Faculty Profiles - FUJIWARA Toshiyoshi

Papers - FUJIWARA Toshiyoshi

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切除可能膵癌における血中循環腫瘍DNA内Kras遺伝子変異とCA19-9値による予後層別化の試み

宮本耕吉, 吉田龍一, 重安邦俊, 安井和也, 高木弘誠, 藤智和, 楳田祐三, 八木孝仁, 藤原俊義

日本分子腫瘍マーカー研究会誌 38 20 - 21 2022.12

ロボット支援膵頭十二指腸切除術:手技の工夫と成績当院におけるロボット支援下膵頭十二指腸切除術

高木弘誠, 楳田祐三, 吉田龍一, 藤智和, 安井和也, 木村次郎, 畑七々子, 藤原俊義

日本内視鏡外科学会雑誌 27 ( 7 ) 2595 - 2595 2022.12

十二指腸腫瘍の局在や特性に応じたLECSのアプローチ法や切除法の工夫と成績

菊地覚次, 西崎正彦, 黒田新士, 賀島肇, 松三雄騎, 半澤俊哉, 垣内慶彦, 田辺俊介, 野間和広, 香川俊輔, 楳田祐三, 藤原俊義

日本内視鏡外科学会雑誌 27 ( 7 ) 730 - 730 2022.12

チームで極める栄養管理-急性期から回復期まで- 食道癌周術期管理における早期包括的介入の有用性岡山大学病院におけるPERiOの取り組み

野間和広, 橋本将志, 前田直見, 菊地覚次, 田辺俊介, 白川靖博, 藤原俊義

学会誌JSPEN 4 ( Suppl.2 ) 128 - 129 2022.12

Involvement in the tumor-infiltrating CD8+ T cell expression by the initial disease of remnant gastric cancer. International journal

Yoshihiko Kakiuchi, Satoru Kikuchi, Shinji Kuroda, Shunsuke Kagawa, Toshiyoshi Fujiwara

World journal of surgical oncology 20 ( 1 ) 374 - 374 2022.11

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

BACKGROUND: Remnant gastric cancer (RGC) has been increasing for various reasons such as a longer life span, medical progress, and others. It generally has a poor prognosis, and its mechanism of occurrence is unknown. The purpose of this study was to evaluate the clinicopathological features of and clarify the oncological features of RGC. METHODS: Between January 2002 and January 2017, 39 patients with RGC following distal gastrectomy underwent curative surgical resection at the Okayama University Hospital; their medical records and immunohistochemically stained extracted specimens were used for retrospective analysis. RESULTS: On univariate analysis, initial gastric disease, pathological lymph node metastasis, and pathological stage were the significant factors associated with poor overall survival (p=0.014, 0.0061, and 0.016, respectively). Multivariate analysis of these 3 factors showed that only initial gastric disease caused by malignant disease was an independent factor associated with a poor prognosis (p=0.014, hazard ratio: 4.2, 95% confidence interval: 1.3-13.0). In addition, tumor-infiltrating CD8+ T cells expression was higher in the benign disease group than in the malignant group (p=0.046). CONCLUSIONS: Initial gastrectomy caused by malignant disease was an independent poor prognostic factor of RGC, and as one of the causes, lower level of tumor-infiltrating CD8+ T cells in RGC may involve in.

DOI： 10.1186/s12957-022-02853-2

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Surgical Strategies to Dissect around the Superior Mesenteric Artery in Robotic Pancreatoduodenectomy. International journal

Kosei Takagi, Yuzo Umeda, Ryuichi Yoshida, Tomokazu Fuji, Kazuya Yasui, Jiro Kimura, Nanako Hata, Kento Mishima, Takahito Yagi, Toshiyoshi Fujiwara

Journal of clinical medicine 11 ( 23 ) 2022.11

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

The concept of the superior mesenteric artery (SMA)-first approach has been widely accepted in pancreatoduodenectomy. However, few studies have reported surgical approaches to the SMA in robotic pancreatoduodenectomy (RPD). Herein, we present our surgical strategies to dissect around the SMA in RPD. Among the various approaches, our standard protocol for RPD included the right approach to the SMA, which can result in complete tumor resection in most cases. In patients with malignant diseases requiring lymphadenectomy around the SMA, we developed a novel approach by combining the left and right approaches in RPD. Using this approach, circumferential dissection around the SMA can be achieved through both the left and right sides. This approach can also be helpful in patients with obesity or intra-abdominal adhesions. The present study summarizes the advantages and disadvantages of both the approaches during RPD. To perform RPD safely, surgeons should understand the different surgical approaches and select the best approach or a combination of different approaches, depending on demographic, anatomical, and oncological factors.

DOI： 10.3390/jcm11237112

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Oncolytic virus-mediated reducing of myeloid-derived suppressor cells enhances the efficacy of PD-L1 blockade in gemcitabine-resistant pancreatic cancer. International journal

Yoshinori Kajiwara, Hiroshi Tazawa, Motohiko Yamada, Nobuhiko Kanaya, Takuro Fushimi, Satoru Kikuchi, Shinji Kuroda, Toshiaki Ohara, Kazuhiro Noma, Ryuichi Yoshida, Yuzo Umeda, Yasuo Urata, Shunsuke Kagawa, Toshiyoshi Fujiwara

Cancer immunology, immunotherapy : CII 72 ( 5 ) 1285 - 1300 2022.11

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

Pancreatic ductal adenocarcinoma (PDAC) is often refractory to treatment with gemcitabine (GEM) and immune checkpoint inhibitors including anti-programmed cell death ligand 1 (PD-L1) antibody. However, the precise relationship between GEM-resistant PDAC and development of an immunosuppressive tumor microenvironment (TME) remains unclear. In this study, we investigated the immunosuppressive TME in parental and GEM-resistant PDAC tumors and assessed the therapeutic potential of combination therapy with the telomerase-specific replication-competent oncolytic adenovirus OBP-702, which induces tumor suppressor p53 protein and PD-L1 blockade against GEM-resistant PDAC tumors. Mouse PDAC cells (PAN02) and human PDAC cells (MIA PaCa-2, BxPC-3) were used to establish GEM-resistant PDAC lines. PD-L1 expression and the immunosuppressive TME were analyzed using parental and GEM-resistant PDAC cells. A cytokine array was used to investigate the underlying mechanism of immunosuppressive TME induction by GEM-resistant PAN02 cells. The GEM-resistant PAN02 tumor model was used to evaluate the antitumor effect of combination therapy with OBP-702 and PD-L1 blockade. GEM-resistant PDAC cells exhibited higher PD-L1 expression and produced higher granulocyte-macrophage colony-stimulating factor (GM-CSF) levels compared with parental cells, inducing an immunosuppressive TME and the accumulation of myeloid-derived suppressor cells (MDSCs). OBP-702 significantly inhibited GEM-resistant PAN02 tumor growth by suppressing GM-CSF-mediated MDSC accumulation. Moreover, combination treatment with OBP-702 significantly enhanced the antitumor efficacy of PD-L1 blockade against GEM-resistant PAN02 tumors. The present results suggest that combination therapy involving OBP-702 and PD-L1 blockade is a promising antitumor strategy for treating GEM-resistant PDAC with GM-CSF-induced immunosuppressive TME formation.

DOI： 10.1007/s00262-022-03334-x

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Dual-targeted near-infrared photoimmunotherapy for esophageal cancer and cancer-associated fibroblasts in the tumor microenvironment. International journal

Hiroaki Sato, Kazuhiro Noma, Toshiaki Ohara, Kento Kawasaki, Masaaki Akai, Teruki Kobayashi, Noriyuki Nishiwaki, Toru Narusaka, Satoshi Komoto, Hajime Kashima, Yuki Katsura, Takuya Kato, Satoru Kikuchi, Hiroshi Tazawa, Shunsuke Kagawa, Yasuhiro Shirakawa, Hisataka Kobayashi, Toshiyoshi Fujiwara

Scientific reports 12 ( 1 ) 20152 - 20152 2022.11

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

Cancer-associated fibroblasts (CAFs) play a significant role in tumor progression within the tumor microenvironment. Previously, we used near-infrared photoimmunotherapy (NIR-PIT), a next-generation cancer cell-targeted phototherapy, to establish CAF-targeted NIR-PIT. In this study, we investigated whether dual-targeted NIR-PIT, targeting cancer cells and CAFs, could be a therapeutic strategy. A total of 132 cases of esophageal cancer were analyzed for epidermal growth factor receptor (EGFR), human epidermal growth factor 2 (HER2), and fibroblast activation protein (FAP) expression using immunohistochemistry. Human esophageal cancer cells and CAFs were co-cultured and treated with single- or dual-targeted NIR-PIT in vitro. These cells were co-inoculated into BALB/c-nu/nu mice and the tumors were treated with single-targeted NIR-PIT or dual-targeted NIR-PIT in vivo. Survival analysis showed FAP- or EGFR-high patients had worse survival than patients with low expression of FAP or EGFR (log-rank, P < 0.001 and P = 0.074, respectively), while no difference was observed in HER2 status. In vitro, dual (EGFR/FAP)-targeted NIR-PIT induced specific therapeutic effects in cancer cells and CAFs along with suppressing tumor growth in vivo, whereas single-targeted NIR-PIT did not show any significance. Moreover, these experiments demonstrated that dual-targeted NIR-PIT could treat cancer cells and CAFs simultaneously with a single NIR light irradiation. We demonstrated the relationship between EGFR/FAP expression and prognosis of patients with esophageal cancer and the stronger therapeutic effect of dual-targeted NIR-PIT than single-targeted NIR-PIT in experimental models. Thus, dual-targeted NIR-PIT might be a promising therapeutic strategy for cancer treatment.

DOI： 10.1038/s41598-022-24313-3

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腹腔鏡下スリーブ状胃切除(LSG)の安全な導入と普及への課題

菊地覚次, 賀島肇, 香川俊輔, 江口潤, 中司敦子, 高橋絢子, 黒田新士, 半澤俊哉, 庄司良平, 垣内慶彦, 松三雄騎, 野間和広, 楳田祐三, 和田淳, 藤原俊義

肥満研究 28 ( Suppl. ) 354 - 354 2022.11

マジンドール(Mazindol:MZD)先行導入後に腹腔鏡下スリーブ胃切除術を行った高度肥満の2例

賀島肇, 菊地覚次, 香川俊輔, 江口潤, 中司敦子, 高橋絢子, 黒田新士, 半澤俊哉, 庄司良平, 垣内慶彦, 松三雄騎, 野間和広, 楳田祐三, 和田淳, 藤原俊義

肥満研究 28 ( Suppl. ) 352 - 352 2022.11

【ロボット支援下手術の現況と展望】ロボット支援下手術の現況と展望<膵臓>

高木弘誠, 八木孝仁, 楳田祐三, 吉田龍一, 藤智和, 安井和也, 藤原俊義

日本外科学会雑誌 123 ( 6 ) 538 - 545 2022.11

Language：Japanese Publisher：(一社)日本外科学会

ロボット支援下膵切除術は,欧米先進諸国において近年急速に普及し,その手術成績についても一定のエビデンスが得られてきている.一方,本邦では2020年の保険収載以降,大学病院や基幹病院を中心として徐々に普及しつつあるが,標準手術としての定着にはもう少し時間を要するのが現状である.高難度手術である膵頭十二指腸切除術や膵体尾部切除術に対するロボット支援下手術の安全な導入と普及には,術式の定型化とトレーニングシステムの確立が急務である.さらに,安全な手術の実践には,ロボット支援下手術の特性を理解し,外科医個人のみならずチームとして成熟していくことが重要である.今回,ロボット支援下膵切除術の欧米におけるコンセンサスを検討するとともに,当施設におけるロボット支援下膵切除術の定型化に向けた手術概要とトレーニングシステム,チームとしての取り組みを報告する.(著者抄録)

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ASO Visual Abstract: Effect of Patient-Participation Continuous Nutritional Counseling in Gastric Cancer Patients Who Underwent Gastrectomy. International journal

Nobuo Takata, Satoru Kikuchi, Shinji Kuroda, Shunsuke Tanabe, Naoaki Maeda, Kazuhiro Noma, Ayako Takahashi, Yuzo Umeda, Kenichi Shikata, Kazuhide Ozaki, Toshiyoshi Fujiwara

Annals of surgical oncology 30 ( 2 ) 1119 - 1119 2022.10

Genomically stable gastric cancer characterized by hypomethylation in Wnt signal cascade. International journal

Hiroaki Tanioka, Yoshiko Mori, Takehiro Tanaka, Kazuya Yasui, Keisuke Kimura, Yuzo Umeda, Toshiyoshi Fujiwara, Akihiro Nyuya, Shuya Yano, Takeshi Nagasaka, Takeshi Nagasaka

Oncology 101 ( 2 ) 105 - 116 2022.10

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

Introduction Gastric cancer is divided into four subtypes by their molecular features linked with genetic alterations, e.g., Epstein-Barr virus (EBV), microsatellite instability-high (MSI-high), chromosomal instability (CIN), and genomically stable (GS), called as TCGA classification. In this study, we tried to clarify the epigenetic features of the four GC subtypes according to aberrant methylation status in 23 loci. Methods A total of 98 gastric cancers and their normal gastric mucosa samples were included in this study. We divided gastric cancers into TCGA subtypes which were determined in line with MSI-high, EBV, CIN, to GS by their molecular features. The 13 loci of polymorphic microsatellite sequences were used to determine loss of heterogeneity (LOH) for the detection of CIN. The MSI status was determined by three mononucleotide repeat markers. Infection of EBV was determined by recovering EBV BNRF1 sequence from genomic DNA collected from gastric cancers. Methylation status of 23 loci was investigated by the combined bisulfite restriction analysis (COBRA). Status of other findings, e.g., KRAS mutations, HER2 expression status and infection of helicobacter pylori were confirmed. Results Gastric cancers were divided into MSI (13%), EBV (7%), CIN (53%), and GS (27%). By histological classification, poorly differentiated adenocarcinoma (por) was more in tumors categorized in MSI-high, and GS and signet-ring cell carcinoma (sig) was more in GS. Among the 23 loci investigated their methylation status, 18 loci were significantly hypermethylated in caner tissues. A unsupervised clustering divided gastric cancers into two clusters, and revealed that most GS tumors clustered together in a cluster that exhibited lower methylation levels, distinct from the other subtypes. The inter-variable clustering revealed that a cluster contained the three loci (SFRP2-region 1/2 and APC) belonging to the Wnt signal cascade (Wnt-associated loci). The mean methylation score of Wnt-associated loci was the lowest in GS tumors (MSI-high: 2.7 [95% confidence interval (CI), 2.3-2.9]; EBV:2.1[1.2-3.1]; CIN: 2.4 [2.2-2.7]; GS: 1.3 [0.8-0.7]). In contrast, the mean methylation score of the other 15 loci was significantly higher in MSI-high, while that in GS was as same as that in EBV or CIN (MSI- high: 10.4 [8.3-12.4]; EBV:5.7 [1.7-9.7]; CIN: 4.4 [3.6-5.1]; GS: 3.4 [2.2-4.6]). Additionally, the lower methylation score of Wnt-associated loci was observed only in sig tumors. Conclusions GS subtype tumors have the potential to possess distinct signatures in DNA hypomethylation profiles in Wnt signaling pathway, especially in signet-ring cell carcinoma.

DOI： 10.1159/000527098

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Prognostic risk factors for postoperative long-term outcomes in elderly stage IA gastric cancer patients. International journal

Yoshihiko Kakiuchi, Shinji Kuroda, Satoru Kikuchi, Shunsuke Kagawa, Toshiyoshi Fujiwara

Journal of gastrointestinal oncology 13 ( 5 ) 2178 - 2185 2022.10

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

BACKGROUND: The number of gastric cancer (GC) patients with other diseases is increasing due to the aging of the population. In particular, in stage IA GC patients who have multiple diseases, surgical indications should be considered after identifying prognostic factors. We therefore investigated prognostic factors for stage IA GC in the elderly. METHODS: Patient characteristics were collected and analyzed retrospectively for elderly patients with stage IA GC who underwent curative surgical treatment at Okayama University Hospital between 2010 and 2015, and an elderly group (EG; 75-79 years old) and very elderly group (VEG; ≥80 years old) were compared. RESULTS: Fifty-three patient in the EG and 31 patients in the VEG were compared. No factors associated with clinicopathological characteristics or surgical or postoperative short-term outcomes differed significantly between groups. Although no factors in the EG appeared significantly associated with poor overall survival (OS), severe comorbidity [Charlson Comorbidity Index (CCI) ≥2; P=0.019], open gastrectomy (P=0.012), high volume of blood loss (≥300 mL; P=0.013) and long postoperative hospital stay (≥14 days; P=0.041) were significantly associated with poor OS. Furthermore, only CCI ≥2 [hazard ratio (HR) =9.2; 95% confidence interval (CI): 1.2-68.9; P=0.032] was an independent prognostic factor associated with poor OS. Five-year OS was 88.9% for CCI 0/1 patients and 62.3% for CCI ≥2 patients, representing very impressive results. CONCLUSIONS: CCI ≥2 is an important prognostic factor in clinical decisions in stage IA GC patients ≥2, so careful determination of surgical indications is desirable.

DOI： 10.21037/jgo-22-527

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高齢者に対する大腸がん治療の個別化を考える周術期管理チーム介入により高齢Frail大腸癌患者に対する手術の安全性は向上したか

寺石文則, 庄司良平, 賀島肇, 松三雄騎, 重安邦俊, 近藤喜太, 黒田新士, 香川俊輔, 松岡義和, 森松博史, 藤原俊義

日本癌治療学会学術集会抄録集 60回 OWS9 - 3 2022.10

腸内細菌叢からがんを考える腸内細菌叢は潰瘍性大腸炎においてRNA編集を介し発癌を促進する

重安邦俊, 高橋一剛, 近藤喜太, 梅田響, 田澤大, 藤原俊義

日本癌治療学会学術集会抄録集 60回 WS17 - 4 2022.10

RNA編集は大腸癌の発癌や進展を促進するのみならず免疫療法のターゲットとなり得る

重安邦俊, 武田正, 高橋一剛, 小松泰浩, 畑七々子, 梅田響, 高橋利明, 田澤大, 藤原俊義

日本癌治療学会学術集会抄録集 60回 P40 - 5 2022.10

Neoadjuvant chemotherapy for locally advanced esophageal cancer comparing cisplatin and 5-fluorouracil versus docetaxel plus cisplatin and 5-fluorouracil: a propensity score matching analysis.

Noriyuki Nishiwaki, Kazuhiro Noma, Tomoyoshi Kunitomo, Masashi Hashimoto, Naoaki Maeda, Shunsuke Tanabe, Kazufumi Sakurama, Yasuhiro Shirakawa, Toshiyoshi Fujiwara

Esophagus : official journal of the Japan Esophageal Society 19 ( 4 ) 626 - 638 2022.10

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

BACKGROUND: The standard treatment for locally advanced esophageal cancer is preoperative chemotherapy with cisplatin and 5-fluorouracil (CF), followed by surgery. Although docetaxel plus cisplatin and 5-fluorouracil (DCF) has been reported to have favorable outcomes, no study has compared its therapeutic efficacy to that of standard treatment. This study aimed to compare the therapeutic effects of CF and DCF in the real world by matching patient background factors using propensity scores. METHODS: We retrospectively reviewed the data of 237 patients with esophageal squamous cell carcinoma who underwent esophagectomy between January 2008 and December 2018. Patients were divided into two groups based on the preoperative chemotherapy regimens of CF (79 patients) or DCF (158 patients), and 49 matched pairs were finally analyzed using propensity score matching. Short- and long-term outcomes were compared between groups. RESULTS: After matching, although no significant differences in survival were observed among the groups, patients receiving DCF showed a significantly high histological response (P < 0.001). Subgroup analyses demonstrated that DCF therapy had better overall survival (P = 0.046) and relapse-free survival (P = 0.010) among pathological T3 and T4 cases. Whereas, adverse effects of chemotherapy were more frequent in the DCF group. CONCLUSIONS: Patients receiving DCF had higher pathological response and better survival than those receiving CF, especially in pathological T3 and T4 cases matched using propensity scores. Thus, the DCF regimen might be an effective treatment for locally advanced esophageal cancer. However, the adverse side effects of chemotherapy remain high and should be handled appropriately.

DOI： 10.1007/s10388-022-00934-5

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[Telomerase-Specific Oncolytic Adenovirus Expressing p53 Gene Stimulating CD8+ Memory T Cells in Pancreatic Cancer].

Masashi Hashimoto, Shinji Kuroda, Nobuhiko Kanaya, Yoshihiko Kakiuchi, Satoru Kikuchi, Hiroshi Tazawa, Shunsuke Kagawa, Yasuo Urata, Toshiyoshi Fujiwara

Gan to kagaku ryoho. Cancer & chemotherapy 49 ( 10 ) 1127 - 1129 2022.10

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

Pancreatic cancer has poor prognosis despite the various developed multimodal treatment strategies. Currently, neoadjuvant chemotherapy and immunotherapy have attracted substantial attention as effective treatment strategies. However, amplifying immune response with existing treatments is difficult. We developed telomerase-specific oncolytic adenoviruses (OAs), including OBP-301 that is currently tested in a clinical trial of combined anti-PD-1 antibody and p53-armed OBP- 301 variant(OBP-702). OAs have immune-modulation functions and induce CD8+ T cells into tumors by releasing immunogenic cell death markers, such as extracellular adenosine triphosphate. Here, we investigated the effectiveness of OBP- 702 in pancreatic cancer treatments, focusing on the influence on CD8+ memory T cells.

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Surgical Resection for Local and Lateral Lymph Node Recurrence of MSI-high Cecal Cancer with the BRAF V600E Mutation.

Fuminori Teraishi, Atsushi Jikuhara, Ryunosuke Ogawa, Toshiyoshi Fujiwara

Acta medica Okayama 76 ( 5 ) 605 - 608 2022.10

Language：English

An 84-year-old female underwent open right hemicolectomy with D3 lymph node dissection for cecal cancer, pathologically identified as pT4aN2M0 Stage IIIc and BRAF mutation-positive. Due to early recurrence of abdominal wall and right lateral lymph nodes, the patient was treated with FOLFOXIRI+Bevacizumab. Imaging after 5 courses of chemotherapy found tumor shrinkage and no new metastases. The patient did not tolerate chemotherapy well, and tumor resection was performed. Microsatellite instability (MSI) testing using multiplex polymerase chain reaction (PCR) fragment analysis revealed MSI-high status. The patient is currently recurrence-free without chemotherapy at 1 year postoperatively. BRAF-mutated colorectal cancer has a poor prognosis, and may require resection of the metastatic or recurrent tumor after comprehensive evaluation.

DOI： 10.18926/AMO/64043

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Papers - FUJIWARA Toshiyoshi