研究者詳細 - 小倉　淳司

Lateral Nodal Features on Restaging Magnetic Resonance Imaging Associated With Lateral Local Recurrence in Low Rectal Cancer After Neoadjuvant Chemoradiotherapy or Radiotherapy 国際誌

Ogura, A; Konishi, T; Beets, GL; Cunningham, C; Garcia-Aguilar, J; Iversen, H; Toda, S; Lee, IK; Lee, HX; Uehara, K; Lee, P; Putter, H; van de Velde, CJH; Rutten, HJT; Tuynman, JB; Kusters, M; Hompes, R; Akiyoshi, T; Schaap, D; Nieuwenhuijzen, GA; Martling, A; van der Valk, MJM; Meershoek-Klein-Kranenbarg, E; Blazic, IM; Gollub, MJ; Aiba, T; Aalbers, AGJ; van der Sande, ME; Beets-Tan, RH; Maas, M; Jozwiak, K; Betts, M; Moore, J; Thomas, M; Sammour, T; Wells, T; Solomon, MJ; Brown, KG; Won, DD; Kim, MK; Oh, SN; Choi, MH; Kuroyanagi, H; Hanaoka, Y; Tomizawa, K

JAMA SURGERY 154 巻 ( 9 ) 頁： e192172 2019年9月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：JAMA Surgery

Importance: Previously, it was shown in patients with low rectal cancer that a short-axis (SA) lateral node size of 7 mm or greater on primary magnetic resonance imaging (MRI) resulted in a high lateral local recurrence (LLR) rate after chemoradiotherapy or radiotherapy ([C]RT) with total mesorectal excision (TME) and that this risk was lowered by a lateral lymph node dissection (LLND). The role of restaging MRI after (C)RT with regard to LLR risk and which specific patients might benefit from an LLND is not fully understood. Objective: To determine the factors on primary and restaging MRI that are associated with LLR in low rectal cancer after (C)RT and to formulate specific guidelines on which patients might benefit from an LLND. Design, Setting, and Participants: In this retrospective, multicenter, pooled cohort study, patients who underwent surgery for cT3 or cT4 low rectal cancer with a curative intent from 12 centers in 7 countries from January 2009 to December 2013 were included. All patients' MRIs were rereviewed according to a standardized protocol, with specific attention to lateral nodal features. The original cohort included 1216 patients. For this study, patients who underwent (C)RT and had a restaging MRI were selected, leaving 741 for analyses across 10 institutions, including 651 who underwent (C)RT with TME and 90 who underwent (C)RT with TME and LLND. Main Outcomes and Measures: The main purpose was to identify the factors on primary and restaging MRI associated with LLR after (C)RT with TME. Whether high-risk patients might benefit in terms of LLR reduction from an LLND was also studied. Results: Of the 741 included patients, 480 (64.8%) were male, and the mean (SD) age was 60.4 (12.0) years. An SA lateral node size of 7 mm or greater on primary MRI resulted in a 5-year LLR rate of 17.9% after (C)RT with TME. At 3 years, there were no LLRs in 28 patients (29.2%) with lateral nodes that were 4 mm or less on restaging MRI. Nodes that were 7 mm or greater on primary MRI and greater than 4 mm on restaging MRI in the internal iliac compartment resulted in a 5-year LLR rate of 52.3%, significantly higher compared with nodes in the obturator compartment of that size (9.5%; hazard ratio, 5.8; 95% CI, 1.6-21.3; P =.003). Compared with (C)RT with TME alone, treatment with (C)RT with TME and LLND in these unresponsive internal nodes resulted in a significantly lower LLR rate of 8.7% (hazard ratio, 6.2; 95% CI, 1.4-28.5; P =.007). Conclusions and Relevance: Restaging MRI is important in clinical decision making in lateral nodal disease. In patients with shrinkage of lateral nodes from an SA node size of 7 mm or greater on primary MRI to an SA node size of 4 mm or less on restaging MRI, which occurs in about 30% of cases, LLND can be avoided. However, persistently enlarged nodes in the internal iliac compartment indicate an extremely high risk of LLR, and an LLND lowered LLR in these cases.

DOI： 10.1001/jamasurg.2019.2172

Pattern of programmed cell death-ligand 1 expression and CD8-positive T-cell infiltration before and after chemoradiotherapy in rectal cancer 国際誌

Ogura, A; Akiyoshi, T; Yamamoto, N; Kawachi, H; Ishikawa, Y; Mori, S; Oba, K; Nagino, M; Fukunaga, Y; Ueno, M

EUROPEAN JOURNAL OF CANCER 91 巻頁： 11 - 20 2018年3月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：European Journal of Cancer

Background The synergistic effect of combining immune checkpoint inhibitors with radiotherapy was reported recently, but there are few studies on programmed cell death-ligand 1 (PD-L1) expression in rectal cancer treated by preoperative chemoradiotherapy (CRT). The aim of the present study was to investigate the PD-L1 expression status before and after CRT and its association with clinicopathological characteristics and recurrence in rectal cancer. Methods Immunostainings of PD-L1 and CD8 were performed in 287 patients with rectal cancer treated by CRT. PD-L1 expression on the tumour cells (tPD-L1) and on the stromal immune cells (iPD-L1) was evaluated before and after CRT. CD8+ cell density in tumour area (tCD8+) before CRT and in the stromal area (sCD8+) before and after CRT was also evaluated. Results High tPD-L1 expression was observed in only three patients (1.0%). High iPD-L1 expression significantly increased from 31.7% before CRT to 49.2% after CRT (P < 0.0001). The increase in high iPD-L1 expression after CRT was only observed in patients with tumour regression grades 1 and 2. High iPD-L1 expression was associated with high tCD8+ cell density before CRT (P < 0.0001) and sCD8+ cell density after CRT (P < 0.0001). High tCD8+ cell density before CRT was associated with better disease-free survival (DFS) (P = 0.0331), but its improved effect on DFS could be observed in patients with high iPD-L1 expression (P = 0.0081), not in patients with low iPD-L1 expression (P = 0.516). Conclusion The present study demonstrated the significant correlations between iPD-L1 expression and CD8+ cell density both before and after CRT.

DOI： 10.1016/j.ejca.2017.12.005

Indications for neoadjuvant treatment based on risk factors for poor prognosis before and after neoadjuvant chemotherapy alone in patients with locally advanced rectal cancer 査読有り国際誌

Ogura, A; Uehara, K; Aiba, T; Sando, M; Tanaka, A; Ohara, N; Murata, Y; Sato, Y; Hattori, N; Nakayama, G; Ebata, T; Kodera, Y; Nagino, M

EJSO 47 巻 ( 5 ) 頁： 1005 - 1011 2021年5月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：European Journal of Surgical Oncology

Introduction: The oncological benefit of neoadjuvant chemotherapy (NAC) alone for locally advanced rectal cancer (LARC) remains controversial. The aim of this study was to clarify the clinical risk factors for poor prognosis before and after NAC for decision making regarding additional treatment in patients with LARC. Materials and methods: We examined a total of 96 patients with MRI-defined poor-risk locally advanced mid-low rectal cancer treated by NAC alone between 2006 and 2018. Survival outcomes and clinical risk factors for poor prognosis before and after NAC were analyzed. Results: In the median follow-up duration after surgery of 60 months (3–120), the rates of 5-year overall survival (OS), relapse-free survival (RFS), and local recurrence (LR) were 83.6%, 78.4%, and 8.2%, respectively. In the multivariate analyses, patients with cT4 disease had a significantly higher risk of poor OS (HR; 6.10, 95% CI; 1.32–28.15, P = 0.021) than those with cT3 disease. After NAC, ycN+ was significantly associated with a higher risk of poor OS (HR; 5.92, 95% CI; 1.27–27.62, P = 0.024) and RFS (HR; 2.55, 95% CI; 1.01–6.48, P = 0.048) than ycN-. In addition, patients with CEA after NAC (post-CEA) ≥ 5 ng/ml had a significantly higher risk LR (HR; 5.63, 95% CI; 1.06–29.93, P = 0.043). Conclusion: NAC alone had an insufficient survival effect on patients with cT4 disease, ycN+, or an elevated post-CEA level. In contrast, NAC alone is a potential treatment for other patients with LARC.

DOI： 10.1016/j.ejso.2020.10.038

What is the impact of systemic chemotherapy for lateral lymph nodes in patients with locally advanced low rectal cancer? 査読有り国際誌

Ogura, A; Uehara, K; Aiba, T; Hattori, N; Nakayama, G; Maeda, O; Ando, Y; Kodera, Y; Ebata, T; Nagino, M

INTERNATIONAL JOURNAL OF COLORECTAL DISEASE 35 巻 ( 11 ) 頁： 2073 - 2080 2020年11月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：International Journal of Colorectal Disease

Purpose: Systemic chemotherapy (SC) before surgery is a potential treatment to improve survival in patients with advanced rectal cancer. However, the impact of SC on lateral lymph nodes (LLNs) remains unclear. Methods: A total of 78 patients with stage II/III low rectal cancer, who received 3-month oxaliplatin-based SC followed by LLN dissection (LLND) in principle, were analysed retrospectively. “Total lateral lymph node metastases (tLLNMs)” was defined as having either pathological LLNMs (pLLNMs) or lateral local recurrences (LLRs). Patients with the maximum short-axis size of LLNs ≥ 7 mm were classified into the swollen group (n = 21). Results: In the total cohort, tLLNMs included 6 pLLNMs (7.7%) and 2 LLRs (2.6%). In the non-swollen group, no patients had pLLNMs, but one had LLR (1.8%). In the swollen group, pLLNMs and LLRs were detected in 6 (28.6%) and 1 (4.8%), respectively. The swollen group was an independent risk factor for tLLNMs (P < 0.001), leading to the significantly worse 5-year relapse-free survival (RFS) of 52.4% than the others. Conclusion: For patients without swollen LLNs, SC could allow for omission both of lateral irradiation and LLND. For patients with swollen LLNs, the lateral local control was favourable after SC and LLND without chemoradiotherapy (CRT); however, oxaliplatin-based SC might be insufficient to improve survival, requiring more intensive chemotherapy. CRT should be indicated according to the other risk factors of central local recurrence, although the swollen LLNs should be removed.

DOI： 10.1007/s00384-020-03690-z

Loss of Trefoil Factor 1 Accelerates the Immune Response to Colorectal Cancer

Jinno, T; Yamaguchi, J; Ogura, A; Kokuryo, T; Yokoyama, Y; Sunagawa, M; Baba, T; Murata, Y; Ebata, T

ANTICANCER RESEARCH 44 巻 ( 9 ) 頁： 3757 - 3769 2024年9月

記述言語：英語出版者・発行元：Anticancer Research

Background/Aim: Recent studies suggest that PD-L1 expression in immune cells, rather than tumor cells, plays a key role in tumor immunity. Trefoil factor family 1 (TFF1) is a secreted protein expressed mainly by the gastrointestinal epithelium and is related to the development of malignant disease. This study investigated the effects of TFF1 on tumor immunity in a xenograft mouse model of colorectal cancer (CRC). Materials and Methods: MC38 cells were implanted in wild-type (WT) and TFF1KO mice, and the tumor microenvironment was investigated using immunohistochemistry. The circulating immune cells were analyzed using flow cytometry. Results: Tumor growth was suppressed in TFF1KO mice. In the tumor microenvironment, CD8- and CD4-positive T cells and CD11c-positive dendritic cells (DCs) were frequently found in TFF1KO mice. When an immune checkpoint inhibitor was administered to these mice, almost half of the tumors in TFF1KO mice showed a complete response. The number of circulating PD-L1/DCs was markedly associated with tumor volume, with TFF1 deletion accelerating this effect and its injection decreasing it. These findings indicate that loss of TFF1 activates tumor immunity via frequent T-cell priming by DCs, and eventually suppresses tumor growth in CRC. In addition, the number of circulating PD-L1/DCs was identified as a predictive marker of checkpoint-inhibiting therapy efficacy. Conclusion: Loss of TFF1 resulted in accelerated immune response to colorectal cancer. Further studies are needed to investigate the precise mechanisms of TFF1 in immunotolerance and develop a novel TFF1-inhibiting immunotherapeutic strategy for CRC.

DOI： 10.21873/anticanres.17200

Two-team laparoscopic extended lateral lymph node dissection with transperineal resection of the distal main trunk of internal iliac vein using a linear stapler-A video vignette

Murata, Y; Ogura, A; Jinno, T; Yogo, K; Mizuno, T; Ebata, T

COLORECTAL DISEASE 2024年8月

TLK1 Inhibition Enhances the Anticancer Effect of Deep UV Irradiation Through CHK1 Activation

Koike, Y; Kokuryo, T; Yamaguchi, J; Sunagawa, M; Ogura, A; Watanabe, N; Onoe, S; Miyata, K; Mizuno, T; Uehara, K; Igami, T; Yokoyama, Y; Ebata, T; Nagino, M

ANTICANCER RESEARCH 44 巻 ( 7 ) 頁： 2827 - 2836 2024年7月

記述言語：英語出版者・発行元：Anticancer Research

Background/Aim: A deep ultraviolet (DUV) light-emitting diode (LED) is a device that can irradiate electromagnetic waves from 250 nm to 350 nm. Tousled-like kinase 1 (TLK1) encodes a nuclear serine/threonine kinase, which is thought to influence the effects of DUV irradiation in cancer. The aim of this study was to clarify the interaction of TLK1 with DUV irradiation-induced DNA damage in cancer cells. Materials and Methods: Pancreatic cancer cell lines were treated with or without DUV. TLK1 expression and phosphorylation in the two groups were examined. Then, these cancer cell lines were treated with thioridazine (THD), DUV or both. Thereafter, cytomorphology and apoptosis were assessed. Several proteins related to DNA damage, were analyzed in cancer cells treated with DUV and THD. Tumors in a subcutaneous xenograft model were treated with THD, DUV, or both for six weeks. Results: DUV irradiation induced the phosphorylation of TLK1 in pancreatic cancer cell lines. Cytomorphology was significantly changed in pancreatic cancer cells treated with DUV and THD. TLK1 inhibition enhanced DUV irradiation-induced apoptosis in cancer cells. Interestingly, CHK1 and pCHK1 expression was suppressed after TLK1 inhibition. In addition, inhibition of MRE11 led to a decrease in the expression of CHK1 and pCHK1, accompanied by a notable increase in apoptosis. In the subcutaneous xenograft models, the tumor volume in the DUV and THD groups was lower than that in the other groups. Conclusion: TLK1 phosphorylation is an important event in DUV irradiation. DUV irradiation combined with TLK1 inhibition has therapeutic potential in pancreatic cancer cells.

DOI： 10.21873/anticanres.17095

Trefoil factor 1 suppresses stemness and enhances chemosensitivity of pancreatic cancer

Yamaguchi, J; Kokuryo, T; Yokoyama, Y; Oishi, S; Sunagawa, M; Mizuno, T; Onoe, S; Watanabe, N; Ogura, A; Ebata, T

CANCER MEDICINE 13 巻 ( 11 ) 頁： e7395 2024年6月

記述言語：英語出版者・発行元：Cancer Medicine

Background and Aims: Pancreatic cancer is one of the most lethal malignancies, partly due to resistance to conventional chemotherapy. The chemoresistance of malignant tumors is associated with epithelial-mesenchymal transition (EMT) and the stemness of cancer cells. The aim of this study is to investigate the availability and functional mechanisms of trefoil factor family 1 (TFF1), a tumor-suppressive protein in pancreatic carcinogenesis, to treat pancreatic cancer. Methods: To investigate the role of endogenous TFF1 in human and mice, specimens of human pancreatic cancer and genetically engineered mouse model of pancreatic cancer (KPC/TFF1KO; Pdx1-Cre/LSL-KRASG12D/LSL-p53R172H/TFF1−/−) were analyzed by immunohistochemistry (IHC). To explore the efficacy of extracellular administration of TFF1, recombinant and chemically synthesized TFF1 were administered to pancreatic cancer cell lines, a xenograft mouse model and a transgenic mouse model. Results: The deficiency of TFF1 was associated with increased EMT of cancer cells in mouse models of pancreatic cancer, KPC. The expression of TFF1 in cancer cells was associated with better survival rate of the patients who underwent chemotherapy, and loss of TFF1 deteriorated the benefit of gemcitabine in KPC mice. Extracellular administration of TFF1 inhibited gemcitabine-induced EMT, Wnt pathway activation and cancer stemness, eventually increased apoptosis of pancreatic cancer cells in vitro. In vivo, combined treatment of gemcitabine and subcutaneous administration of TFF1 arrested tumor growth in xenograft mouse model and resulted in the better survival of KPC mice by inhibiting EMT and cancer stemness. Conclusion: These results indicate that TFF1 can contribute to establishing a novel strategy to treat pancreatic cancer patients by enhancing chemosensitivity.

DOI： 10.1002/cam4.7395

Usefulness of fluorescent ureteral navigation in total pelvic exenteration using a two-team approach for locally recurrent pelvic malignancies-A video vignette

Ogura, A; Murata, Y; Jinno, T; Yoshikawa, N; Kajiyama, H; Ebata, T

COLORECTAL DISEASE 26 巻 ( 4 ) 頁： 812 - 813 2024年4月

Prediction model of the risk for lateral local recurrence in locally advanced rectal cancer without enlarged lateral lymph nodes: Lessons from a Japanese multicenter pooled analysis of 812 patients

Ogura, A; Shiomi, A; Yamamoto, S; Komori, K; Hamamoto, H; Manabe, S; Miyakita, H; Okuda, J; Yatsuya, H; Uehara, K

ANNALS OF GASTROENTEROLOGICAL SURGERY 8 巻 ( 2 ) 頁： 284 - 292 2024年3月

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

Aim: Although the oncological impact of lateral lymph node dissection on enlarged lateral lymph nodes has been gradually accepted over the last decade, that on lateral lymph nodes without swelling remains doubtful. This study aimed to develop a prediction model for the future risk of lateral local recurrence and to clarify the value of adding lateral lymph node dissection in locally advanced rectal cancer without enlarged lateral lymph nodes. Methods: This retrospective, multi-institutional study recruited 812 patients with cStage II/III low rectal cancer without enlarged lateral lymph nodes <7 mm. Total lateral local recurrence was a hypothetical value of future risk of lateral local recurrence when lateral lymph node dissection was never performed. Results: Overall, total lateral local recurrences were observed in 67 patients (8.3%). In the multivariate analyses, the strongest risk factor for total local recurrences was no preoperative chemoradiotherapy (odds ratio [OR][95%Cl]: 33.2 [4.56–241.7], P < 0.001), followed by tumor distance ≤40 mm (OR [95%Cl]: 2.71 [1.51–4.86], P < 0.001) and lateral lymph node 5–7 mm (OR[95%Cl]: 2.38 [1.26–4.48], P = 0.007). In patients with lateral lymph nodes of 5–7 mm, the total lateral recurrence rate was 4.8% after preoperative chemoradiotherapy. Lateral lymph node dissection could reduce from a total lateral local recurrence of 21.6% to an actual lateral local recurrence of 8.0% in patients without preoperative treatment. Conclusion: We introduce a novel prediction model of future risk of lateral local recurrences, which has the potential to enable us to indicate lateral lymph node dissection selectively according to the patients' risks.

DOI： 10.1002/ags3.12742

Standardization of laparoscopic pelvic exenteration; usefulness of <i>lateral-first approach</i> using the umbilical ligament as a reliable surgical landmark-A Video Vignette

Ogura, A; Murata, Y; Uehara, K; Kobayashi, R; Sando, M; Ebata, T

COLORECTAL DISEASE 26 巻 ( 2 ) 頁： 399 - 400 2024年2月

クローン病再手術症例に対する低侵襲手術の治療成績

服部憲史, 中山吾郎, 梅田晋一, 岸田貴喜, 小倉淳司, 村田悠記, 中西香企, 清水大, 神田光郎, 田中千恵, 藤原道隆, 小寺泰弘

日本内視鏡外科学会雑誌 28 巻 ( 7 ) 頁： 2164 - 2164 2023年12月

特集見てわかる! 下部消化管手術における最適な剝離層悪性疾患の手術骨盤内臓全摘術の剝離層の選択-膀胱下腹筋膜を意識したumbilicalアプローチを中心に

村田悠記, 上原圭, 小倉淳司, 小林龍太朗, 深田浩志, 余語孝乃助, 江畑智希

臨床外科 78 巻 ( 9 ) 頁： 1093 - 1098 2023年9月

Impact of combined resection of the internal iliac artery on loss of volume of the gluteus muscles after pelvic exenteration

Murata, Y; Uehara, K; Ogura, A; Ishigaki, S; Aiba, T; Mizuno, T; Kokuryo, T; Yokoyama, Y; Yatsuya, H; Ebata, T

SURGERY TODAY 53 巻 ( 7 ) 頁： 791 - 799 2023年7月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Surgery Today

Purpose: To clarify the influence of additional internal iliac artery (IIA) resection on the loss of the gluteus muscle volume after pelvic exenteration (PE). Methods: The subjects of this retrospective analysis were 78 patients who underwent PE with or without IIA resection (n = 44 and n = 34, respectively) between 2006 and 2018. The areas of gluteal muscles (GMs) and psoas muscles (PSMs) were calculated using CT images before and 6 months after PE, and the difference was compared. Results: The volumes of the GMs and PSMs were significantly reduced after PE (P < 0.001 and P = 0.005, respectively). In the IIA resection group, the GMs were significantly reduced after surgery, but the PSMs were not. The maximum GM (Gmax) was the most atrophied among the GMs. Multivariable analysis revealed that complete IIA resection was an independent promotor of the loss of volume of the Gmax (P = 0.044). In 18 patients with unilateral IIA resection, the downsizing rate of the Gmax was significantly greater on the resected side than on the non-resected side (P = 0.008). Conclusions: The GMs and PSMs were significantly smaller after PE. Complete IIA resection reduced the Gmax area remarkably. Preservation of the superior gluteus artery is likely to help maintain Gmax size, suggesting a potential preventative measure against secondary sarcopenia.

DOI： 10.1007/s00595-022-02635-z