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

Involvement of the aryl hydrocarbon receptor (AHR) in carcinogenesis has been suggested in many studies. Upregulation of AHR has been reported in some cancer species, and an association between single-nucleotide polymorphisms (SNPs) of AHR and cancer risk or cancer development has also been reported. This evidence suggests the involvement of some specific SNPs in AHR transcriptional regulation in the process of carcinogenesis or cancer development, but there have been no studies to elucidate the mechanism involved. In this study, we identified the transcription factor Nuclear Factor 1-C (NF1C) as a candidate to regulate AHR transcription in a polymorphism-dependent manner. SNP rs10249788 was included in a consensus binding site for NF1C. Our results suggested that NF1C preferred the C allele to the T allele at rs10249788 for binding. Forced expression of NF1C suppressed the activity of the AHR promoter with C at rs10249788 stronger than that with T. Moreover, expression analysis of human uterine endometrial cancer (HEC) specimens showed greater upregulation of AHR and downregulation of NF1C than those of normal endometrium specimens. Sequence analysis showed HEC patients at advanced stages tended to possess T/T alleles more frequently than healthy women. We also demonstrated that NF1C suppressed proliferation, motility and invasion of HEC cells. This function was at least partially mediated by AHR. This study is the first to report that a polymorphism on the AHR regulatory region affected transcriptional regulation of the AHR gene in vitro. Because NF1C is a tumor suppressor, our new insights into AHR deregulation and its polymorphisms could reveal novel mechanisms of genetic susceptibility to cancer.

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

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

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

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

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

DOI： 10.1016/S0888-7543(02)00011-3

Language：English   Publishing type：Research paper (scientific journal)   Publisher：Journal of Obstetrics and Gynaecology Research  

Aim: Clear cell carcinoma of the uterine cervix (CCCUC) is a rare disease, accounting for 4% to 9% of cervical adenocarcinomas. Because it is so rare, its pathogenesis is largely unknown, and the standard treatment is unclear due to a lack of prospective studies. Our aim is to investigate the clinical features, treatment, and prognosis of CCCUC. Methods: We retrospectively evaluated the clinical characteristics, treatment choices, and outcomes of 12 patients with CCCUC treated at our institution between January 2009 and July 2024. Results: The median patient age was 62.5 years (range, 14–90 years). The most common stage was IB (IA, n = 3; IB, n = 4; IIB, n = 1; IIIC, n = 2; IVB, n = 2). Ten patients underwent surgery as initial treatment: 6 underwent radical hysterectomy plus pelvic lymphadenectomy (PLD) or sentinel lymph node biopsy (SLNB), with or without para-aortic lymphadenectomy (PALD); 3 underwent modified radical hysterectomy plus PLD with or without PALD; and 1 underwent radical trachelectomy with SLNB as fertility-preserving surgery. All patients underwent bilateral salpingo-oophorectomy except for the patient who opted for radical trachelectomy. Five patients received adjuvant treatment: 3 received platinum-based systemic chemotherapy (2 of whom had combination therapy with bevacizumab), and 2 received concurrent chemoradiotherapy. The median follow-up was 43.5 months (range, 1–123 months). The 5-year progression-free survival rate was 64.5%. Conclusion: Systemic platinum-based chemotherapy with bevacizumab may be more effective than concurrent chemoradiotherapy as adjuvant therapy for CCCUC.

DOI： 10.1111/jog.16300

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Language：English   Publishing type：Research paper (conference, symposium, etc.)   Publisher：John Wiley & Sons Australia, Ltd  

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

Background: A molecular classification of endometrial cancer was developed based on an analysis of The Cancer Genome Atlas. In this classification, the group characterized by abnormal p53 immunohistochemical expression showed the poorest prognosis. However, there may be no need to apply a molecular classification in low-grade endometrial cancer. In this study, we investigated the clinical significance of abnormal p53 immunohistochemical expression in low-grade endometrial cancer. Methods: We obtained nine frozen samples of endometrial cancer [low-grade endometrial cancer with wild-type p53 expression (EC^lop53^wt group): n = 3, low-grade endometrial cancer with abnormal p53 expression (EC^lop53^ab group): n = 3, and high-grade endometrial cancer (EC^hi group): n = 3]. RNA sequencing was performed for each sample. All the samples passed RNA quality control. In addition, an immunohistochemical analysis was performed for 44 formalin-fixed paraffin-embedded samples. Results: Differentially expressed genes were identified in the RNA sequencing results (1811 genes between the EC^lop53^ab group and the EC^hi group, and 1088 genes between the EC^lop53^ab group and the EC^lop53^wt group). In a principal component analysis, the EC^lop53^ab group was more similar to the EC^lop53^wt group than to the EC^hi group. In the immunohistochemical analysis, L1CAM expression was significantly less frequently observed in the EC^lop53^ab group than in the EC^hi group. Moreover, p21 expression tended to be more frequently observed in the EC^lop53^ab group than in the EC^hi group. Conclusions: In this study, the RNA sequencing and immunohistochemical results revealed that the EC^lop53^ab group is a separate entity from the EC^hi group. While the abnormal p53 group is considered the most prognostically unfavorable in molecular classification, these findings suggest that routine molecular profiling is not necessary for patients with low-grade endometrial cancer. However, there is insufficient evidence to modify adjuvant treatment in low-grade endometrial cancer patients. Further investigation is needed on the clinical application of molecular classification to low-grade endometrial cancer.

DOI： 10.3390/diagnostics15060671

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Language：English   Publisher：John Wiley & Sons Australia, Ltd  

再発低リスクと術前に判定された子宮内膜癌患者においてセンチネルリンパ節(SLN)の同定に影響を及ぼす因子について検討した。当院で腹腔鏡下手術またはロボット支援手術を受け、フィチン酸テクネチウム99m(99mTc)を子宮頸部に注入してSLNの同定を図った子宮内膜癌患者97例(中央値54.0歳)を対象とした。Hot nodeの検出には術前SPECTと術中ガンマ線プローブを用い、SLNマッピング不良と関連する因子を探索した。SPECTによるSLN同定成功は47例、同定不良は50例、ガンマ線プローブによるSLN同定成功は71例、同定不良は26例であり、多重ロジスティック回帰分析では、SPECTによるSLN同定不良と年齢、ガンマ線プローブによるSLN同定不良と年齢およびBMIとの間にそれぞれ強い関連が認められた。SPECTによるSLN同定不良であった50例のうち、ガンマ線プローブによるSLN同定不良は23例(46%)であり、BMIとガンマ線プローブによる同定不良との間に有意な関連がみられた。高齢患者と肥満患者に対してSLNの検出能を向上させる必要があると考えられた。

Publisher：International Journal of Gynecological Pathology  

The administration of immune checkpoint inhibitors (ICIs) is increasing in endometrial cancer, especially in the mismatch repair (MMR)-deficient group. To prevent unnecessary immune-related adverse events, ICIs need to be administered to more appropriate patients. The tumor immune microenvironment has been reported to be a predictive marker of the efficacy of ICI therapies. This study evaluated CD8, FoxP3, CD68, PD-L1, and β-catenin expression in endometrial endometrioid carcinoma, grade 1 (G1) with DNA mismatch repair protein loss (MMR loss), and their association with clinicopathological features. We retrospectively analyzed tumor samples from 107 patients with endometrial endometrioid carcinoma, G1 (MMR-deficient group: n=67; MMR-proficient group: n=40). Overall, 47 cases of MLH1/PMS2 loss and 20 cases of MSH2/MSH6 loss were observed. The patients with low intraepithelial CD8 expression significantly more frequently exhibited deep myometrial invasion, and the elderly group (≥60 y) significantly more frequently showed low stromal CD8 expression. In addition, FoxP3-positive cell count and FoxP3/CD8+ ratio were significantly correlated with the International Federation of Obstetrics and Gynecology 2023 stage and lymph node metastasis. In the Kaplan-Meier analysis, the patients with low intraepithelial or stromal CD8 expression had shorter progression-free survival (PFS) than those with high intraepithelial or stromal CD8 expression, albeit not significantly. We clarified that the tumor immune microenvironment had an impact on clinicopathological features within the group with MMR loss, which is the main target for ICIs, limited to endometrioid carcinoma, G1. Further studies are needed, including on patients administered ICIs.

DOI： 10.1097/PGP.0000000000001020

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Language：English   Publisher：Cell Communication and Signaling  

Background: We previously identified Il17RB, a member of the IL17 superfamily, as a candidate marker gene for endometrial aging. While IL17RB has been linked to inflammation and malignancies in several organ systems, its function in the endometrium has not been investigated and is thus poorly understood. In the present study, we performed a functional analysis of this receptor with the aim of determining the effects of its age-associated overexpression on the uterine environment. Methods: We analyzed IL17RB-related signaling pathways and downstream gene expression in an immortalized human endometrial glandular epithelial cell line (“hEM”) forced to express the receptor via lentiviral transduction (“IL17RB-hEM”). We also prepared endometrial organoids from human endometrial tissue sourced from hysterectomy patients (“patient-derived EOs”) and exposed them to cytokines that are upregulated by IL17RB expression to investigate changes in organoid-forming capacity and senescence markers. We analyzed RNA-seq data (GEO accession number GSE132886) from our previous study to identify the signaling pathways associated with altered IL17RB expression. We also analyzed the effects of the JNK pathway on organoid-forming capacity. Results: Stimulation with interleukin 17B enhanced the NF-κB pathway in IL17RB-hEM, resulting in significantly elevated expression of the genes encoding the senescence associated secretory phenotype (SASP) factors IL6, IL8, and IL1β. Of these cytokines, IL1β inhibited endometrial organoid growth. Bioinformatics analysis showed that the JNK signaling pathway was associated with age-related variation in IL17RB expression. When IL17RB-positive cells were cultured in the presence of IL17B, their organoid-forming capacity was slightly but non-significantly lower than in unexposed IL17RB-positive cells, but when IL17B was paired with a JNK inhibitor (SP600125), it was restored to control levels. Further, IL1β exposure significantly reduced organoid-forming capacity and increased p21 expression in endometrial organoids relative to non-exposure (control), but when IL1β was paired with SP600125, both indicators were restored to levels comparable to the control condition. Conclusions: We have revealed an association between IL17RB, whose expression increases in the endometrial glandular epithelium with advancing age, and cellular senescence. Using human endometrial organoids as in vitro model, we found that IL1β inhibits cell proliferation and leads to endometrial senescence via the JNK pathway.

DOI： 10.1186/s12964-024-01740-5

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：シュプリンガー・ジャパン(株)  

症例は72歳女性、2妊2産であった。卵巣悪性腫瘍に対して52歳時に開腹子宮全摘術、両側卵管卵巣摘出術、大網切除術、骨盤リンパ節郭清術を施行され、最終診断はステージIaの成人型顆粒膜細胞腫(AGCT)であった。初回手術から19年後、他施設で受けたCTで後腹膜腫瘍が偶然発見された。腫瘍は直径11×10cmで、肝門部、下大静脈、右腎静脈が隆起していた。CTガイド下腫瘍生検によりAGCTの再発が確認された。腫瘍が巨大であり、完全切除を行うと出血多量による術中死亡のリスクがあると考えられた。そこで、パクリタキセル+カルボプラチン(PC)による術前化学療法を行い、再発腫瘍を縮小させた。その後、縮小手術を行った。再発腫瘍の完全切除に成功し、手術時間は12時間54分、出血量は700gであった。切除標本の病理所見からAGCTの再発と診断した。術後1年経過時点で再発は認められなかった。

Language：English  

DOI： 10.1007/s13691-024-00659-5

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Language：English   Publisher：Wiley  

Indocyanine green (ICG) with near-infrared (NIR) fluorescence imaging is used for lymphatic mapping. However, binding of ICG to blood proteins like serum albumin can shorten its retention time in sentinel lymph nodes (SLNs). Here, we investigated the efficacy and safety of a new fluorescence tracer comprising phytate and liposome (LP)-encapsulated ICG. Coadministration of phytate with LP containing phosphatidic acid promotes chelation mediated by Ca^<2+> in bodily fluids to enhance SLN retention. Uniformly sized LPs (100 nm) encapsulating ICG under conditions that minimized fluorescence self-quenching during storage were produced. We analyzed the behavior of the new tracer (ICG-phytate-LP) and control tracers (ICG and ICG-LP) in the lymphatic flow of mice in terms of lymph node retention time. We also tested lymphatic flow and safety in pigs that have a more human-like lymphatic system. LPs encapsulating stabilized ICG were successfully prepared. Mixing LP with phytate in the presence of Ca^<2+> increased both the particle size and negative surface charge. In mice, ICG-phytate-LP had the best lymph node retention, with a fluorescence intensity ratio that increased over 6 h and then decreased slowly over the next 24 h. In pigs, administration of ICG and ICG-phytate-LP resulted in no death or weight loss. There were no obvious differences between blood test results for the ICG and ICG-phytate-LP groups, and the overall safety was good. ICG-phytate-LP may be a useful new tracer for gynecological cancers that require time for lymph node identification due to a retroperitoneal approach.

DOI： 10.1111/cas.15927

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Language：English   Publisher：John Wiley & Sons Australia, Ltd  

センチネルリンパ節(SLN)を同定するためのトレーサーとして、リポソーム封入インドシアニングリーン(ICG)とフィチン酸塩で構成される新規な蛍光トレーサーを開発し、その有効性と安全性を調査した。まず、安定化したICGが封入されているリポソームを調製した。次にキレート反応が発揮されることを期待し、Ca2+の存在下でリポソームとフィチン酸塩を混和した。その結果、生成される粒子のサイズとその表面の陰電荷が共に増加した。このようにICG、リポソーム、フィチン酸塩を構成要素とした新規トレーサーがマウスのリンパ節内に滞留する時間を評価した。その結果、対照のトレーサー(ICGおよびリポソーム封入ICG)と比較して最も良好な滞留性を発揮した。その蛍光強度比は6時間かけて上昇し、次いで24時間かけて緩やかに低下していった。ブタで安全性評価を行ったが、本新規トレーサーを投与しても死亡または体重減少は発生しなかった。ICGのみ投与した場合との明確な違いも示されず、全安全性は良好であった。本新規トレーサーは、後腹膜アプローチのためリンパ節を同定する時間が必要になる婦人科癌で有用なものになると考えられた。

Language：English   Publisher：American Journal of Clinical Oncology Cancer Clinical Trials  

Objective: The aim of this study was to evaluate the progression-free survival (PFS) and overall response rate (ORR) of patients with recurrent endometrial cancer (REC) or advanced endometrial cancer (AEC) retreated with platinum-containing chemotherapy (PCC) based on the platinum-free interval (PFI). We compared our results with those reported in the KEYNOTE-775 study (that used pembrolizumab plus lenvatinib). Methods: A retrospective analysis was conducted of 65 patients with REC or AEC retreated with PCC between 2005 and 2020 at our hospital. Various clinicopathologic variables were analyzed: (1) age, (2) performance status, (3) histology, (4) history of pelvic irradiation in the adjuvant setting, (5) PFI, (6) chemotherapy regimen, (7) PFS and overall survival after retreatment with PCC, and (8) best ORR. Survival analyses were performed using Kaplan-Meier curves and log-rank tests. Results: The best ORR and PFS were 43.3% and 9.5 months, respectively, in patients with REC/AEC with a PFI ≥6 months. These results were comparable with those of patients treated with pembrolizumab and lenvatinib. The best ORR and PFS of patients with a PFI of <6 months appeared to be inferior to those of patients treated with pembrolizumab plus lenvatinib. Conclusions: Pembrolizumab plus lenvatinib seems to be a better treatment choice for patients with REC or AEC with a PFI of <6 months. For a PFI of ≥6 months, pembrolizumab plus lenvatinib or PCC can be used depending on the degree of residual side -effects associated with cytotoxic agents.

DOI： 10.1097/COC.0000000000001021

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

DOI： 10.3390/reports6020018

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Language：English   Publisher：Gynecologic Oncology  

Objective: This multicenter study aimed to evaluate the accuracy of the one-step nucleic acid amplification (OSNA) assay in diagnosing lymph node metastasis (LNM) in patients with cervical and endometrial cancers. Methods: Surgically removed LNs from patients with cervical and endometrial cancer were sectioned at 2-mm intervals along the short axis direction and alternately examined using the OSNA assay and conventional histopathological examination. Ultrastaging (200-μm LN sections) was performed for metastatic LNs using hematoxylin and eosin staining and immunostaining with an anti-CK19 antibody in cases where the OSNA assay and histopathological examination (performed using 2-mm LN sections) results showed discordance. Results: A total of 437 LNs from 133 patients were included; 61 patients (14%) showed metastasis by histopathological examination, with a concordance rate of 0.979 (95% confidence interval [CI]: 0.961–0.991) with the OSNA assay. The sensitivity and specificity of the OSNA assay were 0.918 (95% CI: 0.819–0.973) and 0.989 (95% CI: 0.973–0.997), respectively. Discordance between the two methods was observed in nine LNs (2.1%), and allocation bias of metastatic foci was identified as the major cause of discordance. Conclusions: The OSNA assay showed equally accurate detection of LN metastasis as the histopathological examination. We suggest that the OSNA assay may be a useful tool for the rapid intraoperative diagnosis of LN metastasis in patients with cervical and endometrial cancers.

DOI： 10.1016/j.ygyno.2022.12.016

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Cancer Gene Therapy  

Dysregulated G protein-coupled receptor signaling is involved in the formation and progression of human cancers. The heterotrimeric G protein Gα<inf>13</inf> is highly expressed in various cancers and regulates diverse cancer-related transcriptional networks and cellular functions by activating Rho. Herein, we demonstrate that increased expression of Gα<inf>13</inf> promotes cell proliferation through activation of Rho and the transcription factor AP-1 in human endometrial cancer. Of interest, the RhoGTPase activating protein (RhoGAP), ARHGAP35 is frequently mutated in human endometrial cancers. Among the 509 endometrial cancer samples in The Cancer Genome Atlas database, 108 harbor 152 mutations at 126 different positions within ARHGAP35, representing a somatic mutation frequency of 20.2%. We evaluated the effect of 124 tumor-derived ARHGAP35 mutations on Gα<inf>13</inf>-mediated Rho and AP-1 activation. The RhoGAP activity of ARHGAP35 was impaired by 55 of 124 tumor-derived mutations, comprised of 23 nonsense, 15 frame-shift, 15 missense mutations, and two in-frame deletions. Considering that ARHGAP35 is mutated in >2% of all tumors, it ranks among the top 30 most significantly mutated genes in human cancer. Our data suggest potential roles of ARHGAP35 as an oncogenic driver gene, providing novel therapeutic opportunities for endometrial cancer.

DOI： 10.1038/s41417-022-00547-1

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Language：English   Publisher：Asian Society of Gynecologic Oncology  

Objective: / To apply the International Federation of Gynecology and Obstetrics (FIGO) 2018 staging system to all patients who underwent trachelectomy in our previous study and to update the oncologic and obstetric results. / Methods: / We retrospectively reviewed the medical records of patients in whom abdominal trachelectomy was attempted between June 2005 and September 2021. The FIGO 2018 staging system for cervical cancer was applied to all patients. / Results: / Abdominal trachelectomy was attempted for 265 patients. Trachelectomy was converted to hysterectomy in 35 patients, and trachelectomy was completed successfully in 230 (conversion rate: 13%). Applying the FIGO 2018 staging system, 40% of the patients who underwent radical trachelectomy had stage IA tumors. Among 71 patients who had tumors measuring ≥2 cm, 8 patients were classified as stage IA1 and 14 as stage IA2. Overall recurrence and mortality rates were 2.2% and 1.3%, respectively. One hundred twelve patients attempted to conceive after trachelectomy; 69 pregnancies were achieved in 46 patients (pregnancy rate: 41%). Twenty-three pregnancies ended in first-trimester miscarriage, and 41 infants were delivered between gestational weeks 23 and 37; 16 were deliveries at term (39%) and 25 were premature deliveries (61%). / Conclusion: / This study suggested that patients judged to be ineligible for trachelectomy and patients receiving overtreatment will continue to appear using the current standard eligibility criteria. With the revisions to the FIGO 2018 staging system, the preoperative eligibility criteria for trachelectomy, which were based on the FIGO 2009 staging system and tumor size, should be changed.

DOI： 10.3802/jgo.2023.34.e41

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Language：Japanese   Publisher：福岡産科婦人科学会  

症例は76歳、3妊3産。不正性器出血を主訴に前医を受診し、子宮内膜肥厚を認め、精査加療目的に当科を紹介受診した。当科の子宮内膜全面掻爬にて子宮内膜異型増殖症の診断で、全腹腔鏡下単純子宮全摘出術+両側付属器摘出術を施行した。最終診断は子宮体癌IA期、類内膜癌G1の診断で、再発低リスク群であり、追加治療は施行せず経過観察とした。2年後の造影CT検査で大網左側に結節状の軟部陰影と周囲脂肪織混濁を認め再発が疑われた。CTガイド下生検を施行し、病理組織検査で非特異的な炎症所見を認めるのみで、悪性所見は認めなかった。更に1年後のCTで軟部陰影は増大傾向であり、子宮体癌再発の可能性も否定できず、診断確定目的に大網部分切除術を施行した。最終病理組織診断の結果は放線菌症の診断であった。放線菌症は悪性腫瘍との鑑別が難しいため、非典型的な臨床経過の場合は放線菌感染も鑑別の一つとして念頭においておくべきと思われた。(著者抄録)

Language：English   Publisher：John Wiley & Sons Australia, Ltd  

ロボット支援手術が施行された子宮内膜癌患者63例を対象とした後向きコホート研究を実施し、肥満がロボット支援手術の安全性および質に及ぼす影響について検討した。患者を非肥満群40例(BMI:30未満、中央値54歳)、肥満群13例(BMI:30以上35未満、中央値54歳)、病的肥満10例(BMI;35以上、中央値50歳)に分類した。評価項目は手術時間、出血量、周術期合併症、再発率とした。その結果、開腹術への移行は非肥満群1例、病的肥満群1例であった。総手術時間、セッティング時間(トロッカー留置、ダヴィンチロボットドッキングを含む)、コンソール時間、創部閉鎖時間に群間差は認められなかったが、セッティングおよび創部閉鎖の合計時間に群間差が認められた。出血量や合併症には群間差が認められた。非肥満群3例、肥満群2例に対して、術後補助療法が実施されたが、平均観察期間21ヵ月において再発は認められなかった。非肥満群2例、肥満群1例が平均観察期間38ヵ月に再発していた。以上から、肥満を呈する子宮内膜癌患者に対するロボット支援手術の安全性が示された。

Language：English   Publishing type：Research paper (scientific journal)   Publisher：(公社)宮崎県医師会  

動脈-腸管瘻は消化管出血の原因としてはまれであるが,初発症状が致死性の大量出血の場合もある緊急性の高い疾患である。症例は44歳,9妊7産,子宮頸癌IB3期(扁平上皮癌)に対して広汎子宮全摘出術,両側付属器摘出術,術後補助療法として同時化学放射線療法を施行した。治療終了6ヵ月後に骨盤内再発を認め,全身化学療法を施行したが奏効しなかった。MSI検査の結果,MSI-highであったためペムブロリズマブ療法を開始した。腫瘍の著明な縮小を認め,4コース後の治療効果判定はPRであった。ペムブロリズマブ療法4コース目day7,当科入院中に突然,多量の下血,意識レベルの低下を認めた。緊急造影CTの結果,左内腸骨動脈からS状結腸への造影剤の漏出を認め,左内腸骨動脈-S状結腸瘻と診断した。直ちに左内腸骨動脈塞栓術を施行し止血した。発症から止血まで3時間の間に赤血球32単位,新鮮凍結血漿28単位,血小板10単位の輸血を要した。(著者抄録)

Language：English   Publishing type：Research paper (scientific journal)   Publisher：Taiwanese Journal of Obstetrics and Gynecology  

Objective: Recent randomized phase III trial has shown significant benefit in overall survival (OS) for patients with advanced cervical cancer by adding bevacizumab to conventional chemotherapy. The aim of this study was to evaluate the prognostic impact for Japanese recurrent, persistent, or metastatic cervical cancer patients where bevacizumab was added to paclitaxel plus carboplatin. Materials and methods: A retrospective analysis was performed on 90 patients with recurrent, persistent, or metastatic cervical cancer mainly treated by paclitaxel plus carboplatin between 2005 and 2019 at our hospital. Data for the following clinicopathological variables were analyzed: (1) bevacizumab use; (2) histology; (3) disease presentation; (4) performance status; (5) prior chemotherapy containing platinum agent; (6) pelvic disease; (7) prior pelvic radiotherapy; (8) location of target lesions. Survival analysis was performed using Kaplan–Meier curves, log-rank tests, Wilcoxon tests, and Cox proportional hazards models combined with propensity score matching. Results: Adding bevacizumab to paclitaxel plus carboplatin showed significantly increased complete response to compared with that of non-users. In a Cox regression hazard model, bevacizumab use tended to show better OS though without statistically significance. After propensity score matching, adding bevacizumab to paclitaxel plus carboplatin showed a significant better OS by univariate analysis using Wilcoxon test, not by log-rank test. Conclusion: Adding bevacizumab to paclitaxel plus carboplatin showed a limited prognostic impact for recurrent, persistent or advanced cervical cancer patients in the real world. Further effective second-line treatments are needed to prolong OS of patients with recurrent, persistent or advanced cervical cancer.

DOI： 10.1016/j.tjog.2022.06.005

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PubMed

Language：English   Publisher：Pathology Research and Practice  

Cyclin-dependent kinase 8 (CDK8) is associated with the transcriptional mediator complex and regulates several transcription factors implicated in cancer. CDK8 expression is a poor prognostic marker in colon and breast cancer by immunohistochemistry. However, somatic mutations in exon 2 of the RNA polymerase II transcriptional mediator subunit MED12 occur in 7–30% of cases of uterine leiomyosarcoma (ULMS), suggesting that these alterations contribute to tumorigenesis. Public genomic mutation data of 80 patients with ULMS were used for MED12 and CDK8 mutation analysis. The expression of MED12, CDK8 and β-catenin was evaluated by immunohistochemistry in our cohort of 60 patients with ULMS, in addition with MED12 mutation status and survival stage. Univariate analysis was performed using the log-rank test, and Cox regression was used to identify independent prognostic factors. Multivariate Cox regression analysis revealed that advanced stage (p < 0.0001) and high CDK8 expression (p = 0.0014) were independent predictors of poor prognosis. MED12 mutation status was not significantly associated with CDK8 expression (p = 0.6873) and DSS (p = 0.8075). In conclusion, our data suggest that CDK8 expression may identify a subset of ULMS patients with a poor prognosis.

DOI： 10.1016/j.prp.2022.153920

Web of Science

Scopus

PubMed

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

Objective: Sentinel node biopsy alone (SNB) reduces the postoperative complications of pelvic lymphadenectomy, such as lymphedema and lymphangitis; however, the long-term prognosis after SNB is unclear. The objective of this study was to evaluate the long-term outcome and complications of patients with early-stage cervical cancer who underwent SNB for hysterectomy or trachelectomy. Methods: We performed SNB for cervical cancer using a radioisotope method in 181 patients between 2009 and 2017. If the intraoperative sentinel lymph node evaluation was negative for metastasis, no further lymph nodes were removed. Results: The median age of the patients was 34 years (range, 21–73 years). The International Federation of Gynecology and Obstetrics 2008 stage was IA1 in 6 patients, IA2 in 18, IB1 in 154, and IIA1 in 3. Of the 181 patients (44 with hysterectomy, 137 with trachelectomy), 8 did not undergo pelvic lymphadenectomy because of a false-negative intraoperative diagnosis, 20 received adjuvant therapy after surgery, and 4 (2.2%) experienced recurrence over a median follow-up period of 83.5 months (range, 25–145 months). In the four recurrent cases, recurrence occurred in the pelvis, lung, and bone in one patient each, while the remaining patient developed pelvic and para-aortic lymph node metastases. Of these four patients, one died, and the remaining three are alive without disease after multidisciplinary therapy. The 5-year progression-free and overall survival rates were 98.8% and 99.4%, respectively. Postoperative complications, such as lymphedema, were very low rate. Conclusions: SNB for early-stage cervical cancer might be safe and effective, with no increase in the recurrence and postoperative complications rate.

DOI： 10.1016/j.ygyno.2022.01.031

Web of Science

Scopus

PubMed

Language：English   Publisher：Oncology Switzerland  

Introduction: The prognostic significance of lymphovascular space invasion (LVSI) in stage IA endometrial cancer remains unclear. The aim of this study was to evaluate the clinical significance of LVSI in stage IA endometrial cancer. Methods: Clinical data of patients with stage IA endometrial cancer who underwent initial surgery at our institution between January 2008 and December 2018 were reviewed retrospectively. Information of patients, surgery, and characteristics of cancer were obtained from medical records and pathological reports. Results: Two hundred ninety-seven patients were enrolled in this study. With a median follow-up of 60 months, 15 patients experienced recurrence (5.1%) and 4 patients died of endometrial cancer (1.3%). The recurrence and mortality rates did not differ significantly between the LVSI-positive and-negative groups (p = 0.07 and p = 0.41, respectively). Recurrence-free survival and endometrial cancer-specific survival also did not differ significantly between these groups (p = 0.11 and p = 0.49, respectively). The 5-year endometrial cancer-specific survival rates for tumors with and without LVSI were 97.0% and 98.9%, respectively. Among patients with low-grade tumors, recurrence-free survival and endometrial cancer-specific survival did not differ significantly between patients with tumors with and without LVSI (p = 0.92 and p = 0.72, respectively). The 5-year endometrial cancer-specific survival rates for low-grade tumors with and without LVSI were 100% and 99.3%, respectively. Conclusion: LVSI was not a prognostic factor of not only stage IA endometrial cancer but also stage IA low-grade cancer.

DOI： 10.1159/000521382

Web of Science

Scopus

PubMed

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

DOI： 10.1007/s10147-020-01848-x

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

DOI： 10.1111/jog.14680

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

DOI： 10.1007/s10147-021-01908-w

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

DOI： 10.1093/molehr/gaaa078

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

DOI： 10.1038/s41598-021-83200-5

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

DOI： 10.1186/s12885-021-07875-9

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

DOI： 10.1007/s10147-020-01778-8

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

DOI： 10.1371/journal.pone.0241482

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

DOI： 10.1002/ijc.32965

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

DOI： 10.1159/000508569

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

DOI： 10.1093/biolre/ioaa044

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

DOI： 10.1096/fj.201901278R

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

Aim: To evaluate how the desire to have children and engage in sexual activity change after trachelectomy in Japanese women with early-stage cervical cancer who strongly desired to have children before surgery. Methods: Desire to have children, coital pain, fear of sexual intercourse, sexual activity frequency and libido were assessed in cervical cancer patients who received follow-up after trachelectomy. An anonymous questionnaire survey was conducted via informed consent. Results: Of the 151 patients who underwent trachelectomy at Kyushu University Hospital between 2005 and 2015, 46 patients were evaluated; the response rate was 30%. The desire to have children disappeared in 13 of 46 (28%) patients, and 14 (30%) patients experienced increased coital pain. Moreover, 19 (41%) patients experienced fear of sexual intercourse, and sexual frequency decreased in 24 (52%) patients. Conclusion: Trachelectomy is an important fertility-sparing surgical method; however, this study revealed loss of the desire to have children and/or to engage in sexual activity in some patients after surgery. Counseling about these issues is important and should be addressed.

DOI： 10.1111/jog.14099

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

Although fibrosis is one of the most prominent pathologic features of preeclamptic (PE) placentas, its mechanism remains largely unknown. Consistent with previous reports, we observed overexpression of collagen; actin, α2, smooth muscle, aorta; connective tissue growth factor; and fibronectin in PE placentas compared with control ones. To investigate the mechanism of fibrosis in PE placentas, placental fibroblasts were isolated from PE placentas or normal pregnancies at delivery. The expression of fibrosis-related factors in fibroblasts was evaluated by real-time RT-PCR, Western blotting, enzyme-linked immunosorbent assay, and gene microarrays. An in vitro collagen gel contraction assay was also performed. Fibroblasts isolated from PE placentas showed higher expression levels of fibrosis-related factors compared with those from control ones. Global gene expression profiling of PE fibroblasts was contrasted with that of control ones and indicated an intimate association with transforming growth factor-β1 (TGFB1) signaling. Furthermore, the PE fibroblasts expressed abundant phosphorylated SMAD family member 2 and showed higher expression levels of target genes of TGFB1 signaling compared with the control ones. The PE fibroblasts also had a greater ability to contract compared with the control ones. Contractility also depended on TGFB1 signaling. Our results suggest that TGFB1 signaling is activated in the fibroblasts in PE placentas and that these active fibroblasts contribute to fibrosis.

DOI： 10.1016/j.ajpath.2017.11.008

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

FBXW7 is a ubiquitin ligase that mediates ubiquitylation of oncoproteins, such as c-Myc, cyclin E, Notch and c-Jun. FBXW7 is a known tumor-suppressor gene, and mutations in FBXW7 have been reported in various human malignancies. In this study, we examined the sequences of the FBXW7 and p53 genes in 57 ovarian cancer clinical samples. Interestingly, we found no FBXW7 mutations associated with amino acid changes. We also investigated FBXW7 expression levels in 126 epithelial ovarian tumors. FBXW7 expression was negatively correlated with the malignant potential of ovarian tumors. That is to say, FBXW7 expression levels in ovarian cancer samples were significantly lower than those in borderline and benign tumors (P < 0.01). FBXW7 expression levels in serous carcinoma samples were the lowest among four major histological subtypes. In addition, p53-mutated ovarian cancer samples showed significantly lower levels of FBXW7 expression compared with p53 wild-type cancer samples (P < 0.001). DNA methylation arrays and bisulfite PCR sequencing experiments revealed that 5′-upstream regions of FBXW7 gene in p53-mutated samples were significantly higher methylated compared with those in p53 wild-type samples (P < 0.01). This data indicates that p53 mutations might suppress FBXW7 expression through DNA hypermethylation of FBXW7 5′-upstream regions. Thus, FBXW7 expression was downregulated in ovarian cancers, and was associated with p53 mutations and the DNA methylation status of the 5′-upstream regions of FBXW7.

DOI： 10.1111/cas.13026

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

G-protein-coupled receptors (GPCRs) and their ligands function in the progression of human malignancies. G₁₂ and G₁₃, encoded by GNA12 and GNA13, respectively, are referred to as the GEP oncogene and are implicated in tumor progression. However, the molecular mechanisms by which G_12/13 activation promotes cancer progression are not fully elucidated. Here, we demonstrate elevated expression of G_12/13 in human ovarian cancer tissues. G_12/13 activation did not promote cellular migration in the ovarian cancer cell lines examined. Rather, G_12/13 activation promoted cell growth. We used a synthetic biology approach using chimeric G proteins and GPCRs activated solely by artificial ligands to selectively trigger signaling pathways downstream of specific G proteins. We found that G_12/13 promotes proliferation of ovarian cancer cells by activating the transcriptional coactivator YAP, a critical component of the Hippo signaling pathway. Furthermore, we reveal that inhibition of YAP by short hairpin RNA or a specific inhibitor prevented the growth of ovarian cancer cells. Therefore, YAP may be a suitable therapeutic target in ovarian cancer.

DOI： 10.1038/onc.2015.505

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

Background: Although several studies have demonstrated the tumor suppressive function of CNN1 (calponin 1), no studies have performed a site-specific analysis of CNN1 on tumor cell activities. Materials and Methods: We herein studied the site-specific effects of CNN1 in ovarian cancer cells using full-length CNN1 (fCNN1), three CNN1 repeats (3CNRs), or the first CNN1 repeat (CNR1) expression vectors. Ovarian cancer cells stably expressing each construct were analyzed for in vitro proliferation, cell motility, invasion, and soft agar assays. An in vitro model of pleural dissemination was also established. Results: Cell proliferation, anchorageindependent colony formation, cell motility, and cell invasion were all suppressed in fCNN1, 3CNRs, and CNR1-stably-expressing cells. CNN1 expression in mesothelial cells suppressed cancer cell invasion into a monolayer of mesothelial cells. Conclusion: CNR1 showed similar suppressive effects as fCNN1. Results suggest CNR1 as a potential small synthetic peptide candidate for therapeutic strategies against ovarian cancer.

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

Background: The functional single nucleotide polymorphism (SNP) in the MDM2 promoter region, SNP309, is known to be associated with various diseases, particularly cancer. Although many studies have been performed to demonstrate the mechanism of allele-specific expression (ASE) on SNP309, they have only utilized in vitro techniques. It is unknown whether ASE of MDM2 is ascribed solely to SNP309, in vivo. Methods: We attempted to evaluate ASE of MDM2 in vivo using post-labeling followed by automated capillary electrophoresis under single-strand conformation polymorphism conditions. For measuring a quantitative difference, we utilized the SNPs on the exons of MDM2 as markers, the status of which was heterozygous in a large population. To address the cause of ASE beyond 20 %, we confirmed sequences of both MDM2-3'UTR and promoter regions. We assessed the SNP which might be the cause of ASE using biomolecular interaction analysis and luciferase assay. Results: ASE beyond 20 % was detected in endometrial cancers, but not in cancer-free endometria samples only when an SNP rs1690916 was used as a marker. We suspected that this ASE in endometrial cancer was caused by the sequence heterogeneity in the MDM2-P2 promoter, and found a new functional polymorphism, which we labelled SNP55. There was no difference between cancer-free endometria and endometrial cancer samples neither for SNP55 genotype frequencies nor allele frequencies, and so, SNP55 alone does not affect endometrial cancer risk. The SNP55 status affected the DNA binding affinity of transcription factor Sp1 and nuclear factor kappa-B (NFκB). Transcriptional activity of the P2 promoter containing SNP55C was suppressed by NFκB p50 homodimers, but that of SNP55T was not. Only ASE-positive endometrial cancer samples displayed nuclear localization of NFκB p50. Conclusions: Our findings suggest that both the SNP55 status and the NFκB p50 activity are important in the transcriptional regulation of MDM2 in endometrial cancers.

DOI： 10.1186/s12881-015-0216-8

Language：English  

DOI： 10.1016/j.toxlet.2014.11.025

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

Tssc3 is a maternally expressed/paternally silenced imprinted gene. Recent evidence suggests that the loss of TSSC3 results in placental overgrowth in mice. These findings showed that the TSSC3 gene functions as a negative regulator of placental growth. In this study, we describe the function of TSSC3 and its signaling pathway in mouse trophoblast stem (TS) cell differentiation. First of all, we tested Tssc3 expression levels in TS cells. TS cells expressed Tssc3, and its expression level was the highest from day 1 to 4 but was down-regulated at day 5 after the induction of differentiation. Overexpression of TSSC3 in TS cells up-regulated Gcm1 and Mash2, which are marker genes of mouse trophoblast differentiation. Down-regulation of TSSC3 by siRNA enhanced Pl1 and Tpbpa expression in TS cells cultured under stem cell conditions, suggesting the contribution of TSSC3 to the differentiation from TS to trophoblast progenitors and/or labyrinth trophoblasts. TSSC3 activated the PI3K/AKT pathway through binding with phosphatidylinositol phosphate lipids and enhanced the activity of a promoter containing an E-box structure, which is the binding sequence of the Mash2 downstream target gene promoter. PI3K inhibitor suppressed the promoter activity induced by TSSC3. TSSC3 induced Sp1 translocation from cytoplasm to nucleus through the PI3K/AKT pathway. Nuclear Sp1 activated the Mash2 transcription by Sp1 binding with a consensus Sp1-binding motif. This is the first report describing that TSSC3 plays an important role in the differentiation from TS to trophoblast progenitors and/or labyrinth trophoblasts through the TSSC3/PI3K/AKT/MASH2 signaling pathway.

DOI： 10.1074/jbc.M112.388777

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

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

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

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

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

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

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

DOI： 10.1097/01.pas.0000162757.91649.a3

Language：English   Publishing type：Research paper (international conference proceedings)  

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

DOI： 10.1016/j.ygyno.2004.07.050

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

DOI： 10.1006/geno.2002.6860

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

DOI： 10.1054/bjoc.1999.0943

Event date： 2021.5

Language：English   Presentation type：Oral presentation (general)  

Venue：米子   Country：Japan  

Event date： 2021.5

Language：English   Presentation type：Symposium, workshop panel (public)  

Venue：広島   Country：Japan  

Event date： 2021.5

Language：English   Presentation type：Oral presentation (general)  

Country：Japan  

Event date： 2021.5

Language：English   Presentation type：Oral presentation (general)  

Venue：Kyoto   Country：Japan  

Event date： 2021.5

Language：English   Presentation type：Oral presentation (general)  

Venue：名古屋   Country：Japan  

Event date： 2021.5

Language：Japanese   Presentation type：Symposium, workshop panel (public)  

Venue：東京   Country：Japan  

Event date： 2021.5

Language：English   Presentation type：Oral presentation (general)  

Venue：仙台   Country：Japan  

Event date： 2013.7

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：東京   Country：Japan  

Event date： 2013.7

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：奈良   Country：Japan  

Event date： 2013.5

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：札幌   Country：Japan  

Event date： 2012.4

Presentation type：Oral presentation (general)  

Venue：神戸   Country：Japan  

Event date： 2011.8

Presentation type：Oral presentation (general)  

Venue：Osaka   Country：Japan  

Event date： 2011.2

Presentation type：Oral presentation (general)  

Venue：Kansas City   Country：United States  

Other Link： http://www2.kumc.edu/crs/greenwald/index.html

Event date： 2010.9 - 2010.10

Presentation type：Oral presentation (general)  

Venue：熊本市   Country：Japan  

Event date： 2008.6 - 2011.6

Presentation type：Oral presentation (general)  

Venue：Philadelphia   Country：United States  

Other Link： http://www.isscr.org/

Presentation type：Oral presentation (general)  

Venue：大分   Country：Japan  

Presentation type：Oral presentation (general)  

Venue：佐賀市   Country：Japan  

Presentation type：Oral presentation (general)  

Venue：東京   Country：Japan  

Presentation type：Oral presentation (general)  

Venue：佐賀   Country：Japan  

Presentation type：Oral presentation (general)  

Venue：大分   Country：Japan  

Presentation type：Oral presentation (general)  

Venue：徳島   Country：Japan  

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Venue：福岡   Country：Japan  

Presentation type：Oral presentation (general)  

Venue：Singapore   Country：Singapore  

Presentation type：Oral presentation (general)  

Venue：神戸   Country：Japan  

Presentation type：Oral presentation (general)  

Venue：久留米   Country：Japan  

Presentation type：Oral presentation (general)  

Venue：大阪   Country：Japan  

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Venue：東京   Country：Japan  

Presentation type：Oral presentation (general)  

Venue：岐阜   Country：Japan  

Presentation type：Oral presentation (general)  

Venue：福岡   Country：Japan  

Presentation type：Oral presentation (general)  

Venue：Boston, MA   Country：United States  

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Venue：東京   Country：Japan  

Presentation type：Oral presentation (general)  

Venue：東京   Country：Japan  

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Venue：京都   Country：Japan  

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Venue：富山   Country：Japan  

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Venue：横浜   Country：Japan  

Presentation type：Oral presentation (general)  

Venue：横浜   Country：Japan  

Presentation type：Oral presentation (general)  

Venue：京都   Country：Japan  

Language：English  

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Language：English   Presentation type：Oral presentation (general)  

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Language：English   Presentation type：Oral presentation (general)  

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Language：English   Presentation type：Oral presentation (general)  

Language：Japanese   Presentation type：Oral presentation (general)  

Language：English   Presentation type：Oral presentation (general)  

Language：English   Presentation type：Oral presentation (general)  

Language：English   Presentation type：Oral presentation (general)  

Language：English   Presentation type：Oral presentation (general)  

Language：English   Presentation type：Oral presentation (general)  

Language：English   Presentation type：Oral presentation (general)  

Language：Japanese   Presentation type：Oral presentation (general)  

Language：Japanese   Presentation type：Oral presentation (general)  

Language：Japanese   Presentation type：Oral presentation (general)  

Language：Japanese   Presentation type：Oral presentation (general)  

Language：English   Presentation type：Oral presentation (general)  

Language：Japanese   Presentation type：Oral presentation (general)  

Language：English   Presentation type：Oral presentation (general)  

Language：Japanese   Presentation type：Oral presentation (general)  

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Language：Japanese   Presentation type：Oral presentation (general)  

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Language：Japanese   Presentation type：Symposium, workshop panel (public)  

DOI： 10.18888/sp.0000003244

CiNii Research

Language：Japanese   Presentation type：Oral presentation (general)  

Language：Japanese   Presentation type：Oral presentation (general)  

Language：Japanese   Presentation type：Oral presentation (general)  

Language：English   Presentation type：Oral presentation (general)  

Language：English   Presentation type：Oral presentation (general)  

Web of Science

Language：English   Publishing type：Meeting report  

Web of Science

Language：English  

Web of Science

Language：English   Publishing type：Article, review, commentary, editorial, etc. (scientific journal)  

Language：English   Publishing type：Article, review, commentary, editorial, etc. (scientific journal)  

Language：Japanese   Publishing type：Article, review, commentary, editorial, etc. (scientific journal)  

Language：Japanese   Publishing type：Article, review, commentary, editorial, etc. (scientific journal)  

Type：Peer review 

Number of peer-reviewed articles in foreign language journals：3

Type：Peer review 

Number of peer-reviewed articles in foreign language journals：1