Faculty Profiles - YAMAMOTO HIDETAKA

Papers - YAMAMOTO HIDETAKA

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Prognostic value of nuclear morphometry in myxoid liposarcoma. International journal

Kengo Kawaguchi, Kenichi Kohashi, Takeshi Iwasaki, Takeo Yamamoto, Shin Ishihara, Yu Toda, Hidetaka Yamamoto, Yasuharu Nakashima, Yoshinao Oda

Cancer science 114 ( 5 ) 2178 - 2188 2023.1

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

Myxoid liposarcoma (MLS) accounts for 20%-30% of liposarcoma and the round cell component (RCC) is believed to be a specific poor prognostic factor. However, the RCC assessment criteria are vaguely defined and, therefore, are inconsistently employed by pathologists. In this study, we modified and applied two established grading systems to evaluate nuclear atypia (namely, the World Health Organization / International Society of Urological Pathology and the Fuhrman grading in renal cell carcinoma) in 64 MLS cases. Detailed software-based assessments of the morphology and the cellularity were performed. DNA mutation analysis, comprehensive mRNA expression analysis, and immunohistochemistry were also performed. Our findings revealed that the high nuclear grade group according to the modified Fuhrman grading system exhibited a significantly poor disease-free survival (hazard ratio: 4.43; 95% confidence interval: 0.9-22.6; p = 0.047). On the other hand, the cellularity was significantly higher in the modified Fuhrman high-grade group (p = 0.010 at the percentage of the hypercellular area; p = 0.003 at the maximum cell density), but did not qualify per se as a poor prognostic factor in the survival analyses. Furthermore, the modified Fuhrman high-grade group significantly expressed the cell cycle-related genes (such as FOXM1, PLK1, and CDK1). In conclusion, our analyses suggest that an evaluation focusing on nuclear morphology (rather than on cellular density) can be more reliable in predicting the MLS prognosis.

DOI： 10.1111/cas.15729

Liquid biopsy with multiplex ligation-dependent probe amplification targeting cell-free tumor DNA in cerebrospinal fluid from patients with adult diffuse glioma. International journal

Ryosuke Otsuji, Yutaka Fujioka, Nobuhiro Hata, Daisuke Kuga, Yuhei Sangatsuda, Kosuke Takigawa, Yusuke Funakoshi, Aki Sako, Hidetaka Yamamoto, Akira Nakamizo, Masahiro Mizoguchi, Koji Yoshimoto

Neuro-oncology advances 5 ( 1 ) vdac178 2023

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

BACKGROUND: Copy number alterations (CNAs) are common in diffuse gliomas and have been shown to have diagnostic significance. While liquid biopsy for diffuse glioma has been widely investigated, techniques for detecting CNAs are currently limited to methods such as next-generation sequencing. Multiplex ligation-dependent probe amplification (MLPA) is an established method for copy number analysis in pre-specified loci. In this study, we investigated whether CNAs could be detected by MLPA using patients' cerebrospinal fluid (CSF). METHODS: Twenty-five cases of adult diffuse glioma with CNAs were selected. Cell-free DNA (cfDNA) was extracted from the CSF, and DNA sizes and concentrations were recorded. Twelve samples, which had appropriate DNA sizes and concentrations, were subsequently used for analysis. RESULTS: MLPA could be successfully performed in all 12 cases, and the detected CNAs were concordant with those detected using tumor tissues. Cases with epidermal growth factor receptor (EGFR) amplification, combination of gain of chromosome 7 and loss of chromosome 10, platelet-derived growth factor receptor alpha amplification, cyclin-dependent kinase 4 amplification, and cyclin-dependent kinase inhibitor 2A (CDKN2A) homozygous deletion were clearly distinguished from those with normal copy numbers. Moreover, EGFR variant III was accurately detected based on CNA. CONCLUSIONS: Thus, our results demonstrate that copy number analysis can be successfully performed by MLPA of cfDNA extracted from the CSF of patients with diffuse glioma.

DOI： 10.1093/noajnl/vdac178

Sessile serrated lesion of the rectum in ulcerative colitis observed by image-enhanced endoscopy. International journal

Keisuke Kawasaki, Shinichiro Kawatoko, Hidetaka Yamamoto, Takehiro Torisu

The American journal of gastroenterology 118 ( 5 ) 771 - 771 2022.12

Grading of gliomas using 3D CEST imaging with compressed sensing and sensitivity encoding. International journal

Tatsuhiro Wada, Osamu Togao, Chiaki Tokunaga, Masahiro Oga, Kazufumi Kikuchi, Koji Yamashita, Hidetaka Yamamoto, Masami Yoneyama, Koji Kobayashi, Toyoyuki Kato, Kousei Ishigami, Hidetake Yabuuchi

European journal of radiology 158 110654 - 110654 2022.12

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

PURPOSE: We evaluated the usefulness of three-dimensional (3D) chemical exchange saturation transfer (CEST) imaging with compressed sensing and sensitivity encoding (CS-SENSE) for differentiating low-grade gliomas (LGGs) from high-grade gliomas (HGGs). METHODS: We evaluated 28 patients (mean age 51.0 ± 13.9 years, 13 males, 15 females) including 12 with LGGs and 16 with HGGs, all acquired using a 3 T magnetic resonance (MR) scanner. Nine slices were acquired for 3D CEST imaging, and one slice was acquired for two-dimensional (2D) CEST imaging. Two radiological technologists each drew a region of interest (ROI) surrounding the high-signal-intensity area(s) on the fluid-attenuated inversion recovery image of each patient. We compared the magnetization transfer ratio asymmetry (MTRasym) at 3.5 ppm in the tumors among the (i) single-slice 2D CEST imaging ("2D"), (ii) all tumor slices of the 3D CEST imaging (3Dall), and (iii) a representative tumor slice of 3D CEST imaging (maximum signal intensity [3Dmax]). The relationship between the MTRasym at 3.5 ppm values measured by these three methods and the Ki-67 labeling index (LI) of the tumors was assessed. Diagnostic performance was evaluated with a receiver operating characteristic analysis. The Ki-67LI and MTRasym at 3.5 ppm values were compared between the LGGs and HGGs. RESULTS: A moderate positive correlation between the MTRasym at 3.5 ppm and the Ki-67LI was observed with all three methods. All methods proved a significantly larger MTRasym at 3.5 ppm for the HGGs compared to the LGGs. All methods showed equivalent diagnostic performance. The signal intensity varied depending on the slice position in each case. CONCLUSIONS: The 3D CEST imaging provided the MTRasym at 3.5 ppm for each slice cross-section; its diagnostic performance was also equivalent to that of 2D CEST imaging.

DOI： 10.1016/j.ejrad.2022.110654

Quantitative relaxometry using synthetic MRI could be better than T2-FLAIR mismatch sign for differentiation of IDH-mutant gliomas: a pilot study International journal

Kazufumi Kikuchi, Osamu Togao, Koji Yamashita, Daichi Momosaka, Yoshitomo Kikuchi, Daisuke Kuga, Nobuhiro Hata, Masahiro Mizoguchi, Hidetaka Yamamoto, Toru Iwaki, Akio Hiwatashi, Kousei Ishigami

Scientific Reports 12 ( 1 ) 9197 - 9197 2022.12

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

This study aimed to determine whether quantitative relaxometry using synthetic magnetic resonance imaging (SyMRI) could differentiate between two diffuse glioma groups with isocitrate dehydrogenase (IDH)-mutant tumors, achieving an increased sensitivity compared to the qualitative T2-fluid-attenuated inversion recovery (FLAIR) mismatch sign. Between May 2019 and May 2020, thirteen patients with IDH-mutant diffuse gliomas, including seven with astrocytomas and six with oligodendrogliomas, were evaluated. Five neuroradiologists independently evaluated the presence of the qualitative T2-FLAIR mismatch sign. Interrater agreement on the presence of the T2-FLAIR mismatch sign was calculated using the Fleiss kappa coefficient. SyMRI parameters (T1 and T2 relaxation times and proton density) were measured in the gliomas and compared by the Mann–Whitney U test. Receiver operating characteristic curve analysis was used to evaluate the diagnostic performance. The sensitivity, specificity, and kappa coefficient were 57.1%, 100%, and 0.60, respectively, for the qualitative T2-FLAIR mismatch sign. The two types of diffuse gliomas could be differentiated using a cutoff value of 178 ms for the T2 relaxation time parameter with 100% sensitivity, specificity, accuracy, and positive and negative predictive values, with an area under the curve (AUC) of 1.00. Quantitative relaxometry using SyMRI could differentiate astrocytomas from oligodendrogliomas, achieving an increased sensitivity and objectivity compared to the qualitative T2-FLAIR mismatch sign.

DOI： 10.1038/s41598-022-13036-0

Auxiliary diagnosis of subepithelial lesions by impedance measurement during endoscopic ultrasound guided fine-needle biopsy. International journal

Yosuke Minoda, Mitsuru Esaki, Eikichi Ihara, Shuzaburo Nagatomo, Kei Nishioka, Nao Fujimori, Haruei Ogino, Xiaopeng Bai, Yoshimasa Tanaka, Takatoshi Chinen, Qingjiang Hu, Mitsuhiko Ota, Shinya Umekita, Hidetaka Yamamoto, Yoshihiro Ogawa

Gastrointestinal endoscopy 97 ( 5 ) 977 - 984 2022.11

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

INTRODUCTION: Endoscopic ultrasound guided fine-needle aspiration/biopsy (EUS-FNA/B) is the gold standard for diagnosing subepithelial lesions (SELs); however, its diagnostic ability for SELs <20 mm is low. We developed a new diagnostic method to differentiate between gastrointestinal stromal tumor (GIST) and non-GIST by measuring high-frequency impedance (H-impedance) using an EUS-FNB needle. METHODS: The H-impedance of gastric epithelial neoplasms from 16 cases were measured using a conventional impedance probe to confirm whether H-impedance is clinically useful for assessing cell density (Study 1). The H-impedance values of exposed SELs from 25 cases using the conventional probe (Study 2) and non-exposed SELs from 20 cases using the EUS-FNB needle probe (Study 3) were measured to determine the diagnostic ability of H-impedance for differentiating GISTs from non-GISTs. RESULTS: H-impedance significantly positively correlated with cell density (P=0.030) (Study 1). The H-impedance of GIST (99.5) measured using conventional probe was significantly higher than those of the muscular layer (82.4) and leiomyoma (89.2) (P<0.01) (Study 2). The H-impedance of GIST measured using the EUS-FNB needle was also significantly higher than that of leiomyoma (GIST: 80.2 vs. leiomyoma: 71.8, P=0.015). The diagnostic yield of the impedance method for differentiating GISTs from non-GISTs had 94.4% accuracy, 88.9% sensitivity, 100% specificity, and 0.95 area under the curve. Diagnostic ability was not affected by lesion size (P=0.86) (Study 3). CONCLUSION: Auxiliary differential diagnosis between gastric GISTs and non-GISTs by the H-impedance measurement during EUS-FNB could be a good option especially when the lesion is smaller than 20 mm.

DOI： 10.1016/j.gie.2022.11.022

Expression of SATB2, RUNX2, and SOX9 and possible osteoblastic and chondroblastic differentiation in chondroblastoma. International journal

Yu Toda, Hidetaka Yamamoto, Takeshi Iwasaki, Shin Ishihara, Yoshihiro Ito, Yosuke Susuki, Kengo Kawaguchi, Izumi Kinoshita, Daisuke Kiyozawa, Yuichi Yamada, Kenichi Kohashi, Atsushi Kimura, Toshifumi Fujiwara, Nokitaka Setsu, Makoto Endo, Yoshihiro Matsumoto, Yasuharu Nakashima, Masaaki Mawatari, Yoshinao Oda

Pathology, research and practice 241 154239 - 154239 2022.11

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

Chondroblastoma (CB) is histologically characterized by oval to polygonal-shaped mononuclear neoplastic cells, multinucleated osteoclastic giant cells, and eosinophilic matrix with occasional calcification. Genetically, the majority of CBs harbor H3F3B p.K36M mutation. Despite the historical nomenclature, it has been reported that the matrix of CB is similar to osteoid rather than true cartilage; however, it remains unclear whether neoplastic cells in CB have the potential for osteoblastic differentiation. To clarify this issue, we immunohistochemically examined the expression of osteogenic and chondrogenic markers (SATB2, RUNX2, p63, and SOX9) as well as H3K36M mutant protein in 33 cases of CB. All 33 cases of CB were positive for H3K36M, while SATB2, RUNX2, p63, and SOX9 were expressed in 30/33 (91%), 33/33 (100%), 29/33 (88%), and 31/32 (97%) CB cases, respectively. Our immunohistochemical results suggest that neoplastic cells in CB frequently express both osteogenic and chondrogenic markers and may have an intermediate feature of osteoblastic and chondroblastic nature.

DOI： 10.1016/j.prp.2022.154239

Nuclear expression of AFF2 C-terminus is a sensitive and specific ancillary marker for DEK::AFF2 carcinoma of the sinonasal tract. International journal

Ying-Ju Kuo, James S Lewis Jr, Tra Truong, Yi-Chen Yeh, Rebecca D Chernock, Changwen Zhai, Yun-An Chen, Takahiro Hongo, Chien-Kuan Lee, Qiuying Shi, Jaylou M Velez Torres, Ariana B Geromes, Ying-Hsia Chu, Min-Shu Hsieh, Hidetaka Yamamoto, Ilan Weinreb, Jen-Fan Hang

Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc 35 ( 11 ) 1587 - 1595 2022.11

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

DEK::AFF2 carcinoma of the sinonasal tract is an emerging entity. The tumor is typically characterized by papillary proliferation of non-keratinizing squamous epithelial cells with monotonous cytologic features, which may mimic other sinonasal tumors. The confirmation of this gene fusion has thus far relied solely on next-generation sequencing, fluorescence in situ hybridization (FISH), or reverse transcription polymerase chain reaction (RT-PCR). This current study aimed to validate an immunohistochemical assay for AFF2 C-terminus as an ancillary marker. We first analyzed publicly available RNA sequencing data of sinonasal tumors from the national center for biotechnology information (NCBI) sequence read archive and identified 3 DEK::AFF2 carcinomas out of 28 sinonasal tumors. The gene expression of AFF2 was significantly higher in the fusion-positive cases compared to the wild-type tumors (p < 0.001), while DEK was not. We then optimized an immunohistochemical assay with an anti-AFF2 C-terminus antibody for ancillary diagnosis. Seventeen DEK::AFF2 carcinomas, including 11 cases with predominantly low-grade morphology and one showing glandular differentiation, as well as 78 DEK FISH-negative sinonasal tumors were evaluated by AFF2 immunohistochemistry (IHC). Sixteen of the 17 DEK::AFF2 carcinomas showed nuclear AFF2 expression in ≥30% of tumor cells, including one decalcified case that failed FISH and RT-PCR confirmation. The one case that was negative for AFF2 IHC in the tumor cells also lacked expression in the internal positive control. It was thus considered a failure of the IHC rather than a truly negative case and was excluded from the statistical analysis. All DEK FISH-negative sinonasal tumors were negative for nuclear AFF2 expression. The nuclear expression of AFF2 IHC showed 100% sensitivity and specificity for DEK::AFF2 carcinoma. Accordingly, AFF2 IHC is a highly sensitive and specific ancillary marker that distinguishes DEK-AFF2 carcinoma from the other sinonasal tumors with overlapping morphological features and may be an especially useful alternative for decalcified specimens.

DOI： 10.1038/s41379-022-01117-4

Mucin-rich traditional serrated adenoma with dysplasia of the rectum observed by magnifying endoscopy. International journal

Keisuke Kawasaki, Shinichiro Kawatoko, Shota Yamamoto, Hidetaka Yamamoto, Takehiro Torisu

Gastrointestinal endoscopy 97 ( 3 ) 599 - 600 2022.10

Surgical resection of a tuberculoma in the diaphragm: a case report. International journal

Asato Hashinokuchi, Mikihiro Kohno, Keisuke Kosai, Yuki Ono, Naoki Haratake, Daiki Shibata, Hidetaka Yamamoto, Tomoyoshi Takenaka, Tomoharu Yoshizumi

Surgical case reports 8 ( 1 ) 198 - 198 2022.10

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

BACKGROUND: Extrapulmonary tuberculosis commonly affects the lymphatic system, nervous system, and gastrointestinal system. Tuberculous infection in the muscle is very rare. Moreover, tuberculous infection in the diaphragm is extremely rare. We herein report a case of tuberculomas in the diaphragm and posterior mediastinum that were successfully diagnosed and treated. CASE PRESENTATION: We encountered a 62-year-old woman with a tuberculoma in the diaphragm. The patient presented with mild dyspnea. Computed tomography showed a mass in the left diaphragm, focal thickening of the posterior mediastinum, and multiple nodules in the lungs. Positron emission tomography-computed tomography showed increased uptake in the left diaphragm mass and thickening of the posterior mediastinum; therefore, we considered the masses to be malignant and planned surgical resection. However, the patient was diagnosed with tuberculosis from a sputum culture, and she was treated with anti-tuberculous therapy. The masses in the diaphragm and posterior mediastinum had become enlarged after 6 months of anti-tuberculous therapy; therefore, the patient underwent resection of both masses. Tuberculous infection was histologically confirmed in each lesion. She was pathologically diagnosed with tuberculous abscesses in the diaphragm and posterior mediastinum and began treatment with anti-tuberculosis drugs. CONCLUSIONS: Preoperative diagnosis of a tuberculoma in the diaphragm is usually difficult, and surgical intervention is important for both diagnosis and treatment.

DOI： 10.1186/s40792-022-01554-y

Efficacy of ultrasound endoscopy with artificial intelligence for the differential diagnosis of non-gastric gastrointestinal stromal tumors. International journal

Yosuke Minoda, Eikichi Ihara, Nao Fujimori, Shuzaburo Nagatomo, Mitsuru Esaki, Yoshitaka Hata, Xiaopeng Bai, Yoshimasa Tanaka, Haruei Ogino, Takatoshi Chinen, Qingjiang Hu, Eiji Oki, Hidetaka Yamamoto, Yoshihiro Ogawa

Scientific reports 12 ( 1 ) 16640 - 16640 2022.10

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

Gastrointestinal stromal tumors (GISTs) are common subepithelial lesions (SELs) and require treatment considering their malignant potential. We recently developed an endoscopic ultrasound-based artificial intelligence (EUS-AI) system to differentiate GISTs from non-GISTs in gastric SELs, which were used to train the system. We assessed whether the EUS-AI system designed for diagnosing gastric GISTs could be applied to non-gastric GISTs. Between January 2015 and January 2021, 52 patients with non-gastric SELs (esophagus, n = 15; duodenum, n = 26; colon, n = 11) were enrolled. The ability of EUS-AI to differentiate GISTs from non-GISTs in non-gastric SELs was examined. The accuracy, sensitivity, and specificity of EUS-AI for discriminating GISTs from non-GISTs in non-gastric SELs were 94.4%, 100%, and 86.1%, respectively, with an area under the curve of 0.98 based on the cutoff value set using the Youden index. In the subanalysis, the accuracy, sensitivity, and specificity of EUS-AI were highest in the esophagus (100%, 100%, 100%; duodenum, 96.2%, 100%, 0%; colon, 90.9%, 100%, 0%); the cutoff values were determined using the Youden index or the value determined using stomach cases. The diagnostic accuracy of EUS-AI increased as lesion size increased, regardless of lesion location. EUS-AI based on gastric SELs had good diagnostic ability for non-gastric GISTs.

DOI： 10.1038/s41598-022-20863-8

Hypopharyngeal dedifferentiated liposarcoma treated by endoscopic submucosal dissection. International journal

Keisuke Kawasaki, Shinichiro Kawatoko, Hidetaka Yamamoto, Takehiro Torisu

Digestive and liver disease : official journal of the Italian Society of Gastroenterology and the Italian Association for the Study of the Liver 55 ( 1 ) 137 - 138 2022.9

Nuclear β-catenin translocation plays a key role in osteoblast differentiation of giant cell tumor of bone. International journal

Atsushi Kimura, Yu Toda, Yoshihiro Matsumoto, Hidetaka Yamamoto, Kenichiro Yahiro, Eijiro Shimada, Masaya Kanahori, Ryunosuke Oyama, Suguru Fukushima, Makoto Nakagawa, Nokitaka Setsu, Makoto Endo, Toshifumi Fujiwara, Tomoya Matsunobu, Yoshinao Oda, Yasuharu Nakashima

Scientific reports 12 ( 1 ) 13438 - 13438 2022.8

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

Denosumab is a game-changing drug for giant cell tumor of bone (GCTB); however, its clinical biomarker regarding tumor ossification of GCTB has not been elucidated. In this study, we investigated the relationship between Wnt/β-catenin signaling and the ossification of GCTB and evaluated whether endogenous nuclear β-catenin expression predicted denosumab-induced bone formation in GCTB. Genuine patient-derived primary GCTB tumor stromal cells exhibited osteoblastic characteristics. Identified osteoblastic markers and nuclear β-catenin translocation were significantly upregulated via differentiation induction and were inhibited by treating with Wnt signaling inhibitor, GGTI-286, or selective Rac1-LEF inhibitor, NSC23766. Furthermore, we reviewed the endogenous ossification and nuclear β-catenin translocation of 86 GCTB clinical samples and elucidated that intra-tumoral ossification was significantly associated with the nuclear translocation. Three-dimensional quantitative analyses (n = 13) of tumoral CT images have revealed that the nuclear β-catenin translocation of naïve GCTB samples was significantly involved with the denosumab-induced tumor ossification. Our findings suggest a close relationship between the nuclear β-catenin translocation and the osteoblastic differentiation of GCTB. Investigations of the nuclear β-catenin in naïve GCTB samples may provide a promising biomarker for predicting the ossification of GCTB following denosumab treatment.

DOI： 10.1038/s41598-022-17728-5

Idiopathic myointimal hyperplasia of mesenteric veins depicted by barium enema examination, and conventional and magnifying colonoscopy.

Keisuke Kawasaki, Shinichiro Kawatoko, Takehiro Torisu, Yusuke Mizuuchi, Toshimi Iura, Hiroshi Ohtani, Katsuki Okamura, Hidetaka Yamamoto, Masafumi Nakamura, Takanari Kitazono

Clinical journal of gastroenterology 15 ( 4 ) 734 - 739 2022.8

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

A 71-year-old man was admitted to our institution complaining of abdominal pain and constipation. Barium enema examination revealed narrowing, cobble stoning, and longitudinal ulcerations in the sigmoid colon and upper rectum. Conventional colonoscopy, magnifying narrow-band imaging endoscopy, and magnifying chromoendoscopy revealed edematous mucosa, longitudinal ulcerations with luminal narrowing, and multiple pseudopolyps. The histologic examination of the biopsy specimens showed thick-walled (arterialized) capillaries and subendothelial fibrin deposits in the mucosa and submucosa. Based on a preoperative diagnosis of idiopathic myointimal hyperplasia of mesenteric veins (IMHMV), he underwent a laparoscopic resection of the sigmoid colon and upper rectum. The histologic examination of the resected specimens showed marked proliferation of venous walls with marked myointimal thickening and luminal occlusion from the submucosa to the mesentery throughout the entire resected tissue section. The final diagnosis was IMHMV.

DOI： 10.1007/s12328-022-01647-z

Salivary Gland Polymorphous Adenocarcinoma: Clinicopathological Features and Gene Alterations in 36 Japanese Patients International journal

Masahiro Fukumura, Kenichiro Ishibashi, Masato Nakaguro, Toshitaka Nagao, Kosuke Saida, Makoto Urano, Maki Tanigawa, Hideaki Hirai, Takahiro Yagyuu, Kentaro Kikuchi, Naomi Yada, Yoshihiko Sugita, Megumi Miyabe, Shogo Hasegawa, Mitsuo Goto, Hidetaka Yamamoto, Tomoyuki Ohuchi, Kimihide Kusafuka, Ikuko Ogawa, Hiroaki Suzuki, Kenji Notohara, Masayuki Shimoda, Yuichiro Tada, Tadaaki Kirita, Takashi Takata, Shojiroh Morinaga, Hatsuhiko Maeda, Saman Warnakulasuriya, Satoru Miyabe, Toru Nagao

Journal of Oral Pathology & Medicine 51 ( 8 ) 710 - 720 2022.7

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

OBJECTIVES: Polymorphous adenocarcinoma (PAC) 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 PAC-associated genes, such as (e.g., PRKD1/2/3, ARID1A, and DDX3X) in a large cohort of Japanese patients with PAC. MATERIALS AND METHODS: We examined the cases of 36 Japanese patients with salivary gland PAC and 26 cases involving histopathological mimics. To detect gene splits, fluorescence in situ hybridization was carried out for PAC-associated genes. Additionally, we applied a SNaPshot multiplex assay to identify PRKD1 hotspot mutations. RESULTS: This study revealed the indolent clinical course of PAC with a high 10-year overall survival rate (92.9%), accompanied by occasional local recurrences and cervical lymph node metastasis (both 23.3%). Twenty cases (55.6%) of PAC (but none of the mimics) exhibited alterations in at least one PAC-associated gene. Rearrangement of PAC-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 PAC showed clinicopathological features similar to those reported in Western countries. This study disclosed that PAC-associated genetic alterations were common and specific findings in PACs. The diagnostic role and possible prognostic significance of PAC-associated genetic alterations in PACs were suggested.

DOI： 10.1111/jop.13336

Negligible procedure-related dissemination risk of mucosal incision-assisted biopsy for gastrointestinal stromal tumors versus endoscopic ultrasound-guided fine-needle aspiration/biopsy. International journal

Yosuke Minoda, Eikichi Ihara, Soichi Itaba, Yorinobu Sumida, Kazuhiro Haraguchi, Akira Aso, Takahiro Mizutani, Takashi Osoegawa, Mitsuru Esaki, Shuzaburo Nagatomo, Kei Nishioka, Kazumasa Muta, Xiaopeng Bai, Haruei Ogino, Nao Fujimori, Daisuke Tsurumaru, Kenoki Ohuchida, Hu Qingjiang, Eiji Oki, Hidetaka Yamamoto, Yoshihiro Ogawa

Surgical endoscopy 37 ( 1 ) 101 - 108 2022.7

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

BACKGROUND: Mucosal incision-assisted biopsy (MIAB) is a valuable alternative to endoscopic ultrasound-guided fine-needle aspiration/biopsy (EUS-FNAB) for sampling gastric subepithelial lesions (SELs). This study aimed to evaluate the potential risk of dissemination and impact on postoperative prognosis associated with MIAB, which has not yet been investigated. METHODS: Study 1: A prospective observational study was conducted to examine the presence or absence and growth rate of tumor cells in gastric juice before and after the procedure in patients with SELs who underwent MIAB (n = 25) or EUS-FNAB (n = 22) between September 2018 and August 2021. Study 2: A retrospective study was conducted to examine the impact of MIAB on postoperative prognosis in 107 patients with gastrointestinal stromal tumors diagnosed using MIAB (n = 39) or EUS-FNAB (n = 68) who underwent surgery between January 2001 and July 2020. RESULTS: In study 1, although no tumor cells were observed in gastric juice in MIAB before the procedure, they were observed in 64% of patients after obtaining samples (P < 0.001). In contrast, no tumor cells were observed in the gastric juice in EUS-FNAB before and after the procedure. In study 2, there was no significant difference in 5-year disease-free survival between MIAB (100%) and EUS-FNAB (97.1%) (P = 0.27). CONCLUSION: MIAB is safe, with little impact on postoperative prognosis, although the procedure releases some tumor cells after damaging the SEL's pseudocapsule.

DOI： 10.1007/s00464-022-09419-z

Real-world Experience With Pembrolizumab for Advanced-stage Head and Neck Cancer Patients: A Retrospective, Multicenter Study. International journal

Takafumi Nakano, Ryuji Yasumatsu, Kazuki Hashimoto, Ryosuke Kuga, Takahiro Hongo, Hidetaka Yamamoto, Mioko Matsuo, Takahiro Wakasaki, Rina Jiromaru, Tomomi Manako, Satoshi Toh, Muneyuki Masuda, Moriyasu Yamauchi, Yuichiro Kuratomi, Masahiko Taura, Toranoshin Takeuchi, Takashi Nakagawa

Anticancer research 42 ( 7 ) 3653 - 3664 2022.7

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

BACKGROUND/AIM: This study investigated the effectiveness of pembrolizumab with or without chemotherapy on advanced-stage head and neck cancer (HNC), including nasopharyngeal, sinonasal cavity and external auditory canal cancer, in a real-world setting. PATIENTS AND METHODS: We retrospectively collected data from 97 HNC patients who were treated with pembrolizumab alone (n=60) or with chemotherapy (n=37), and we investigated the association between clinicopathological findings and treatment response or prognosis. RESULTS: Patients treated with pembrolizumab and chemotherapy had a 1-year overall survival (OS) of 72.8%, objective response rate (ORR) of 48.6%, and serious (≥G3) adverse events (AEs) of 29.7%. Patients treated with pembrolizumab alone had a 1-year OS of 51.9%, ORR of 21.7%, and ≥G3 AEs of 6.7%. Both the ORR and disease control rate (DCR) in the pembrolizumab with chemotherapy group were significantly better than those in the pembrolizumab group (p=0.074 and p=0.00101, respectively). Among patients with distant metastasis, patients on pembrolizumab with chemotherapy achieved significantly better OS than pembrolizumab alone (p=0.0039). Among patients in the pembrolizumab group, both AE-positive and better performance status were associated with longer OS (p=0.011 and p=0.0037, respectively). CONCLUSION: Our real-world experience reinforces the durability and effectiveness of pembrolizumab for HNC patients. Additionally, our results suggest that pembrolizumab with chemotherapy might be recommended for patients with distant metastasis and no prior treatment. Further studies are needed to determine the optimal treatment strategy for HNC.

DOI： 10.21873/anticanres.15854

A clinical analysis of oropharyngeal squamous cell carcinoma: a single-institution's experience. International journal

Rina Jiromaru, Ryuji Yasumatsu, Hidetaka Yamamoto, Ryosuke Kuga, Takahiro Hongo, Takafumi Nakano, Tomomi Manako, Kazuki Hashimoto, Takahiro Wakasaki, Mioko Matsuo, Takashi Nakagawa

European archives of oto-rhino-laryngology : official journal of the European Federation of Oto-Rhino-Laryngological Societies (EUFOS) : affiliated with the German Society for Oto-Rhino-Laryngology - Head and Neck Surgery 279 ( 7 ) 3717 - 3725 2022.7

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

PURPOSE: We herein report the treatment outcome of oropharyngeal squamous cell carcinoma (OPSCC) at Kyushu University Hospital, the total number of OPSCC cases, and changes in the proportion of human papilloma virus (HPV)-related carcinomas over time. METHOD: We performed a retrospective analysis of 237 cases treated for OPSCC at Kyushu University Hospital between 2013 and 2019. We performed HPV-mRNA in situ hybridization and p16 immunohistochemistry. RESULT: This study included 197 males (82.1%) and 40 females (17.9%). The disease-specific, progression-free and overall survival (OS) were 69%, 62% and 61%, respectively, over the decade-long study period. p16-Immunohistochemistory and highrisk HPV mRNA in situ hybridization were positive in 114 (48.1%) and 105 (44.3%) cases, respectively. The number of HPV-related OPSCC cases increased according to an annual analysis. HPV+ cases had a significantly better prognosis than HPV- cases. In addition, p16+/HPV- cases had a significantly worse prognosis than p16+/HPV+ cases (OS: p = 0.0484). HPV+ OPSCC cases were associated with a younger age (< 60 years old) (p = 0.0429), non-smoker (p = 0.0001), lateral tumor site (< 0.00001), lymphoid metastasis (< 0.0001) and low clinical stage (< 0.0001). CONCLUSION: The frequency of HPV-related OPSCC cases is increasing in Japan as well as worldwide, and such cases are characterized by no smoking habit, a young age, and a good prognosis. Even in p16+ OPSCC, HPV- cases had a poor prognosis, suggesting the importance of accurate HPV determination. To determine the intensity of treatment for HPV-related and non-related OPSCC, it is necessary to accumulate cases for the accurate HPV determination and comparison of treatment effects.

DOI： 10.1007/s00405-021-07236-z

The implicated clinical factors for outcomes in 304 patients with salivary duct carcinoma: Multi-institutional retrospective analysis in Japan. International journal

Kimihide Kusafuka, Yoko Sato, Eiji Nakatani, Satoshi Baba, Matsuyoshi Maeda, Koji Yamanegi, Kaori Ueda, Hiroshi Inagaki, Yoshiro Otsuki, Naoto Kuroda, Kensuke Suzuki, Hiroshi Iwai, Yoshiaki Imamura, Junya Itakura, Shoji Yamanaka, Hideaki Takahashi, Ichiro Ito, Takumi Akashi, Tsutomu Daa, Mei Hamada, Masanori Yasuda, Ryo Kawata, Hidetaka Yamamoto, Yuri Tachibana, Junya Fukuoka, Aya Muramatsu, Kazumori Arai, Makoto Suzuki

Head & neck 44 ( 6 ) 1430 - 1441 2022.6

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

BACKGROUND: Salivary duct carcinoma (SDC) is a high-grade salivary malignancy that frequently occurs as the carcinomatous component of carcinoma ex pleomorphic adenoma. We herein examined the clinical factors affecting outcomes in a large cohort of SDC. METHODS: We selected 304 SDC cases and investigated clinical characteristics and the factors affecting outcomes. RESULTS: The median age of the cases examined was 68 years, the most common primary site was the parotid gland (238 cases), and there was a male predominance (M/F = 5:1). Outcomes were significantly worse when the primary tumor site was the minor salivary glands (SG) than when it was the major SG. Outcomes were also significantly worse in pN(+) cases (161 cases) than in pN0 cases, particularly those with a metastatic lymph node number ≥11. The cumulative incidence of relapse and distant metastases was significantly higher in stage IV cases than in stage 0-III cases. CONCLUSIONS: The absolute number of lymph node metastases, higher stages, and the minor SG as the primary tumor site were identified as factors affecting the outcome of SDC.

DOI： 10.1002/hed.27034

Distinct disease-specific Tfh cell populations in two different fibrotic diseases: IgG4-related disease and Kimura's disease. International journal

Ryusuke Munemura, Takashi Maehara, Yuka Murakami, Risako Koga, Ryuichi Aoyagi, Naoki Kaneko, Atsushi Doi, Cory A Perugino, Emanuel Della-Torre, Takako Saeki, Yasuharu Sato, Hidetaka Yamamoto, Tamotsu Kiyoshima, John H Stone, Shiv Pillai, Seiji Nakamura

The Journal of allergy and clinical immunology 150 ( 2 ) 440 - 455 2022.5

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

BACKGROUND: How T follicular (Tfh) cells contribute to many different B-cell class-switching events during T cell-dependent immune responses has been unclear. Diseases with polarized isotype switching offer a unique opportunity for the exploration of Tfh subsets. Secondary and tertiary lymphoid organs (SLOs and TLOs) in patients with elevated tissue expression levels of IgE (Kimura's disease, KD) and those of IgG4 (IgG4-related disease, IgG4-RD) can provide important insights regarding cytokine expression by Tfh cells. OBJECTIVE: To identify disease-specific Tfh cell subsets in SLOs and TLOs expressing IL-10 or IL-13 and thus identify different cellular drivers of class switching in two distinct types of fibrotic disorders: allergic fibrosis (driven by type 2 immune cells) and inflammatory fibrosis (driven by cytotoxic T lymphocytes). METHODS: Single-cell RNA-sequencing, in situ sequencing, and multi-color immunofluorescence analysis was used to investigate B cells, Tfh cells and infiltrating type 2 cells in lesion tissues from patients with KD or IgG4-RD. RESULTS: Infiltrating Tfh cells in TLOs from IgG4-RD were divided into six main clusters. We encountered abundant infiltrating IL-10-expressing LAG3+ Tfh cells in patients with IgG4-RD. Furthermore, we found that infiltrating AID+CD19+B cells expressing IL-4, IL-10, and IL-21 receptors correlated with IgG4 expression. In contrast, we found that infiltrating IL-13-expressing Tfh cells were abundant in affected tissues from patients with KD. Moreover, we observed few infiltrating IL-13-expressing Tfh cells in tissues from patients with IgG4-RD, despite high serum levels of IgE (but low IgE in the disease lesions). Cytotoxic T cells were abundant in IgG4-RD, and in contrast Type 2 immune cells were abundant in KD. CONCLUSIONS: This single-cell dataset revealed a novel subset of IL10+LAG3+Tfh cells infiltrating the affected organs of IgG4-RD patients. In contrast, IL13+Tfh cells and type 2 immune cells infiltrated those of KD patients.

DOI： 10.1016/j.jaci.2022.03.034

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