with IP alone, and those with dysplasia or SCC revealed significant differences in the mutation rate of the KRAS gene. Conclusion: Identification of genetic mutations in KRAS is effective for predicting the malignant transformation of IP.

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In vitro 3D blood/lymph-vascularized human stromal tissues for preclinical assays of cancer metastasis

Nishiguchi A., Matsusaki M., Kano M., Nishihara H., Okano D., Asano Y., Shimoda H., Kishimoto S., Iwai S., Akashi M.

Biomaterials （Biomaterials） 179 144 - 155 2018年10月

共著, ISSN 01429612

© 2018 Elsevier Ltd Tumour models mimicking in vivo three-dimensional (3D) microenvironments are of increasing interest in drug discovery because of the limitations inherent to current models. For example, preclinical assays that rely on monolayer or spheroid cell cultures cannot easily predict 3D cancer behaviours because they have no vasculature. Furthermore, there are major differences in cancer behaviour between human and animal experiments. Here, we show the construction of 3D blood/lymph-vascularized human stromal tissues that can be combined with cancer cells to mimic dynamic metastasis for real-time throughput screening of secreted proteinases. We validated this tool using three human carcinoma cell types that are known to invade blood/lymph vessels and promote angiogenesis. These cell types exhibited characteristic haematogenous/lymphogenous metastasis and tumour angiogenesis properties. Importantly, these carcinoma cells selectively secreted different matrix metalloproteinases depending on their metastasis stage and target vasculature, suggesting the possibility of developing drugs that can target each secreted proteinase. We conclude that the 3D tissue tool will be a powerful throughput system for predicting cancer cell responses and time-dependent secretion of molecules in preclinical assays.

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Genomic testing for pancreatic cancer in clinical practice as real-world evidence

Hayashi H., Tanishima S., Fujii K., Mori R., Okamura Y., Yanagita E., Matsuoka R., Amano T., Kinoshita I., Komatsu Y., Dosaka-Akita H., Nishihara H.

Pancreatology （Pancreatology） 18 （ 6 ） 647 - 654 2018年09月

共著, 査読有り, ISSN 14243903

© 2018 IAP and EPC Background: Precision medicine guided by comprehensive genome sequencing represents a potential treatment strategy for pancreatic cancer. However, clinical sequencing for pancreatic cancer entails several practical difficulties. We have launched an in-house clinical sequencing system and started genomic testing for patients with cancer in clinical practice. We have analyzed the clinical utility of this system in pancreatic cancer. Methods: We retrospectively reviewed 20 patients with pancreatic cancer who visited our division. Genomic DNA was extracted from both tumor tissue and peripheral blood mononuclear cells obtained from the patients. We performed a comprehensive genomic testing using targeted amplicon sequencing for 160 cancer-related genes. The primary endpoints were the detection rates of potential actionable and druggable gene alterations. The secondary endpoints were the detection rate of secondary germline findings, the rate of re-biopsy required for genome sequencing, survival time after the initial visit (post-sequencing survival time), and turnaround time. Results: Although re-biopsy was required for 25% (5/20) of all patients, genomic testing was performed in all patients. Actionable and druggable gene alterations were detected in 100% (20/20) and 35% (7/20) of patients, respectively, whereas secondary germline findings were detected in 5% (1/20) of patients. The median turnaround times for physicians and patients were 20 and 26 days, respectively. The median post-sequencing survival time was 10.3 months. Only 10% (2/20) of all patients were treated with therapeutic agents based on the outcomes of genomic testing. Conclusions: The clinical application of comprehensive genomic testing for pancreatic cancer was feasible and promising in clinical practice.

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Tumor budding and human chorionic gonadotropin-β expression correlate with unfavorable patient outcome in colorectal carcinoma

Konishi Y., Kawamata F., Nishihara H., Homma S., Kato Y., Tsuda M., Kohsaka S., Einama T., Liu C., Yoshida T., Nagatsu A., Tanino M., Tanaka S., Kawamura H., Kamiyama T., Taketomi A.

Medical Oncology （Medical Oncology） 35 （ 7 ） 104 - 104 2018年07月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 13570560

© 2018, Springer Science+Business Media, LLC, part of Springer Nature. Tumor budding is thought to represent a manifestation of epithelial-to-mesenchymal transition (EMT) and it has been correlated with poor patient outcomes in colorectal cancer (CRC). Our group recently demonstrated that human chorionic gonadotropin-β (hCGβ) modulates EMT in CRC. In the current study, based on the likely relationships between tumor budding and hCGβ expression, we examined their clinicopathologic significance in CRC. Twenty-eight of 80 (35.0%) CRC showed tumor budding. Tumor budding significantly correlated with lymph node metastasis (P < 0.01), pathologic stage (P < 0.01), lymphatic invasion (P = 0.044), and vascular invasion (P = 0.013). Thirteen of 80 (16.3%) CRC were hCGβ positive on immunohistochemistry. More tumor buds were present in the hCGβ-positive cases (P < 0.01), and tumor budding was significantly correlated with hCGβ positivity (P < 0.01). Cases with both tumor budding and hCGβ expression had the poorest prognosis compared with all other groups (P < 0.01). In conclusion, tumor budding and hCGβ expression are closely associated with EMT, and they are independent prognostic factors in CRC. They identify patients with an “EMT phenotype” who may respond to targeted molecular therapies.

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がんゲノム医療における臨床検査技師の役割

柳田絵美衣, 西原広史

臨床病理（(一社)日本臨床検査医学会） 66 （ 5 ） 479 - 489 2018年05月

ISSN 0047-1860

「がん遺伝子診断部」を開設し、専門の遺伝外来、診療(医療面接)、患者採血、DNA抽出、ライブラリー調整、シークエンス、ゲノム解析、カンファレンス、遺伝カウンセリング、結果報告をすべてインハウスで行う院内完結型クリニカルシークエンス(CLHURC検査)を開始した。次に腫瘍センター内にゲノム医療ユニットを設置し、CLHURC検査と同様に次世代シークエンサー(NGS)を用いてパネル化したがんドライバー遺伝子160種類を解析する網羅的がん遺伝子パネル検査「PleSSision検査」を実施した。従来までの臨床検査とは異なり、専門としている検査分野のみの知識や技術、経験だけでは、がんゲノム医療に携わることは困難で、他職種の医療従事者や専門家との連携が非常に重要であった。臨床検査技師がゲノム医療における多くの役割を求められることによるデメリットは、新しい分野の検査が導入され、臨床検査技師の役割が増すことで人手や環境、設備が不足し、現場が混乱する可能性が高いことであった。メリットは「専門分野の検査」についての知識や技術、経験以外にも、様々な知識や技術を得ることができることであった。

GPR68, a proton-sensing GPCR, mediates interaction of cancer-associated fibroblasts and cancer cells

Wiley S., Sriram K., Liang W., Chang S., French R., McCann T., Sicklick J., Nishihara H., Lowy A., Insel P.

FASEB Journal （FASEB Journal） 32 （ 3 ） 1170 - 1183 2018年03月

研究論文（学術雑誌）, 共著, ISSN 08926638

© FASEB. Themicroenvironment of pancreatic ductal adenocarcinoma (PDAC) is characterized by a dense fibrotic stroma (desmoplasia) generated by pancreatic cancer-associated fibroblasts (CAFs) derived from pancreatic stellate cells (PSCs) and pancreatic fibroblasts (PFs). Using an unbiased GPCRomic array approach, we identified 82 G-protein-coupled receptors (GPCRs) commonly expressed by CAFs derived from 5 primary PDAC tumors. Comparedwith PSCs and PFs, CAFs have increased expression ofGPR68 (a proton-sensingGPCR), with the results confirmed by immunoblotting, The Cancer Genome Atlas data, and immunohistochemistry of PDAC tumors. Coculture of PSCs with PDAC cells, or incubation with TNF-α, induced GPR68 expression. GPR68 activation (by decreasing the extracellular pH) enhanced IL-6 expression via a cAMP/PKA/cAMP response element binding protein signaling pathway. Knockdown of GPR68 by short interfering RNA diminished low pH-induced production of IL-6 and enhancement of PDAC cell proliferation by CAF conditioned media. CAFs from other gastrointestinal cancers also express GPR68. PDAC cells thus induce expression by CAFs of GPR68, which senses the acidic microenvironment, thereby increasing production of fibrotic markers and IL-6 and promoting PDAC cell proliferation. CAF-expressed GPR68 is a mediator of low-pH-promoted regulation of the tumor microenvironments, in particular to PDAC cell-CAF interaction and may be a novel therapeutic target for pancreatic and perhaps other types of cancers.

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心外膜脂肪組織におけるミトコンドリア機能障害は冠動脈狭窄と関連している(Mitochondrial Dysfunction in Epicardial Adipose Tissue is Associated with Coronary Artery Stenosis)

Nakajima Takayuki, Yokota Takashi, Shingu Yasushige, Yamada Akira, Iba Yutaka, Ujihira Kosuke, Wakasa Satoru, Ooka Tomonori, Takada Shingo, Shirakawa Ryosuke, Furihata Takaaki, Tsuda Masaya, Matsumoto Junichi, Katayama Takashi, Fukushima Arata, Saito Akimichi, Matsuoka Ryosuke, Nishihara Hiroshi, Matsui Yoshiro, Kinugawa Shintaro

日本循環器学会学術集会抄録集（(一社)日本循環器学会） 82回 YIA - 1 2018年03月

査読有り

The Japanese Society of Pathology Guidelines on the handling of pathological tissue samples for genomic research: Standard operating procedures based on empirical analyses

Kanai Y., Nishihara H., Miyagi Y., Tsuruyama T., Taguchi K., Katoh H., Takeuchi T., Gotoh M., Kuramoto J., Arai E., Ojima H., Shibuya A., Yoshida T., Akahane T., Kasajima R., Morita K., Inazawa J., Sasaki T., Fukayama M., Oda Y.

Pathology International （Pathology International） 68 （ 2 ） 63 - 90 2018年02月

研究論文（学術雑誌）, 共著, ISSN 13205463

© 2018 The Authors. Pathology International published by Japanese Society of Pathology and John Wiley & Sons Australia, Ltd Genome research using appropriately collected pathological tissue samples is expected to yield breakthroughs in the development of biomarkers and identification of therapeutic targets for diseases such as cancers. In this connection, the Japanese Society of Pathology (JSP) has developed “The JSP Guidelines on the Handling of Pathological Tissue Samples for Genomic Research” based on an abundance of data from empirical analyses of tissue samples collected and stored under various conditions. Tissue samples should be collected from appropriate sites within surgically resected specimens, without disturbing the features on which pathological diagnosis is based, while avoiding bleeding or necrotic foci. They should be collected as soon as possible after resection: at the latest within about 3 h of storage at 4°C. Preferably, snap-frozen samples should be stored in liquid nitrogen (about −180°C) until use. When intending to use genomic DNA extracted from formalin-fixed paraffin-embedded tissue, 10% neutral buffered formalin should be used. Insufficient fixation and overfixation must both be avoided. We hope that pathologists, clinicians, clinical laboratory technicians and biobank operators will come to master the handling of pathological tissue samples based on the standard operating procedures in these Guidelines to yield results that will assist in the realization of genomic medicine.

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Chorionic Gonadotropin-β Modulates Epithelial-Mesenchymal Transition in Colorectal Carcinoma Metastasis

Kawamata F., Nishihara H., Homma S., Kato Y., Tsuda M., Konishi Y., Wang L., Kohsaka S., Liu C., Yoshida T., Tanino M., Tanaka S., Kawamura H., Kamiyama T., Taketomi A.

American Journal of Pathology （American Journal of Pathology） 188 （ 1 ） 204 - 215 2018年01月

共著, ISSN 00029440

© 2018 American Society for Investigative Pathology Ectopic production of free β human chorionic gonadotropin (hCGβ) has been associated with aggressive behavior in non-trophoblastic tumors. hCGβ shares common evolutionary sequences with transforming growth factor-β (TGF-β), which represents a major driving force of epithelial-to-mesenchymal transition (EMT). In this study, we examined the biological roles of hCGβ during EMT and its clinical significance in colorectal cancer (CRC) progression. Eighty CRC specimens and 54 preoperative serum samples were analyzed. hCGβ-overexpressing human CRC cell lines were examined for invasiveness and tumorigenicity, and the expression of EMT-associated genes was investigated. In human CRC, histologic hCGβ positivity [13/80 (16.3%)] was lower than serologic hCGβ positivity [13/54 (24.1%)]. However, it was significantly correlated with several clinicopathological features and unfavorable outcome (P < 0.05). hCGβ-overexpressing cell lines had increased invasiveness, migratory ability, and metastatic potential in mice (P < 0.01). Western blot, PCR, and microarray analyses showed hCGβ altered expression of EMT-related genes, including E-cadherin, phosphorylated SMAD2, SNAIL, and TWIST. hCGβ-induced SNAIL and TWIST overexpression levels were reversible by type I and type II TGF-β receptor inhibitors (P < 0.05). hCGβ thus induces EMT via the TGF-β signaling pathway, and it may represent a molecular target in CRC treatment.

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A clinicopathological analysis of six autopsy cases of sudden unexpected death due to infectious aortitis in patients with aortic tears

Ishikawa M., Tanino M., Miyazaki M., Kimura T., Ishida Y., Wang L., Tsuda M., Nishihara H., Nagashima K., Tanaka S.

Internal Medicine （Internal Medicine） 57 （ 10 ） 1375 - 1380 2018年

研究論文（学術雑誌）, 共著, ISSN 09182918

© 2018 The Japanese Society of Internal Medicine. Objective Cardiovascular disease is a leading cause of sudden unexpected death even in hospitalized patients. Infectious aortitis is a rare disease that has the potential to cause aortic tears and hemorrhage followed by sudden death. The aim of this study was to reveal the clinicopathological features of infectious aortitis that are related to sudden unexpected death. Methods We retrospectively reviewed 1,310 autopsy cases over 15 years and selected the cases involving patients who died suddenly due to aortic tears. We analyzed the clinical information and pathological findings. Results One hundred thirty-three of 1,310 cases (10.2%) were autopsied under the clinical diagnosis of unexpected sudden death. Aortic tears were identified in 33 cases (2.5%) and infectious aortitis was diagnosed in 6 (18.2%) of these cases. All cases involved male patients (middle-aged to elderly) with risk factors for atherosclerosis (i.e., hypertension). The laboratory data showed continuous leukocytosis and C-reactive protein elevation, even during the improvement phase, in patients with pre-existing infectious disease. The autopsy findings revealed three types of aortic tears (aneurysms, dissections and penetrating atherosclerotic ulcers with moderate to severe atherosclerosis), and the infiltration of numerous neutrophils at the site of rupture. Gram-positive bacteria were detected in four cases and Gram-negative bacteria were detected in two cases. Discussion We demonstrated that sudden unexpected death caused by infectious aortitis rarely occurred in hospitalized patients, even in the recovery phase of the preceding infectious disease. We therefore recommend that clinicians pay attention to infectious aortitis in patients with infectious disease, particularly elderly patients with atherosclerotic disease, even those who are in the improvement phase. Conclusion Unexpected sudden death by infectious aortitis in the recovery phase of antecedent infection.

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Pathological quantification of carotid artery plaque instability in patients undergoing carotid endarterectomy

Konishi T., Funayama N., Yamamoto T., Morita T., Hotta D., Nomura R., Nakagaki Y., Murahashi T., Kamiyama K., Yoshimoto T., Aoki T., Nishihara H., Tanaka S.

Circulation Journal （Circulation Journal） 82 （ 1 ） 258 - 266 2018年

共著, 査読有り, ISSN 13469843

© 2018, Japanese Circulation Society. All rights reserved. Background: Unstable atherosclerotic carotid plaques cause cerebral thromboemboli and ischemic events. However, this instability has not been pathologically quantified, so we sought to quantify it in patients undergoing carotid endarterectomy (CEA). Methods and Results: Carotid plaques were collected during CEA from 67 symptomatic and 15 asymptomatic patients between May 2015 and August 2016. The specimens were stained with hematoxylin-eosin and elastica-Masson. Immunohistochemistry was performed using an endothelial-specific antibody to CD31, CD34 and PDGFRβ. The histopathological characteristics of the plaques were studied. By multiple-variable logistic regression analysis, plaque instability correlated with the presence of plaque rupture [odds ratio (OR), 9.75; P=0.013], minimum fibrous cap thickness (OR per 10 μm 0.70; P=0.025), presence of microcalcifications in the fibrous cap (OR 7.82; P=0.022) and intraplaque microvessels (OR 1.91; P=0.043). Receiver-operating characteristics analyses showed that these factors combined into a single score diagnosed symptomatic carotid plaques in patients with carotid artery stenosis with a high level of accuracy (area under the curve 0.92; 95% confidence interval 0.85-0.99 vs. asymptomatic). Conclusions: This analysis of carotid plaque instability strongly suggested that the diagnostic scoring of carotid plaque instability improves the understanding and treatment of carotid artery disease in patients undergoing CEA.

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Effectiveness of indocyanine green fluorescence in endoscopic marking in gastric cancer surgery: A feasibility study for replacing India ink

Ono H., Kusano M., Nihei M., Hayashi H., Fukushima H., Kawakami M., Danjo Y., Nagashima K., Shimizu Y., Kawamata F., Honda S., Shimamura T., Nishihara H.

Journal of Japanese Society of Gastroenterology （Journal of Japanese Society of Gastroenterology） 115 （ 4 ） 385 - 393 2018年

共著, ISSN 04466586

© 2018 Japanese Society of Gastroenterology. All rights reserved. When injected, indocyanine green (ICG) immediately combines with lipoproteins to fluoresce. Here, we studied whether ICG fluorescence is effective for endoscopic marking in gastric cancer surgery using a photodynamic eye (PDE) camera and fluorescent endoscope. An ICG solution was endoscopically injected into the submucosal layer of the gastric tumor 3 days before surgery. We observed the lesions using both a PDE camera and a fluorescent endoscope during laparotomy and laparoscopy, respectively; we also observed the fluorescent luminance and fluorescent size of the resected lesions. We could intraoperatively detect the size of the resected lesions in eight patients with early gastric cancer and six patients with advanced gastric cancer. We believe that the use of ICG fluorescence in endoscopic marking requires additional information, such as the volume of the ICG solution and the timing of the ICG injection.

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Copy number profiles of paired primary and metastatic colorectal cancers

Kawamata F., Patch A., Nones K., Bond C., McKeone D., Pearson S., Homma S., Liu C., Fennell L., Dumenil T., Hartel G., Kobayasi N., Yokoo H., Fukai M., Nishihara H., Kamiyama T., Burge M., Karapetis C., Taketomi A., Leggett B., Waddell N., Whitehall V.

Oncotarget （Oncotarget） 9 （ 3 ） 3394 - 3405 2018年

共著

© Kawamata et al. Liver metastasis is the major cause of death following a diagnosis of colorectal cancer (CRC). In this study, we compared the copy number profiles of paired primary and liver metastatic CRC to better understand how the genomic structure of primary CRC differs from the metastasis. Paired primary and metastatic tumors from 16 patients and their adjacent normal tissue samples were analyzed using single nucleotide polymorphism arrays. Genome-wide chromosomal copy number alterations were assessed, with particular attention to 188 genes known to be somatically altered in CRC and 24 genes that are clinically actionable in CRC. These data were analyzed with respect to the timing of primary and metastatic tissue resection and with exposure to chemotherapy. The genomic differences between the tumor and paired metastases revealed an average copy number discordance of 22.0%. The pairs of tumor samples collected prior to treatment revealed significantly higher copy number differences compared to post-therapy liver metastases (P = 0.014). Loss of heterozygosity acquired in liver metastases was significantly higher in previously treated liver metastasis samples compared to treatment naive liver metastasis samples (P = 0.003). Amplification of the clinically actionable genes ERBB2, FGFR1, PIK3CA or CDK8 was observed in the metastatic tissue of 4 patients but not in the paired primary CRC. These examples highlight the intra-patient genomic discrepancies that can occur between metastases and the primary tumors from which they arose. We propose that precision medicine strategies may therefore identify different actionable targets in metastatic tissue, compared to primary tumors, due to substantial genomic differences.

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Role of insulin receptor substrates in the progression of hepatocellular carcinoma

Sakurai Y., Kubota N., Takamoto I., Obata A., Iwamoto M., Hayashi T., Aihara M., Kubota T., Nishihara H., Kadowaki T.

Scientific Reports （Scientific Reports） 7 （ 1 ） 5387 - 5387 2017年12月

研究論文（学術雑誌）, 共著, 査読有り, ISSN 2045-2322

© 2017 The Author(s). Several cellular signaling pathways, including insulin/IGF signaling, are known to be activated in hepatocellular carcinoma (HCC). Here, we investigated the roles of insulin receptor substrate (Irs) 1 and Irs2, both of which are the major molecules to be responsible for transducing insulin/IGF signaling in the liver, in the development of HCC by inducing chemical carcinogenesis using diethylnitrosamine (DEN) in mice. The Irs1 mRNA and protein expressions were upregulated in the tumors, along with enhanced insulin signaling. Liver-specific Irs1-knockout (LIrs1KO) mice exhibited suppression of DEN-induced HCC development, accompanied by reduced cancer cell proliferative activity and reduced activation of Akt. Gene expression analyses revealed that the tumors in the DEN-treated LIrs1KO mice showed modest metabolic alterations during hepatocarcinogenesis as well as decreased inflammation and invasion potentials. On the other hand, liver-specific Irs2-knockout (LIrs2KO) mice showed a similar pattern of HCC development to the DEN-treated control wild-type mice. Based on the knowledge that Wnt/β-catenin signaling is activated in HCC, we focused on Wnt/β-catenin signaling and demonstrated that Irs1 expression was induced by Wnt3a stimulation in the primary hepatocytes, associated with insulin-stimulated Akt activation. These data suggest that upregulated Irs1 by Wnt/β-catenin signaling plays a crucial role in the progression of HCC.

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