論文 - 西原　広史

Profiling the inhibitory receptors LAG-3, TIM-3, and TIGIT in renal cell carcinoma reveals malignancy.

Takamatsu K, Tanaka N, Hakozaki K, Takahashi R, Teranishi Y, Murakami T, Kufukihara R, Niwa N, Mikami S, Shinojima T, Sasaki T, Sato Y, Kume H, Ogawa S, Kakimi K, Kamatani T, Miya F, Tsunoda T, Aimono E, Nishihara H, Sawada K, Imamura T, Mizuno R, Oya M

Nature communications 12 （ 1 ） 5547 - 5547 2021年09月

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A cutting edge therapy for future immuno-oncology is targeting a new series of inhibitory receptors (IRs): LAG-3, TIM-3, and TIGIT. Both immunogenomic analyses and diagnostic platforms to distinguish candidates and predict good responders to these IR-related agents are vital in clinical pathology. By applying an automated single-cell count for immunolabelled LAG-3, TIM-3, and TIGIT, we reveal that individual IR levels with exclusive domination in each tumour can serve as valid biomarkers for profiling human renal cell carcinoma (RCC). We uncover the immunogenomic landscape associated with individual IR levels in human RCC tumours with metastases in various organs and histological subtypes. We then externally validate our results and devise a workflow with optimal biomarker cut-offs for discriminating the LAG-3, TIM-3, and TIGIT tumour profiles. The discrimination of LAG-3, TIM-3, and TIGIT profiles in tumours may have a broad impact on investigations of immunotherapy responses after targeting a new series of IRs.

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ARID1A mutation/ARID1A loss is associated with a high immunogenic profile in clear cell ovarian cancer.

Kuroda Y, Chiyoda T, Kawaida M, Nakamura K, Aimono E, Yoshimura T, Takahashi M, Saotome K, Yoshihama T, Iwasa N, Sakai K, Yamagami W, Nishihara H, Aoki D

Gynecologic oncology 162 （ 3 ） 679 - 685 2021年09月

査読有り,  ISSN  0090-8258

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OBJECTIVES: ARID1A mutation is frequently found in clear cell ovarian cancer (CCC) and endometrioid ovarian cancer (EC). Anti-PD-1 monotherapy has been found to have limited efficacy in epithelial ovarian cancer; however, anti-PD-1 therapy showed significant clinical benefit in some CCC. We sought to define the relationship of ARID1A mutation/ARID1A expression to the immunogenic profile of different histologic subtypes of ovarian cancer. METHODS: We performed next-generation sequencing of 160 cancer-related genes. Also, we analyzed the immunohistochemical status of ARID1A, PD-L1, and CD8 with survival in different histologic subtypes of ovarian cancer in a total of 103 cases. RESULTS: ARID1A mutation was found in 0% of the high-grade serous ovarian cancer (HGSC) (n = 36), 41.5% of the CCC (n = 41), 45.0% of the EC (n = 20), and 33.3% of the mucinous ovarian cancer (MC) (n = 6) cases. ARID1A loss was found in 19.4% of the HGSC, 75.6% of the CCC, 60.0% of the EC and 0% of the MC cases. ARID1A mutation was found to be associated with high PD-L1 (p < 0.001) or CD8 levels (p < 0.001) in CCC but not in other histologic subtypes. Meanwhile, ARID1A loss was associated with high PD-L1 or CD8 levels in CCC (p < 0.001) and HGSC (p < 0.001) but not in EC and MC. In addition, ARID1A mutation was associated with high tumor mutation burden in CCC (p = 0.006). CONCLUSIONS: ARID1A mutation/ARID1A expression is associated with immune microenvironmental factors in CCC but not in EC. ARID1A status can be a biomarker for selecting candidates for immune checkpoint blockade in CCC.

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Spiradenoma of the breast: a rare diagnostic pitfall in the evaluation of solid-basaloid breast lesions with a dual cell population.

Matsumoto H, Takamatsu R, Abe N, Unesoko M, Zaha H, Ishii A, Nakada N, Nishihara H, Tan PH, Yoshimi N

Virchows Archiv : an international journal of pathology 479 （ 2 ） 401 - 405 2021年08月

査読有り,  ISSN  0945-6317

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Resection of a desmoid-type fibromatosis with a CTNNB1 p.S45P mutation using a cervico-thoracic approach: A case report and literature review.

Sato R, Bandoh N, Goto T, Uemura A, Inoue N, Otomo Y, Nakano H, Yamaguchi T, Kato Y, Nishihara H, Takei H, Harabuchi Y

Auris, nasus, larynx 48 （ 4 ） 777 - 782 2021年08月

査読有り,  ISSN  0385-8146

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Desmoid-type fibromatosis (DF) is a rare, locally infiltrative, and fibroblastic proliferative disease. DF usually arises from abdominal fascial tissue, but in rare cases, it can occur in extra-abdominal areas. A 73-year-old Japanese male complained of a painless, left anterior neck mass of 3-month duration. Computed tomography revealed the mass measured 9 × 7 × 6 cm and extended to the anterior mediastinum, with invasion of the left clavicle. En bloc resection of the tumor with the left sternoclavicular joint and the medial portion of the left clavicle was performed by cervico-thoracic approach with L-shaped partial sternotomy. Histopathologic examination showed fascicular growth of spindle-shaped cells separated by abundant collagen. Immunohistologic examination revealed nuclear staining of β-catenin and cytoplasmic staining of vimentin. Genetic analysis of 160 cancer-related genes by next-generation sequencing (NGS) demonstrated only a missense mutation in the CTNNB1 gene (c.133T>C, p.S45P). DF extending from the neck to the anterior mediastinum is rare. We report the complete resection of a large-sized DF with the clavicular invasion. A low-frequency CTNNB1 mutation of DF was identified. Genetic analysis with NGS was beneficial for the diagnosis.

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Germline Whole-Gene Deletion of FH Diagnosed from Tumor Profiling.

Ueki A, Sugano K, Misu K, Aimono E, Nakamura K, Tanishima S, Tanaka N, Mikami S, Hirasawa A, Ando M, Yoshida T, Oya M, Nishihara H, Kosaki K

International journal of molecular sciences 22 （ 15 ）  2021年07月

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Hereditary leiomyomatosis and renal cell carcinoma (HL (RCC)) entails cutaneous and uterine leiomyomatosis with aggressive type 2 papillary RCC-like histology. HLRCC is caused by pathogenic variants in the FH gene, which encodes fumarate hydratase (FH). Here, we describe an episode of young-onset RCC caused by a genomic FH deletion that was diagnosed via clinical sequencing. A 35-year-old woman was diagnosed with RCC and multiple metastases: histopathological analyses supported a diagnosis of FH-deficient RCC. Although the patient had neither skin tumors nor a family history of HLRCC, an aggressive clinical course at her age and pathological diagnosis of FH-deficient RCC suggested a germline FH variant. After counseling, the patient provided written informed consent for germline genetic testing. She was simultaneously subjected to paired tumor profiling tests targeting the exome to identify a therapeutic target. Although conventional germline sequencing did not detect FH variants, exome sequencing revealed a heterozygous germline FH deletion. As such, paired tumor profiling, not conventional sequencing, was required to identify this genetic deletion. RCC caused by a germline FH deletion has hitherto not been described in Japan, and the FH deletion detected in this patient was presumed to be of maternal European origin. Although the genotype-phenotype correlation in HLRCC-related tumors is unclear, the patient's family was advised to undergo genetic counseling to consider additional RCC screening.

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Prominent response to platinum-based chemotherapy in a patient with BRCA2 mutant-neuroendocrine prostate cancer and MDM2 amplification.

Daimon T, Kosaka T, Hongo H, Aimono E, Nakamura K, Mikami S, Nishihara H, Oya M

IJU case reports 4 （ 4 ） 216 - 219 2021年07月

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INTRODUCTION: Genomic profiling provides useful information for diagnosis, treatment, and prognosis, and detection of certain defects, such as DNA repair gene aberrations or microsatellite instability, can possibly lead to optimal treatment, but this testing has not been widely used to inform prostate cancer treatment. CASE PRESENTATION: A 55-year-old man sequentially treated for prostate cancer was diagnosed as neuroendocrine prostate cancer from prostate specimens resected because of urinary retention. Subsequently, he received five cycles of platinum-based chemotherapy in total and responded well. We also performed next-generation sequencing of a sample from the prostate specimen and identified a breast cancer susceptibility gene mutation with Murine Double Minute 2 amplification and loss of heterozygosity in retinoblastoma 1. CONCLUSION: We report a neuroendocrine prostate cancer patient with Murine Double Minute 2 amplification who experienced an aggressive course and for whom platinum-based chemotherapy was effective, and one of the reasons for the good response might be the breast cancer susceptibility gene mutation.

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A first Japanese case of BRCA2 and RB1 co-loss organ-confined prostate cancer successfully treated by radical prostatectomy.

Matsumoto K, Kosaka T, Nakamura K, Nishihara H, Oya M

International cancer conference journal 10 （ 3 ） 170 - 173 2021年07月

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We report a rare case of localized prostate cancer with BRCA2 and RB1 co-loss, which is usually found at a more advanced stage with a poor prognosis. A 59-year-old male with prostate cancer was referred to our hospital for surgical treatment. He had schizophrenia that was well controlled by medicine. He had no family history of prostate cancer, breast cancer, or ovarian cancer. His initial PSA was 4.5 ng/mL, and Gleason score 3 + 4 adenocarcinoma was detected in one of 12 needle biopsy cores. Imaging studies demonstrated the clinical stage to be cT2aN0M0. Therefore, robot-assisted laparoscopic radical prostatectomy (RALP) with bilateral nerve sparing was performed. Based on histopathological analysis, the Gleason score was 4 + 3 and the pathological stage was pT2N0M0 with a negative surgical margin. Genetic sequencing identified BRCA2 and RB1 co-loss with limited loss of heterogeneity (LOH). At 12 months after surgery, his PSA level remained < 0.01 ng/mL. This case suggests the importance of early detection of prostate cancer and the possibility of cure for prostate cancer with high malignant potential. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s13691-021-00469-z.

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RT-PCR Screening Tests for SARS-CoV-2 with Saliva Samples in Asymptomatic People: Strategy to Maintain Social and Economic Activities while Reducing the Risk of Spreading the Virus.

Oba J, Taniguchi H, Sato M, Takamatsu R, Morikawa S, Nakagawa T, Takaishi H, Saya H, Matsuo K, Nishihara H

The Keio journal of medicine 70 （ 2 ） 35 - 43 2021年06月

査読有り,  ISSN  0022-9717

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The year 2020 will be remembered for the coronavirus disease 2019 (COVID-19) pandemic, which continues to affect the whole world. Early and accurate identification of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is fundamental to combat the disease. Among the current diagnostic tests, real-time reverse transcriptase-polymerase chain reaction (RT-qPCR) is the most reliable and frequently used method. Herein, we discuss the interpretation of RT-qPCR results relative to viral infectivity. Although nasopharyngeal swab samples are often used for RT-qPCR testing, they require collection by trained medical staff. Saliva samples are emerging as an inexpensive and efficient alternative for large-scale screening. Pooled-sample testing of saliva has been applied for mass screening of SARS-CoV-2 infection. Current policies recommend isolating people with borderline cycle threshold (Ct) values (35<Ct <40), despite these Ct values indicating minimal infection risk. We propose the new concept of a "social cut-off" Ct value and risk stratification based on the correlation of Ct with infectivity. We also describe the experience of RT-qPCR screening of saliva samples at our institution. It is important to implement a scientific approach to minimize viral transmission while allowing economic and social activities to continue.

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Determination of brain tumor recurrence using (11) C-methionine positron emission tomography after radiotherapy.

Yamaguchi S, Hirata K, Okamoto M, Shimosegawa E, Hatazawa J, Hirayama R, Kagawa N, Kishima H, Oriuchi N, Fujii M, Kobayashi K, Kobayashi H, Terasaka S, Nishijima KI, Kuge Y, Ito YM, Nishihara H, Tamaki N, Shiga T

Cancer science （Wiley）  112 （ 10 ） 4246 - 4256 2021年06月

査読有り,  ISSN  1347-9032

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Kimura Disease Presenting with Buccal Mass: A Case Report and Literature Review.

Sato R, Bandoh N, Goto T, Ichikawa H, Uemura A, Suzuki S, Yamaguchi T, Aimono E, Nishihara H, Katada A, Harabuchi Y

Head and neck pathology 15 （ 2 ） 657 - 662 2021年06月

査読有り,  ISSN  1936-055X

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Germline BRCA2 mutation in a case of aggressive prostate cancer accompanied by spinal bulbar muscular atrophy.

Hongo H, Kosaka T, Hayashi H, Nakamura K, Nishihara H, Mikami S, Beltran H, Oya M

Asian journal of andrology 24 （ 1 ） 116 - 118 2021年05月

査読有り,  ISSN  1008-682X

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Biglycan, tumor endothelial cell secreting proteoglycan, as possible biomarker for lung cancer.

Morimoto H, Hida Y, Maishi N, Nishihara H, Hatanaka Y, Li C, Matsuno Y, Nakamura T, Hirano S, Hida K

Thoracic cancer 12 （ 9 ） 1347 - 1357 2021年05月

査読有り,  ISSN  1759-7706

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OBJECTIVES: In lung cancer, surgery remains the most curative treatment and limited resection is beneficial for patients with low cardiopulmonary function and low malignancy tumors. However, there are no biomarkers of low malignancy to select candidates for limited resection without compromising the outcome of treatments. Recently we identified biglycan (BGN) as a tumor endothelial cell (TEC) marker that is associated with tumor progression in various cancers. In this study, we analyzed the association between BGN expression in TECs in lung cancer and cancer progression in patients. MATERIALS AND METHODS: First, we performed immunohistochemistry of BGN with resected lung tumor tissues of 155 patients who had undergone thoracic surgery and analyzed the correlation between BGN-positive vessel density in primary lung tumors and clinicopathological factors. Second, we measured the BGN levels in preoperative serum of other 46 patients with lung cancer by ELISA, and analyzed the correlation between BGN expression in tumor tissues and blood BGN levels. RESULTS: High BGN expression in the TECs was significantly associated with T factor, and was a significant negative predictor. BGN levels in preoperative serum of 46 patients with lung cancer was significantly correlated with BGN expression in the TECs. Preoperative serum BGN level was significantly lower in healthy volunteers and less invasive adenocarcinoma than in invasive adenocarcinoma and other lung carcinomas. These results suggest that low BGN level in preoperative serum in patients with lung cancer might indicate low malignancy. CONCLUSIONS: BGN can be a potential biomarker for lung cancer.

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First case of ductal adenocarcinoma of the prostate with MAP3K1 homozygous deletion.

Shojo K, Kosaka T, Nakamura K, Hongo H, Kobayashi H, Mikami S, Nishihara H, Oya M

IJU case reports 4 （ 3 ） 176 - 179 2021年05月

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Introduction: Ductal adenocarcinoma of the prostate is a rare prostate cancer variant and associated with higher stage and greater risk of mortality. Optimal systemic therapy for metastatic ductal adenocarcinoma is not known. Case presentation: A 67-year-old man presented with ductal adenocarcinoma of the prostate accompanied by multiple lung metastases and advanced bone metastases. We performed channel transurethral resection of the prostate and confirmed the diagnosis of ductal adenocarcinoma of the prostate. DNA sequencing identified a TP53 somatic point mutation (p.Gly245Ser) as the pathogenic variant. Furthermore, a homozygous deletion was observed in mitogen-activated protein kinase kinase kinase 1. The patient received enzalutamide but deceased 5 months after presenting to our institution. Conclusion: To our knowledge, this is the first report of ductal adenocarcinoma of the prostate with a mitogen-activated protein kinase kinase kinase 1 homozygous deletion. Accumulation of whole-exome sequencing data is expected to inform future advances in therapy development.

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Impact of clinical targeted sequencing on endocrine responsiveness in estrogen receptor-positive, HER2-negative metastatic breast cancer.

Hagio K, Amano T, Hayashi H, Takeshita T, Oshino T, Kikuchi J, Ohhara Y, Yabe I, Kinoshita I, Nishihara H, Yamashita H

Scientific reports 11 （ 1 ） 8109 - 8109 2021年04月

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Clinical targeted sequencing allows for the selection of patients expected to have a better treatment response, and reveals mechanisms of resistance to molecular targeted therapies based on actionable gene mutations. We underwent comprehensive genomic testing with either our original in-house CLHURC system or with OncoPrime. Samples from 24 patients with estrogen receptor-positive, human epidermal growth factor receptor 2-negative metastatic breast cancer underwent targeted sequencing between 2016 and 2018. Germline and somatic gene alterations and patients' prognosis were retrospectively analyzed according to the response to endocrine therapy. All of the patients had one or more germline and/or somatic gene alterations. Four patients with primary or secondary endocrine-resistant breast cancer harbored germline pathogenic variants of BRCA1, BRCA2, or PTEN. Among somatic gene alterations, TP53, PIK3CA, AKT1, ESR1, and MYC were the most frequently mutated genes. TP53 gene mutation was more frequently observed in patients with primary endocrine resistance compared to those with secondary endocrine resistance or endocrine-responsive breast cancer. Recurrent breast cancer patients carrying TP53-mutant tumors had significantly worse overall survival compared to those with TP53-wild type tumors. Our 160-gene cancer panel will be useful to identify clinically actionable gene alterations in breast cancer in clinical practice.

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Hamster PIWI proteins bind to piRNAs with stage-specific size variations during oocyte maturation.

Ishino K, Hasuwa H, Yoshimura J, Iwasaki YW, Nishihara H, Seki NM, Hirano T, Tsuchiya M, Ishizaki H, Masuda H, Kuramoto T, Saito K, Sakakibara Y, Toyoda A, Itoh T, Siomi MC, Morishita S, Siomi H

Nucleic acids research 49 （ 5 ） 2700 - 2720 2021年03月

査読有り,  ISSN  0305-1048

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Estimating copy number using next-generation sequencing to determine ERBB2 amplification status.

Nakamura K, Aimono E, Oba J, Hayashi H, Tanishima S, Hayashida T, Chiyoda T, Kosaka T, Hishida T, Kawakubo H, Kitago M, Okabayashi K, Funakoshi T, Okita H, Ikeda S, Takaishi H, Nishihara H

Medical oncology (Northwood, London, England) 38 （ 4 ） 36 - 36 2021年03月

査読有り,  ISSN  1357-0560

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Assessing Erb-b2 receptor tyrosine kinase 2 (ERBB2) amplification status in breast and gastric cancer is necessary for deciding the best therapeutic strategy. Immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) are currently used for assessing protein levels and gene copy number (CN), respectively. The use of next-generation sequencing (NGS) to measure ERBB2 CN in breast cancer is approved by the United States Federal Drug Administration as a companion diagnostic. However, a CN of less than 8 is evaluated as "equivocal", which means that some ERBB2 amplification cases diagnosed as "HER2 negative" might be false-negative cases. We reviewed the results of gene profiling targeting 160 cancer-related genes in breast (N = 90) and non-breast (N = 19) cancer tissue, and compared the ERBB2 CN results with the IHC/FISH scores. We obtained an estimated CN from the measured CN by factoring in the histological proportion of tumor cells and found that an ERBB2-estimated CN of 3.2 or higher was concordant with the combined IHC/FISH outcome in 98.4% (88/90) of breast cancer cases, while this was not always evident among non-breast cancer cases. Therefore, NGS-estimated ERBB2 CN could be considered a diagnostic test for anti-HER2 therapy after the completion of adequate prospective clinical trials.

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Delta-like 1 homolog (DLK1) as a possible therapeutic target and its application to radioimmunotherapy using (125)I-labelled anti-DLK1 antibody in lung cancer models (HOT1801 and FIGHT004).

Takagi H, Zhao S, Muto S, Yokouchi H, Nishihara H, Harada T, Yamaguchi H, Mine H, Watanabe M, Ozaki Y, Inoue T, Yamaura T, Fukuhara M, Okabe N, Matsumura Y, Hasegawa T, Osugi J, Hoshino M, Higuchi M, Shio Y, Kanno R, Aoki M, Tan C, Shimoyama S, Yamazaki S, Kikuchi H, Sakakibara-Konishi J, Oizumi S, Harada M, Akie K, Sugaya F, Fujita Y, Takamura K, Kojima T, Honjo O, Minami Y, Nishimura M, Dosaka-Akita H, Nakamura K, Inano A, Isobe H, Suzuki H

Lung cancer (Amsterdam, Netherlands) （Elsevier BV）  153   134 - 142 2021年03月

査読有り,  ISSN  0169-5002

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Genetic Profiling of Malignant Melanoma Arising from an Ovarian Mature Cystic Teratoma: A Case Report.

Nakamura K, Aimono E, Takamatsu R, Tanishima S, Tohyama T, Sasano K, Sakuma H, Nishihara H

International journal of molecular sciences （MDPI AG）  22 （ 5 ） 2436 - 2436 2021年02月

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Ovarian mature cystic teratomas comprise tissues derived from all three germ layers. In rare cases, malignant tumors arise from ovarian mature cystic teratoma. A variety of tumors can arise from mature cystic teratoma, among which primary malignant melanoma (MM), for which no molecular analyses such as genomic sequencing have been reported to date, is exceedingly rare, thereby limiting possible therapeutic options using precision medicine. We used targeted gene sequencing to analyze the status of 160 cancer-related genes in a patient with MM arising from an ovarian mature cystic teratoma (MM-MCT). KRAS amplification and homozygous deletion in PTEN and RB1 were detected in tumor samples collected from the patient. No KRAS amplification has been previously reported in cutaneous MM, indicating that the carcinogenesis of MM-MCT differs from that of primary cutaneous melanomas. A better understanding of the underlying genetic mechanisms will help clarify the carcinogenesis of MM-MCT. In turn, this will enable treatment with novel targeting agents as well as the initial exploration of gene-based precision oncological therapies, which aim to improve treatment outcomes for patients with this disease.

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Multiple squamous cell carcinomas arising on an epidermal nevus harboring HRAS p.G13R mutation.

Narahira A, Kitamura S, Maeda T, Nishihara H, Yanagi T

The Journal of dermatology 48 （ 2 ） e92-e93 - e93 2021年02月

査読有り,  ISSN  0385-2407

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Prognostic significance of OX40(+) lymphocytes in tumor stroma of surgically resected small-cell lung cancer.

Yokouchi H, Nishihara H, Harada T, Amano T, Ohkuri T, Yamazaki S, Kikuchi H, Oizumi S, Uramoto H, Tanaka F, Harada M, Akie K, Sugaya F, Fujita Y, Takamura K, Kojima T, Higuchi M, Honjo O, Minami Y, Watanabe N, Nishimura M, Suzuki H, Dosaka-Akita H, Isobe H

Oncoimmunology （Informa UK Limited）  10 （ 1 ） 1971430 2021年01月

査読有り,  ISSN  2162-4011

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