論文 - 齋藤　豪

Possibility of Targeting Claudin-2 in Therapy for Human Endometrioid Endometrial Carcinoma.

Tadahi Okada, Takumi Konno, Takayuki Kohno, Hiroshi Shimada, Kimihito Saito, Seiro Satohisa, Tsuyoshi Saito, Takashi Kojima

Reproductive sciences (Thousand Oaks, Calif.)   27 ( 11 ) 2092 - 2103  2020年11月  [国際誌]

　概要を見る

Claudin-2 (CLDN-2) is a leaky-type tight junction protein, and its overexpression increases tumorigenesis of some types of cancer cells. In the present study, to examine the possibility of targeting CLDN-2 in the therapy for endometrioid endometrial adenocarcinoma, we investigated the regulation and role of CLDN-2 in endometriosis and endometrioid endometrial adenocarcinoma. In endometrioid endometrial adenocarcinoma tissues, marked upregulation of CLDN-2 was observed together with malignancy, while in endometriosis tissues, a change in the localization of CLDN-2 was observed. In cells of the endometrial adenocarcinoma cell line Sawano, which highly express CLDN-2, downregulation of CLDN-2 induced by the siRNA upregulated the epithelial barrier and inhibited cell migration. Furthermore, the downregulation of CLDN-2 affected the cell cycle and inhibited cell proliferation. In Sawano cells cultured with high-glucose medium, CLDN-2 expression was downregulated at the mRNA and protein levels. The high-glucose medium upregulated the epithelial barrier, cell proliferation, and migration, and inhibited cell invasion. The histone deacetylase (HDAC) inhibitor tricostatin A (TSA), which has antitumor effects, downregulated CLDN-2 expression, cell proliferation, invasion, and migration, and upregulated the epithelial barrier. The mitochondrial respiration level, an indicator of cancer metabolism, was downregulated by CLDN-2 knockdown and upregulated by the high-glucose condition. Taken together, these results indicated that overexpression of CLDN-2 closely contributed to the malignancy of endometrioid endometrial adenocarcinoma. Downregulation of CLDN-2 via the changes of the glucose concentration and treatment with HDAC inhibitors may be important in the therapy for endometrial cancer.

DOI PubMed

腹腔鏡下子宮全摘出術施行時に偶発的に副脾を認めた一例

長尾 沙智子, 有元 千紘, 山崎 智子, 玉手 雅人, 恐神 博行, 高田 さくら, 松浦 基樹, 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 - 046]  2020年11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

Association between cancer immunity and treatment results in uterine cervical cancer patients treated with radiotherapy

Masanori Someya, Takaaki Tsuchiya, Yuki Fukushima, Tomokazu Hasegawa, Yu Takada, Masakazu Hori, Katsutoshi Miura, Mio Kitagawa, Toshio Gocho, Yoshihiko Hirohashi, Toshihiko Torigoe, Masahiro Iwasaki, Motoki Matsuura, Tsuyoshi Saito, Koh-ichi Sakata

Japanese Journal of Clinical Oncology ( Oxford University Press (OUP) )   2020年08月

　概要を見る

To evaluate proteins related to tumor immune response and treatment outcome from radiotherapy for uterine cervical cancer patients. We performed a retrospective immunohistochemical staining of 81 patients with uterine cervical cancer who underwent definitive radiotherapy. We examined the expression of programmed death ligand 1, human leukocyte antigen class I, tumor-infiltrating CD8+, and forkhead box P3+ (FoxP3+) T cells in tumor tissues. In biopsy specimen, patients with a higher number of CD8+ T cells and FoxP3+ T cells had a better disease-specific survival than patients with a lower number of CD8+ T cells and FoxP3+ cells (P = 0.018 and P = 0.009). Multivariate analysis showed that equivalent dose in 2 Gy fractions (EQD2) of the minimum dose to 90% of the high-risk clinical target volume, FoxP3+ T cells and expression of human leukocyte antigen class I were significant prognostic factors. When the EQD2 is 70 Gy or more, a higher local control rate is obtained regardless of the number of CD8- or FoxP3-positive cells. When EQD2 is <70 Gy, the number of CD8-positive cells has a significant impact on treatment outcome: the recurrence rate (local recurrence rate + distant metastasis rate) was 46.2% in the group with a CD8 value of 230 or higher, whereas the recurrence rate was 75.7% in the group with a CD8 value of less than 230. The combination of CD8 or FoxP3 with EQD2 can be potentially useful to predict the treatment results of radiotherapy for cervical cancer, leading to individualized optimal selection of treatment for cervical cancer.

DOI

Association between radiotherapy-induced alteration of programmed death ligand 1 and survival in patients with uterine cervical cancer undergoing preoperative radiotherapy.

Takaaki Tsuchiya, Masanori Someya, Yu Takada, Tomokazu Hasegawa, Mio Kitagawa, Yuki Fukushima, Toshio Gocho, Masakazu Hori, Kensei Nakata, Yoshihiko Hirohashi, Toshihiko Torigoe, Tsuyoshi Saito, Koh-Ichi Sakata

Strahlentherapie und Onkologie : Organ der Deutschen Rontgengesellschaft ... [et al]   196 ( 8 ) 725 - 735  2020年08月  [国際誌]

　概要を見る

PURPOSE: To evaluate radiotherapy-induced changes in the expression of programmed death ligand 1 (PD-L1), programmed death 1 (PD-1), and human leukocyte antigen class I (HLA-1) in patients with uterine cervical cancer, as well as infiltration of CD8+ and Forkhead box P3+ (FoxP3+) T lymphocytes into tumor tissue and the prognostic value of these parameters. MATERIALS AND METHODS: We performed immunohistochemical analysis of pre-radiotherapy biopsies and corresponding post-radiotherapy resected tissues in 104 uterine cervical cancer patients undergoing preoperative chemoradiotherapy or radiotherapy alone. We scored the expression of various proteins to distinguish positive from negative samples. RESULTS: PD-L1-expressing tumor cells (PD-L1 TC) increased significantly after chemoradiotherapy (p = 0.043). CD8+ T cell infiltration (p = 0.002) and FoxP3+ T cell infiltration (p = 0.003) decreased significantly after chemoradiotherapy. Expression of PD‑1, PD-L1-expressing immune cells (PD-L1 IC), and HLA‑1 did not change after chemoradiotherapy. In biopsy specimens obtained before chemoradiotherapy or radiotherapy, greater infiltration of CD8+ T cells (p = 0.001) and FoxP3+ T cells (p = 0.003) were significant predictors of better overall survival (OS). In surgical specimens obtained after chemoradiotherapy or radiotherapy, greater infiltration of PD-L1 TC was the only significant predictor of better OS (p < 0.001) and was related to a significantly lower probability of out-of-field recurrence (p = 0.005). CONCLUSION: Chemoradiotherapy induced an immunologic shift that increased PD-L1 TC. Chemoradiotherapy has immunological effects that can influence the results of treatment for uterine cervical cancer.

DOI PubMed

Aldolase A promotes epithelial-mesenchymal transition to increase malignant potentials of cervical adenocarcinoma.

Yuki Saito, Akira Takasawa, Kumi Takasawa, Tomoyuki Aoyama, Taishi Akimoto, Misaki Ota, Kazufumi Magara, Masaki Murata, Yoshihiko Hirohashi, Tadashi Hasegawa, Norimasa Sawada, Tsuyoshi Saito, Makoto Osanai

Cancer science   111 ( 8 ) 3071 - 3081  2020年08月  [国際誌]

　概要を見る

Recent studies have revealed that metabolic reprogramming is closely associated with epithelial-mesenchymal transition (EMT) during cancer progression. Aldolase A (ALDOA) is a key glycolytic enzyme that is highly expressed in several types of cancer. In this study, we found that ALDOA is highly expressed in uterine cervical adenocarcinoma and that high ALDOA expression promotes EMT to increase malignant potentials, such as metastasis and invasiveness, in cervical adenocarcinoma cells. In human surgical specimens, ALDOA was highly expressed in cervical adenocarcinoma and high ALDOA expression was correlated with lymph node metastasis, lymphovascular infiltration, and short overall survival. Suppression of ALDOA expression significantly reduced cell growth, migration, and invasiveness of cervical cancer cells. Aldolase A expression was partially regulated by hypoxia-inducible factor-1α (HIF-1α). Shotgun proteome analysis revealed that cell-cell adhesion-related proteins were significantly increased in ALDOA-overexpressing cells. Interestingly, overexpression of ALDOA caused severe morphological changes, including a cuboidal-to-spindle shape shift and reduced microvilli formation, coincident with modulation of the expression of typical EMT-related proteins. Overexpression of ALDOA increased migration and invasion in vitro. Furthermore, overexpression of ALDOA induced HIF-1α, suggesting a positive feedback loop between ALDOA and HIF-1α. In conclusion, ALDOA is overexpressed in cervical adenocarcinoma and contributes to malignant potentials of tumor cells through modulation of HIF-1α signaling. The feedback loop between ALDOA and HIF-1α could become a therapeutic target to improve the prognosis of this malignancy.

DOI PubMed

ASPP2 suppression promotes malignancy via LSR and YAP in human endometrial cancer.

Takumi Konno, Takayuki Kohno, Tadahi Okada, Hiroshi Shimada, Seiro Satohisa, Shin Kikuchi, Tsuyoshi Saito, Takashi Kojima

Histochemistry and cell biology   154 ( 2 ) 197 - 213  2020年08月  [国際誌]

　概要を見る

Apoptosis-stimulating p53 protein 2 (ASPP2) is an apoptosis inducer that acts via binding with p53 and epithelial polarity molecule PAR3. Lipolysis-stimulated lipoprotein receptor (LSR) is an important molecule at tricellular contacts, and loss of LSR promotes cell migration and invasion via Yes-associated protein (YAP) in human endometrial cancer cells. In the present study, to find how ASPP2 suppression promotes malignancy in human endometrial cancer, we investigated its mechanisms including the relationship with LSR. In endometriosis and endometrial cancers (G1 and G2), ASPP2 was observed as well as PAR3 and LSR in the subapical region. ASPP2 decreased in G3 endometrial cancer compared to G1. In human endometrial cancer cell line Sawano, ASPP2 was colocalized with LSR and tricellulin at tricellular contacts and binding to PAR3, LSR, and tricellulin in the confluent state. ASPP2 suppression promoted cell migration and invasion, decreased LSR expression, and induced expression of phosphorylated YAP, claudin-1, -4, and -7 as effectively as the loss of LSR. Knockdown of YAP prevented the upregulation of pYAP, cell migration and invasion induced by the ASPP2 suppression. Treatment with a specific antibody against ASPP2 downregulated ASPP2 and LSR, affected F-actin at tricellular contacts, upregulated expression of pYAP and claudin-1, and induced cell migration and invasion via YAP. In normal human endometrial epithelial cells, ASPP2 was in part colocalized with LSR at tricellular contacts and knockdown of ASPP2 or LSR induced expression of claudin-1 and claudin-4. ASPP2 suppression promoted cell invasion and migration via LSR and YAP in human endometrial cancer cells.

DOI PubMed

ロボット手術におけるPeNのコツ

松浦 基樹, 西村 庸子, 黒川 晶子, 玉手 雅人, 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 ) 155 - 155  2020年08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

Mucinous carcinoma originating in the peritoneum diagnosed by an ascites cell block: a case report.

Sachiko Nagao, Motoki Matsuura, Masato Tamate, Shintaro Sugita, Tsuyoshi Saito

Journal of medical case reports   14 ( 1 ) 99 - 99  2020年07月  [国際誌]

　概要を見る

BACKGROUND: Peritoneal carcinoma is a rare disease that is diagnosed and treated in a manner similar to ovarian cancer. In most cases, the histological type is serous carcinoma, and chemotherapy is effective. However, there are a few case reports of mucinous peritoneal carcinoma. We inferred the histological type before surgery using an ascites cell block sample, which was useful for determining the treatment plan. CASE PRESENTATION: Our patient was a 60-year-old Japanese woman. She presented with a feeling of fullness in the abdomen. A computed tomographic scan showed a large quantity of ascitic fluid and thickening of the greater omentum, as well as thickening of the peritoneum at the pouch of Douglas and diaphragm. Hence, peritoneal carcinoma was suspected. The tumor markers carcinoembryonic antigen, cancer antigen 19-9, and cancer antigen 125 were all increased, and no malignant findings were observed in the uterus or ovaries. Cells suggestive of carcinoma were found in the ascitic fluid, and immunostaining by the cell block method suggested the possibility of mucinous carcinoma. The preoperative chemotherapy strategy was changed to short courses, and tumor reduction surgery was planned. Similar to the suspicion before surgery, the pathology results indicated mucinous carcinoma, and the therapeutic effect of chemotherapy was grade 0. CONCLUSIONS: Determining whether peritoneal carcinoma is serous carcinoma is important for therapy and prognostic prediction. In this case, we encountered a patient for whom surgery was chosen because of drug therapy resistance inferred through histological type estimation using the cell block method. Inferring the histological type by cell block preparation is useful for diagnosis and treatment selection.

DOI PubMed

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

【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

　概要を見る

＜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。

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]

DOI PubMed

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

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

　概要を見る

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。

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

早期子宮体癌における腹腔細胞診に関する検討

西村 庸子, 松浦 基樹, 玉手 雅人, 寺田 倫子, 郷久 晴朗, 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 )  59 ( 3 ) 125 - 128  2020年05月

　概要を見る

目的:子宮体癌における腹腔細胞診の結果は2008年のFIGO分類において進行期の決定に考慮されなくなった。独立した予後因子になるとするいくつかの報告もあるが、現在のところ腹腔細胞診と予後との関係については、結論が得られていない。今回われわれは、術前1A期の診断で腹腔鏡下手術を行い、術後病理でも1Aと診断された症例の腹腔細胞診に関して検討した。方法:2014年7月〜2018年12月に術前1A期の診断で腹腔鏡下子宮全摘、両側付属器摘出術(症例によっては骨盤リンパ節郭清)を行った82例について検討した。成績:82例のうち、5例(6.1%)は腹腔細胞診が陽性であった。5例のうち、1例は脈管侵襲陽性であり、4例は脈管侵襲陰性で、その他のリスク因子も認めなかった。5例のうち、2例は術後化学療法が行われ、いずれも再発はみられていないが、術後化学療法を行わなかった3例はいずれも再発を認めた。腹腔細胞診が陰性であった77例の中で再発をきたした症例は2例あり、1例は肺転移、もう1例は腹膜播種再発であった。結論:今回の結果はフォローアップ期間も、症例数も限定的なものではあるが、低リスク子宮体癌であっても腹腔細胞診陽性であれば術後補助療法を施行した方が予後が改善する可能性が示唆された。(著者抄録)

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]

　概要を見る

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.

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