研究者詳細 - 中黒　匡人

Salivary gland polymorphous adenocarcinoma: Clinicopathological features and gene alterations in 36 Japanese patients 査読有り国際誌

Fukumura, M; Ishibashi, K; Nakaguro, M; Nagao, T; Saida, K; Urano, M; Tanigawa, M; Hirai, H; Yagyuu, T; Kikuchi, K; Yada, N; Sugita, Y; Miyabe, M; Hasegawa, S; Goto, M; Yamamoto, H; Ohuchi, T; Kusafuka, K; Ogawa, I; Suzuki, H; Notohara, K; Shimoda, M; Tada, Y; Kirita, T; Takata, T; Morinaga, S; Maeda, H; Warnakulasuriya, S; Miyabe, S; Nagao, T

JOURNAL OF ORAL PATHOLOGY & MEDICINE 51 巻 ( 8 ) 頁： 710 - 720 2022年9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：Journal of Oral Pathology and Medicine

Background: Polymorphous adenocarcinoma is a common intraoral minor salivary gland carcinoma in Western countries but is extremely rare in Japan. The current study aimed to characterize the clinicopathological features and status of molecular alterations of polymorphous adenocarcinoma-associated genes, such as PRKD1/2/3, ARID1A, and DDX3X, in a large cohort of Japanese patients with polymorphous adenocarcinoma. Methods: We examined the cases of 36 Japanese patients with salivary gland polymorphous adenocarcinoma and 26 cases involving histopathological mimics. To detect gene splits, fluorescence in situ hybridization was carried out for polymorphous adenocarcinoma-associated genes. Additionally, we applied a SNaPshot multiplex assay to identify PRKD1 hotspot mutations. Results: This study revealed the indolent clinical course of polymorphous adenocarcinoma with a high 10-year overall survival rate (92.9%), accompanied by occasional local recurrences and cervical lymph node metastasis (23.3%). Twenty cases (55.6%) of polymorphous adenocarcinoma (but none of the mimics) exhibited alterations in at least one polymorphous adenocarcinoma-associated gene. Rearrangement of polymorphous adenocarcinoma-associated genes and PRKD1 E710D were identified in 17 (47.2%) and 4 (11.1%) cases, respectively; one case showed coexisting PRKD3 split and PRKD1 E710D. In the multivariate analysis, high clinical stage (p = 0.0005), the presence of prominent nucleoli (p = 0.0003), and ARID1A split positivity (p = 0.004) were independent risk factors for disease-free survival. Conclusion: Japanese patients with polymorphous adenocarcinoma showed clinicopathological features similar to those reported in Western countries. This study disclosed that polymorphous adenocarcinoma-associated genetic alterations were common and specific findings in polymorphous adenocarcinomas. The diagnostic role and possible prognostic significance of polymorphous adenocarcinoma-associated genetic alterations in polymorphous adenocarcinomas were suggested.

DOI： 10.1111/jop.13336

Survival benefit of HER2-targeted or androgen deprivation therapy in salivary duct carcinoma 査読有り国際誌

Kawakita, D; Nagao, T; Takahashi, H; Kano, S; Honma, Y; Hirai, H; Saigusa, N; Akazawa, K; Tani, K; Ojiri, H; Tsukahara, K; Ozawa, H; Okami, K; Kondo, T; Togashi, T; Fushimi, C; Shimura, T; Shimizu, A; Okamoto, I; Okada, T; Imanishi, Y; Watanabe, Y; Otsuka, K; Sakai, A; Ebisumoto, K; Sato, Y; Yamazaki, K; Ueki, Y; Hanazawa, T; Saito, Y; Ando, M; Matsuki, T; Nakaguro, M; Sato, Y; Urano, M; Utsumi, Y; Kohsaka, S; Saotome, T; Tada, Y

THERAPEUTIC ADVANCES IN MEDICAL ONCOLOGY 14 巻頁： 17588359221119538 - 17588359221119538 2022年9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：Therapeutic Advances in Medical Oncology

Background: The efficacy and safety of human epidermal growth factor receptor 2 (HER2)-targeted therapy and androgen deprivation therapy (ADT) for locally advanced or recurrent or metastatic (LA/RM) salivary duct carcinoma (SDC) have been reported in prospective studies. However, the survival benefit of these therapies to conventional therapy remains controversial, and whether HER2-targeted therapy or ADT should be chosen in HER2- and androgen receptor (AR)-positive SDC patients remains unknown. Methods: Overall, 323 LA/RM SDC patients treated at seven institutions between August 1992 and June 2020 were retrospectively enrolled. The primary aim was to analyze the effect of HER2-targeted therapy and ADT on overall survival from the diagnosis of LA/RM disease to death from any cause (OS1). The secondary indicators included the overall response rate (ORR), clinical benefit rate (CBR), overall survival from therapy initiation for LA/RM disease (OS2), progression-free survival (PFS), time to second progression (PFS2), duration of response (DoR), and duration of clinical benefit (DoCB) of HER2-targeted therapy or ADT as first-line therapy for HER2-positive/AR-positive SDC. Results: Patients treated with HER2-targeted therapy or ADT had longer OS1 than those treated without these therapies (Median OS1: historical control, 21.6 months; HER2-targeted therapy, 50.6 months; ADT, 32.8 months; HER2-targeted therapy followed by ADT, 42.4 months; and ADT followed by HER2-targeted therapy, 45.2 months, p < 0.001). Among HER2-positive/AR-positive SDC patients, although HER2-targeted therapy had better ORR, CBR, and PFS than those of ADT as first-line therapy, we found no significant differences between HER2-targeted therapy and ADT regarding OS2, PFS2, DoR, and DoCB. Conclusion: Patients treated with HER2-targeted therapy and ADT showed longer survival in LA/RM SDC. HER2-targeted therapy can be recommended prior to ADT for HER2-positive/AR-positive SDC. It is warranted to establish a biomarker that could predict the efficacy of clinical benefit or better response in ADT.

DOI： 10.1177/17588359221119538

今月の話題唾液腺腫瘍の病理診断における遺伝子異常の代替的免疫染色マーカー

中黒匡人, 長尾俊孝

病理と臨床 40 巻 ( 9 ) 頁： 0940 - 0944 2022年9月

Microsatellite instability-high is rare events in refractory pediatric solid tumors 査読有り国際誌

Yoshida, T; Muramatsu, H; Wakamatsu, M; Taniguchi, R; Ichikawa, D; Nakaguro, M; Natsume, A; Takahashi, Y

PEDIATRIC HEMATOLOGY AND ONCOLOGY 39 巻 ( 5 ) 頁： 468 - 474 2022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：Pediatric Hematology and Oncology

Microsatellite instability (MSI)-high status is associated with good responsiveness to immune checkpoint inhibitors. Although MSI-high status has been actively investigated in pediatric brain tumors, studies of other pediatric solid tumors are lacking. Among 334 consecutive pediatric patients with solid tumors, we retrospectively analyzed formalin-fixed paraffin-embedded tumor tissues of 36 of 74 patients (49%) who died of disease. We assessed the MSI status in these tissues using five multiplexed markers. The results revealed that none of the patients had an MSI-high status. These results indicate that MSI-high status is a rare event in pediatric patients with refractory/relapsed solid tumors. Supplemental data for this article is available online at https://doi.org/10.1080/08880018.2021.1998266.

DOI： 10.1080/08880018.2021.1998266

Non-sebaceous lymphadenoma-like mucoepidermoid carcinoma: A case report 査読有り国際誌

Sakamoto, S; Miyauchi, M; Ando, T; Fujihara, M; Nakaguro, M; Nagao, T; Ogawa, I

PATHOLOGY INTERNATIONAL 72 巻 ( 7 ) 頁： 371 - 375 2022年7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：Pathology International

Non-sebaceous lymphadenoma is a rare benign salivary gland tumor comprised of non-sebaceous epithelial cells and lymphoid tissue. Although its clinicopathological features have been described, its histogenesis and genetic background have not yet been elucidated. MAML2 rearrangement and the resultant CRTC1/3-MAML2 fusion gene are well-known specific genetic changes in mucoepidermoid carcinoma. Here, we present a case of lymphoepithelial tumor characterized by histomorphology of the non-sebaceous lymphadenoma and CRTC1-MAML2 fusion gene. The patient was an 83-year-old woman with an 8-year history of a solid, well-circumscribed tumor in the parotid gland. Histologically, the tumor was surrounded by thin fibrous connective tissue and was composed of tubular-cystic and solid nests of epithelial cells equally distributed in the lymphoid tissue. The histological features were suggestive of non-sebaceous lymphadenoma. Although the histomorphology was not consistent with mucoepidermoid carcinoma, a diagnosis of non-sebaceous lymphadenoma-like mucoepidermoid carcinoma was made based on the presence of the CRTC1-MAML2 fusion gene. The histological features alone could not establish the diagnosis, and ancillary molecular analysis was required.

DOI： 10.1111/pin.13236

Subtype classification of malignant lymphoma using immunohistochemical staining pattern 査読有り国際誌

Hashimoto, N; Ko, K; Yokota, T; Kohno, K; Nakaguro, M; Nakamura, S; Takeuchi, I; Hontani, H

INTERNATIONAL JOURNAL OF COMPUTER ASSISTED RADIOLOGY AND SURGERY 17 巻 ( 7 ) 頁： 1379 - 1389 2022年7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：International Journal of Computer Assisted Radiology and Surgery

Purpose: For the image classification problem, the construction of appropriate training data is important for improving the generalization ability of the classifier in particular when the size of the training data is small. We propose a method that quantitatively evaluates the typicality of a hematoxylin-and-eosin (H&E)-stained tissue slide from a set of immunohistochemical (IHC) stains and applies the typicality to instance selection for the construction of classifiers that predict the subtype of malignant lymphoma to improve the generalization ability. Methods: We define the typicality of the H&E-stained tissue slides by the ratio of the probability density of the IHC staining patterns on low-dimensional embedded space. Employing a multiple-instance-learning-based convolutional neural network for the construction of the subtype classifier without the annotations indicating cancerous regions in whole slide images, we select the training data by referring to the evaluated typicality to improve the generalization ability. We demonstrate the effectiveness of the instance selection based on the proposed typicality in a three-class subtype classification of 262 malignant lymphoma cases. Results: In the experiment, we confirmed that the subtypes of typical instances could be predicted more accurately than those of atypical instances. Furthermore, it was confirmed that instance selection for the training data based on the proposed typicality improved the generalization ability of the classifier, wherein the classification accuracy was improved from 0.664 to 0.683 compared with the baseline method when the training data was constructed focusing on typical instances. Conclusion: The experimental results showed that the typicality of the H&E-stained tissue slides computed from IHC staining patterns is useful as a criterion for instance selection to enhance the generalization ability, and this typicality could be employed for instance selection under some practical limitations.

DOI： 10.1007/s11548-021-02549-0

その他リンク： https://link.springer.com/article/10.1007/s11548-021-02549-0/fulltext.html

増刊号結果の読み方がよくわかる!　耳鼻咽喉科検査ガイド Ⅵ.頭頸部腫瘍の検査融合遺伝子

中黒匡人

耳鼻咽喉科・頭頸部外科 94 巻 ( 5 ) 頁： 218 - 223 2022年4月

Predictors of Failure of Mitral Valve Repair Using Artificial Chordae 査読有り国際誌

Mutsuga, M; Narita, Y; Tokuda, Y; Uchida, W; Ito, H; Terazawa, S; Nakaguro, M; Usui, A

ANNALS OF THORACIC SURGERY 113 巻 ( 4 ) 頁： 1136 - 1143 2022年4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：Annals of Thoracic Surgery

Background: We investigated predictors of failure of mitral valve repair (MVr) using expanded polytetrafluoroethylene (ePTFE) and its durability in the long term in a single institution. Methods: Four hundred twenty-one consecutive patients with primary mitral valve disease underwent MVr using artificial chordae (group A, n = 304) and suture repair (group S, n = 117) at our institution from January 2002 to April 2020. A comparison study was performed to examine the long-term outcomes, reoperation rate, and risk factors for reoperation. Results: One hospital death and 5 late deaths occurred in group S, and 20 late deaths occurred in group A. The reoperation rates were similar: group A, n = 8 (2.6%); and group S, n = 6 (5%). The major cause of reoperation was ruptured ePTFE (CV-4, n = 1; CV-5, n = 6) in group A, and suture rupture in group S. Reoperation was performed after a median of 88 months for ruptured ePTFE, and 26 months for group S. The rate of ePTFE rupture was 1.8% with CV-5 and 0.2% with CV-4. Risk factors for reoperation included postoperative arrhythmia, urgent operation, no annular ring, ruptured ePTFE, and suture rupture. The rates of freedom from reoperation and actuarial mitral valve survival rates at 5, 10, and 15 years were 99%, 95%, and 93% and 96%, 91%, and 89%, respectively, in group A; and 96%, 91%, and 91% and 95%, 94%, and 94%, respectively, in group S. Conclusions: The long-term surgical outcomes of MVr using both techniques were feasible. Over the long term, the ePTFE rupture rate of CV-5 was higher than that of CV-4.

DOI： 10.1016/j.athoracsur.2021.04.084

CDKN2A/B Loss in High-Grade Transformation of Salivary Gland Carcinoma: High-Grade Malignant Potential in Histologically Low-Grade Component 査読有り

Nakaguro, M; Faquin, W; Snuderl, M; Baloch, Z; Cantley, R; Compton, M; Ely, K; Holmes, B; Hu, R; Kerr, D; Montone, K; Nishino, M; Pantanowitz, L; Rossi, E; Nagao, T; Sadow, P

MODERN PATHOLOGY 35 巻 ( SUPPL 2 ) 頁： 894 - 895 2022年3月

CDKN2A/B Loss in High-Grade Transformation of Salivary Gland Carcinoma: High-Grade Malignant Potential in Histologically Low-Grade Component 査読有り

Nakaguro, M; Faquin, W; Snuderl, M; Baloch, Z; Cantley, R; Compton, M; Ely, K; Holmes, B; Hu, R; Kerr, D; Montone, K; Nishino, M; Pantanowitz, L; Rossi, E; Nagao, T; Sadow, P

LABORATORY INVESTIGATION 102 巻 ( SUPPL 1 ) 頁： 894 - 895 2022年3月

The Role of the EZH2 and H3K27me3 Expression as a Predictor of Clinical Outcomes in Salivary Duct Carcinoma Patients: A Large-Series Study With Emphasis on the Relevance to the Combined Androgen Blockade and HER2-Targeted Therapy 査読有り国際誌

Saigusa, N; Hirai, H; Tada, Y; Kawakita, D; Nakaguro, M; Tsukahara, K; Kano, S; Ozawa, H; Kondo, T; Okami, K; Togashi, T; Sato, Y; Urano, M; Kajiwara, M; Shimura, T; Fushimi, C; Shimizu, A; Okamoto, I; Okada, T; Suzuki, T; Imanishi, Y; Watanabe, Y; Sakai, A; Ebisumoto, K; Sato, Y; Honma, Y; Yamazaki, K; Ueki, Y; Hanazawa, T; Saito, Y; Takahashi, H; Ando, M; Kohsaka, S; Matsuki, T; Nagao, T

FRONTIERS IN ONCOLOGY 11 巻頁： 779882 - 779882 2022年2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：Frontiers in Oncology

Objective: Salivary duct carcinoma (SDC) is a highly aggressive and uncommon tumor arising not only de novo but also in pleomorphic adenoma. Androgen receptor (AR)- and HER2-targeted therapy have recently been introduced for SDC as promising treatment options; however, no predictive biomarkers have yet been established. EZH2 and H3K27me3 are closely linked to the development and progression of various cancers, and EZH2 is also expected to be a desirable therapeutic target. We therefore explored the clinicopathological and prognostic implications of EZH2 and H3K27me3 in a large cohort of SDC patients, focusing on their impact on the therapeutic efficacy of AR- or HER2-targeted therapy. Materials and Methods: The EZH2 and H3K27me3 immunohistochemical expression and EZH2 Y646 gain-of-function mutation status were examined in 226 SDCs, and the relationship with the clinicopathological factors as well as clinical outcomes were evaluated within the three groups depending on the treatment: AR-targeted (combined androgen blockade with leuprorelin acetate and bicalutamide; 89 cases), HER2-targeted (trastuzumab and docetaxel; 42 cases), and conventional therapy (112 cases). Results: EZH2 and H3K27me3 were variably immunoreactive in most SDCs. A positive correlation was found between the expression of EZH2 and H3K27me3. The EZH2 expression in the SDC component was significantly higher than that in the pre-existing pleomorphic adenoma component. EZH2 Y646 was not identified in any cases. EZH2-high cases more frequently had an advanced clinical stage and aggressive histological features than EZH2-low cases. An EZH2-high status in patients treated with AR-targeted therapy was associated with a significantly shorter progression-free and overall survival as well as a lower objective response rate and clinical benefit rate. In addition, a H3K27me3-high status in patients treated with AR-targeted therapy was related to a shorter overall survival. Conversely, there was no association between the EZH2 and H3K27me3 expression and the clinical outcomes in the conventional or HER2-targeted therapy groups. Conclusions: A high expression of EZH2 and H3K27me3 in SDC might be a predictor of a poor efficacy of AR-targeted therapy. Our data provide new insights into the role of EZH2 and H3K27me3 in therapeutic strategies for SDC.

DOI： 10.3389/fonc.2021.779882

NR4A3 Immunostain Is a Highly Sensitive and Specific Marker for Acinic Cell Carcinoma in Cytologic and Surgical Specimens. 査読有り国際誌

Viswanathan K, Beg S, He B, Zhang T, Cantley R, Lubin DJ, Shi Q, Maleki Z, Asiry S, Rao R, Katabi N, Nakaguro M, Faquin WC, Sadow PM, Siddiqui MT, Scognamiglio T

American journal of clinical pathology 157 巻 ( 1 ) 頁： 98 - 108 2022年1月

A multi-institutional study of salivary gland cytopathology: Application of the milan system for reporting salivary gland cytopathology in Japan 査読有り国際誌

Higuchi, K; Urano, M; Akiba, J; Nogami, M; Hirata, Y; Zukeran, Y; Moriyoshi, K; Tada, Y; Fukushima, M; Obayashi, M; Sakamoto, S; Kuraoka, K; Kira, K; Kawahara, A; Kato, T; Tanigawa, M; Nakaguro, M; Yamamoto, H; Nagao, T

CANCER CYTOPATHOLOGY 130 巻 ( 1 ) 頁： 30 - 40 2022年1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：Cancer Cytopathology

Background: The Milan System for Reporting Salivary Gland Cytopathology (MSRSGC) is a risk-stratification reporting system that was introduced in 2018. The objective of this multi-institutional study was to evaluate the utility of the MSRSGC in Japan. Methods: In total, 1608 fine-needle aspiration samples with matching histologic diagnoses were retrieved from 12 large institutions in Japan. The diagnostic categories of the MSRSGC were assigned prospectively or retrospectively, and the results were compared with the histologic diagnoses. Results: The cases were classified as follows: nondiagnostic, 18.1%; non-neoplastic, 4.1%; atypia of undetermined significance, 11.5%; neoplasm-benign, 43.7%; salivary gland neoplasm of uncertain malignant potential, 9.6%; suspicious for malignancy, 3.6%; and malignant, 9.4%. The risk of neoplasm and the risk of malignancy in each MSRSGC category were as follows: nondiagnostic, 72.9% and 13.4%, respectively; non-neoplastic, 15.2% and 9.1%, respectively; atypia of undetermined significance, 77.9% and 24.9%, respectively; neoplasm-benign, 99% and 1.8%, respectively; salivary gland neoplasm of uncertain malignant potential, 94.8% and 37%, respectively; suspicious for malignancy, 100% and 89.7%, respectively; and malignant, 100% and 99.3%, respectively. The accuracy of the MSRSGC for diagnosing neoplasms was 97.8%, and its accuracy for diagnosing malignancy was 97.3%. Institutions that used Romanowsky-stained preparations had lower nondiagnostic rates and lower risks of neoplasm and malignancy in the non-neoplastic category. Conclusions: The MSRSGC is useful for risk stratification and quality control. Widespread use of the MSRSGC would improve the accuracy of salivary gland cytology and lead to better patient care in Japan.

DOI： 10.1002/cncy.22505

その他リンク： https://onlinelibrary.wiley.com/doi/full-xml/10.1002/cncy.22505

Microsecretory Adenocarcinoma of Salivary Glands: An Expanded Series of 24 Cases 査読有り国際誌

Bishop, JA; Sajed, DP; Weinreb, I; Dickson, BC; Bilodeau, EA; Agaimy, A; Franchi, A; Khurram, SA; Da Forno, P; Robledo, J; Kalmar, JR; Aguirre, S; Krane, JF; Tapia, JL; Kiss, K; Cordell, K; Rosebush, M; Barrett, AW; Oda, D; Assaad, A; Nagao, T; Kawakami, F; Nakaguro, M; Zahir, I; Wakeman, K; Ihrler, S; Chenevert, J; Lin, YL; Westra, WH; Gagan, J; Rooper, LM

HEAD & NECK PATHOLOGY 15 巻 ( 4 ) 頁： 1192 - 1201 2021年12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：Head and Neck Pathology

Microsecretory adenocarcinoma (MSA) is a recently described salivary gland tumor with a characteristic histologic and immunophenotypic profile and recurrent MEF2C-SS18 fusions. Because only six cases of MSA have been published, its complete clinicopathologic spectrum is unclear, and its biologic behavior has not been documented. Here, we present an updated and expanded experience of 24 MSA cases. All cases of MSA were obtained from the authors’ files. Immunohistochemistry for S100, SOX10, p63, p40, SMA, calponin, and mammaglobin was performed. Molecular analysis was performed by targeted RNA sequencing, SS18 break apart fluorescence in situ hybridization, and/or reverse transcriptase polymerase chain reaction for MEF2C-SS18 fusion. Clinical follow-up was obtained from medical records. A total of 24 MSA cases were collected, from 13 women and 11 men, ranging from 17 to 83 years (mean 49.5 years). The vast majority (23 of 24) arose in the oral cavity, with the palate (n = 14) and buccal mucosa (n = 6) as the most frequent subsites. Tumors showed consistent histologic features including: (1) microcystic tubules, (2) flattened intercalated duct-like cells, (3) monotonous oval hyperchromatic nuclei, (4) abundant basophilic luminal secretions, (5) fibromyxoid stroma, and (6) circumscribed borders with subtle infiltration. The tumors were very consistently positive for S100 (24 of 24), p63 (24 of 24), and SOX10 (14 of 14) and negative for p40 (0 of 21), calponin (0 of 12) and mammaglobin (0 of 16), while SMA (4 of 20) was variable. MEF2C-SS18 fusion was demonstrated in 21 of 24 cases; in the remaining 3 cases with insufficient RNA, SS18 break apart FISH was positive. Treatment information was available in 17 cases, all of which were managed with surgery only. In 14 cases with follow-up (1–216 months, mean 30), no cases recurred or metastasized. MSA is a distinct salivary gland neoplasm with remarkably consistent clinical, histologic, immunophenotypic, and genetic features that generally behaves in an indolent manner following surgery alone. These observations solidify MSA as a unique, low-grade salivary gland carcinoma that warrants inclusion in the next version of the WHO classification of head and neck tumors.

DOI： 10.1007/s12105-021-01331-7