研究者詳細 - 山元　英崇

論文 - 山元　英崇

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High Prevalence of MYD88 and CD79B Mutations in Primary Sinonasal Diffuse Large B-Cell Lymphoma: Identification of an MCD-like Subtype. 査読国際誌

Fangli Peng, Takuro Igawa, Tomohiro Urata, Hiroki Kobayashi, Tetsuya Isoda, Sawako Ono, Takehiro Tanaka, Daisuke Ennisshi, Yoshinobu Maeda, Hidetaka Yamamoto

The American journal of surgical pathology 2024年10月

担当区分：最終著者記述言語：英語掲載種別：研究論文（学術雑誌）

Primary sinonasal diffuse large B-cell lymphoma (PSDLBCL) is a rare aggressive lymphoma. Recently, genetic classification using Next Generation Sequencing (NGS) demonstrated that PSDLBCL largely consists of the MCD genotype, which has a poor prognosis mainly driven by MYD88 L265P and CD79B gene abnormalities. This study investigated the prevalence and clinicopathological significance of MYD88 L265P and CD79B Y196 mutations using droplet digital PCR in 55 patients with PSDLBCL, as well as the translocation of BCL2/BCL6/c-Myc with FISH. We found mutations in MYD88 L265P (29/55, 52.7%) and CD79B Y196 (20/55, 36.4%). The MCD-like subtype, defined by the mutation of MYD88 and/or CD79B, was found in 32 out of 55 cases (58.2%). This subtype largely consists of non-GCB type (31/32, 96.9%; P<0.01) and double-expressor cases (20/32, 62.5%; P=0.01) compared with the MYD88/CD79B co-wild type, with BCL6 translocation in a small subset (2/32, 6.3%) and no translocations of BCL2 (0/32) or c-Myc (0/32). The MCD-like subtype tended to relapse in specific sites such as the central nervous system, testis, and/or skin compared with the co-wild type (P=0.03), showing poorer outcomes in overall survival (P=0.02) and progression-free survival (P=0.01). In conclusion, our study highlights a high prevalence of MYD88 and CD79B mutations in PSDLBCL, identifying an aggressive MCD-like subtype with a distinct relapse pattern. This molecular subclassification can be helpful for both prognostic prediction and therapeutic strategy in patients with PSDLBCL.

DOI： 10.1097/PAS.0000000000002329

Re-evaluation of histopathological factors for the outcome of salivary duct carcinoma patients: A multi-institutional retrospective study of 240 cases in a Japanese cohort. 国際誌

Kimihide Kusafuka, Eiji Nakatani, Satoshi Baba, Yoshifumi Arai, Matsuyoshi Maeda, Koji Yamanegi, Takayuki Murase, Hiroshi Inagaki, Yoshiro Otsuki, Kensuke Suzuki, Hiroshi Iwai, Yoshiaki Imamura, Shoji Yamanaka, Ichiro Ito, Midori Sato, Morito Kurata, Tsutomu Daa, Tomonori Kawasaki, Ryo Kawata, Yuri Tachibana, Junya Fukuoka, Takashi Suzuki, Hidetaka Yamamoto, Kazumori Arai, Makoto Suzuki

Human pathology 105736 - 105736 2025年2月

記述言語：英語掲載種別：研究論文（学術雑誌）

AIMS: Salivary duct carcinoma (SDC) is a relatively common, high-grade salivary gland malignancy that can often occur as a carcinomatous component of carcinoma ex pleomorphic adenoma (CXPA). This study aimed to elucidate the histological factors which are related to the outcome of SDC. METHODS AND RESULTS: We conducted a comprehensive histological review of 240 SDC cases and we analyzed the association between the histomorpholgical parameters and the clinical outcomes to identify new histological prognostic factors. The majority of cases involved the parotid glands (n = 197 cases). SDC showed a marked male predilection (M/F = 5.3:1), and the median age was 66 years-old. This study included 110 de novo cases and 130 CXPA cases. Multivariate analysis revealed that only the pathological stage was significantly associated with overall survival (OS), whereas previously reported histological parameters, such as poorly differentiated clusters, nuclear polymorphism, and mitotic index were not significantly associated with OS and progression-free survival (PFS). Vascular invasion (V [+]) was significantly associated with PFS, and lymphatic invasion was associated with late lymph node metastases. Even in the same pathological stage, V (+) cases always had the worse PFS than V (-) cases. CONCLUSIONS: The histopathological review determined that as distant metastasis relapse was the most important prognostic factor in patients with SDC, V (+) status was also a significant outcome indicator.

DOI： 10.1016/j.humpath.2025.105736

Kikuchi-Fujimoto disease: investigating comprehensive clinicopathological features and risk factors for recurrence. 国際誌

Midori Filiz Nishimura, Chikako Sakao, Yuka Kurokawa, Yoshito Nishimura, Asami Nishikori, Hidetaka Yamamoto, Yasuharu Sato

Histopathology 2025年2月

記述言語：英語掲載種別：研究論文（学術雑誌）

AIMS: Kikuchi-Fujimoto disease (KFD) is a rare disease that typically manifests with fever and cervical lymphadenopathy. Little is known about the risk factors associated with recurrence and their correlation with clinicopathologic features. METHODS AND RESULTS: We analysed 112 patients with KFD, predominantly female (61/112, 54.5%), with an average age of 29.4 years. The incidence was higher in males up to the age of 20 and higher in females from their 30s onwards. Of the 70 patients with follow-up data, 23% experienced recurrence. Recurrence was associated with lower C4 levels (P = 0.038) and higher antinuclear antibody (ANA) rates (P = 0.007) compared to transient disease. The mean duration of symptoms was 71.5 days. Lymph node histology in 98 cases (excluding 14 needle biopsy specimens) was classified into three patterns: proliferative (n = 75, 77%), necrotizing (n = 22, 22%), and xanthomatous (n = 1, 1%). The necrotizing pattern associated with significantly enlarged lymph nodes (P = 0.047) and a longer symptom duration (P = 0.009) than the proliferating pattern. The number of CD4-positive lymphocytes was significantly lower in the necrotizing type than in the proliferative type (P < 0.001). CONCLUSION: These results indicated that low C4 levels and positive ANA were associated with KFD recurrence. Although the aetiology of KFD remains elusive, given that some cases develop autoimmune disease, the results suggest that patients with recurrent KFD represent an intermediate status between those with transient KFD and those with overt autoimmune disease. The comprehensive clinicopathological findings of this study may be useful for elucidating its pathogenesis and predicting the clinical course.

DOI： 10.1111/his.15427

Myeloid Cells Induce Infiltration and Activation of B Cells and CD4+ T Follicular Helper Cells to Sensitize Brain Metastases to Combination Immunotherapy. 国際誌

Toshifumi Ninomiya, Naoya Kemmotsu, Fumiaki Mukohara, Masaki Magari, Ai Miyamoto, Youki Ueda, Takamasa Ishino, Joji Nagasaki, Tomohiro Fujiwara, Hidetaka Yamamoto, Hidetoshi Hayashi, Kota Tachibana, Joji Ishida, Yoshihiro Otani, Shota Tanaka, Shinichi Toyooka, Isamu Okamoto, Yosuke Togashi

Cancer research 2025年1月

記述言語：英語掲載種別：研究論文（学術雑誌）

Brain metastasis (BM) is a poor prognostic factor in cancer patients. Despite showing efficacy in many extracranial tumors, immunotherapy with anti-PD-1 monoclonal antibody (mAb) or anti-CTLA-4 mAb appears to be less effective against intracranial tumors. Promisingly, recent clinical studies have reported that combination therapy with anti-PD-1 and anti-CTLA-4 mAbs has a potent antitumor effect on BM, highlighting the need to elucidate the detailed mechanisms controlling the intracranial tumor microenvironment (TME) to develop effective immunotherapeutic strategies. Here, we analyzed the tumor-infiltrating lymphocytes in murine models of BM that responded to anti-CTLA-4 mAb to anti-PD-1 mAb. Activated CD4+ T follicular helper (TFH) cells with high CTLA-4 expression characteristically infiltrated the intracranial TME, which were activated by the combination anti-CTLA-4 and anti-PD-1 treatment. Loss of TFH cells suppressed the additive effect of CTLA-4 blockade on anti-PD-1 mAb. B cell-activating factor belonging to the TNF family (BAFF) and a proliferation-inducing ligand (APRIL) produced by abundant myeloid cells, particularly CD80hiCD206lo pro-inflammatory M1-like macrophages, in the intracranial TME, induced B cell and TFH cell infiltration and activation. Furthermore, the intracranial TME of patients with non-small cell lung cancer featured TFH and B cell infiltration as tertiary lymphoid structures. Together, these findings provide insights into the immune cell crosstalk in the intracranial TME that facilitates an additive anti-tumor effect of CTLA-4 blockade with anti-PD-1 treatment, supporting the potential of a combination immunotherapeutic strategy for BM.

DOI： 10.1158/0008-5472.CAN-24-2274

唾液腺粘液腺癌の遺伝子異常

中黒匡人, 浦野誠, 八木春奈, 山元英崇, 駄阿勉, 矢田直美, 辻隆裕, 中村康平, 長尾俊孝

日本唾液腺学会誌 64 34 - 34 2024年12月

唾液腺粘液腺癌の遺伝子異常

中黒匡人, 浦野誠, 八木春奈, 山元英崇, 駄阿勉, 矢田直美, 辻隆裕, 中村康平, 長尾俊孝

日本唾液腺学会誌 64 34 - 34 2024年12月

Spatial dynamics of CD39+CD8+ exhausted T cell reveal tertiary lymphoid structures-mediated response to PD-1 blockade in esophageal cancer. 査読国際誌

Kenro Tanoue, Hirofumi Ohmura, Koki Uehara, Mamoru Ito, Kyoko Yamaguchi, Kenji Tsuchihashi, Yudai Shinohara, Peng Lu, Shingo Tamura, Hozumi Shimokawa, Taichi Isobe, Hiroshi Ariyama, Yoshihiro Shibata, Risa Tanaka, Hitoshi Kusaba, Taito Esaki, Kenji Mitsugi, Daisuke Kiyozawa, Takeshi Iwasaki, Hidetaka Yamamoto, Yoshinao Oda, Koichi Akashi, Eishi Baba

Nature communications 15 ( 1 ) 9033 - 9033 2024年10月

記述言語：英語掲載種別：研究論文（学術雑誌）

Despite the success of immune checkpoint blockade (ICB) therapy for esophageal squamous cell cancer, the key immune cell populations that affect ICB efficacy remain unclear. Here, imaging mass cytometry of tumor tissues from ICB-treated patients identifies a distinct cell population of CD39+PD-1+CD8+ T cells, specifically the TCF1+ subset, precursor exhausted T (CD39+ Tpex) cells, which positively correlate with ICB benefit. CD39+ Tpex cells are predominantly in the stroma, while differentiated CD39+ exhausted T cells are abundantly and proximally within the parenchyma. Notably, CD39+ Tpex cells are concentrated within and around tertiary lymphoid structure (TLS). Accordingly, tumors harboring TLSs have more of these cells in tumor areas than tumors lacking TLSs, suggesting Tpex cell recruitment from TLSs to tumors. In addition, circulating CD39+ Tpex cells are also increased in responders following ICB therapy. Our findings show that this unique subpopulation of CD39+PD-1+CD8+ T cells is crucial for ICB benefit, and suggest a key role in TLS-mediated immune responses against tumors.

DOI： 10.1038/s41467-024-53262-w

The combination of p16 and Rb expression pattern is helpful to predict high-risk HPV infection and the primary site in lymph node metastases of squamous cell carcinoma. 査読国際誌

Ryosuke Kuga, Hidetaka Yamamoto, Fumiya Narutomi, Misa Suzuki, Rina Jiromaru, Takahiro Hongo, Kazuhisa Hachisuga, Nobuko Yasutake, Kiyoko Kato, Takashi Nakagawa, Yoshinao Oda

Pathology, research and practice 263 155642 - 155642 2024年10月

担当区分：責任著者記述言語：英語掲載種別：研究論文（学術雑誌）

Identifying the primary site of metastatic squamous cell carcinoma in lymph nodes can be challenging. An immunohistochemistry (IHC) analysis recently revealed that high-risk human papillomavirus (HR-HPV)-associated oropharyngeal squamous cell carcinomas (OPSCCs) typically show overexpression of p16 protein and a partial loss pattern of Rb. Nevertheless, the status of these markers in metastatic lesions is still unclear. In this study, we examined p16 and Rb expression status by IHC and transcriptionally active HR-HPV infection by mRNA in situ hybridization in paired primary and metastatic SCC lesions. A total of 50 patients with OPSCCs (n=17), hypopharyngeal SCCs (n=16), laryngeal SCCs (n=6), or uterine cervical SCCs (n=11) were enrolled. HR-HPV and p16 were positive in 21/50 (42 %) and 23/50 (46 %) patients, respectively. Primary and metastatic lesions showed concordant results for those three markers in individual patients. Among the p16-positive patients (n=23), HPV-positive cases typically showed a partial loss of Rb (n=20) and, rarely, a complete loss of Rb (n=1), whereas HPV-negative cases showed preserved Rb expression (n=2). All 27 p16-negative cases lacked HPV infection, while preserved expression and complete loss of Rb were observed in 26 and 1 of the p16-negative cases, respectively. Compared to standalone p16, the combination of p16 overexpression and Rb-partial/complete loss showed equally excellent sensitivity and negative predictive value (each 100 %) as well as improved specificity (100 % versus 93.1 %) and positive predictive value (100 % versus 91.3 %). Our results suggest that combining p16 and Rb expression patterns may be helpful in screening for HR-HPV infection in metastatic lymph nodes and in estimating the primary site of SCC.

DOI： 10.1016/j.prp.2024.155642

Clinicopathological Review of Head and Neck Squamous Cell Carcinomas After Neoadjuvant Chemotherapy. 査読国際誌

Ryosuke Kuga, Kazuki Hashimoto, Hidetaka Yamamoto, Midori Taniguchi, Tomomi Manako, Masanobu Sato, Ryunosuke Kogo, Mioko Matsuo, Yoshinao Oda, Takashi Nakagawa

Anticancer research 44 ( 10 ) 4593 - 4603 2024年10月

記述言語：英語掲載種別：研究論文（学術雑誌）

BACKGROUND/AIM: The benefit of neoadjuvant chemotherapy (NAC) in the treatment of head and neck squamous cell carcinoma (HNSCC) remains unclear. PATIENTS AND METHODS: We retrospectively collected 30 patients with HNSCC who had undergone radical resection after NAC. We pathologically evaluated the therapeutic response to NAC, and classified the residual tumor patterns. In addition, we compared the maximum horizontal diameter on pathology with imaging. RESULTS: The residual patterns were categorized as follows: 10 cases of shrunken type, 11 cases of mixed type, and seven cases of fragmented type. The majority of underestimation cases - those cases in which the maximum horizontal diameter measured on post-NAC imaging was less than the pathological size after resection - were multifocal residual lesions, with a tendency for more frequent "positive" or "close" surgical margins. CONCLUSION: The strategy of performing NAC to reduce resection volume is not appropriate, and resection margins should be based on the assessment before NAC.

DOI： 10.21873/anticanres.17289

Breast mucoepidermoid carcinoma with a rare CRTC3–MAML2 fusion 査読国際誌

Kana Kawaguchi, Hideki Ijichi, Hiroki Ueo, Yuichi Hisamatsu, Sachie Omori, Tomoko Shigechi, Kengo Kawaguchi, Hidetaka Yamamoto, Yoshinao Oda, Makoto Kubo, Tomoharu Yoshizumi

International Cancer Conference Journal 13 ( 4 ) 481 - 487 2024年8月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Springer Science and Business Media LLC

Mucoepidermoid carcinoma is the most prevalent malignancy in the salivary gland and is sporadic in the breast. Here, we report a case of breast mucoepidermoid carcinoma with a rare CREB-regulated transcription coactivator 3-mastermind-like transcriptional coactivator 2 (CRTC3-MAML2) fusion. A 23-year-old female was admitted to our hospital with a left breast palpable mass. Histologic findings of the core-needle biopsy indicated breast cancer. The section revealed a squamoid tumor-cell proliferation with enlarged nuclei and eosinophilic cytoplasm among smaller intermediate cells and abundant cystic spaces containing secretory materials. The features were compatible with mucoepidermoid carcinoma in low-grade, confirmed by detecting the CRTC3-MAML2 fusion using reverse transcription polymerase chain reaction and direct sequencing. We only administered tamoxifen postoperatively without other adjuvant therapy because her tumor partially expressed hormonal receptors. No signs indicate a recurrence or metastasis in our over 3 year follow-up. The genetic analysis helps in definitively diagnosing breast mucoepidermoid carcinoma, and the treatment strategy should be considered based on the histologic findings.

DOI： 10.1007/s13691-024-00713-2

その他リンク： https://link.springer.com/article/10.1007/s13691-024-00713-2/fulltext.html

Expression of Forkhead Box M1 and Anticancer Effects of FOXM1 Inhibition in Epithelioid Sarcoma. 査読国際誌

Yuichi Shibui, Kenichi Kohashi, Yuko Hino, Akihiko Tamaki, Izumi Kinoshita, Hidetaka Yamamoto, Yasuharu Nakashima, Tatsuro Tajiri, Yoshinao Oda

Laboratory investigation; a journal of technical methods and pathology 104 ( 8 ) 102093 - 102093 2024年8月

記述言語：英語掲載種別：研究論文（学術雑誌）

Epithelioid sarcoma (ES) is a rare aggressive sarcoma that, unlike most soft-tissue sarcomas, shows a tendency toward local recurrence and lymph node metastasis. Novel antitumor agents are needed for ES patients. Forkhead box transcription factor 1 (FOXM1) is a member of the Forkhead transcription factor family and is associated with multiple oncogenic functions; FOXM1 is known to be overexpressed and correlated with pathogenesis in various malignancies. In this study, we immunohistochemically analyzed FOXM1 expression levels and their clinical, clinicopathologic, and prognostic significance in 38 ES specimens. In addition, to investigate potential correlations between FOXM1 downregulation and oncologic characteristics, we treated ES cell lines with thiostrepton, a naturally occurring antibiotic that inhibits both small interfering RNA (siRNA) and FOXM1. In the analyses using ES samples, all 38 specimens were diagnosed as positive for FOXM1 by immunohistochemistry. We separated specimens into high (n = 19) and low (n = 19) FOXM1-protein expression groups by staining index score, and into large (n = 12), small (n = 25), and unknown (n = 1) tumor-size groups using a cutoff of 5 cm maximum diameter. Although there were significantly more samples with high FOXM1 expression in the large tumor group (P = .013), there were no significant differences with respect to age (P = 1.00), sex (P = .51), primary site of origin (P = .74), histologic subtypes (P = 1.00), depth (P = .74), or survival rate (P = .288) between the high and low FOXM1-protein expression groups. In the in vitro experiments using ES cell lines, FOXM1 siRNA and thiostrepton successfully downregulated FOXM1 mRNA and protein expression. Furthermore, downregulation of FOXM1 inhibited cell proliferation, drug resistance against chemotherapeutic agents, migration, and invasion and caused cell cycle arrest in the ES cell lines. Finally, cDNA microarray analysis data showed that FOXM1 regulated cIAP2, which is one of the apoptosis inhibitors activated by the TNFα-mediated NF-κB pathway. In conclusion, the FOXM1 gene may be a promising therapeutic target for ES.

DOI： 10.1016/j.labinv.2024.102093

Reappraisal of bone and soft tissue cytopathology classification using the modified Milan system. 査読国際誌

Masaki Naka, Hidetaka Yamamoto, Kenichi Kohashi, Takeshi Iwasaki, Taro Mori, Miwako Nogami, Fumihiko Ookubo, Kayoko Higuchi, Toru Motoi, Yoshinao Oda

Cancer cytopathology 132 ( 11 ) 696 - 706 2024年7月

担当区分：責任著者記述言語：英語掲載種別：研究論文（学術雑誌）

BACKGROUND: A standardized reporting system for bone and soft tissue tumor cytopathology has not yet been established. The objective of this study was to explore the potential utility of a classification modified from the Milan System for Salivary Gland Cytopathology and compared it with the upcoming World Health Organization (WHO) system for fine-needle aspiration of soft tissue lesions. METHODS: The authors reviewed 285 cytology cases of bone/joint (n = 173) and soft tissue (n = 112) lesions, scoring each within diagnostic categories. The results were compared with histologic diagnoses and the risk of malignancy (ROM) for each category, and diagnostic reliability was analyzed. RESULTS: All 285 cases were successfully classified into one of the following categories: nondiagnostic (6.3%), non-neoplastic (11.9%), atypia of uncertain significance (11.9%), benign neoplasm (5.6%), bone and soft tissue neoplasm of uncertain malignant potential (25.3%), suspicious for malignancy (1.4%), and malignant (37.5%). The ROM was 44.4% (eight of /18 cases) in nondiagnostic, 0% (zero of 34 cases) in non-neoplastic, 32.4% (11 of 34 cases) in atypia of uncertain significance, 0% (zero of 16 cases) in benign neoplasm, 16.7% (12 of 72 cases) in bone and soft tissue neoplasm of uncertain malignant potential, 75.0% (three of four cases) in suspicious for malignancy, and 100% (107 of 107 cases) in malignant categories. Using the WHO system, the proportion and ROM of the benign category (non-neoplastic and benign neoplasm) was 17.5% and 0%, respectively. Among benign and malignant lesions, the diagnostic accuracy, sensitivity, and specificity for detecting malignancy were 99.4%, 100%, and 98.0%, respectively. CONCLUSIONS: The modified Milan system as well as the WHO system may be a useful cytopathologic classification tool for both bone and soft tissue lesions.

DOI： 10.1002/cncy.22888

English version of Japanese Clinical Practice Guidelines 2022 for gastrointestinal stromal tumor (GIST) issued by the Japan Society of Clinical Oncology. 査読

Seiichi Hirota, Ukihide Tateishi, Yuji Nakamoto, Hidetaka Yamamoto, Shinji Sakurai, Hirotoshi Kikuchi, Tatsuo Kanda, Yukinori Kurokawa, Haruhiko Cho, Toshirou Nishida, Akira Sawaki, Masato Ozaka, Yoshito Komatsu, Yoichi Naito, Yoshitaka Honma, Fumiaki Takahashi, Hironobu Hashimoto, Midori Udo, Minako Araki, Sumito Nishidate

International journal of clinical oncology 29 ( 6 ) 647 - 680 2024年6月

記述言語：英語掲載種別：研究論文（学術雑誌）

The Japan Society of Clinical Oncology Clinical Practice Guidelines 2022 for gastrointestinal stromal tumor (GIST) have been published in accordance with the Minds Manual for Guideline Development 2014 and 2017. A specialized team independent of the working group for the revision performed a systematic review. Since GIST is a rare type of tumor, clinical evidence is not sufficient to answer several clinical and background questions. Thus, in these guidelines, we considered that consensus among the experts who manage GIST, the balance between benefits and harms, patients' wishes, medical economic perspective, etc. are important considerations in addition to the evidence. Although guidelines for the treatment of GIST have also been published by the National Comprehensive Cancer Network (NCCN) and the European Society for Medical Oncology (ESMO), there are some differences between the treatments proposed in those guidelines and the treatments in the present guidelines because of the differences in health insurance systems among countries.

DOI： 10.1007/s10147-024-02488-1

Hemizygous deletion of CDKN2A/B with p16 immuno-negative and methylthioadenosine phosphorylase retention predicts poor prognosis in IDH-mutant adult glioma 査読国際誌

Ryosuke Otsuji, Nobuhiro Hata, Hidetaka Yamamoto, Daisuke Kuga, Ryusuke Hatae, Yuhei Sangatsuda, Yutaka Fujioka, Naoki Noguchi, Aki Sako, Osamu Togao, Tadamasa Yoshitake, Akira Nakamizo, Masahiro Mizoguchi, Koji Yoshimoto

Neuro-Oncology Advances 6 ( 1 ) vdae069 2024年5月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Oxford University Press (OUP)

Abstract

Background

Homozygous deletion of the tumor suppression genes cyclin-dependent kinase inhibitor 2A/B (CDKN2A/B) is a strong adverse prognostic factor in IDH-mutant gliomas, particularly astrocytoma. However, the impact of hemizygous deletion of CDKN2A/B is unknown. Furthermore, the influence of CDKN2A/B status in IDH-mutant and 1p/19q-codeleted oligodendroglioma remains controversial. We examined the impact of CDKN2A/B status classification, including hemizygous deletions, on the prognosis of IDH-mutant gliomas.

Methods

We enrolled 101 adults with IDH-mutant glioma between December 2002 and November 2021. CDKN2A/B deletion was evaluated with multiplex ligation-dependent probe amplification (MLPA). Immunohistochemical analysis of p16/MTAP and promoter methylation analysis with methylation-specific MLPA was performed for cases with CDKN2A/B deletion. Kaplan−Meier plots and Cox proportion hazards model analyses were performed to evaluate the impact on overall (OS) and progression-free survival.

Results

Of 101 cases, 12 and 4 were classified as hemizygous and homozygous deletion, respectively. Immunohistochemistry revealed p16-negative and MTAP retention in cases with hemizygous deletion, whereas homozygous deletions had p16-negative and MTAP loss. In astrocytoma, OS was shorter in the order of homozygous deletion, hemizygous deletion, and copy-neutral groups (median OS: 38.5, 59.5, and 93.1 months, respectively). Multivariate analysis revealed hazard ratios of 9.30 (p=0.0191) and 2.44 (p=0.0943) for homozygous and hemizygous deletions, respectively.

Conclusions

CDKN2A/B hemizygous deletions exerted a negative impact on OS in astrocytoma. Immunohistochemistry of p16/MTAP can be utilized to validate hemizygous or homozygous deletions in combination with conventional molecular diagnosis.

DOI： 10.1093/noajnl/vdae069

Squamous cell carcinoma initially occurring on the tongue dorsum: a case series report with molecular analysis. 国際誌

Sawako Ono, Katsutoshi Hirose, Shintaro Sukegawa, Kyoichi Obata, Masanori Masui, Kazuaki Hasegawa, Ai Fujimura, Katsumitsu Shimada, Satoko Nakamura, Akari Teramoto, Yumiko Hori, Eiichi Morii, Daisuke Motooka, Takuro Igawa, Takehiro Tanaka, Hitoshi Nagatsuka, Satoru Toyosawa, Hidetaka Yamamoto

Diagnostic pathology 19 ( 1 ) 63 - 63 2024年4月

担当区分：最終著者記述言語：英語掲載種別：研究論文（学術雑誌）

BACKGROUND: Squamous cell carcinoma (SCC) of the dorsum of the tongue is extremely rare, and it clinically resembles various benign lesions. Somatic mutations in TP53 and some driver genes were implicated in the development of SCC; however, the somatic genetic characteristics of dorsal tongue SCC remain unknown. With a detailed analysis of gene mutations in dorsal tongue SCC, we aimed to better understand its biology. METHODS: Four cases of SCC initially occurring on the tongue dorsum were evaluated for clinical and histological findings and immunohistochemical expression of p53 and p16. Gene mutations were analyzed using next-generation sequencing with a custom panel of driver genes. RESULTS: We retrospectively investigated 557 cases of tongue SCC, and only four cases of SCC initially occurred on the tongue dorsum. The four patients (cases 1-4) were one woman and three men with a mean age of 53.75 years (range: 15-74 years). Histological analysis revealed well-differentiated SCC. Through molecular analysis, we identified pathogenic somatic mutations, namely, TP53 p.C176F (c.527G > T) in case 3 and TP53 p.R282W (c.844 C > T) in case 4. No pathogenic variants were identified in the PI3K/AKT or RAS/RAF pathways. The p53 immunohistochemical examination revealed a wild-type expression pattern in cases 1-3 and strong expression in case 4. The results of p16 immunostaining were negative in all cases. CONCLUSIONS: We described four previously unreported genetic characteristics of dorsal tongue SCC. Somatic TP53 mutations may contribute to the development of a subset of dorsal tongue SCC; however, more cases with genetic analysis need to be accumulated.

DOI： 10.1186/s13000-024-01487-0

Immunohistochemical p16 overexpression and Rb loss correlate with high-risk human papillomavirus infection in endocervical adenocarcinomas. 査読国際誌

Nobuko Yasutake, Hidetaka Yamamoto, Ryosuke Kuga, Rina Jiromaru, Takahiro Hongo, Yoshihiro Katayama, Kenzo Sonoda, Hideaki Yahata, Kiyoko Kato, Yoshinao Oda

Histopathology 84 ( 7 ) 1178 - 1191 2024年3月

担当区分：責任著者記述言語：英語掲載種別：研究論文（学術雑誌）

AIMS: p16 is a sensitive surrogate marker for transcriptionally active high-risk human papillomavirus (HR-HPV) infection in endocervical adenocarcinoma (ECA); however, its specificity is not perfect. METHODS AND RESULTS: We examined p16 and Rb expressions by immunohistochemistry (IHC) and the transcriptionally active HR-HPV infection by mRNA in-situ hybridisation (ISH) with histological review in 108 ECA cases. Thirteen adenocarcinomas of endometrial or equivocal origin (six endometrioid and seven serous carcinomas) were compared as the control group. HR-HPV was detected in 83 of 108 ECA cases (77%), including five HPV-associated adenocarcinomas in situ and 78 invasive HPV-associated adenocarcinomas. All 83 HPV-positive cases showed consistent morphology, p16 positivity and partial loss pattern of Rb. Among the 25 cases of HPV-independent adenocarcinoma, four (16%) were positive for p16, and of these four cases, three of 14 (21%) were gastric type adenocarcinomas and one of 10 (10%) was a clear cell type adenocarcinoma. All 25 HPV-independent adenocarcinomas showed preserved expression of Rb irrespective of the p16 status. Similarly, all 13 cases of the control group were negative for HR-HPV with preserved expression of Rb, even though six of 13 (46%) cases were positive for p16. Compared with p16 alone, the combination of p16 overexpression and Rb partial loss pattern showed equally excellent sensitivity (each 100%) and improved specificity (100 versus 73.6%) and positive predictive values (100 versus 89.2%) in the ECA and control groups. Furthermore, HR-HPV infection correlated with better prognosis among invasive ECAs. CONCLUSIONS: The results suggest that the combined use of p16 and Rb IHC could be a reliable method to predict HR-HPV infection in primary ECAs and mimics. This finding may contribute to prognostic prediction and therapeutic strategy.

DOI： 10.1111/his.15169

DDIT3-amplified or low-polysomic pleomorphic sarcomas without MDM2 amplification: Clinicopathological review and immunohistochemical profile of nine cases. 査読国際誌

Taro Mori, Takeshi Iwasaki, Hiroki Sonoda, Kengo Kawaguchi, Takumi Tomonaga, Hiroshi Furukawa, Chiaki Sato, Sakura Shiraishi, Kenichi Taguchi, Sadafumi Tamiya, Reiko Yoneda, Yumi Oshiro, Tomoya Matsunobu, Chie Abe, Yusuke Kuboyama, Nozomi Ueki, Kenichi Kohashi, Hidetaka Yamamoto, Yasuharu Nakashima, Yoshinao Oda

Human pathology 145 56 - 62 2024年3月

記述言語：英語掲載種別：研究論文（学術雑誌）

Several high-grade pleomorphic sarcoma cases that cannot be classified into any existing established categories have been reported. These cases were provisionally classified into undifferentiated pleomorphic sarcoma (UPS). Some dedifferentiated liposarcoma (DDLS) cases may also have been classified into the UPS category due to the absence of MDM2 amplification or an atypical lipomatous tumor/well-differentiated liposarcoma component. We retrieved and reviewed 77 high-grade pleomorphic sarcoma cases, initially diagnosed as UPS in 66 cases and DDLS in 11 cases. Fluorescence in situ hybridization (FISH) analyses of DDIT3 and MDM2 were performed for available cases. Of the cases successfully subjected to DDIT3 FISH (n = 56), nine (7 UPS and 2 DDLS) showed DDIT3 amplification but no MDM2 amplification. Two UPS cases showed both telomeric (5') and centromeric (3') amplification of DDIT3 or low polysomy of chromosome 12, whereas 5 UPS and 2 DDLS cases showed 5'-predominant DDIT3 amplification. Histopathologically, all cases showed UPS-like proliferation of atypical pleomorphic tumor cells. Immunohistochemically, only one case showed focal nuclear positivity for DDIT3, supporting the previous finding that DDIT3 expression was not correlated with DDIT3 amplification. All three cases with focal MDM2 expression involved 5'-predominant amplification, two of which showed DDLS-like histological features. The majority of cases (7/9) showed decreased expression in p53 staining, suggesting that DDIT3 amplification regulates the expression of TP53 like MDM2. From a clinicopathological perspective, we hypothesize that DDIT3-amplified sarcoma, especially with 5'-predominant amplification, can be reclassified out of the UPS category.

DOI： 10.1016/j.humpath.2024.02.007

Diagnostic challenges of the idiopathic plasmacytic lymphadenopathy (IPL) subtype of idiopathic multicentric Castleman disease (iMCD): Factors to differentiate from IgG4-related disease. 査読国際誌

Asami Nishikori, Midori Filiz Nishimura, David C Fajgenbaum, Yoshito Nishimura, Kanna Maehama, Tomoka Haratake, Tetsuya Tabata, Mitsuhiro Kawano, Naoya Nakamura, Shuji Momose, Remi Sumiyoshi, Tomohiro Koga, Hidetaka Yamamoto, Frits van Rhee, Atsushi Kawakami, Yasuharu Sato

Journal of clinical pathology 2024年2月

記述言語：英語掲載種別：研究論文（学術雑誌）

AIMS AND METHODS: Idiopathic multicentric Castleman disease (iMCD) is currently considered to be classified into three clinical subtypes, including idiopathic plasmacytic lymphadenopathy (IPL), thrombocytopaenia, anasarca, fever, reticulin fibrosis/renal dysfunction, organomegaly (TAFRO) and not otherwise specified (NOS). Among the three, iMCD-IPL closely mimics IgG4-related disease (IgG4-RD). In diagnosing IgG4-RD, it is sometimes challenging to distinguish iMCD-IPL patients that also meet the histological diagnostic criteria for IgG4-RD. In this study, we focused on the number of IgG4-positive cells in the lymph nodes and analysed the relationship with laboratory findings to distinguish iMCD-IPL from IgG4-RD. Thirty-nine patients with iMCD-IPL and 22 patients with IgG4-RD were included. RESULTS: Among the cases considered to be iMCD-IPL, 33.3% (13/39) cases also met the histological diagnostic criteria for IgG4-RD and serum IgG4 levels were not different between the two groups. However, the serum IgG4/IgG ratio was significantly higher in IgG4-RD, with a cut-off value of 19.0%. Additionally, a significant positive correlation between serum IgG levels and the number of IgG4-positive cells was observed in iMCD-IPL (p=0.001). The serum IgG cut-off value for distinguishing iMCD-IPL meeting histological criteria for IgG4-RD from other iMCD-IPL was 5381 mg/dL. CONCLUSIONS: iMCD-IPL cases with high serum IgG levels (>5000 mg/dL) were likely to meet the diagnostic criteria for IgG4-RD because of the numerous IgG4-positive cells observed. A combination of clinical presentations, laboratory values including the serum IgG4/IgG ratios and histological analysis is crucial for diagnosis of IgG4-RD and iMCD-IPL.

DOI： 10.1136/jcp-2023-209280

Analysis of Notch1 protein expression in methotrexate-associated lymphoproliferative disorders. 査読

Takeshi Okatani, Midori Filiz Nishimura, Yuria Egusa, Sayako Yoshida, Yoshito Nishimura, Asami Nishikori, Tadashi Yoshino, Hidetaka Yamamoto, Yasuharu Sato

Journal of clinical and experimental hematopathology : JCEH 64 ( 1 ) 1 - 9 2024年1月

記述言語：英語掲載種別：研究論文（学術雑誌）

Methotrexate (MTX)-associated lymphoproliferative disorder (MTX-LPD) is a lymphoproliferative disorder in patients treated with MTX. The mechanism of pathogenesis is still elusive, but it is thought to be a complex interplay of factors, such as underlying autoimmune disease activity, MTX use, Epstein-Barr virus infection, and aging. The NOTCH genes encode receptors for a signaling pathway that regulates various fundamental cellular processes, such as proliferation and differentiation during embryonic development. Mutations of NOTCH1 have been reported in B-cell tumors, including chronic lymphocytic leukemia/lymphoma, mantle cell lymphoma, and diffuse large B-cell lymphoma (DLBCL). Recently, it has also been reported that NOTCH1 mutations are found in post-transplant lymphoproliferative disorders, and in CD20-positive cells in angioimmunoblastic T-cell lymphoma, which might be associated with lymphomagenesis in immunodeficiency. In this study, to investigate the association of NOTCH1 in the pathogenesis of MTX-LPD, we evaluated protein expression of Notch1 in nuclei immunohistochemically in MTX-LPD cases [histologically DLBCL-type (n = 24) and classical Hodgkin lymphoma (CHL)-type (n = 24)] and de novo lymphoma cases [DLBCL (n = 19) and CHL (n = 15)]. The results showed that among MTX-LPD cases, the expression of Notch1 protein was significantly higher in the DLBCL type than in the CHL type (P < 0.001). In addition, among DLBCL morphology cases, expression of Notch1 tended to be higher in MTX-LPD than in the de novo group; however this difference was not significant (P = 0.0605). The results showed that NOTCH1 may be involved in the proliferation and tumorigenesis of B cells under the use of MTX. Further research, including genetic studies, is necessary.

DOI： 10.3960/jslrt.23038

Granzyme K- and amphiregulin-expressing cytotoxic T cells and activated extrafollicular B cells are potential drivers of IgG4-related disease. 査読国際誌

Risako Koga, Takashi Maehara, Ryuichi Aoyagi, Ryusuke Munemura, Yuka Murakami, Atsushi Doi, Michihito Kono, Hidetaka Yamamoto, Hiroaki Niiro, Tamotsu Kiyoshima, Mika Tanabe, Toshiaki Nakano, Yuta Matsukuma, Mitsuhiro Kawano, John H Stone, Shiv Pillai, Seiji Nakamura, Shintaro Kawano

The Journal of allergy and clinical immunology 153 ( 4 ) 1095 - 1112 2023年12月

記述言語：英語掲載種別：研究論文（学術雑誌）

BACKGROUND: IgG4-related disease (IgG4-RD), an example of a type I immune disease, is an immune-mediated fibrotic disorder characterized by dysregulated resolution of severe inflammation and wound healing. However, truly dominant or pathognomonic autoantibodies related to IgG4-RD are not identified. OBJECTIVE: We performed single-cell RNA sequencing (scRNA-seq) and T-cell receptor (TCR) and B-cell receptor (BCR) sequencing to obtain a comprehensive, unbiased view of tissue-infiltrating T- and B-cells. METHODS: We performed unbiased scRNA-seq analysis for the transcriptome and TCR-seq and BCR-seq on sorted CD3+ T- or CD19+ B-cells from affected tissues of patients with IgG4-RD. We also conducted quantitative analyses of CD3+ T and CD19+ B subsets in 68 IgG4-RD and 30 Sjögren's syndrome (SjS) patients. RESULTS: Almost all clonally expanded T cells in these lesions were either Granzyme K (GZMK)-expressing CD4+ cytotoxic T cells (CTLs) or GZMK+CD8+ T cells. These GZMK-expressing CTLs also expressed amphiregulin and TGFβ but did not express immune-checkpoints, and the tissue-infiltrating CD8+ T cells were phenotypically heterogeneous. MKI67+ B cells and IgD-CD27-CD11c-CXCR5- double-negative 3 B cells were clonally expanded and infiltrated affected tissue lesions. GZMK+CD4+ CTLs co-localized with MKI67+ B cells in the extrafollicular area from affected tissue sites. CONCLUSION: The abovementioned cells likely participate in T-B collaborative events, suggesting possible avenues for targeted therapies. Our findings were validated using orthogonal approaches, including multicolor immunofluorescence and the use of comparator disease groups, to support the central role of cytotoxic CD4+ and CD8+ T cells expressing GZMK, amphiregulin, and TGFβ in the pathogenesis of inflammatory fibrotic disorders.

DOI： 10.1016/j.jaci.2023.11.916

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