研究者詳細 - 真里谷　奨

論文 - 真里谷　奨

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Large number of CD68+/CD163+ Hofbauer cells and characteristic vascular structural alterations in the placental villi of cases with placenta accreta spectrum.

Hazuki Kashiwagi, Kengo Shigehara, Terufumi Kubo, Yoshihiko Hirohashi, Tasuku Mariya, Kazuhiko Matsuo, Tomoyuki Minowa, Shin-Ichi Ishioka, Kenji Murata, Takayuki Kanaseki, Tomohide Tsukahara, Tadashi Hasegawa, Tsuyoshi Saito, Toshihiko Torigoe

Medical molecular morphology 2025年03月 [国内誌]

Placenta accreta spectrum (PAS) is a serious disease leading to complications and maternal death. The objective of the study was to characterize the placental villi and blood vessels of PAS villi histopathologically. We investigated 10 cases of PAS (five cases of placenta increta, two cases of placenta accreta, and three cases of placenta percreta) histologically. Immunohistochemical staining using anti-CD68 or anti-CD163 antibodies was performed to detect and count Hofbauer cells. Immunohistochemical staining with an anti-CD34 antibody was used to detect vascular endothelial cells, and the number and area of vessels were analyzed. The numbers of CD68-positive or CD163-positive Hofbauer cells were larger in PAS cases compared with control cases. The vascular area in villi was smaller in PAS cases compared with control cases. The number of blood vessels in villi was slightly higher in PAS cases than in control cases. The numbers of Hofbauer cells and vessels in villi were larger in PAS cases compared with control cases, whereas the area of vessels in villi was smaller in PAS cases compared with control cases. Although their biological meaning is elusive, these findings provide novel insights into the pathogenesis of PAS, particularly regarding the role of Hofbauer cells in immune-suppressive role and angiogenesis and the alterations in vascular structure and hemodynamics in the chorionic villi.

Identification and Phenotypic Characterization of Neoantigen-Specific Cytotoxic CD4+ T Cells in Endometrial Cancer

Minami Fusagawa, Serina Tokita, Kenji Murata, Tasuku Mariya, Mina Umemoto, Shintaro Sugita, Kazuhiko Matsuo, Yoshihiko Hirohashi, Tsuyoshi Saito, Takayuki Kanaseki, Toshihiko Torigoe

Cancer Immunology Research 2025年02月

Maternal age and the rising incidence of hypertensive disorders of pregnancy: A comprehensive analysis of national claims data from Japan.

Naomi Maeda, Masayuki Koyama, Shintaro Takatsuka, Keisuke Oyatani, Nobuaki Himuro, Tasuku Mariya, Yoshika Kuno, Shiro Hinotsu, Tsuyoshi Saito, Hirofumi Ohnishi

PloS one 20 ( 2 ) e0319177 2025年 [国際誌]

BACKGROUND: Hypertensive disorders of pregnancy (HDP) significantly increase the risk of developing hypertension and cardiovascular disease (CVD) later in life and are a major cause of maternal mortality. However, little is known about the nationwide, long-term, all-inclusive status of HDP. OBJECTIVE: To estimate the incidence of HDP from 2011 to 2019 in Hokkaido, Japan, with a focus on age groups. METHODS: Using National Database (NDB) insurance medical data, a retrospective analysis was conducted. Due to the absence of direct pregnancy data, birth numbers were used as a surrogate for the number of pregnant women to calculate the incidence of HDP. RESULTS: The average incidence rate of HDP over 9 years was 6.37%. The incidence rate was lowest among women aged 25-29 years, at 5.58% (95% confidence interval [CI]: 5.43-5.73), and increased with age, peaking at 10.58% (95% CI: 10.10-11.09) among women over 40 years. Notably, the incidence rate for women under 20 years of age was 6.70% (95% CI: 5.97-7.51), which was higher than that for women in their 20s. A mean annual increase of 0.25% in age-adjusted incidence was observed during this period, which was statistically significant (R² = 0.87, p < 0.01). CONCLUSION: This study reveals that the risk of developing HDP is associated with both older childbearing and younger pregnancies and follows a J-curve, suggesting that factors other than maternal aging also contribute to the increased incidence of HDP and that further research on risk factors for HDP, which is on the rise worldwide, is urgently needed.

遺伝子関連検査を知る近年のPGT-Mの検査法について

真里谷奨

遺伝子医学 ( (株)メディカルドゥ ) 14 ( 4 ) 101 - 106 2024年12月

PGT-M(preimplantation genetic testing for monogenic/single-gene defects)に用いる胚の生検検体は5～10細胞とごくわずかであり,全ゲノム増幅を経る必要があるため特有の検査上のピットフォールが存在する。そのため,個々の単一遺伝子疾患の確実な検査系の構築はテーラーメイドかつ複雑であるが,ロングリードシーケンサー等の新たなツールの活用により,複雑な構造異常を伴うバリアントやde noveの発端者など,多様な症例にも対応可能となっている。(著者抄録)

Impact of colposcopy-guided carbon dioxide laser vaporization therapy on peripheral cervical intraepithelial neoplasia lesions.

Tasuku Mariya, Akira Nishikawa, Mina Umemoto, Shiori Ogawa, Tsuyoshi Saito

Taiwanese journal of obstetrics & gynecology 63 ( 6 ) 846 - 852 2024年11月 [国際誌]

OBJECTIVE: Laser vaporization is less invasive than conization for cervical intraepithelial neoplasia (CIN). The outcome of laser vaporization for CIN is empirically known to depend on the colposcopic findings, especially localization of the lesion. In this study, we sought to identify factors involved in the outcome of laser vaporization. MATERIALS AND METHODS: We retrospectively investigated 290 cases of CIN (CIN2, n = 180; CIN3, n = 110) treated with laser evaporation at Nishikawa Women's Health Clinic between 2018 and 2021. All treatments were performed using a carbon dioxide laser under either colposcopic vision (n = 172) or direct vision using a vaginal speculum (n = 118). Risk factors were statistically examined for cure rate after treatment. RESULTS: Multivariate analysis using a logistic regression model identified independent factors affecting the success of treatment to be high-risk human papillomavirus infection status preoperatively, CIN grade, presence of CIN lesions at the periphery of the cervix, and the surgical method used. Colposcopy-guided laser vaporization reduced the risk of treatment failure by 84% (odds ratio 0.16, 95% confidence interval 0.06-0.46; p = 0.001) compared with direct vision using a vaginal speculum. For lesions at the periphery of the cervix, most of the treatment failures were in the group that was not guided by colposcopy (p = 0.031). CONCLUSION: The presence of a peripheral CIN lesion was suggested to be a risk factor for treatment failure. Laser vaporization under colposcopic vision is recommended for treatment of peripheral CIN lesions.

【遺伝学的検査Up to Date】遺伝学的検査の応用法を知ろう! 着床前診断を知ろう!

真里谷奨, 倉橋浩樹

小児科診療 ( (株)診断と治療社 ) 87 ( 11 ) 1579 - 1584 2024年11月

＜文献概要＞▽網羅的染色体解析による検査手法の確立により,着床前診断(preimplantation genetic testing:PGT)の診断精度は大きく向上した.▽PGTにまつわる倫理的な議論,特にPGT-M(重篤な遺伝性疾患を対象とした着床前遺伝学的検査)に関連した内容は継続して行われており,検査適応については症例ごとの詳細な検討が必要となる.▽PGTに関連した技術は現在も進歩を続けており,検査の応用範囲は今後さらに拡大していく可能性が高い.

Successful Outcome of Stage IB3 Cervical Cancer Treated With Neoadjuvant Chemotherapy Followed by Vaginal Radical Trachelectomy: A Case Report.

Masato Tamate, Motoki Matsuura, Masayuki Someya, Tasuku Mariya, Shinichi Ishioka, Tsuyoshi Saito

Cureus 16 ( 10 ) e71626 2024年10月 [国際誌]

Vaginal trachelectomy, which involves resecting the cervix and its parametrium, is a fertility-sparing option for the treatment of early-stage cervical cancer. Although no consensus has been reached on whether simple or radical trachelectomy is preferable, the vaginal approach is typically avoided for tumors larger than 2 cm due to concerns about recurrence. However, some evidence suggests that fertility preservation may still be viable for select patients with larger tumors. This case report describes a woman with bulky cervical cancer who wished to preserve her fertility. After undergoing neoadjuvant chemotherapy (NAC) and vaginal radical trachelectomy (VRT), she achieved a favorable oncological and perinatal outcome, successfully giving birth to a near-full-term baby. The report outlines the patient's management before, during, and after the procedure, including perinatal care. While careful selection of candidates is crucial, accumulating case reports and future trials are expected to shed more light on this treatment approach.

Identification of immunogenic HLA class I and II neoantigens using surrogate immunopeptidomes.

Serina Tokita, Minami Fusagawa, Satoru Matsumoto, Tasuku Mariya, Mina Umemoto, Yoshihiko Hirohashi, Fumitake Hata, Tsuyoshi Saito, Takayuki Kanaseki, Toshihiko Torigoe

Science advances 10 ( 38 ) eado6491 2024年09月 [国際誌]

Neoantigens arising from somatic mutations are tumor specific and induce antitumor host T cell responses. However, their sequences are individual specific and need to be identified for each patient for therapeutic applications. Here, we present a proteogenomic approach for neoantigen identification, named Neoantigen Selection using a Surrogate Immunopeptidome (NESSIE). This approach uses an autologous wild-type immunopeptidome as a surrogate for the tumor immunopeptidome and allows human leukocyte antigen (HLA)-agnostic identification of both HLA class I (HLA-I) and HLA class II (HLA-II) neoantigens. We demonstrate the direct identification of highly immunogenic HLA-I and HLA-II neoantigens using NESSIE in patients with colorectal cancer and endometrial cancer. Fresh or frozen tumor samples are not required for analysis, making it applicable to many patients in clinical settings. We also demonstrate tumor prevention by vaccination with selected neoantigens in a preclinical mouse model. This approach may benefit personalized T cell-mediated immunotherapies.

Microbiological investigation of pregnancies following vaginal radical trachelectomy using 16S rRNA sequencing of FFPE placental specimens.

Risa Tsunematsu, Tasuku Mariya, Mina Umemoto, Shiori Ogawa, Wataru Arai, Suguru E Tanaka, Kyota Ashikawa, Terufumi Kubo, Yoshiyuki Sakuraba, Tsuyoshi Baba, Shinichi Ishioka, Toshiaki Endo, Tsuyoshi Saito

FEBS open bio 2024年09月 [国際誌]

This study examined the risk of intrauterine infection associated with radical trachelectomy (RT) in early-stage cervical cancer patients. This procedure preserves fertility but is linked to increased risk of intrauterine infection due to cervical defects during pregnancy. DNA was extracted from the formalin-fixed paraffin-embedded (FFPE) placental specimens of 23 pregnant post-RT patients and 16S rRNA gene sequencing was used for bacterial identification. The prevalence of Lactobacillus crispatus and Burkholderia stabilis was significantly higher in the non-chorioamnionitis group. In contrast, alpha diversity analysis using the PD index showed significantly higher diversity in the chorioamnionitis group (P = 0.04). The demonstrated relationship between chorioamnionitis and microbial diversity affirms the importance of controlling the genital bacterial flora in pregnancies following RT.

Prediction of Mismatch Repair Status in Endometrial Cancer from Histological Slide Images Using Various Deep Learning-Based Algorithms.

Mina Umemoto, Tasuku Mariya, Yuta Nambu, Mai Nagata, Toshihiro Horimai, Shintaro Sugita, Takayuki Kanaseki, Yuka Takenaka, Shota Shinkai, Motoki Matsuura, Masahiro Iwasaki, Yoshihiko Hirohashi, Tadashi Hasegawa, Toshihiko Torigoe, Yuichi Fujino, Tsuyoshi Saito

Cancers 16 ( 10 ) 2024年05月 [国際誌]

The application of deep learning algorithms to predict the molecular profiles of various cancers from digital images of hematoxylin and eosin (H&E)-stained slides has been reported in recent years, mainly for gastric and colon cancers. In this study, we investigated the potential use of H&E-stained endometrial cancer slide images to predict the associated mismatch repair (MMR) status. H&E-stained slide images were collected from 127 cases of the primary lesion of endometrial cancer. After digitization using a Nanozoomer virtual slide scanner (Hamamatsu Photonics), we segmented the scanned images into 5397 tiles of 512 × 512 pixels. The MMR proteins (PMS2, MSH6) were immunohistochemically stained, classified into MMR proficient/deficient, and annotated for each case and tile. We trained several neural networks, including convolutional and attention-based networks, using tiles annotated with the MMR status. Among the tested networks, ResNet50 exhibited the highest area under the receiver operating characteristic curve (AUROC) of 0.91 for predicting the MMR status. The constructed prediction algorithm may be applicable to other molecular profiles and useful for pre-screening before implementing other, more costly genetic profiling tests.

Placenta Percreta Progression to Resistance Against Uterine Artery Embolization and Penetration Into the Bladder.

Yukiko Miyashita, Tasuku Mariya, Masayuki Someya, Shinichi Ishioka, Tsuyoshi Saito

Cureus 16 ( 3 ) e55651 2024年03月 [国際誌]

A 31-year-old female sought termination of pregnancy due to a fetal body stalk anomaly diagnosed at 18 weeks of gestation. Despite an anterior placenta previa, successful vaginal delivery occurred. However, placental adhesion over a previous cesarean scar occurred, and part of the placenta could not be removed. Immediate postpartum bleeding prompted imaging studies, revealing extravasation from adherent placental remnants. Uterine artery embolization (UAE) provided initial hemostasis, but recurrent bleeding necessitated re-embolization. Although conservative treatment was initially pursued, significant hematuria prompted reevaluation, revealing extensive uterine wall and bladder penetration. Surgical intervention with total hysterectomy and partial bladder resection was performed, leading to the successful recovery of bladder function following surgical repair. While this case achieved a positive outcome, there is a potential for permanent urinary dysfunction if lesions are more extensive. While achieving a conservative cure is ideal, it is essential to assess the timing for opting for surgical intervention.

The frequency and pathogenicity of BRCA1 and BRCA2 variants in the general Japanese population.

Masashi Idogawa, Tasuku Mariya, Yumi Tanaka, Tsuyoshi Saito, Hiroshi Nakase, Takashi Tokino, Akihiro Sakurai

Journal of human genetics ( (一社)日本癌学会 ) 83回 J - 1048 2024年02月 [国際誌]

Hereditary breast and ovarian cancer syndrome (HBOC) resulting from pathogenic variants of BRCA1 or BRCA2 is the most common and well-documented hereditary tumor. Although founder variants have been identified in population-based surveys in various countries, the types of variants are not uniform across races and regions. Recently, the Tohoku Medical Megabank Organization (ToMMo) released whole-genome sequence data including approximately 54,000 individuals from the general population of the Tohoku area in Japan. We analyzed these data and comprehensively identified the prevalence of BRCA1/2 pathogenic and truncating variants. We believe that an accurate understanding of the unique distribution and characteristics of pathogenic BRCA1/2 variants in Japan through this analysis will enable better surveillance and intervention for HBOC patients, not only in Japan but also worldwide.

Restoration of ARID1A Protein in ARID1A-deficient Clear Cell Carcinoma of the Ovary Attenuates Reactivity to Cytotoxic T Lymphocytes.

Risa Tsunematsu, Aiko Murai, Yuka Mizue, Terufumi Kubo, Tasuku Mariya, Rena Morita, Kenji Murata, Takayuki Kanaseki, Tomohide Tsukahara, Yoshihiko Hirohashi, Tsuyoshi Saito, Toshihiko Torigoe

Cancer genomics & proteomics 21 ( 4 ) 414 - 420 2024年 [国際誌]

BACKGROUND/AIM: Clear cell carcinoma is a prevalent histological type of ovarian cancer in East Asia, particularly in Japan, known for its resistance to chemotherapeutic agents and poor prognosis. ARID1A gene mutations, commonly found in ovarian clear cell carcinoma (OCCC), contribute to its pathogenesis. Recent data revealed that the ARID1A mutation is related to better outcomes of cancer immunotherapy. Thus, this study aimed to investigate the immunotherapy treatment susceptibility of OCCC bearing ARID1A mutations. MATERIALS AND METHODS: Expression of ARID1A was analyzed using western blotting in ovarian cancer cell lines. OCCC cell lines JHOC-9 and RMG-V were engineered to overexpress NY-ESO-1, HLA-A*02:01, and ARID1A. Sensitivity to chemotherapy and T cell receptor-transduced T (TCR-T) cells specific for NY-ESO-1 was assessed in ARID1A-restored cells compared to ARID1A-deficient wild-type cells. RESULTS: JHOC-9 cells and RMG-V cells showed no expression of ARID1A protein. Overexpression of ARID1A in JHOC-9 and RMG-V cells did not impact sensitivity to gemcitabine. While ARID1A overexpression decreased sensitivity to cisplatin in RMG-V cells, it had no such effect in JHOC-9 cells. ARID1A overexpression reduced the reactivity of NY-ESO-1-specific TCR-T cells, as observed by the IFNγ ESLIPOT assay. CONCLUSION: Cancer immunotherapy is an effective approach to target ARID1A-deficient clear cell carcinoma of the ovary.

Pregnancy-specific beta-1-glycoprotein 6 is a potential novel diagnostic biomarker of placenta accreta spectrum.

Hazuki Kashiwagi, Tasuku Mariya, Mina Umemoto, Shiori Ogawa, Yoshihiko Hirohashi, Yuya Fujibe, Terufumi Kubo, Masayuki Someya, Tsuyoshi Baba, Shinichi Ishioka, Toshihiko Torigoe, Tsuyoshi Saito

Medical molecular morphology 2023年10月 [国内誌]

Early diagnosis is essential for the safer perinatal management of placenta accreta spectrum (PAS). We used transcriptome analysis to investigate diagnostic maternal serum biomarkers and the mechanisms of PAS development. We analyzed eight formalin-fixed paraffin-embedded placental specimens from two placenta increta and three placenta percreta cases who underwent cesarean hysterectomy at Sapporo Medical University Hospital between 2013 and 2019. Invaded placental regions were isolated from the uterine myometrium and RNA was extracted. The transcriptome difference between normal placenta and PAS was analyzed by microarray analysis. The PAS group showed markedly decreased expression of placenta-specific genes such as LGALS13 and the pregnancy-specific beta-1-glycoprotein (PSG) family. Term enrichment analysis revealed changes in genes related to cellular protein catabolic process, female pregnancy, autophagy, and metabolism of lipids. From the highly dysregulated genes in the PAS group, we investigated the expression of PSG family members, which are secreted into the intervillous space and can be detected in maternal serum from the early stage of pregnancy. The gene expression level of PSG6 in particular was progressively decreased from placenta increta to percreta. The PSG family, especially PSG6, is a potential biomarker for PAS diagnosis.

Endocrinological and Metabolic Heterogeneity is low in Japanese Women with Polycystic Ovary Syndrome.

Tsuyoshi Baba, Toshiaki Endo, Tasuku Mariya, Yoshika Kuno, Hiroyuki Honnma, Mika Kanaya, Tsuyoshi Saito

Journal of obstetrics and gynaecology Canada : JOGC = Journal d'obstetrique et gynecologie du Canada : JOGC 102217 - 102217 2023年09月 [国際誌]

OBJECTIVE: This study aims to evaluate the endocrine differences among polycystic ovary syndrome (PCOS) phenotypes in Japanese women. METHODS: 118 Japanese women that we diagnosed with PCOS agreed to be included in the study. The study group was classified into the following four phenotypes: A) hyperandrogenism (HA); ovulatory disorder (OvD) and polycystic ovary morphology (PCOM); B) HA and OvD; C) HA and PCOM; and D) OvD and PCOM. We also recruited 66 healthy Japanese women to the study as control participants. Age, body mass index, androgens, luteinizing hormone, follicle-stimulating hormone, and insulin resistance index were evaluated and compared. RESULTS: The proportions of phenotypes A, B, C, and D were 57/120 (47.5%), 4/120 (3.3%), 13/120 (10.8%), and 46/120 (38.3%), respectively. The proportion of phenotype B was too small; therefore, phenotypes A and B were grouped as classical PCOS for intergroup comparisons. The luteinizing hormone/follicle-stimulating hormone ratio in the classical PCOS group was higher than that in the phenotype D group (P < 0.001). Androgen concentrations in the phenotype D group were significantly lower than those in the other groups (P < 0.01). Phenotype D was more common in lean women with PCOS. The surrogate marker of insulin resistance (homeostasis model assessment of insulin resistance (HOMA-IR)) was not different irrespective of PCOS and its phenotypes. CONCLUSION: Except for androgens, endocrine differences by PCOS phenotype are not evident, suggesting that diversity among patients with PCOS is relatively low in Japanese women.

Breakpoints in complex chromosomal rearrangements correspond to transposase-accessible regions of DNA from mature sperm.

Takeshi Sugimoto, Hidehito Inagaki, Tasuku Mariya, Rie Kawamura, Mariko Taniguchi-Ikeda, Seiji Mizuno, Yukako Muramatsu, Ikuya Tsuge, Hirofumi Ohashi, Nakamichi Saito, Yuiko Hasegawa, Nobuhiko Ochi, Masatoshi Yamaguchi, Jun Murotsuki, Hiroki Kurahashi

Human genetics 2023年08月 [国際誌]

Constitutional complex chromosomal rearrangements (CCRs) are rare cytogenetic aberrations arising in the germline via an unknown mechanism. Here we analyzed the breakpoint junctions of microscopically three-way or more complex translocations using comprehensive genomic and epigenomic analyses. All of these translocation junctions showed submicroscopic genomic complexity reminiscent of chromothripsis. The breakpoints were clustered within small genomic domains with junctions showing microhomology or microinsertions. Notably, all of the de novo cases were of paternal origin. The breakpoint distributions corresponded specifically to the ATAC-seq (assay for transposase-accessible chromatin with sequencing) read data peak of mature sperm and not to other chromatin markers or tissues. We propose that DNA breaks in CCRs may develop in an accessible region of densely packaged chromatin during post-meiotic spermiogenesis.

Changes in preterm and extremely preterm birth rates in Japan after the introduction of obstetrical practice guidelines in 2008.

Satoshi Shimano, Takashi Yamada, Kazutoshi Cho, Kazuo Sengoku, Tasuku Mariya, Tsuyoshi Saito

The journal of obstetrics and gynaecology research 2023年07月 [国際誌]

AIM: Obstetrical guidelines were established in Japan in 2008, and obstetrical diagnoses and treatments were subsequently standardized nationally. We examined changes in the preterm birth rate (PTBR) and extremely preterm birth rate (EPTBR) following the introduction of such guidelines. METHODS: Information on 50 706 432 live births in Japan between 1979 and 2021, including Japanese reproductive medicine, the childbearing age of pregnant women, and the employment status of reproductive-age women between 2007 and 2020, were obtained from the Japanese government and academic societies. Regression analysis was used to compare chronological changes nationally and those of eight Japanese regions. Regional and national average PTBRs and EPTBRs from 2007 to 2020 were compared by using a repeated measures analysis of variance. RESULTS: From 1979 to 2007, PTBRs and EPTBRs in Japan increased significantly. However, from 2008, the national PTBR and EPTBR decreased until 2020 (p < 0.001) and 2019 (p = 0.02), respectively. From 2007 to 2020, overall PTBR and EPTBR were 5.68% and 0.255%, respectively. A significant difference in the PTBR and EPTBR existed between the eight Japanese regions. During this period, the number of pregnancies using assisted reproductive technology increased from 19 595 to 60 381, pregnant women became older, the employment rate of those of reproductive age increased, and nonregular employment was 54%, which was 2.5 times higher than for men. CONCLUSIONS: In Japan, after obstetrical guidelines were enacted in 2008, PTRBs decreased significantly even under the pressure of increasing preterm births. Countermeasures may be necessary for regions showing high PTBRs.

深層学習によるHE染色データを用いた子宮内膜癌プロファイル判定の適否に関する検討

梅本美菜, 真里谷奨, 永田舞, 堀米俊弘, 新開翔太, 杉田真太朗, 金関貴幸, 松浦基樹, 岩崎雅宏, 廣橋良彦, 長谷川匡, 鳥越俊彦, 齋藤豪, 藤野雄一

日本医療情報学会春季学術大会プログラム・抄録集 ( (一社)日本医療情報学会 ) 27回 122 - 123 2023年06月

Clinical application of long-read nanopore sequencing in a preimplantation genetic testing pre-clinical workup to identify the junction for complex Xq chromosome rearrangement-related disease.

Tasuku Mariya, Yui Shichiri, Takeshi Sugimoto, Rie Kawamura, Syunsuke Miyai, Hidehito Inagaki, Eiji Sugihara, Keiko Ikeda, Tsuyoshi Baba, Aki Ishikawa, Michiko Ammae, Yoshiharu Nakaoka, Tsuyoshi Saito, Akihiro Sakurai, Hiroki Kurahashi

Prenatal diagnosis 43 ( 3 ) 304 - 313 2023年02月 [国際誌]

OBJECTIVE: Xq chromosome duplication with complex rearrangements is generally acknowledged to be associated with neurodevelopmental disorders such as Pelizaeus-Merzbacher disease (PMD) and MECP2 duplication syndrome. For couples who required a PGT-M (pre-implantation genetic testing for monogenic disease) for these disorders, junction-specific PCR is useful to directly detect pathogenic variants. Therefore, pre-clinical workup for PGT-M requires the identification of the junction of duplicated segments in PMD and MECP2 duplication syndrome, which is generally difficult. METHODS: In this report, we used nanopore long-read sequencing targeting the X chromosome using an adaptive sampling method to identify breakpoint junctions in disease-causing triplications. RESULTS: By long-read sequencing, we successfully identified breakpoint junctions in one PMD case with PLP1 triplication and in another MECP2 triplication case in a single sequencing run. Surprisingly, the duplicated region involving MECP2 was inserted 45 Mb proximal to the original position. This inserted region was confirmed by FISH analysis. With the help of precise mapping of the pathogenic variant, we successfully re-established STR haplotyping for PGT-M and avoided any potential misinterpretation of the pathogenic allele due to recombination. CONCLUSION: Long-read sequencing with adaptive sampling in a PGT-M pre-clinical workup is a beneficial method for identifying junctions of chromosomal complex structural rearrangements. This article is protected by copyright. All rights reserved.

深層学習を用いたHE染色からの子宮内膜癌分子生物学的プロファイル推定の適否に関する検討

梅本美菜, 真里谷奨, 新開翔太, 松浦基樹, 岩崎雅宏, 齋藤豪

日本産科婦人科学会雑誌 ( (公社)日本産科婦人科学会 ) 75 ( 臨増 ) S - 260 2023年02月

The age-related required number of zygotes estimated from prior clinical studies of preimplantation genetic testing for aneuploidy (PGT-A).

Tasuku Mariya, Takeshi Sugimoto, Takema Kato, Toshiaki Endo, Hiroki Kurahashi

Systems biology in reproductive medicine 69 ( 1 ) 1 - 7 2023年01月 [国際誌]

Women who are undergoing preimplantation genetic testing for aneuploidy (PGT-A) often wish to know how many eggs will be required to optimize the chances of a live birth. However, no precise data on this can yet be provided during genetic counseling for this procedure. On the basis of PGT-A data from related studies and current databases, we have estimated that the number of zygotes required for a 50% chance of a live birth is 8 at age 40 but increases markedly to 21 at age 43. PGT-A markedly reduces the miscarriage rate per embryo transfer but does not alleviate the extremely high number of zygotes required for a live birth in women of an advanced maternal age. Detailed genetic counseling will therefore be desirable prior to undergoing this procedure.

Letrozole increases preantral follicle growth and decreases estradiol production without impairing follicle survival.

Fukiko Kasuga-Yamashita, Tsuyoshi Baba, Sachiko Nagao, Yuya Fujibe, Miyuki Morishita, Yoshika Kuno, Tasuku Mariya, Hiroyuki Honnma, Toshiaki Endo, Tamotsu Kiya, Tsuyoshi Saito

Journal of ovarian research 15 ( 1 ) 136 - 136 2022年12月 [国際誌]

BACKGROUND: Letrozole has been reported to be effective in treating anovulation, preventing ovarian hyperstimulation syndrome (OHSS), and retrieving oocytes in breast cancer patients. However, the role and mechanism of letrozole in follicular development remain unclear. RESULTS: We treated mouse preantral follicles with various treatments; we found no significant difference in follicle survival rates in the letrozole (LET) group compared with the control group, but the average diameter of follicles in the LET group tended to be larger (CTRL vs. LET 30, p = 0.064; CTRL vs. LET 100, p = 0.025). The estradiol concentrations in culture media of the LET group were significantly lower than those observed in the control group (CTRL vs. LET 30, p = 0.038; CTRL vs. LET 100, p = 0.025). We further found a marked increase in follicle-stimulating hormone receptor (FSHR) gene expression in response to letrozole treatment (CTRL vs. LET 30, p = 0.075; CTRL vs. LET 100, p = 0.034). This result suggested that increased FSHR expression promotes follicle development. Letrozole inhibited aromatase activity, but the effect was limited. Letrozole did not significantly reduce vascular endothelial growth factor (VEGF) gene expression. CONCLUSIONS: Letrozole may promote follicle development by increasing the expression of FSHR. Letrozole may be useful for fertility preservation of patients with estrogen-dependent cancers such as breast cancer and various other cancers. Whether letrozole has a direct effect in reducing OHSS requires further investigation.

Maple syrup urine disease due to a paracentric inversion of chr 19 that disrupts BCKDHA: A case report.

Katsuyuki Yokoi, Yoko Nakajima, Yuta Sudo, Tasuku Mariya, Rie Kawamura, Makiko Tsutsumi, Hidehito Inagaki, Tetsushi Yoshikawa, Tetsuya Ito, Hiroki Kurahashi

JIMD reports 63 ( 6 ) 575 - 580 2022年11月 [国際誌]

Maple syrup urine disease (MSUD) is a rare autosomal recessive inherited disorder of branched-chain amino acid metabolism caused by mutations in BCKDHA, BCKDHB, and DBT that encode the E1α, E1β, and E2 subunits of the branched-chain α-ketoacid dehydrogenase (BCKD) complex. Various MSUD-causing variants have been described; however, no structural rearrangements in BCKDHA have been reported to cause the classic MSUD phenotype. Here, we describe the classic patient with MSUD with compound heterozygous pathogenic variants in BCKDHA: a missense variant (NM_000709.3:c.757G > A, NP_000700.1:p.Ala253Thr) and a paracentric inversion disrupting Intron 1 of BCKDHA, which was identified by whole-genome sequencing and validated by fluorescence in situ hybridization. Using the sequence information of the breakpoint junction, we gained mechanistic insight into the development of this structural rearrangement. Furthermore, the establishment of junction-specific polymerase chain reaction could facilitate identification of the variant in case carrier or future prenatal/preimplantation tests are necessary.

Target enrichment long-read sequencing with adaptive sampling can determine the structure of the small supernumerary marker chromosomes.

Tasuku Mariya, Takema Kato, Takeshi Sugimoto, Syunsuke Miyai, Hidehito Inagaki, Tamae Ohye, Eiji Sugihara, Yukako Muramatsu, Seiji Mizuno, Hiroki Kurahashi

Journal of human genetics 67 ( 6 ) 363 - 368 2022年01月 [国際誌]

Structural analysis of small supernumerary marker chromosomes (sSMCs) has revealed that many have complex structures. Structural analysis of sSMCs by whole genome sequencing using short-read sequencers is challenging however because most present with a low level of mosaicism and consist of a small region of the involved chromosome. In this present study, we applied adaptive sampling using nanopore long-read sequencing technology to enrich the target region and thereby attempted to determine the structure of two sSMCs with complex structural rearrangements previously revealed by cytogenetic microarray. In adaptive sampling, simple specification of the target region in the FASTA file enables to identify whether or not the sequencing DNA is included in the target, thus promoting efficient long-read sequencing. To evaluate the target enrichment efficiency, we performed conventional pair-end short-read sequencing in parallel. Sequencing with adaptive sampling achieved a target enrichment at about a 11.0- to 11.5-fold higher coverage rate than conventional pair-end sequencing. This enabled us to quickly identify all breakpoint junctions and determine the exact sSMC structure as a ring chromosome. In addition to the microhomology and microinsertion at the junctions, we identified inverted repeat structure in both sSMCs, suggesting the common generation mechanism involving replication impairment. Adaptive sampling is thus an easy and beneficial method of determining the structures of complex chromosomal rearrangements.

Twin pregnancy with untyped Ehlers-Danlos syndrome requiring prompt genetic testing: A case report.

Shiori Ogawa, Tasuku Mariya, Yuya Fujibe, Marie Ogawa, Keiko Ikeda, Miyako Mizukami, Yoshika Kuno, Aki Ishikawa, Shinichi Ishioka, Akihiro Sakurai, Tsuyoshi Saito

Case reports in women's health 33 e00384 2022年01月 [国際誌]

Ehlers-Danlos syndrome is a rare genetic disorder that presents with a variety of pathologies depending on the disease type. Among them, vascular Ehlers-Danlos syndrome requires extremely careful management as there have been many reports of fatal perinatal complications such as uterine rupture. Although hypermobile Ehlers-Danlos syndrome is less likely to cause fatal complications, symptoms such as arthralgia, hip dislocation, and depression may be seen throughout pregnancy. We report here a case of twin pregnancy in which Ehlers-Danlos syndrome was first suspected at 19 weeks of gestation. Vascular Ehlers-Danlos syndrome could not be ruled out based on family medical history, making it difficult to determine the perinatal management strategy. Prompt genetic testing did however rule out the vascular type and the patient was diagnosed with hypermobile Ehlers-Danlos syndrome from the clinical symptoms, enabling us to manage the pregnancy safely until 34 weeks of gestation.

Radical Vaginal Trachelectomy.

Tsuyoshi Saito, Motoki Matsuura, Masato Tamate, Masahiro Iwasaki, Tasuku Mariya

Surgery journal (New York, N.Y.) 7 ( Suppl 2 ) S103-S107 2021年12月 [国際誌]

Recently, radical vaginal hysterectomy (RVH) has developed into laparoscopically assisted radical vaginal hysterectomy (LARVH), which is associated with the laparoscopical procedure, and it is applied as radical vaginal trachelectomy and semi-radical vaginal hysterectomy. LARVH is indicated for patients with stage IB1 and IIA1 cervical carcinoma, especially those with a tumor size of less than 2 cm, because the cardinal ligaments cannot be resected widely. Although RVH that is associated with laparoscopic pelvic lymphadenectomy is the most used surgical procedure, radical trachelectomy may be performed either abdominally or vaginally (laparoscopic or robotic). One report found that the pregnancy rate was higher in patients who underwent minimally invasive or radical vaginal trachelectomy than in those who underwent radical abdominal trachelectomy.

A screening assistance system for cervical cytology of squamous cell atypia based on a two-step combined CNN algorithm with label smoothing.

Yuta Nambu, Tasuku Mariya, Shota Shinkai, Mina Umemoto, Hiroko Asanuma, Ikuma Sato, Yoshihiko Hirohashi, Toshihiko Torigoe, Yuichi Fujino, Tsuyoshi Saito

Cancer medicine 11 ( 2 ) 520 - 529 2021年11月 [国際誌]

BACKGROUND: Although many cervical cytology diagnostic support systems have been developed, it is challenging to classify overlapping cell clusters with a variety of patterns in the same way that humans do. In this study, we developed a fast and accurate system for the detection and classification of atypical cell clusters by using a two-step algorithm based on two different deep learning algorithms. METHODS: We created 919 cell images from liquid-based cervical cytological samples collected at Sapporo Medical University and annotated them based on the Bethesda system as a dataset for machine learning. Most of the images captured overlapping and crowded cells, and images were oversampled by digital processing. The detection system consists of two steps: (1) detection of atypical cells using You Only Look Once v4 (YOLOv4) and (2) classification of the detected cells using ResNeSt. A label smoothing algorithm was used for the dataset in the second classification step. This method annotates multiple correct classes from a single cell image with a smooth probability distribution. RESULTS: The first step, cell detection by YOLOv4, was able to detect all atypical cells above ASC-US without any observed false negatives. The detected cell images were then analyzed in the second step, cell classification by the ResNeSt algorithm, which exhibited average accuracy and F-measure values of 90.5% and 70.5%, respectively. The oversampling of the training image and label smoothing algorithm contributed to the improvement of the system's accuracy. CONCLUSION: This system combines two deep learning algorithms to enable accurate detection and classification of cell clusters based on the Bethesda system, which has been difficult to achieve in the past. We will conduct further research and development of this system as a platform for augmented reality microscopes for cytological diagnosis.

Next-generation sequencing of 16S rRNA for identification of invasive bacterial pathogens in a formalin-fixed paraffin-embedded placental specimen: a case report of perinatal fulminant Streptococcus pyogenes infection.

Tasuku Mariya, Toyotaka Sato, Yuya Fujibe, Manami Ishido, Hiroshi Shimada, Terufumi Kubo, Yoko Nagai, Wataru Arai, Suguru E Tanaka, Kyota Ashikawa, Yoshiyuki Sakuraba, Shinichi Ishioka, Shin-Ichi Yokota, Tsuyoshi Saito

Medical molecular morphology 54 ( 4 ) 374 - 379 2021年07月 [国内誌]

Intrauterine infection is one of the most important causes of maternal death. In perinatal emergency, we often miss an opportunity to obtain culture specimens. In this study, we tried to examine whether we investigated whether bacteria causing infection can be detected from a formalin-fixed paraffin-embedded (FFPE) placental specimen. We examined the placenta from a maternal invasive infection that resulted in infectious abortion at 18 weeks of gestation. The case was diagnosed by acute fever and abdominal pain, and the patient was cured after 3 weeks of intensive antimicrobial treatment. Four Streptococcus pyogenes strains were isolated from vaginal fluid and blood cultures of the patient. All of the strain types were emm1/ST28. We amplified the V1-V2 region of 16S rRNA from an FFPE placental specimen and sequencing was performed using a next-generation sequencer (NGS). Taxonomic analysis was then performed for sequenced data. We succeeded in detecting causative pathogens from the FFPE placenta: 69.1% of the predominantly identified bacteria were S. pyogenes and other small populations of bacteria were detected. Our results revealed the utility of NGS for 16S rRNA analysis of an FFPE placenta. This method may reveal previous perinatal invasive infections of unknown origin retrospectively.

Effectiveness of cross double mcdonald cerclage for intractable bleeding from a cervical varix in pregnant women

Yuya Fujibe, Tasuku Mariya, Masahito Mizuuchi, Shinichi Ishioka, Tsuyoshi Saito

Gynecology and Minimally Invasive Therapy ( Wolters Kluwer Medknow Publications ) 10 ( 3 ) 177 - 180 2021年07月

Cervical varix during pregnancy is a rare condition, and standard management for bleeding from a varix has not been established. We performed cross double cervical cerclage and effectively stopped bleeding. A 41-year-old female had a twin pregnancy. The development of a cervical varix was observed during pregnancy and bleeding from ruptured varix started at 20 weeks of gestation. We performed surgical hemostasis by cervical cerclage. In the first cerclage, we could not stop the bleeding from the varix. For further restriction of blood supply to the cervical varix, we performed a second cerclage in a crossed position on a deeper side of the vagina than the first cerclage. Then the bleeding completely stopped and there was no bleeding until delivery. The 'cross double McDonald cerclage' performed in our patient may be a useful modified cerclage method for stopping intractable bleeding from the cervix during pregnancy.

子宮温存している若年発症子宮体部腺肉腫の2例

寺田倫子, 松浦基樹, 野藤五沙, 西村庸子, 真里谷奨, 玉手雅人, 岩崎雅宏, 齋藤豪

日本婦人科腫瘍学会学術講演会プログラム・抄録集 ( (公社)日本婦人科腫瘍学会 ) 63回 292 - 292 2021年07月

Increased cervical Chlamydia trachomatis and syphilis infections in Japanese females of reproductive age in the late 2010s: Possible cause.

Satoshi Shimano, Tasuku Mariya, Tsuyoshi Saito

Journal of infection and chemotherapy : official journal of the Japan Society of Chemotherapy 2021年05月 [国際誌]

From 2000 to 2019, Japan's reproductive-age population gradually declined by 24%. In comparison, the Chlamydia trachomatis infection rate increased from 2016, with the syphilis infection rate increasing more sharply from 2014. Since 2013, the numbers of foreign tourists to Japan have also increased. From 2011 to 2018, the rate of increase in tourists was 5.02 times, while the rate of increase in syphilis patients was higher at 22.4 times. The lack of a one-to-one relationship between foreign tourists and syphilis cases suggests that cases of syphilis were transmitted to others. Although the prevalence of syphilis in the tourists' home countries (Korea in 2014 and China in 2013) was 20-30 times higher than that in Japan, the Japanese sex industry did not discriminate against foreign tourists, leading to increased STI infections in Japanese female sex workers. Indeed, from 2017 to 2018, a history of working in the sex industry for six months was identified as a risk factor for syphilis. The rise in Chlamydia trachomatis infections has lagged behind that of syphilis by two years, with the rate of increase lower. We suspect the difference in increasing rates of syphilis and chlamydial infections is due to the different methods of infection: syphilis can be transmitted by light physical contact, such as a kiss, whereas chlamydia requires close sexual contact, such as oral sex or sexual intercourse. Regardless, examinations and infection control are necessary to prevent the spread of STIs in Japan due to inbound tourists.

Does Radical trachelectomy (RT) during pregnancy have higher obstetrical and oncological risks than RT before pregnancy?

Shota Shinkai, Shinichi Ishioka, Tasuku Mariya, Yuya Fujibe, Miseon Kim, Masayuki Someya, Tsuyoshi Saito

( Research Square Platform LLC ) 2021年03月

Abstract Purpose Radical trachelectomy (RT) with pelvic lymphadenectomy has become a new treatment option for young patients with uterine cervical cancer stages 1A2–1B1 who desire the preservation of their fertility. However, the application of RT for pregnant patients is still controversial. We comparatively studied both obstetrical and oncological outcomes of pregnant patients who underwent vaginal RT during pregnancy and those who underwent vaginal RT before pregnancy. Methods Both obstetrical and oncological results of eight patients who underwent vaginal RT with pelvic lymphadenectomy during pregnancy in our institute between 2010 and 2020 (Group A), and ten pregnant patients who underwent vaginal RT with pelvic lymphadenectomy before pregnancy during the same period (Group B) were reviewed based on their medical charts. Results There were no significant differences in blood loss, surgical time, or surgical completeness between Group A and Group B. Nor were there significant differences in obstetrical outcomes between the two groups. However, two of the eight patients in Group A had recurrence of the cancer. None of the patients in Group B has shown any signs of recurrence thus far. Conclusion Vaginal RT during pregnancy does not affect the obstetrical prognoses of patients with early invasive uterine cervical cancer, and it might be a tolerable treatment modality for them. However, oncologically, it should be performed carefully as there is a risk of recurrence.

Common iliac artery dissection as a complication of common iliac artery balloon occlusion for placenta percreta: A case report.

Kimihito Saito, Tasuku Mariya, Yuya Fujibe, Masato Saito, Naoki Hirokawa, Shinichi Ishioka, Tsuyoshi Saito

The journal of obstetrics and gynaecology research 47 ( 3 ) 1172 - 1177 2021年03月 [国際誌]

A 37-year-old pregnant woman who had undergone three previous cesarean sections was diagnosed as having placenta percreta. We decided to perform cesarean hysterectomy with bilateral common iliac artery balloon occlusion (CIABO). The duration of surgery was 2 h and 2 min and total estimated blood loss was 2600 mL. Surgery was completed without any surgical complications, but the pulse oximeter waveform of the left leg became undetectable during surgery. We immediately performed angiography after closure of laparotomy and found abnormal pooling of contrast media at the left common iliac artery in the region in which the balloon was positioned. We made a diagnosis of left common iliac artery dissection caused by CIABO. We performed emergent revascularization by intravascular stenting. We conclude that CIABO can cause common iliac artery dissection by mechanical stimulation of the inflated balloon. Careful intraoperative evaluation of limb ischemia and preparation of intravascular treatment is needed for a safe procedure.

Less correlation between mismatch repair proteins deficiency and decreased expression of HLA class I molecules in endometrial carcinoma: a different propensity from colorectal cancer.

Tasuku Mariya, Terufumi Kubo, Yoshihiko Hirohashi, Junko Yanagawa, Yuta Tabuchi, Kazuhiko Matsuo, Kiyoshi Furumura, Rena Morita, Munehide Nakatsugawa, Takayuki Kanaseki, Tomohide Tsukahara, Tadashi Hasegawa, Tsuyoshi Saito, Toshihiko Torigoe

Medical molecular morphology 54 ( 1 ) 14 - 22 2021年03月 [国内誌]

Mismatch repair protein deficiency (dMMR) is a favorable prognostic factor in colorectal cancer. It is also associated with aberrant expression of HLA class I molecules, which are required for cytotoxic T lymphocyte-mediated cancer immunotherapy. Because dMMR is frequently also found in endometrial cancers (ECs), we retrospectively investigated the expression of mismatch repair proteins and HLA class I molecules in 127 EC patients. In this study, EC patients being treated in our hospital were recruited from 2005 to 2009 and observed until December 2017. Lesion specimens were evaluated via immunohistochemistry for MSH6 and PMS2 (mismatch repair proteins) and HLA class I molecules. Expression of these molecules was statistically related to clinical and pathological factors and prognosis. dMMR was detected in 33 patients and did not correlate with the expression level of HLA class I molecules (P = 0.60). On the other hand, unexpectedly, multivariate analysis revealed that intact expression of HLA class I molecules was associated with p53 overexpression (P = 0.004). Neither dMMR nor decreased expression of HLA class I molecules were prognostic factors. These results are inconsistent with previous findings for colorectal cancer. A distinctive local tissue immune microenvironment would underlie the discrepancy in the results between EC and colorectal cancer.

Umbilical cyst associated with patent urachus that spontaneously disappeared: A case report.

Yuya Fujibe, Tasuku Mariya, Masahito Mizuuchi

Prenatal diagnosis 41 ( 3 ) 384 - 385 2021年02月 [国際誌]

ERα increases endometrial cancer cell resistance to cisplatin via upregulation of BAG3.

Shuetsu Abe, Masahiro Iwasaki, Shutaro Habata, Tasuku Mariya, Masato Tamate, Motoki Matsuura, Seiro Satohisa, Tsuyoshi Saito

Oncology letters 21 ( 1 ) 20 - 20 2021年01月 [国際誌]

Endometrial cancer is a leading cause of cancer-associated mortality in women and has a poor prognosis in advanced stages. Our previous study revealed that BCL-2-associated athanogene 3 (BAG3) may contribute to enhancing cell viability through downregulation of microRNA (miR)-29b in endometrial cancer cell lines. In addition, a relationship between estrogen receptor α (ERα) and BAG3 was recently reported in several cancer cell types. The present study investigated the relationship between ERα and BAG3 in endometrial cancer cell lines. The results demonstrated that exogenous ERα overexpression enhanced BAG3 expression in the EMTOKA endometrial cancer cell line, which does not endogenously express ERα, but had no effect on BAG3 expression levels in the Ishikawa cell line, which does endogenously express ERα. In addition, ERα overexpression suppressed miR-29b expression and enhanced the expression of Mcl-1, a mediator situated downstream of BAG3, in EMTOKA cells, but not Ishikawa cells. ERα overexpression also enhanced EMTOKA, but not Ishikawa, endometrial cancer cell viability in the presence of cisplatin. These findings suggested that ERα may contribute to enhancing endometrial cancer cell resistance to anticancer agents through BAG3 overexpression.

骨盤解剖学をCadaver Surgery Trainingで理解する混合研究の試み

玉手雅人, 松浦基樹, 阿部秀悦, 西村庸子, 常松梨沙, 寺田倫子, 真里谷奨, 岩崎雅宏, 金尾祐之, 齋藤豪

日本婦人科腫瘍学会雑誌 ( (公社)日本婦人科腫瘍学会 ) 39 ( 1 ) 311 - 311 2021年01月

Deep Learning(YOLOv3)を用いたリアルタイム婦人科細胞診断支援システム設計の試み

真里谷奨, 新開翔太, 松浦基樹, 郷久晴朗, 岩崎雅宏, 南部優太, 藤野雄一, 淺沼広子, 廣橋良彦, 鳥越俊彦, 齋藤豪

日本婦人科腫瘍学会雑誌 ( (公社)日本婦人科腫瘍学会 ) 39 ( 1 ) 278 - 278 2021年01月

【産婦人科感染症の最新知見】注目されている産婦人科感染症細菌性腟症、性器クラミジア感染症

島野敏司, 真里谷奨, 長井陽子, 芦川享大, 荒井渉, 斎藤豪

臨床と微生物 ( (株)近代出版 ) 48 ( 1 ) 041 - 045 2021年01月

ERα発現および非発現子宮体癌細胞株に於けるBAG3発現および増殖能との関連

阿部秀悦, 岩崎雅宏, 幅田周太朗, 真里谷奨, 小川万梨絵, 郷久晴朗, 齋藤豪

日本婦人科腫瘍学会雑誌 ( (公社)日本婦人科腫瘍学会 ) 39 ( 1 ) 285 - 285 2021年01月

胎児期に診断に苦慮した先天性嚢胞状腺腫様形成異常に胸腔外肺分画症を合併した一例

染谷真行, 古来愛香, 新開翔太, 真里谷奨, 石岡伸一, 齋藤豪

超音波医学 ( (公社)日本超音波医学会 ) 47 ( Suppl. ) S418 - S418 2020年11月

腹腔鏡下子宮筋腫核出術後に発生したparasitic myomaの1例

岩崎雅宏, 真里谷奨, 阿部秀悦, 松浦基樹, 玉手雅人, 齋藤豪

日本産科婦人科内視鏡学会雑誌 ( (一社)日本産科婦人科内視鏡学会 ) 36 ( Suppl.I ) [O - 196] 2020年11月

深層学習を用いた子宮頸部細胞診人工知能診断支援システムの有用性について

真里谷奨, 南部優太, 淺沼広子, 廣橋良彦, 岩崎雅宏, 藤野雄一, 鳥越俊彦, 齋藤豪

日本癌学会総会記事 ( (一社)日本癌学会 ) 79回 OJ15 - 7 2020年10月

Cadaver Surgery Trainingの壁を超える意義

玉手雅人, 松浦基樹, 西村庸子, 真里谷奨, 磯山響子, 寺田倫子, 郷久晴朗, 岩崎雅宏, 齋藤豪

産婦人科手術 ( (株)メジカルビュー社 ) ( 31 ) 189 - 189 2020年08月

当院婦人科領域におけるBRCA遺伝子検査状況の変化

真里谷奨, 寺田倫子, 宮崎幸子, 石川亜貴, 岩崎雅宏, 齋藤豪, 櫻井晃洋

日本遺伝カウンセリング学会誌 ( 日本遺伝カウンセリング学会 ) 41 ( 2 ) 75 - 75 2020年06月

Transabdominal cerclage (TAC) as a new tool for the treatment of cervical incompetence (CI).

Shinichi Ishioka, Tasuku Mariya, Masayuki Someya, Tsuyoshi Saito

Annals of translational medicine 8 ( 9 ) 571 - 571 2020年05月 [国際誌]

【専門医はもういらない? せまりくるAI時代】AIによる病理組織診断支援

真里谷奨, 久保輝文, 齋藤豪, 鳥越俊彦

産婦人科の実際 ( 金原出版(株) ) 69 ( 5 ) 463 - 468 2020年05月

＜文献概要＞AIによる画像認識は,深層学習による画像特徴の自動解析が実用化して以後,多分野への応用が試みられている。医療画像におけるAI研究も深層学習の登場によりパラダイムシフトが起こっており,わが国が豊富なリソースを有する放射線画像や内視鏡画像,ならびに病理組織画像について多種多様な検討が行われてきた。本稿では,AIによる病理組織診断支援の概要と実際について,特に実臨床における有用性および発展性を主体に述べる。

妊娠中の広汎子宮頸部摘出術(RT)後子宮頸部細胞診における異型細胞の出現

石岡伸一, 真里谷奨, 金美善, 新開翔太, 齋藤豪

日本臨床細胞学会雑誌 ( (公社)日本臨床細胞学会 ) 59 ( Suppl.1 ) 232 - 232 2020年05月

Deep Learning(YOLO)を用いた子宮頸部細胞診診断支援の有用性

新開翔太, 真里谷奨, 郷久晴朗, 岩崎雅宏, 南部優太, 藤野雄一, 淺沼広子, 廣橋良彦, 鳥越俊彦, 齋藤豪

日本臨床細胞学会雑誌 ( (公社)日本臨床細胞学会 ) 59 ( Suppl.1 ) 207 - 207 2020年05月

開腹子宮頸部縫縮術(TAC)後妊娠初期流産症例に対するmethotrexate(MTX)療法の一例

石堂茉泉, 石岡伸一, 藤部佑哉, 鈴木美紀, 嶋田浩志, 真里谷奨, 馬場剛, 齋藤豪

日本周産期・新生児医学会雑誌 ( (一社)日本周産期・新生児医学会 ) 56 ( 1 ) 198 - 202 2020年05月

34歳。子宮頸癌のため腟式広汎子宮頸部摘出術+骨盤リンパ節郭清術の既往で有った。その2年後に体外受精により妊娠し、妊娠19週で帝王切開による分娩となった。この分娩から3年後にテフロンテープを用いた開腹子宮頸部縫縮術(TAC)を施行し、TAC後6ヵ月で体外受精にて妊娠したが、妊娠8週で稽留流産となった。流産後3ヵ月経過しても子宮内容物が排出されず絨毛組織の筋層内浸潤が疑われ、流産後12週よりMTX投与1日20mg・5日間を2週間毎に開始し、3コース終了後に血清ヒト絨毛性ゴナドトロピン値がほぼ正常化した。治療終了後3ヵ月で月経が再開し、その後に再度妊娠8週相当で流産となったが、子宮内容物は流産判明から1ヵ月以内に自然排出された。さらに6ヵ月後に体外受精で妊娠し、妊娠33週6日に帝王切開にて男児1912g、アプガースコア8/9点を出産し、術後経過順調で8日目に退院した。

Pregnancies after vaginal radical trachelectomy (RT) in patients with early invasive uterine cervical cancer: results from a single institute.

Shota Shinkai, Shinichi Ishioka, Tasuku Mariya, Yuya Fujibe, Miseon Kim, Masayuki Someya, Tsuyoshi Saito

BMC pregnancy and childbirth 20 ( 1 ) 248 - 248 2020年04月 [国際誌]

BACKGROUND: Radical tracheletomy (RT) with pelvic lymphadenectomy has become an option for young patients with early invasive uterine cervical cancer who desire to maintain their fertility. However, this operative method entails a high risk for the following pregnancy due to its radicality. METHODS: We have performed vaginal RT for 71 patients and have experienced 28 pregnancies in 21 patients. They were followed up carefully according to the follow-up methods we reported previously. Their pregnancy courses and prognoses after the pregnancy were retrospectively reviewed. RESULTS: All the vaginal RTs were performed safely without serious complications, including 6 patients who underwent the operation during pregnancy. The median time to be pregnant after RT was 29.5 months. 13 patients (46%) became pregnant without artificial insemination by husband or assisted reproductive technology. Cesarean section was performed for all of them. The median time of pregnancy was 34 weeks, and emergent cesarean section was performed for 7 pregnancies (25%). The median birth weight was 2156 g. Four patients had trouble with cervical cerclage, and they suffered from sudden premature preterm rupture of the membrane (pPROM) during the second trimester of pregnancy. We underwent transabdominal cerclage (TAC) for all of them and careful management for the prevention of uterine infection was performed. One patient had a recurrence of cancer during pregnancy. CONCLUSIONS: Both the obstetrical prognosis and oncological prognosis after vaginal RT have become favorable for pregnant patients after vaginal RT.

妊娠中の広汎子宮頸部全摘出術腟式トラケレクトミー

齋藤豪, 岩崎雅宏, 松浦基樹, 玉手雅人, 真里谷奨, 石岡伸一

日本婦人科腫瘍学会雑誌 ( (公社)日本婦人科腫瘍学会 ) 38 ( 2 ) 145 - 150 2020年04月

われわれの教室では従来腟式準広汎性子宮全摘術に取り組んでいたが、平成16年より本術式を応用し腟式トラケレクトミーに取り組んでいる。これまで79例の腟式トラケレクトミーを行ってきたが、このうち2010年以来7例に対し妊娠初期の子宮頸がんに対し本術式を行う機会があったので報告する。症例は妊娠12週から26週で、6例がIB1期で、1例がIB2期であった。手術は腹式に骨盤リンパ郭清術を施行して、腟式に子宮頸部の操作を行い、最終的に子宮動脈本幹起始部レベルで子宮頸部を切断する。その後、頸部をナイロン糸でマクドナルド縫合し腟壁と縫合した。本術式の適応に関する基本方針は腫瘍径2cm以下のIB1期までとしているが、患者の希望が極めて強くリスクを説明してもなお妊娠の継続を望む症例に関して、7例中2例に関してはそれ以上の症例で手術を施行した。IB2期の症例は骨盤リンパ転移を認め、16週で妊娠を中断し子宮全摘・CCRTを施行した。他の1例はリンパ転移を認めたが、妊娠継続の希望が強く、再発リスクを説明した上で妊娠中に化学療法を施行し30週で妊娠を中断、子宮全摘・CCRTを施行した。その他の5例はリンパ転移を認めずtermで帝王切開術にて分娩している。今回の7例すべての症例において再発は認めておらず、破水などの産科合併症も認められなかった。今回の検討で6例の生児を得たが、児には発達の障害は認められていない。これまでの経験を通じ、妊娠中のリンパ郭清および腟式トラケレクトミーに関しては、大きな合併症を引き起こすリスクはそれほど高くはないことが示唆された。しかし、症例の適応、手術の時期、その他の治療法の選択などについては検討の余地は多く、他施設での症例の蓄積が必要と考える。(著者抄録)

子宮頸がんにおける当院のVaginal Trachelectomyの成績と意義

玉手雅人, 松浦基樹, 黒川晶子, 西村庸子, 磯山響子, 寺田倫子, 真里谷奨, 岩崎雅宏, 石岡伸一, 齋藤豪

日本産科婦人科学会雑誌 ( (公社)日本産科婦人科学会 ) 72 ( 臨増 ) S - 359 2020年03月

女性診療科として考えるライフステージごとの尿路感染症

真里谷奨, 齋藤豪, 高橋聡

感染症学雑誌 ( (一社)日本感染症学会 ) 94 ( 2 ) 219 - 220 2020年03月

難治性尿路感染症に隠れたものは? 女性診療科として考えるライフステージごとの尿路感染症

真里谷奨, 齋藤豪, 高橋聡

日本化学療法学会雑誌 ( (公社)日本化学療法学会 ) 68 ( 2 ) 246 - 246 2020年03月

Successful administration of recombinant human antithrombin in a pregnant Japanese woman with hereditary antithrombin deficiency.

Yuya Fujibe, Tasuku Mariya, Masahito Mizuuchi, Shinichi Ishioka, Masahiro Yoshida, Tsuyoshi Saito

Taiwanese journal of obstetrics & gynecology 58 ( 6 ) 849 - 851 2019年11月 [国際誌]

OBJECTIVE: Hereditary antithrombin (AT) deficiency increases the risk of venous thromboembolism (VTE) in pregnant woman. We report the first case of administration of recombinant human antithrombin (rhAT) to a pregnant Japanese woman with AT deficiency. CASE REPORT: A 30-year-old woman, gravida 2 para 0, was referred to our hospital because of AT deficiency. Unfractionated heparin was administered from 13 weeks of gestation and rhAT was administered from labor onset. A cesarean section was performed and the patient and her baby were healthy, with no sequelae. CONCLUSION: We concluded that rhAT was effective for preventing VTE during delivery, with no potential infection risks.

当科において妊娠初期子宮頸部細胞診HSIL/ASC-H以上を認めた症例の検討

真里谷奨, 石岡伸一, 玉手雅人, 郷久晴朗, 松浦基樹, 岩崎雅宏, 齋藤豪

日本臨床細胞学会雑誌 ( (公社)日本臨床細胞学会 ) 58 ( Suppl.2 ) 587 - 587 2019年10月

転移性女性生殖器がんにおける臨床像と捺印細胞像

玉手雅人, 松浦基樹, 長尾沙智子, 西村庸子, 真里谷奨, 寺田倫子, 郷久晴朗, 杉田真太朗, 岩崎雅宏, 齋藤豪

日本臨床細胞学会雑誌 ( (公社)日本臨床細胞学会 ) 58 ( Suppl.2 ) 601 - 601 2019年10月

重症子宮内膜症を有する不妊治療における手術とART介入のタイミング

森下美幸, 長尾沙智子, 新開翔太, 久野芳佳, 真里谷奨, 馬場剛, 遠藤俊明, 齋藤豪

日本産科婦人科内視鏡学会雑誌 ( (一社)日本産科婦人科内視鏡学会 ) 35 ( Suppl.I ) 252 - 252 2019年08月

Obstetrical prognosis of patients who underwent vaginal radical trachelectomy during pregnancy.

Mina Umemoto, Shinichi Ishioka, Yuko Mizugaki, Yuya Fujibe, Tasuku Mariya, Akari Kawamata, Masahito Mizuuchi, Miyuki Morishita, Tsuyoshi Baba, Tsuyoshi Saito

The journal of obstetrics and gynaecology research 45 ( 6 ) 1167 - 1172 2019年06月 [国際誌]

AIM: Radical trachelectomy (RT) with pelvic lymphadenectomy has become an option for young patients with early invasive uterine cervical cancer who decide to maintain their fertility. However, this operative method entails a high risk for the following pregnancy due to its radicality. Therefore, RT for pregnant patients can be a challenge both for gynecologic oncologists and obstetricians. METHODS: We have performed vaginal RT for five pregnant patients with uterine cervical cancer stage 1B1 according to the method of Dargent et al. The operations were performed between 16 and 26 weeks of pregnancy, and the patients were followed up carefully according to the follow-up methods we reported previously. RESULTS: Vaginal RT was performed for five patients without any troubles. Four of the patients continued their pregnancies until almost 34 weeks or longer under our previously published follow-up schedule. The pregnancy of one patient was terminated at 26 weeks due to recurrence of the cancer. CONCLUSION: Expansion of vaginal RT for pregnant patients with uterine cervical cancer could be a practical option for pregnant patients with early invasive uterine cervical cancer.

Clonal analysis revealed functional heterogeneity in cancer stem-like cell phenotypes in uterine endometrioid adenocarcinoma.

Yuta Tabuchi, Yoshihiko Hirohashi, Shinichi Hashimoto, Tasuku Mariya, Takuya Asano, Kazuho Ikeo, Takafumi Kuroda, Masahito Mizuuchi, Aiko Murai, Sei Uno, Noriko Kawai, Terufumi Kubo, Munehide Nakatsugawa, Takayuki Kanaseki, Tomohide Tsukahara, Tsuyoshi Saito, Toshihiko Torigoe

Experimental and molecular pathology 106 78 - 88 2019年02月 [国際誌]

Uterine endometrial carcinoma is one of the common cancers in females. Cancer stem-like cells (CSCs)/cancer-initiating cells (CICs) are a small subpopulation of cancer cells that are tumorigenic and are resistant to treatments, thus they are focused as treatment targets. However, the heterogeneity of CSCs/CICs is still elusive, and we therefore analyzed CSCs/CICs at the clonal level. We previously established sphere-cultured CSCs/CICs from primary human uterine endometrial carcinoma, and we isolated several clones from CSCs/CICs in this study. Interestingly, we established two types of clones based on the growth pattern. The clones were termed sphere clones (S clones) and leukemia-like clones (LL clones). Functional analysis revealed that S clones are resistant to chemotherapy, whereas LL clones are sensitive to chemotherapy. On the other hand, S clones are less tumorigenic, while LL clones are highly tumorigenic. Transcriptome analysis using serial analysis of gene expression sequencing (SAGE-Seq) revealed distinctive gene expression profiles in S clone cells and LL clone cells. The results indicate that CSCs/CICs are composed of functionally heterogenic subpopulations including highly tumorigenic clones and treatment-resistant clones and that the characteristics of CSCs/CICs might be determined by the characteristics of different clones that compose CSCs/CICs.

Recurrent Massive Uterine Bleeding from a Cesarean Scar Treated Successfully by Laparoscopic Surgery.

Tasuku Mariya, Mina Umemoto, Naoko Sugita, Masahiro Suzuki, Tsuyoshi Saito

Gynecology and minimally invasive therapy 8 ( 1 ) 36 - 39 2019年 [国際誌]

A cesarean scar can cause abnormal uterine bleeding including prolonged menstruation or postmenstrual spotting. Our patient showed massive uterine bleeding from a cesarean scar and needed blood transfusion for hemorrhagic shock. A cesarean section had only been performed once for delivery stop 9 years ago. Recurrent hemorrhage could not be controlled by conservative treatment, and we performed laparoscopic scar resection and repair. The abnormal uterine bleeding was successfully stopped, and the menstrual cycle was normalized after surgical treatment. We should be aware that even an uneventful cesarean section may have a risk of massive hemorrhage postoperatively as in the present case.

Multiple part umbilical cord entanglement and neonatal outcomes.

Tasuku Mariya, Yuya Fujibe, Shota Shinkai, Naoko Sugita, Masahiro Suzuki, Toshiaki Endo, Tsuyoshi Saito

Taiwanese journal of obstetrics & gynecology 57 ( 5 ) 672 - 676 2018年10月 [国際誌]

OBJECTIVE: Umbilical cord entanglement is known to be a major cause of fetal hypoxia and to be correlated with several neonatal complications, but almost all of the previous reports were restricted to nuchal cord. In this study, we retrospectively examined the correlation between multiple part cord entanglement and pregnancy outcomes. MATERIALS AND METHODS: A total of 2156 cases were recruited from term deliveries in our hospital from 2008 to 2012. We counted umbilical cord loop numbers not only for nuchal cord but also for trunk and limb cord entanglement. We classified the cases into three groups: no loop, single loop and multiple loops group. We statistically analyzed pregnancy outcomes statistically in the three groups. RESULTS: One thousand, four hundred and fifty-eight cases had no cord entanglement, 594 cases had single loop entanglement and 104 cases had multiple loops entanglement. Values of umbilical artery blood, pH (p = 0.002) and base excess (p < 0.001) showed significantly unfavorable status in entanglement cases, especially in the multiple loops group. A significantly larger percentage of neonates in the multiple loops group needed for oxygen (p < 0.001). CONCLUSION: Multiple umbilical cord entanglement is highly correlated with early neonatal unfavorable status and need for resuscitation.

Comprehensive single-cell transcriptome analysis reveals heterogeneity in endometrioid adenocarcinoma tissues.

Shinichi Hashimoto, Yuta Tabuchi, Hideaki Yurino, Yoshihiko Hirohashi, Shungo Deshimaru, Takuya Asano, Tasuku Mariya, Kenshiro Oshima, Yuzuru Takamura, Yoshiaki Ukita, Akio Ametani, Naoto Kondo, Norikazu Monma, Tadayuki Takeda, Sadahiko Misu, Toshitugu Okayama, Kazuho Ikeo, Tsuyoshi Saito, Shuich Kaneko, Yutaka Suzuki, Masahira Hattori, Kouji Matsushima, Toshihiko Torigoe

Scientific reports 7 ( 1 ) 14225 - 14225 2017年10月 [国際誌]

Single cell transcriptome analysis of a cancer tissue can provide objective assessment of subtype population or the activation of each of various microenvironment component cells. In this study, we applied our newly developed technique of single cell analysis to the myometrial infiltration side (M-side) and the endometrial side (E-side) of a human endometrioid adenocarcinoma with squamous differentiation tissues. We also analyzed spherogenic cultures derived from the same tissue to identify putative regulators of stemness in vivo. Cancer cells in the E-side were highly malignant compared with those in the M-side. Many cells on the E-side were positive for spheroid-specific tumorigenesis-related markers including SOX2. In addition, there were higher numbers of epithelial-to-mesenchymal transition (EMT) cells in the E-side compared with the M-side. This study identified a site containing cells with high malignant potential such as EMT and cancer stem-like cells in cancer tissues. Finally, we demonstrate that established endometrioid adenocarcinoma subtype classifiers were variably expressed across individual cells within a tumor. Thus, such intratumoral heterogeneity may be related to prognostic implications.

Phosphorylation of HSF1 at serine 326 residue is related to the maintenance of gynecologic cancer stem cells through expression of HSP27.

Kazuyo Yasuda, Yoshihiko Hirohashi, Tasuku Mariya, Aiko Murai, Yuta Tabuchi, Takafumi Kuroda, Hiroki Kusumoto, Akari Takaya, Eri Yamamoto, Terufumi Kubo, Munehide Nakatsugawa, Takayuki Kanaseki, Tomohide Tsukahara, Yasuaki Tamura, Hiroshi Hirano, Tadashi Hasegawa, Tsuyoshi Saito, Noriyuki Sato, Toshihiko Torigoe

Oncotarget 8 ( 19 ) 31540 - 31553 2017年05月 [国際誌]

Cancer stem-like cells (CSCs)/ cancer-initiating cells (CICs) are defined by their higher tumor-initiating ability, self-renewal capacity and differentiation capacity. CSCs/CICs are resistant to several therapies including chemotherapy and radiotherapy. CSCs/CICs thus are thought to be responsible for recurrence and distant metastasis, and elucidation of the molecular mechanisms of CSCs/CICs are essential to design CSC/CIC-targeting therapy. In this study, we analyzed the molecular aspects of gynecological CSCs/CICs. Gynecological CSCs/CICs were isolated as ALDH1high cell by Aldefluor assay. The gene expression profile of CSCs/CICs revealed that several genes related to stress responses are preferentially expressed in gynecological CSCs/CICs. Among the stress response genes, a small heat shock protein HSP27 has a role in the maintenance of gynecological CSCs/CICs. The upstream transcription factor of HSP27, heat shock factior-1 (HSF1) was activated by phosphorylation at serine 326 residue (pSer326) in CSCs/CICs, and phosphorylation at serine 326 residue is essential for induction of HSP27. Immunohistochemical staining using clinical ovarian cancer samples revealed that higher expressions of HSF1 pSer326 was related to poorer prognosis. These findings indicate that activation of HSF1 at Ser326 residue and transcription of HSP27 is related to the maintenance of gynecological CSCs/CICs.

Brother of the regulator of the imprinted site (BORIS) variant subfamily 6 is a novel target of lung cancer stem-like cell immunotherapy.

Ryota Horibe, Yoshihiko Hirohashi, Takuya Asano, Tasuku Mariya, Takeshi Suzuki, Akari Takaya, Hiroshi Saijo, Yosuke Shionoya, Terufumi Kubo, Munehide Nakatsugawa, Takayuki Kanaseki, Tomohide Tsukahara, Kazue Watanabe, Eri Atsuyama, Shingo Toji, Hiroshi Hirano, Tadashi Hasegawa, Hiroki Takahashi, Noriyuki Sato, Toshihiko Torigoe

PloS one 12 ( 3 ) e0171460 2017年 [国際誌]

Lung cancer is one of the most common malignancies with a high rate of mortality. Lung cancer stem-like cells (CSCs)/ cancer-initiating cells (CICs) play major role in resistance to treatments, recurrence and distant metastasis and eradication of CSCs/CICs is crucial to improve recent therapy. Cytotoxic T lymphocytes (CTLs) are major effectors of cancer immunotherapy, and CTLs recognize antigenic peptides derived from antigens that are presented by major histocompatibility complex (MHC) class I molecules. In this study, we analyzed the potency of a cancer-testis (CT) antigen, brother of the regulator of the imprinted site variant subfamily 6 (BORIS sf6), in lung CSC/CIC immunotherapy. BORIS sf6 mRNA was expressed in lung carcinoma cells (9/19), especially in sphere-cultured lung cancer stem-like cells, and in primary lung carcinoma tissues (4/9) by RT-PCR. Immunohistochemical staining using BORIS sf6-specific antibody revealed that high expression of BORIS sf6 is related to poorer prognosis. CTLs could be induced by using a human leukocyte antigen, (HLA)-A2 restricted antigenic peptide (BORIS C34_24(9)), from all of 3 HLA-A2-positive individuals, and CTL clone cells specific for BORIS C34_24(9) peptide could recognize BORIS sf6-positive, HLA-A2-positive lung carcinoma cells. These results indicate that BORIS sf6 is a novel target of lung cancer immunotherapy that might be useful for targeting treatment-resistant lung cancer stem-like cells.

Virological and cytological clearance in laser vaporization and conization for cervical intra-epithelial neoplasia grade 3.

Tasuku Mariya, Akira Nishikawa, Kanae Sogawa, Riri Suzuki, Masae Saito, Akari Kawamata, Ayumi Shimizu, Takehito Nihei, Tomoko Sonoda, Tsuyoshi Saito

The journal of obstetrics and gynaecology research 42 ( 12 ) 1808 - 1813 2016年12月 [国際誌]

AIM: Cervical intra-epithelial neoplasia (CIN) is the precancerous stage of cervical cancer. Standard treatment for high-grade CIN is conization of the cervix. The risk of preterm birth following conization has been discussed recently. In contrast, laser vaporization is believed not to affect perinatal outcome, but the long-term effectiveness of each surgical procedure is still unclear. The aim of this prospective unmatched-cohort study was therefore to compare virological and cytological clearance and recurrence risk between conization and vaporization for CIN3. METHODS: Subject consisted of CIN3 patients treated at the present hospital between 2007 to 2011 and followed up until December 2014. One hundred and one patients were treated with laser conization, and 137 with vaporization. The surgical procedure was selected on the basis of colposcopy, pathological grade and patient's hope for pregnancy. RESULTS: There were no significant differences in cure rate, human papilloma virus (HPV) clearance rate or recurrence rates between the conization and vaporization groups. Risk ratio of recurrence for each surgical procedure adjusted for age and HPV persistence status were analyzed on Cox proportional hazards modeling. Recurrence risk ratio for patients treated by vaporization was 6.21 (95%CI: 0.65-59.19; P = 0.111) compared with conization and there were no significant differences. No adverse pregnancy outcome was observed in the vaporization group compared with conization. CONCLUSIONS: Laser vaporization is useful for young patients with CIN3 who hope for pregnancy in the future.

Olfactory Receptor Family 7 Subfamily C Member 1 Is a Novel Marker of Colon Cancer-Initiating Cells and Is a Potent Target of Immunotherapy.

Rena Morita, Yoshihiko Hirohashi, Toshihiko Torigoe, Satoko Ito-Inoda, Akari Takahashi, Tasuku Mariya, Hiroko Asanuma, Yasuaki Tamura, Tomohide Tsukahara, Takayuki Kanaseki, Terufumi Kubo, Goro Kutomi, Toru Mizuguchi, Takeshi Terui, Kunihiko Ishitani, Satoshi Hashino, Toru Kondo, Nozomi Minagawa, Norihiko Takahashi, Akinobu Taketomi, Satoru Todo, Masahiro Asaka, Noriyuki Sato

Clinical cancer research : an official journal of the American Association for Cancer Research 22 ( 13 ) 3298 - 309 2016年07月 [国際誌]

PURPOSE: Cancer-initiating cells (CICs) are thought to be essential for tumor maintenance, recurrence, and distant metastasis, and they are therefore reasonable targets for cancer therapy. Cancer immunotherapy is a novel approach to target cancer. In this study, we aimed to establish novel CIC-targeting immunotherapy. EXPERIMENTAL DESIGN: Colorectal cancer (CRC) CICs were isolated as side population (SP) cells. The gene expression profile of CRC CICs was analyzed by cDNA microarray and RT-PCR. Protein expression of olfactory receptor family 7 subfamily C member 1 (OR7C1) were analyzed by Western blot and immunohistochemical staining. The functions of OR7C1 were analyzed by gene overexpression and gene knockdown using siRNAs. OR7C1-positive cells were isolated by a flow cytometer and analyzed. CTLs specific for OR7C1 peptide were generated, and the antitumor effect was addressed by mice adoptive transfer model. RESULTS: OR7C1 has essential roles in the maintenance of colon CICs, and the OR7C1-positive population showed higher tumorigenicity than that of the OR7C1-negative population, indicating that OR7C1 is a novel functional marker for colon CIC. Immunohistochemical staining revealed that OR7C1 high expression was correlated with poorer prognosis in CRC patients. OR7C1-derived antigenic peptide-specific CTLs showed specific cytotoxicity for CICs, and an OR7C1-specific CTL clone showed a greater antitumor effect than did a CTL clone targeting all cancer cells in a CTL adoptive transfer mouse model. CONCLUSIONS: OR7C1 is a novel marker for colon CICs and can be a target of potent CIC-targeting immunotherapy. Clin Cancer Res; 22(13); 3298-309. ©2016 AACR.

Matrix metalloproteinase-10 regulates stemness of ovarian cancer stem-like cells by activation of canonical Wnt signaling and can be a target of chemotherapy-resistant ovarian cancer.

Tasuku Mariya, Yoshihiko Hirohashi, Toshihiko Torigoe, Yuta Tabuchi, Takuya Asano, Hiroshi Saijo, Takafumi Kuroda, Kazuyo Yasuda, Masahito Mizuuchi, Tsuyoshi Saito, Noriyuki Sato

Oncotarget 7 ( 18 ) 26806 - 22 2016年05月 [国際誌]

Epithelial ovarian cancer (EOC) is one of the most lethal cancers in females. Cancer stem-like cells (CSCs)/cancer-initiating cells (CICs) have been reported to be origin of primary and recurrent cancers and to be resistant to several treatments. In this study, we identified matrix metalloproteinase-10 (MMP10) is expressed in CSCs/CICs of EOC. An immunohistochemical study revealed that a high expression level of MMP10 is a marker for poor prognosis and platinum resistance in multivariate analysis. MMP10 gene overexpression experiments and MMP10 gene knockdown experiments using siRNAs revealed that MMP10 has a role in the maintenance of CSCs/CICs in EOC and resistance to platinum reagent. Furthermore, MMP10 activate canonical Wnt signaling by inhibiting noncanonical Wnt signaling ligand Wnt5a. Therefore, MMP10 is a novel marker for CSCs/CICs in EOC and that targeting MMP10 is a novel promising approach for chemotherapy-resistant CSCs/CICs in EOC.

Brother of the regulator of the imprinted site (BORIS) variant subfamily 6 is involved in cervical cancer stemness and can be a target of immunotherapy.

Takuya Asano, Yoshihiko Hirohashi, Toshihiko Torigoe, Tasuku Mariya, Ryota Horibe, Takafumi Kuroda, Yuta Tabuchi, Hiroshi Saijo, Kazuyo Yasuda, Masahito Mizuuchi, Akari Takahashi, Hiroko Asanuma, Tadashi Hasegawa, Tsuyoshi Saito, Noriyuki Sato

Oncotarget 7 ( 10 ) 11223 - 37 2016年03月 [国際誌]

Cervical cancer is a major cause of cancer death in females worldwide. Cervical cancer stem-like cells (CSCs)/cancer-initiating cells (CICs) are resistant to conventional radiotherapy and chemotherapy, and CSCs/CICs are thought to be responsible for recurrence. Eradication of CSCs/CICs is thus essential to cure cervical cancer. In this study, we isolated cervical CSCs/CICs by sphere culture, and we identified a cancer testis (CT) antigen, CTCFL/BORIS, that is expressed in cervical CSCs/CICs. BORIS has 23 mRNA isoform variants classified by 6 subfamilies (sfs), and they encode 17 different BORIS peptides. BORIS sf1 and sf4 are expressed in both CSCs/CICs and non-CSCs/CICs, whereas BORIS sf6 is expressed only in CSCs/CICs. Overexpression of BORIS sf6 in cervical cancer cells increased sphere formation and tumor-initiating ability compared with those in control cells, whereas overexpression of BORIS sf1 and BORIS sf4 resulted in only slight increases. Thus, BORIS sf6 is a cervical CSC/CIC-specific subfamily and has a role in the maintenance of cervical CSCs/CICs. BORIS sf6 contains a specific c-terminal domain (C34), and we identified a human leukocyte antigen (HLA)-A2-restricted antigenic peptide, BORIS C34_24(9) encoded by BORIS sf6. A BORIS C34_24(9)-specific cytotoxic T cell (CTL) clone showed cytotoxicity for BORIS sf6-overexpressing cervical cancer cells. Furthermore, the CTL clone significantly suppressed sphere formation of CaSki cells. Taken together, the results indicate that the CT antigen BORIS sf6 is specifically expressed in cervical CSCs/CICs, that BORIS sf6 has a role in the maintenance of CSCs/CICs, and that BORIS C34_24(9) peptide is a promising candidate for cervical CSC/CIC-targeting immunotherapy.

HLA class I as a predictor of clinical prognosis and CTL infiltration as a predictor of chemosensitivity in ovarian cancer.

Yoshihiko Hirohashi, Toshihiko Torigoe, Tasuku Mariya, Vitaly Kochin, Tsuyoshi Saito, Noriyuki Sato

Oncoimmunology 4 ( 5 ) e1005507 2015年05月 [国際誌]

HLA class I as a predictor of clinical prognosis and CTL infiltration as a predictor of chemosensitivity in ovarian cancer

Yoshihiko Hirohashi, Toshihiko Torigoe, Tasuku Mariya, Vitaly Kochin, Tsuyoshi Saito, Noriyuki Sato

ONCOIMMUNOLOGY ( TAYLOR & FRANCIS INC ) 4 ( 5 ) 2015年05月 [査読有り]

Fibroblasts induce expression of FGF4 in ovarian cancer stem-like cells/cancer-initiating cells and upregulate their tumor initiation capacity.

Kazuyo Yasuda, Toshihiko Torigoe, Tasuku Mariya, Takuya Asano, Takafumi Kuroda, Junichi Matsuzaki, Kanae Ikeda, Makoto Yamauchi, Makoto Emori, Hiroko Asanuma, Tadashi Hasegawa, Tsuyoshi Saito, Yoshihiko Hirohashi, Noriyuki Sato

Laboratory investigation; a journal of technical methods and pathology 94 ( 12 ) 1355 - 69 2014年12月 [国際誌]

Cancer stem-like cells (CSCs)/cancer-initiating cells (CICs) are defined as a small population of cells within cancer that contribute to cancer initiation and progression. Cancer-associated fibroblasts (CAFs) are stromal fibroblasts surrounding tumor cells, and they have important roles in tumor growth and tumor progression. It has been suggested that stromal fibroblasts and CSCs/CICs might mutually cooperate to enhance their growth and tumorigenic capacity. In this study, we investigated the effects of fibroblasts on tumor-initiating capacity and stem-like properties of ovarian CSCs/CICs. CSCs/CICs were isolated from the ovarian carcinoma cell line HTBoA as aldehyde dehydrogenase 1 high (ALDH1(high)) population by the ALDEFLUOR assay. Histological examination of tumor tissues derived from ALDH1(high) cells revealed few fibrous stroma, whereas those derived from fibroblast-mixed ALDH1(high) cells showed abundant fibrous stroma formation. In vivo tumor-initiating capacity and in vitro sphere-forming capacity of ALDH1(high) cells were enhanced in the presence of fibroblasts. Gene expression analysis revealed that fibroblast-mixed ALDH1(high) cells had enhanced expression of fibroblast growth factor 4 (FGF4) as well as stemness-associated genes such as SOX2 and POU5F1. Sphere-forming capacity of ALDH1(high) cells was suppressed by small-interfering RNA (siRNA)-mediated knockdown of FGFR2, the receptor for FGF4 which was expressed preferentially in ALDH1(high) cells. Taken together, the results indicate that interaction of fibroblasts with ovarian CSCs/CICs enhanced tumor-initiating capacity and stem-like properties through autocrine and paracrine FGF4-FGFR2 signaling.

Prognostic impact of human leukocyte antigen class I expression and association of platinum resistance with immunologic profiles in epithelial ovarian cancer.

Tasuku Mariya, Yoshihiko Hirohashi, Toshihiko Torigoe, Takuya Asano, Takafumi Kuroda, Kazuyo Yasuda, Masahito Mizuuchi, Tomoko Sonoda, Tsuyoshi Saito, Noriyuki Sato

Cancer immunology research 2 ( 12 ) 1220 - 9 2014年12月 [国際誌]

Epithelial ovarian cancer (EOC) is one of the most deadly carcinomas in females. Immune systems can recognize EOCs; however, a defect of human leukocyte antigen (HLA) class I expression is known to be a major mechanism for escape from immune systems, resulting in poor prognosis. The purpose of this study is to identify novel correlations between immunologic responses and other clinical factors. We investigated the expression of immunologic components in 122 cases of EOCs for which surgical operations were performed between 2001 and 2011. We immunohistochemically stained EOC specimens using an anti-pan HLA class I monoclonal antibody (EMR8-5) and anti-CD3, -CD4, and -CD8 antibodies, and we analyzed correlations between immunologic parameters and clinical factors. In multivariate analysis that used the Cox proportional hazards model, independent prognostic factors for overall survival in advanced EOCs included low expression level of HLA class I [risk ratio (RR), 1.97; 95% confidence interval (CI), 1.01-3.83; P = 0.046] and loss of intraepithelial cytotoxic T lymphocyte (CTL) infiltration (RR, 2.11; 95% CI, 1.06-4.20; P = 0.033). Interestingly, almost all platinum-resistant cases showed a significantly low rate of intraepithelial CTL infiltration in the χ(2) test (positive vs. negative: 9.0% vs. 97.7%; P < 0.001). Results from a logistic regression model revealed that low CTL infiltration rate was an independent factor of platinum resistance in multivariate analysis (OR, 3.77; 95% CI, 1.08-13.12; P = 0.037). Platinum-resistant EOCs show poor immunologic responses. The immune escape system of EOCs may be one of the mechanisms of platinum resistance.

BAG3 upregulates Mcl-1 through downregulation of miR-29b to induce anticancer drug resistance in ovarian cancer.

Asuka Sugio, Masahiro Iwasaki, Shutaro Habata, Tasuku Mariya, Miwa Suzuki, Hiroyuki Osogami, Masato Tamate, Ryoichi Tanaka, Tsuyoshi Saito

Gynecologic oncology 134 ( 3 ) 615 - 23 2014年09月 [国際誌]

OBJECTIVE: Ovarian cancer is the leading cause of death from gynecologic cancer, reflecting its often late diagnosis and its chemoresistance. We identified a set of microRNAs whose expression is altered upon BAG3 knockdown. Our primary objective was to examine the relationships between BAG3, miR-29b and Mcl-1, an antiapoptotic Bcl-2 family protein, in ovarian cancer cells. METHODS: Ovarian cancer cells were cultured and their responsiveness to paclitaxel was tested. Microarray analysis was performed to identify microRNAs differentially expressed in ES2 BAG3 knockdown ovarian cancer cells and their control cells. Primary ovarian cancer tissues were obtained from 56 patients operated on for ovarian cancer. The patients' clinical and pathological data were obtained from their medical records. RESULTS: BAG3 knockdown increased the chemosensitivity to paclitaxel of ES2 ovarian clear cell carcinoma cells to a greater degree than AMOC2 serous adenocarcinoma cells. qRT-PCR analysis showed that miR-29b expression was significantly upregulated in primary cancer tissue expressing low levels of BAG3, as compared to tissue expressing high levels. Moreover, levels of miR-29b correlated significantly with progression-free survival. Upregulation of miR-29b also reduced levels of Mcl-1 and sensitized ES2 cells to low-dose paclitaxel. CONCLUSIONS: BAG3 knockdown appears to downregulate expression of Mcl-1 through upregulation of miR-29b, thereby increasing the chemosensitivity of ovarian clear cell carcinoma cells. This suggests that BAG3 is a key determinant of the responsiveness of ovarian cancer cells, especially clear cell carcinoma, to paclitaxel and that BAG3 may be a useful therapeutic target for the treatment of ovarian cancer.

ASC-US における HPV-DNA 検査の有用性に関する検討

玉手雅人, 松浦基樹, 竹浪奈穂子, 真里谷奨, 郷久晴朗, 田中綾一, 早川修, 齋藤豪

日本臨床細胞学会雑誌 ( The Japanese Society of Clinical Cytology ) 53 ( 5 ) 362 - 365 2014年

目的 : 子宮頸部細胞診 ASC-US 例に対する HPV の検査はコルポスコープの必要性をはじめとする管理方針を決める際に重要であるため, 臨床背景や転帰を検討した.
方法 : 2010 年 1 月∼2011 年 12 月, 子宮頸部細胞診を施行した 12141 例のうち ASC-US と診断され, High Risk HPV の検索を行った例を対象に統計処理し, 検討した.
成績 : ASC-US は全体の 1.9%であった. HPV 検査を行った 73 例のうち, 66%が HPV 陽性であった. 組織診では CIN 1 が 25%, CIN 2 以上が 21%に認められた. CIN 1 であった 19 人中 15 人が細胞診陰性化した. CIN 2・3 の 12 人は, 4 人が円錐切除術となり, 残りは経過観察となった. 年齢・経産の有無・喫煙を項目に logistic 解析を行った結果, HPV 陽性であることが病変の進行に関わってくるとことが示唆された. さらに CIN をスコア化し, 年齢や HPV-DNA 検査を項目とした多変量解析を行った結果, ASC-US 例において High Risk HPV 陽性であることが CIN 進行因子となることが示された.
結論 : 適切な検体から得られた ASC-US の異形成度は多岐にわたるため, HPV 検査が判断材料となりうる. 今回, 単一施設における検討から ASC-US 例へ HPV 検査を行う重要性を再確認した.

ALDH1-high ovarian cancer stem-like cells can be isolated from serous and clear cell adenocarcinoma cells, and ALDH1 high expression is associated with poor prognosis.

Takafumi Kuroda, Yoshihiko Hirohashi, Toshihiko Torigoe, Kazuyo Yasuda, Akari Takahashi, Hiroko Asanuma, Rena Morita, Tasuku Mariya, Takuya Asano, Masahito Mizuuchi, Tsuyoshi Saito, Noriyuki Sato

PloS one 8 ( 6 ) e65158 2013年 [国際誌]

Cancer stem-like cells (CSCs)/cancer-initiating cells (CICs) are defined as a small population of cancer cells that have high tumorigenicity. Furthermore, CSCs/CICs are resistant to several cancer therapies, and CSCs/CICs are therefore thought to be responsible for cancer recurrence after treatment and distant metastasis. In epithelial ovarian cancer (EOC) cases, disease recurrence after chemotherapy is frequently observed, suggesting ovarian CSCs/CICs are involved. There are four major histological subtypes in EOC, and serous adenocarcinoma and clear cell adenocarcinoma are high-grade malignancies. We therefore analyzed ovarian CSCs/CICs from ovarian carcinoma cell lines (serous adenocarcinoma and clear cell adenocarcinoma) and primary ovarian cancer cells in this study. We isolated ovarian CSCs/CICs as an aldehyde dehydrogenase 1 high (ALDH1(high)) population from 6 EOC cell lines (3 serous adenocarcinomas and 3 clear cell adenocarcinomas) by the ALDEFLUOR assay. ALDH1(high) cells showed greater sphere-forming ability, higher tumorigenicity and greater invasive capability, indicating that ovarian CSCs/CICs are enriched in ALDH1(high) cells. ALDH1(high) cells could also be isolated from 8 of 11 primary ovarian carcinoma samples. Immunohistochemical staining revealed that higher ALDH1 expression levels in ovary cancer cases are related to poorer prognosis in both serous adenocarcinoma cases and clear cell adenocarcinoma cases. Taken together, the results indicate that ALDH1 is a marker for ovarian CSCs/CICs and that the expression level of ALDH1 might be a novel biomarker for prediction of poor prognosis.

First case of vaginal radical trachelectomy in a pregnant Japanese woman.

Nanako Iwami, Shin-ichi Ishioka, Toshiaki Endo, Tsuyoshi Baba, Kunihiko Nagasawa, Madoka Takahashi, Asuka Sugio, Sakura Takada, Tasuku Mariya, Masahiro Mizunuma, Tsuyoshi Saito

International journal of clinical oncology 16 ( 6 ) 737 - 40 2011年12月 [国内誌]

A diagnosis of cervical cancer during pregnancy poses difficult management and ethical problems. Survival of the patient is the foremost concern, but fetal viability and well-being must also be addressed. Radical trachelectomy (RT) has recently begun to be performed as a possible treatment modality for early stage invasive uterine cervical cancer in pregnant patients who would like to continue their pregnancy. A 32-year-old Japanese woman visited a local hospital for prenatal care, and was diagnosed with a FIGO I B1 adenocarcinoma of the uterine cervix. She had a strong desire to avoid pregnancy termination, so she was admitted to our hospital for fertility-preserving surgery. After extensive counseling, vaginal radical trachelectomy with abdominal pelvic lymphadenectomy was performed in the 16th gestational week. The excised uterine cervix and lymph nodes were pathologically negative for cancer. To maintain her pregnancy, daily vaginal disinfection with povidone iodine, bed rest, and administration of ritodrine and an ulinastatin vaginal suppository were continued until the delivery. At 34 weeks' gestation, an emergency cesarean section was performed because of sudden premature rupture of the membranes. A baby girl was born weighing 2112 g, with Apgar score of 8/9. The mother remains without evidence of recurrence at the time of this report. This is the first case of successful pregnancy and delivery in Japan after vaginal RT.

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