Faculty Profiles - SATO Yasuharu

Papers - SATO Yasuharu

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Clinicopathological differential diagnosis of IgG4-related disease: A historical overview and a proposal of the criteria for excluding mimickers of IgG4-related disease. Reviewed International journal

Akira Satou, Kenji Notohara, Yoh Zen, Shigeo Nakamura, Tadashi Yoshino, Kazuichi Okazaki, Yasuharu Sato

Pathology international 70 ( 7 ) 391 - 402 2020.7

Authorship：Last author Language：English Publishing type：Research paper (scientific journal)

IgG4-related disease (RD) is a relatively new entity, which was first proposed in 2001. Since then, clinical and pathological characteristics of the disease have been investigated. As IgG4-RD has been studied extensively, the diagnostic criteria for IgG4-RD of each organ and the comprehensive diagnostic criteria for IgG4-RD have also been developed. However, one of the biggest challenges in the field is distinguishing between IgG4-RD and mimickers, which show overlapping features with IgG4-RD. It is now known that some non-IgG4-RDs may meet the diagnostic criteria of IgG4-RD and can be misdiagnosed as IgG4-RD. However, accurate diagnosis is crucial, as the treatments for IgG4-RD and those for other diseases that may be misdiagnosed as IgG4-RD are different. This prompted us to create and propose comprehensive exclusion criteria for IgG4-RD. In this review, we have described the comprehensive exclusion criteria for IgG4-RD, with a historical overview of the disease. These exclusion criteria were recently created by the Research Program for Intractable Disease of the Ministry of Health, Labor, and Welfare of Japan, All Japan IgG4 team, to support correct and accurate diagnosis of IgG4-RD.

DOI： 10.1111/pin.12932

MACC1 expression is an indicator of recurrence in early-stage glottic cancer. Reviewed International journal

Takuma Makino, Yorihisa Orita, Yuka Gion, Tomoyasu Tachibana, Soshi Takao, Hidenori Marunaka, Kentaro Miki, Naoki Akisada, Yusuke Akagi, Tadashi Yoshino, Kazunori Nishizaki, Yasuharu Sato

Japanese journal of clinical oncology 50 ( 4 ) 392 - 398 2020.4

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

BACKGROUND: Metastasis-associated in colon cancer 1 (MACC1) has been reported to be an independent indicator of poor prognoses in some kinds of cancer due to disease metastasis or recurrence. We investigated the correlation between MACC1 expression and the prognosis of glottic cancer. METHODS: Paraffin-embedded, early-stage (I or II) glottic cancer specimens (n = 52) were immunohistochemically analyzed to explore MACC1 expression. The clinical records associated with each case were also examined. Recurrence-free survival (RFS) was estimated using the Kaplan-Meier method, and between-group RFS differences were assessed using the log-rank test. The multivariate analyses were evaluated using the Cox's proportional-hazard model. RESULTS: Patients were treated with only radiotherapy (RT) (n = 37, including 18 with T1 disease and 19 with T2 disease), or with chemoradiotherapy (CRT) (n = 15, including 1 with T1 disease and 14 with T2 disease). Eleven patients demonstrated local recurrence and two patients experienced cervical lymph node recurrence. Tumor specimens were MACC1-positive in 9 of the 13 (69.2%) patients with local or neck recurrence, and 7 of the 11 (63.6%) patients with local recurrence. The RFS rate of patients who were treated with only RT was significantly lower than that of patients who were treated with CRT (P = 0.0243). The RFS rate was significantly lower in cases with MACC1 expression than in those without MACC1 expression (P = 0.0003). Multivariate analysis revealed that MACC1 expression was an independent risk factor of local recurrence (P = 0.0016). CONCLUSION: MACC1 is an independent indicator of recurrence related to RFS in early-stage glottic cancer.

DOI： 10.1093/jjco/hyz206

Hemosiderin deposition in lymph nodes of patients with plasma cell-type Castleman disease. Reviewed

Yanyan Han, Takuro Igawa, Kyohei Ogino, Asami Nishikori, Yuka Gion, Tadashi Yoshino, Yasuharu Sato

Journal of clinical and experimental hematopathology : JCEH 60 ( 1 ) 1 - 6 2020.3

Authorship：Last author Language：English Publishing type：Research paper (scientific journal)

Plasma cell-type Castleman disease (PCD) is a rare idiopathic atypical lymphoproliferative disorder. It is difficult to differentiate between PCD and IgG4-related disease (IgG4-RD) based on histology alone. As PCD often presents with abundant hemosiderin deposition, lymph node lesions obtained from 22 PCD patients and 12 IgG4-RD patients were analyzed using Prussian blue staining to clarify whether hemosiderin deposition is effective in distinguishing between these two diseases. The analysis disclosed that hemosiderin was more densely deposited in PCD than in IgG4-RD. The median number of Prussian blue-positive cells ± standard deviation (SD) in PCD and IgG4-RD cases was 13 ± 36 cells/3HPFs and 4 ± 8 cells/3HPFs (P = 0.034), respectively. In addition, we analyzed the relationship between hemosiderin deposition and levels of serum interleukin (IL)-6, serum C-reactive protein (CRP), and anemia-related biomarkers. We found that hemosiderin deposition was significantly correlated with the level of serum CRP (P = 0.045); however, no significant correlation was observed between hemosiderin deposition and serum IL-6 levels (P = 0.204). A non-significant positive correlation was observed between hemosiderin deposition and serum hemoglobin levels (P=0.09). Furthermore, no significant correlation was observed between hemosiderin deposition and serum iron levels (P = 0.799). In conclusion, hemosiderin deposition characteristically observed in PCD may be related to the inflammatory aggressiveness of the disease and could be used for its differential diagnosis.

DOI： 10.3960/jslrt.19037

Serum IgG4 as a biomarker reflecting pathophysiology and post-operative recurrence in chronic rhinosinusitis. Reviewed International journal

Oka A, Ninomiya T, Fujiwara T, Takao S, Sato Y, Gion Y, Minoura A, Haruna SI, Yoshida N, Sakuma Y, Izuhara K, Ono J, Taniguchi M, Haruna T, Higaki T, Kariya S, Koyama T, Takabayashi T, Imoto Y, Sakashita M, Kidoguchi M, Nishizaki K, Fujieda S, Okano M

Allergology international : official journal of the Japanese Society of Allergology 69 ( 3 ) 417 - 423 2020.1

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

BACKGROUND: Type 2 chronic rhinosinusitis (CRS), especially eosinophilic CRS (ECRS), is an intractable upper airway inflammatory disease. Establishment of serum biomarkers reflecting the pathophysiology of CRS is desirable in a clinical setting. As IgG4 production is regulated by type 2 cytokines, we sought to determine whether serum IgG4 levels can be used as a biomarker for CRS. METHODS: Association between the serum IgG4 levels and clinicopathological factors was analyzed in 336 CRS patients. Receiver operating characteristics (ROC) analysis was performed to determine the cut-off value of serum IgG4 levels that can be used to predict the post-operative recurrence. RESULTS: Serum IgG4 levels were significantly higher in patients with moderate to severe ECRS versus those with non to mild ECRS. The levels were also significantly higher in asthmatic patients and patients exhibiting recurrence after surgery compared to controls. ROC analysis determined that the best cut-off value for the serum IgG4 level to predict the post-operative recurrence was 95 mg/dL. The corresponding sensitivity and specificity were 39.7% and 80.5%, respectively. When we combined the two cut-off values for the serum IgG4 and periostin, patients with high serum levels of either IgG4 or periostin exhibited a high post-operative recurrence (OR: 3.95) as compared to patients having low serum levels of both IgG4 and periostin. CONCLUSIONS: The present results demonstrate that the serum IgG4 level is associated with disease severity and post-operative course in CRS. In particular, the combination of serum IgG4 and periostin could be a novel biomarker that predicts post-operative recurrence.

DOI： 10.1016/j.alit.2019.12.004

Clinical significance of cytoplasmic IgE-positive mast cells in eosinophilic chronic rhinosinusitis Reviewed International journal

Gion Y, Okano M, Koyama Y, Oura T, Nishikori A, Orita Y, Tachibana T, Marunaka H, Makino T, Nishizaki K, Sato Y

Int J Mol Sci 7 ( 21 ) 2020

Authorship：Last author,　Corresponding author Language：English Publishing type：Research paper (scientific journal)

Cross-linking of antigen-specific IgE bound to the high-affinity IgE receptor (FcεRI) on the surface of mast cells with multivalent antigens results in the release of mediators and development of type 2 inflammation. FcεRI expression and IgE synthesis are, therefore, critical for type 2 inflammatory disease development. In an attempt to clarify the relationship between eosinophilic chronic rhinosinusitis (ECRS) and mast cell infiltration, we analyzed mast cell infiltration at lesion sites and determined its clinical significance. Mast cells are positive for c-kit, and IgE in uncinated tissues (UT) and nasal polyps (NP) were examined by immunohistochemistry. The number of positive cells and clinicopathological factors were analyzed. Patients with ECRS exhibited high levels of total IgE serum levels and elevated peripheral blood eosinophil ratios. As a result, the number of mast cells with membranes positive for c-kit and IgE increased significantly in lesions forming NP. Therefore, we classified IgE-positive mast cells into two groups: membrane IgE-positive cells and cytoplasmic IgE-positive cells. The amount of membrane IgE-positive mast cells was significantly increased in moderate ECRS. A positive correlation was found between the membrane IgE-positive cells and the radiological severity score, the ratio of eosinophils, and the total serum IgE level. The number of cytoplasmic IgE-positive mast cells was significantly increased in moderate and severe ECRS. A positive correlation was observed between the cytoplasmic IgE-positive cells and the radiological severity score, the ratio of eosinophils in the blood, and the total IgE level. These results suggest that the process of mast cell internalization of antigens via the IgE receptor is involved in ECRS pathogenesis.

DOI： 10.3390/ijms21051843

Clinical and Pathological Characteristics of IgG4-Related Periaortitis/Periarteritis and Retroperitoneal Fibrosis Diagnosed Based on Experts' Diagnosis. Reviewed

Ichiro Mizushima, Satomi Kasashima, Yasunari Fujinaga, Kenji Notohara, Takako Saeki, Yoh Zen, Dai Inoue, Motohisa Yamamoto, Fuminari Kasashima, Yasushi Matsumoto, Eisuke Amiya, Yasuharu Sato, Kazunori Yamada, Yukako Domoto, Shigeyuki Kawa, Mitsuhiro Kawano, Nobukazu Ishizaka

Annals of vascular diseases 12 ( 4 ) 460 - 472 2019.12

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

IgG4-related disease is a systemic disease, characterized by elevation of serum IgG4 and, histopathologically, massive infiltration of IgG4+ lymphocyte and plasma cell infiltration, storiform fibrosis, causing enlargement, nodules or thickening. It may affect various organs simultaneously or metachronously. Here we analyzed the clinical and pathological characteristics of 99 patients diagnosed with IgG4-related periaortitis/periarteritis and retroperitoneal fibrosis. Of 99 patients (women/men, 15/84; mean age 67.3±9.5 years), 33 were diagnosed based on the histopathological findings of perivascular/retroperitoneal lesions, 50 were diagnosed based on the characteristic imaging findings of perivascular/retroperitoneal lesions and the presence of definitive IgG4-related disease in other organ(s), and the remaining 16 patients were diagnosed by experts based on the characteristic imaging findings of perivascular/retroperitoneal legions, serological findings, response to glucocorticoid treatment, and/or the presence of suspected IgG4-related disease in other organ(s). According to the new organ-specific criteria proposed by experts, 73 (73.7%) diagnoses were categorized to be definitive, and 6 (6.1%) and 17 (17.2%) diagnoses were categorized to be probable and possible, respectively. Further analyses are needed to clarify the optimal diagnostic and therapeutic strategy of IgG4-related periaortitis/periarteritis and retroperitoneal fibrosis. (This is a translation of J Jpn Coll Angiol 2018; 58: 117-129.).

DOI： 10.3400/avd.oa.19-00085

Molecular heterogeneity in peripheral T-cell lymphoma, not otherwise specified revealed by comprehensive genetic profiling. Reviewed International journal

Yosaku Watatani, Yasuharu Sato, Hiroaki Miyoshi, Kana Sakamoto, Kenji Nishida, Yuka Gion, Yasunobu Nagata, Yuichi Shiraishi, Kenichi Chiba, Hiroko Tanaka, Lanying Zhao, Yotaro Ochi, Yasuhide Takeuchi, June Takeda, Hiroo Ueno, Yasunori Kogure, Yusuke Shiozawa, Nobuyuki Kakiuchi, Tetsuichi Yoshizato, Masahiro M Nakagawa, Yasuhito Nanya, Kenichi Yoshida, Hideki Makishima, Masashi Sanada, Mamiko Sakata-Yanagimoto, Shigeru Chiba, Ryota Matsuoka, Masayuki Noguchi, Nobuhiro Hiramoto, Takayuki Ishikawa, Junichi Kitagawa, Nobuhiko Nakamura, Hisashi Tsurumi, Tatsuhiko Miyazaki, Yusuke Kito, Satoru Miyano, Kazuya Shimoda, Kengo Takeuchi, Koichi Ohshima, Tadashi Yoshino, Seishi Ogawa, Keisuke Kataoka

Leukemia 33 ( 12 ) 2867 - 2883 2019.12

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

Peripheral T-cell lymphoma, not otherwise specified (PTCL, NOS) is a diagnosis of exclusion, being the most common entity in mature T-cell neoplasms, and its molecular pathogenesis remains significantly understudied. Here, combining whole-exome and targeted-capture sequencing, gene-expression profiling, and immunohistochemical analysis of tumor samples from 133 cases, we have delineated the entire landscape of somatic alterations, and discovered frequently affected driver pathways in PTCL, NOS, with and without a T-follicular helper (TFH) cell phenotype. In addition to previously reported mutational targets, we identified a number of novel recurrently altered genes, such as KMT2C, SETD1B, YTHDF2, and PDCD1. We integrated these genetic drivers using hierarchical clustering and identified a previously undescribed molecular subtype characterized by TP53 and/or CDKN2A mutations and deletions in non-TFH PTCL, NOS. This subtype exhibited different prognosis and unique genetic features associated with extensive chromosomal instability, which preferentially affected molecules involved in immune escape and transcriptional regulation, such as HLA-A/B and IKZF2. Taken together, our findings provide novel insights into the molecular pathogenesis of PTCL, NOS by highlighting their genetic heterogeneity. These results should help to devise a novel molecular classification of PTCLs and to exploit a new therapeutic strategy for this group of aggressive malignancies.

DOI： 10.1038/s41375-019-0473-1

Hepatic Campylobacter jejuni infection in patients with Castleman-Kojima disease (idiopathic multicentric Castleman disease with thrombocytopenia, anasarca, fever, reticulin fibrosis, and organomegaly (TAFRO) syndrome). Reviewed International journal

Chihiro Kageyama, Takuro Igawa, Yuka Gion, Noriko Iwaki, Tetsuya Tabata, Takehiro Tanaka, Eisei Kondo, Hajime Sakai, Koichi Tsuneyama, Kazuhiro Nomoto, Hiroko Noguchi, Tadashi Yoshino, Kenji Yokota, Yasuharu Sato

Pathology international 69 ( 10 ) 572 - 579 2019.10

Authorship：Last author,　Corresponding author Language：English Publishing type：Research paper (scientific journal)

Castleman-Kojima disease, also known as idiopathic multicentric Castleman disease with TAFRO syndrome (iMCD-TAFRO), is a recently recognized systemic inflammatory disorder with a characteristic series of clinical symptoms, including thrombocytopenia (T), anasarca (A), fever (F), reticulin fibrosis (R), and organomegaly (O). Patients with iMCD-TAFRO often develop severe abdominal pain, elevated alkaline phosphatase levels, and systemic inflammation, but the etiological factors are unknown. To investigate the potential role of bacterial infection in the pathogenesis of iMCD-TAFRO, we performed polymerase chain reaction (PCR) for the bacterial 16S rRNA gene with DNA extracted from liver specimens of three patients with iMCD-TAFRO, four patients with amyotrophic lateral sclerosis, and seven patients with inflammatory conditions. Sequencing of the PCR product showed 99% DNA sequence identity with Campylobacter jejuni in all three patients with iMCD-TAFRO and in two patients with inflammatory conditions. Immunohistochemical and electron microscopy analyses could not identify C. jejuni in patients with iMCD-TAFRO. The findings indicated that C. jejuni infection is not the pathological cause of iMCD-TAFRO; however, this ubiquitous bacterium may play a role in uncontrolled systemic hypercytokinemia, possibly through the development of cross-reactive autoantibodies.

DOI： 10.1111/pin.12856

The efficacy of OK-432 sclerotherapy on thyroglossal duct cyst and the influence on a subsequent surgical procedure. Reviewed International journal

Tomoyasu Tachibana, Shin Kariya, Yorihisa Orita, Takuma Makino, Takenori Haruna, Yuko Matsuyama, Yasutoshi Komatsubara, Yuto Naoi, Michihiro Nakada, Yoji Wani, Soichiro Fushimi, Machiko Hotta, Katsuya Haruna, Tami Nagatani, Yasuharu Sato, Kazunori Nishizaki

Acta oto-laryngologica 139 ( 9 ) 788 - 792 2019.9

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

Background: Although there are studies regarding the efficacy of OK-432 sclerotherapy on thyroglossal duct cyst (TDC), its effects on surgical procedure following this therapy have not been properly described. Objectives: The present study aimed to delineate the prognostic factors of OK-432 sclerotherapy in patients with TDC and investigate its influence on subsequent surgical procedure and the histological characteristics in patients with poor response to OK-432 sclerotherapy. Material and methods: We conducted a retrospective analysis of the medical records of 20 TDC patients treated with OK-432 sclerotherapy. Results: Of the 20 patients, OK-432 sclerotherapy was effective in 5 patients (25.0%). OK-432 showed a lower effective rate in multilocular cysts (9.1%) than in unilocular cysts (44.4%), although not significantly. Five cases were treated with surgery following OK-432 sclerotherapy. There was no significant difference in the operating time and the amount of bleeding between patients with and without OK-432 sclerotherapy. From the results of the histological examination of the cyst wall, two cases had stratified squamous epithelium and two cases showed the absence of lymphocyte infiltration. Conclusion and significance: OK-432 sclerotherapy is an acceptable initial treatment for TDC, especially in unilocular cysts, because of lack of influence on surgical procedure.

DOI： 10.1080/00016489.2019.1633019

Focus on immunodeficiency-associated lymphoproliferative disorders. Invited Reviewed

Sato Y

J Clin Exp Hematop. 59 ( 2 ) 64 - 71 2019.8

Clinical and biochemical characteristics of patients having general symptoms with increased serum IgG4. Reviewed International journal

Kou Hasegawa, Yoshihisa Hanayama, Mikako Obika, Tomoko Miyoshi, Hiroko Ogawa, Eisei Kondo, Hitomi Kataoka, Yasuharu Sato, Fumio Otsuka

Modern rheumatology 30 ( 4 ) 721 - 728 2019.8

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

Objective: To differentiate patients with IgG4-related diseases (RD) from patients with other hyper IgG4 conditions who visit general medicine department.Methods: Fifty-six patients with high serum IgG4 levels (>135 mg/dL) were classified into three groups based on the final diagnosis: definite and possible IgG4-RD and others. Clinical and laboratory characteristics of the three groups of patients were retrospectively analyzed.Results: Major manifestations were renal dysfunction and general malaise, while thirst was the most frequent symptom in the definite group, in which submandibular glands and lymph nodes were likely to be affected. Biopsy of minor salivary glands was the least diagnostic for IgG4-RD despite the high frequency of biopsy. In the definite group, serum levels of IgG4 and IgG, IgG4/IgG ratio and basophil number were increased, while serum levels of CRP, IgA and complements were decreased. A negative correlation between serum levels of IgG4 and IgM was found in the definite group.Conclusion: The results indicated that in patients with renal dysfunction, malaise, thirst or weight loss, measurements of the levels of basophils, immunoglobulins and complements are helpful for diagnosing IgG4-RD. Considering distribution of affected tissues and localization of diagnostic biopsies, physical examination and laboratory workup are required for early diagnosis.

DOI： 10.1080/14397595.2019.1642291

A review of EBV-positive mucocutaneous ulcers focusing on clinical and pathological aspects. Invited Reviewed

Tomoka Ikeda, Yuka Gion, Tadashi Yoshino, Yasuharu Sato

Journal of clinical and experimental hematopathology 59 ( 2 ) 64 - 71 2019.8

Authorship：Last author,　Corresponding author Language：English Publishing type：Research paper (scientific journal)

Epstein-Barr virus (EBV)-positive mucocutaneous ulcers (EBVMCUs) were first described as a lymphoproliferative disorder in 2010. Clinically, EBVMCUs are shallow, sharply circumscribed, unifocal mucosal or cutaneous ulcers that occur in immunosuppressed patients, including those with advanced age-associated immunosenescence, iatrogenic immunosuppression, primary immune disorders, and HIV/AIDS-associated immune deficiencies. In general, patients exhibit indolent disease progression and spontaneous regression. Histologically, EBVMCUs are characterized by the proliferation of EBV-positive, variable-sized, atypical B-cells. According to conventional histopathologic criteria, EBVMCUs may diagnosed as lymphomas. However, EBVMCUs are recognized as pseudomalignant lesions because they spontaneously regress without anti-cancer treatment. Therefore, overtreatment must be carefully avoided and multilateral differentiation is important. In this article, we reviewed previously reported EBVMCUs focusing on their clinical and pathological aspects in comparison with other EBV-positive B-cell neoplasms.

DOI： 10.3960/jslrt.18039

Methotrexate-associated lymphoproliferative disorders of T-cell phenotype: clinicopathological analysis of 28 cases. Reviewed International journal

Akira Satou, Tetsuya Tabata, Hiroaki Miyoshi, Kei Kohno, Yuka Suzuki, Daisuke Yamashita, Kazuyuki Shimada, Tomonori Kawasaki, Yasuharu Sato, Tadashi Yoshino, Koichi Ohshima, Taishi Takahara, Toyonori Tsuzuki, Shigeo Nakamura

Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc 32 ( 8 ) 1135 - 1146 2019.7

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

Methotrexate-associated lymphoproliferative disorders are categorized as "other immunodeficiency-associated lymphoproliferative disorders in the WHO classification. Methotrexate-associated lymphoproliferative disorder is mainly a B-cell lymphoproliferative disorders or Hodgkin lymphoma type, whereas T-cell lymphoproliferative disorders are relatively rare (4-8%). Only a small number of methotrexate-associated T-cell lymphoproliferative disorders have been detailed thus far. Because of the rarity, methotrexate-associated T-cell lymphoproliferative disorder has not been well studied and its clinicopathological characteristics are unknown. A total of 28 cases of methotrexate-associated T-cell lymphoproliferative disorders were retrospectively analyzed. Histologically and immunohistochemically, they were divided into three main types: angioimmunoblastic T-cell lymphoma (n = 19), peripheral T-cell lymphoma, NOS (n = 6), and CD8+ cytotoxic T-cell lymphoma (n = 3). Among the 28 cases, only one CD8+ cytotoxic T-cell lymphoma case was Epstein-Barr virus-positive. The other 27 cases were negative for Epstein-Barr virus on tumor cells, but scattered Epstein-Barr virus-infected B-cells were detected in 24 cases (89%), implying the reactivation of Epstein-Barr virus caused by immunodeficient status of the patients. After the diagnosis of methotrexate-associated T-cell lymphoproliferative disorder, methotrexate was immediately withdrawn in 26 cases. Twenty (77%) cases presented with spontaneous regression. Compared to methotrexate-associated B-cell lymphoproliferative disorder, patients with methotrexate-associated T-cell lymphoproliferative disorder had a significantly higher proportion of males (p = 0.035) and presence of B-symptoms (p = 0.036), and lower proportion of Epstein-Barr virus+ tumor cells (p < 0.001). Although the difference was not significant, the methotrexate-associated T-cell lymphoproliferative disorder also had more frequent spontaneous regression (p = 0.061). In conclusion, methotrexate-associated T-cell lymphoproliferative disorder was divided into three main types: angioimmunoblastic T-cell lymphoma, peripheral T-cell lymphoma, NOS, and CD8+ cytotoxic T-cell lymphoma. Angioimmunoblastic T-cell lymphoma was the most common type. Methotrexate-associated T-cell lymphoproliferative disorder was characterized by a high rate of spontaneous regression after methotrexate cessation. Epstein-Barr virus positivity was relatively rare in methotrexate-associated T-cell lymphoproliferative disorder, significantly less frequent than methotrexate-associated B-cell lymphoproliferative disorder, suggesting different pathogenesis.

DOI： 10.1038/s41379-019-0264-2

Activated M2 Macrophages Contribute to the Pathogenesis of IgG4-Related Disease via Toll-like Receptor 7/Interleukin-33 Signaling. Reviewed International journal

Noriko Ishiguro, Masafumi Moriyama, Katsuhiro Furusho, Sachiko Furukawa, Takuma Shibata, Yusuke Murakami, Akira Chinju, A S M Rafiul Haque, Yuka Gion, Miho Ohta, Takashi Maehara, Akihiko Tanaka, Masaki Yamauchi, Mizuki Sakamoto, Keita Mochizuki, Yuko Ono, Jun-Nosuke Hayashida, Yasuharu Sato, Tamotsu Kiyoshima, Hidetaka Yamamoto, Kensuke Miyake, Seiji Nakamura

Arthritis & rheumatology (Hoboken, N.J.) 72 ( 1 ) 166 - 178 2019.7

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

OBJECTIVE: IgG4-related disease (IgG4-RD) is a unique inflammatory disorder in which Th2 cytokines promote IgG4 production. In addition, recent studies have implicated the Toll-like receptor (TLR) pathway. This study was undertaken to examine the expression of TLRs in salivary glands (SGs) from patients with IgG4-RD. METHODS: SGs from 15 patients with IgG4-RD, 15 patients with Sjögren's syndrome (SS), 10 patients with chronic sialadenitis, and 10 healthy controls were examined histologically. TLR family gene expression (TLR-1 through TLR-10) was analyzed by DNA microarray in the submandibular glands (SMGs). Up-regulation of TLRs was confirmed in SGs from patients with IgG4-RD. Finally, the phenotype of human TLR-7 (huTLR-7)-transgenic C57BL/6 mice was assessed before and after stimulation with TLR agonist. RESULTS: In patients with IgG4-RD, TLR-4, TLR-7, TLR-8, and TLR-9 were overexpressed. Polymerase chain reaction validated the up-regulation of TLR-7 in IgG4-RD compared with the other groups. Immunohistochemical analysis confirmed strong infiltration of TLR-7-positive cells in the SGs of patients with IgG4-RD. Double immunohistochemical staining showed that TLR-7 expression colocalized with CD163+ M2 macrophages. After in vitro stimulation with a TLR-7 agonist, CD163+ M2 macrophages produced higher levels of interleukin-33 (IL-33), which is a Th2-activating cytokine. In huTLR-7-transgenic mice, the focus and fibrosis scores in SMGs, pancreas, and lungs were significantly higher than those in wild-type mice (P < 0.05). Moreover, the concentration of serum IgG, IgG1, and IL-33 in huTLR-7-transgenic mice was distinctly increased upon stimulation with a TLR-7 agonist (P < 0.05). CONCLUSION: TLR-7-expressing M2 macrophages may promote the activation of Th2 immune responses via IL-33 secretion in IgG4-RD.

DOI： 10.1002/art.41052

KRAS mutations in tongue squamous cell carcinoma Reviewed

Yusuke Akagi, Tomoyasu Tachibana, Yorihisa Orita, Yuka Gion, Hidenori Marunaka, Takuma Makino, Kentaro Miki, Naoki Akisada, Tadashi Yoshino, Kazunori Nishizaki, Yasuharu Sato

Acta Oto-Laryngologica 139 ( 7 ) 647 - 651 2019.7

Authorship：Last author Language：English Publishing type：Research paper (scientific journal)

Background: p16 (p16) expression in tongue cancer (TC) is reportedly not associated with human papilloma virus (HPV). Mutations of KRAS in cancer cells are most frequently observed within codon 12. However, few reports have investigated the association between KRAS mutations and p16 status in TC. Objectives: This study aimed to evaluate the influence of KRAS mutations on TC. Methods: Clinical records and surgically resected specimens of 85 TC patients were analyzed. Tumor samples were analyzed for mutations of KRAS located within codons 12 and 13. p16 staining was performed and considered positive in cases with moderate to strong nuclear and cytoplasmic staining. Results: Positive p16 staining was observed in 10 cases (11.8%). A KRAS mutation was detected in one case (1.2%). The case with KRAS mutation showed negative p16 staining. Despite being at an early stage, the patient died of lung metastasis at 43 months from initial treatment. Conclusions and Significance:KRAS mutations are not associated with p16 expression in TC and may predict poor prognosis in TC patients. Further analysis of mutations in regions other than codons 12 and 13 of KRAS will be necessary to determine the relationship between KRAS mutations and prognosis of this disease. INK4a

DOI： 10.1080/00016489.2019.1610574

Spontaneous closure of traumatic tympanic membrane perforation following long-term observation Reviewed

Tomoyasu Tachibana, Shin Kariya, Yorihisa Orita, Takuma Makino, Takenori Haruna, Yuko Matsuyama, Yasutoshi Komatsubara, Yuto Naoi, Michihiro Nakada, Yohei Noda, Yasuharu Sato, Kazunori Nishizaki

Acta Oto-Laryngologica 139 ( 6 ) 487 - 491 2019.6

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

Background: Traumatic tympanic membrane perforation (TTMP) is usually managed conservatively because most close spontaneously within a few months. Nevertheless, spontaneous closure of TTMP during long-term observation has not been well described in the literature. Objectives: The present study investigated factors associated with spontaneous closure of TTMP, and the characteristics of cases exhibiting spontaneous closure following long-term observation. Materials and Methods: The medical records of 40 patients with TTMP who visited the authors’ hospital were retrospectively reviewed. Results: Spontaneous closure was observed in 27 (67.5%) patients. The healing period was <2 weeks in 6 cases, <4 weeks in 9, <3 months in 5, <6 months in 3, and ≥6 months in 4. All four cases in which spontaneous closure took ≥6 months exhibited a sign of spontaneous closure at 6 months following injury. Perforation in contact with the malleus was associated with a lower frequency of spontaneous closure. Conclusions and Significance: In TTMP, surgery should be considered in patients who exhibit perforation in contact with the malleus. However, it has also been suggested that long-term observation may be a viable treatment option when a sign of spontaneous closure is observed within 6 months following injury.

DOI： 10.1080/00016489.2019.1592225

Virome capture sequencing does not identify active viral infection in unicentric and idiopathic multicentric Castleman disease. Reviewed International journal

Christopher S Nabel, Stephen Sameroff, Dustin Shilling, Daisy Alapat, Jason R Ruth, Mitsuhiro Kawano, Yasuharu Sato, Katie Stone, Signe Spetalen, Federico Valdivieso, Michael D Feldman, Amy Chadburn, Alexander Fosså, Frits van Rhee, W Ian Lipkin, David C Fajgenbaum

PloS one 14 ( 6 ) e0218660 2019.6

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

Castleman disease (CD) describes a spectrum of heterogeneous disorders defined by characteristic lymph node histopathology. Enlarged lymph nodes demonstrating CD histopathology can occur in isolation (unicentric CD; UCD) sometimes accompanied by mild symptoms, or at multiple sites (multicentric CD, MCD) with systemic inflammation and cytokine-driven multi-organ dysfunction. The discovery that Kaposi sarcoma herpesvirus/human herpesvirus (HHV)-8 drives MCD in a subset of patients has led to the hypotheses that UCD and MCD patients with negative HHV-8 testing by conventional methods may represent false negatives, or that these cases are driven by another virus, known or unknown. To investigate these hypotheses, the virome capture sequencing for vertebrate viruses (VirCapSeq-VERT) platform was employed to detect RNA transcripts from known and novel viruses in fresh frozen lymph node tissue from CD patients (12 UCD, 11 HHV-8-negative MCD [idiopathic MCD; iMCD], and two HHV-8-positive MCD) and related diseases (three T cell lymphoma and three Hodgkin lymphoma). This assay detected HHV-8 in both HHV-8-positive cases; however, HHV-8 was not found in clinically HHV-8-negative iMCD or UCD cases. Additionally, no novel viruses were discovered, and no single known virus was detected with apparent association to HHV-8-negative CD cases. Herpesviridae family members, notably including Epstein-Barr virus (EBV), were detected in 7 out of 12 UCD and 5 of 11 iMCD cases with apparent correlations with markers of disease severity in iMCD. Analysis of a separate cohort of archival formalin-fixed, paraffin-embedded lymph node tissue by In situ hybridization revealed significantly fewer EBV-positive cells in UCD and iMCD compared to tissue from HHV-8-positive MCD and EBV-associated lymphoproliferative disorder. In an additional cohort, quantitative testing for EBV by PCR in peripheral blood during disease flare did not detect systemic EBV viremia, suggesting detection lymph node tissue is due to occult, local reactivation in UCD and iMCD. This study confirms that HHV-8 is not present in UCD and iMCD patients. Further, it fails to establish a clear association between any single virus, novel or known, and CD in HHV-8-negative cases. Given that distinct forms of CD exist with viral and non-viral etiological drivers, CD should be considered a group of distinct and separate diseases with heterogeneous causes worthy of further study.

DOI： 10.1371/journal.pone.0218660

包括的遺伝学的特性分析により明らかになった非特定型末梢T細胞リンパ腫における分子的異質性(Molecular heterogeneity in peripheral T-cell lymphoma, not otherwise specified revealed by comprehensive genetic profiling) Reviewed

綿谷陽作, 佐藤康晴, 三好寛明, 坂本佳奈, 西田賢司, 祇園由佳, 坂田麻実子, 中村信彦, 平本展大, 白石友一, 宮野悟, 真田昌, 千葉滋, 石川隆之, 鶴見寿, 竹内賢吾, 大島孝一, 吉野正, 小川誠司, 片岡圭亮

日本リンパ網内系学会会誌 59 113 - 113 2019.5

Significance of IgG4-positive cells in severe eosinophilic chronic rhinosinusitis Reviewed

Takahisa Koyama, Shin Kariya, Yasuharu Sato, Yuka Gion, Takaya Higaki, Takenori Haruna, Tazuko Fujiwara, Akira Minoura, Soshi Takao, Yorihisa Orita, Kengo Kanai, Masami Taniguchi, Kazunori Nishizaki, Mitsuhiro Okano

Allergology International 68 ( 2 ) 216 - 224 2019.4

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

Background: IgG4 production is regulated by type 2 (IL-4 and IL-13) and regulatory (IL-10) cytokines involved in the pathophysiology of chronic rhinosinusitis (CRS). We sought to determine the pathophysiological characteristics of IgG4-positive cells in sinonasal tissues in CRS, especially eosinophilic CRS (ECRS). Methods: IgG4-positive cells in uncinate tissues (UT) and nasal polyps (NP) were examined by immunohistochemistry. Associations between the number of IgG4-positive cells and clinicopathological factors were analyzed. Receiver operating characteristics (ROC) analysis was performed to determine the cut-off value of IgG4-positive cells in tissue that can predict the post-operative course. Results: IgG4 was mainly expressed in infiltrating plasma and plasmacytoid cells, and the number of IgG4-positive cells was significantly higher in NP, especially those from severe ECRS patients, than in UT. In CRS patients, the number of IgG4-positive cells significantly and positively correlated with blood and tissue eosinophilia, radiological severity, and serum level of total IgE. The number of infiltrating IgG4-positive cells was significantly higher in patients with a poor post-operative course (sustained sinus shadow 6 months after surgery) than in those with a good one. The number of IgG4-positive cells in NP could discriminate patients with a good or a poor post-operative course (area under the curve: 0.769). Also, 73.3% sensitivity and 82.5% specificity were achieved when the cut-off value was set at 17 cells/high-power field. Conclusions: Our results suggest that the local expression of IgG4 on cells may be used as a biomarker that reflects the pathophysiology of CRS, including the post-operative course.

DOI： 10.1016/j.alit.2018.09.002

Up-regulation of activation-induced cytidine deaminase and its strong expression in extra- germinal centres in IgG4-related disease Reviewed

Yuka Gion, Mai Takeuchi, Rei Shibata, Katsuyoshi Takata, Tomoko Miyata-Takata, Yorihisa Orita, Tomoyasu Tachibana, Tadashi Yoshino, Yasuharu Sato

SCIENTIFIC REPORTS 9 ( 1 ) 761 2019.1

Authorship：Last author,　Corresponding author Language：English Publishing type：Research paper (scientific journal) Publisher：NATURE PUBLISHING GROUP

Immunoglobulin (Ig) G4-related disease (IgG4-RD) is a systemic disorder involving benign mass formation due to fibrosis and intense lymphoplasmacytosis; the chronic inflammation associated with the disease might also contribute to oncogenesis. Activation-induced cytidine deaminase (AID), normally expressed in germinal centre activated B-cells, is an enzyme that edits DNA/RNA and induces somatic hypermutation and Ig class switching. AID expression is strictly controlled under physiological conditions; however, chronic inflammation and some infectious agents induce its up-regulation. AID is overexpressed in various cancers and may be important in chronic inflammation-associated oncogenesis. We examined AID expression in IgG4-related sialadenitis (n = 14), sialolithiasis (nonspecific inflammation, n = 13), and normal submandibular glands (n = 13) using immunohistochemistry and quantitative real-time polymerase chain reaction (qPCR). Immunohistochemistry revealed significantly more AID-expressing cells in IgG4-related sialadenitis than in sialolithiasis or normal submandibular gland samples (P = 0.02 and P < 0.01, respectively); qPCR yielded similar results. Thus, AID was significantly more up-regulated and had higher expression in extra-germinal centres in IgG4-RD than in non-specific inflammation or normal conditions. This report suggests that IgG4-RD has several specific causes of AID up-regulation in addition to inflammation. Furthermore, chronic inflammation-associated AID-mediated oncogenesis is possible in IgG4-RD.

DOI： 10.1038/s41598-018-37404-x

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