記述言語：英語   出版者・発行元：International Journal of Oncology  

Colorectal cancer (CRC) is widely prevalent and represents a significant contributor to global cancer‑related mortality. There remains a pressing demand for advance‑ ments in CRC treatment modalities. The E3 ubiquitin ligase is a critical enzyme involved in modulating protein expression levels via posttranslational ubiquitin‑mediated proteolysis, and it is reportedly involved in the progression of various cancers, making it a target of recent interest in anticancer therapy. In the present study, using comprehensive expression analysis involving spatial transcriptomic analysis with single‑cell RNA sequencing in clinical CRC datasets, the ubiquitin‑associated protein Shank‑associated RH domain interactor (SHARPIN) was identified, located on amplified chromosome 8q, which could promote CRC progression. SHARPIN was found to be upregulated in tumor cells, with elevated expression observed in tumor tissues. This heightened expression of SHARPIN was positively associated with lymphatic invasion and served as an independent predictor of a poor prognosis in patients with CRC. In vitro and in vivo analyses using SHARPIN‑overexpressing or ‑knockout CRC cells revealed that SHARPIN overexpression upregulated MDM2, resulting in the downregulation of p53, while SHARPIN silencing or knockout downregulated MDM2, leading to p53 upregulation, which affects cell cycle progression, tumor cell apoptosis and tumor growth in CRC. Furthermore, SHARPIN was found to be overexpressed in several cancer types, exerting significant effects on survival outcomes. In conclusion, SHARPIN represents a newly identified novel gene with the potential to promote tumor growth following apoptosis inhibition and cell cycle progression in part by inhibiting p53 expression via MDM2 upregulation; therefore, SHARPIN represents a potential therapeutic target for CRC.

DOI： 10.3892/ijo.2024.5701

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記述言語：英語  

DOI： 10.1186/s40792-024-02033-2

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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23歳女性で、左乳房の腫瘤を自覚しており、他院で受けたコア針生検で乳癌の診断が確定したため、精査加療目的で当院を受診した。家族歴や既往歴に特記すべき点はなかった。マンモグラフィー、乳房超音波検査、乳房MRIの臨床画像に基づき乳癌と診断し、生検標本の組織学的所見は粘表皮癌であった。このため左乳房全摘出術とセンチネルリンパ節生検を実施したが、センチネルリンパ節に癌細胞は存在しなかった。HE染色では、好酸性細胞質や特徴を有する軽度異型核を伴う扁平上皮様新生腫瘍細胞増殖が明らかとなり、免疫組織化学的には扁平上皮様細胞はp63に対してび漫性に陽性、核内のS-100タンパク質およびpan-TRKには陰性であった。さらに特定の融合遺伝子CRTC3-MAML2が逆転写PCRと直接配列決定で検出されたことから、低悪性度の粘表皮癌と診断した。切除断端に腫瘍細胞は存在せず、術後タモキシフェン療法を開始した。38ヵ月間の経過観察中に再発の徴候は見られていない。

DOI： 10.1016/j.annonc.2024.07.574

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記述言語：英語  

DOI： 10.1111/1759-7714.15444

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記述言語：英語  

DOI： 10.1007/s13691-024-00713-2

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記述言語：英語   出版者・発行元：(一社)日本外科学会  

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

血漿中の微量な循環腫瘍DNA(ctDNA)のメチル化を検出することによりステージIIIの大腸癌患者の術後の微小残存病変(MRD)をモニターできるか評価した。公開データベースを解析し、FGD5、GPC6、MSC遺伝子のメチル化されたプロモーター領域を同定した。デジタルPCRを用いた特異的酵素を用いたメチル化部位のアンプリコンアッセイを「AMUSE」と名付けた。病理学的ステージIIIの大腸癌再発患者28例および無再発患者19例それぞれの術前術後の連続血漿検体、180検体および114検体を調べた。その結果、再発患者28例中22例がAMUSE陽性(感度78.6%)、無再発患者19例中17例がAMUSE陰性(特異度89.5%)であった。AMUSEはX線画像診断による従来の診断より208日早く再発を予測した。反応性応答による術後補助化学放射線療法(ACT)評価に関しては、2回目または3回目の採血でAMUSE陽性の患者19例は、他の患者より有意に予後不良であった。AMUSEアッセイにより、術後の腫瘍負荷の変化パターンによって4群に層別化された。以上より、AMUSEアッセイは、正確なMRDモニタリングに対する臨床的ニーズに対応し、普遍的な適用性、最小限の侵襲性、費用対効果により、タイムリーな再発の発見を可能にすることが示唆された。

記述言語：英語   出版者・発行元：Cancer Science  

Considering the cost and invasiveness of monitoring postoperative minimal residual disease (MRD) of colorectal cancer (CRC) after adjuvant chemoradiotherapy (ACT), we developed a favorable approach based on methylated circulating tumor DNA to detect MRD after radical resection. Analyzing the public database, we identified the methylated promoter regions of the genes FGD5, GPC6, and MSC. Using digital polymerase chain reaction (dPCR), we termed the “amplicon of methylated sites using a specific enzyme” assay as “AMUSE.” We examined 180 and 114 pre- and postoperative serial plasma samples from 28 recurrent and 19 recurrence-free pathological stage III CRC patients, respectively. The results showed 22 AMUSE-positive of 28 recurrent patients (sensitivity, 78.6%) and 17 AMUSE-negative of 19 recurrence-free patients (specificity, 89.5%). AMUSE predicted recurrence 208 days before conventional diagnosis using radiological imaging. Regarding ACT evaluation by the reactive response, 19 AMUSE-positive patients during their second or third blood samples showed a significantly poorer prognosis than the other patients (p = 9E-04). The AMUSE assay stratified four groups by the altered patterns of tumor burden postoperatively. Interestingly, only 34.8% of cases tested AMUSE-negative during ACT treatment, indicating eligibility for ACT. The AMUSE assay addresses the clinical need for accurate MRD monitoring with universal applicability, minimal invasiveness, and cost-effectiveness, thereby enabling the timely detection of recurrences. This assay can effectively evaluate the efficacy of ACT in patients with stage III CRC following curative resection. Our study strongly recommends reevaluating the clinical application of ACT using the AMUSE assay.

DOI： 10.1111/cas.16149

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記述言語：英語   出版者・発行元：Cancer Science  

Bromodomain and extraterminal domain (BET) family proteins are epigenetic master regulators of gene expression via recognition of acetylated histones and recruitment of transcription factors and co-activators to chromatin. Hence, BET family proteins have emerged as promising therapeutic targets in cancer. In this study, we examined the functional role of bromodomain containing 3 (BRD3), a BET family protein, in colorectal cancer (CRC). In vitro and vivo analyses using BRD3-knockdown or BRD3-overexpressing CRC cells showed that BRD3 suppressed tumor growth and cell cycle G1/S transition and induced p21 expression. Clinical analysis of CRC datasets from our hospital or The Cancer Genome Atlas revealed that BET family genes, including BRD3, were overexpressed in tumor tissues. In immunohistochemical analyses, BRD3 was observed mainly in the nucleus of CRC cells. According to single-cell RNA sequencing in untreated CRC tissues, BRD3 was highly expressed in malignant epithelial cells, and cell cycle checkpoint-related pathways were enriched in the epithelial cells with high BRD3 expression. Spatial transcriptomic and single-cell RNA sequencing analyses of CRC tissues showed that BRD3 expression was positively associated with high p21 expression. Furthermore, overexpression of BRD3 combined with knockdown of, a driver gene in the BRD family, showed strong inhibition of CRC cells in vitro. In conclusion, we demonstrated a novel tumor suppressive role of BRD3 that inhibits tumor growth by cell cycle inhibition in part via induction of p21 expression. BRD3 activation might be a novel therapeutic approach for CRC.

DOI： 10.1111/cas.16129

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

ブロモドメインとエクストラターミナル(BET)蛋白質ファミリーに属するブロモドメイン含有蛋白質3(BRD3)の大腸癌における臨床的および生物学的役割を検討した。その結果、BRD3ノックダウンまたはBRD3過剰発現大腸癌細胞を用いたin vitroおよびin vivo解析により、BRD3が腫瘍増殖と細胞周期G1/S相転移を抑制し、p21発現を誘導することが示された。当院およびThe Cancer Genome Atlasの大腸癌データセットの臨床解析から、BRD3を含むBETファミリー遺伝子が腫瘍組織で過剰発現していることが明らかになった。免疫組織化学的解析では、BRD3は主に大腸癌細胞の核で観察された。未治療の大腸癌組織におけるシングルセルRNAシーケンス解析では、BRD3は悪性上皮細胞で高発現しており、BRD3が高発現している上皮細胞では細胞周期チェックポイント関連経路が濃縮されていた。大腸癌組織の空間トランスクリプトーム解析とシングルセルRNAシーケンス解析から、BRD3の発現はp21の高発現と正の相関があった。さらに、BRD3の過剰発現とBRDファミリーのドライバー遺伝子のノックダウンの組み合わせにより大腸癌細胞に対する強い抑制が認められた。以上より、BRD3が部分的なp21の発現誘導を介して細胞周期を阻害することにより腫瘍増殖を阻害するというBRD3の新たな腫瘍抑制的役割が示唆された。

記述言語：英語   出版者・発行元：Ebiomedicine  

Background: Cell–cell interaction factors that facilitate the progression of adenoma to sporadic colorectal cancer (CRC) remain unclear, thereby hindering patient survival. Methods: We performed spatial transcriptomics on five early CRC cases, which included adenoma and carcinoma, and one advanced CRC. To elucidate cell–cell interactions within the tumour microenvironment (TME), we investigated the colocalisation network at single-cell resolution using a deep generative model for colocalisation analysis, combined with a single-cell transcriptome, and assessed the clinical significance in CRC patients. Findings: CRC cells colocalised with regulatory T cells (Tregs) at the adenoma–carcinoma interface. At early-stage carcinogenesis, cell–cell interaction inference between colocalised adenoma and cancer epithelial cells and Tregs based on the spatial distribution of single cells highlighted midkine (MDK) as a prominent signalling molecule sent from tumour epithelial cells to Tregs. Interaction between MDK-high CRC cells and SPP1+ macrophages and stromal cells proved to be the mechanism underlying immunosuppression in the TME. Additionally, we identified syndecan4 (SDC4) as a receptor for MDK associated with Treg colocalisation. Finally, clinical analysis using CRC datasets indicated that increased MDK/SDC4 levels correlated with poor overall survival in CRC patients. Interpretation: MDK is involved in the immune tolerance shown by Tregs to tumour growth. MDK-mediated formation of the TME could be a potential target for early diagnosis and treatment of CRC. Funding: Japan Society for the Promotion of Science (JSPS) Grant-in-Aid for Science Research; OITA Cancer Research Foundation; AMED under Grant Number; Japan Science and Technology Agency (JST); Takeda Science Foundation; The Princess Takamatsu Cancer Research Fund.

DOI： 10.1016/j.ebiom.2024.105102

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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)  

手術室と遠隔地にそれぞれ触覚フィードバック付きの術者用コンソールを設置し、遠隔手術における触覚フィードバックの有用性を検証し、さらに遠隔ロボット手術の安全性向上を目的として、動物実験を行った。術者用コンソールは福岡市と別府市の手術室に設置し、3段階の触覚フィードバックレベルをランダム順に設定した。術者(現地5名、遠隔地5名)を盲検化し、各触覚レベルでロボット鉗子によりブタの腸を把持する、持ち上げる、下げる、離すという一連の動作を10回繰り返してもらった。その結果、課題の精度や平均把持力には、術者の場所による顕著な差は見られなかった。しかし、遠隔地の場合は現地よりも平均課題完了時間が有意に長く、system usability scaleが有意に低かった。触覚フィードバックレベル間で、課題の精度や課題完了時間に顕著な差はなかったが、触覚フィードバックがある場合はない場合よりも有意に弱い力で臓器を把持することができた。さらに、触覚フィードバックがある場合、ロボット手術の経験が豊富な外科医は、経験の浅い外科医よりも弱い把持力で同等のタスクを行う傾向があった。

記述言語：英語   出版者・発行元：(一社)日本外科学会  

症例は69歳女性。特記すべき既往歴はなかったが、7日前からの上腹部不快感が続くため来院した。身体所見では軽度の腹部膨満と右下腹部の圧痛を認め、血液検査で総白血球数上昇とCRP上昇が明らかになった。腹部造影CTで門脈血栓症(PVT)と腸間膜静脈血栓症、肝門部のcavernous transformationを認め、小腸ループの造影は不良であった。PVTの危険因子はなく、特発性PVTによる腸管壊死と診断し、緊急手術を行った。回腸の末端30cmは赤黒く変色しており、腸管壊死を示していた。壊死部を切除し、切除標本の病理学的検査ではうっ血と浮腫を伴う全周性の粘膜壊死が認められた。術後2日目に呼吸困難となり、心肺停止となった。心肺蘇生により一旦は回復したが、肺塞栓症が明らかになったため、直ちにV-A ECMOと抗凝固療法を開始した。2日後、V-A ECMOから離脱し、抗凝固療法を継続した。その後、神経学的障害を残すことなく回復し、術後26日目に退院した。

記述言語：英語   出版者・発行元：Surgery Today  

Purpose: To verify the usefulness of haptic feedback in telesurgery and improve the safety of telerobotic surgery. Methods: The surgeon's console was installed at two sites (Fukuoka and Beppu; 140 km apart), and the patient cart was installed in Fukuoka. During the experiment, the surgeon was blinded to the haptic feedback levels and asked to grasp the intestinal tract in an animal model. The surgeon then performed the tasks at each location. Results: No marked differences in task accuracy or average grasping force were observed between the surgeon locations. However, the average task completion time was significantly longer, and the system usability scale (SUS) was significantly lower rating for remote operations than for local ones. No marked differences in task accuracy or task completion time were observed between the haptic feedback levels. However, with haptic feedback, the organ was grasped with a significantly weaker force than that without it. Furthermore, with haptic feedback, experienced surgeons in robotic surgery tended to perform an equivalent task with weaker grasping forces than inexperienced surgeons. Conclusion: The haptic feedback function is a tool that allows the surgeon to perform surgery with an appropriate grasping force, both on site and remotely. Improved safety is necessary in telesurgery; haptic feedback will thus be an essential technology in robotic telesurgery going forward.

DOI： 10.1007/s00595-023-02732-7

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記述言語：英語  

DOI： 10.1186/s40792-024-01820-1

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記述言語：英語   出版者・発行元：(一社)日本外科学会  

49歳男性。特に既往や家族歴、飲酒歴、ウイルス感染歴などなかった。定期検診の腹部超音波検査で肝S7/8に2cm径の腫瘍および軽度の脂肪肝を伴う低エコー病変が認められた。単純CTでは高吸収域を示した。MRIでは、腫瘍はT1強調画像で境界部に高信号、内部に低信号を呈し、T2強調画像では低信号を示した。Gd-EOB-DTPA造影MRIでは、病変に脂肪が含まれており、EOB取り込みも認められた。以上より高分化型肝細胞癌(HCC)を疑い、腹腔鏡下S7/8部分切除術を施行した。患者は術後10日目に合併症なく退院した。病理組織検査の結果、過形成性病変や腺腫などの腫瘍性病変は認められず、肝小葉壊死を伴う再生性肝変化と診断した。

記述言語：日本語   出版者・発行元：日本分子腫瘍マーカー研究会  

DOI： 10.11241/jsmtmr.39.18

CiNii Research

記述言語：英語   出版者・発行元：Surgical Endoscopy  

Background: In telementoring, differences in teaching methods affect local surgeons’ comprehension. Because the object to be operated on is a three-dimensional (3D) structure, voice or 2D annotation may not be sufficient to convey the instructor’s intention. In this study, we examined the usefulness of telementoring using 3D drawing annotations in robotic surgery. Methods: Kyushu University and Beppu Hospital are located 140 km apart, and the study was conducted using a Saroa™ surgical robot by RIVERFIELD Inc. using a commercial guarantee network on optical fiber. Twenty medical students performed vertical mattress suturing using a swine intestinal tract under surgical guidance at the Center for Advanced Medical Innovation Kyushu University. Surgical guidance was provided by Beppu Hospital using voice, 2D, and 3D drawing annotations. All robot operations were performed using 3D images, and only the annotations were independently switched between voice and 2D and 3D images. The operation time, needle movement, and performance were also evaluated. Results: The 3D annotation group tended to have a shorter working time than the control group (25.6 ± 63.2 vs. − 36.7 ± 65.4 min, P = 0.06). The 3D annotation group had fewer retries than the control group (1.3 ± 1.7 vs. − 1.1 ± 0.7, P = 0.006), and there was a tendency for fewer needle drops (0.4 ± 0.7 vs. − 0.5 ± 0.9, P = 0.06). The 3D annotation group scored significantly higher than the control group on the Global Evaluate Assessment of Robot Skills (16.8 ± 2.0 vs. 22.8 ± 2.4, P = 0.04). The 3D annotation group also scored higher than the voice (13.4 ± 1.2) and 2D annotation (16.2 ± 1.8) groups (3D vs. voice: P = 0.03, 3D vs. 2D: P = 0.03). Conclusion: Telementoring using 3D drawing annotation was shown to provide good comprehension and a smooth operation for local surgeons. Graphical abstract: [Figure not available: see fulltext.]

DOI： 10.1007/s00464-023-10521-z

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記述言語：英語   出版者・発行元：British Journal of Cancer  

Background: Intratumor heterogeneity (ITH) in microsatellite instability-high (MSI-H) colorectal cancer (CRC) has been poorly studied. We aimed to clarify how the ITH of MSI-H CRCs is generated in cancer evolution and how immune selective pressure affects ITH. Methods: We reanalyzed public whole-exome sequencing data on 246 MSI-H CRCs. In addition, we performed a multi-region analysis from 6 MSI-H CRCs. To verify the process of subclonal immune escape accumulation, a novel computational model of cancer evolution under immune pressure was developed. Results: Our analysis presented the enrichment of functional genomic alterations in antigen-presentation machinery (APM). Associative analysis of neoantigens indicated the generation of immune escape mechanisms via HLA alterations. Multiregion analysis revealed the clonal acquisition of driver mutations and subclonal accumulation of APM defects in MSI-H CRCs. Examination of variant allele frequencies demonstrated that subclonal mutations tend to be subjected to selective sweep. Computational simulations of tumour progression with the interaction of immune cells successfully verified the subclonal accumulation of immune escape mutations and suggested the efficacy of early initiation of an immune checkpoint inhibitor (ICI) -based treatment. Conclusions: Our results demonstrate the heterogeneous acquisition of immune escape mechanisms in MSI-H CRCs by Darwinian selection, providing novel insights into ICI-based treatment strategies.

DOI： 10.1038/s41416-023-02395-8

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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90歳女性。非B非C型肝炎であり、18ヵ月前に原発性肝細胞癌に対して腹腔鏡下肝切除術が施行された。術後6ヵ月、肝細胞癌再発に対して経カテーテル的肝動脈化学塞栓療法(TACE)が施行されたが、その1年後に2回目の再発が認められた。レンバチニブ(LEN)8mg/日投与を開始したところ、1週間後に極度の疲労や食欲不振などの重篤な有害事象(AE)が出現し、投与量を4mg/日に減量したがAEの管理は困難であった。そこで、LEN導入から1ヵ月後に化学療法をアテゾリズマブ+ベバシズマブ併用療法に変更した。その結果、副作用はほとんど認められず、腫瘍の退縮が認められた。本レジメンを8ヵ月間、10サイクル続け、最終的に完全奏効(CR)を達成した。CR達成後1年経過しても再発はみられていない。

記述言語：英語  

DOI： 10.1007/s13691-023-00618-6

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記述言語：英語   出版者・発行元：Surgical Endoscopy  

Background: Although several studies on telesurgery have been reported globally, a clinically applicable technique has not yet been developed. As part of a telesurgical study series conducted by the Japan Surgical Society, this study describes the first application of a double-surgeon cockpit system to telesurgery. Methods: Surgeon cockpits were installed at a local site and a remote site 140 km away. Three healthy pigs weighing between 26 and 29 kg were selected for surgery. Non-specialized surgeons performed emergency hemostasis, cholecystectomy, and renal vein ligation with remote assistance using the double-surgeon cockpits and specialized surgeons performed actual telesurgery. Additionally, the impact of adding internet protocol security (IPsec) encryption to the internet protocol-virtual private network (IP-VPN) line on communication was evaluated to address clinical security concerns. Results: The average time required for remote emergency hemostasis with the double-surgeon cockpit system was 10.64 s. A non-specialized surgeon could safely perform cholecystectomy or renal vein ligation with remote assistance. Global Evaluative Assessment of Robotic Skills and System Usability Scale scores were higher for telesurgical support-assisted surgery by a non-specialized surgeon using the double-surgeon cockpits than for telesurgery performed by a specialized surgeon without the double-cockpit system. Adding IPsec encryption to the IP-VPN did not have a significant impact on communication. Conclusion: Telesurgical support through our double-surgeon cockpit system is feasible as first step toward clinical telesurgery.

DOI： 10.1007/s00464-023-10061-6

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記述言語：英語   出版者・発行元：Cancer Genomics and Proteomics  

Background/Aim: The immune system has a pivotal role in modulating the response to chemotherapy in breast cancer (BC). However, the immune status during chemotherapy remains unclear. We evaluated the sequential changes in peripheral systemic immunity markers in BC patients treated with various chemotherapeutic agents. Materials and Methods: We examined the correlation between the peripheral systemic immunity markers, neutrophil-to-lymphocyte ratio (NLR), absolute lymphocyte count (ALC) and the local cytolytic activity (CYT) score obtained by quantitative reverse-transcription polymerase chain reaction of 84 preoperative BC patients. Next, we observed the sequential changes in the peripheral systemic immunity markers during treatment with four anticancer drugs: oral 5-fluorouracil derivative; S-1, epirubicin plus cyclophosphamide; paclitaxel plus the anti-vascular endothelial growth factor antibody bevacizumab, and eribulin in 172 HER2-negative advanced BC patients. Finally, we examined the correlation between the changes in the peripheral systemic immunity markers, time to treatment failure (TTF) and progression-free survival (PFS). Results: A negative correlation was found between ALC and NLR. ALC-low and NLR-high cases were positively associated with CYT score-low cases. The ratio of ALC-increase and NLR-decrease varies depending on the anticancer drugs used. The responder group (TTF .3 months) had a higher NLR-decrease ratio than the nonresponder group (TTF <3 months). Patients with a high NLR-decrease ratio showed higher PFS. Conclusion: The change in ALC or NLR varies according to the anticancer drugs, suggesting differential immunomodulatory effects of the drugs. Furthermore, the change in NLR reflects the therapeutic efficacy of chemotherapy in advanced BC.

DOI： 10.21873/cgp.20373

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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)  

日本人虫垂杯細胞腺癌(GCA)患者の臨床的特徴について検討した。2000年1月～2017年12月に、日本の43施設で治療した虫垂腫瘍患者922例を後向き研究に登録した。このうち組織学的に虫垂杯細胞カルチノイド(GCC)と診断された患者32例(3.5%)の組織標本を虫垂GCAの新規評価基準で診断し、最終的に20例を対象に解析した。その結果、5年生存率は61.4%、生存期間中央値は93.1ヵ月であった。腹膜播種と有意に関連のある因子は局所リンパ節転移で、関連する可能性のある因子はグレード3であった。T1/2の患者(2例)とグレード1の患者(4例)に腹膜播種は認められず、局所リンパ節転移の有意な関連因子は検出されなかった。2019年に改定されたWHO分類のgrading systemとの有意な関連性は認められなかった。

記述言語：英語   出版者・発行元：Surgery Today  

Purpose: In the 5th edition of the World Health Organization classification, appendiceal goblet cell adenocarcinoma (GCA) is categorized separately from neuroendocrine tumors and other appendiceal adenocarcinomas. We clarified the clinicopathological characteristics of Japanese appendiceal GCA. Methods: We designed a retrospective multicenter cohort study and retrieved the data of patients with appendiceal neoplasms and histologically diagnosed appendiceal goblet cell carcinoid (GCC) treated from January 2000 to December 2017 in Japan. The available GCC slides were reviewed and diagnosed with a new grading system of GCA. Results: A total of 922 patients from 43 institutions were enrolled; of these, 32 cases were patients with GCC (3.5%), and 20 cases were ultimately analyzed. The 5-year survival rate was 61.4% (95% confidence interval: 27.4–83.2), and the median survival time was 93.1 months. For peritoneal metastasis, regional lymph node metastasis was a significant factor (p = 0.04), and Grade 3 was a potential factor (p = 0.07). No peritoneal metastasis was observed in either T1/2 patients (n = 2) or Grade 1 patients (n = 4). We were unable to detect any significant factors associated with regional lymph node metastasis. Conclusion: For peritoneal metastasis, regional lymph node metastasis was a significant factor, and Grade 3 was a potential factor.

DOI： 10.1007/s00595-022-02562-z

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記述言語：英語   出版者・発行元：Cell Reports  

The cellular interactions in the tumor microenvironment of colorectal cancer (CRC) are poorly understood, hindering patient treatment. In the current study, we investigate whether events occurring at the invasion front are of particular importance for CRC treatment strategies. To this end, we analyze CRC tissues by combining spatial transcriptomics from patients with a public single-cell transcriptomic atlas to determine cell-cell interactions at the invasion front. We show that CRC cells are localized specifically at the invasion front. These cells induce human leukocyte antigen G (HLA-G) to produce secreted phosphoprotein 1 (SPP1)+ macrophages while conferring CRC cells with anti-tumor immunity, as well as proliferative and invasive properties. Taken together, these findings highlight the signaling between CRC cell populations and stromal cell populations at the cellular level.

DOI： 10.1016/j.celrep.2022.111929

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

本研究の目的は、血中マイクロRNA(miRNA)をバイオマーカーとして検出することで、胃癌リスクの高い症例を同定することである。スクリーニングを行った1206名のうち、血清抗体検査でヘリコバクター・ピロリ(H.pylori)陽性で、内視鏡検査を受けた144名を本研究の対象とした。粘膜炎症の肉眼的評価には、正常粘膜をグレード0、萎縮をグレード1(C-1、C-2)、グレード2(C-3、O-1)、グレード3(O-2、O-3)に分類する木村・竹本分類を適用した。血清サンプルは2相に分け、miRNAマイクロアレイプロファイリングに使用した。グレード3の粘膜とその他のグレードの粘膜におけるmiRNAの発現を比較した。胃癌における発現は、TCGAのデータで確認した。miR-196b-3pは有意に増加し、miR-92a-2-5pは減少していた(P<0.05、q<0.2)。TCGAのデータでは、胃癌症例においてmiR-196b-3pの発現が高いことが示された(P<0.001)。グレード3とそれ以外を比較すると、検出されたmiRNAを用いた受信者動作特性曲線下面積は0.7であった。さらに、miRNAを組み合わせることで、より高い精度が得られた。miRNAを組み合わせる場合、3種類のmiRNA(miR-196b-3p、miR-92a-2-5p、miR-6791-3p)の組み合わせが高い感度と特異性を示し、曲線下面積は0.8を超えていた。ここに示されたmiRNAの組み合わせは、胃癌の前癌病変のバイオマーカーとして有望である可能性がある。

記述言語：英語   出版者・発行元：Cancer Genomics and Proteomics  

Background/Aim: Peritoneal metastasis (PM) of gastric cancer (GC) leads to poor clinical outcomes. Tumor-derived exosomes promote metastasis via communication between tumor cells and host cells. In this study, we investigated the effect of Rab27, which is required for exosome secretion, on the PM of GC. Materials and Methods: We established a stable knockdown of two Rab27 homologs, Rab27a and Rab27b, in human GC cells (58As9) with a high potential of PM. We examined the level of exosome secretion from Rab27-knockdown 58As9 cells by Western blotting and the ability of Rab27b knockdown to suppress PM in 58As9 cells using a mouse xenograft model. In vitro proliferation and invasion assays were performed in the Rab27b-knockdown cells. Next, Rab27b expression was evaluated in human GC tissues by immunohistochemistry. Finally, we assessed the clinicopathological and prognostic significance of Rab27b expression by RT-qPCR in both our and other TCGA datasets of GC. Results: Rab27a and Rab27b knockdown in 58As9 cells decreased the secretion of exosomes, characterized by the endocytic marker CD63.

DOI： 10.21873/cgp.20362

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記述言語：英語   出版者・発行元：Annals of Gastroenterological Surgery  

Aim: Gastric mucosal changes associated with chronic gastritis are known to be precancerous lesions of gastric cancer. We aimed to identify individuals with a high risk of gastric cancer by detection of microRNAs (miRNA) in the blood as biomarkers. Methods: Of 1206 individuals screened, 144 who were positive for Helicobacter pylori (H. pylori) by the serum antibody test and who underwent endoscopy were the subjects of this study. For the gross assessment of mucosal inflammation, we applied the Kimura–Takemoto classification, in which normal mucosa was defined as grade 0, and atrophy was categorized as grade 1 (C-1 and C-2), grade 2 (C-3 and O-1), and grade 3 (O-2 and O-3). Serum samples were divided into two phases and used for miRNA microarray profiling. We compared the expression of miRNAs in grade 3 mucosa and other grades. Expression in gastric cancer was confirmed with TCGA data. Results: miR-196b-3p was significantly upregulated, and miR-92a-2-5p was downregulated (P <.05 and q < 0.2). TCGA data showed a high expression of miR-196b-3p in gastric cancer cases (P <.001). Comparing grade 3 and the others, the area under the receiver operating characteristic curve using the detected miRNAs was as high as about 0.7. Furthermore, the combination of miRNAs resulted in higher accuracy. In terms of the significance of the combinatory mRNAs, the combination of three miRNAs (miR-196b-3p, miR-92a-2-5p, and miR-6791-3p) revealed high sensitivity and specificity, with the area under the curve exceeding 0.8. Conclusion: The identified combinatory miRNAs may represent promising biomarkers of precancerous lesions in gastric cancer.

DOI： 10.1002/ags3.12610

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記述言語：英語   出版者・発行元：Plos One  

Background Colorectal cancer (CRC) can be classified into four consensus molecular subtypes (CMS) according to genomic aberrations and gene expression profiles. CMS is expected to be useful in predicting prognosis and selecting chemotherapy regimens. However, there are still no reports on the relationship between the morphology and CMS. Methods This retrospective study included 55 subjects with T2 CRC undergoing surgical resection, of whom 30 had the depressed type and 25 the protruded type. In the classification of the CMS, we first defined cases with deficient mismatch repair as CMS1. And then, CMS2/3 and CMS4 were classified using an online classifier developed by Trinh et al. The staining intensity of CDX2, HTR2B, FRMD6, ZEB1, and KER and the percentage contents of CDX2, FRMD6, and KER are input into the classifier to obtain automatic output classifying the specimen as CMS2/3 or CMS4. Results According to the results yielded by the online classifier, of the 30 depressed-type cases, 15 (50%) were classified as CMS2/3 and 15 (50%) as CMS4. Of the 25 protruded-type cases, 3 (12%) were classified as CMS1 and 22 (88%) as CMS2/3. All of the T2 CRCs classified as CMS4 were depressed CRCs. More malignant pathological findings such as lymphatic invasion were associated with the depressed rather than protruded T2 CRC cases. Conclusions Depressed-type T2 CRC had a significant association with CMS4, showing more malignant pathological findings such as lymphatic invasion than the protruded-type, which could explain the reported association between CMS4 CRC and poor prognosis.

DOI： 10.1371/journal.pone.0273566

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記述言語：英語   出版者・発行元：Surgical Laparoscopy Endoscopy and Percutaneous Techniques  

Aim: This study was performed to clarify the relationship between robotic rectal resection and postoperative ileus (POI) by comparing robotic surgery with laparoscopic surgery. Materials and Methods: We retrospectively reviewed 238 patients who underwent robotic (n=41) or laparoscopic (n=197) rectal resection for rectal cancer in our institution from January 2013 to June 2020. First, we compared the background factors and short-term surgical outcomes between robotic and laparoscopic surgery. Next, we investigated the postoperative complications of robotic and laparoscopic rectal resection. Finally, we identified the risk factors for POI following rectal cancer resection. Results: The percentages of patients with an Rb tumor location, treatment by abdominoperitoneal resection/intersphincteric resection/low anterior resection, a temporary diverting ileostomy, and a long operation time were significantly higher in robotic than laparoscopic surgery (P<0.0001, P=0.0002, P=0.0078, and P=0.0001, respectively). There was no significant difference in any individual postoperative complication between robotic and laparoscopic surgery. Risk factors for POI were male sex (P=0.0078), neoadjuvant chemoradiotherapy (P=0.0007), an Rb tumor location (P=0.0005), treatment by abdominoperitoneal resection/intersphincteric resection/low anterior resection (P=0.0044), a temporary diverting ileostomy (P<0.0001), and operation time of ≥240 minutes (P=0.0024). Notably, robotic surgery was not a risk factor for POI following rectal resection relative to laparoscopic surgery. Conclusion: Although patients who underwent robotic surgery had more risk factors for POI, the risk of POI was similar between robotic and laparoscopic rectal resection.

DOI： 10.1097/SLE.0000000000001056

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記述言語：英語   出版者・発行元：Cancer Medicine  

Anal canal cancer (ACC) has been reported to be an uncommon cancer in Japan, as in the USA, Europe, and Australia. This retrospective multi-institutional study was conducted to clarify the characteristics of ACC in Japan. First, the histological ACC type cases treated between 1991 and 2015 were collected. A detailed analysis of the characteristics of anal canal squamous cell carcinoma (SCC) cases was then conducted. The results of the histological types revealed that of the 1781 ACC cases, 435 cases (24.4%) including seven cases of adenosquamous cell carcinomas were SCC and 1260 cases (70.7%) were adenocarcinoma. However, the most common histological type reported in the USA, Europe, and Australia is SCC. Most ACC cases are adenocarcinomas and there is a low incidence of SCC in Japan which is different from the above-mentioned countries. Moreover, we reclassified T4 into the following two groups based on tumor size: T4a (tumor diameter of 5 cm or less) and T4b (tumor diameter of more than 5 cm). The results of the TNM classification of SCC revealed that the hazard ratio (HR) to T1 of T2, T3, T4a, and T4b was 2.45, 2.28, 2.89, and 4.97, respectively. As T4b cases had a worse prognosis than T4a cases, we propose that T4 for anal canal SCC in Japan be subclassified into T4a and T4b.

DOI： 10.1002/cam4.4631

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

直腸癌手術後に生じる吻合部漏に対する三層サーキュラーステープラーと二層サーキュラーステープラーの有効性を比較検討した。ブタ回結腸吻合部における三層サーキュラーステープラーと二層サーキュラーステープラーの破裂圧を比較した。さらに、直腸癌に対して大腸吻合術を施行された194例を対象とする多施設後ろ向きコホート研究を実施して重度吻合部漏の術後発症率を評価した。二層サーキュラーステープラー使用群(EEA群)が153例(男性84例、女性69例、中央値66歳)、三層サーキュラーステープラー使用群(tri-EEA群)が41例(男性23例、女性18例、中央値67歳)であった。ブタを用いた実験での破裂圧は三層サーキュラーステープラーが26.4±6.2mmHg、二層サーキュラーステープラーが14.5±4.3mmHgと三層の方が有意に高値を示していた。臨床研究ではtri-EEA群の方がEEA群と比較して手術時間は有意に長く、術後在院期間と術後合併症の発症率に関してtri-EEA群とEEA群との間に有意差はみられなかったが、グレード3以上の吻合部漏の発症率はtri-EEA群の方が有意に低かった(0.0% vs 5.8%)。多変量解析ではtri-EEAの施行が吻合部漏の非発症を示す独立関連因子として抽出された。

記述言語：英語   出版者・発行元：Annals of Gastroenterological Surgery  

Aim: To investigate the impact of the triple-layered circular stapler compared with the double-layered circular stapler on anastomotic leakage after rectal cancer surgery. Methods: The bursting pressure was compared between porcine ileocolic anastomoses created using a double- or triple-layered stapler. We also retrospectively analyzed the incidence of severe anastomotic leakage in 194 patients who underwent colorectal anastomosis using a double- or triple-layered circular stapler during rectal cancer resection performed in two cancer centers between January 2015 and April 2021. Results: In the porcine model, the bursting pressure was higher in anastomoses created using the triple-layered stapler than the double-layered stapler (end-to-end anastomosis: 26.4 ± 6.2 mm Hg vs 14.5 ± 4.3 mm Hg, P =.0031; side-to-side anastomosis: 27.7 ± 5.0 mm Hg vs 18.0 ± 2.9 mm Hg, P =.0275). Intersectional leakage occurred in 41% and 83% of anastomoses created using the triple- or double-layered stapler, respectively (P =.0821). In the clinical cohort, the double- and triple-layered stapler was used in 153 and 41 patients, respectively. The incidence of anastomotic leakage was lower for anastomoses created using the triple-layered stapler vs the double-layered stapler (0.0% vs 5.8%, P =.0362). In multivariate analysis, the factors independently associated with a lower incidence of anastomotic leakage were female sex (odds ratio: 0.16, 95% confidence interval: 0.01-0.90, P =.0354) and triple-layered stapler usage (odds ratio: 0.00, 95% confidence interval: 0.00-0.96, P =.0465). Conclusion: Anastomoses created using a triple-layered circular stapler had high bursting pressure, which might contribute to a lower incidence of anastomotic leakage after rectal cancer surgery.

DOI： 10.1002/ags3.12516

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DOI： 10.1200/JCO.2022.40.4_suppl.161

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記述言語：英語   出版者・発行元：Cancer Reports  

Background: ARID1A is a component of the SWI/SNF complex, which controls the accessibility of proteins to DNA. ARID1A mutations are frequently observed in colorectal cancers (CRCs) and have been reported to be associated with high mutational burden and tumor PD-L1 expression in vitro. Aim: To clarify the role of ARID1A mutation in CRC. Method and results: We used next generation sequencing (NGS) and immunohistochemistry on clinically obtained samples. A total of 201 CRC tissues from Niigata University and Niigata Center Hospital were processed by NGS using the CANCERPLEX panel. Immunohistochemistry for ARID1A, PD-L1, MLH1, and MSH2 was performed on 66 propensity-matched (33 microsatellite instability-high [MSI-H] and 33 microsatellite-stable [MSS]) cases among 499 cases from Kyushu University. TCGA data were downloaded from cBioPortal. NGS showed significantly more mutations in ARID1A mutated CRCs (p = 0.01), and the trend was stronger for right-sided CRCs than left-sided. TCGA data confirmed these findings (p < 0.01). BRAF V600E and ATM mutations were also found at higher frequencies. Immunohistochemistry showed that 30% of MSI-H CRCs had ARID1A loss, while this was true in only 6% of MSS CRCs. In both MSI-H and MSS, PD-L1 expression by stromal cells was enhanced in the ARID1A-mutant groups (90% vs 39% in MSI-H, 100% vs 26% in MSS). Conclusion: We found a higher mutational burden in ARID1A-mutant CRCs, and IHC study showed that ARID1A loss was correlated with high PD-L1 expression in stromal cells regardless of MSI status. These data support the idea that mutant ARID1A is a potential biomarker for CRCs.

DOI： 10.1002/cnr2.1420

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記述言語：日本語   出版者・発行元：日本分子腫瘍マーカー研究会  

DOI： 10.11241/jsmtmr.38.24

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