Web of Science

記述言語：英語   出版者・発行元：John Wiley & Sons Australia, Ltd  

出版者・発行元：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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記述言語：英語   出版者・発行元：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。

記述言語：英語  

DOI： 10.1007/s13691-024-00659-5

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PubMed

記述言語：英語   出版者・発行元：Journal of Biological Chemistry  

BHLHE40 is a basic helix-loop-helix transcription factor that is involved in multiple cell activities including differentiation, cell cycle, and epithelial-to-mesenchymal transition. While there is growing evidence to support the functions of BHLHE40 in energy metabolism, little is known about the mechanism. In this study, we found that BHLHE40 expression was downregulated in cases of endometrial cancer of higher grade and advanced disease. Knockdown of BHLHE40 in endometrial cancer cells resulted in suppressed oxygen consumption and enhanced extracellular acidification. Suppressed pyruvate dehydrogenase (PDH) activity and enhanced lactated dehydrogenase (LDH) activity were observed in the knockdown cells. Knockdown of BHLHE40 also led to dephosphorylation of AMPKα Thr172 and enhanced phosphorylation of pyruvate dehydrogenase E1 subunit alpha 1 (PDHA1) Ser293 and lactate dehydrogenase A (LDHA) Tyr10. These results suggested that BHLHE40 modulates PDH and LDH activity by regulating the phosphorylation status of PDHA1 and LDHA. We found that BHLHE40 enhanced AMPKα phosphorylation by directly suppressing the transcription of an AMPKα-specific phosphatase, PPM1F. Our immunohistochemical study showed that the expression of BHLHE40, PPM1F, and phosphorylated AMPKα correlated with the prognosis of endometrial cancer patients. Because AMPK is a central regulator of energy metabolism in cancer cells, targeting the BHLHE40‒PPM1F‒AMPK axis may represent a strategy to control cancer development.

DOI： 10.1016/j.jbc.2024.105695

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記述言語：英語   出版者・発行元：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 Ca2+ 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 Ca2+ 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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CiNii Research

記述言語：英語   出版者・発行元：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。

記述言語：英語   出版者・発行元：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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記述言語：英語   出版者・発行元：Life Science Alliance  

Ubiquitin-like with PHD and RING finger domains 1 (UHRF1) is a protein essential for the maintenance of DNA methylation in somatic cells. However, UHRF1 is predominantly localized in the cytoplasm of mouse oocytes and preimplantation embryos, where it may play a role unrelated to the nuclear function. We herein report that oocyte-specific Uhrf1 KO results in impaired chromosome segregation, abnormal cleavage division, and preimplantation lethality of derived embryos. Our nuclear transfer experiment showed that the phenotype is attributable to cytoplasmic rather than nuclear defects of the zygotes. A proteomic analysis of KO oocytes revealed the down-regulation of proteins associated with microtubules including tubulins, which occurred independently of transcriptomic changes. Intriguingly, cytoplasmic lattices were disorganized, and mitochondria, endoplasmic reticulum, and components of the subcortical maternal complex were mislocalized. Thus, maternal UHRF1 regulates the proper cytoplasmic architecture and function of oocytes and preimplantation embryos, likely through a mechanism unrelated to DNA methylation.

DOI： 10.26508/lsa.202301904

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DOI： 10.3390/reports6020018

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出版者・発行元：金原出版  

DOI： 10.18888/sp.0000002454

CiNii Research

Web of Science

記述言語：英語   出版者・発行元：Cancer Gene Therapy  

Dysregulated G protein-coupled receptor signaling is involved in the formation and progression of human cancers. The heterotrimeric G protein Gα13 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 Gα13 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 Gα13-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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Web of Science

記述言語：日本語   出版者・発行元：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)

記述言語：英語   出版者・発行元：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

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