Faculty Profiles - KANDA Mitsuro

Preclinical toxicological assessment of amido-bridged nucleic acid-modified antisense oligonucleotides targeting synaptotagmin XIII for intra-abdominal treatment of peritoneal metastasis of gastric cancer Reviewed

Mitsuro Kanda, Nao Takano, Hiroshi Miyauchi, Kohei Ueda, Masaaki Mizuno, Yuuya Kasahara, Yasuhiro Kodera, Satoshi Obika

Gastric Cancer 2024.8

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

Background: Peritoneal metastasis of gastric cancer is closely associated with dismal prognosis. In previous preclinical proof-of-concept studies, an amido-bridged nucleic acid (AmNA)-modified antisense oligonucleotide (ASO), designated ASO-4733 that targets the gene encoding synaptotagmin XIII (SYT13), inhibited cellular functions required for the formation of peritoneal metastasis of gastric cancer cells. ASO-4733 achieved therapeutic effects when intra-abdominally administered to mouse xenograft models. Here, we conducted an analysis of Syt13-deficient mice to determine the pharmacokinetics and toxicity of intra-abdominal administration of ASO-4733. Methods: The effects of Syt13-deficiency in mice were determined. Good Laboratory Practice toxicity tests and the toxicokinetics of intra-abdominal administration of ASO-4733 were conducted in cynomolgus monkeys and rats. The pharmacokinetics of ASO-4733 administered intravenously or intra-abdominally to rats were investigated. Results: Syt13-deficient mice exhibited normal reproduction, organ functions, and motor functions. Weekly intra-abdominal administration of ASO-4733 (125 mg/kg), corresponding to a 50-fold increase of the estimated clinical dose for 4 weeks, was well tolerated by cynomolgus monkeys. In rats, off-target toxicity (not attributable to hybridization) was observed after weekly intra-abdominal administration of ASO-4733. Blood concentrations of ASO-4733 were lower and rose more slowly after intra-abdominal administration compared with intravenous administration. Conclusions: The preclinical profile of intra-abdominal administration of ASO-4733 demonstrated its suitability for entry into clinical trials of patients with peritoneal metastasis of gastric cancer.

DOI： 10.1007/s10120-024-01548-9

Koki Nakanishi, Mitsuro Kanda, Seiji Ito, Yoshinari Mochizuki, Hitoshi Teramoto, Kiyoshi Ishigure, Toshifumi Murai, Takahiro Asada, Akiharu Ishiyama, Hidenobu Matsushita, Dai Shimizu, Chie Tanaka, Michitaka Fujiwara, Kenta Murotani, Yasuhiro Kodera

Gastric cancer : official journal of the International Gastric Cancer Association and the Japanese Gastric Cancer Association 2024.8

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

BACKGROUND: Large type 3 (diameter ≥ 8 cm) and type 4 gastric cancers have been arbitrarily combined in Japan as a single entity. However, whether these two types are oncologically similar remain unclear. This study aimed to clarify this issue. METHODS: In this retrospective study, we analyzed a database of 3,575 patients from nine institutions who underwent gastrectomy between 2010 and 2014. Using propensity scores to balance significant variables, we compared prognoses and tumor recurrences. RESULTS: Of patients with clinical T3/T4 who underwent R0 resection, 75 and 73 had large type 3 and 4 tumors, respectively. Patients with type 4 tumors had significantly lower overall survival rates than those of patients with large type 3 tumors (hazard ratio [HR] 1.77; 95% confidence interval [CI] 1.14-2.74). However, among the large type 3 tumors, a remarkable difference in prognosis was observed between the differentiated and undifferentiated histological types. A comparison was made between large type 3 with undifferentiated phenotype and type 4, each with 39 patients after propensity score matching. Outcomes in both groups were similar in terms of overall survival (HR 1.28; 95% CI 0.73-2.25) and relapse-free survival (HR 1.34; 95% CI 0.80-2.27). No statistically significant differences were observed in the incidence of peritoneal recurrence (35.9% vs. 46.1%, P = 0.36) and lymph node recurrence (25.6% vs. 12.8%, P = 0.15). CONCLUSIONS: Large type 3 tumors with undifferentiated phenotype and type 4 tumors were oncologically similar. This subgroup could be considered as a new entity for future clinical trials.

DOI： 10.1007/s10120-024-01546-x

ASO Author Reflections: Evaluating NPTXR as a Prognostic Biomarker and Therapeutic Target in Esophageal Squamous Cell Carcinoma Reviewed

Shinozuka, T; Kanda, M; Kodera, Y

ANNALS OF SURGICAL ONCOLOGY Vol. 31 ( 8 ) page： 5263 - 5272 2024.8

Exacerbated prognostic impact of multiple intramural metastasis versus single intramural metastasis of thoracic esophageal squamous cell carcinoma: evidence from an Uzbekistan cohort Reviewed

Yusupbekov, A; Shinozuka, T; Juraev, E; Usmanov, B; Kanda, M; Sakamoto, J; Tuychiev, O

SURGERY TODAY Vol. 54 ( 7 ) page： 771 - 778 2024.7

The long-term quality of life after distal and pylorus-preserving gastrectomy for stage I gastric cancer: A prospective multi-institutional study (CCOG1601). Reviewed

Chie Tanaka, Mitsuro Kanda, Kazunari Misawa, Yoshinari Mochizuki, Takuya Watanabe, Masashi Hattori, Kiyoshi Ishigure, Satoshi Sueoka, Hitoshi Teramoto, Akiharu Ishiyama, Ikue Nonogaki, Hidenobu Matsushita, Kenta Murotani, Yasuhiro Kodera

Surgery today 2024.6

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

PURPOSE: While regarded as function-preserving gastrectomy, few prospective longitudinal clinical trials have addressed the postoperative quality of life (QOL) after pylorus-preserving gastrectomy (PPG). We prospectively compared chronological changes in postoperative body weight and the QOL between PPG and distal gastrectomy (DG) for pathological Stage I gastric cancer (GC). METHODS: We conducted a multi-institutional prospective study (CCOG1601) to evaluate patients who underwent DG and PPG. The QOL was examined using the European Organization for Research and Treatment of Cancer Quality of life questionnaire-C30 (EORTC QLQ-C30) and the Post-Gastrectomy Syndrome Assessment Scale-37 (PGSAS-37). A total of 295 patients were enrolled from 15 institutions, and propensity score matching was performed to adjust for the essential variables for comparison analyses. RESULTS: After propensity score matching, 25 pairs of patients were identified. In the first postoperative month, DG achieved a superior nausea and vomiting score (EORTC QLQ-C30) and meal-related distress, indigestion, and dumping scores (PGSAS-37). No significant differences were noted between DG and PPG in the long-term QOL. Postoperative body weight loss was similar in both groups. CONCLUSIONS: This prospective observational study failed to demonstrate the superiority of PPG over DG in terms of postoperative body weight changes and the QOL.

DOI： 10.1007/s00595-024-02881-3

Prognostic Impact of CDKN2A Mutations Associated With Smoking and Drinking History in Japanese Digestive Cancers Reviewed

Fujita, K; Hayashi, M; Nakagawa, N; Kurimoto, K; Inokawa, Y; Takami, H; Nakanishi, K; Umeda, S; Shimizu, D; Hattori, N; Kanda, M; Tanaka, C; Nakayama, G; Kodera, Y

ANTICANCER RESEARCH Vol. 44 ( 6 ) page： 2699 - 2707 2024.6

Clinical practice guidelines for esophagogastric junction cancer: Upper GI Oncology Summit 2023 Reviewed

Kitagawa, Y; Matsuda, S; Gotoda, T; Kato, K; Wijnhoven, B; Lordick, F; Bhandari, P; Kawakubo, H; Kodera, Y; Terashima, M; Muro, K; Takeuchi, H; Mansfield, PF; Kurokawa, Y; So, J; Mönig, SP; Shitara, K; Rha, SY; Janjigian, Y; Takahari, D; Chau, I; Sharma, P; Ji, JF; de Manzoni, G; Nilsson, M; Kassab, P; Hofstetter, WL; Smyth, EC; Lorenzen, S; Doki, Y; Law, S; Oh, D; Ho, KY; Koike, T; Shen, L; van Hillegersberg, R; Kawakami, H; Xu, RH; Wainberg, Z; Yahagi, N; Lee, YY; Singh, R; Ryu, MH; Ishihara, R; Xiao, ZL; Kusano, C; Grabsch, HI; Hara, H; Mukaisho, KI; Makino, T; Kanda, M; Booka, E; Suzuki, S; Hatta, W; Kato, M; Maekawa, A; Kawazoe, A; Yamamoto, S; Nakayama, I; Narita, Y; Yang, HK; Yoshida, M; Sano, T

GASTRIC CANCER Vol. 27 ( 3 ) page： 401 - 425 2024.5

Outcomes of surgical treatment for enterovesical fistula in Crohn's disease. Reviewed

Hattori N, Nakayama G, Umeda S, Nakamura M, Yamamura T, Sawada T, Nakanishi K, Shimizu D, Kanda M, Hayashi M, Tanaka C, Kodera Y

Nagoya journal of medical science Vol. 86 ( 2 ) page： 280 - 291 2024.5

Killer cell lectin-like receptor G2 facilitates aggressive phenotypes of gastric cancer cells via dual activation of the ERK1/2 and JAK/STAT pathways Reviewed

Ito, Y; Kanda, M; Sasahara, M; Tanaka, C; Shimizu, D; Umeda, S; Inokawa, Y; Hattori, N; Hayashi, M; Nakayama, G; Kodera, Y

GASTRIC CANCER Vol. 27 ( 3 ) page： 506 - 518 2024.5

Long-term quality of life after open and laparoscopic total gastrectomy for stage I gastric cancer: A prospective multi-institutional study (CCOG1504) Reviewed

Tanaka, C; Kanda, M; Misawa, K; Mochizuki, Y; Hattori, M; Sueoka, S; Watanabe, T; Yamada, T; Murotani, K; Kodera, Y

ANNALS OF GASTROENTEROLOGICAL SURGERY 2024.4

Therapeutic antibody targeting natriuretic peptide receptor 1 inhibits gastric cancer growth via BCL-2-mediated intrinsic apoptosis Reviewed

Sasahara, M; Kanda, M; Tanaka, C; Shimizu, D; Umeda, S; Takami, H; Inokawa, Y; Hattori, N; Hayashi, M; Nakayama, G; Kodera, Y

INTERNATIONAL JOURNAL OF CANCER Vol. 154 ( 7 ) page： 1272 - 1284 2024.4

Risk Factors for Long-term Body Weight Loss After Proximal Gastrectomy: A Retrospective Analysis. Reviewed International journal

Yuya Agatsuma, Koki Nakanishi, Chie Tanaka, Mitsuro Kanda, Dai Shimizu, Shinichi Umeda, Keisuke Kurimoto, Yoshikuni Inokawa, Hideki Takami, Norifumi Hattori, Masamichi Hayashi, Goro Nakayama, Michitaka Fujiwara, Yasuhiro Kodera

Anticancer research Vol. 44 ( 4 ) page： 1645 - 1651 2024.4

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

BACKGROUND/AIM: Proximal gastrectomy (PG) is a therapy for early-stage proximal gastric cancer and offers advantages such as the preservation of food storage capacity and less body weight loss (BWL). Nevertheless, significant BWL following PG may occur, affecting the patient's well-being and survival. In this study, we aimed to identify the relevant factors for BWL following PG by analyzing an institutional database of patients. PATIENTS AND METHODS: We enrolled 58 consecutive patients who underwent PG for gastric or esophagogastric junction cancer at our institution between April 2004 and March 2021. Based on BWL at 12 months postoperatively, we retrospectively compared and examined patient characteristics, surgical details, and nutritional markers. RESULTS: The mean BWL of the 58 patients included in this analysis was 14.0±7.2%. When the patients were divided into BWL-moderate (n=29) and BWL-severe (n=29) groups using a cutoff value of 15.7%, the latter experienced early BWL within 1 month postoperatively, primarily due to body fat mass reduction, with no recovery during the 60 months of follow up. In contrast, gradual recovery was observed among patients in the BWL-moderate group after experiencing the lowest body weight 24 months postoperatively. A greater decrease in body fat mass than in muscle mass was observed in both groups. Blood hemoglobin levels did not recover in the BWL-severe group. CONCLUSION: The BWL-severe group after proximal gastrectomy demonstrated significantly greater early postoperative BWL, primarily attributed to a reduction in body fat mass, with hardly any recovery. Early postoperative nutritional intervention might be proposed to prevent long-term BWL.

DOI： 10.21873/anticanres.16963

希少癌に対する治療戦略-標準化に向けた取り組み- 十二指腸癌に対する膵頭十二指腸切除術施行症例のNCDデータベースを用いた観察研究リンパ節郭清範囲,周術期化学療法,解剖学的部位別リンパ節転移率の分析 Reviewed

林真路, 高見秀樹, 猪川祥邦, 田中晴祥, 栗本景介, 中川暢彦, 山本博之, 服部憲史, 神田光郎, 田中千恵, 中山吾郎, 山上裕機, 小寺泰弘

日本外科学会定期学術集会抄録集 Vol. 124回 page： WS - 1 2024.4

A multi-institutional prospective observational study to compare postoperative quality of life of patients who undergo total or proximal gastrectomy for early gastric cancer (CCOG1602). Reviewed International journal

Mitsuro Kanda, Chie Tanaka, Kazunari Misawa, Yoshinari Mochizuki, Takuya Watanabe, Satoshi Sueoka, Akiharu Ishiyama, Takanobu Yamada, Takashi Oshima, Masashi Hattori, Shinya Koike, Kiyoshi Ishigure, Hitoshi Teramoto, Kenta Murotani, Yasuhiro Kodera

World journal of surgery Vol. 48 ( 3 ) page： 681 - 691 2024.3

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

BACKGROUND: Proximal gastrectomy (PG) has become an increasingly preferred procedure for treating early cancer in the upper third of the stomach. However, advantages of PG in postoperative quality of life (QOL) over total gastrectomy (TG) has not fully proven. METHODS: We conducted a multi-institutional prospective observational study (CCOG1602) of patients who undergo TG or PG for cStage I gastric cancer. We used the PGSAS-37 and EORTC-QLQ-C30 to evaluate the changes in body weight and QOL over a 3-year postoperative period. The primary endpoint was the weight loss rate 3 years after surgery. RESULTS: We enrolled 109 patients from 18 institutions and selected 65 and 19 patients for inclusion in the TG and PG groups, respectively. Mean postoperative weight loss rates were 16.0% and 11.7% for the TG and PG groups, respectively (p = 0.056, Cohen's d 0.656) during postoperative year 1% and 15.0% and 10.8% for TG and PG (p = 0.068, Cohen's d 0.543), respectively, during postoperative year 3, indicating that the PG group achieved a better trend with a moderate effect size. According to the PGSAS-37, the PG group experienced a better trend in the indigestion subscale (p < 0.001, Cohen's d -1.085) and total symptom score (p = 0.050, Cohen's d -0.59) during postoperative year 3 compared with the TG group. In contrast, the EORTC-QLQ-C30 detected no difference between the groups at any time point during 3-year postoperative period. CONCLUSIONS: This prospective study demonstrates that PG tended to be more favorable compared with TG with respect to postoperative weight loss and QOL, particularly regarding indigestion.

DOI： 10.1002/wjs.12088

ASO Visual Abstract: Absence of Hypercoagulation Status After Neoadjuvant Treatment is Associated with Favorable Prognosis in Patients Undergoing Subtotal Esophagectomy for Esophageal Squamous Cell Carcinoma Reviewed

Sugiyama, F; Kanda, M; Shimizu, D; Umeda, S; Inokawa, Y; Hattori, N; Hayashi, M; Tanaka, C; Nakayama, G; Kodera, Y

ANNALS OF SURGICAL ONCOLOGY 2024.2

胃癌診療におけるバイオマーカーの意義胃癌転移形式特異的バイオマーカーの同定と創薬への展開 Reviewed

神田光郎, 田中千恵, 清水大, 中西香企, 梅田晋一, 高見秀樹, 猪川祥邦, 服部憲史, 林真路, 中山吾郎, 藤原道隆, 小寺泰弘

日本胃癌学会総会記事 Vol. 96回 page： 162 - 162 2024.2

術後合併症の予測と対策ドレーンアミラーゼ値を用いた腹腔内感染症の早期予測法 Reviewed

中西香企, 神田光郎, 田中千恵, 杉田静紀, 清水大, 宮田一志, 藤原道隆, 江畑智希, 小寺泰弘

日本胃癌学会総会記事 Vol. 96回 page： 179 - 179 2024.2

血清胃癌診断マーカーとしてのstromal cell-derived factor 4の同定 Reviewed

篠塚高宏, 神田光郎, 中西香企, 清水大, 田中千恵, 梅田晋一, 猪川祥邦, 高見秀樹, 服部憲史, 林真路, 中山吾郎, 藤原道隆, 小寺泰弘

日本胃癌学会総会記事 Vol. 96回 page： 307 - 307 2024.2

Development of Unmanned Remote System to Find Radiation Sources Based on 4π Gamma Imaging Reviewed

Mukai, A; Kanda, M; Shimazoe, K; Ishida, F; Takada, E; Tamura, Y; Woo, H; Takahashi, H; Uenomachi, M; Asama, H; Kawarabayashi, J; Tanabe, K; Tsuchiya, K; Kamada, K; Tomita, H

JOURNAL OF ROBOTICS AND MECHATRONICS Vol. 36 ( 1 ) page： 79 - 87 2024.2

早期胃癌に対する低侵襲手術におけるIndocyanine Green蛍光マーキングの有用性 Reviewed

冨永奈沙, 田中千恵, 中西香企, 清水大, 神田光郎, 中山吾郎, 藤原道隆, 小寺泰弘

日本胃癌学会総会記事 Vol. 96回 page： 465 - 465 2024.2

当科における噴門側胃切除術後再建の治療成績 Reviewed

田中千恵, 中西香企, 清水大, 神田光郎, 藤原道隆, 小寺泰弘

日本胃癌学会総会記事 Vol. 96回 page： 265 - 265 2024.2

サルコペニアに対する治療戦略と成績胃癌手術におけるサルコペニアが短期成績とADLに与える影響の検討 Reviewed

杉田静紀, 田中千恵, 中西香企, 神田光郎, 小寺泰弘, 江畑智希

日本胃癌学会総会記事 Vol. 96回 page： 206 - 206 2024.2

Protocol of a phase II study investigating the efficacy and safety of trifluridine/tipiracil plus ramucirumab as a third-line or later treatment for advanced gastric cancer. Reviewed

Koki Nakanishi, Chie Tanaka, Mitsuro Kanda, Kazushi Miyata, Nozomu Machida, Mitsuru Sakai, Daisuke Kobayashi, Hitoshi Teramoto, Akiharu Ishiyama, Bin Sato, Takashi Oshima, Masaki Kajikawa, Hidenobu Matsushita, Kiyoshi Ishigure, Katsuya Yamashita, Shinichi Fujitake, Satoshi Sueoka, Takahiro Asada, Dai Shimizu, Shizuki Sugita, Yachiyo Kuwatsuka, Osamu Maeda, Satoshi Furune, Kenta Murotani, Yuichi Ando, Tomoki Ebata, Yasuhiro Kodera

Nagoya journal of medical science Vol. 86 ( 1 ) page： 43 - 51 2024.2

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

In Japan, systemic chemotherapy is the standard treatment for unresectable, advanced, or recurrent gastric cancer. However, numerous patients with gastric cancer do not receive late-line treatment because of the rapid progression of gastric cancer. Additionally, late-line treatments, such as nivolumab, trifluridine tipiracil (FTD/TPI), or irinotecan, have limited effects on improving clinical symptoms and delaying the onset of symptoms associated with cancer progression. Recently, a combination of FTD/TPI and ramucirumab was reported to have a high response rate in late-line treatment; however, owing to patient selection bias and a high rate of hematologic toxicity in that previous study, this regimen may not be feasible in real-world clinical applications. Our objective is to conduct a single-arm phase II study to assess the safety and efficacy of FTD/TPI plus ramucirumab combination therapy for gastric cancer after third-line treatment under real-world clinical conditions. This study will recruit 32 patients according to eligibility criteria and administer FTD/TPI (35 mg/m2) and intravenous ramucirumab (8 mg/kg). The primary endpoint will be the time to treatment failure. The secondary endpoints will include the overall survival time, progression-free survival time, overall response rate, disease control rate, relative dose intensity, and incidence of adverse events. The results will add new insights for improving the late-line treatment of advanced gastric cancer.

DOI： 10.18999/nagjms.86.1.43

Genetic polymorphisms as predictive biomarkers of adverse events during preoperative chemotherapy in esophageal cancer. Reviewed International journal

Yao Liang, Osamu Maeda, Kazushi Miyata, Mitsuro Kanda, Shizuki Sugita, Dai Shimizu, Kazuki Nishida, Yasuhiro Kodera, Yuichi Ando

Cancer chemotherapy and pharmacology Vol. 93 ( 2 ) page： 121 - 127 2024.2

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

PURPOSE: This study aimed to explore associations between genetic polymorphisms and adverse effects due to preoperative chemotherapy with docetaxel, cisplatin, and fluorouracil (DCF) for esophageal cancer. METHODS: Preoperative DCF (docetaxel, 70 mg/m2/day, day 1; cisplatin, 70 mg/m2/day, day 1; fluorouracil, 750 mg/m2/day, days 1-5) was repeated every 3 weeks for up to three cycles. Genotyping of nine candidate genetic polymorphisms was conducted using blood samples from the enrolled patients. RESULTS: According to a multivariable analysis evaluating 50 patients, grade 3 or worse neutropenia was more likely to occur in those with the ABCC2-24C/T or T/T genotype (rs717620) (OR, 5.30, P = 0.013). Additionally, patients with the TYMS 3'-UTR 0 bp/0 bp genotype (rs151264360) showed a trend toward grade 3 or worse hyponatremia (OR, 0.16, P = 0.005). Grade 2 or worse thrombocytopenia was more likely to occur in patients with the TNF-α-1031C/T or T/T genotype (rs1799964) (OR, 6.30, P = 0.016) and IL-6-634C/C genotype (rs1800796) (OR, 0.18, P = 0.034), and grade 2 or worse anemia was more likely to occur in patients with the MCP-1-2518G/G genotype (rs1024611) (OR, 0.19, P = 0.027). CONCLUSIONS: ABCC2-24C > T (rs717620), TYMS 3'-UTR 6-bp indel (rs151264360), TNF-α-1031T > C (rs1799964) as well as IL-6-634G > C (rs1800796), and MCP-1-2518A > G (rs1024611) polymorphisms might serve as independent and predictive biomarkers for neutropenia, hyponatremia, thrombocytopenia, and anemia, respectively, during preoperative chemotherapy with docetaxel, cisplatin, and fluorouracil for patients with esophageal cancer.

DOI： 10.1007/s00280-023-04607-7

ASO Author Reflections: Association Between Preoperative Coagulation Status and Prognosis in Patients Undergoing Subtotal Esophagectomy for Esophageal Squamous Cell Carcinoma After Neoadjuvant Treatment Reviewed

Sugiyama, F; Kanda, M; Kodera, Y

ANNALS OF SURGICAL ONCOLOGY Vol. 31 ( 5 ) page： 3473 - 3474 2024.1

A multi-institutional prospective study to compare postoperative quality of life of patients who undergo proximal or total gastrectomy for early gastric cancer (CCOG1602). Reviewed

Kanda, M; Mochizuki, Y; Tanaka, C; Ito, S; Watanabe, T; Sueoka, S; Ishiyama, A; Yamada, T; Oshima, T; Hattori, M; Koike, S; Ishigure, K; Teramoto, H; Murotani, K; Kodera, Y

JOURNAL OF CLINICAL ONCOLOGY Vol. 42 ( 3_SUPPL ) page： 296 - 296 2024.1

Absence of Hypercoagulation Status after Neoadjuvant Treatment is Associated with Favorable Prognosis in Patients Undergoing Subtotal Esophagectomy for Esophageal Squamous Cell Carcinoma Reviewed

Sugiyama, F; Kanda, M; Shimizu, D; Umeda, S; Inokawa, Y; Hattori, N; Hayashi, M; Tanaka, C; Nakayama, G; Kodera, Y

ANNALS OF SURGICAL ONCOLOGY Vol. 31 ( 5 ) page： 3417 - 3425 2024.1

肥満外科治療の現状と課題当院における肥満外科治療の現状と課題 Reviewed

田中千恵, 中西香企, 清水大, 神田光郎, 小寺泰弘

日本消化管学会雑誌 Vol. 8 ( Suppl. ) page： 191 - 191 2024.1

Docetaxel, cisplatin, and fluorouracil with pegfilgrastim on day 3 as neoadjuvant chemotherapy for esophageal cancer. Reviewed International journal

Osamu Maeda, Satoshi Furune, Mitsuro Kanda, Kazushi Miyata, Dai Shimizu, Shizuki Sugita, Kazuki Nishida, Masahiko Ando, Yasuhiro Kodera, Yuichi Ando

Cancer medicine Vol. 13 ( 2 ) page： e6974 2024.1

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

PURPOSE: A high risk of febrile neutropenia (FN) from neoadjuvant chemotherapy with docetaxel, cisplatin, and fluorouracil (DCF) for esophageal cancer has been reported. The optimal timing of prophylactic use of pegfilgrastim remains to be elucidated. To evaluate the effect of pegfilgrastim administered on day 3, we conducted a feasibility study. METHODS: Chemotherapy consisted of intravenous administration of docetaxel (70 mg/m2 per day) and cisplatin (70 mg/m2 per day) on day 1 and continuous infusion of 5-fluorouracil (750 mg/m2 per day) on days 1-5. Pegfilgrastim was given as a single subcutaneous injection at a dose of 3.6 mg on day 3 during each treatment course. This regimen was repeated every 3 weeks for up to a maximum of three courses. Prophylactic antibiotics were not needed but were allowed to be given at the discretion of the physician. The primary endpoint was the incidence of FN. RESULTS: Twenty-six patients were administered DCF in combination with pegfilgrastim on day 3. After the first course of DCF, 10 out of 26 patients (38.5%) experienced grade 4 neutropenia, and two patients (7.7%) experienced FN. Of the 14 patients who did not receive prophylactic antibiotics, four had grade 4 neutropenia, including two who developed FN. On the contrary, of the 12 patients who received prophylactic levofloxacin, six had grade 4 neutropenia, but no cases of FN were observed. CONCLUSION: Administration of pegfilgrastim on day 3 was not sufficient to prevent FN due to DCF treatment, and prophylactic administration of both pegfilgrastim and antibiotics could be a solution.

DOI： 10.1002/cam4.6974

Increased STX3 transcript and protein levels were associated with poor prognosis in two independent cohorts of esophageal squamous cell carcinoma patients Reviewed

Shinozuka, T; Kanda, M; Sato, Y; Shimizu, D; Tanaka, C; Umeda, S; Inokawa, Y; Hattori, N; Hayashi, M; Nakayama, G; Kodera, Y

CANCER MEDICINE Vol. 12 ( 24 ) page： 22185 - 22195 2023.12

徐々に適応を拡大したロボット支援胃切除の短期成績 Reviewed

杉田静紀, 田中千恵, 宮田一志, 中西香企, 稲田亘佑, 田根雄一郎, 神田光郎, 清水大, 小寺泰弘, 江畑智希

日本内視鏡外科学会雑誌 Vol. 28 ( 7 ) page： 1969 - 1969 2023.12

噴門側胃切除における至適再建法当科における噴門側胃切除術後のダブルトラクト再建法の工夫と成績 Reviewed

田中千恵, 中西香企, 梅田晋一, 清水大, 猪川祥邦, 高見秀樹, 服部憲史, 林真路, 神田光郎, 中山吾郎, 藤原道隆, 小寺泰弘

日本内視鏡外科学会雑誌 Vol. 28 ( 7 ) page： 2033 - 2033 2023.12

トラブル例・緊急開腹移行例から考える安全な内視鏡外科手術-ロボット支援導入で変わるか- 当科の低侵襲手術におけるトラブルとその対処 Reviewed

田中千恵, 中西香企, 清水大, 梅田晋一, 猪川祥邦, 高見秀樹, 服部憲史, 林真路, 神田光郎, 中山吾郎, 藤原道隆, 小寺泰弘

日本内視鏡外科学会雑誌 Vol. 28 ( 7 ) page： 1608 - 1608 2023.12

クローン病再手術症例に対する低侵襲手術の治療成績 Reviewed

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 Vol. 28 ( 7 ) page： 2164 - 2164 2023.12

Proposal of the second cutoff of serum carcinoembryonic antigen levels to stratify patients into low, intermediate, and high risks at recurrences after curative resection of gastric cancer. Reviewed International journal

Bin Sato, Mitsuro Kanda, Seiji Ito, Yoshinari Mochizuki, Hitoshi Teramoto, Kiyoshi Ishigure, Toshifumi Murai, Takahiro Asada, Akiharu Ishiyama, Hidenobu Matsushita, Koki Nakanishi, Dai Shimizu, Chie Tanaka, Michitaka Fujiwara, Kenta Murotani, Yasuhiro Kodera

Digestive surgery Vol. 40 ( 6 ) page： 187 - 195 2023.12

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

INTRODUCTION: Carcinoembryonic antigen (CEA) and carbohydrate antigen 19-9 (CA19-9) are widely used for various cancers, with the cut-off values of 5.0 ng/mL and 37.0 IU/mL, respectively. However, these cutoff values are not for specific diseases or purposes but are uniformly used for any disease and any purpose . It is also unclear as to whether patients are at equal risk of recurrence if they are below the cutoff values. This study aimed to investigate the optimal cutoff of serum tumor markers in the stratification of recurrence risk after curative resection of gastric cancer. METHODS: We constructed a nine-center integrated database of patients recieved gastrectomy between January 2010 and December 2014 with a 5-year follow-up period. We determined the cutoff value of preoperative serum tumor marker levels correlated with postoperative recurrences and evaluated its performance in risk stratification for recurrences in 948 patients with pStage II/III gastric cancer who underwent radical resection. RESULTS: The hazard ratio for postoperative recurrences increased at two points of preoperative CEA levels; 3.6 ng/mL and 5.0 ng/mL, which were set as cutoffs. These two cutoffs stratified relapse-free survival into three levels. CONCLUSIONS: By adding a second cutoff value for preoperative serum CEA, which was proposed specifically for the prediction of recurrences, patients can be stratified into low-, intermediate-, and high-risk recurrences after curative resection of gastric cancer.

DOI： 10.1159/000533143

A multicenter randomized open-label phase II study investigating optimal antiemetic therapy for patients with advanced/recurrent gastric cancer treated with trastuzumab deruxtecan (T-DXd): EN-hance study Reviewed

Ooki, A; Aoyama, T; Oba, K; Nishikawa, K; Kawabata, R; Honda, M; Maeda, H; Kanda, M; Sugiyama, K; Makiyama, A; Segami, K; Takahashi, M; Shindo, Y; Namikawa, T; Oshima, T; Katayama, A; Shiosakai, K; Sakamoto, J

ANNALS OF ONCOLOGY Vol. 34 page： S1639 - S1640 2023.11

Risk Stratification by Tissue GAD1 Expression Level in Curatively Resected Esophageal Squamous Cell Carcinoma Reviewed

Kishida, T; Kanda, M; Sato, Y; Shimizu, D; Inokawa, Y; Hattori, N; Hayashi, M; Tanaka, C; Nakayama, G; Kodera, Y

CANCER GENOMICS & PROTEOMICS Vol. 20 ( 6 ) page： 617 - 625 2023.11

Real clinical impact of postoperative surgical complications after colon cancer surgery Reviewed

Aoyama, T; Oba, K; Honda, M; Mayanagi, S; Maeda, H; Kanda, M; Kashiwabara, K; Muto, M; Sakamoto, J; Yoshikawa, T

ANNALS OF ONCOLOGY Vol. 34 page： S1509 - S1509 2023.11

Predictive impacts of peritoneal washing cytology for surgical resection-intended pancreatic cancer cases: Establishment of planned staging laparoscopy criteria Reviewed

Tanaka, N; Takami, H; Hayashi, M; Inokawa, Y; Kurimoto, K; Hattori, N; Kanda, M; Tanaka, C; Nakayama, G; Kodera, Y

JOURNAL OF HEPATO-BILIARY-PANCREATIC SCIENCES Vol. 30 ( 11 ) page： 1273 - 1281 2023.11

Mobilization of Circulating Tumor Cells after Short- and Long-Term FOLFIRINOX and GEM/nab-PTX Chemotherapy in Xenograft Mouse Models of Human Pancreatic Cancer Reviewed

Ito, Y; Kobuchi, S; Kawakita, A; Tosaka, K; Matsunaga, Y; Yoshioka, S; Jonan, S; Amagase, K; Hashimoto, K; Kanda, M; Saito, T; Nakanishi, H

CANCERS Vol. 15 ( 22 ) 2023.11

Low Expectancy of Conversion Surgery with R0 Resection in Patients with CEA > 5.0 ng/mL at the Initial RECIST Evaluation for Metastatic Gastric Cancer Reviewed

Koki Nakanishi, Chie Tanaka, Mitsuro Kanda, Kazushi Miyata, Kazuhiro Furukawa, Osamu Maeda, Dai Shimizu, Shizuki Sugita, Naomi Kakushima, Satoshi Furune, Hiroki Kawashima, Yuichi Ando, Tomoki Ebata, Yasuhiro Kodera

Cancers Vol. 15 ( 21 ) 2023.11

進行再発大腸癌に対するFOLFIRI(irinotecan日本標準量:150mg/m2)+ramucirumab療法 Reviewed

服部憲史, 中山吾郎, 室谷健太, 梅田晋一, 川瀬義久, 江坂和大, 筒山将之, 阪井満, 片岡政人, 伊藤武, 神田光郎, 田中千恵, 藤原道隆, 安藤昌彦, 小寺泰弘

日本癌治療学会学術集会抄録集 Vol. 61回 page： O16 - 1 2023.10

進行再発大腸癌に対するFOLFIRI(irinotecan日本標準量:150mg/m2)+ramucirumab療法 Reviewed

日本癌治療学会学術集会抄録集 Vol. 61回 page： O16 - 1 2023.10

Identification of stromal cell-derived factor 4 as a liquid biopsy-based diagnostic marker in solid cancers Reviewed

Shinozuka, T; Kanda, M; Shimizu, D; Umeda, S; Takami, H; Inokawa, Y; Hattori, N; Hayashi, M; Tanaka, C; Nakayama, G; Kodera, Y

SCIENTIFIC REPORTS Vol. 13 ( 1 ) page： 15540 2023.9

Site-specific protein biomarkers in gastric cancer: a comprehensive review of novel biomarkers and clinical applications Reviewed

Shinozuka Takahiro, Kanda Mitsuro, Kodera Yasuhiro

EXPERT REVIEW OF MOLECULAR DIAGNOSTICS Vol. 23 ( 8 ) page： 701 - 712 2023.8

The preoperative systemic immune-inflammation index is associated with an unfavorable prognosis for patients undergoing curative resection of esophageal squamous cell carcinoma after neoadjuvant therapy Reviewed

Obata Yuma, Kanda Mitsuro, Shimizu Dai, Takami Hideki, Inokawa Yoshikuni, Hattori Norifumi, Hayashi Masamichi, Tanaka Chie, Nakayama Goro, Kodera Yasuhiro

SURGERY TODAY Vol. 53 ( 8 ) page： 964 - 972 2023.8

A feasibility study of modified docetaxel, cisplatin, and capecitabine for advanced gastric cancer followed by gastrectomy. Reviewed International journal

Yao Liang, Osamu Maeda, Kazushi Miyata, Chie Tanaka, Mitsuro Kanda, Dai Shimizu, Masahide Fukaya, Masahiko Koike, Yasuhiro Kodera, Yuichi Ando

Asia-Pacific journal of clinical oncology 2023.7

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

AIMS: To explore the feasibility of modified docetaxel, cisplatin, and capecitabine (mDCX) chemotherapy with a lower dose of docetaxel than previously reported for stage III resectable gastric cancer patients with a high risk of recurrence or for stage IV gastric cancer patients aiming for conversion surgery. METHODS: Patients with stage III resectable HER2-negative gastric cancer with large type 3 or type 4 tumors or extensive lymph node metastasis (bulky N or cN3) and those who had stage IV HER2-negative gastric cancer with distant metastasis were enrolled to receive 30 mg/m2 docetaxel and 60 mg/m2 cisplatin on day 1, followed by 2000 mg/m2 capecitabine per day for 2 weeks every 3 weeks. RESULTS: Five patients with stage III gastric cancer with a high risk of recurrence received three courses of mDCX, and four patients with stage IV gastric cancer received three or four courses of mDCX. In terms of grade 3 or worse adverse events, leukopenia was observed in one (11%) patient, neutropenia in two (22%) patients, anemia in one (11%) patient, anorexia in two (22%) patients and nausea in two (22%) patients. All six patients with measurable lesions achieved a partial response. All nine patients underwent subsequent surgeries. The histological responses of the nine patients revealed grade 3 in one (11%) patient, grade 2 in five (56%) patients, and grade 1a in three (33%) patients. Three of the nine patients survived without recurrence, and two of them survived for more than four years. CONCLUSIONS: mDCX seems to be feasible and may be helpful as neoadjuvant chemotherapy for patients at high risk of recurrence or as chemotherapy for patients who are likely to undergo conversion surgery.

DOI： 10.1111/ajco.13995

High Preoperative Serum D-dimer Predicts Unfavorable Survival Outcomes for Pancreatic Cancer Patients. Reviewed International journal

Tomohisa Otsu, Masamichi Hayashi, Hideki Takami, Yoshikuni Inokawa, Nobutake Tanaka, Keisuke Kurimoto, Koki Nakanishi, Shinichi Umeda, Dai Shimizu, Norifumi Hattori, Mitsuro Kanda, Chie Tanaka, Goro Nakayama, Yasuhiro Kodera

Anticancer research Vol. 43 ( 7 ) page： 3173 - 3181 2023.7

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

BACKGROUND/AIM: Pancreatic cancer cells release certain tissue factors into the bloodstream. It is well known that pancreatic cancer progresses with thrombus formation. Because we routinely measure serum D-dimer levels in preoperative patients as a screening marker of deep venous thrombosis, we examined its association with high serum D-dimer in our cohort of pancreatic cancer resected cases. PATIENTS AND METHODS: We examined 315 patients with pancreatic ductal adenocarcinoma who underwent surgical resection in our department from January 2012 to July 2021. All cases were divided into high D-dimer cases (n=118) and low D-dimer cases (n=197) using the cut-off value of 1.0 μg/ml, an institutional upper limit. Clinicohistological characteristics and postoperative survival outcomes were evaluated. RESULTS: Preoperative high D-dimer cases showed significantly worse progression-free survival (PFS) (p=0.021) and overall survival (OS) (p=0.027) than low D-dimer cases; median PFS was 13.9 months versus 21.4 months, and that of OS was 33.4 months versus 68.0 months. Clinicohistological characteristics of high D-dimer cases were age over 70 years (p<0.001), pathological portal vein invasion (p=0.003), and initially borderline resectable or unresectable cases (p=0.027). Multivariate analysis indicated that preoperative high D-dimer was a significant prognostic factor of PFS (hazard ratio=1.42, p=0.025) and OS (hazard ratio=1.51, p=0.036). CONCLUSION: Preoperative high serum D-dimer over 1.0 μg/ml was associated with pathological portal vein invasion and could be an unfavorable prognostic marker of PFS and OS after surgery, typically due to distant metastasis.

DOI： 10.21873/anticanres.16491

Feasibility and Safety of Adjuvant Chemotherapy for Resected Colorectal Cancer in Patients With Renal Insufficiency: A Pooled Analysis of Individual Patient Data from Five Japanese Large-scale Clinical Trials. Reviewed International journal

Shuhei Mayanagi, Koji Oba, Toru Aoyama, Kenji Tanaka, Mitsuro Kanda, Michitaka Honda, Hiromichi Maeda, Kosuke Kashiwabara, Masaru Muto, Junichi Sakamoto, Hisakazu Yamagishi, Takaki Yoshikawa

Anticancer research Vol. 43 ( 7 ) page： 3089 - 3095 2023.7

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

BACKGROUND/AIM: The incidence of chemotherapy-related adverse events in colorectal cancer patients with renal insufficiency has been compared to patients with normal renal function in only a few studies. The purpose of this analysis was to verify the feasibility and safety of adjuvant chemotherapy for postoperative colorectal cancer patients with renal insufficiency. PATIENTS AND METHODS: Adverse events and discontinuation of adjuvant chemotherapy for patients with curatively resected locally advanced colorectal cancer were examined using a combined database of individual patient data obtained from five large-scale clinical trials (n=4,106). The renal function of patients was classified into Level (L) 1-2: ≥60 ml/min and L3-4: <60 ml/min. RESULTS: As Grade 3 adverse events, hematological toxicities, such as neutropenia and anemia, and gastrointestinal disorders, such as diarrhea and vomiting, were significantly more frequent in the L3-4 group. Moreover, the time-to-treatment discontinuation in the L3-4 group was higher (hazard ratio=1.21, p=0.0012). T factor, N factor, and creatinine clearance level were found to be independent risk factors for the discontinuation of adjuvant chemotherapy. In the subgroup analysis of FOLFOX, neutropenia and diarrhea were significantly common in the L3-4 group, but neurotoxicities were not different. There was no significant difference in the discontinuation of adjuvant FOLFOX. CONCLUSION: Adverse events of adjuvant chemotherapy in patients with resected colorectal cancer were associated with renal insufficiencies. Since adverse events have the potential to shorten the duration of treatment, especially when using chemotherapy without oxaliplatin, careful management, including dose reduction, may be important in patients with renal insufficiency.

DOI： 10.21873/anticanres.16480

High Preoperative Platelet to Lymphocyte Ratio is Associated with a Greater Risk of Postoperative Complications and Hematogenous Recurrences in Esophageal Squamous Cell Carcinoma Patients Receiving Neoadjuvant Treatment Reviewed

Sasahara Masahiro, Kanda Mitsuro, Shimizu Dai, Takami Hideki, Inokawa Yoshikuni, Hattori Norifumi, Hayashi Masamichi, Tanaka Chie, Fujiwara Michitaka, Nakayama Goro, Kodera Yasuhiro

DIGESTIVE SURGERY Vol. 40 ( 1-2 ) page： 48 - 57 2023.7

食道扁平上皮癌における術前凝固状態と術後再発の関連性 Reviewed

杉山史剛, 神田光郎, 清水大, 田中千恵, 中西香企, 服部憲史, 林真路, 中山吾郎, 藤原道隆, 小寺泰弘

日本消化器外科学会総会 Vol. 78回 page： P217 - 2 2023.7

腹腔鏡下切除術を施行した食道重複嚢胞の一例 Reviewed

武田洋平, 清水大, 中西香企, 高見秀樹, 猪川祥邦, 服部憲史, 林真路, 神田光郎, 田中千恵, 中山吾郎, 藤原道隆, 小寺泰弘

日本臨床外科学会雑誌 Vol. 84 ( 7 ) page： 1129 - 1129 2023.7

胸骨後経路再建による食道亜全摘術後縫合不全と胸郭入口部気管食道間角度・胸骨椎骨間距離長の関連性の検討 Reviewed

呂成九, 神田光郎, 清水大, 田中千恵, 中西香企, 服部憲史, 林真路, 中山吾郎, 藤原道隆, 小寺泰弘

日本消化器外科学会総会 Vol. 78回 page： P206 - 2 2023.7

【上部】【Challenges beyond borders】高度進行胃癌に対するconversion surgeryの現状と新たな治療戦略高齢者における治癒切除不能胃癌に対するconversion surgeryの治療成績 Reviewed

中西香企, 田中千恵, 神田光郎, 宮田一志, 清水大, 杉田静紀, 藤原道隆, 江畑智希, 小寺泰弘

日本消化器外科学会総会 Vol. 78回 page： PD3 - 9 2023.7

The clinical impacts of postoperative complications after colon cancer surgery for the clinical course of adjuvant treatment and survival. Reviewed

Toru Aoyama, Koji Oba, Michitaka Honda, Masaru Muto, Shuhei Mayanagi, Hiromichi Maeda, Mitsuro Kanda, Kosuke Kashiwabara, Junichi Sakamoto, Takaki Yoshikawa

International journal of clinical oncology Vol. 28 ( 6 ) page： 777 - 784 2023.6

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

AIM: We investigated whether or not postoperative complications (POCs) themselves have a negative survival impact or indirectly worsen the survival due to insufficient adjuvant chemotherapy in a pooled analysis of two large phase III studies performed in Japan PATIENTS AND METHODS: The study examined the patients who enrolled in 1304, phase III study comparing the efficacy of 6 and 12 months of capecitabine as adjuvant chemotherapy for stage III colon cancer patients and in 882, a phase III study to confirm the tolerability of oxaliplatin, fluorouracil, and l-leucovorin in Japanese stage II/III colon cancer patients. In our study, POCs were defined as the following major surgical complications: anastomotic leakage, pneumonia, bowel obstruction/ileus, surgical site infection, postoperative bleeding, urinary tract infection, and fistula. Patients were classified as those with POCs (C group) and those without POCs (NC group). RESULTS: A total of 2095 patients were examined in the present study. POCs were observed in 169 patients (8.1%). The overall survival (OS) rates at 5 years after surgery were 75.3% in the C group and 86.5% in the NC group (p = 0.0017). The hazard ratio of POCs for the OS in multivariate analysis was 1.70 (95% confidence interval, 1.19 to 2.45; p = 0.0040). The time to adjuvant treatment failure (TTF) of adjuvant chemotherapy was similar between the groups, being 68.6% in the C group and 67.1% in the NC group for the 6-month continuation rate of adjuvant chemotherapy. The dose reduction rate of adjuvant chemotherapy and adjuvant treatment suspension rate were also similar between the groups (C vs. NC groups: 45.0% vs. 48.7%, p = 0.3520; and 52.7% vs. 55.0%, p = 0.5522, respectively). CONCLUSION: POCs were associated with a poor prognosis but did not affect the intensity of adjuvant chemotherapy. These results suggested that POCs themselves negatively influence the survival.

DOI： 10.1007/s10147-023-02332-y

Targeting Pancreatic Cancer with Novel Plumbagin Derivatives: Design, Synthesis, Molecular Mechanism, In Vitro and In Vivo Evaluation Reviewed

Awale Suresh, Baba Hayato, Phan Nguyen Duy, Kim Min Jo, Maneenet Juthamart, Sawaki Koichi, Kanda Mitsuro, Okumura Tomoyuki, Fujii Tsutomu, Okada Takuya, Maruyama Takahiro, Okada Takahiro, Toyooka Naoki

JOURNAL OF MEDICINAL CHEMISTRY Vol. 66 ( 12 ) page： 8054 - 8065 2023.5

Albumin-Globulin Ratio Indicates the Survival Outcome of Pancreatic Cancer Cases Who Underwent Preoperative Treatment and Curative Surgical Resection. Reviewed International journal

Masamichi Hayashi, Daigo Kobayashi, Hideki Takami, Yoshikuni Inokawa, Nobutake Tanaka, Keisuke Kurimoto, Koki Nakanishi, Shinichi Umeda, Dai Shimizu, Norifumi Hattori, Mitsuro Kanda, Chie Tanaka, Goro Nakayama, Yasuhiro Kodera

Nutrition and cancer Vol. 75 ( 5 ) page： 1330 - 1339 2023.5

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

BACKGROUND: The pretreatment albumin-globulin ratio (AGR) is a frequently used inflammation-associated factor that has been reported to have associations with the survival outcomes of various malignancies. METHODS: We retrospectively analyzed 162 patients with pancreatic cancer who underwent preoperative treatment followed by curative surgery at Nagoya University Hospital between April 2010 and December 2020. Representative nutritional status indicators of neutrophil-lymphocyte ratio (NLR), platelet-lymphocyte ratio (PLR), prognostic nutritional index (PNI), and albumin-globulin ratio (AGR) were calculated for each case. RESULTS: Among pretreatment blood examination parameters, only AGR (cutoff: 1.33) showed a significant difference in overall survival time (OS) and progression-free survival time (PFS) from the beginning of the preoperative treatment. Median PFS was 22.3 mo, in high AGR cases and 17.1 mo, in low AGR cases (P = 0.019). Median OS was 48.7 mo, in high AGR cases and 32.9 mo, in low AGR cases (P = 0.043). CONCLUSION: High pretreatment AGR may be a favorable prognostic factor for pancreatic cancer patients who received preoperative multimodal therapy followed by curative cancer resection. It may imply that nutritional status and inflammation control before the multimodal treatment affect the survival outcomes of pancreatic cancer cases and needs to be optimized.

DOI： 10.1080/01635581.2023.2191384

A liquid biopsy signature for predicting early recurrence in patients with gastric cancer Reviewed

Okuno Keisuke, Watanabe Shuichi, Roy Souvick, Kanda Mitsuro, Tokunaga Masanori, Kodera Yasuhiro, Kinugasa Yusuke, Goel Ajay

BRITISH JOURNAL OF CANCER Vol. 128 ( 6 ) page： 1105 - 1116 2023.4

Effectiveness of taxanes following nivolumab in patients with advanced esophageal squamous cell carcinoma: a retrospective chart review of patients in ATTRACTION-3 Reviewed

Chin Keisho, Yamamoto Shun, Takahashi Masanobu, Kadowaki Shigenori, Kubota Yutaro, Amanuma Yusuke, Okada Morihito, Kanda Mitsuro, Kimura Yasue, Nogi Yuhiko, Arimitsu Yuko, Kitagawa Yuko

ESOPHAGUS Vol. 20 ( 2 ) page： 302 - 308 2023.4

治癒切除不能胃癌におけるconversion surgery対象選択の客観的指標とはなにか? Reviewed

中西香企, 田中千恵, 神田光郎, 宮田一志, 清水大, 杉田静紀, 藤原道隆, 江畑智希, 小寺泰弘

日本外科学会定期学術集会抄録集 Vol. 123回 page： SF - 5 2023.4

治癒切除不能胃癌におけるconversion surgery対象選択の客観的指標とはなにか? Reviewed

中西香企, 田中千恵, 神田光郎, 宮田一志, 清水大, 杉田静紀, 藤原道隆, 江畑智希, 小寺泰弘

日本外科学会定期学術集会抄録集 Vol. 123回 page： SF - 5 2023.4

胃癌術後の他病死リスク予測モデルの構築 Reviewed

伊藤雄貴, 三輪高嗣, 神田光郎, 伊藤誠二, 望月能成, 中西香企, 清水大, 田中千恵, 藤原道隆, 小寺泰弘

日本外科学会定期学術集会抄録集 Vol. 123回 page： DP - 4 2023.4

膵IPMN切除後予後に関連する因子および術後補助療法の影響に関する検討 Reviewed

猪川祥邦, 高見秀樹, 栗本景介, 田中伸孟, 林真路, 中西香企, 梅田晋一, 清水大, 服部憲史, 神田光郎, 田中千恵, 中山吾郎, 小寺泰弘

日本外科学会定期学術集会抄録集 Vol. 123回 page： DP - 5 2023.4

術前血清C reactive proteinとprognostic nutritional indexの組み合わせは大腸癌術後長期予後を予測する Reviewed

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

日本外科学会定期学術集会抄録集 Vol. 123回 page： SF - 8 2023.4

切除可能・切除可能境界型膵癌に対する腹腔洗浄細胞診の意義と治療戦略 Reviewed

田中伸孟, 高見秀樹, 栗本景介, 林真路, 中西香企, 梅田晋一, 清水大, 服部憲史, 神田光郎, 田中千恵, 中山吾郎, 小寺泰弘

日本外科学会定期学術集会抄録集 Vol. 123回 page： SF - 4 2023.4

Feasibility assessment of global standard chemoradiotherapy followed by surgery in patients with esophageal cancer. Reviewed International journal

Yao Liang, Osamu Maeda, Kazushi Miyata, Mitsuro Kanda, Dai Shimizu, Shizuki Sugita, Tohru Okada, Junji Ito, Mariko Kawamura, Shunichi Ishihara, Masahiro Nakatochi, Masahiko Ando, Yasuhiro Kodera, Yuichi Ando

Molecular and clinical oncology Vol. 18 ( 4 ) page： 34 - 34 2023.4

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

The present study aimed to assess the feasibility of global standard chemoradiotherapy (CRT) followed by surgery in patients with esophageal cancer. A prospective study was conducted at Nagoya University Hospital (Nagoya, Japan) to evaluate global standard CRT followed by surgery in patients with esophageal cancer. The CRT regimen consisted of 75 mg/m2 cisplatin on day 1 and 1,000 mg/m2 fluorouracil daily on days 1-4 given twice 4 weeks apart together with concurrent esophageal irradiation starting on day 1 (group A). For comparison, 17 patients with esophageal cancer who had received the same chemotherapy regimen but with lower drug doses were retrospectively reviewed: 70 mg/m2 cisplatin on day 1 and 700 mg/m2 fluorouracil daily on days 1-4 given twice 4 weeks apart together with concurrent esophageal irradiation starting on day 1 (group B). Grade 3 or worse adverse events were observed in 9 of the 12 patients (75%) in group A and in 5 of the 17 patients (29%) in group B. The patients in group A were more likely to experience grade 3 or worse neutropenia (50%) than those in group B (6%). No febrile neutropenia or treatment-related deaths occurred in either group. A total of 11 patients (92%) in group A and 16 patients (94%) in group B subsequently underwent an esophagectomy, and 9 (82%) and 14 (88%) of these patients, respectively, achieved microscopically margin-negative resection (R0 resection). In conclusion, global standard CRT was more likely to cause severe but manageable adverse events. There was no apparent difference in the R0 resection rate or postoperative complications between the two treatments. This clinical trial was registered at the Japan Registry of Clinical Trials (trial registration number: jRCT1041180004) on September 11, 2018.

DOI： 10.3892/mco.2023.2630

Modified Albumin-Bilirubin Grade optimized for risk stratification of patients with stage II-III gastric cancer. Reviewed

Michita Shoka, Mitsuro Kanda, Seiji Ito, Yoshinari Mochizuki, Hitoshi Teramoto, Kiyoshi Ishigure, Toshifumi Murai, Takahiro Asada, Akiharu Ishiyama, Hidenobu Matsushita, Dai Shimizu, Chie Tanaka, Michitaka Fujiwara, Kenta Murotani, Yasuhiro Kodera

Surgery today 2023.3

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

PURPOSE: The albumin-bilirubin (ALBI) grade is calculated using albumin and bilirubin values. We determined the optimal cutoff value of the ALBI grade for predicting the postoperative prognosis of gastric cancer (GC). METHODS: We retrospectively reviewed a multicenter database of 3571 patients who underwent gastrectomy for GC between January 2010 and December 2014. The modified ALBI (mALBI) grade was determined using cutoff values: grade 1 (mALBI ≤ - 2.70), 2 (mALBI - 2.70 to - 2.10), and 3 (mALBI > - 2.10). We used a validation cohort to evaluate reproducibility. RESULTS: The entire cohort (n = 956) was randomly assigned to the learning or validation cohorts (n = 478 each). The former was categorized into the following groups by the preoperative mALBI grade: grade 1 (n = 235), grade 2 (n = 162), and grade 3 (n = 81). The disease-specific survival (DSS) rates of the learning and validation cohorts were significantly shortened in association with higher mALBI grade (learning, p = 0.0068; validation, p = 0.0100). A multivariate analysis revealed that mALBI grade 3 served as an independent prognostic factor for DSS. Furthermore, mALBI grade 2 or 3 was associated with a greater risk of disease-specific death in most subgroups. CONCLUSION: The mALBI grade accurately predicted the long-term postoperative prognosis of locally advanced GC.

DOI： 10.1007/s00595-023-02669-x

Risk score for predicting death from other causes after curative gastrectomy for gastric cancer. Reviewed

Yuki Ito, Takashi Miwa, Mitsuro Kanda, Seiji Ito, Yoshinari Mochizuki, Hitoshi Teramoto, Kiyoshi Ishigure, Toshifumi Murai, Takahiro Asada, Akiharu Ishiyama, Hidenobu Matsushita, Chie Tanaka, Daisuke Kobayashi, Michitaka Fujiwara, Kenta Murotani, Yasuhiro Kodera

Gastric cancer : official journal of the International Gastric Cancer Association and the Japanese Gastric Cancer Association Vol. 26 ( 2 ) page： 317 - 323 2023.3

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

BACKGROUND: The number of patients who die from causes other than gastric cancer after R0 resection is increasing in Japan, due in part to the aging population. However, few studies have comprehensively investigated the clinicopathological risks associated with deaths from other causes after gastrectomy. This study aimed to build a risk score for predicting such deaths. METHODS: We retrospectively reviewed clinical data for 3575 patients who underwent gastrectomy for gastric cancer at nine institutions in Japan between January 2010 and December 2014. RESULTS: The final study population of 1758 patients were assigned to Group A (n = 187): patients who died from other causes within 5 years of surgery, and Group B (n = 1571): patients who survived ≥ 5 years after surgery. Multivariate analysis identified nine characteristics as risk factors for poor survival: age ≥ 75 years, male sex, body mass index < 22 kg/m2, Eastern Cooperative Oncology Group Performance Status (≥ 1), diabetes mellitus, cardiovascular/cerebrovascular disease, other malignant diseases, preoperative albumin level < 3.5 g/dL, and total gastrectomy. Patients with risk scores of 0-2, 3-4, or 5-9 (based on 1 point per characteristics) were classified into Low-risk, Intermediate-risk, and High-risk groups, respectively. The 5-year survival rates were 96.5%, 85.3%, and 56.5%, for the Low-, Intermediate-, and High-risk groups, respectively, and the hazard ratio (95% confidence intervals) was 16.33 (10.85-24.58, p < 0.001) for the High-risk group. CONCLUSIONS: The risk score defined here may be useful for predicting deaths from other causes after curative gastrectomy.

DOI： 10.1007/s10120-022-01354-1

Combined intraperitoneal and systemic chemotherapy as adjuvant or perioperative chemotherapy for patients with type 4 scirrhous gastric cancer: PHOENIX-GC2 trial. Reviewed

Ishigami, H; Omori, T; Tsuji, Y; Shinohara, H; Yabusaki, H; Kobayashi, D; Takahari, D; Hata, H; Kusumoto, T; Kanda, M; Oba, K; Kitayama, J; Seto, Y

JOURNAL OF CLINICAL ONCOLOGY Vol. 41 page： TPS477 - TPS477 2023.2

Proposal of a coagulation score to predict postoperative survival of patients undergoing neoadjuvant therapy followed by subtotal esophagectomy for squamous cell carcinoma of the esophagus. Reviewed

Sugiyama, F; Shimizu, D; Kanda, M; Tanaka, C; Takami, H; Inokawa, Y; Hattori, N; Hayashi, M; Nakayama, G; Fujiwara, M; Kodera, Y

JOURNAL OF CLINICAL ONCOLOGY Vol. 41 page： 448 - 448 2023.2

Perioperative changes in geriatric functions of elderly patients undergoing surgical resection for gastric cancer. Reviewed

Tanaka, C; Kanda, M; Nakanishi, K; Umeda, S; Shimizu, D; Inokawa, Y; Takami, H; Hayashi, M; Nakayama, G; Fujiwara, M; Kodera, Y; Hattori, N

JOURNAL OF CLINICAL ONCOLOGY Vol. 41 page： 811 - 811 2023.2

Preoperative neutrophil-to-platelet ratio as a potential prognostic factor for gastric cancer with positive peritoneal lavage cytology in the absence of other non-curative factors: a multi-institutional dataset analysis. Reviewed

Akira Nonogaki, Mitsuro Kanda, Seiji Ito, Yoshinari Mochizuki, Hitoshi Teramoto, Kiyoshi Ishigure, Toshifumi Murai, Takahiro Asada, Akiharu Ishiyama, Hidenobu Matsushita, Chie Tanaka, Daisuke Kobayashi, Michitaka Fujiwara, Kenta Murotani, Yasuhiro Kodera

Surgery today Vol. 53 ( 2 ) page： 198 - 206 2023.2

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

PURPOSE: Peritoneal dissemination is the key to the prognosis of gastric cancer (GC) and can be detected early with peritoneal lavage cytology. No studies have examined preoperative prognostic factors in GC patients who have positive cytology but no other non-curative factors. METHODS: We conducted a retrospective analysis using a multicenter database of 3575 patients who underwent gastrectomy between 2010 and 2014. Patients with positive peritoneal lavage cytology as a sole non-curative factor were retrieved, and correlations between parameters and the prognosis were compared. RESULTS: A total of 66 patients were identified as eligible. In the receiver operating characteristic (ROC) curve analysis, the neutrophil-to-platelet ratio (NPR) had the greatest area under the curve value and was selected. We divided the NPR into two groups based on the optimal cutoff value of the NPR (2.000), as determined by the ROC curve analysis. A high preoperative NPR was the only prognostic factor. The NPR-high group had shorter overall survival than the NPR-low group (hazard ratio 1.85, 95% confidence interval 1.05-3.28, P = 0.032). CONCLUSION: Our analysis indicated that the preoperative NPR serves as a prognostic factor in GC patients with positive peritoneal lavage cytology in the absence of other non-curative factors.

DOI： 10.1007/s00595-022-02539-y

胃癌術後5年以内の他病死リスク予測モデルの構築 Reviewed

伊藤雄貴, 三輪高嗣, 神田光郎, 伊藤誠二, 望月能成, 中西香企, 清水大, 田中千恵, 藤原道隆, 小寺泰弘

日本胃癌学会総会記事 Vol. 95回 page： 443 - 443 2023.2

胃癌術後肺転移に対する手術の治療成績 Reviewed

野々垣彰, 中西香企, 田中千恵, 神田光郎, 清水大, 猪川祥邦, 服部憲史, 中山吾郎, 藤原道隆, 小寺泰弘

日本胃癌学会総会記事 Vol. 95回 page： 323 - 323 2023.2

薬物療法の新展開胃癌転移制御を目指した創薬研究の展開 Reviewed

神田光郎, 田中千恵, 清水大, 中西香企, 高見秀樹, 猪川祥邦, 服部憲史, 林真路, 中山吾郎, 藤原道隆, 小寺泰弘

日本胃癌学会総会記事 Vol. 95回 page： 164 - 164 2023.2

進行胃癌に対しての腹腔鏡下胃切除術の注意点と短期成績 Reviewed

杉田静紀, 宮田一志, 田中千恵, 神田光郎, 中西香企, 小寺泰弘, 江畑智希

日本胃癌学会総会記事 Vol. 95回 page： 345 - 345 2023.2

内視鏡下胃切除の教育・トレーニング当院におけるロボット支援下胃切除術のトレーニング法 Reviewed

田中千恵, 中西香企, 清水大, 杉田静紀, 梅田晋一, 猪川祥邦, 高見秀樹, 服部憲史, 林真路, 神田光郎, 中山吾郎, 藤原道隆, 小寺泰弘

日本胃癌学会総会記事 Vol. 95回 page： 225 - 225 2023.2

Conversion surgeryの適応と成績 Conversion surgeryを目指すうえでの客観的指標とは? Reviewed

中西香企, 田中千恵, 神田光郎, 清水大, 杉田静紀, 藤原道隆, 小寺泰弘

日本胃癌学会総会記事 Vol. 95回 page： 159 - 159 2023.2

miR-877-3p as a Potential Tumour Suppressor of Oesophageal Squamous Cell Carcinoma Reviewed

Fukuda Takuma, Baba Hayato, Okumura Tomoyuki, Kanda Mitsuro, Akashi Takahisa, Tanaka Haruyoshi, Miwa Takeshi, Watanabe Toru, Hirano Katsuhisa, Sekine Shinichi, Hashimoto Isaya, Shibuya Kazuto, Hojo Shozo, Yoshioka Isaku, Matsui Koshi, Kodera Yasuhiro, Fujii Tsutomu

ANTICANCER RESEARCH Vol. 43 ( 1 ) page： 35 - 43 2023.1

A multi-institutional study to evaluate the feasibility of next-generation sequencing and genomic analysis using formalin-fixed, paraffin-embedded biopsies of gastric cancer Reviewed

Kanda Mitsuro, Terashima Masanori, Kinoshita Takahiro, Yabusaki Hiroshi, Tokunaga Masanori, Kodera Yasuhiro

GASTRIC CANCER Vol. 26 ( 1 ) page： 108 - 115 2023.1

ASO Author Reflections: Gamma-Aminobutyric Acid Type A Receptor Subunit Delta as a Potential Therapeutic Target in Gastric Cancer Reviewed

Sawaki Koichi, Kanda Mitsuro, Kodera Yasuhiro

ANNALS OF SURGICAL ONCOLOGY Vol. 30 ( 1 ) page： 637 - 638 2023.1

Preoperative indocyanine green fluorescence injection to accurately determine a proximal margin during robotic distal gastrectomy. Reviewed

Koki Nakanishi, Chie Tanaka, Mitsuro Kanda, Dai Shimizu, Kazuhiro Furukawa, Michitaka Fujiwara, Hiroki Kawashima, Yasuhiro Kodera

Asian journal of endoscopic surgery Vol. 16 ( 1 ) page： 152 - 156 2023.1

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

INTRODUCTION: Adequate surgical margins following gastrectomy for gastric cancer are required. In addition, a method for accurately detecting tumor location without palpation is needed during robotic surgery. Although several methods have been reported, most of these either lack accuracy or require increased time and effort during intraoperative detection. Herein, we introduce a new method for detecting tumor location using preoperative indocyanine green (ICG) marking and the built-in ICG detection system of the da Vinci Xi Surgical System in robotic gastrectomy to determine appropriate surgical margins. MATERIALS AND SURGICAL TECHNIQUE: We used this method to determine the resection line in six patients who underwent robotic distal gastrectomy for clinical T1 gastric cancer. One to three days before surgery, ICG was diluted to 1.0 mg/mL, and 0.1 mL of this diluted ICG solution was endoscopically injected at one site into the submucosal layer of the stomach, 1 cm proximal to the tumor edge. Gastrectomy was performed using the da Vinci Xi surgical platform, equipped with a near-infrared fluorescence imaging system (Firefly®). The diameter of the fluorescent signal during gastrectomy was estimated to be approximately 2 cm. The resection line was determined on the outer edge of the fluorescent signal, which ensured a tumor-free margin of ≥2 cm. Fluorescent signals were successfully observed in all cases. Moreover, the required 2-cm surgical margin was achieved in all cases. DISCUSSION: We could successfully determine proximal margins using preoperative ICG injection marking during robotic distal gastrectomy for gastric cancer.

DOI： 10.1111/ases.13121

Gamma-aminobutyric Acid Type A Receptor Subunit Delta as a Potential Therapeutic Target in Gastric Cancer Reviewed

Sawaki Koichi, Kanda Mitsuro, Baba Hayato, Inokawa Yoshikuni, Hattori Norifumi, Hayashi Masamichi, Tanaka Chie, Kodera Yasuhiro

ANNALS OF SURGICAL ONCOLOGY Vol. 30 ( 1 ) page： 628 - 636 2023.1

Controlling Nutritional Status Score Serves as a Prognosticator in Esophageal Squamous Cell Carcinoma: Optimal Timing of Evaluation of Patients Undergoing Neoadjuvant Treatment Reviewed

Nonogaki Ikue, Kanda Mitsuro, Shimizu Dai, Inokawa Yoshikuni, Hattori Norifumi, Hayashi Masamichi, Tanaka Chie, Koike Masahiko, Nakayama Goro, Kodera Yasuhiro

WORLD JOURNAL OF SURGERY Vol. 47 ( 1 ) page： 217 - 226 2023.1

OPLAH Protein Expression Stratifies the Prognosis of Patients With Squamous Cell Carcinoma of the Esophagus Reviewed

Shimizu Dai, Kanda Mitsuro, Kishida Takayoshi, Nakamura Shunsuke, Sasahara Masahiro, Ueda Sei, Sato Yusuke, Inokawa Yoshikuni, Hattori Norifumi, Hayashi Masamichi, Tanaka Chie, Motoyama Satoru, Kodera Yasuhiro

CANCER GENOMICS & PROTEOMICS Vol. 20 ( 4 ) page： 343 - 353 2023

A Multicenter Randomized Phase II Trial Investigating the Effect of Polyglycolic Acid Sheet on the Prevention of Pancreatic Fistula After Gastrectomy with Prophylactic Lymph Node Dissection. Reviewed International journal

Dai Shimizu, Chie Tanaka, Mitsuro Kanda, Koki Nakanishi, Seiji Ito, Yachiyo Kuwatsuka, Masahiko Ando, Kenta Murotani, Michitaka Fujiwara, Yasuhiro Kodera

Clinical and experimental gastroenterology Vol. 16 page： 169 - 172 2023

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

Pancreatic fistula after gastrectomy with lymph node dissection is associated with prolonged hospital stay and critical complications such as intra-abdominal bleeding and sepsis. Polyglycolic acid (PGA) sheets are absorbable suture reinforcement materials. A randomized Phase II trial has been planned to evaluate the effect of PGA sheets on preventing postoperative pancreatic fistula. A total of 320 patients will be recruited from thirteen institutions. Patients who are scheduled to undergo distal or total gastrectomy will be randomly allocated into the PGA group or control group, and the dissected area around the pancreas will be covered by the PGA sheet in the PGA group. The primary endpoint will be the maximum value of drain amylase concentration up to 5 days after surgery. The secondary endpoints will be as follows: transition of value of amylases of drain discharge, incidence of pancreatic fistula, incidence of intra-abdominal abscess, white blood cell count, value of C-reactive protein, incidence of postoperative complication, duration of antibiotic agents administration, duration of abdominal drainage, usage of octreotide, duration of hospital stay, incidence of bleeding in abdominal cavity, mortality, and incidence of reoperation.

DOI： 10.2147/CEG.S421531

Preoperative docetaxel, cisplatin, and fluorouracil treatment with pegfilgrastim on day 7 for patients with esophageal cancer: A phase II study. Reviewed International journal

Osamu Maeda, Masahide Fukaya, Masahiko Koike, Kazushi Miyata, Mitsuro Kanda, Kazuki Nishida, Masahiko Ando, Yasuhiro Kodera, Yuichi Ando

Asia-Pacific journal of clinical oncology Vol. 18 ( 6 ) page： 578 - 585 2022.12

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

AIMS: The docetaxel and cisplatin plus 5-fluorouracil (5-FU) (DCF) regimen is expected to be superior to cisplatin plus 5-FU for the preoperative treatment of esophageal cancer. However, a high risk of adverse effects, including febrile neutropenia (FN), has been reported. To evaluate the effectiveness and safety of DCF with prophylactic pegfilgrastim, we conducted a phase II study. METHODS: The regimen consisted of intravenous administration of docetaxel (70 mg/m2 per day) and cisplatin (70 mg/m2 per day) on day 1 and a continuous infusion of 5-FU (750 mg/m2 per day) on days 1-5. A single 3.6-mg dose of pegfilgrastim was given as a subcutaneous injection on day 7 of each cycle. This regimen was repeated every 3 weeks for a maximum of three cycles. The primary endpoint was the grade-2/3 histopathological response rate. RESULTS: Thirty-seven eligible patients were enrolled and received DCF. Thirty-four patients underwent esophagectomy. Two patients received chemoradiotherapy or radiotherapy without surgery. One patient withdrew consent and ended his hospital visit. One patient received additional radiotherapy before surgery. Histopathological responses of grade 3, grade 2, grade 1b, and grade 1a were observed in two (5.4%), 14 (37.8%), 10 (27.0%), and seven (18.9%) patients, respectively, and the primary endpoint was met. Of the 37 eligible patients, 11 (29.7%) developed FN in the first cycle. CONCLUSIONS: Since the histopathological responses were as expected, DCF with prophylactic pegfilgrastim is considered to be effective as preoperative chemotherapy. However, the prophylactic use of pegfilgrastim on day 7 was insufficient to prevent FN.

DOI： 10.1111/ajco.13755

高齢者に対する周術期感染症の予防策高齢者胃癌に対する術後感染性合併症発生の現状と対策肺炎を中心に Reviewed

胃切除術におけるインドシアニングリーンを用いた病変のマーキング法 Reviewed

飯塚彬光, 田中千恵, 中西香企, 清水大, 神田光郎, 林真路, 中山吾郎, 小寺泰弘

日本内視鏡外科学会雑誌 Vol. 27 ( 7 ) page： 2072 - 2072 2022.12

胃切除術におけるインドシアニングリーンを用いた病変のマーキング法 Reviewed

飯塚彬光, 田中千恵, 中西香企, 清水大, 神田光郎, 林真路, 中山吾郎, 小寺泰弘

日本内視鏡外科学会雑誌 Vol. 27 ( 7 ) page： 2072 - 2072 2022.12

当院におけるロボット支援下胃切除術教育の工夫 Reviewed

田中千恵, 中西香企, 清水大, 梅田晋一, 猪川祥邦, 高見秀樹, 服部憲史, 林真路, 神田光郎, 中山吾郎, 小寺泰弘

日本内視鏡外科学会雑誌 Vol. 27 ( 7 ) page： 1649 - 1649 2022.12

女性医師の活躍できる内視鏡外科手術と働き方改革の在り方とは? 腹腔鏡下手術における使用デバイスの操作性に関する検討 Reviewed

田中千恵, 中西香企, 清水大, 梅田晋一, 猪川祥邦, 田中伸孟, 高見秀樹, 服部憲史, 林真路, 神田光郎, 中山吾郎, 小寺泰弘

日本内視鏡外科学会雑誌 Vol. 27 ( 7 ) page： 415 - 415 2022.12

女性医師の活躍できる内視鏡外科手術と働き方改革の在り方とは? 腹腔鏡下手術における使用デバイスの操作性に関する検討 Reviewed

田中千恵, 中西香企, 清水大, 梅田晋一, 猪川祥邦, 田中伸孟, 高見秀樹, 服部憲史, 林真路, 神田光郎, 中山吾郎, 小寺泰弘

日本内視鏡外科学会雑誌 Vol. 27 ( 7 ) page： 415 - 415 2022.12

当院におけるロボット支援下胃切除術教育の工夫 Reviewed

田中千恵, 中西香企, 清水大, 梅田晋一, 猪川祥邦, 高見秀樹, 服部憲史, 林真路, 神田光郎, 中山吾郎, 小寺泰弘

日本内視鏡外科学会雑誌 Vol. 27 ( 7 ) page： 1649 - 1649 2022.12

胃癌腹膜播種に対するPTEGの使用経験 Reviewed

杉山史剛, 中西香企, 田中千恵, 神田光郎, 清水大, 高見秀樹, 猪川祥邦, 服部憲史, 林真路, 中山吾郎, 藤原道隆, 小寺泰弘

日本消化器病学会東海支部例会プログラム抄録集 Vol. 137回 page： 73 - 73 2022.11

胃癌腹膜播種に対するPTEGの使用経験 Reviewed

杉山史剛, 中西香企, 田中千恵, 神田光郎, 清水大, 高見秀樹, 猪川祥邦, 服部憲史, 林真路, 中山吾郎, 藤原道隆, 小寺泰弘

日本消化器病学会東海支部例会プログラム抄録集 Vol. 137回 page： 73 - 73 2022.11

ASO Visual Abstract: Gamma-Aminobutyric Acid Type A Receptor Subunit Delta as a Potential Therapeutic Target in Gastric Cancer Reviewed

Sawaki Koichi, Kanda Mitsuro, Baba Hayato, Inokawa Yoshikuni, Hattori Norifumi, Hayashi Masamichi, Tanaka Chie, Kodera Yasuhiro

ANNALS OF SURGICAL ONCOLOGY Vol. 30 ( 1 ) page： 639 - 640 2022.10

Downregulation of ROBO4 in Pancreatic Cancer Serves as a Biomarker of Poor Prognosis and Indicates Increased Cell Motility and Proliferation Through Activation of MMP-9 Reviewed

Yamanaka Masaya, Hayashi Masamichi, Sonohara Fuminori, Yamada Suguru, Tanaka Haruyoshi, Sakai Akihiro, Mii Shinji, Kobayashi Daigo, Kurimoto Keisuke, Tanaka Nobutake, Inokawa Yoshikuni, Takami Hideki, Hattori Norifumi, Kanda Mitsuro, Tanaka Chie, Nakayama Goro, Koike Masahiko, Kodera Yasuhiro

ANNALS OF SURGICAL ONCOLOGY Vol. 29 ( 11 ) page： 7180 - 7189 2022.10

ASO Visual Abstract: Downregulation of ROBO4 in Pancreatic Cancer Serves as a Biomarker of Poor Prognosis and Indicates Increased Cell Motility and Proliferation Through Activation of MMP-9 Reviewed

ANNALS OF SURGICAL ONCOLOGY Vol. 29 ( 11 ) page： 7192 - 7193 2022.10

田中千恵, 中西香企, 清水大, 猪川祥邦, 高見秀樹, 服部憲史, 神田光郎, 林真路, 中山吾郎, 藤原道隆, 小寺泰弘

日本外科感染症学会雑誌 Vol. 19 ( 1 ) page： 216 - 216 2022.10

術前治療後の食道癌患者における術前PLR値の術後合併症・予後予測因子としての意義 Reviewed

笹原正寛, 神田光郎, 清水大, 中西香企, 田中千恵, 猪川祥邦, 高見秀樹, 服部憲史, 林真路, 中山吾郎, 藤原道隆, 小寺泰弘

日本癌治療学会学術集会抄録集 Vol. 60回 page： P33 - 2 2022.10

術前治療後の食道癌患者における術前PLR値の術後合併症・予後予測因子としての意義 Reviewed

笹原正寛, 神田光郎, 清水大, 中西香企, 田中千恵, 猪川祥邦, 高見秀樹, 服部憲史, 林真路, 中山吾郎, 藤原道隆, 小寺泰弘

日本癌治療学会学術集会抄録集 Vol. 60回 page： P33 - 2 2022.10

高齢者に対する周術期感染症の予防策高齢者胃癌に対する術後感染性合併症発生の現状と対策肺炎を中心に Reviewed

田中千恵, 中西香企, 清水大, 猪川祥邦, 高見秀樹, 服部憲史, 神田光郎, 林真路, 中山吾郎, 藤原道隆, 小寺泰弘

日本外科感染症学会雑誌 Vol. 19 ( 1 ) page： 216 - 216 2022.10

胃癌に対するナビゲーションサージェリーの工夫胃癌に対する低侵襲手術における術中マーキング法 Reviewed

田中千恵, 中西香企, 清水大, 猪川祥邦, 高見秀樹, 服部憲史, 神田光郎, 林真路, 中山吾郎, 藤原道隆, 小寺泰弘

日本臨床外科学会雑誌 Vol. 83 ( 増刊 ) page： S161 - S161 2022.10

食道扁平上皮癌におけるOPLAHタンパク発現意義 Reviewed

清水大, 神田光郎, 佐藤雄亮, 本山悟, 小寺泰弘

日本分子腫瘍マーカー研究会プログラム・講演抄録 Vol. 42回 page： 110 - 111 2022.9

Transcriptomic profiling on localized gastric cancer identified CPLX1 as a gene promoting malignant phenotype of gastric cancer and a predictor of recurrence after surgery and subsequent chemotherapy Reviewed

Haruyoshi Tanaka, Mitsuro Kanda, Dai Shimizu, Chie Tanaka, Yoshikuni Inokawa, Norifumi Hattori, Masamichi Hayashi, Goro Nakayama, Yasuhiro Kodera

Journal of Gastroenterology Vol. 57 ( 9 ) page： 640 - 653 2022.9

ASO Author Reflections: Optimized Cutoff Value of Albumin-Bilirubin Score to Predict Prognosis of Patients with Esophageal Squamous Cell Carcinoma After Radical Resection. Reviewed International journal

Takahiro Shinozuka, Mitsuro Kanda, Yasuhiro Kodera

Annals of surgical oncology Vol. 29 ( 8 ) page： 4897 - 4898 2022.8

Prognostic Value of a Modified Albumin-Bilirubin Score Designed for Patients with Esophageal Squamous Cell Carcinoma After Radical Resection. Reviewed International journal

Takahiro Shinozuka, Mitsuro Kanda, Dai Shimizu, Chie Tanaka, Yoshikuni Inokawa, Norifumi Hattori, Masamichi Hayashi, Masahiko Koike, Yasuhiro Kodera

Annals of surgical oncology Vol. 29 ( 8 ) page： 4889 - 4896 2022.8

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

BACKGROUND: The albumin-bilirubin (ALBI) score was originally developed to assess the severity of liver dysfunction in patients with hepatocellular carcinoma and has subsequently been used as a prognostic marker for that disease. Here, we examined the value of the preoperative ALBI score as a prognostic marker for patients with esophageal squamous cell carcinoma (ESCC) after radical esophagectomy. METHODS: We retrospectively analyzed data from 449 patients who underwent curative resection for ESCC. The ALBI score was calculated as (log10 serum bilirubin [μmol/l] × 0.66) + (serum albumin [g/l] × - 0.0852). Receiver operating characteristic curve analysis was used to define a preoperative modified ALBI (mALBI) score for patient stratification. RESULTS: Of the 449 ESCC patients, 232 and 217 were assigned to mALBI Grade 1 or Grade 2 groups based on preoperative ALBI scores of ≤ - 3.33 or > - 3.33, respectively. Preoperative mALBI grade was significantly associated with age, excessive alcohol consumption, squamous cell carcinoma antigen level, and clinical disease stage. The mALBI Grade 2 group had significantly shorter disease-specific and recurrence-free survival than the mALBI Grade 1 group. Multivariate analysis demonstrated that mALBI Grade 2 was an independent prognostic factor for disease-specific survival (hazard ratio 1.86, 95% confidence interval 1.18-2.93, P = 0.0074). In most subgroup analyses, mALBI Grade 2 was associated with a greater risk of disease-specific death. CONCLUSIONS: mALBI grade serves as a simple and useful prognostic marker for disease-specific survival in patients with ESCC after radical esophagectomy.

DOI： 10.1245/s10434-022-11654-6

Comparison Between FOLFIRINOX and nal-IRI/FL as Second-line Treatment After Gemcitabine Plus Nab-paclitaxel for Pancreatic Cancer br Reviewed

Otsu Tomohisa, Inokawa Yoshikuni, Takami Hideki, Hayashi Masamichi, Kurimoto Keisuke, Tanaka Nobutake, Tanaka Haruyoshi, Shimizu Dai, Hattori Norifumi, Kanda Mitsuro, Tanaka Chie, Nakayama Goro, Kodera Yasuhiro

ANTICANCER RESEARCH Vol. 42 ( 8 ) page： 3889 - 3894 2022.8

胃癌術後早期ドレーンアミラーゼ値の有用性早期治療介入にむけて Reviewed

中西香企, 神田光郎, 田中千恵, 清水大, 猪川祥邦, 服部憲史, 林真路, 中山吾郎, 藤原道隆, 小寺泰弘

日本消化器外科学会総会 Vol. 77回 page： O6 - 4 2022.7

局所進行食道扁平上皮癌に対する術前ドセタキセル、オキサリプラチン、S-1併用療法の開発臨床試験 Reviewed

神田光郎, 清水大, 宮田一志, 江畑智希, 小寺泰弘

日本消化器外科学会総会 Vol. 77回 page： O1 - 3 2022.7

E-PASS scoring system serves as a predictor of short- and long-term outcomes in gastric cancer surgery. Reviewed

Koki Nakanishi, Mitsuro Kanda, Seiji Ito, Yoshinari Mochizuki, Hitoshi Teramoto, Kiyoshi Ishigure, Toshifumi Murai, Takahiro Asada, Akiharu Ishiyama, Hidenobu Matsushita, Daisuke Kobayashi, Dai Shimizu, Chie Tanaka, Michitaka Fujiwara, Kenta Murotani, Yasuhiro Kodera

Surgery today Vol. 52 ( 6 ) page： 914 - 922 2022.6

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

PURPOSES: This study aimed to evaluate the estimation of the physiological ability and surgical stress (E-PASS) scoring system for predicting the short- and long-term outcomes in gastric cancer (GC) surgery. METHODS: We analyzed a multi-institutional dataset to study patients who underwent gastrectomy with a curative intent between 2010 and 2014. This study evaluated the associations between the optimal E-PASS score cutoff value and the following outcomes: (1) the incidence of postoperative complications in stage I-III GC patients and (2) the prognosis in stage II-III GC patients. RESULTS: A total of 2495 GC patients were included. A cutoff value of 0.419 was determined using the ROC curve analysis. Postoperative complications were observed more frequently in the E-PASS-high group than that in the E-PASS-low group (30% vs. 17%, p < 0.0001). Among pStage II-III GC patients (n = 1009), the overall survival time of the E-PASS-high group was significantly shorter than that of the E-PASS-low group (hazard ratio 2.08; 95% confidence interval 1.64-2.65; p < 0.0001). A forest plot revealed that E-PASS-high was associated with a greater prognostic factor for overall survival in most subgroups. CONCLUSIONS: The E-PASS scoring system may therefore be a useful predictor of the short- and long-term outcomes in patients with GC who have undergone radical gastrectomy.

DOI： 10.1007/s00595-021-02394-3

Expression of cellular retinoic acid binding protein 1 predicts peritoneal recurrence of gastric cancer. Reviewed International journal

Kazuki Sakata, Mitsuro Kanda, Dai Shimizu, Shunsuke Nakamura, Yoshikuni Inokawa, Norifumi Hattori, Masamichi Hayashi, Chie Tanaka, Goro Nakayama, Yasuhiro Kodera

International journal of oncology Vol. 60 ( 6 ) 2022.6

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

To improve the outcome of gastric cancer, novel markers that predict postoperative prognosis are required. For this purpose, the function of cellular retinoic acid binding protein 1 (CRABP1) in gastric cancer cells was investigated and it was determined whether it serves as a novel biomarker for gastric cancer. Reverse transcription‑quantitative (RT‑q)PCR and a PCR‑array method were used to determine whether the expression of CRABP1 mRNA in gastric cancer cell lines correlated with the expression of cancer‑related genes. The correlations of CRABP1 mRNA expression in tissues with clinicopathological factors of 230 patients who underwent radical gastrectomy were further evaluated. CRABP1 mRNA levels varied among gastric cancer cell lines and showed significant positive correlations with numerous epithelial‑mesenchymal transition factors. Additionally, CRABP1 knockdown significantly suppressed the proliferation, migration and invasion of gastric cancer cell lines. In a mouse xenograft model of peritoneal metastasis of gastric cancer, it was found that the total weight of disseminated nodules was lower in the group, in which CRABP1 mRNA levels were knocked down compared with those of the untransfected group. Disease‑free survival (DFS) was significantly shorter in patients with high expression of CRABP1, and multivariate analysis of DFS revealed that high expression of CRABP1 in the tumor area and lymph node metastasis served as an independent factor associated with poor prognosis. High expression of CRABP1 in cancer tissues was associated with a greater incidence of peritoneal recurrences after curative gastrectomy. These findings indicated that CRABP1 contributes to the malignant phenotype of gastric cancer cells and may serve as a biomarker for prognosing recurrence after curative resection, particularly peritoneal dissemination.

DOI： 10.3892/ijo.2022.5353

Lysosomal-associated membrane protein family member 5 promotes the metastatic potential of gastric cancer cells. Reviewed

Shinichi Umeda, Mitsuro Kanda, Dai Shimizu, Shunsuke Nakamura, Koichi Sawaki, Yoshikuni Inokawa, Norifumi Hattori, Masamichi Hayashi, Chie Tanaka, Goro Nakayama, Yasuhiro Kodera

Gastric cancer : official journal of the International Gastric Cancer Association and the Japanese Gastric Cancer Association Vol. 25 ( 3 ) page： 558 - 572 2022.5

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

BACKGROUND: Metastatic gastric cancer (GC) has a poor prognosis, and elucidating the molecular mechanisms involved in metastasis may lead to the development of novel therapeutic modalities. METHODS: Transcriptome analysis of surgically resected metastatic tissue from GC patients and noncancerous tissue was performed to identify novel metastasis-related genes. Analyses of in vitro cell function, apoptosis, the cell cycle and cancer stemness were performed using GC cell lines with a stable knockout of a candidate gene. In vivo percutaneous, peritoneal dissemination and liver metastasis xenograft models were also generated. PCR array and proteome analyses were performed. Expression of the candidate gene was analyzed in GC tissues from 300 patients. RESULTS: Lysosomal Associated Membrane Protein Family Member 5 (LAMP5) was upregulated in the metastatic tissues. LAMP5 knockout significantly suppressed proliferation, invasion, and migration of GC cells and increased apoptosis, cell cycle arrest and cancer stemness. LAMP5 knockout virtually suppressed tumor growth in in vivo percutaneous, peritoneal dissemination and liver metastasis models. EMT- and autophagy-related genes were associated with LAMP5. High LAMP5 mRNA levels were significantly associated with a worse prognosis. CONCLUSION: LAMP5 plays a vital role in metastasis formation and may be a promising novel target of drug development for metastatic GC in the future.

DOI： 10.1007/s10120-022-01284-y

特集そろそろ真剣に考えよう胃癌に対するロボット支援手術ロボット支援手術を始めるためにロボット支援下胃切除術の準備と立ち上げ-マイナスからのスタート Reviewed

がんトランスレーショナルリサーチ外科臨床検体を用いたトランスクリプトーム解析からの癌治療抗体医薬開発研究 Reviewed

神田光郎, 清水大, 中西香企, 田中千恵, 猪川祥邦, 高見秀樹, 服部憲史, 林真路, 中山吾郎, 藤原道隆, 小寺泰弘

日本外科系連合学会誌 Vol. 47 ( 3 ) page： 401 - 401 2022.5

田中千恵, 中西香企, 神田光郎, 小寺泰弘

臨床外科 Vol. 77 ( 4 ) page： 393 - 397 2022.4

ASO Visual Abstract: Prognostic Value of a Modified Albumin-Bilirubin Grade Designed for Patients with Esophageal Squamous Cell Carcinoma after Radical Resection. Reviewed International journal

Takahiro Shinozuka, Mitsuro Kanda, Dai Shimizu, Chie Tanaka, Yoshikuni Inokawa, Norifumi Hattori, Masamichi Hayashi, Masahiko Koike, Yasuhiro Kodera

Annals of surgical oncology 2022.4

Prognostic impact of a microscopic positive margin in patients undergoing gastrectomy for gastric cancer: a propensity score‑matched analysis of a multi‑institutional dataset. Reviewed

Surgery today Vol. 52 ( 4 ) page： 559 - 566 2022.4

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

PURPOSE: We analyzed the effect of a microscopic positive margin on survival outcomes after gastrectomy for gastric cancer METHODS: We analyzed a multi-institutional dataset to study patients who underwent gastrectomy with curative intent between 2010 and 2014. We used propensity score matching to strictly balance the patients' oncological features, backgrounds, and postoperative treatment to compare the survival outcomes of those with microscopic positive margins and those with negative margins. RESULTS: Among 3029 patients, 32 (1.1%) had positive margins. After matching, we enrolled 128 patients in this retrospective analysis: 32 with a positive margin and 96 with a negative margin. The recurrence-free survival of the positive-margin group was significantly shorter than that of the negative-margin group (hazard ratio [HR], 1.62, 95% confidence interval, 1.00-2.63, p = 0.0485). Consistent results were observed for patients with pStages I-III disease (HR, 1.65, p = 0.0835), whereas the survival curves overlapped in those with pStage IV disease (HR, 1.29, p = 0.5934). The prevalence of overall recurrence in the positive-margin group was higher than that in the negative-margin group (75% vs 58%, p = 0.0917). This trend was consistent with locoregional recurrence (9% vs 3%) and distant recurrence (69% vs 55%). CONCLUSIONS: The survival of patients after curative gastrectomy for gastric cancer was worse in those with microscopic positive margins than in those with negative margins.

DOI： 10.1007/s00595-021-02365-8

食道扁平上皮癌予後マーカーとしてのOPLAH発現 Reviewed

清水大, 神田光郎, 小池聖彦, 佐藤雄亮, 猪川祥邦, 高見秀樹, 服部憲史, 林真路, 田中千恵, 中山吾郎, 本山悟, 藤原道隆, 小寺泰弘

日本外科学会定期学術集会抄録集 Vol. 122回 page： DP - 5 2022.4

ASO Visual Abstract: SLC7A9 as a Potential Biomarker for Lymph Node Metastasis of Esophageal Squamous Cell Carcinoma. Reviewed International journal

Hayato Baba, Mitsuro Kanda, Koichi Sawaki, Shunsuke Nakamura, Sei Ueda, Dai Shimizu, Masahiko Koike, Yasuhiro Kodera, Tsutomu Fujii

Annals of surgical oncology Vol. 29 ( 4 ) page： 2710 - 2710 2022.4

SLC7A9 as a Potential Biomarker for Lymph Node Metastasis of Esophageal Squamous Cell Carcinoma. Reviewed International journal

Hayato Baba, Mitsuro Kanda, Koichi Sawaki, Shunsuke Nakamura, Sei Ueda, Dai Shimizu, Masahiko Koike, Yasuhiro Kodera, Tsutomu Fujii

Annals of surgical oncology Vol. 29 ( 4 ) page： 2699 - 2709 2022.4

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

BACKGROUND: The expression of solute carrier (SLC) 7 family genes is reportedly associated with several malignancies. Here, we focused on SLC7A9 and investigated its expression, function, and clinical significance in esophageal squamous cell carcinoma (ESCC). METHODS: SLC7A9 transcription levels were evaluated in 13 ESCC cell lines, and polymerase chain reaction (PCR) array analysis was conducted to detect coordinately expressed genes with SLC7A9. SLC7A9 contributions to proliferation, invasion, and migration were evaluated in ESCC cells subjected to siRNA-mediated gene knockdown and pCMV6-entry plasmid-mediated overexpression. SLC7A9 expression was detected in 189 ESCC tissues by quantitative reverse-transcription (qRT)-PCR and correlated with clinicopathological parameters. RESULTS: The expression levels of SLC7A9 varied widely in ESCC cell lines and correlated with FGFBP1 expression. Knockdown of SLC7A9 significantly suppressed the proliferation, invasion, and migration of the ESCC cell lines. Moreover, overexpression of SLC7A9 enhanced cell proliferation and migration. In analyses of clinical specimens, SLC7A9 mRNA was overexpressed in the ESCC tissues compared with the adjacent normal esophageal tissues. High mRNA expression was significantly associated with high levels of squamous cell carcinoma-related antigen and carcinoembryonic antigen, advanced disease stage, and lymph node metastasis. High SLC7A9 expression was also significantly associated with poor disease-specific and disease-free survival, and lymph node recurrence after radical surgery, but not with the other recurrence patterns. On multivariate analysis, high SLC7A9 expression was an independent predictor of lymph node recurrence. CONCLUSIONS: SLC7A9 influences the malignant behavior of ESCC cells. Tumor SLC7A9 expression may serve as a novel biomarker for predicting lymph node metastasis and recurrence in ESCC patients.

DOI： 10.1245/s10434-021-11001-1

Stage II/III胃癌患者における術前Prognostic Nutritional Index値と術後合併症・長期予後との関連 Reviewed

笹原正寛, 神田光郎, 伊藤誠二, 望月能成, 寺本仁, 石榑清, 村井俊文, 浅田崇洋, 石山聡治, 松下英信, 田中千恵, 小林大介, 藤原道隆, 室谷健太, 小寺泰弘

日本外科学会定期学術集会抄録集 Vol. 122回 page： DP - 1 2022.4

高齢者の上部消化管癌に対する治療方針高齢者機能評価から考える高齢者胃癌に対する治療法 Reviewed

田中千恵, 中西香企, 梅田晋一, 清水大, 猪川祥邦, 高見秀樹, 服部憲史, 神田光郎, 林真路, 中山吾郎, 藤原道隆, 小寺泰弘

日本外科学会定期学術集会抄録集 Vol. 122回 page： WS - 4 2022.4

治癒切除不能胃癌に対するconversion surgeryの治療実態を調査する多施設共同前向き観察研究 Reviewed

中西香企, 田中千恵, 神田光郎, 清水大, 宮田一志, 藤原道隆, 小寺泰弘

日本外科学会定期学術集会抄録集 Vol. 122回 page： SF - 1 2022.4

Stage II/III胃癌患者における術前Prognostic Nutritional Index値と術後合併症・長期予後との関連 Reviewed

日本外科学会定期学術集会抄録集 Vol. 122回 page： DP - 1 2022.4

Drain Amylase Concentrations at 3 h After Gastrectomy Enhance Early Prediction of Postoperative Peripancreatic Inflammatory Fluid Collection. Reviewed International journal

Koki Nakanishi, Mitsuro Kanda, Chie Tanaka, Shigeomi Takeda, Katsuhito Tanaka, Dai Shimizu, Yoshikuni Inokawa, Norifumi Hattori, Masamichi Hayashi, Goro Nakayama, Michitaka Fujiwara, Yasuhiro Kodera

World journal of surgery Vol. 46 ( 3 ) page： 648 - 655 2022.3

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

BACKGROUND: Despite numerous studies of peripancreatic inflammatory fluid collection (PIFC) that report on the relevance of the drain amylase concentration (D-AMY), early prediction using this assay is problematic. This study aimed to investigate the clinical significance of measuring the D-AMY at 3 h after gastrectomy (POD0) for gastric cancer. METHODS: This retrospective analysis included consecutive patients who underwent gastrectomy combined with peripancreatic lymph node dissection. The predictive value of D-AMY on POD0 and postoperative day 1 (POD1) for clinically relevant PIFC was evaluated together or individually. RESULTS: Analyses were performed in 204 patients. Twenty (9.8%) patients experienced PIFC. D-AMY cutoffs of 721 IU/L on POD0 and 1695 IU/L on POD1 were determined using the receiver operating characteristic curve analysis for predicting PIFC. The D-AMY on POD0 had higher sensitivity (80%) but lower specificity (66.3%) for prediction of PIFC, compared with those of D-AMY on POD1 (65%, 89.1%, respectively). When combination marker analysis was performed, the highest risk group (D-AMY ≥ the cutoff values of POD0 and POD1) were associated with an elevated rate of occurrence (44%) and a high positive likelihood ratio (7.36) compared with those of the single cutoff group. The lowest risk group (D-AMY < the cutoff values on POD0 and POD1) was associated with a low rate of occurrence (2.5%) and low negative likelihood ratio (0.24) compared with those of the single cutoff group. CONCLUSIONS: Combined measurements of D-AMYs on POD0 and POD1 enhanced early prediction of PIFC after gastrectomy.

DOI： 10.1007/s00268-021-06401-z

Comprehensive Genomic Profiling of Neuroendocrine Carcinomas of the Gastrointestinal System Reviewed

Yachida Shinichi, Totoki Yasushi, Noe Michael, Nakatani Yoichiro, Horie Masafumi, Kawasaki Kenta, Nakamura Hiromi, Saito-Adachi Mihoko, Suzuki Masami, Takai Erina, Hama Natsuko, Higuchi Ryota, Hirono Seiko, Shiba Satoshi, Kato Mamoru, Furukawa Eisaku, Arai Yasuhito, Rokutan Hirofumi, Hashimoto Taiki, Mitsunaga Shuichi, Kanda Mitsuro, Tanaka Hidenori, Takata So, Shimomura Ayaka, Oshima Minoru, Hackeng Wenzel M., Okumura Tomoyuki, Okano Keiichi, Yamamoto Masakazu, Yamaue Hiroki, Morizane Chigusa, Arihiro Koji, Furukawa Toru, Sato Toshiro, Kiyono Tohru, Brosens Lodewijk A. A., Wood Laura D., Hruban Ralph H., Shibata Tatsuhiro

CANCER DISCOVERY Vol. 12 ( 3 ) page： 692 - 711 2022.3

腹腔鏡下胃切除術における臨床病期Iから病理学的病期II/IIIへと移行した患者の予後(Prognosis of patients with stage migration from cStage I to pStage II/III after laparoscopic surgery) Reviewed

伊藤雄貴, 神田光郎, 伊藤誠二, 望月能成, 寺本仁, 石榑清, 村井俊文, 浅田崇洋, 石山聡治, 松下英信, 田中千恵, 小林大介, 藤原道隆, 室谷健太, 藤田恵三, 三輪高嗣, 田中友理, 間下直樹, 小寺泰弘

日本胃癌学会総会記事 Vol. 94回 page： 439 - 439 2022.3

A microRNA-based liquid biopsy signature for the early detection of esophageal squamous cell carcinoma: a retrospective, prospective and multicenter study. Reviewed International journal

Jinsei Miyoshi, Zhongxu Zhu, Aiping Luo, Shusuke Toden, Xuantong Zhou, Daisuke Izumi, Mitsuro Kanda, Tetsuji Takayama, Iqbal M Parker, Minjie Wang, Feng Gao, Ali H Zaidi, Hideo Baba, Yasuhiro Kodera, Yongping Cui, Xin Wang, Zhihua Liu, Ajay Goel

Molecular cancer Vol. 21 ( 1 ) page： 44 - 44 2022.2

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

BACKGROUND: Currently, there is no clinically relevant non-invasive biomarker for early detection of esophageal squamous cell carcinoma (ESCC). Herein, we established and evaluated a circulating microRNA (miRNA)-based signature for the early detection of ESCC using a systematic genome-wide miRNA expression profiling analysis. METHODS: We performed miRNA candidate discovery using three ESCC tissue miRNA datasets (n = 108, 238, and 216) and the candidate miRNAs were confirmed in tissue specimens (n = 64) by qRT-PCR. Using a serum training cohort (n = 408), we conducted multivariate logistic regression analysis to develop an ESCC circulating miRNA signature and the signature was subsequently validated in two independent retrospective and two prospective cohorts. RESULTS: We identified eighteen initial miRNA candidates from three miRNA expression datasets (n = 108, 238, and 216) and subsequently validated their expression in ESCC tissues. We thereafter confirmed the overexpression of 8 miRNAs (miR-103, miR-106b, miR-151, miR-17, miR-181a, miR-21, miR-25, and miR-93) in serum specimens. Using a serum training cohort, we developed a circulating miRNA signature (AUC:0.83 [95%CI:0.79-0.87]) and the diagnostic performance of the miRNA signature was confirmed in two independent validation cohorts (n = 126, AUC:0.80 [95%CI:0.69-0.91]; and n = 165, AUC:0.89 [95%CI:0.83-0.94]). Finally, we demonstrated the diagnostic performance of the 8-miRNA signature in two prospective cohorts (n = 185, AUC:0.92, [95%CI:0.87-0.96]); and (n = 188, AUC:0.93, [95%CI:0.88-0.97]). Importantly, the 8-miRNA signature was superior to current clinical serological markers in discriminating early stage ESCC patients from healthy controls (p < 0.001). CONCLUSIONS: We have developed a novel and robust circulating miRNA-based signature for early detection of ESCC, which was successfully validated in multiple retrospective and prospective multinational, multicenter cohorts.

DOI： 10.1186/s12943-022-01507-x

Diagnostic efficacy of circular RNAs as noninvasive, liquid biopsy biomarkers for early detection of gastric cancer. Reviewed International journal

Souvick Roy, Mitsuro Kanda, Sachiyo Nomura, Zhongxu Zhu, Yuji Toiyama, Akinobu Taketomi, James Goldenring, Hideo Baba, Yasuhiro Kodera, Ajay Goel

Molecular cancer Vol. 21 ( 1 ) page： 42 - 42 2022.2

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

BACKGROUND: Majority of gastric cancers (GC) are diagnosed at advanced stages which contributes towards their poor prognosis. In view of this clinical challenge, identification of non-invasive biomarker for early diagnosis is imperative. Herein, we aimed to develop a non-invasive, liquid-biopsy based assay by using circular RNAs (circRNAs) as molecular biomarkers for early detection of GC. METHODS: We performed systematic biomarker discovery and validation of the candidate circRNAs in matched tissue specimens of GC and adjacent normal mucosa. Next, we translated the discovered circRNA based biomarker panel into serum samples in a training and validation cohort of GC patients (n = 194) and non-disease controls (n = 94) and evaluated their diagnostic performance. In addition, we measured the expression of circRNAs in serum samples of pre- and post-surgical GC patients and evaluated the specificity of circRNAs biomarker panel with respect to other gastro-intestinal (GI) malignancies. RESULTS: We identified 10-circRNAs in the discovery phase with subsequent validation in a pilot cohort of GC tissue specimens. Using a training cohort of patients, we developed an 8-circRNA based risk-prediction model for the diagnosis of GC. We observed that our biomarker panel robustly discriminated GC patients from non-disease controls with an AUC of 0.87 in the training, and AUC of 0.83 in the validation cohort. Notably, the biomarker panel could robustly identify even early-stage GC patients, regardless of their tumor histology (diffuse vs. intestinal). The decreased expression of circRNAs in post-surgery serum specimens indicated their tumor-specificity and their potential source of origin in the systemic circulation. CONCLUSIONS: We identified a panel of 8-circRNAs as non-invasive, liquid-biopsy biomarkers which might serve as potential diagnostic biomarkers for the early detection of GC.

DOI： 10.1186/s12943-022-01527-7

Optimal preoperative multidisciplinary treatment in borderline resectable pancreatic cancer: Results of a dual-center study Reviewed

Kimura Nana, Yamada Suguru, Takami Hideki, Murotani Kenta, Yoshioka Isaku, Shibuya Kazuto, Sonohara Fuminori, Hoshino Yui, Hirano Katsuhisa, Watanabe Toru, Baba Hayato, Mori Kosuke, Miwa Takeshi, Tanaka Haruyoshi, Kanda Mitsuro, Hayashi Masamichi, Matsui Koshi, Okumura Tomoyuki, Kodera Yasuhiro, Fujii Tsutomu

JOURNAL OF CLINICAL ONCOLOGY Vol. 40 ( 4 ) 2022.2

Platelet isoform of phosphofructokinase accelerates malignant features in breast cancer. Reviewed International journal

Takahiro Inaishi, Masahiro Shibata, Takahiro Ichikawa, Mitsuro Kanda, Masamichi Hayashi, Ikumi Soeda, Dai Takeuchi, Yuko Takano, Nobuyuki Tsunoda, Yasuhiro Kodera, Toyone Kikumori

Oncology reports Vol. 47 ( 1 ) 2022.1

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

The platelet isoform of phosphofructokinase (PFKP) is one of the key enzymes in the glycolytic pathway. PFKP is highly expressed in several cancers, and it has been reported to be involved in the progression of cancer cells. However, its oncological role in breast cancer (BC) remains unclear. The present study aimed to evaluate the function of PFKP in BC cells and its expression level in patients with BC. Firstly, the mRNA and protein expression of PFKP was evaluated in BC and non‑cancerous mammary cell lines. Polymerase chain reaction (PCR) array analysis was conducted to evaluate the correlation between PFKP and 84 cancer‑related genes. Then, PFKP knockdown was conducted using small interfering RNA, and cell proliferation, invasiveness and migration were analyzed. Furthermore, the association between PFKP mRNA expression and clinicopathological factors was investigated in 167 patients with BC. PFKP was highly expressed in estrogen receptor‑negative and human epidermal growth factor receptor 2‑negative BC cell lines. PCR array analysis demonstrated that the expression level of PFKP was significantly correlated with that of transforming growth factor‑β1 and MYC proto‑oncogene. PFKP knockdown significantly decreased the proliferation and invasiveness of MCF7, SK‑BR‑3, and MDA‑MB‑231 cells. Furthermore, cell migration was inhibited in SK‑BR‑3 and MDA‑MB‑231 cells. In the clinical specimens, patients with T2/T3/T4, lymph node metastasis, or stage II/III/IV exhibited higher expression of PFKP mRNA than patients with less severe disease. In conclusion, the present findings indicated that PFKP is involved in promoting tumor‑progressive oncological roles in BC cells across different subtypes and is considered a possible novel therapeutic target for BC.

DOI： 10.3892/or.2021.8220

Impact of molecular surgical margin analysis on the prediction of pancreatic cancer recurrences after pancreaticoduodenectomy. Reviewed International journal

Yuki Sunagawa, Masamichi Hayashi, Suguru Yamada, Hiroshi Tanabe, Keisuke Kurimoto, Nobutake Tanaka, Fuminori Sonohara, Yoshikuni Inokawa, Hideki Takami, Mitsuro Kanda, Chie Tanaka, Goro Nakayama, Masahiko Koike, Yasuhiro Kodera

Clinical epigenetics Vol. 13 ( 1 ) page： 172 - 172 2021.12

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

BACKGROUND: Pancreatic cancer is one of the lethal cancers among solid malignancies. Pathological diagnosis of surgical margins is sometimes unreliable due to tissue shrinkage, invisible field cancerization and skipped lesions like tumor budding. As a result, tumor recurrences sometimes occur even from the pathologically negative surgical margins. METHODS: We applied molecular surgical margin (MSM) analysis by tissue imprinting procedure to improve the detection sensitivity of tiny cancerous cells on the surgical specimen surface after pancreatoduodenectomy. Surgical specimens were collected from 45 pancreatic cancer cases who received subtotal stomach preserving pancreatoduodenectomy at Nagoya University Hospital during 2017-2019. Quantitative methylation-specific PCR (QMSP) of the original methylation marker panel (CD1D, KCNK12, PAX5) were performed and analyzed with postoperative survival outcomes. RESULTS: Among 45 tumors, 26 cases (58%) were QMSP-positive for CD1D, 25 (56%) for KCNK12 and 27 (60%) for PAX5. Among the 38 tumors in which at least one of the three markers was positive, CD1D-positive cancer cells, KCNK12-positive cancer cells, and PAX5-positive cancer cells were detected at the surgical margin in 8 cases, 7 cases and 10 cases, respectively. Consequently, a total of 17 patients had at least one marker detected at the surgical margin by QMSP, and these patients were defined as MSM-positive. They were associated with significantly poor recurrence-free survival (p = 0.002) and overall survival (p = 0.005) than MSM-negative patients. Multivariable analysis showed that MSM-positive was the only significant independent factor for worse recurrence-free survival (hazard ratio: 3.522, 95% confidence interval: 1.352-9.179, p = 0.010). On the other hand, a significant proportion of MSM-negative cases were found to have received neoadjuvant chemotherapy (p = 0.019). CONCLUSION: Pancreatic cancer-specific methylation marker panel was established to perform MSM analysis. MSM-positive status might represent microscopically undetectable cancer cells on the surgical margin and might influence the postoperative long-term outcomes.

DOI： 10.1186/s13148-021-01165-8

Intraperitoneal Chemotherapy as Adjuvant or Perioperative Chemotherapy for Patients with Type 4 Scirrhous Gastric Cancer: PHOENIX-GC2 Trial. Reviewed International journal

Hironori Ishigami, Yasushi Tsuji, Hisashi Shinohara, Yasuhiro Kodera, Mitsuro Kanda, Hiroshi Yabusaki, Seiji Ito, Motohiro Imano, Hiroharu Yamashita, Akio Hidemura, Hironori Yamaguchi, Takeo Fukagawa, Koji Oba, Joji Kitayama, Yasuyuki Seto

Journal of clinical medicine Vol. 10 ( 23 ) 2021.12

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

The prognosis of patients with type 4 scirrhous gastric cancer remains poor due to a high risk of peritoneal metastasis. We have previously developed combined chemotherapy regimens of intraperitoneal (IP) paclitaxel (PTX) and systemic chemotherapy, and promising clinical efficacy was reported in gastric cancer with peritoneal metastasis. Herein, a randomized, phase III study is proposed to verify the efficacy of IP PTX to prevent peritoneal recurrence. Gastric cancer patients with type 4 tumors and without apparent distant metastasis, including peritoneal metastasis, will be randomized for standard systemic chemotherapy or combined IP and systemic chemotherapy based on peritoneal lavage cytology findings. Those with negative peritoneal cytology will receive radical gastrectomy and adjuvant chemotherapy of S-1 plus docetaxel (control arm), or S-1 plus intravenous and IP PTX (experimental arm). Those with positive peritoneal cytology will receive three courses of S-1 plus oxaliplatin (control arm), or S-1 plus oxaliplatin and IP PTX (experimental arm). Subsequently, they undergo gastrectomy and receive postoperative chemotherapy of S-1 plus docetaxel (control arm), or S-1 plus intravenous and IP PTX (experimental arm). The primary endpoint is disease free survival after a 3-year follow-up period. Secondary endpoints are overall survival, survival without peritoneal metastasis, safety, completion rate, curative resection rate, and histological response of preoperative chemotherapy. A total of 300 patients are to be enrolled.

DOI： 10.3390/jcm10235666

Neoadjuvant docetaxel, oxaliplatin plus S-1 for treating clinical stage III squamous cell carcinoma of the esophagus: Study protocol of an open-label phase II trial. Reviewed International journal

Mitsuro Kanda, Dai Shimizu, Kazushi Miyata, Osamu Maeda, Chie Tanaka, Yoshikuni Inokawa, Norofumi Hattori, Masamichi Hayashi, Masahiko Ando, Yachiyo Kuwatsuka, Kenta Murotani, Goro Nakayama, Masahiko Koike, Yuichi Ando, Tomoki Ebata, Yasuhiro Kodera

Contemporary clinical trials communications Vol. 24 page： 100853 - 100853 2021.12

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

In Japan, esophagectomy after two courses of 5-fluorouracil plus cisplatin is regarded a standard strategy for treating resectable stage II or III esophageal squamous cell carcinoma (ESCC). However, 5-fluorouracil plus cisplatin does not benefit cohorts with clinical stage III ESCC, suggesting the requirement for a more effective regimen. We are conducting a single-arm phase II study to assess the safety and efficacy of neoadjuvant docetaxel, oxaliplatin plus S-1 (DOS) for treating patients with clinical stage III ESCC. The primary endpoint is the pathological response rate, and the target number is 45 patients. Safety, response rate, R0 resection rate, and survival are secondary endpoints. This trial is registered in the Japan Registry of Clinical Trials as jRCTs041210023. We are conducting a prospective phase II trial to evaluate the safety and efficacy of three courses of neoadjuvant DOS treatment followed by radical esophagectomy for clinical stage III ESCC.

DOI： 10.1016/j.conctc.2021.100853

Genomewide Expression Profiling Identifies a Novel miRNA-Based Signature for the Detection of Peritoneal Metastasis in Patients With Gastric Cancer. Reviewed International journal

Shimura T, Toden S, Kandimalla R, Toiyama Y, Okugawa Y, Kanda M, Baba H, Kodera Y, Kusunoki M, Goel A

Annals of surgery Vol. 274 ( 5 ) page： E425 - E434 2021.11

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

OBJECTIVE: This study aimed to conduct a genomewide transcriptomic profiling to develop a microRNA (miRNA)-based signature for the identification of peritoneal metastasis (PM) in patients with gastric cancer (GC). SUMMARY BACKGROUND DATA: Even though PM in patients with GC has long been recognized to associate with poor prognosis, currently there is lack of availability of molecular biomarkers for its robust diagnosis. METHODS: We performed a systematic biomarker discovery by analyzing miRNA expression profiles in primary tumors from GC patients with and without PM, and subsequently validated the expression of candidate miRNA biomarkers in 3 independent clinical cohorts of 354 patients with advanced GC. RESULTS: Five miRNAs (miR-30a-5p, -134-5p, -337-3p, -659-3p, and -3917) were identified during the initial discovery phase; three of which (miR-30a-5p, -659-3p, and -3917) were significantly overexpressed in the primary tumors from PM-positive patients in the testing cohort (P = 0.002, 0.04, and 0.007, respectively), and distinguished patients with versus without peritoneal metastasis with the value of area under the curve (AUC) of 0.82. Furthermore, high expression of these miRNAs also associated with poor prognosis (hazard ratio = 2.18, P = 0.04). The efficacy of the combination miRNA signature was subsequently validated in an independent validation cohort (AUC = 0.74). Finally, our miRNA signature when combined together with the macroscopic Borrmann's type score offered a much superior diagnostic in all 3 cohorts (AUC = 0.87, 0.76, and 0.79, respectively). CONCLUSIONS: We have established an miRNA-based signature that have a potential to identify peritoneal metastasis in GC patients.

DOI： 10.1097/SLA.0000000000003647

Synaptotagmin 13 Is Highly Expressed in Estrogen Receptor-Positive Breast Cancer. Reviewed International journal

Takahiro Ichikawa, Masahiro Shibata, Takahiro Inaishi, Ikumi Soeda, Mitsuro Kanda, Masamichi Hayashi, Yuko Takano, Dai Takeuchi, Nobuyuki Tsunoda, Yasuhiro Kodera, Toyone Kikumori

Current oncology (Toronto, Ont.) Vol. 28 ( 5 ) page： 4080 - 4092 2021.10

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

BACKGROUND: Accumulating evidence indicates tumor-promoting roles of synaptotagmin 13 (SYT13) in several cancers; however, no studies have investigated its expression in breast cancer (BC). This study aimed to clarify the significance of SYT13 in BC. METHODS: SYT13 mRNA expression levels were evaluated in BC cell lines. Polymerase chain reaction (PCR) array analysis was conducted to determine the correlation between expression levels of SYT13 and other tumor-associated genes. Then, the association of SYT13 expression levels in the clinical BC specimens with patients' clinicopathological factors was evaluated. These findings were subsequently validated using The Cancer Genome Atlas (TCGA) database. RESULTS: Among 13 BC cell lines, estrogen receptor (ER)-positive cells showed higher SYT13 mRNA levels than ER-negative cells. PCR array analysis revealed positive correlations between SYT13 and several oncogenes predominantly expressed in ER-positive BC, such as estrogen receptor 1, AKT serine/threonine kinase 1, and cyclin-dependent kinases 4. In 165 patients, ER-positive specimens exhibited higher SYT13 mRNA expression levels than ER-negative specimens. The TCGA database analysis confirmed that patients with ER-positive BC expressed higher SYT13 levels than ER-negative patients. CONCLUSION: This study suggests that SYT13 is highly expressed in ER-positive BC cells and clinical specimens, and there is a positive association of SYT13 with the ER signaling pathways.

DOI： 10.3390/curroncol28050346

Blockade of CHRNB2 signaling with a therapeutic monoclonal antibody attenuates the aggressiveness of gastric cancer cells. Reviewed International journal

Mitsuro Kanda, Dai Shimizu, Shunsuke Nakamura, Koichi Sawaki, Shinichi Umeda, Takashi Miwa, Haruyoshi Tanaka, Yoshikuni Inokawa, Norifumi Hattori, Masamichi Hayashi, Chie Tanaka, Goro Nakayama, Yohei Iguchi, Masahisa Katsuno, Yasuhiro Kodera

Oncogene Vol. 40 ( 36 ) page： 5495 - 5504 2021.9

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

Here, we evaluated the therapeutic potential of antibodies (Abs) targeting cholinergic receptor nicotinic beta 2 subunit (CHRNB2) in gastric cancer. To investigate the effects of these Abs on malignant phenotypes in vitro and in mouse xenograft models, we generated gene knockouts through genome editing, performed RNA interference-mediated knockdown of gene expression, and ectopically expressed CHRNB2 in gastric cancer cells. The effects of anti-CHRNB2 Abs on the proliferation of cancer cells were evaluated both in vitro and in vivo. We determined the effects of Chrnb2 deficiency on mice and the clinical significance of CHRNB2 expression in gastric cancer clinical specimens. Knockdown of CHRNB2 attenuated gastric cancer cell proliferation, whereas forced overexpression of CHRNB2 increased cell proliferation. Knockout of CHRNB2 significantly influenced cell survival and functions associated with metastasis. The effects of polyclonal Abs targeting the C- and N-termini of CHRNB2 guided the development of anti-CHRNB2 monoclonal Abs that inhibited the growth of gastric cancer cells in vitro and in vivo. Pathway analysis revealed that CHRNB2 interfered with signaling through the PI3K-AKT and JAK-STAT pathways. Chrnb2-deficient mice exhibited normal reproduction, organ functions, and motor functions. CHRNB2 regulates multiple oncological phenotypes associated with metastasis, and blockade of CHRNB2 expression using specific Abs shows promise for controlling metastasis in gastric cancer.

DOI： 10.1038/s41388-021-01945-9

Efficacy of Splenectomy for Proximal Gastric Cancer with Greater Curvature Invasion or Type 4 Tumor: a Propensity Score Analysis of a Multi-Institutional Dataset. Reviewed International journal

Seiji Ito, Mitsuro Kanda, Yoshinari Mochizuki, Hitoshi Teramoto, Kiyoshi Ishigure, Toshifumi Murai, Takahiro Asada, Akiharu Ishiyama, Hidenobu Matsushita, Chie Tanaka, Daisuke Kobayashi, Michitaka Fujiwara, Kenta Murotani, Yasuhiro Kodera

World journal of surgery Vol. 45 ( 9 ) page： 2840 - 2848 2021.9

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

BACKGROUND: Splenectomy for proximal gastric cancer was found to have no survival benefit in a randomized trial clarifying the role of splenectomy (JCOG0110 study). However, since tumor with invasion to the greater curvature and Type 4 tumor were excluded in JCOG0110, the benefit of splenectomy for these tumors is not known. METHODS: A multicenter dataset of patients with gastric cancer who underwent gastrectomy between 2010 and 2014 was created. From the dataset, 114 eligible patients with proximal advanced gastric cancer with invasion to the greater curvature or Type 4 tumor were enrolled. There were 60 patients in the gastrectomy with splenectomy (Spx) group and 54 patients in the spleen-preserving (Prs) group. To balance the essential variables, propensity score analysis was performed, estimating the propensity score with a logistic regression model. Adjusted overall survival (OS) and adjusted disease-free survival (DFS) were estimated using the inverse probability of treatment weighting (IPTW) method. RESULTS: There were significant differences in age, performance status, comorbidity, macroscopic type, and clinical T stage between the Spx and Prs groups. The model for estimating the propensity score was well adapted (c-statistic: 0.830, 95%CI: 0.754-0.906). Adjusted OS was identical between the two groups (HR = 1.089, 95%CI: 0.759-1.563; p = 0.644). The DFS curve of Prs group was consistently tended to be lower than Spx, but the difference was not significant (HR = 0.813, 95%CI: 0.572-1.156; p = 0.249). CONCLUSIONS: The efficacy of splenectomy was minimal for proximal advanced gastric cancer even with invasion to the greater curvature or Type 4 tumor.

DOI： 10.1007/s00268-021-06173-6

食道扁平上皮癌予後マーカーとしてのOPLAH発現 Reviewed

清水大, 神田光郎, 小池聖彦, 佐藤雄亮, 林真路, 田中千恵, 中山吾郎, 本山悟, 藤原道隆, 小寺泰弘

日本食道学会学術集会プログラム・抄録集 Vol. 75回 page： 279 - 279 2021.9

Assessment of the Diagnostic Efficiency of a Liquid Biopsy Assay for Early Detection of Gastric Cancer. Reviewed International journal

Daisuke Izumi, Zhongxu Zhu, Yuetong Chen, Shusuke Toden, Xinying Huo, Mitsuro Kanda, Takatsugu Ishimoto, Dongying Gu, Miaomiao Tan, Yasuhiro Kodera, Hideo Baba, Wei Li, Jinfei Chen, Xin Wang, Ajay Goel

JAMA network open Vol. 4 ( 8 ) page： e2121129 2021.8

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

Importance: Noninvasive detection of early-stage disease is a key strategy for reducing gastric cancer (GC)-associated patient mortality. Objective: To establish a novel, noninvasive, microRNA (miRNA)-based signature for the early detection of GC using a comprehensive biomarker discovery approach with retrospective and prospective validation. Design, Setting, and Participants: This diagnostic study was conducted in 4 phases using publicly available genome sequences and tissue samples from patients at an academic medical center in Japan, and validated with retrospective multicenter cohorts of patients with GC. Three tissue miRNA data sets were used to identify a miRNA signature that discriminated GC vs normal tissues. The robustness of this signature was assessed in serum from 2 retrospective cohorts of patients with GC. A risk-scoring model was derived, then the performance of the miRNA signature was evaluated in a prospective cohort of patients with GC. The robustness of the miRNA signature was compared with current blood-based markers, and a cost-effectiveness analysis of the miRNA signature against the current practice of endoscopy was performed. All clinical samples used for this study were collected and data analyzed between April 1997 and March 2018. Main Outcomes and Measures: Assessment of diagnostic efficiency on the basis of area under the curve (AUC), specificity, and sensitivity. Results: The data sets for the genome-wide expression profiling analysis stage included 598 total patient samples (284 [55.4%] from men; mean [SE] patient age, 65.7 [0.5] years). The resulting 10-miRNA signature was validated in 2 retrospective GC serum cohorts (586 patients; 348 [59.4%] men, mean [SE] age, 66.0 [0.7] years), which led to the establishment of a 5-miRNA signature (AUC, 0.90; 95% CI, 0.85-0.94) that also exhibited high levels of diagnostic performance in patients with stage I disease (AUC, 0.89; 95% CI, 0.83-0.94). A risk-scoring model was derived and the assay was optimized to a minimal number of miRNAs. The performance of the resulting 3-miRNA signature was then validated in a prospective cohort of patients with GC (349 patients; 124 [70.5%] men, median [range] age, 66.0 [0.66] years). The final 3-miRNA signature (miR-18a, miR-181b, and miR-335) exhibited high diagnostic accuracy in all stages of patients (AUC, 0.86; 95% CI 0.83-0.90), including in patients with stage I disease (AUC, 0.85; 95% CI, 0.79-0.91). Furthermore, this miRNA signature was superior to currently used blood markers and outperformed the endoscopic screening in a cost-effectiveness analysis (incremental cost-effectiveness ratio, CNY \16162.5 per quality-adjusted life-year [USD $2304.80 per quality-adjusted life-year]). Conclusions and Relevance: These results suggest the potential clinical significance of the 3-miRNA signature as a noninvasive, cost-effective, and facile assay for the early detection of GC.

DOI： 10.1001/jamanetworkopen.2021.21129

A Possible Definition of Oligometastasis in Pancreatic Cancer and Associated Survival Outcomes. Reviewed International journal

Masaya Yamanaka, Masamichi Hayashi, Suguru Yamada, Fuminori Sonohara, Hideki Takami, Yoshikuni Inokawa, Dai Shimizu, Norifumi Hattori, Mitsuro Kanda, Chie Tanaka, Goro Nakayama, Masahiko Koike, Yasuhiro Kodera

Anticancer research Vol. 41 ( 8 ) page： 3933 - 3940 2021.8

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

BACKGROUND: Oligometastatic cancer (OM) is possibly associated with relatively better survival outcomes. We attempted to identify cases in line with this OM concept. PATIENTS AND METHODS: A total of 130 cases with unresectable metastatic pancreatic cancer underwent non-curative surgery from April 2001 to December 2019. Sites of metastasis, clinicopathological information, and surgical outcomes were collected to formulate a better definition of OM. RESULTS: OM criteria were defined as having metastasis to a single organ, few countable lesions and low serum cancer antigen 19-9 level. The median overall survival after non-curative surgery of OM cases was 13.0 months and was significantly better than that of non-OM cases (8.4 months, p=0.003). CONCLUSION: We propose single-organ metastasis of limited tumor volume (H1 or P1/2 by the Japanese Society of Cancer of the Colon and Rectum classification) and low serum cancer antigen 19-9 level (<2,000 U/ml) as new criteria for defining OM pancreatic cancer.

DOI： 10.21873/anticanres.15189

Accurate Prediction of Prognosis After Radical Resection of Gastric Cancer by the Modified Systemic Inflammation Score; a Multicenter Dataset Analysis. Reviewed International journal

Kota Inagaki, Mitsuro Kanda, Koki Nakanishi, Seiji Ito, Yoshinari Mochizuki, Hitoshi Teramoto, Kiyoshi Ishigure, Toshifumi Murai, Takahiro Asada, Akiharu Ishiyama, Hidenobu Matsushita, Chie Tanaka, Daisuke Kobayashi, Michitaka Fujiwara, Kenta Murotani, Yasuhiro Kodera

World journal of surgery Vol. 45 ( 8 ) page： 2513 - 2520 2021.8

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

BACKGROUND: The presence of chronic inflammation and nutritional status in cancer patients affects its prognosis. There is a clinical need for a prognostic predictor that is objective and accurate, and that can be easily evaluated by preoperative screening. We evaluated the importance and usefulness of the preoperative modified systemic inflammation score (mSIS) to predict the long-term outcome of patients undergoing curative resection for gastric cancer (GC). METHODS: Of the 3571 patients who underwent curative resection for GC in nine institutions between January 2010 and December 2014, 1764 patients who met the inclusion criteria were included. The mSIS was formulated according to the serum albumin level (ALB) and lymphocyte-to-monocyte ratio (LMR) as follows: mSIS 0 (ALB ≥ 4.0 g/dL and LMR ≥ 3.4), mSIS 1 (ALB < 4.0 g/dL or LMR < 3.4), and mSIS 2 (ALB < 4.0 g/dL and LMR < 3.4). RESULTS: Patients were categorized into preoperative mSIS 0 (n = 955), mSIS 1 (n = 584), and mSIS 2 (n = 225) groups. The overall survival times and the disease-free survival times of patients in preoperative mSIS 0,1 and 2 sequentially shortened (P < 0.0001), and mSIS 1 and 2 were identified as an independent prognostic factor (hazard ratio [HR] 1.35, 95% confidence interval [CI] 1.06-1.272, P = 0.0125 and HR 1.63, 95% CI 1.21-2.19, P = 0.0012). A stepwise increase in the prevalence of hematogenous recurrences was directly proportional to the mSIS. A forest plot revealed that mSIS 0,1 was associated with a greater risk of overall survival in most subgroups. CONCLUSION: Preoperative mSIS can be easily calculated, and it is suggested that it is useful as a prognostic predictor of patients with different disease stages, for stratifying and evaluating clinical outcomes.

DOI： 10.1007/s00268-021-06138-9

Update on molecular biomarkers for diagnosis and prediction of prognosis and treatment responses in gastric cancer. Reviewed International journal

Masahiro Sasahara, Mitsuro Kanda, Yasuhiro Kodera

Histology and histopathology Vol. 36 ( 8 ) page： 817 - 832 2021.8

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

Gastric cancer (GC) is one of the leading causes of cancer-related deaths worldwide, and its high mortality rate is a serious problem in many regions. To improve prognosis, it is necessary to identify novel biomarkers for the early detection of GC, along with its prognosis, risk of metastatic recurrence, and predicted response to chemotherapy, and to develop individualized treatment strategies. Advances in microarray and sequencing techniques have led to the elucidation of cancer-related gene mutations and aberrant expression levels, which have deepened our knowledge of GC. Further searches for sensitive biomarkers are needed to improve the management of patients with GC. In this review article, we update the current knowledge of GC biomarkers, examine recently published literature, and introduce some representative molecules.

DOI： 10.14670/HH-18-326

G-protein subunit gamma-4 expression has potential for detection, prediction and therapeutic targeting in liver metastasis of gastric cancer. Reviewed International journal

Haruyoshi Tanaka, Mitsuro Kanda, Takashi Miwa, Shinichi Umeda, Koichi Sawaki, Chie Tanaka, Daisuke Kobayashi, Masamichi Hayashi, Suguru Yamada, Goro Nakayama, Masahiko Koike, Yasuhiro Kodera

British journal of cancer Vol. 125 ( 2 ) page： 220 - 228 2021.7

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

BACKGROUND: The liver is the most common site for haematogenous metastasis of gastric cancer, and liver metastasis is fatal. METHODS: We conducted a transcriptomic analysis between metastatic foci in the liver, primary tumour and adjacent tissues from gastric cancer patients with metastasis limited to the liver. We determined mRNA expression levels in tumour tissues of 300 patients with gastric cancer via quantitative RT-PCR. The oncogenic phenotypes of GNG4 were determined with knockdown, knockout and forced expression experiments. We established and compared subcutaneous and liver metastatic mouse xenograft models of gastric cancer to reveal the roles of GNG4 in tumorigenesis in the liver. RESULTS: GNG4 was upregulated substantially in primary gastric cancer tissues as well as liver metastatic lesions. High levels of GNG4 in primary cancer tissues were associated with short overall survival and the likelihood of liver recurrence. Functional assays revealed that GNG4 promoted cancer cell proliferation, the cell cycle and adhesiveness. Tumour formation by GNG4-knockout cells was moderately reduced in the subcutaneous mouse model and strikingly attenuated in the liver metastasis mouse model. CONCLUSIONS: GNG4 expression may provide better disease monitoring for liver metastasis, and GNG4 may be a novel candidate therapeutic target for liver metastasis.

DOI： 10.1038/s41416-021-01366-1

High Serum Uric Acid Levels Could Be a Risk Factor of Hepatocellular Carcinoma Recurrences. Reviewed International journal

Masamichi Hayashi, Suguru Yamada, Hiroshi Tanabe, Hideki Takami, Yoshikuni Inokawa, Fuminori Sonohara, Dai Shimizu, Norifumi Hattori, Mitsuro Kanda, Chie Tanaka, Goro Nakayama, Masahiko Koike, Michitaka Fujiwara, Yasuhiro Kodera

Nutrition and cancer Vol. 73 ( 6 ) page： 996 - 1003 2021.7

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

BACKGROUND: The Apolipoprotein-related MORtality RISk (AMORIS) study in Sweden revealed that serum uric acid (SUA) was significantly associated with hepatobiliary cancer occurrence. However, the association with postoperative hepatocellular carcinoma (HCC) recurrence has not been reported. METHODS: A total of 256 surgically resected HCC patients were included (from January 2003 to December 2017) in this study. Comparisons in terms of clinicopathologic factors and long-term outcomes were made between patients with high SUA (>6.1 mg/dl) at the time of hepatectomy and low SUA. Besides, SUA data at one postoperative year (1POY) of the same cohort were collected and analyzed in the same manner. RESULTS: About 88.8% of tumor relapse sites were the remnant liver. High SUA levels were associated with male and well-differentiated HCCs. Recurrence-free survival (RFS) of high SUA patients was significantly inferior to low SUA patients [median survival time (MST): 22.7 vs. 28.5 mo, P = 0.033], whereas no difference was observed in overall survival (MST: both not reached, P = 0.771). RFS of high SUA patients at 1POY also showed significantly poorer outcomes than low SUA patients (MST: 29.3 vs. 57.0 mo, P = 0.049). CONCLUSIONS: High SUA implies a significant risk factor of activating hepatocarcinogenesis. Keeping the SUA level low may be recommended after HCC resections.

DOI： 10.1080/01635581.2020.1779758

Novel prognostic implications of YTH domain family 2 in resected hepatocellular carcinoma. Reviewed International journal

Nobuhiko Nakagawa, Fuminori Sonohara, Katsuhito Tanaka, Yuki Sunagawa, Yoshikuni Inokawa, Hideki Takami, Masamichi Hayashi, Suguru Yamada, Mitsuro Kanda, Chie Tanaka, Goro Nakayama, Masahiko Koike, Yasuhiro Kodera

Oncology letters Vol. 22 ( 1 ) page： 538 - 538 2021.7

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

N6-methyladenosine (m6A), the most abundant internal RNA modification, serves a critical role in cancer development. However, the clinical implications of m6A in hepatocellular carcinoma (HCC) remain unclear. The present study sought to reveal the potential roles of m6A readers, which recognize m6A, in HCC. A total of 177 HCC and paired non-cancerous liver tissues from patients who underwent hepatectomy were analysed using quantitative PCR for the expression of m6A readers: YT521-B homology domain family 1 (YTHDF1) and YT521-B homology domain family 2 (YTHDF2). The expression levels of both YTHDF1 and YTHDF2 were not significantly different between tumour and non-cancerous tissues (P=0.93 and P=0.7, respectively). Analysis of the association between clinical features and m6A reader expression revealed that YTHDF1 expression was associated with formation of capsule (P=0.02), whereas low YTHDF2 expression was associated with septal formation (P=0.02). Furthermore, high YTHDF1 expression and high YTHDF2 expression were significantly associated with shorter recurrence-free survival (RFS) [YTHDF1: Mean survival time (MST), 34.0 vs. 19.0 months, P=0.014; YTHDF2: MST, 30.1 vs. 12.9 months, P=0.0032], whereas YTHDF1 and YTHDF2 expression was not significantly associated with overall survival (OS) (YTHDF1: MST, 99.4 vs. 70.2 months, P=0.74; YTHDF2: MST, 98.4 vs. 64.1 months, P=0.28). According to multivariate analysis, serosal invasion [hazard ratio (HR), 2.39; 95% CI 1.30-4.42; P=0.005), portal vein or hepatic vein invasion (HR, 2.82; 95% CI 1.26-6.28; P=0.01) and YTHDF2 expression in HCC tissues (HR, 1.85; 95% CI 1.09-3.15; P=0.02) were identified as significant independent prognostic factors for RFS. α-fetoprotein (HR, 1.79; 95% CI 1.10-2.92; P=0.02), serosal invasion (HR, 1.99; 95% CI 1.17-3.34; P=0.01) and portal vein or hepatic vein invasion (HR, 3.02; 95% CI 1.38-6.61; P=0.006) were identified as significant independent prognostic factors for OS. In conclusion, the present study revealed that high YTHDF2 expression, an m6A reader, in HCC tissues was associated with cancer recurrence.

DOI： 10.3892/ol.2021.12799

食道扁平上皮癌におけるOPLAH発現の意義 Reviewed

清水大, 神田光郎, 佐藤雄亮, 林真路, 田中千恵, 中山吾郎, 本山悟, 小池聖彦, 藤原道隆, 小寺泰弘

日本消化器外科学会総会 Vol. 76回 page： P021 - 5 2021.7

BRA膵癌に対する治療戦略 BR-A膵癌に対する集学的治療の術後成績 Reviewed

猪川祥邦, 田中伸孟, 園原史訓, 高見秀樹, 林真路, 神田光郎, 田中千恵, 中山吾郎, 小池聖彦, 小寺泰弘

日本消化器外科学会総会 Vol. 76回 page： O34 - 5 2021.7

後期高齢者肝細胞癌における肝切除術の安全性と妥当性に関する検討 Reviewed

田中伸孟, 林真路, 園原史訓, 猪川祥邦, 高見秀樹, 神田光郎, 田中千恵, 中山吾郎, 小池聖彦, 小寺泰弘

日本消化器外科学会総会 Vol. 76回 page： P163 - 7 2021.7

膵癌におけるEat me signalの関与 Reviewed

林真路, 高見秀樹, 猪川祥邦, 園原史訓, 田中伸孟, 神田光郎, 田中千恵, 中山吾郎, 小池聖彦, 小寺泰弘

日本消化器外科学会総会 Vol. 76回 page： P186 - 1 2021.7

E-PASS scoring systemによる胃癌術後短期・長期予後予測能の有用性の検討 Reviewed

中西香企, 神田光郎, 伊藤誠二, 望月能成, 寺本仁, 石榑清, 清水大, 田中千恵, 藤原道隆, 小寺泰弘

日本消化器外科学会総会 Vol. 76回 page： P153 - 1 2021.7

高齢者胃癌に対する治療の工夫高齢者胃癌手術症例に対する高齢者機能の転帰と工夫 Reviewed

田中千恵, 中西香企, 清水大, 服部憲史, 神田光郎, 中山吾郎, 小池聖彦, 小寺泰弘

日本消化器外科学会総会 Vol. 76回 page： WS10 - 9 2021.7

高齢者胃癌に対する治療の工夫高齢者胃癌手術症例に対する高齢者機能の転帰と工夫 Reviewed

田中千恵, 中西香企, 清水大, 服部憲史, 神田光郎, 中山吾郎, 小池聖彦, 小寺泰弘

日本消化器外科学会総会 Vol. 76回 page： WS10 - 9 2021.7

E-PASS scoring systemによる胃癌術後短期・長期予後予測能の有用性の検討 Reviewed

中西香企, 神田光郎, 伊藤誠二, 望月能成, 寺本仁, 石榑清, 清水大, 田中千恵, 藤原道隆, 小寺泰弘

日本消化器外科学会総会 Vol. 76回 page： P153 - 1 2021.7

miR-23b-3p Plays an Oncogenic Role in Hepatocellular Carcinoma. Reviewed International journal

Masamichi Hayashi, Suguru Yamada, Keisuke Kurimoto, Hiroshi Tanabe, Sho Hirabayashi, Fuminori Sonohara, Yoshikuni Inokawa, Hideki Takami, Mitsuro Kanda, Chie Tanaka, Goro Nakayama, Masahiko Koike, Yasuhiro Kodera

Annals of surgical oncology Vol. 28 ( 6 ) page： 3416 - 3426 2021.6

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

BACKGROUND: Reports show miR-23b to be a cancer-related biomarker in various cancer types. Interestingly, it has a dual role of oncogenic and tumor-suppressive functions, depending on the cancer type. This study focused on the unknown association of miR-23b-3p with hepatocellular carcinoma (HCC). METHODS: Expression of miR-23b-3p was measured in nine HCC cell lines and 125 resected human HCC samples by TaqMan microRNA assays. To detect its downstream target, miR-23b-3p mimic and inhibitor constructs were transfected and analyzed. RESULTS: HepG2, a high miR-23b-3p-expressing cell line, was transfected with a miR-23b-3p inhibitor construct, whereas SK-Hep1, a low miR-23b-3p-expressing cell line, was transfected with a mimic construct. Proliferation of HCC cells was activated by miR-23b-3p overexpression and diminished by its knockdown. Then, 125 clinical HCC samples were examined to measure miR-23b-3p expression. Tumor expression of miR-23b-3p was upregulated in 48 cases (38%) and downregulated in 77 cases (62%). The upregulated cases were correlated with elderly patients (P = 0.015). These patients also showed significantly poor overall survival [hazard ratio (HR), 3.10; 95% conflidence interval (CI), 1.57-6.29; P = 0.001] in a multivariate analysis. Furthermore, mitochondrial metabolism-related genes (MICU3 and AUH) were detected as specific binding targets. CONCLUSION: The study showed that miR-23b-3p functions as an oncogenic microRNA in HCC cell lines. Its overexpression in resected HCC tissues was a significant prognostic factor of overall survival. Both MICU3 and AUH may be candidate gene targets of miR-23b-3p.

DOI： 10.1245/s10434-020-09283-y

Short-term outcomes of gastrectomy after neoadjuvant chemotherapy for clinical stage III gastric cancer: propensity score-matched analysis of a multi-institutional database. Reviewed

Shinichi Umeda, Mitsuro Kanda, Koki Nakanishi, Seiji Ito, Yoshinari Mochizuki, Hitoshi Teramoto, Kiyoshi Ishigure, Toshifumi Murai, Takahiro Asada, Akiharu Ishiyama, Hidenobu Matsushita, Dai Shimizu, Daisuke Kobayashi, Chie Tanaka, Michitaka Fujiwara, Kenta Murotani, Yasuhiro Kodera

Surgery today Vol. 51 ( 5 ) page： 821 - 828 2021.5

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

PURPOSE: Preoperative chemotherapy for gastric cancer may be effective from the standpoint of compliance, although there is insufficient evidence of its efficacy. We analyzed a multicenter database to clarify whether preoperative chemotherapy influenced the short-term outcomes of gastrectomy. METHODS: We analyzed, retrospectively, 3571 patients who underwent gastrectomy between January, 2010 and December, 2014. Patients with clinical stage-III gastric adenocarcinoma were divided into a neoadjuvant chemotherapy (NAC) group and a non-NAC group. We performed propensity-matched comparative analysis to stratify the groups according to age, sex, tumor region, tumor type, preoperative stage, procedure, lymph node dissection, and tumor differentiation. Preoperative blood data, surgical findings, and postoperative complications were analyzed. RESULTS: Analysis of the matched NAC (n = 64) and non-NAC (n = 128) groups revealed that the preoperative values of neutrophils, platelets, and Hb were significantly lower in the NAC group. Blood loss during surgery was significantly higher, surgical times were longer, and the rate of repeat surgery was significantly lower in the NAC group; however, the rates of rehospitalization did not differ between the groups and mortality was 0% in both groups. Postoperative complications were not significantly different between the groups. CONCLUSIONS: NAC did not increase the complication rate of gastrectomy for gastric cancer.

DOI： 10.1007/s00595-020-02179-0

十二指腸肉腫の1例 Reviewed

山中雅也, 高見秀樹, 園原史訓, 猪川祥邦, 林真路, 神田光郎, 田中千恵, 中山吾郎, 小池聖彦, 藤原道隆, 小寺泰弘

日本臨床外科学会雑誌 Vol. 82 ( 5 ) page： 1023 - 1023 2021.5

Transcriptomic Profiling Identifies a Risk Stratification Signature for Predicting Peritoneal Recurrence and Micrometastasis in Gastric Cancer. Reviewed International journal

In-Seob Lee, Heonyi Lee, Hoon Hur, Mitsuro Kanda, Jeong-Hwan Yook, Byung-Sik Kim, Yanghee Woo, Yasuhiro Kodera, Kwangsoo Kim, Ajay Goel

Clinical cancer research : an official journal of the American Association for Cancer Research Vol. 27 ( 8 ) page： 2292 - 2300 2021.4

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

PURPOSE: Gastric cancer peritoneal carcinomatosis is fatal. Delay in detection of peritoneal metastases contributes to high mortality, highlighting the need to develop biomarkers that can help identify patients at high risk for peritoneal recurrence or metastasis. EXPERIMENTAL DESIGN: We performed a systematic discovery and validation for the identification of peritoneal recurrence prediction and peritoneal metastasis detection biomarkers by analyzing expression profiling datasets from 249 patients with gastric cancer, followed by analysis of 426 patients from three cohorts for clinical validation. RESULTS: Genome-wide expression profiling identified a 12-gene panel for robust prediction of peritoneal recurrence in patients with gastric cancer (AUC = 0.95), which was successfully validated in a second dataset (AUC = 0.86). Examination of 216 specimens from a training cohort allowed us to establish a six gene-based risk-prediction model [AUC = 0.72; 95% confidence interval (CI): 0.66-0.78], which was subsequently validated in an independent cohort of 111 patients with gastric cancer (AUC = 0.76; 95% CI: 0.67-0.83). In both cohorts, combining tumor morphology and depth of invasion further improved the predictive accuracy of the prediction model (AUC = 0.84). Thereafter, we evaluated the performance of the identical six-gene panel for its ability to detect peritoneal metastasis by analyzing 210 gastric cancer specimens (prior 111 patients plus additional 99 cases), which discriminated patients with and without peritoneal metastasis (AUC = 0.72). Finally, our biomarker panel was also remarkably effective for identifying peritoneal micrometastasis (AUC = 0.72), and its diagnostic accuracy was significantly enhanced when depth of invasion was included in the model (AUC = 0.85). CONCLUSIONS: Our novel transcriptomic signature for risk stratification and identification of high-risk patients with peritoneal carcinomatosis might serve as an important clinical decision making in patients with gastric cancer.

DOI： 10.1158/1078-0432.CCR-20-3835

Hepatic metastasis of gastric cancer is associated with enhanced expression of ethanolamine kinase 2 via the p53-Bcl-2 intrinsic apoptosis pathway. Reviewed International journal

Takashi Miwa, Mitsuro Kanda, Dai Shimizu, Shinichi Umeda, Koichi Sawaki, Haruyoshi Tanaka, Chie Tanaka, Norifumi Hattori, Masamichi Hayashi, Suguru Yamada, Goro Nakayama, Masahiko Koike, Yasuhiro Kodera

British journal of cancer Vol. 124 ( 8 ) page： 1449 - 1460 2021.4

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

BACKGROUND: Gastric cancer (GC) with hepatic metastasis has a poor prognosis. Understanding the molecular mechanisms involved in hepatic metastasis may contribute to the development of sensitive diagnostic biomarkers and novel therapeutic strategies. METHODS: We performed transcriptome analysis of surgically resected specimens from patients with advanced GC. One of the genes identified as specifically associated with hepatic metastasis was selected for detailed analysis. GC cell lines with knockout of the candidate gene were evaluated in vitro and in vivo. Expression of the candidate gene was analysed in GC tissues from 300 patients. RESULTS: Ethanolamine kinase 2 (ETNK2) was differentially upregulated in GC patients with hepatic metastasis. ETNK2 expression was elevated in GC cell lines derived from haematogenous metastases. ETNK2 knockout significantly suppressed proliferation, invasion, and migration; increased apoptosis; reduced Bcl-2 protein expression; and increased phosphorylated p53 expression. In mouse xenograft models, ETNK2 knockout virtually abolished hepatic metastasis. Stratification of GC patients based on ETNK2 mRNA level revealed significant associations between high ETNK2 tumour expression and both hepatic recurrence and worse prognosis. CONCLUSIONS: Upregulation of ETNK2 in GC enhances hepatic metastasis, possibly via dysregulation of p53-Bcl-2-associated apoptosis. ETNK2 expression may serve as a biomarker for predicting hepatic recurrence and a therapeutic target.

DOI： 10.1038/s41416-021-01271-7

Peritoneal Lavage Tumor DNA as a Novel Biomarker for Predicting Peritoneal Recurrence in Pancreatic Ductal Adenocarcinoma. Reviewed International journal

Masaya Suenaga, Tsutomu Fujii, Suguru Yamada, Masamichi Hayashi, Keiko Shinjo, Hideki Takami, Yukiko Niwa, Fuminori Sonohara, Dai Shimizu, Mitsuro Kanda, Daisuke Kobayashi, Chie Tanaka, Goro Nakayama, Masahiko Koike, Michitaka Fujiwara, Yutaka Kondo, Yasuhiro Kodera

Annals of surgical oncology Vol. 28 ( 4 ) page： 2277 - 2286 2021.4

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

BACKGROUND: The clinical role of peritoneal lavage cytology (CY) in pancreatic ductal adenocarcinoma (PDAC) remains controversial, partly due to its low sensitivity. This study aimed to develop a new biomarker, defined as peritoneal lavage tumor DNA (ptDNA), using DNAs extracted from peritoneal lavage samples from patients with PDAC. METHODS: Samples were collected intraoperatively from 89 PDAC patients who underwent pancreatectomy between 2012 and 2017. Droplet digital polymerase chain reaction (PCR) was used to measure ptDNA for detection of KRAS mutations. The ptDNA status and clinical characteristics were retrospectively evaluated. RESULTS: Positive ptDNA was found in 41 patients, including all 9 patients positive for CY (CY+) and 32 patients negative for CY (CY-). The mutant allele frequency was significantly higher in the CY+ patients than in the CY- patients. The disease-free survival (DFS) and overall survival (OS) were significantly poorer in the high-ptDNA group than in the low-ptDNA group (median DFS, 11.0 vs. 18.8 months; p = 0.007; median OS, 28.7 vs not reached; p = 0.001). The survival curves of DFS and OS in the CY+ group were almost equal to those in the CY- and high-ptDNA group. In a multivariable analysis, ptDNA was an independent predictive factor for DFS (p = 0.025) and OS (p = 0.047). The estimated cumulative incidence of peritoneal recurrence was 45.5% in the high-ptDNA group. The ptDNA biomarker had a much higher sensitivity for peritoneal recurrence than CY, whereas CY had higher specificity. CONCLUSIONS: As a promising biomarker, ptDNA may predict poor prognosis and peritoneal recurrence in PDAC, resolving the controversy surrounding CY.

DOI： 10.1245/s10434-020-08990-w

GAD1の食道扁平上皮癌根治的切除後予後予測バイオマーカーとしての意義 Reviewed

岸田貴喜, 神田光郎, 清水大, 田中千恵, 園原史訓, 猪川祥邦, 高見秀樹, 服部憲史, 林真路, 山田豪, 中山吾郎, 小池聖彦, 藤原道隆, 小寺泰弘

日本外科学会定期学術集会抄録集 Vol. 121回 page： PS - 4 2021.4

胃癌における組織中RNFT2遺伝子発現と予後の関連性の検討 Reviewed

笹原正寛, 神田光郎, 清水大, 田中千恵, 園原史訓, 高見秀樹, 猪川祥邦, 服部憲史, 林真路, 山田豪, 中山吾郎, 小池聖彦, 藤原道隆, 小寺泰弘

日本外科学会定期学術集会抄録集 Vol. 121回 page： PS - 4 2021.4

肝胆膵領域癌におけるサルコペニアの臨床的意義と当教室の周術期対策 Reviewed

猪川祥邦, 山田豪, 横山幸浩, 薮崎紀充, 二宮豪, 田中伸孟, 園原史訓, 高見秀樹, 服部憲史, 林真路, 神田光郎, 田中千恵, 中山吾郎, 小池聖彦, 小寺泰弘

日本外科学会定期学術集会抄録集 Vol. 121回 page： SF - 3 2021.4

片側肝動脈合併切除を伴う膵頭十二指腸切除後の肝動脈血流の評価と早期合併症に関する検討 Reviewed

鈴木雄之典, 山田豪, 猪川祥邦, 田中伸孟, 園原史訓, 高見秀樹, 服部憲史, 林真路, 神田光郎, 田中千恵, 中山吾郎, 小池聖彦, 小寺泰弘

日本外科学会定期学術集会抄録集 Vol. 121回 page： PS - 1 2021.4

当教室における膵頭十二指腸切除術後出血に対する対策と治療効果の検討 Reviewed

田中伸孟, 山田豪, 園原史訓, 猪川祥邦, 高見秀樹, 服部憲史, 林真路, 神田光郎, 田中千恵, 中山吾郎, 小池聖彦, 小寺泰弘

日本外科学会定期学術集会抄録集 Vol. 121回 page： SF - 4 2021.4

切除肝細胞癌におけるYTH domain family 2の臨床的意義 Reviewed

中川暢彦, 園原史訓, 田中克仁, 砂川祐輝, 猪川祥邦, 高見秀樹, 林真路, 山田豪, 神田光郎, 田中千恵, 中山吾郎, 小池聖彦, 小寺泰弘

日本外科学会定期学術集会抄録集 Vol. 121回 page： SF - 7 2021.4

パンデミック下における外科卒前教育の工夫 Reviewed

高見秀樹, 小池聖彦, 鈴木雄之典, 栗本景介, 田中伸孟, 柴田雅央, 園原史訓, 武内大, 猪川祥邦, 服部憲史, 林真路, 神田光郎, 田中知恵, 山田豪, 中山吾郎, 菊森豊根, 藤原道隆, 小寺泰弘

日本外科学会定期学術集会抄録集 Vol. 121回 page： SP - 7 2021.4

ゲノム編集技術を用いたLAMP5遺伝子の胃癌転移巣形成における役割の検討 Reviewed

梅田晋一, 神田光郎, 清水大, 田中千恵, 園原史訓, 高見秀樹, 猪川祥邦, 服部憲史, 林真路, 山田豪, 中山吾郎, 小池聖彦, Fujiwara Michitaka, 小寺泰弘

日本外科学会定期学術集会抄録集 Vol. 121回 page： SF - 5 2021.4

UR-M膵癌に対するconversion surgeryの課題 Reviewed

加藤吉康, 山田豪, 田中伸孟, 園原史訓, 高見秀樹, 猪川祥邦, 林真路, 服部憲史, 清水大, 神田光郎, 田中千恵, 中山吾郎, 小池聖彦, 小寺泰弘

日本外科学会定期学術集会抄録集 Vol. 121回 page： SF - 6 2021.4

胃癌に対する腹腔鏡下手術でのIndocyanine Green蛍光法を用いたマーキング法の成績 Reviewed

佐藤敏, 田中千恵, 園原史訓, 清水大, 高見秀樹, 猪川祥邦, 服部憲史, 林真路, 神田光郎, 山田豪, 中山吾郎, 小池聖彦, 藤原道隆, 小寺泰弘

日本外科学会定期学術集会抄録集 Vol. 121回 page： PS - 6 2021.4

食道扁平上皮癌術後長期生存例における多重癌発生状況 Reviewed

清水大, 小池聖彦, 神田光郎, 園原史訓, 高見秀樹, 猪川祥邦, 服部憲史, 林真路, 田中千恵, 山田豪, 中山吾郎, 藤原道隆, 小寺泰弘

日本外科学会定期学術集会抄録集 Vol. 121回 page： SF - 1 2021.4

膵癌における術前治療中の腫瘍マーカーの比較・検討 Reviewed

砂川祐輝, 山田豪, 田中伸孟, 園原史訓, 猪川祥邦, 高見秀樹, 林真路, 服部憲史, 神田光郎, 田中千恵, 中山吾郎, 小池聖彦, 小寺泰弘

日本外科学会定期学術集会抄録集 Vol. 121回 page： PS - 4 2021.4

膵癌におけるオリゴメタスタシスの臨床的意義 Reviewed

山中雅也, 山田豪, 林真路, 園原史訓, 猪川祥邦, 高見秀樹, 服部憲史, 神田光郎, 田中千恵, 中山吾郎, 小池聖彦, 藤原道隆, 小寺泰弘

日本外科学会定期学術集会抄録集 Vol. 121回 page： SF - 5 2021.4

胃癌切除後予後と原発巣組織中CRABP1発現の相関性の検討 Reviewed

坂田和規, 神田光郎, 清水大, 園原史訓, 高見秀樹, 猪川祥邦, 服部憲史, 林真路, 田中千恵, 山田豪, 中山吾郎, 小池聖彦, 藤原道隆, 小寺泰弘

日本外科学会定期学術集会抄録集 Vol. 121回 page： PS - 5 2021.4

クローン病再手術症例に対する腹腔鏡手術の検討 Reviewed

服部憲史, 中山吾郎, 上原圭, 相場利貞, 佐藤雄介, 小倉淳司, 神田光郎, 田中千恵, 山田豪, 小池聖彦, 藤原道隆, 江畑智希, 小寺泰弘

日本外科学会定期学術集会抄録集 Vol. 121回 page： PS - 2 2021.4

Genome-wide identification and characterization of circular RNA in resected hepatocellular carcinoma and background liver tissue. Reviewed International journal

Yuki Sunagawa, Suguru Yamada, Fuminori Sonohara, Keisuke Kurimoto, Nobutake Tanaka, Yunosuke Suzuki, Yoshikuni Inokawa, Hideki Takami, Masamichi Hayashi, Mitsuro Kanda, Chie Tanaka, Goro Nakayama, Masahiko Koike, Yasuhiro Kodera

Scientific reports Vol. 11 ( 1 ) page： 6016 - 6016 2021.3

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

Circular RNA (circRNA) is a type of non-coding RNA known to affect cancer-related micro RNAs and various transcription factors. circRNA has promise as a cancer-related biomarker because its circular structure affords high stability. We found using high-throughput sequencing that seven candidate circRNAs (hsa_circ_0041150, hsa_circ_0025624, hsa_circ_0001020, hsa_circ_0028129, hsa_circ_0008558, hsa_circ_0036683, hsa_circ_0058087) were downregulated in HCC. The expression of these circRNAs was examined by quantitative PCR in 233 sets of HCC and matched background normal liver tissues, and correlations between candidate circRNA expression and prognosis were evaluated. The results of quantitative PCR showed that expression of hsa_circ_0041150, hsa_circ_0001020 and hsa_circ_0008558 was significantly lower in HCC than in background normal liver tissues. Kaplan-Meier analysis revealed that low expression of hsa_circ_0001020, hsa_circ_0036683, and hsa_circ_0058087 was associated with poor recurrence-free (RFS) and overall survival (OS) in HCC. Additionally, multivariate analysis revealed that low hsa_circ_0036683 expression was a significant prognostic factor, independent from other clinicopathological features, for inferior RFS and OS. There was no significant association between the expression of these circRNAs and hepatitis B/C status or cirrhosis. This study therefore identified circRNAs as potential prognostic markers for patients who undergo curative surgery for HCC and highlighted hsa_circ_0036683 as the most useful biomarker.

DOI： 10.1038/s41598-021-85237-y

ETNK2のアポトーシス調整を介した胃癌肝転移形成との関連性(ETNK2 promotes hepatic metastasis of gastric cancer via the p53-Bcl-2 related apoptosis) Reviewed

三輪高嗣, 神田光郎, 田中千恵, 清水大, 園原史訓, 高見秀樹, 猪川祥邦, 服部憲史, 林真路, 山田豪, 中山吾郎, 小池聖彦, 藤原道隆, 小寺泰弘

日本胃癌学会総会記事 Vol. 93回 page： 244 - 244 2021.3

StageIII胃癌に対する術前化学療法後胃切除術の短期成績の検討(Short-term outcomes of gastrectomy after neoadjuvant chemotherapy for stage III gastric cance) Reviewed

梅田晋一, 神田光郎, 中西香企, 清水大, 田中千恵, 藤原道隆, 小寺泰弘

日本胃癌学会総会記事 Vol. 93回 page： 288 - 288 2021.3

顕微鏡的断端陽性が予後に与える影響(Microscopic Positive Margin After Gastrectomy Increases Recurrences of Gastric Cancer) Reviewed

中西香企, 神田光郎, 伊藤誠二, 望月能成, 寺本仁, 石榑清, 村井俊文, 浅田崇洋, 清水大, 田中千恵, 藤原道隆, 小寺泰弘

日本胃癌学会総会記事 Vol. 93回 page： 259 - 259 2021.3

StageIII胃癌に対する術前化学療法後胃切除術の短期成績の検討(Short-term outcomes of gastrectomy after neoadjuvant chemotherapy for stage III gastric cance) Reviewed

梅田晋一, 神田光郎, 中西香企, 清水大, 田中千恵, 藤原道隆, 小寺泰弘

日本胃癌学会総会記事 Vol. 93回 page： 288 - 288 2021.3

顕微鏡的断端陽性が予後に与える影響(Microscopic Positive Margin After Gastrectomy Increases Recurrences of Gastric Cancer) Reviewed

中西香企, 神田光郎, 伊藤誠二, 望月能成, 寺本仁, 石榑清, 村井俊文, 浅田崇洋, 清水大, 田中千恵, 藤原道隆, 小寺泰弘

日本胃癌学会総会記事 Vol. 93回 page： 259 - 259 2021.3

Development of novel combination cancer immunotherapy using anti-PD-1 and anti-PD-L1 antibody Reviewed

Hasegawa Hirotaka, Sugiyama Daisuke, Kanda Mitsuro, Hayashi Masamichi, Tanaka Chie, Yamada Suguru, Nakayama Goro, Koike Masahiko, Nomoto Shuji, Fujiwara Michitaka, Kodera Yasuhiro, Nishikawa Hiroyoshi

CANCER SCIENCE Vol. 112 page： 741 - 741 2021.2

Function and prognostic value of melanoma-associated antigen-D4 protein in esophageal squamous cell carcinoma Reviewed

Sawaki Koichi, Kanda Mitsuro, Sato Yusuke, Shimizu Dai, Uno Yasuo, Umeda Shinichi, Hattori Norifumi, Hayashi Masamichi, Tanaka Chie, Yamada Suguru, Nakayama Goro, Motoyama Satoru, Koike Masahiko, Fujiwara Michitaka, Kodera Yasuhiro

CANCER SCIENCE Vol. 112 page： 531 - 531 2021.2

STRA6 expression serves as a prognostic biomarker of gastric cancer Reviewed

Nakamura Shunsuke, Kanda Mitsuro, Shimizu Dai, Sawaki Koichi, Tanaka Chie, Hattori Norifumi, Hayashi Masamichi, Yamada Suguru, Koike Masahiko, Kodera Yasuhiro

CANCER SCIENCE Vol. 112 page： 780 - 780 2021.2

Circulating miRNA signature of esophageal squamous cell carcinoma diagnosis:retro-prospective multinational cohort study Reviewed

Miyoshi Jinsei, Toden Shusuke, Izumi Daisuke, Kanda Mitsuro, Sato Yasushi, Muguruma Naoki, Baba Hideo, Kodera Yasuhiro, Goel Ajay, Takayama Tetsuji

CANCER SCIENCE Vol. 112 page： 527 - 527 2021.2

Randomised phase II trial of capecitabine plus oxaliplatin with continuous versus intermittent use of oxaliplatin as adjuvant chemotherapy for stage II/III colon cancer (CCOG-1302 study) Reviewed

Nakayama Goro, Takano Nao, Taniguchi Hiroya, Ishigure Kiyoshi, Yokoyama Hiroyuki, Teramoto Hitoshi, Hashimoto Ryoji, Sakai Mitsuru, Ishiyama Akiharu, Kinoshita Takashi, Hayashi Naomi, Nakamura Masanori, Hattori Norifumi, Sato Yusuke, Umeda Shinichi, Uehara Kei, Aiba Toshisada, Sonohara Fuminori, Hayashi Masamichi, Kanda Mitsuro, Kobayashi Daisuke, Tanaka Chie, Yamada Suguru, Koike Masahiko, Fujiwara Michitaka, Murotani Kenta, Ando Masahiko, Ando Yuichi, Muro Kei, Kodera Yasuhiro

EUROPEAN JOURNAL OF CANCER Vol. 144 page： 61 - 71 2021.2

Tissue RNFT2 Expression Levels Are Associated With Peritoneal Recurrence and Poor Prognosis in Gastric Cancer. Reviewed International journal

Masahiro Sasahara, Mitsuro Kanda, Dai Shimizu, Chie Tanaka, Yoshikuni Inokawa, Norifumi Hattori, Masamichi Hayashi, Goro Nakayama, Yasuhiro Kodera

Anticancer research Vol. 41 ( 2 ) page： 609 - 617 2021.2

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

BACKGROUND/AIM: Disease recurrence is frequently observed after curative resection of advanced gastric cancer resulting in a poor prognosis. In the present study, we identified a candidate biomarker to predict recurrence and prognosis after curative resection of gastric cancer. MATERIALS AND METHODS: A transcriptome analysis was conducted using surgically resected cancerous tissue from patients with metastatic gastric cancer to identify genes that are upregulated in primary and metastatic tissues. RESULTS: Ring finger protein, transmembrane 2 (RNFT2) mRNA expression was upregulated in primary gastric cancer tissues and metastases compared with non-cancerous tissues. RNFT2 expression in gastric cancer cell lines was positively correlated with the EMT-related molecules GSC, MMP9, and RAC1. The RNFT2 high expression group exhibited a significantly shorter postoperative overall survival. Peritoneal recurrence was significantly higher in the RNFT2 high expression group. CONCLUSION: RNFT2 mRNA expression predicts peritoneal recurrence and is a potential prognostic biomarker for gastric cancer following curative gastrectomy.

DOI： 10.21873/anticanres.14812

Age-Related Differences in the Prognosis of Pancreatic Cancer According to Perioperative Systemic Therapy. Reviewed International journal

Fuminori Sonohara, Suguru Yamada, Keisuke Kurimoto, Yoshikuni Inokawa, Hideki Takami, Masamichi Hayashi, Dai Shimizu, Norifumi Hattori, Mitsuro Kanda, Chie Tanaka, Goro Nakayama, Masahiko Koike, Tsutomu Fujii, Yasuhiro Kodera

Pancreas Vol. 50 ( 1 ) page： 37 - 46 2021.1

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

OBJECTIVES: In this study, we retrospectively assessed the feasibility and prognostic efficacy of perioperative chemo(radio)therapy for pancreatic cancer (PC) patients according to age. METHODS: A total of 556 consecutive patients who underwent curative-intent pancreatectomy for PC between 2000 and 2018 were enrolled. RESULTS: Of the 556 patients who underwent resection, 95 (17%) were elderly (age, ≥75 years). Postoperative complications did not significantly differ between the 2 age groups, and postoperative prognoses were also similar (recurrence-free survival [RFS], P = 0.68; overall survival [OS], P = 0.28). In this cohort, 103 patients (19%) underwent preoperative chemo(radio)therapy, and 417 (77%) underwent postoperative chemotherapy. Perioperative therapy was found to be significantly beneficial for younger patients (preoperative therapy: RFS, P = 0.006; OS, P < 0.001; postoperative therapy: RFS, P < 0.001; OS, P < 0.001). Conversely, no significant survival benefit of perioperative therapy was found for the elderly (preoperative therapy: RFS, P = 0.28; OS, P = 0.44; postoperative therapy: RFS, P = 0.77; OS, P = 0.08). CONCLUSIONS: This study demonstrated that, although perioperative therapy is feasible for selected elderly patients with PC, this approach might not be as beneficial as it is for younger PC patients.

DOI： 10.1097/MPA.0000000000001712

Pancreatic Fat and Body Composition Measurements by Computed Tomography are Associated with Pancreatic Fistula After Pancreatectomy. Reviewed International journal

Katsuhito Tanaka, Suguru Yamada, Fuminori Sonohara, Hideki Takami, Masamichi Hayashi, Mitsuro Kanda, Daisuke Kobayashi, Chie Tanaka, Goro Nakayama, Masahiko Koike, Michitaka Fujiwara, Yasuhiro Kodera

Annals of surgical oncology Vol. 28 ( 1 ) page： 530 - 538 2021.1

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

OBJECTIVES: Postoperative pancreatic fistula (POPF) is the most threatening complication after pancreatectomy. This study aimed to directly assess pancreatic fatty infiltration with preoperative computed tomography (CT) imaging and to investigate whether a preoperative analysis of patient variables, including CT characteristics and clinical factors, can predict POPF. METHODS: We enrolled 150 consecutive patients who underwent curative pancreatectomy. Radiographic factors, including pancreatic fat volume, were measured using preoperative CT imaging and the predictive factors were explored using univariate and multivariate analyses. RESULTS: POPF developed in 30 patients (20.0%). The ratio of pancreatic fat (RPF) ≥ 4.83% was associated with a risk of POPF, high body mass index (BMI), and obese body habitus. Patients with POPF were significantly more likely to have high BMI (≥ 25 kg/m2), obese body habitus, and an RPF ≥ 4.83% than patients without POPF. In the multivariate analysis, visceral fat area/skeletal muscle index (VFA/SMI) ≥ 1.94 (odds ratio [OR] 4.28, 95% confidence interval [CI] 1.43-12.9, p = 0.0095) was the sole independent predictive factor for POPF. For patients with a soft pancreas, VFA/SMI ≥ 1.94 (OR 5.67, 95% CI 2.05-15.7, p = 0.0008) was again the sole independent predictive factor for POPF. CONCLUSION: Preoperative CT images can examine pancreatic fatty infiltration, and patients who had POPF were significantly associated with a high RPF. Among several parameters, VFA/SMI was the only independent predictive factor for clinically relevant POPF. Preoperative evaluation of these body composition variables and the pancreatic configuration could be useful for predicting POPF.

DOI： 10.1245/s10434-020-08581-9

Newly developed primary malignancies in long-term survivors who underwent curative esophagectomy for squamous cell carcinoma of the esophagus. Reviewed

Dai Shimizu, Masahiko Koike, Mitsuro Kanda, Fuminori Sonohara, Norifumi Hattori, Masamichi Hayashi, Chie Tanaka, Suguru Yamada, Yasuhiro Kodera

Surgery today Vol. 51 ( 1 ) page： 153 - 158 2021.1

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

PURPOSE: We evaluated the efficacy of the long-term follow-up of patients who underwent radical esophagectomy for esophageal squamous cell carcinoma (ESCC) to screen for recurrence and new primary malignancies. METHODS: We retrospectively collected 448 ESCC patients who underwent radical esophagectomy. Esophagogastroduodenoscopy, computed tomography, a stool test and the assessment of the serum concentration of squamous cell carcinoma antigen and carcinoembryonic antigen were performed annually, even over 5 years after esophagectomy. The incidence of ESCC recurrence and new primary malignancies was investigated. RESULTS: We enrolled 222 patients who survived at least 5 years after esophagectomy. A total of 104 new primary malignancies occurred in 82 patients (36.9%) after esophagectomy. Twenty-one malignancies were in the head and neck region, 14 in the residual esophagus, 13 in the prostate and 11 in the gastric tube and lung. Patients who developed new primary malignancies after esophagectomy had a significantly higher Brinkman index than those without new malignancies. An endoscopic approach successfully treated 92.9% of carcinomas in the residual esophagus, 90.9% of cancers in the gastric tube and 42.9% of carcinomas in the head and neck region. CONCLUSION: The incidence of new primary malignancies was higher than the age-standardized incidence. Long-term follow-up and systemic screening may increase the probability of an early diagnosis and subsequent low-invasive treatment.

DOI： 10.1007/s00595-020-02072-w

Optimal Preoperative Multidisciplinary Treatment in Borderline Resectable Pancreatic Cancer. Reviewed International journal

Nana Kimura, Suguru Yamada, Hideki Takami, Kenta Murotani, Isaku Yoshioka, Kazuto Shibuya, Fuminori Sonohara, Yui Hoshino, Katsuhisa Hirano, Toru Watanabe, Hayato Baba, Kosuke Mori, Takeshi Miwa, Mitsuro Kanda, Masamichi Hayashi, Koshi Matsui, Tomoyuki Okumura, Yasuhiro Kodera, Tsutomu Fujii

Cancers Vol. 13 ( 1 ) 2021.1

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

Background: The objective of this study was to investigate the optimal neoadjuvant therapy (NAT) for borderline resectable pancreatic cancer invading the portal vein (BR-PV) or abutting major arteries (BR-A). Methods: We retrospectively analyzed 88 patients with BR-PV and 111 patients with BR-A. Results: In BR-PV patients who underwent upfront surgery (n = 46)/NAT (n = 42), survival was significantly better in the NAT group (3-year overall survival (OS): 5.8%/35.5%, p = 0.004). In BR-A patients who underwent upfront surgery (n = 48)/NAT (n = 63), survival was also significantly better in the NAT group (3-year OS:15.5%/41.7%, p < 0.001). The prognosis tended to be better in patients who received newer chemotherapeutic regimens, such as FOLFIRINOX and gemcitabine with nab-paclitaxel. In 36 BR-PV patients who underwent surgery after NAT, univariate analysis revealed that normalization of tumor marker (TM) levels (p = 0.028) and preoperative high prognostic nutritional index (PNI) (p = 0.022) were significantly associated with a favorable prognosis. In 39 BR-A patients who underwent surgery after NAT, multivariate analysis revealed that preoperative PNI > 42.5 was an independent prognostic factor (HR: 0.15, p = 0.014). Conclusions: NAT using newer chemotherapy is essential for improving the prognosis of BR pancreatic cancer. These findings suggest that prognosis may be prolonged by maintaining good nutritional status during preoperative treatment.

DOI： 10.3390/cancers13010036

Different Characteristics of Serum Alfa Fetoprotein and Serum Des-gamma-carboxy Prothrombin in Resected Hepatocellular Carcinoma Reviewed

Hayashi Masamichi, Yamada Suguru, Takano Nao, Okamura Yukiyasu, Takami Hideki, Inokawa Yoshikuni, Sonohara Fuminori, Tanaka Nobutake, Shimizu Dai, Hattori Norifumi, Kanda Mitsuro, Tanaka Chie, Nakayama Goro, Koike Masahiko, Kodera Yasuhiro

IN VIVO Vol. 35 ( 3 ) page： 1749 - 1760 2021

Amido-Bridged Nucleic Acid-Modified Antisense Oligonucleotides Targeting SYT13 to Treat Peritoneal Metastasis of Gastric Cancer Reviewed

Mitsuro Kanda, Yuuya Kasahara, Dai Shimizu, Takashi Miwa, Shinichi Umeda, Koichi Sawaki, Shunsuke Nakamura, Yasuhiro Kodera, Satoshi Obika

Molecular Therapy - Nucleic Acids Vol. 22 page： 791 - 802 2020.12

Novel Prognostic Implications of Methylated RNA and Demethylases in Resected HCC and Background Liver Tissue. Reviewed International journal

Nobuhiko Nakagawa, Katsuhito Tanaka, Fuminori Sonohara, Raju Kandimalla, Yuki Sunagawa, Yoshikuni Inokawa, Hideki Takami, Masamichi Hayashi, Suguru Yamada, Mitsuro Kanda, Chie Tanaka, Goro Nakayama, Masahiko Koike, Yasuhiro Kodera

Anticancer research Vol. 40 ( 12 ) page： 6665 - 6676 2020.12

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

BACKGROUND/AIM: N6-Methyladenosine (m6A), the most abundant internal modification of RNA, plays a critical role in cancer development. However, the clinical implications of m6A in hepatocellular carcinoma (HCC) remain unclear. MATERIALS AND METHODS: We analyzed 177 HCC and paired noncancerous liver tissues from patients who underwent hepatectomy according to global m6A quantification and expression of m6A demethylases fat mass and obesity-associated protein (FTO) and alpha-ketoglutarate-dependent dioxygenase alkB homolog 5 (ALKBH5). RESULTS: The global m6A quantification revealed no significant difference between HCC and non-cancerous tissue. The expression of m6A demethylases FTO and ALKBH5, was significantly lower in HCC than in non-cancerous tissues (both p<0.001). Furthermore, low ALKBH5 expression in non-cancerous tissues was significantly correlated with worse recurrence-free survival (median of 16.3 vs. 38.9 months, p=0.001). CONCLUSION: m6A in HCC and its demethylase in surrounding non-cancerous liver tissues might be involved in inherent mechanisms for HCC development and affect malignant potential after HCC resection.

DOI： 10.21873/anticanres.14690

Accurate Risk Stratification of Patients with Node-Positive Gastric Cancer by Lymph Node Ratio. Reviewed International journal

Shunsuke Nakamura, Mitsuro Kanda, Seiji Ito, Yoshinari Mochizuki, Hitoshi Teramoto, Kiyoshi Ishigure, Toshifumi Murai, Takahiro Asada, Akiharu Ishiyama, Hidenobu Matsushita, Chie Tanaka, Daisuke Kobayashi, Michitaka Fujiwara, Kenta Murotani, Yasuhiro Kodera

World journal of surgery Vol. 44 ( 12 ) page： 4184 - 4192 2020.12

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

BACKGROUND: We aimed to clarify the utility of lymph node ratio (LNR) for assessing the prognosis of patients with node-positive gastric cancer after curative gastrectomy. METHODS: We retrospectively analyzed data of 973 patients with node-positive gastric cancer who had undergone curative gastrectomy at nine institutions from 2010 to 2014. Survival analysis was performed by comparing LNR low and high groups according to the optimal cutoff value of LNR, which was determined using receiver operating characteristic curve analysis. RESULTS: LNR high was significantly associated with shorter disease-free survival and was an independent predictor of recurrence in all patients. Moreover, we obtained the similar results from analysis of each N stage. The prevalence of lymph node and peritoneal recurrence appeared to be higher in the LNR high group. Correlation analysis showed that LNR was negatively correlated with the number of retrieved nodes within every N stage; however, disease-free survival did not differ significantly between LNR low and high groups of each N stage with 16-30, 31-40, or >40 retrieved nodes. CONCLUSIONS: LNR is a strong prognostic factor and predictor of recurrence in patients with node-positive gastric cancer who have undergone curative gastrectomy. The combination of LNR and N staging permits more accurate prognostic stratification of patients with gastric cancer and may contribute to developing novel prognostic models.

DOI： 10.1007/s00268-020-05739-0

AMIGO2 Expression as a Potential Prognostic Biomarker for Gastric Cancer. Reviewed International journal

Shunsuke Nakamura, Mitsuro Kanda, Dai Shimizu, Chie Tanaka, Yoshikuni Inokawa, Norifumi Hattori, Masamichi Hayashi, Suguru Yamada, Goro Nakayama, Kenji Omae, Masahiko Koike, Yasuhiro Kodera

Anticancer research Vol. 40 ( 12 ) page： 6713 - 6721 2020.12

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

BACKGROUND/AIM: Although our understanding of the molecular mechanisms of gastric cancer (GC) development and progression is steadily deepening, the clinical outcome of GC patients remains inadequate. The identification of molecules associated with GC will help improve prognosis. We aimed to identify the molecules involved in GC progression and metastasis. MATERIALS AND METHODS: Transcriptome analysis was performed on surgically resected gastric tissue from patients with hepatic metastasis. Fourteen cell lines and 230 pairs of primary GC tissues and their corresponding normal adjacent tissues were included in the mRNA expression analysis. RESULTS: Adhesion molecule with Ig like domain 2 (AMIGO2) was identified as a gene of interest. The levels of AMIGO2 mRNA positively correlated with those encoding FOXC2, NODAL, GEMIN2 and negatively correlated with TFPI2. Patients with high AMIGO2 expression experienced significantly shorter disease-free survival and overall survival. High levels of AMIGO2 were associated with poor prognosis. CONCLUSION: Patients with GC with high AMIGO2 mRNA levels experienced significantly shorter survival, suggesting that AMIGO2 may serve as a prognostic biomarker for GC.

DOI： 10.21873/anticanres.14694

DAA時代のHCV治療がもたらす切除可能HCCへの臨床的影響の検討 Reviewed

園原史訓, 山田豪, 高見秀樹, 猪川祥邦, 林真路, 神田光郎, 田中千恵, 中山吾郎, 小池聖彦, 小寺泰弘

日本消化器外科学会総会 Vol. 75回 page： O12 - 3 2020.12

尿中cell free DNAを用いた膵癌診断法の開発 Reviewed

林真路, 山田豪, 高見秀樹, 猪川祥邦, 園原史訓, 神田光郎, 田中千恵, 中山吾郎, 小池聖彦, 小寺泰弘

日本消化器外科学会総会 Vol. 75回 page： P276 - 5 2020.12

胃癌における周術期化学療法の新知見胃癌に対するS-1補助療法の臨床問題に答えるための多施設データセット解析(New findings on perioperative chemotherapy for gastric cancer Multi-institutional dataset analysis to answer clinical questions of adjuvant S-1 for gastric cancer) Reviewed

Nakanishi Koki, Kanda Mitsuro, Ito Seiji, Mochizuki Yoshinari, Teramoto Hitoshi, Ishigure Kiyoshi, Shimizu Dai, Tanaka Chie, Fujiwara Michitaka, Kodera Yasuhiro

日本消化器外科学会総会 Vol. 75回 page： WS4 - 6 2020.12

MZB1 expression indicates poor prognosis in estrogen receptor-positive breast cancer. Reviewed International journal

Manabu Watanabe, Masahiro Shibata, Takahiro Inaishi, Takahiro Ichikawa, Ikumi Soeda, Noriyuki Miyajima, Yuko Takano, Dai Takeuchi, Nobuyuki Tsunoda, Mitsuro Kanda, Toyone Kikumori, Yasuhiro Kodera, Masato Nagino

Oncology letters Vol. 20 ( 5 ) page： 198 - 198 2020.11

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

Breast cancer (BC) is the most common malignant tumor in females. Development of novel biomarkers or therapeutic targets may contribute toward the improvement of a patient's prognosis. Marginal zone B and B1 cell-specific protein (MZB1) is an unfolded protein response-related chaperone and mainly exists in the endoplasmic reticulum of B lymphocytes, although little is known regarding its role in BC cells. The present study aimed to investigate the significance of MZB1 expression in BC. To begin with, MZB1 mRNA expression levels in 13 BC cell lines and two non-cancerous mammary cell lines were evaluated. Next, mRNA and protein expression of MZB1 in BC patient tumor specimens was evaluated to assess the association between expression and clinicopathological factors or prognosis. MZB1 mRNA expression levels were detectable in four estrogen receptor (ER)-positive BC cell lines. When ratios of MZB1 mRNA expression levels between BC and non-cancerous specimens were evaluated, patients with stage III disease exhibited a higher ratio than patients with stage 0/I/II disease (P=0.009). Using immunohistochemistry, patients with ER-positive BC more frequently expressed MZB1, compared with patients with ER-negative BC (P=0.003). In patients with ER-positive BC, patients with MZB1-positive BC experienced shorter disease-free survival (DFS) times than patients with negative BC (P=0.026). Multivariate analysis of DFS demonstrated that MZB1 positivity was an independent prognostic factor (P=0.022). The results of the present study suggested that MZB1 expression may be associated with a more advanced stage of BC. Furthermore, in patients with ER-positive BC, MZB1 may be a potential prognostic marker.

DOI： 10.3892/ol.2020.12059

An Open-Label Single-Arm Phase II Study of Treatment with Neoadjuvant S-1 Plus Cisplatin for Clinical Stage III Squamous Cell Carcinoma of the Esophagus. Reviewed International journal

Mitsuro Kanda, Masahiko Koike, Naoki Iwata, Dai Shimizu, Chie Tanaka, Norifumi Hattori, Masamichi Hayashi, Suguru Yamada, Kenji Omae, Goro Nakayama, Yasuhiro Kodera

The oncologist Vol. 25 ( 11 ) page： E1650 - E1654 2020.11

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

LESSONS LEARNED: Two courses of neoadjuvant therapy using S-1 plus cisplatin for clinical stage III esophageal squamous cell carcinoma did not achieve expected response rate according to endoscopic evaluation of primary tumors. Subsequent esophagectomy was safely performed. BACKGROUND: In Japan, esophagectomy after two courses of 5-fluorouracil plus cisplatin is regarded a standard strategy for treating stage II or III esophageal squamous cell carcinoma (ESCC). However, 5-fluorouracil plus cisplatin does not benefit cohorts with clinical stage III ESCC, suggesting the need for a more effective regimen. METHODS: A single-arm, open-label phase II trial was conducted to evaluate the safety and efficacy of two courses of neoadjuvant chemotherapy using S-1 plus cisplatin (NAC-SP) for clinical stage III ESCC. The primary endpoint was overall response rate as defined by endoscopic evaluation of primary tumors. RESULTS: We enrolled 26 patients. The completion rate for the two courses of NAC-SP was 61.5%. Grade 3 or higher adverse events were experienced by 38.4% of patients. The treatment response rate according to endoscopic findings, acquired before the second course, was 34.6% and below the expected level (55.0%). The morbidity rate of patients who underwent radical subtotal esophagectomy (96.2%) was 32.0%. Repeat surgery was unnecessary, and surgery-associated deaths did not occur. The 5-year progression-free survival (PFS) and overall survival (OS) rates were 84.6% and 92.2%, respectively. CONCLUSION: We demonstrate safety of NAC-SP, but not its efficacy, for patients with clinical stage III ESCC. Subsequent esophagectomy was safely performed.

DOI： 10.1634/theoncologist.2020-0546

D2 lymph node dissection confers little benefit on the overall survival of older patients with resectable gastric cancer: a propensity score-matching analysis of a multi-institutional dataset. Reviewed

Takahiro Shinozuka, Mitsuro Kanda, Seiji Ito, Yoshinari Mochizuki, Hitoshi Teramoto, Kiyoshi Ishigure, Toshifumi Murai, Takahiro Asada, Akiharu Ishiyama, Hidenobu Matsushita, Chie Tanaka, Daisuke Kobayashi, Michitaka Fujiwara, Kenta Murotani, Yasuhiro Kodera

Surgery today Vol. 50 ( 11 ) page： 1434 - 1442 2020.11

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

PURPOSE: Aging societies comprise an increasing number of elderly gastric cancer (GC) patients. We herein attempted to determine whether D2 lymphadenectomy is beneficial for older GC patients. METHODS: We retrospectively analyzed a multi-institutional dataset including 3484 patients who received surgical resection for GC. For the analysis, we selected patients aged ≥ 80 years who were clinically diagnosed with T1N + or T2-4 GC. To balance the essential variables including the type of gastrectomy and the stage of progression, propensity score matching was conducted, and we compared the background clinical factors and postoperative outcomes of the patients allocated to the D2 (n = 87) and non-D2 (n = 87) dissection groups. RESULTS: The D2 group had significantly longer operative times, more blood loss, and more retrieved lymph nodes (median 32 vs 24, P < 0.001) than the non-D2 group. The D2 group had a greater incidence of intra-abdominal abscesses (grade ≥ II in the Clavien-Dindo classification) than the non-D2 group (3.5% vs 0%, P = 0.040). The overall disease-specific and relapse-free survival rates of the D2 group tended to be poorer than those of the non-D2 group (hazard ratios 1.49, 1.70 and 1.14, respectively). CONCLUSIONS: D2 lymphadenectomy for older patients with GC conferred little benefit regarding overall survival despite an occurrence of increased complication rates.

DOI： 10.1007/s00595-020-02021-7

Complex roles of the actin-binding protein Girdin/GIV in DNA damage-induced apoptosis of cancer cells. Reviewed International journal

Chen Chen, Atsushi Enomoto, Liang Weng, Tetsuro Taki, Yukihiro Shiraki, Shinji Mii, Ryosuke Ichihara, Mitsuro Kanda, Masahiko Koike, Yasuhiro Kodera, Masahide Takahashi

Cancer science Vol. 111 ( 11 ) page： 4303 - 4317 2020.11

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

The actin-binding protein Girdin is a hub protein that interacts with multiple proteins to regulate motility and Akt and trimeric G protein signaling in cancer cells. Girdin expression correlates with poor outcomes in multiple human cancers. However, those findings are not universal, as they depend on study conditions. Those data suggest that multiple aspects of Girdin function and its role in tumor cell responses to anticancer therapeutics must be reconsidered. In the present study, we found that Girdin is involved in DNA damage-induced cancer cell apoptosis. An esophageal cancer cell line that exhibited high Girdin expression showed a marked sensitivity to UV-mediated DNA damage compared to a line with low Girdin expression. When transcriptional activation of endogenous Girdin was mediated by an engineered CRISPR/Cas9 activation system, sensitivity to DNA damage increased in both stationary and migrating HeLa cancer cells. High Girdin expression was associated with dysregulated cell cycle progression and prolonged G1 and M phases. These features were accompanied by p53 activation, which conceivably increases cancer cell vulnerability to UV exposure. These data highlight the importance of understanding complex Girdin functions that influence cancer cell sensitivity to therapeutics.

DOI： 10.1111/cas.14637

The efficacy of oxaliplatin combination adjuvant chemotherapy for elderly patients with stage III colorectal cancer. Reviewed

Naomi Hayashi, Mitsuro Kanda, Kenji Omae, Yasuhiro Kodera

Nagoya journal of medical science Vol. 82 ( 4 ) page： 603 - 611 2020.11

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

Now we are facing to aging society. We aimed to determine the long-term outcomes receiving adjuvant chemotherapy among elderly patients with stage III colorectal cancer. Elderly patients (≧65 years, n=91) diagnosed as stage III colorectal cancer and received adjuvant chemotherapy were retrieved from the database and classified into two groups according to whether the patient received monotherapy (n=65) or doublet therapy(n=26). Recurrence-free survival and overall survival were compared between the groups. To balance the essential variables, we conducted propensity score matching. After one-to-one propensity score matching, each group consisted of 22 patients. No significant difference was detected by comprehensive geriatric assessment 7. Overall survival was significantly longer in the monotherapy group. Adverse events occurred more frequently in the doublet therapy group. Monotherapy may improve the long-term outcome of elderly patients while the adverse events were less frequent.

DOI： 10.18999/nagjms.82.4.603

劇症型A群β溶連菌感染症による原発性腹膜炎の1例 Reviewed

砂川祐輝, 猪川祥邦, 山田豪, 園原史訓, 高見秀樹, 林真路, 服部憲史, 神田光郎, 田中千恵, 小林大介, 中山吾郎, 小池聖彦, 藤原道隆, 小寺泰弘

日本臨床外科学会雑誌 Vol. 81 ( 11 ) page： 2399 - 2399 2020.11

胃診断 Reviewed

中村俊介, 神田光郎, 清水大, 澤木康一, 田中千恵, 服部憲史, 園原史訓, 高見秀樹, 猪川祥邦, 林真路, 山田豪, 小池聖彦, 小寺泰弘

日本消化器外科学会雑誌 Vol. 53 ( Suppl.2 ) page： 296 - 296 2020.11

膵臓化学療法 Reviewed

砂川祐輝, 山田豪, 山中雅也, 鈴木雄之典, 中川暢彦, 加藤吉康, 田中伸孟, 栗本景介, 園原史訓, 猪川祥邦, 高見秀樹, 林真路, 神田光郎, 田中千恵, 中山吾郎, 小池聖彦, 小寺泰弘

日本消化器外科学会雑誌 Vol. 53 ( Suppl.2 ) page： 311 - 311 2020.11

膵臓悪性 Reviewed

山田豪, 高見秀樹, 園原史訓, 猪川祥邦, 林真路, 服部憲史, 神田光郎, 田中千恵, 中山吾郎, 小池聖彦, 藤井努, 小寺泰弘

日本消化器外科学会雑誌 Vol. 53 ( Suppl.2 ) page： 316 - 316 2020.11

Characteristics Associated with Nodal and Distant Recurrence after Curative Resection of Squamous Cell Carcinoma of the Thoracic Esophagus Reviewed

Kanda Mitsuro, Koike Masahiko, Shimizu Dai, Tanaka Chie, Hayashi Masamichi, Hattori Norifumi, Yamada Suguru, Nakayama Goro, Fujiwara Michitaka, Kodera Yasuhiro

JOURNAL OF THE AMERICAN COLLEGE OF SURGEONS Vol. 231 ( 4 ) page： E121 - E121 2020.10

予定残肝ICG消失率(ICG-Krem)の術後肝不全発症予測因子としての有用性 Reviewed

砂川祐輝, 山田豪, 園原史訓, 猪川祥邦, 高見秀樹, 林真路, 服部憲史, 神田光郎, 田中千恵, 中山吾郎, 小池聖彦, 小寺泰弘

日本癌治療学会学術集会抄録集 Vol. 58回 page： O60 - 4 2020.10

予定残肝ICG消失率(ICG-Krem)の術後肝不全発症予測因子としての有用性 Reviewed

砂川祐輝, 山田豪, 園原史訓, 猪川祥邦, 高見秀樹, 林真路, 服部憲史, 神田光郎, 田中千恵, 中山吾郎, 小池聖彦, 小寺泰弘

日本癌治療学会学術集会抄録集 Vol. 58回 page： O60 - 4 2020.10

胃癌組織中STRA6発現の臨床的意義 Reviewed

中村俊介, 神田光郎, 清水大, 澤木康一, 田中千恵, 服部憲史, 林真路, 山田豪, 小池聖彦, 小寺泰弘

日本癌学会総会記事 Vol. 79回 page： PJ14 - 7 2020.10

食道扁平上皮癌におけるMAGE-D4発現の臨床的意義の検討 Reviewed

澤木康一, 神田光郎, 佐藤雄亮, 清水大, 宇野泰朗, 梅田晋一, 服部憲史, 林真路, 田中千恵, 山田豪, 中山吾郎, 本山悟, 小池聖彦, 藤原道隆, 小寺泰弘

日本癌学会総会記事 Vol. 79回 page： OJ15 - 9 2020.10

血清miRNAシグネチャーを用いた食道扁平上皮癌の早期診断モデルの構築後ろ向き・前向き・多国籍試験 Reviewed

三好人正, 東田周祐, 泉大輔, 神田光郎, 佐藤康史, 六車直樹, 馬場秀夫, 小寺泰弘, ゴエル・アジャイ, 高山哲治

日本癌学会総会記事 Vol. 79回 page： OE15 - 6 2020.10

膵癌における術前治療中のSpan-1の臨床的意義 Reviewed

砂川祐輝, 山田豪, 園原史訓, 猪川祥邦, 高見秀樹, 林真路, 清水大, 服部憲史, 神田光郎, 田中千恵, 中山吾郎, 小池聖彦, 小寺泰弘

日本臨床外科学会雑誌 Vol. 81 ( 増刊 ) page： 463 - 463 2020.10

ASO Author Reflections: Characteristics Associated with Nodal and Distant Recurrence After Radical Esophagectomy for Squamous Cell Carcinoma of the Thoracic Esophagus. Reviewed International journal

Mitsuro Kanda, Masahiko Koike, Yasuhiro Kodera

Annals of surgical oncology Vol. 27 ( 9 ) page： 3206 - 3207 2020.9

ASO Author Reflections: Expression and Malignant Potential of B4GALNT4 in Esophageal Squamous Cell Carcinoma. Reviewed International journal

Hayato Baba, Mitsuro Kanda, Yasuhiro Kodera, Tsutomu Fujii

Annals of surgical oncology Vol. 27 ( 9 ) page： 3257 - 3258 2020.9

Characteristics Associated with Nodal and Distant Recurrence After Radical Esophagectomy for Squamous Cell Carcinoma of the Thoracic Esophagus. Reviewed International journal

Mitsuro Kanda, Masahiko Koike, Dai Shimizu, Chie Tanaka, Norifumi Hattori, Masamichi Hayashi, Suguru Yamada, Kenji Omae, Yasuhiro Kodera

Annals of surgical oncology Vol. 27 ( 9 ) page： 3195 - 3205 2020.9

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

BACKGROUND: Recurrence after radical resection of esophageal squamous cell carcinoma (ESCC) is common. Limited evidence is available about the differences in clinical characteristics, risk factors, and prognostic significance between nodal and distant recurrence of thoracic ESCC. PATIENTS AND METHODS: We retrospectively analyzed 341 patients who underwent radical resection of thoracic ESCC and experienced (1) initial recurrence only in lymph nodes (n = 39), (2) recurrence only at distant organs (n = 57), or (3) no recurrences (n = 245) after follow-up ≥ 24 months. Clinicopathological characteristics, survival times, and risk factors were compared between the nodal and distant recurrence groups. RESULTS: The median follow-up time was 57.8 months. Metastasectomy as initial treatment for the recurrence was performed for six (15.4%) patients in the nodal recurrence group and one patient in the distant recurrence group. Compared with the nodal recurrence group, patients with distant recurrence had significantly shorter disease-free survival [hazard ratio (HR) 1.68, 95% confidence interval (CI) 1.10-2.57, P = 0.0169], postrecurrence survival (HR 1.77, 95% CI 1.01-3.10, P = 0.0476), and overall survival (HR 1.98, 95% CI 1.12-3.51, P = 0.0193). The distant recurrence group had significantly larger macroscopic tumor size and more advanced pathological T stage than the nodal recurrence group, whereas preoperative treatment, tumor location, number of fields dissected, tumor differentiation, lymphatic involvement, and vessel invasion were not significantly different between the two groups. CONCLUSIONS: Survival times and recurrence risk factors differed between patients with nodal and distant recurrence after radical resection of thoracic ESCC.

DOI： 10.1245/s10434-020-08433-6

Expression and Malignant Potential of B4GALNT4 in Esophageal Squamous Cell Carcinoma. Reviewed International journal

Hayato Baba, Mitsuro Kanda, Yusuke Sato, Koichi Sawaki, Dai Shimizu, Masahiko Koike, Satoru Motoyama, Yasuhiro Kodera, Tsutomu Fujii

Annals of surgical oncology Vol. 27 ( 9 ) page： 3247 - 3256 2020.9

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

BACKGROUND: β-1,4-N-Acetyl-galactosaminyltransferase 4 (B4GALNT4), an enzyme involved in ganglioside synthesis, is upregulated in many cancers. We examine B4GALNT4 expression and its relationship to prognosis in esophageal squamous cell carcinoma (ESCC). PATIENTS AND METHODS: Expression of B4GALNT4 mRNA and B4GALNT4 protein was analyzed by quantitative reverse-transcription polymerase chain reaction (qRT-PCR) and immunohistochemistry, respectively, in 17 human ESCC cell lines and/or clinical specimens from two independent cohorts of 147 and 159 ESCC patients. The contributions of B4GALNT4 to proliferation, invasion, migration, and adhesion was evaluated in ESCC cells subjected to siRNA-mediated gene knockdown. Correlations between clinicopathological parameters and B4GALNT4 expression in clinical specimens were analyzed in both patient cohorts. RESULTS: B4GALNT4 mRNA expression levels varied widely in ESCC cell lines, regardless of differentiation status or the originating tissue. Knockdown of B4GALNT4 significantly suppressed the proliferation, invasion, migration, and adhesion of ESCC cell lines compared with control cells. B4GALNT4 mRNA was overexpressed in ESCC tissues compared with adjacent normal esophageal tissues. High mRNA expression was significantly associated with poor disease-free survival and hematogenous recurrence, and high B4GALNT4 protein expression was also significantly related to poor disease-specific survival. On multivariable analysis, high B4GALNT4 expression was an independent predictor of poor prognosis. In both patient cohorts, high B4GALNT4 expression did not correlate with known prognostic factors, such as disease stage, lymphovascular invasion, or squamous cell-carcinoma-related antigen level. CONCLUSIONS: B4GALNT4 influences the malignant behavior of ESCC cells. B4GALNT4 expression may serve as a novel prognostic marker, independent of established risk factors, for ESCC patients.

DOI： 10.1245/s10434-020-08431-8

Systemic Inflammation Score as a Predictor of Pneumonia after Radical Resection of Gastric Cancer: Analysis of a Multi-Institutional Dataset. Reviewed International journal

Michita Shoka, Mitsuro Kanda, Seiji Ito, Yoshinari Mochizuki, Hitoshi Teramoto, Kiyoshi Ishigure, Toshifumi Murai, Takahiro Asada, Akiharu Ishiyama, Hidenobu Matsushita, Chie Tanaka, Daisuke Kobayashi, Michitaka Fujiwara, Kenta Murotani, Yasuhiro Kodera

Digestive surgery Vol. 37 ( 5 ) page： 401 - 410 2020.9

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

BACKGROUND: Curative treatment for gastric cancer (GC) comprising gastrectomy with systematic lymph node dissection can result in postoperative complications. Postoperative pneumonia is sometimes fatal, like surgery-related complications such as anastomotic leakage. In this retrospective study, we analyzed a multi-institutional collaborative dataset with the aim of identifying predictors of postgastrectomy pneumonia. METHODS: From a retrospective database of 3,484 patients who had undergone gastrectomy for GC at nine Japanese institutions between 2010 and 2014, 1,415 patients who met all eligibility criteria were identified as eligible for analysis. Predictive values of 31 candidate variables for postoperative pneumonia were assessed. RESULTS: Forty-two patients (3.0%) had grade II or higher postoperative pneumonia. Preoperative systemic inflammation score (SIS) had the greatest area under the curve (0.655) for predicting postoperative pneumonia (optimal cutoff value = 2). The odds ratio (OR) of high SISs associated with postoperative pneumonia was 3.10 (95% confidence interval [CI], 1.54-6.07; p < 0.001). Multivariate binomial logistic analysis identified high SIS as an independent risk factor for postoperative pneumonia (OR, 2.31; 95% CI, 1.19-4.48; p = 0.013). A forest plot revealed that ORs of high SISs were highest in female patients. CONCLUSIONS: Our findings indicate that the preoperative SIS may serve as a simple predictor of postgastrectomy pneumonia, assisting physicians' efforts to take preventive measures against this complication.

DOI： 10.1159/000506940

Therapeutic monoclonal antibody targeting of neuronal pentraxin receptor to control metastasis in gastric cancer. Reviewed International journal

Mitsuro Kanda, Dai Shimizu, Koichi Sawaki, Shunsuke Nakamura, Shinichi Umeda, Takashi Miwa, Haruyoshi Tanaka, Chie Tanaka, Masamichi Hayashi, Yohei Iguchi, Suguru Yamada, Masahisa Katsuno, Yasuhiro Kodera

Molecular cancer Vol. 19 ( 1 ) page： 131 - 131 2020.8

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

BACKGROUND: Controlling metastasis is essential for improving the prognosis of patients with gastric cancer (GC). Here, we aimed to identify a molecule required for GC metastasis and to investigate its potential utility as a target for the development of therapeutic antibodies (Abs). METHODS: Transcriptome and bioinformatics analyses of human GC cell lines identified the neuronal pentraxin receptor (NPTXR) as a candidate molecule. NPTXR function was probed by modulating its expression in GC cells and assessing the effects on intracellular signaling and malignant behaviors in vitro and in mouse xenograft models. We also generated anti-NPTXR Abs and Nptxr-/- mice, and assessed the clinical significance of NPTXR expression in GC specimens. RESULTS: NPTXR mRNA expression in clinical specimens was associated with disease progression and was significantly higher in tissues from GC patients with distant metastasis compared with those without. NPTXR regulated expression of genes involved in metastatic behaviors as well as activation of the PI3K-AKT-mTOR, FAK-JNK, and YAP signaling pathways. NPTXR silencing promoted caspase-mediated apoptosis and attenuated GC cell proliferation, cell cycle progression, migration, invasion, adhesion, stem cell-like properties, and resistance to 5-fluorouracil in vitro, and also inhibited the tumorigenicity of GC cells in vivo. Anti-NPTXR Abs inhibited GC peritoneal metastasis in mice. Nptxr-/- mice showed no abnormalities in reproduction, development, metabolism, or motor function. CONCLUSIONS: NPTXR plays an essential role in controlling the malignant behavior of GC cells in vitro and in vivo. NPTXR-targeting Abs may thus have utility as novel diagnostic tools and/or treatment modalities for GC.

DOI： 10.1186/s12943-020-01251-0

Surveillance of Esophageal Cancer in the Republic of Uzbekistan from 2000 to 2018. Reviewed

Yusupbekov A, Kanda M, Usmanov B, Tuychiev O, Baymakov S, Sakamoto J, Yusupbekov A

Asian Pacific journal of cancer prevention : APJCP Vol. 21 ( 8 ) page： 2281 - 2285 2020.8

The impact of cancer stem cell markers in the tissues of pancreatic ductal adenocarcinoma for prognosis after surgical resections Reviewed

Inokawa Yoshikuni, Yamada Suguru, Hayashi Masamichi, Sunagawa Yuki, Sonohara Fuminori, Takami Hideki, Hattori Norifumi, Kanda Mitsuro, Kobayashi Daisuke, Tanaka Chie, Nakayama Goro, Koike Masahiko, Kodera Yasuhiro

CANCER RESEARCH Vol. 80 ( 16 ) 2020.8

Survival times are similar among patients with peritoneal, hematogenous, and nodal recurrences after curative resections for gastric cancer. Reviewed International journal

Koichi Sawaki, Mitsuro Kanda, Seiji Ito, Yoshinari Mochizuki, Hitoshi Teramoto, Kiyoshi Ishigure, Toshifumi Murai, Takahiro Asada, Akiharu Ishiyama, Hidenobu Matsushita, Chie Tanaka, Daisuke Kobayashi, Michitaka Fujiwara, Kenta Murotani, Yasuhiro Kodera

Cancer medicine Vol. 9 ( 15 ) page： 5392 - 5399 2020.8

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

BACKGROUND: The three dominant recurrence patterns of gastric cancer are peritoneal, hematogenous, and nodal recurrence. Correlation between initial recurrence site and prognosis is poorly understood, particularly after standardization of postoperative S-1 adjuvant chemotherapy. METHODS: We analyzed a multi-institutional database of 3484 patients who underwent gastrectomy for gastric cancer between 2010 and 2014. Patients who experienced recurrences after curative gastrectomy classified into peritoneal, hematogenous, or nodal recurrence groups, according to their initial recurrence sites, and their prognoses were compared. RESULTS: We included 313 patients in the analysis, of whom 190 patients (63%) were treated with postoperative adjuvant chemotherapy. Pathological disease states were stage I: n = 20 (6%), stage II: n = 62 (20%), and stage III: n = 231 (74%). Patients were categorized into groups by peritoneal (n = 127), hematogenous (n = 123), and nodal (n = 63) recurrence. The peritoneal recurrence group tended to have longer recurrence-free survival, but shorter post-recurrence survival, than the other two groups. Median disease-specific survival after curative resection by group were peritoneal: 25.8 months, hematogenous: 29.0 months, and nodal: 27.8 months (peritoneal vs hematogenous, P = .152; hematogenous vs nodal, P = .955; peritoneal vs nodal, P = .213). CONCLUSIONS: Prognoses after curative resection for gastric cancer were similar among patients with peritoneal, hematogenous, or nodal recurrences.

DOI： 10.1002/cam4.3208

ETNK2のアポトーシス調節を介した胃癌細胞肝転移への関与 Reviewed

三輪高嗣, 神田光郎, 田中千恵, 小林大介, 清水大, 園原史訓, 高見秀樹, 服部憲史, 林真路, 山田豪, 中山吾郎, 小池聖彦, 藤原道隆, 小寺泰弘

日本外科学会定期学術集会抄録集 Vol. 120回 page： SF - 5 2020.8

当院における消化器外科領域のCALNA参入と現状について Reviewed

宮田一志, 深谷昌秀, 山崎健太, 石井健太, 冨永健太, 西村康大, 小池聖彦, 小林大介, 田中千恵, 神田光郎, 清水大, 佐藤敏, 中西香企, 江畑智希, 小寺泰弘, 梛野正人

日本外科学会定期学術集会抄録集 Vol. 120回 page： SF - 7 2020.8

当科におけるUnresectable膵癌治療の検討 Reviewed

加藤吉康, 山田豪, 高見秀樹, 園原史訓, 猪川祥邦, 林真路, 服部憲史, 神田光郎, 小林大介, 田中千恵, 中山吾郎, 小池聖彦, 藤原道隆, 小寺泰弘

日本外科学会定期学術集会抄録集 Vol. 120回 page： SF - 4 2020.8

幽門側胃切除術後の再建法が術後合併症に及ぼす影響 B-I法とR-Y法の比較 Reviewed

中西香企, 神田光郎, 伊藤誠二, 望月能成, 寺本仁, 石榑清, 村井俊文, 浅田崇洋, 石山聡治, 松下英信, 清水大, 田中千恵, 小林大介, 藤原道隆, 室谷健太, 小寺泰弘

日本外科学会定期学術集会抄録集 Vol. 120回 page： SF - 6 2020.8

幽門側胃切除術後の再建法が術後合併症に及ぼす影響 B-I法とR-Y法の比較 Reviewed

日本外科学会定期学術集会抄録集 Vol. 120回 page： SF - 6 2020.8

大腸癌初回肝転移手術後の早期再発予測因子の検討 Reviewed

林真路, 山田豪, 高見秀樹, 猪川祥邦, 園原史訓, 砂川祐輝, 田中伸孟, 栗本景介, 加藤吉康, 中川暢彦, 鈴木雄之典, 神田光郎, 田中千恵, 小林大介, 中山吾郎, 小池聖彦, 藤原道隆, 小寺泰弘

日本外科学会定期学術集会抄録集 Vol. 120回 page： DP - 4 2020.8

多施設共同胃癌データベースを利用した胃切除術後肺炎発生に関する予測因子の検討 Reviewed

荘加道太, 神田光郎, 伊藤誠二, 望月能也, 寺本仁, 石榑清, 村井俊文, 浅田崇洋, 石山聡治, 松下英信, 田中千恵, 小林大介, 藤原道隆, 室谷健太, 小寺泰弘

日本外科学会定期学術集会抄録集 Vol. 120回 page： SF - 4 2020.8

多施設共同胃癌データベースを利用した胃切除術後肺炎発生に関する予測因子の検討 Reviewed

日本外科学会定期学術集会抄録集 Vol. 120回 page： SF - 4 2020.8

切除不能胃癌に対する集学的治療としてのconversion surgeryの適応について Reviewed

小林大介, 神田光郎, 田中千恵, 清水大, 園原史訓, 猪川祥邦, 高見秀樹, 服部憲史, 林真路, 山田豪, 中山吾郎, 小池聖彦, 藤原道隆, 小寺泰弘

日本外科学会定期学術集会抄録集 Vol. 120回 page： SF - 3 2020.8

傾向スコアマッチングを用いた後期高齢者における食道亜全摘術の短期成績と術前免疫栄養因子の検討 Reviewed

神田光郎, 小池聖彦, 清水大, 田中千恵, 小林大介, 園原史訓, 猪川祥邦, 高見秀樹, 服部憲史, 林真路, 山田豪, 中山吾郎, 藤原道隆, 小寺泰弘

日本外科学会定期学術集会抄録集 Vol. 120回 page： DP - 4 2020.8

Ivor Lewis手術は超高齢者に対する低侵襲手術となり得るか? Reviewed

小池聖彦, 神田光郎, 高見秀樹, 服部憲史, 林真路, 田中千恵, 山田豪, 中山吾郎, 藤原道隆, 小寺泰弘

日本外科学会定期学術集会抄録集 Vol. 120回 page： DP - 6 2020.8

Initial systemic therapy時代における高齢者膵癌集学的治療の意義と限界 Reviewed

園原史訓, 山田豪, 高見秀樹, 猪川祥邦, 林真路, 清水大, 服部憲史, 神田光郎, 田中千恵, 小林大介, 中山吾郎, 小池聖彦, 藤原道隆, 藤井努, 小寺泰弘

日本外科学会定期学術集会抄録集 Vol. 120回 page： SF - 6 2020.8

膵癌に対する膵頭十二指腸切除術の分子生物学的なsurgical marginの評価 Reviewed

砂川祐輝, 山田豪, 林真路, 高見秀樹, 猪川祥邦, 園原史訓, 栗本景介, 田中伸孟, 加藤吉康, 中川暢彦, 鈴木雄之典, 神田光郎, 田中千恵, 小林大介, 中山吾郎, 小池聖彦, 藤原道隆, 小寺泰弘

日本外科学会定期学術集会抄録集 Vol. 120回 page： SF - 2 2020.8

高齢者胃切除手術症例における前向き高齢者機能評価 Reviewed

田中千恵, 神田光郎, 猪川祥邦, 小林大介, 清水大, 園原史訓, 高見秀樹, 服部憲史, 林真路, 山田豪, 中山吾郎, 小池聖彦, 藤原道隆, 小寺泰弘

日本外科学会定期学術集会抄録集 Vol. 120回 page： SF - 4 2020.8

食道癌術前化学療法中にRenal Salt-Wasting Syndromeを生じた1例 Reviewed

山本周平, 神田光郎, 小池聖彦, 高見秀樹, 清水大, 田中千恵, 小林大介, 園原史訓, 猪川祥邦, 服部憲史, 林真路, 山田豪, 中山吾郎, 藤原道隆, 小寺泰弘

日本外科学会定期学術集会抄録集 Vol. 120回 page： RS - 4 2020.8

食道扁平上皮癌の術後長期予後因子としてのmodified systemic inflammation scoreの意義 Reviewed

清水大, 神田光郎, 小池聖彦, 園原史訓, 高見秀樹, 猪川祥邦, 服部憲史, 林真路, 田中千恵, 小林大介, 山田豪, 中山吾郎, 藤原道隆, 小寺泰弘

日本外科学会定期学術集会抄録集 Vol. 120回 page： DP - 5 2020.8

食道扁平上皮癌におけるMAGE-D4蛋白の発現、機能、予後の検討 Reviewed

宇野泰朗, 神田光郎, 佐藤雄亮, 清水大, 梅田晋一, 服部憲史, 林真路, 田中千恵, 小林大介, 山田豪, 中山吾郎, 小池聖彦, 本山悟, 小寺泰弘

日本外科学会定期学術集会抄録集 Vol. 120回 page： SF - 5 2020.8

食道扁平上皮癌におけるKCNJ15遺伝子の機能解析と、その組織中発現における臨床的意義の検討 Reviewed

中村俊介, 神田光郎, 小池聖彦, 清水大, 小林大介, 田中千恵, 園原史訓, 高見秀樹, 猪川祥邦, 服部憲史, 林真路, 山田豪, 中山吾郎, 藤原道隆, 小寺泰弘

日本外科学会定期学術集会抄録集 Vol. 120回 page： DP - 8 2020.8

食道亜全摘術後肺炎予測因子に関する検討 Reviewed

澤木康一, 神田光郎, 小池聖彦, 清水大, 田中千恵, 小林大介, 園原史訓, 服部憲史, 猪川祥邦, 高見秀樹, 林真路, 山田豪, 中山吾郎, 藤原道隆, 小寺泰弘

日本外科学会定期学術集会抄録集 Vol. 120回 page： SF - 4 2020.8

術前CT画像を利用した膵内脂肪量と体組成による膵液瘻予測因子の検討 Reviewed

田中克仁, 山田豪, 園原史訓, 猪川祥邦, 高見秀樹, 服部憲史, 林真路, 神田光郎, 田中千恵, 小林大介, 中山吾郎, 小池聖彦, 藤原道隆, 小寺泰弘

日本外科学会定期学術集会抄録集 Vol. 120回 page： SF - 1 2020.8

膵頸部癌における臨床病理学的特徴 Reviewed

栗本景介, 山田豪, 鈴木雄之典, 中川暢彦, 加藤吉康, 田中伸孟, 砂川祐輝, 園原史訓, 猪川祥邦, 高見秀樹, 林真路, 神田光郎, 田中千恵, 中山吾郎, 小池聖彦, 小寺泰弘

日本外科学会定期学術集会抄録集 Vol. 120回 page： SF - 3 2020.8

膵頭十二指腸切除術施行膵癌患者における周術期メインおよびリパクレオン投与の安全性と有用性 Reviewed

中川暢彦, 山田豪, 多代充, 栗本景介, 園原史訓, 清水大, 猪川祥邦, 高見秀樹, 服部憲史, 林真路, 神田光郎, 田中千恵, 小林大介, 中山吾郎, 小池聖彦, 藤原道隆, 小寺泰弘, 小寺泰弘

日本外科学会定期学術集会抄録集 Vol. 120回 page： DP - 5 2020.8

膵頭十二指腸切除術における胆管空腸吻合部狭窄のリスクファクターに関する検討 Reviewed

鈴木雄之典, 山田豪, 園原史訓, 猪川祥邦, 高見秀樹, 服部憲史, 林真路, 神田光郎, 小林大介, 田中千恵, 中山吾郎, 小池聖彦, 藤原道隆, 小寺泰弘

日本外科学会定期学術集会抄録集 Vol. 120回 page： DP - 4 2020.8

膵癌組織における癌幹細胞マーカー発現が切除後予後に与える影響についての検討 Reviewed

猪川祥邦, 山田豪, 林真路, 砂川祐輝, 園原史訓, 高見秀樹, 服部憲史, 神田光郎, 小林大介, 田中千恵, 中山吾郎, 小池聖彦, 小寺泰弘

日本外科学会定期学術集会抄録集 Vol. 120回 page： DP - 5 2020.8

胃癌における術前血清腫瘍マーカーの再発予測としての至適カットオフ値の検討 Reviewed

佐藤敏, 神田光郎, 伊藤誠二, 望月能成, 寺本仁, 石榑清, 村井俊文, 浅田崇洋, 石山聡治, 松下英信, 清水大, 宮田一志, 小林大介, 田中千恵, 深谷昌秀, 小池聖彦, 藤原道隆, 小寺泰弘

日本外科学会定期学術集会抄録集 Vol. 120回 page： SF - 2 2020.8

ASO Author Reflections: KCNJ15 Expression and Malignant Behavior of Esophageal Squamous Cell Carcinoma. Reviewed International journal

Shunsuke Nakamura, Mitsuro Kanda, Yasuhiro Kodera

Annals of surgical oncology Vol. 27 ( 7 ) page： 2569 - 2570 2020.7

KCNJ15 Expression and Malignant Behavior of Esophageal Squamous Cell Carcinoma. Reviewed International journal

Shunsuke Nakamura, Mitsuro Kanda, Masahiko Koike, Dai Shimizu, Shinichi Umeda, Norifumi Hattori, Masamichi Hayashi, Chie Tanaka, Daisuke Kobayashi, Suguru Yamada, Kenji Omae, Yasuhiro Kodera

Annals of surgical oncology Vol. 27 ( 7 ) page： 2559 - 2568 2020.7

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

BACKGROUND: We aimed to clarify the role of potassium voltage-gated channel subfamily J member 15 (KCNJ15) in esophageal squamous cell carcinoma (ESCC) cells and its potential as a prognosticator in ESCC patients. METHODS: KCNJ15 transcription levels were evaluated in 13 ESCC cell lines and polymerase chain reaction (PCR) array analysis was conducted to detect coordinately expressed genes with KCNJ15. The biological functions of KCNJ15 in cell invasion, proliferation, migration, and adhesion were validated through small interfering RNA-mediated knockdown experiments. Cell proliferation was further evaluated through the forced expression experiment. KCNJ15 expression was detected in 200 ESCC tissues by quantitative real-time reverse transcription PCR (qRT-PCR) and analyzed in 64 representative tissues by immunohistochemistry. Correlations between KCNJ15 expression levels and clinicopathological features were also analyzed. RESULTS: The KCNJ15 expression levels varied widely in ESCC cell lines and correlated with COL3A1, JAG1, and F11R. Knockdown of KCNJ15 expression significantly repressed cell invasion, proliferation, and migration of ESCC cells in vitro. Furthermore, overexpression of KCNJ15 resulted in increased cell proliferation. Patients were stratified using the cut-off value of KCNJ15 messenger RNA (mRNA) levels in 200 ESCC tissues using receiver operating characteristic curve analysis; the high KCNJ15 expression group had significantly shorter overall and disease-free survival times. In multivariable analysis, high expression of KCNJ15 was identified as an independent poor prognostic factor. Staining intensity of in situ KCNJ15 protein expression tended to be associated with KCNJ15 mRNA expression levels. CONCLUSIONS: KCNJ15 is involved in aggressive tumor phenotypes of ESCC cells and its tissue expression levels may be useful as a prognosticator of patients with ESCC.

DOI： 10.1245/s10434-019-08189-8

Propensity-score-matched analysis of a multi-institutional dataset to compare postoperative complications between Billroth I and Roux-en-Y reconstructions after distal gastrectomy. Reviewed

Koki Nakanishi, Mitsuro Kanda, Seiji Ito, Yoshinari Mochizuki, Hitoshi Teramoto, Kiyoshi Ishigure, Toshifumi Murai, Takahiro Asada, Akiharu Ishiyama, Hidenobu Matsushita, Dai Shimizu, Chie Tanaka, Daisuke Kobayashi, Michitaka Fujiwara, Kenta Murotani, Yasuhiro Kodera

Gastric cancer : official journal of the International Gastric Cancer Association and the Japanese Gastric Cancer Association Vol. 23 ( 4 ) page： 734 - 745 2020.7

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

BACKGROUND: Few well-controlled studies have compared postoperative complications between Billroth I (B-I) and Roux-en-Y (R-Y). The aim of the present study was to compare the incidence of overall and severe postoperative complications by reconstruction method after distal gastrectomy. METHODS: We performed a multi-institutional dataset study of patients who underwent distal gastrectomy with B-I or R-Y reconstruction from 2010 to 2014. Using propensity scores to strictly balance the significant variables, we compared postoperative complications between the techniques. RESULTS: After matching, we enrolled 1014 patients (n = 507 in each group). The incidence of postoperative complications in the R-Y group was significantly higher vs the B-I group (29% vs 17%, P < 0.0001). The incidence of intra-abdominal abscess (4.3% vs 1.8%, P = 0.0177), bowel obstruction (2.6% vs 0.6%, P = 0.0203), and delayed gastric emptying (5.3% vs 1.0%, P < 0.0001) in the R-Y group was significantly higher vs the B-I group, respectively; we saw no significant difference in leakage (3.4% vs 4.1%, P = 0.5084). The incidence of grade ≥ III severe postoperative complications in the R-Y group was significantly higher vs the B-I group (13% vs 7.1%, P = 0.0013). Multivariable analysis showed that R-Y reconstruction was a strong independent risk factor for overall postoperative complications (odds ratio 1.58, P = 0.0044) and grade ≥ III severe postoperative complications (odds ratio 1.75, P = 0.0127). A forest plot revealed that R-Y reconstruction was associated with a greater risk of both overall and grade ≥ III severe postoperative complications in any subgroups. CONCLUSIONS: R-Y reconstruction was associated with increasing overall postoperative complications, as well as severe postoperative complications.

DOI： 10.1007/s10120-020-01048-6

Novel Prognostic Implications of DUPAN-2 in the Era of Initial Systemic Therapy for Pancreatic Cancer. Reviewed International journal

Sunagawa Y, Yamada S, Sato Y, Morimoto D, Sonohara F, Takami H, Inokawa Y, Hayashi M, Kanda M, Tanaka C, Kobayashi D, Nakayama G, Koike M, Fujiwara M, Fujii T, Kodera Y

Annals of surgical oncology Vol. 27 ( 6 ) page： 2081 - 2089 2020.6

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

BACKGROUND: This study aimed to explore the impact of serum tumor markers on survival for patients with pancreatic cancer (PC) who received initial systemic therapy (IST) followed by surgery. METHODS: Between April 2010 and July 2018, 285 consecutive patients who underwent curative intent surgery for PC were enrolled in the study. The relation between carbohydrate antigen 19-9 and duke pancreatic monoclonal antigen type 2 (DUPAN-2) after IST was analyzed as well as PC prognosis. RESULTS: The study identified 95 patients who underwent systemic chemotherapy with or without radiotherapy as IST from the our prospectively maintained database at the Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, Nagoya, Japan. Survival analysis of the 95 patients showed significant differences in recurrence-free survival (RFS) and overall survival (OS) between the DUPAN-2-normalized (D-normalized) and DUPAN-2-unnormalized (D-unnormalized) groups (median RFS, 24.1 vs. 14.2 months, p = 0.003; median OS, not reached vs. 29.6 months, p = 0.003). In addition, a tendency of differences in survival was observed between the D-normalized and D-unnormalized groups with borderline resectable PC (RFS, 20.1 vs. 14.2 months, p = 0.052; OS, not reached vs. 29.6 months, p = 0.081), and significant differences in survival were observed between the D-normalized and D-unnormalized groups with unresectable PC (RFS, 25.1 vs. 12.1 months, p < 0.001; OS, not reached vs. 11.4 months, p < 0.001). Furthermore, multivariate analysis demonstrated that normalized DUPAN-2 independently predicted survival of resected PC [RFS: hazard ratio (HR) 2.180; 95% confidence interval (CI) 1.16-4.08, p = 0.015; OS: HR 2.806; 95% CI 1.19-6.62, p = 0.018]. CONCLUSIONS: During IST, DUPAN-2 normalization may potentially predict prolonged survival for PC patients and optimal timing for conversion surgery in IST.

DOI： 10.1245/s10434-019-07981-w

PRAME as a Potential Biomarker for Liver Metastasis of Gastric Cancer. Reviewed International journal

Hayato Baba, Mitsuro Kanda, Koichi Sawaki, Shinichi Umeda, Takashi Miwa, Dai Shimizu, Chie Tanaka, Daisuke Kobayashi, Michitaka Fujiwara, Yasuhiro Kodera, Tsutomu Fujii

Annals of surgical oncology Vol. 27 ( 6 ) page： 2071 - 2080 2020.6

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

BACKGROUND: Liver metastasis of gastric cancer (GC) is highly associated with poor prognosis. The development of sensitive biomarkers for detecting and predicting liver metastasis is required for better clinical outcome. OBJECTIVE: In this study, we aimed to identify novel genes associated with liver metastasis of GC. METHODS: Global expression profiling of 57,749 genes was performed using surgically resected gastric tissues from four patients with liver metastasis to identify candidate genes. The mRNA expression levels of the selected candidate gene were analyzed in the resected gastric tissues of 300 GC patients and correlated with clinicopathological parameters. Fourteen GC cell lines were subjected to mRNA expression and polymerase chain reaction (PCR) array analysis. RESULTS: Among 25 candidate genes identified by transcriptome analysis, preferentially expressed antigen of melanoma (PRAME) was selected for subsequent analyses. mRNA expression analysis of clinical samples revealed the aberrant expression of PRAME in GC tissues, and its high expression was significantly related to differentiated phenotype and vessel invasion, as well as liver metastasis. High PRAME expression was significantly associated with hepatic recurrence after curative surgery, and cumulative incidences of hepatic recurrence were significantly greater in patients with high PRAME expression compared with patients with low PRAME expression. In an in vitro analysis, overexpression was observed in all GC cell lines compared with a normal epithelial cell line. PCR array analysis revealed the coordinate expression of MMP9, OCLN, IL1RN, and MST1R. CONCLUSIONS: PRAME is related to the malignant potential of GC and could serve as a novel biomarker for the detection and prediction of liver metastasis.

DOI： 10.1245/s10434-019-07985-6

集学的治療による病勢コントロール後に外腸骨リンパ節転移を切除しえた膵NETの1例 Reviewed

鈴木雄之典, 山田豪, 高見秀樹, 園原史訓, 猪川祥邦, 服部憲史, 林真路, 神田光郎, 田中千恵, 中山吾郎, 小池聖彦, 藤原道隆, 小寺泰弘

日本消化器病学会東海支部例会プログラム抄録集 Vol. 132回 page： 55 - 55 2020.6

Fraser extracellular matrix complex subunit 1 promotes liver metastasis of gastric cancer. Reviewed International journal

Umeda S, Kanda M, Miwa T, Tanaka H, Tanaka C, Kobayashi D, Hayashi M, Yamada S, Nakayama G, Koike M, Kodera Y

International journal of cancer Vol. 146 ( 10 ) page： 2865 - 2876 2020.5

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

Liver metastasis is often fatal in patients with gastric cancer, therefore, we aimed to identify genes associated with the mechanisms of liver metastasis of gastric cancer (GC) and to investigate their potential to predict recurrence and to serve as targets of therapy. Recurrence pattern-specific transcriptome analysis was performed to identify liver metastasis-associated genes. A stable knockout cell line was generated to investigate metabolic pathways that contribute to the malignant phenotype in vitro and vivo. Three hundred GC patients were analyzed to demonstrate an association between gene expression levels and clinicopathological parameters. As a results extracellular matrix complex subunit 1 (FRAS1) was identified as a liver metastasis-associated gene. Pathway analysis revealed that FRAS1 expression was significantly correlated with the expression of genes encoding TGFB1, MAP1B, AHNAK, BMP2, MUC1, BIRC5, MET, CDH1, RB1 and MKI67. FRAS1 expression was associated with the activation of the EGFR and PI3K signaling pathways. The proliferation ability of FRAS1 knockout cell line (FRAS1-KO) was inhibited compared to that of the parent cell line through caspase activity increment and cell cycle alteration. FRAS1-KO cells exhibited increased responsiveness to oxygen stress and diminished stemness, invasiveness, and migration. Mouse models of GC revealed decreases in tumor formation and generation of metastasis by FRAS1-KO cells. Moreover, the cumulative liver recurrence rate was significantly increased in patients with GC with high FRAS1 expression levels. We concluded that FRAS1 contributes to the malignant phenotype of GC, especially liver metastasis, and may therefore serve as a predictive marker or a target for treating liver metastasis.

DOI： 10.1002/ijc.32705

Clinical impact of additional therapy for residual pancreatic cancer. Reviewed

Yamada S, Sonohara F, Tashiro M, Murotani K, Takami H, Hayashi M, Kanda M, Tanaka C, Kobayashi D, Nakayama G, Koike M, Fujii T, Kodera Y

Surgery today Vol. 50 ( 5 ) page： 440 - 448 2020.5

Is the measurement of drain amylase content useful for predicting pancreas-related complications after gastrectomy with systematic lymphadenectomy? Reviewed International journal

Koki Nakanishi, Mitsuro Kanda, Junichi Sakamoto, Yasuhiro Kodera

World journal of gastroenterology Vol. 26 ( 14 ) page： 1594 - 1600 2020.4

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

Many studies investigating postoperative pancreatic fistula (POPF) after gastrectomy, including studies measuring drain amylase content (D-AMY) as a predictive factor have been reported. This article reviews previous studies and looks to the future of measuring D-AMY in patients after gastrectomy. The causes of pancreatic fluid leakage are; the parenchymal and/or thermal injury to the pancreas, and blunt injury to the pancreas by compression and retraction. Measurement of D-AMY to predict POPF has become common in clinical practice after pancreatic surgery and was later extended to the gastric surgery. Several studies have reported associations between D-AMY and POPF after gastrectomy, and the high value of D-AMY on postoperative day (POD) 1 was an independent risk factor. To improve both sensitivity and specificity, attempts have been made to enhance the predictive accuracy of factors on POD 1 as well as on POD 3 as combined markers. Although several studies have shown a high predictive ability of POPF, it has not necessarily been exploited in clinical practice. Many problems remain unresolved; ideal timing for measurement, optimal cut-off value, and means of intervention after prediction. Prospective clinical trial could be imperative in order to develop D-AMY measurement in common clinical practice for gastric surgery.

DOI： 10.3748/wjg.v26.i14.1594

Detection of indocyanine green fluorescence to determine tumor location during laparoscopic gastrectomy for gastric cancer: Results of a prospective study.

Tanaka C, Kanda M, Funasaka K, Miyahara R, Murotani K, Tanaka Y, Takeda S, Kobayashi D, Hirooka Y, Fujiwara M, Goto H, Kodera Y

Asian journal of endoscopic surgery Vol. 13 ( 2 ) page： 160 - 167 2020.4

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

INTRODUCTION: In laparoscopic gastrectomy, a method to locate the margin of an early-stage cancerous lesion that is invisible from the serosal surface and impalpable during laparoscopic procedures is needed to determine an appropriate transection line. We conducted a prospective study to develop a new marking method using preoperative submucosal injection of indocyanine green (ICG). METHODS: Patients undergoing laparoscopic gastrectomy for T1 gastric cancer were recruited. The first 11 patients comprised the learning set and the subsequent 18 patients the validation set. ICG was endoscopically injected in the submucosal layer of the stomach approximately 1 cm away from the tumor edge 1 or 3 days before surgery. The diameters of the visualized ICG were compared with those of a conventional marking method using India ink in 10 historical controls. RESULTS: In the learning set, the optimal amount of ICG was determined to be 0.1 mL at a concentration of 0.5 mg/mL. In the validation set, the same procedure was repeated. No technical problems or adverse reactions related to ICG injection were observed. In all cases, ICG was successfully detected, and negative surgical margins were pathologically confirmed. The mean long diameter of the visualized ICG fluorescence measured at the mucosal surface of the stomach was significantly smaller in the current study than in the historical controls in whom India ink was used (21 vs 52 mm, P < 0.0001). CONCLUSIONS: The preoperative submucosal ICG marking was safely performed and successfully detected without excessive blurring during laparoscopic gastrectomy.

DOI： 10.1111/ases.12710

Exploration of Exosomal Micro RNA Biomarkers Related to Epithelial-to-Mesenchymal Transition in Pancreatic Cancer. Reviewed International journal

Fuminori Sonohara, Suguru Yamada, Shigeomi Takeda, Masamichi Hayashi, Masaya Suenaga, Yuki Sunagawa, Mitsuru Tashiro, Hideki Takami, Mitsuro Kanda, Chie Tanaka, Daisuke Kobayashi, Goro Nakayama, Masahiko Koike, Michitaka Fujiwara, Yasuhiro Kodera

Anticancer research Vol. 40 ( 4 ) page： 1843 - 1853 2020.4

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

BACKGROUND/AIM: Epithelial-to-mesenchymal transition (EMT) plays important roles in cancer progression. This study aimed to identify the exosomal miRNA (exo-miRNA) profiles related to the EMT status in pancreatic cancer (PC). MATERIALS AND METHODS: Comprehensive exo-miRNA-expression profiles in the culture media of PC cell lines were analyzed through microarray technology. The identified miRNAs were analyzed to investigate their clinical implication using The Cancer Genome Atlas (TCGA) dataset and clinical samples. RESULTS: We prioritized 291 exo-miRNAs differentially expressed between epithelial and mesenchymal cell types. Among them, survival analysis based on the TCGA dataset revealed that mir-196b and mir-204 significantly stratify the prognosis of PC cases. In addition, analysis of cell lines indicated miR-196b-3p as a mesenchymal marker and miR-204-3p as an epithelial marker. Finally, we demonstrated that miR-196b-3p and miR-204-3p in serum exosomes were differentially expressed among intraductal papillary mucinous neoplasms, mucinous cystic neoplasms, and PC. CONCLUSION: Serum exo-miRNA biomarkers potentially identify the pancreatic tumor status through less-invasive methods.

DOI： 10.21873/anticanres.14138

Optimized Cutoff Value of Serum Squamous Cell Carcinoma Antigen Concentration Accurately Predicts Recurrence After Curative Resection of Squamous Cell Carcinoma of the Esophagus. Reviewed International journal

Kanda M, Koike M, Shimizu D, Tanaka C, Kobayashi D, Hattori N, Hayashi M, Omae K, Yamada S, Nakayama G, Kodera Y

Annals of surgical oncology Vol. 27 ( 4 ) page： 1233 - 1240 2020.4

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

BACKGROUND: Squamous cell carcinoma antigen (SCC-Ag) and carcinoembryonic antigen (CEA) are widely used in clinical practice to predict the prognosis of patients with esophageal squamous cell carcinoma (ESCC). However, their predictive values for prognosis are controversial. This study determined optimal cutoff values of serum SCC-Ag and CEA concentrations for predicting postoperative recurrence of ESCC, which enabled selection of high-risk patients. METHODS: The study retrospectively analyzed 427 patients who underwent curative resection for ESCC. The optimal cutoff values of preoperative SCC-Ag and CEA concentrations for predicting postoperative recurrence were determined using combined analysis of hazard ratios and sensitivities for recurrence. Using the optimal cutoff value, the study evaluated survival, recurrence patterns, and temporal changes in marker concentrations. RESULTS: The preoperative SCC-Ag concentration of 1.1 ng/ml was the optimal cutoff value for predicting postoperative recurrence, whereas precise cutoff values could not be determined for preoperative CEA concentrations. High preoperative SCC-Ag concentrations (> 1.1 ng/ml), which were significantly associated with more aggressive tumor phenotypes and shorter disease-free survival, were identified as an independent prognostic factor in the multivariable analysis. High preoperative SCC-Ag concentrations were significantly associated with greater prevalence of lung/pleura and local recurrences. Normalization of serum SCC-Ag concentrations after neoadjuvant treatment or esophagectomy was not associated with a decreased risk of postoperative recurrence. CONCLUSIONS: The optimal cutoff value of preoperative SCC-Ag concentrations that predicted recurrence of ESCC was 1.1 ng/ml, illuminating the utility of serum SCC-Ag concentrations as an easily measurable tool for selecting a perioperative management strategy.

DOI： 10.1245/s10434-019-07977-6

Anti-thyroid antibodies and thyroid echo pattern at baseline as risk factors for thyroid dysfunction induced by anti-programmed cell death-1 antibodies: a prospective study. Reviewed International journal

Norio Okada, Shintaro Iwama, Takayuki Okuji, Tomoko Kobayashi, Yoshinori Yasuda, Eri Wada, Takeshi Onoue, Motomitsu Goto, Mariko Sugiyama, Taku Tsunekawa, Hiroshi Takagi, Daisuke Hagiwara, Yoshihiro Ito, Hidetaka Suga, Ryoichi Banno, Tetsunari Hase, Masahiro Morise, Mitsuro Kanda, Kenji Yokota, Naozumi Hashimoto, Masahiko Ando, Yasushi Fujimoto, Masato Nagino, Yasuhiro Kodera, Mitsuhiro Fujishiro, Hideharu Hibi, Michihiko Sone, Hitoshi Kiyoi, Momokazu Gotoh, Yuichi Ando, Masashi Akiyama, Yoshinori Hasegawa, Hiroshi Arima

British journal of cancer Vol. 122 ( 6 ) page： 771 - 777 2020.3

Language：English Publishing type：Research paper (scientific journal) Publisher：Springer Science and Business Media LLC

BACKGROUND: Anti-programmed cell death-1 (PD-1) antibodies can cause thyroid dysfunction. However, no predictive biomarkers enabling stratification of thyroid dysfunction risk have been identified. METHODS: A total of 209 patients treated with an anti-PD-1 antibody were evaluated for anti-thyroid antibodies at baseline and prospectively for thyroid function every 6 weeks for 24 weeks after treatment initiation, and then observed until the visits stopped. Thyroid ultrasonography was performed if the patient was positive for anti-thyroid antibodies at baseline. RESULTS: Of the 209 patients, 19 (9.1%) developed thyroid dysfunction (destructive thyroiditis or hypothyroidism). The cumulative incidence of thyroid dysfunction was significantly higher in patients who were positive vs. negative for anti-thyroid antibodies (15/44 [34.1%] vs. 4/165 [2.4%], p < 0.001). Forty-two patients positive for anti-thyroid antibodies at baseline were divided into two groups according to the presence of an irregular echo pattern. The cumulative incidence of thyroid dysfunction was significantly higher in those with an irregular vs. a regular echo pattern (13/23 [56.5%] vs. 1/19 [5.3%], p = 0.001). None of the patients developed thyroid dysfunction after the initial 24-week period. CONCLUSIONS: The risk of thyroid dysfunction induced by anti-PD-1 antibodies can be predicted by evaluation of anti-thyroid antibodies and the thyroid echo pattern at baseline. TRIAL REGISTRATION: UMIN000019024.

DOI： 10.1038/s41416-020-0736-7

Other Link： http://www.nature.com/articles/s41416-020-0736-7

Clinical Implications of Naples Prognostic Score in Patients with Resected Pancreatic Cancer. Reviewed International journal

Nobuhiko Nakagawa, Suguru Yamada, Fuminori Sonohara, Hideki Takami, Masamichi Hayashi, Mitsuro Kanda, Daisuke Kobayashi, Chie Tanaka, Goro Nakayama, Masahiko Koike, Michitaka Fujiwara, Yasuhiro Kodera

Annals of surgical oncology Vol. 27 ( 3 ) page： 887 - 895 2020.3

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

BACKGROUND: Nutritional and immunological statuses are attracting increasing attention for their ability to predict surgical outcomes in various cancers. The Naples prognostic score (NPS) consists of the serum albumin level, total cholesterol level, neutrophil-to-lymphocyte ratio, and lymphocyte-to-monocyte ratio and could be useful for predicting survival. PATIENTS AND METHODS: We retrospectively analyzed 196 patients with pancreatic cancer who underwent curative R0/R1 resection with a surgery-first strategy between June 2003 and August 2016. The NPS of the patients was calculated from preoperative data, and the patients were then divided into three groups based on their NPS. Clinicopathological characteristics, surgical outcomes, and long-term survival were compared, and multivariate analysis of overall survival was conducted. RESULTS: Of a total of 196 patients, 22 were classified into group 0 (NPS 0), 113 into group 1 (NPS 1 or 2), and 61 into group 2 (NPS 3 or 4). Median survival time was 103.4 months in group 0, 33.3 months in group 1, and 21.3 months in group 2. Significant survival differences were observed among the 3 groups (group 1 vs. 2, group 0 vs. 2, P = 0.0380, P = 0.0022, respectively). On multivariate analysis, NPS was identified as an independent prognostic factor [hazard ratio (HR) = 1.78; P = 0.0131]; however, there were no significant differences in the incidence of postoperative morbidity among the NPS groups. CONCLUSIONS: The NPS could be an easy scoring system and an independent preoperative predictor of survival.

DOI： 10.1245/s10434-019-08047-7

Preoperative predictors of postoperative complications after gastric cancer resection (vol 50, pg 3, 2020) Reviewed

Kanda Mitsuro

SURGERY TODAY Vol. 50 ( 3 ) page： 321 - 321 2020.3

Association between Lymphovascular Invasion and Recurrence in Patients with pT1N+ or pT2-3N0 Gastric Cancer: a Multi-institutional Dataset Analysis. Reviewed International journal

Keizo Fujita, Mitsuro Kanda, Seiji Ito, Yoshinari Mochizuki, Hitoshi Teramoto, Kiyoshi Ishigure, Toshifumi Murai, Takahiro Asada, Akiharu Ishiyama, Hidenobu Matsushita, Chie Tanaka, Daisuke Kobayashi, Michitaka Fujiwara, Kenta Murotani, Yasuhiro Kodera

Journal of gastric cancer Vol. 20 ( 1 ) page： 41 - 49 2020.3

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

Purpose: Patients with pathological stage T1N+ or T2-3N0 gastric cancer may experience disease recurrence following curative gastrectomy. However, the current Japanese Gastric Cancer Treatment Guidelines do not recommend postoperative adjuvant chemotherapy for such patients. This study aimed to identify the prognostic factors for patients with pT1N+ or pT2-3N0 gastric cancer using a multi-institutional dataset. Materials and Methods: We retrospectively analyzed the data obtained from 401 patients with pT1N+ or pT2-3N0 gastric cancer who underwent curative gastrectomy at 9 institutions between 2010 and 2014. Results: Of the 401 patients assessed, 24 (6.0%) experienced postoperative disease recurrence. Multivariate analysis revealed that age ≥70 years (hazard ratio [HR], 2.62; 95% confidence interval [CI], 1.09-7.23; P=0.030) and lymphatic and/or venous invasion (lymphovascular invasion (LVI): HR, 7.88; 95% CI, 1.66-140.9; P=0.005) were independent prognostic factors for poor recurrence-free survival. There was no significant association between LVI and the site of initial recurrence. Conclusions: LVI is an indicator of poor prognosis in patients with pT1N+ or pT2-3N0 gastric cancer.

DOI： 10.5230/jgc.2020.20.e3

Serum levels of ANOS1 serve as a diagnostic biomarker of gastric cancer: a prospective multicenter observational study. Reviewed

Mitsuro Kanda, Yun-Suhk Suh, Do Joong Park, Chie Tanaka, Sang-Hoon Ahn, Seong-Ho Kong, Hyuk-Joon Lee, Daisuke Kobayashi, Michitaka Fujiwara, Hideaki Shimada, BeLong Cho, Kenta Murotani, Hyung-Ho Kim, Han-Kwang Yang, Yasuhiro Kodera

Gastric cancer : official journal of the International Gastric Cancer Association and the Japanese Gastric Cancer Association Vol. 23 ( 2 ) page： 203 - 211 2020.3

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

BACKGROUND: Development of high-performance serum biomarkers will likely improve treatment outcomes of patients with gastric cancer (GC). We previously identified the candidate serum markers, anosmin 1 (ANOS1), dihydropyrimidinase-like 3 (DPYSL3), and melanoma-associated antigen D2 (MAGE-D2) and evaluated their clinical significance through a single-center retrospective analysis. Here we conducted a prospective multicenter observational study aimed at validating the diagnostic performance of these potential markers. METHODS: We analyzed serum levels before and after surgery of the three potential biomarkers in patients with GC and healthy volunteers. Quantification of serum and GC tissue levels was performed using an ELISA. RESULTS: Area under the curve (AUC) values that discriminated patients with GC from healthy controls were - 0.7058, 0.6188, and 0.5031 for ANOS1, DPYSL3, and MAGED2, respectively. The sensitivity and specificity of the ANOS1 assay were 0.36 and 0.85, respectively. The AUC value of ANOS1 that discriminated patients with stage I GC from healthy controls was 0.7131. Serum ANOS1 levels were significantly elevated in patients with stage I GC compared with those of healthy controls (median 1179 ng/ml and 461 ng/ml, respectively, P < 0.0001) and decreased after resection of primary GC lesions (P < 0.0001). The combination of serum ANOS1 and DPYSL3 levels increased the AUC value that discriminated patients with GC from healthy controls. Serum levels of ANOS1 did not significantly correlate with those of carcinoembryonic antigen, carbohydrate antigen 19-9, or other markers of inflammation. CONCLUSIONS: Serum levels of ANOS1 may serve as a useful diagnostic tool for managing GC.

DOI： 10.1007/s10120-019-00995-z

FGFR1は胃癌細胞のEMTを促進し腹膜播種形成に関連する Reviewed

清水大, 園原史訓, 高見秀樹, 猪川祥邦, 服部憲史, 林真路, 神田光郎, 田中千恵, 小林大介, 山田豪, 中山吾郎, 小池聖彦, 藤原道隆, 三森功士, 小寺泰弘

日本胃癌学会総会記事 Vol. 92回 page： 393 - 393 2020.3

今後の胃癌バイオマーカー胃癌腹膜播種再発を予測する腹膜洗浄液中の分子バイオマーカー(Upcoming biomarkers for gastric cancer Molecular biomarkers in peritoneal lavages to predict the peritoneal recurrences of gastric cancer) Reviewed

Kanda Mitsuro, Nakanishi Koki, Tanaka Chie, Kobayashi Daisuke, Shimizu Dai, Sonohara Fuminori, Takami Hideki, Inokawa Yoshikuni, Hattori Norifumi, Hayashi Masamichi, Yamada Suguru, Nakayama Goro, Koike Masahiko, Fujiwara Michitaka, Kodera Yasuhiro

日本胃癌学会総会記事 Vol. 92回 page： 233 - 233 2020.3

FGFR1は胃癌細胞のEMTを促進し腹膜播種形成に関連する Reviewed

清水大, 園原史訓, 高見秀樹, 猪川祥邦, 服部憲史, 林真路, 神田光郎, 田中千恵, 小林大介, 山田豪, 中山吾郎, 小池聖彦, 藤原道隆, 三森功士, 小寺泰弘

日本胃癌学会総会記事 Vol. 92回 page： 393 - 393 2020.3

胃癌手術のエビデンスと実際のデータ基礎幽門側胃切除後のBillroth I再建法とRoux-en-Y再建法に関する術後合併症の比較(Evidences and real world data of gastric cancer surgery: Basic Billroth I vs Roux-en-Y after distal gastrectomy in postoperative complications) Reviewed

Nakanishi Koki, Kanda Mitsuro, Ito Seiji, Mochizuki Yoshinari, Teramoto Hitoshi, Ishigure Kiyoshi, Murai Toshifumi, Asada Takahiro, Ishiyama Akiharu, Matsushita Hidenobu, Shimizu Dai, Tanaka Chie, Kobayashi Daisuke, Fujiwara Michitaka, Kodera Yasuhiro

日本胃癌学会総会記事 Vol. 92回 page： 214 - 214 2020.3

高齢者胃切除手術症例における自立度の転帰 Reviewed

田中千恵, 神田光郎, 猪川祥邦, 清水大, 園原史訓, 小林大介, 高見秀樹, 服部憲史, 林真路, 山田豪, 中山吾郎, 小池聖彦, 藤原道隆, 小寺泰弘

日本胃癌学会総会記事 Vol. 92回 page： 251 - 251 2020.3

高齢者胃切除手術症例における自立度の転帰 Reviewed

田中千恵, 神田光郎, 猪川祥邦, 清水大, 園原史訓, 小林大介, 高見秀樹, 服部憲史, 林真路, 山田豪, 中山吾郎, 小池聖彦, 藤原道隆, 小寺泰弘

日本胃癌学会総会記事 Vol. 92回 page： 251 - 251 2020.3

Predictive value of the modified systemic inflammation score in patients undergoing curative resection of squamous cell carcinoma of the esophagus Reviewed

Kanda Mitsuro, Koike Masahiko, Shimizu Dai, Tanaka Chie, Kobayashi Daisuke, Sonohara Fuminori, Takami Hideki, Inokawa Yoshikuni, Hattori Norifumi, Hayashi Masamichi, Yamada Suguru, Nakayama Goro, Fujiwara Michitaka, Kodera Yasuhiro

JOURNAL OF CLINICAL ONCOLOGY Vol. 38 ( 4 ) 2020.2

Propensity-score-matched analysis of a multi-institutional dataset to compare the postoperative complications after distal gastrectomy between Billroth I and Roux-en-Y Reviewed

Nakanishi Koki, Kanda Mitsuro, Ito Seiji, Mochizuki Yoshinari, Teramoto Hitoshi, Ishigure Kiyoshi, Mmurai Toshifumi, Asada Takahiro, Ishiyama Akiharu, Matsushita Hidenobu, Shimizu Dai, Tanaka Chie, Kobayashi Daisuke, Fujiwara Michitaka, Kodera Yasuhiro

JOURNAL OF CLINICAL ONCOLOGY Vol. 38 ( 4 ) 2020.2

A prospective trial to evaluate treatment effects of a β-hydroxy-β-methylbutyrate containing nutrient for leakage at the anastomotic site after esophagectomy. Reviewed

Mitsuro Kanda, Masahiko Koike, Masahide Fukaya, Kazushi Miyata, Chie Tanaka, Daisuke Kobayashi, Masamichi Hayashi, Suguru Yamada, Goro Nakayama, Kenta Murotani, Michitaka Fujiwara, Masato Nagino, Yasuhiro Kodera

Nagoya journal of medical science Vol. 82 ( 1 ) page： 33 - 37 2020.2

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

Anastomotic leakage after esophagectomy is associated with prolonged hospitalization and increased medical cost. Additionally, it sometimes leads to a fatal condition and impaired postoperative quality of life. During the process of wound healing, β-hydroxy-β-methylbutyrate (HMB) is important for collagen biosynthesis. An open-label prospective intervention trial has been designed to evaluate the treatment effect of an enteral nutrient containing HMB with arginine and glutamine (Abound, Abbott Japan Co., Ltd.) for leakage at the anastomotic site after esophagectomy. Patients in whom leakage at the anastomotic site developed within 14 days after esophagectomy are eligible and Abound (24 g) is administered for 14 days through an enteral feeding tube. The target sample size is 10. The primary endpoint is duration between diagnosis and cure of leakage. Surgical procedure, safety, length of fasting, drainage placement and hospital stay, and nutritional status are determined as secondary endpoints. A historical control consisting of 20 patients who had leakage at the anastomotic site after esophagectomy between 2005 and 2018 at Nagoya University Hospital is compared with enrolled patients.

DOI： 10.18999/nagjms.82.1.33

Preoperative six-minute walk distance as a predictor of postoperative complication in patients with esophageal cancer. International journal

Inoue T, Ito S, Kanda M, Niwa Y, Nagaya M, Nishida Y, Hasegawa Y, Koike M, Kodera Y

Diseases of the esophagus : official journal of the International Society for Diseases of the Esophagus Vol. 33 ( 2 ) 2020.2

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

Surgery for esophageal cancer is associated with high morbidity and mortality. Reduced pulmonary functions and exercise capacity are known as risk factors for complications after esophagectomy. The 6-minute walk distance (6MWD) measured by the 6-minute walk test (6MWT) is a simple field test that can be used to evaluate the functional exercise capacity of patients who undergo thoracic surgery. The aim of this study was to evaluate the association of the preoperative 6MWD with postoperative complications in patients with esophageal cancer. Records of a total of 111 patients who underwent thoracic surgery followed by postoperative rehabilitation from January 2013 to December 2015 were retrospectively reviewed. Data of patients who experienced Clavien-Dindo grade II or severer (grade ≥ II) complications were compared with those who experienced grade ≤I complications. The 6MWD was significantly correlated with age, serum albumin concentration, hemoglobin concentration, and hand grip strength. A total of 42 patients experienced grade ≥II. The 6MWD of patients with grade ≥ II complications was significantly shorter than that of those with grade ≤I complications. In receiver operating characteristic analysis, 6MWD ≤ 454 m was a threshold for predicting grade ≥II complications with 71.0% sensitivity and 54.8% specificity. The incidence of grade ≥II complications led to delayed ambulation and longer stays in hospital. In the multiple regression analysis, the preoperative risk factors for incidence of grade ≥II complications included lower levels of preoperative 6MWD and % of the predicted value of forced expiratory volume in 1 second. Our results indicate that the 6MWT is useful to assess preoperative physical status in patients with esophageal cancer.

DOI： 10.1093/dote/doz050

Preoperative predictors of postoperative complications after gastric cancer resection Reviewed

Kanda Mitsuro

SURGERY TODAY Vol. 50 ( 1 ) page： 3 - 11 2020.1

The Significance of Molecular Biomarkers on Clinical Survival Outcome Differs Depending on Colon Cancer Sidedness. Reviewed International journal

Sho Hirabayashi, Masamichi Hayashi, Goro Nakayama, Shinji Mii, Norifumi Hattori, Hiroshi Tanabe, Mitsuro Kanda, Chie Tanaka, Daisuke Kobayashi, Suguru Yamada, Masahiko Koike, Michitaka Fujiwara, Masahide Takahashi, Yasuhiro Kodera

Anticancer research Vol. 40 ( 1 ) page： 201 - 211 2020.1

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

BACKGROUND/AIM: This retrospective study focused on the correlation between molecular markers and prognostic outcomes of colon cancer patients depending on sidedness. MATERIALS AND METHODS: A total of 117 stage I-III colon cancer patients who underwent colectomy were enrolled. Novel methylation markers (KIF1A, PAX5 and VGF) were selected for epigenetic evaluation and p53 and ERCC1 protein expression was examined for the investigation of genetic alterations. RESULTS: High frequency of methylation was observed in 68.2% of right-sided and 39.7% of left-sided colon cancer cases (p=0.004). Abnormal p53 was identified in 52.3% of right-sided and 75.3% of left-sided cases (p=0.015). In right-sided cases, highly methylated genes demonstrated significantly favorable disease-free survival (p=0.049). Regarding left-sided cases, advanced T stage (p=0.028) and abnormal p53 (p=0.028) were revealed to be significant predictive factors of the disease-free survival outcome. CONCLUSION: Molecular alterations, as significant prognostic factors, might differ depending on the sidedness of colon cancers.

DOI： 10.21873/anticanres.13941

Phase I Study of Intraperitoneal Administration of Paclitaxel Combined with S-1 Plus Cisplatin for Gastric Cancer with Peritoneal Metastasis. Reviewed International journal

Kobayashi D, Ishigami H, Kanda M, Tanaka C, Yamaguchi H, Kitayama J, Kodera Y

Oncology Vol. 98 ( 1 ) page： 48 - 52 2020.1

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

INTRODUCTION: Intraperitoneal (IP) chemotherapy is a promising treatment option for gastric cancer (GC) with peritoneal metastasis (PM). Recently, superiority of IP administration of paclitaxel (PTX) combined with S-1 and intravenous PTX over conventional systemic chemotherapy was suggested in a phase III study, although the difference in overall survival did not reach statistical significance in the primary analysis. Thus, attempts to combine IP PTX with other systemic therapies with higher efficacy are warranted. We designed a new regimen combining IP PTX with S-1 plus cisplatin (SP), which is regarded as the standard first-line treatment for metastatic GC in Japan, and subsequently carried out a dose-escalation study. METHODS: The combination was a 5-weekly regimen. IP PTX was to be administered on days 1, 8, and 22 with an initial dose of 15 mg/m2 at level 1 and 20 mg/m2 at level 2. S-1 was to be administered orally at a fixed dose of 80 mg/m2 b.i.d. for 21 days followed by a -14-day rest. Cisplatin was to be administered intravenously at a dose of 60 mg/m2 on day 8. Dose-limiting toxicities (DLTs) were defined as grade 4 leukopenia, grade 3 (G3) febrile neutropenia, G3 thrombocytopenia, and G3 nonhematological toxicity. RESULTS: A total of 9 patients with macroscopic PM were enrolled. No DLTs were observed among the 3 patients at level 1 and 6 patients at level 2. No adverse events or technical problems associated with the IP administration were observed. Consequently, the maximum-tolerated dose was not reached, and the dose for further clinical trials of IP PTX was determined as 20 mg/m2. As for efficacy, peritoneal lavage cytology turned negative after the first course in 4 of 7 patients who had positive cytology before treatment. CONCLUSION: The present study determined the dose for further clinical trials of IP PTX to be 20 mg/m2, when combined with the 5-weekly SP regimen.

DOI： 10.1159/000502484

Prognosis After Laparoscopic Gastrectomy in Patients with Pathological Stage II or III Gastric Cancer Who Were Preoperatively Diagnosed with Clinical Stage I: Propensity Score Matching Analysis of a Multicenter Dataset. Reviewed International journal

Yuki Ito, Mitsuro Kanda, Seiji Ito, Yoshinari Mochizuki, Hitoshi Teramoto, Kiyoshi Ishigure, Toshifumi Murai, Takahiro Asada, Akiharu Ishiyama, Hidenobu Matsushita, Chie Tanaka, Daisuke Kobayashi, Michitaka Fujiwara, Kenta Murotani, Yasuhiro Kodera

Annals of surgical oncology Vol. 27 ( 1 ) page： 268 - 275 2020.1

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

BACKGROUND: Laparoscopic gastrectomy (LG) is a standard approach for patients with clinical stage I gastric cancer in East Asia; however, following surgery, these patients may be pathologically diagnosed with stage II or III cancer. The prognosis of patients with gastric cancer migration from clinical stage I to pathological stage II or III after LG has not been completely clarified. METHODS: To compare the prognosis following LG and open gastrectomy (OG) in patients with pathological stage II or III gastric cancer who were preoperatively diagnosed with stage I cancer, we conducted a retrospective analysis using a multicenter dataset comprising details of 3480 patients who underwent gastrectomy between 2010 and 2014 at nine participating institutions. We used propensity score matching to reduce selection bias. RESULTS: After propensity score matching, 146 patients were finally selected. There were no significant differences in the number of dissected lymph nodes. Morbidity rates, length of postoperative hospital stay, and time between surgery and initiation of adjuvant chemotherapy were comparable between the two groups. Moreover, there were no significant differences in the overall, disease-specific, and relapse-free survival rates between the LG and OG groups. The LG group tended to have more patients with hematogenous recurrence, whereas the OG group tended to have more patients with peritoneal recurrence. CONCLUSIONS: Our multicenter dataset analysis indicated that the prognosis of patients with gastric cancer migration from clinical stage I to pathological stage II or III was independent of the surgical approach.

DOI： 10.1245/s10434-019-07781-2

Phase II study of capecitabine plus oxaliplatin (CapOX) as adjuvant chemotherapy for locally advanced rectal cancer (CORONA II). Reviewed

Norifumi Hattori, Goro Nakayama, Keisuke Uehara, Toshisada Aiba, Kiyoshi Ishigure, Eiji Sakamoto, Yuichiro Tojima, Mitsuro Kanda, Daisuke Kobayashi, Chie Tanaka, Suguru Yamada, Masahiko Koike, Michitaka Fujiwara, Masato Nagino, Yasuhiro Kodera

International journal of clinical oncology Vol. 25 ( 1 ) page： 118 - 125 2020.1

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

OBJECTIVE: This multicenter, single-arm phase II study (UMIN000008429) aimed to evaluate the efficacy and safety of capecitabine plus oxaliplatin (CapOX) as postoperative adjuvant chemotherapy for patients with locally advanced rectal cancer. METHODS: Patients with resectable clinical Stage II or III rectal cancer were enrolled to receive eight cycles of CapOX therapy (130 mg/m2 oxaliplatin on day 1 and 2000 mg/m2 oral capecitabine on days 1-14, every 3 weeks) after curative surgical resection. The primary endpoint was 3-year relapse-free survival (RFS) rate, and secondary endpoints were 3-year overall survival (OS) rate, treatment compliance, and safety. RESULTS: A total of 40 patients (Stage II, 21; Stage III, 19) were enrolled between September 2012 and November 2015 from seven institutions. Thirty-nine patients (97%) received R0 resection, and 32 patients (84%) received postoperative CapOX therapy. The completion rate of all eight cycles of CapOX therapy was 66%. Relative dose intensities were 87% for oxaliplatin and 84% for capecitabine. At a median follow-up period of 46 months, disease recurrence was observed in nine patients, including three with local recurrence. Three-year RFS and OS rates were 75% (95% CI 57-86%) and 96% (95% CI 80-99%), respectively. Frequencies of Grade ≥ 3 hematological and non-hematologic adverse events were 19% and 38%, respectively. CONCLUSION: CapOX therapy is feasible as adjuvant chemotherapy for locally advanced rectal cancer.

DOI： 10.1007/s10147-019-01546-3

Tumor size ≥50 mm as an Independent Prognostic Factor for Patients with Stage II or III Gastric Cancer After Postoperative S-1 Monotherapy: Analysis of a Multi-institution Dataset. Reviewed International journal

Masayuki Tsutsuyama, Mitsuro Kanda, Seiji Ito, Yoshinari Mochizuki, Hitoshi Teramoto, Kiyoshi Ishigure, Toshifumi Murai, Takahiro Asada, Akiharu Ishiyama, Hidenobu Matsushita, Chie Tanaka, Daisuke Kobayashi, Michitaka Fujiwara, Kenta Murotani, Yasuhiro Kodera

World journal of surgery Vol. 44 ( 1 ) page： 194 - 201 2020.1

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

BACKGROUND: Little is known about the changes in prognostic factors after adjuvant S-1 monotherapy has become widespread as a standard of care for patients with gastric cancer (GC) in East Asia. The present study compared prognostic factors of patients with stage II/III GC treated with or without S-1 adjuvant to formulate appropriate risk stratification strategies. METHODS: We designed a large multicenter dataset and retrospectively analyzed 847 patients with GC stage II or III, who underwent curative gastrectomy between 2010 and 2014. Clinicopathological features and prognostic factors were compared between the two patient groups: surgery-alone (n = 266) and S-1 adjuvant (n = 581). RESULTS: There were no significant differences in pathological tumor depths, nodal status, and disease stages between groups. Recurrence-free survival was significantly longer in the S-1 adjuvant group. For the surgery-alone group, independent prognostic factors were (in order of hazard ratio): (1) invasive growth, (2) high preoperative carcinoembryonic antigen levels, (3) total gastrectomy. For the S-1 adjuvant group, macroscopic tumor size (≥50 mm) was identified as another independent prognostic factor next only to pN2/3. There was overlap between the survival curves of patients with tumor size ≥50 mm in both groups. After receiving adjuvant S-1 monotherapy, ≥50 mm patients had significantly higher prevalence of peritoneal and lymph node metastasis as initial recurrences compared with <50 mm patients. CONCLUSIONS: Adjuvant S-1 monotherapy may alter listing of adverse prognostic factors of stage II and III patients. Macroscopic tumor size ≥50 mm may serve as an important determinant for risk stratification to identify patients who require more intensive treatment.

DOI： 10.1007/s00268-019-05198-2

食道亜全摘術後の肺炎発生予測因子の検討 Reviewed

神田光郎, 小池聖彦, 清水大, 田中千恵, 小林大介, 園原史訓, 猪川祥邦, 高見秀樹, 服部憲史, 林真路, 山田豪, 中山吾郎, 藤原道隆, 小寺泰弘

日本消化管学会雑誌 Vol. 4 ( Suppl. ) page： 303 - 303 2020.1

Characteristics of Lung Metastasis as an Initial Recurrence Pattern After Curative Resection of Pancreatic Cancer Reviewed

Morimoto Daishi, Yamada Suguru, Sonohara Fuminori, Takami Hideki, Hayashi Masamichi, Kanda Mitsuro, Tanaka Chie, Kobayashi Daisuke, Nakayama Goro, Koike Masahiko, Fujiwara Michitaka, Fujii Tsutomu, Kodera Yasuhiro

PANCREAS Vol. 49 ( 5 ) page： 699 - 705 2020

Chromobox 2 Expression Predicts Prognosis After Curative Resection of Oesophageal Squamous Cell Carcinoma Reviewed

Ueda Sei, Kanda Mitsuro, Sato Yusuke, Baba Hayato, Nakamura Shunsuke, Sawaki Koichi, Shimizu Dai, Motoyama Satoru, Fujii Tsutomu, Kodera Yasuhiro, Nomoto Shuji

CANCER GENOMICS & PROTEOMICS Vol. 17 ( 4 ) page： 391 - 400 2020

STRA6 Expression Serves as a Prognostic Biomarker of Gastric Cancer Reviewed

Nakamura Shunsuke, Kanda Mitsuro, Shimizu Dai, Sawaki Kouichi, Tanaka Chie, Hattori Norifumi, Hayashi Masamichi, Yamada Suguru, Nakayama Goro, Omae Kenji, Koike Masahiko, Kodera Yasuhiro

CANCER GENOMICS & PROTEOMICS Vol. 17 ( 5 ) page： 509 - 516 2020

The Preoperative Prognostic Nutritional Index Predicts Short-Term and Long-Term Outcomes of Patients with Stage II/III Gastric Cancer: Analysis of a Multi-Institution Dataset. International journal

Sasahara M, Kanda M, Ito S, Mochizuki Y, Teramoto H, Ishigure K, Murai T, Asada T, Ishiyama A, Matsushita H, Tanaka C, Kobayashi D, Fujiwara M, Murotani K, Kodera Y

Digestive surgery Vol. 37 ( 2 ) page： 135 - 144 2020

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

BACKGROUND/AIMS: Identification of nutritional indicators to predict short-term and long-term outcomes is necessary to provide appropriate treatment to patients with gastric cancer. METHODS: We designed an analysis of a multicenter dataset of patients with gastric cancer who underwent gastrectomy between 2010 and 2014. We enrolled 842 eligible patients who had stage II/III gastric cancer. The area under the curve (AUC) values were compared among prognostic nutritional index (PNI), calculated as 10 × albumin g/dL + 0.005 × total lymphocyte count/mm3, and its constituents, and the predictive value of preoperative PNI for postoperative short-term and long-term outcomes was evaluated. RESULTS: Preoperative PNI exhibited higher AUC values (0.719) for 1-year survival than its constituents, and the optimal cutoff value was 47. The disease-free and overall survival of patients in the PNI-low group were significantly shorter compared with those in the PNI-high group. The prognostic difference between the PNI-high and PNI-low groups was significantly greater in the subgroup of patients who underwent total gastrectomy. Clinically relevant postoperative complications were more frequently observed in the PNI-low group. CONCLUSIONS: The preoperative PNI is a useful predictor reflecting the incidence of complications after gastrectomy and the prognosis of patients with stage II/III gastric cancer.

DOI： 10.1159/000497454

ASO Author Reflections: Homeobox C10 Influences on the Malignant Phenotype of Gastric Cancer Cell Lines and its Elevated Expression Positively Correlates with Recurrence and Poor Survival Reviewed

Miwa Takashi, Kanda Mitsuro

ANNALS OF SURGICAL ONCOLOGY Vol. 26 ( Suppl 3 ) page： S596 - S597 2019.12

ASO Author Reflections: Increased Expression of DNAJC12 is Associated with Aggressive Phenotype of Gastric Cancer Reviewed

Uno Yasuo, Kanda Mitsuro

ANNALS OF SURGICAL ONCOLOGY Vol. 26 ( Suppl 3 ) page： S592 - S593 2019.12

Modified Systemic Inflammation Score is Useful for Risk Stratification After Radical Resection of Squamous Cell Carcinoma of the Esophagus. Reviewed International journal

Kanda M, Koike M, Tanaka C, Kobayashi D, Hattori N, Hayashi M, Yamada S, Omae K, Fujiwara M, Kodera Y

Annals of surgical oncology Vol. 26 ( 13 ) page： 4773 - 4781 2019.12

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

BACKGROUND: Inflammation plays a critical role in the development and progression of cancers. We evaluated the clinical significance of the preoperative modified systemic inflammation score (mSIS) to predict long-term outcomes of patients with esophageal squamous cell carcinoma (ESCC). METHODS: We included 443 patients who underwent curative resection of ESCC. The mSIS was formulated according to the serum albumin level (ALB) and lymphocyte-to-monocyte ratio (LMR) as follows: mSIS 0 (ALB ≥ 4.0 g/dL and LMR ≥ 3.4), mSIS 1 (ALB < 4.0 g/dL or LMR < 3.4), and mSIS 2 (ALB < 4.0 g/dL and LMR < 3.4). RESULTS: Patients were categorized into preoperative mSIS 0 (n = 165), mSIS 1 (n = 183), and mSIS 2 (n = 95) groups. Preoperative mSIS was significantly associated with age, preoperative body mass index, and pathological disease stage. The disease-specific survival times of patients in preoperative mSIS 0, 1, and 2 sequentially shortened (P = 0.009), and mSIS 2 was identified as an independent prognostic factor (hazard ratio 2.63, 95% confidence interval 1.33-5.27, P = 0.0053). In most patient subgroups, the mSIS was associated with greater risk of disease-specific death. A stepwise increase in the prevalence of hematogenous recurrences was directly proportion to the mSIS. When patients were subdivided by mSIS before neoadjuvant treatment, there were no significant differences in disease-specific survival. CONCLUSIONS: Our findings demonstrate that the preoperative mSIS may serve as a powerful prognosticator of ESCC that definitively stratifies clinical outcomes as well as a tool for selecting treatment strategies.

DOI： 10.1245/s10434-019-07914-7

ミラーイメージはカメラを180度回転させると操作が容易になる Reviewed

砂川祐輝, 山田豪, 園原史訓, 猪川祥邦, 高見秀樹, 林真路, 神田光郎, 田中千恵, 小林大介, 中山吾郎, 小池聖彦, 藤原道隆, 小寺泰弘

日本内視鏡外科学会雑誌 Vol. 24 ( 7 ) page： SF029 - 4 2019.12

腹腔鏡下手術による膵体尾部切除術後の門脈・脾静脈血栓症に対する影響 Reviewed

山田豪, 園原史訓, 高見秀樹, 猪川祥邦, 林真路, 神田光郎, 小林大介, 田中千恵, 中山吾郎, 小池聖彦, 藤原道隆, 小寺泰弘

日本内視鏡外科学会雑誌 Vol. 24 ( 7 ) page： MO180 - 5 2019.12

食道癌FP療法によるRenal Salt-Wasting Syndromeの2例 Reviewed

梅田晋一, 神田光郎, 小池聖彦, 清水大, 田中千恵, 小林大介, 園原史訓, 高見秀樹, 猪川祥邦, 服部憲史, 林真路, 山田豪, 中山吾郎, 藤原道隆, 小寺泰弘

日本臨床外科学会雑誌 Vol. 80 ( 12 ) page： 2312 - 2312 2019.12

Comparison of non-invasive liver reserve and fibrosis models: implications for surgery and prognosis for hepatocellular carcinoma. Reviewed International journal

Sonohara F, Yamada S, Tanaka N, Tashiro M, Sunagawa Y, Morimoto D, Tanaka H, Takami H, Hayashi M, Kanda M, Tanaka C, Kobayashi D, Nakayama G, Koike M, Fujiwara M, Kodera Y

Hepatology research : the official journal of the Japan Society of Hepatology Vol. 49 ( 11 ) page： 1305 - 1315 2019.11

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

AIM: This study aimed to assess the clinical utility of preoperative evaluation of liver fibrosis using platelet-albumin-bilirubin (PALBI) grade, Fibrosis-4 index (FIB-4), and aspartate transaminase-to-platelet ratio index (APRI) for hepatocellular carcinoma (HCC) patients and explore the clinical impact of these models with regard to perioperative risks and HCC prognosis. METHODS: Between January 2003 and December 2018, 305 consecutive patients who underwent hepatectomy for HCC were enrolled. RESULTS: The APRI showed the most robust diagnostic performance through each fibrosis stage among three models (PALBI, FIB-4, and APRI): fibrosis stage 3 (f3), area under the curve [AUC] = 0.55, 0.72, and 0.76; and f4, AUC = 0.51, 0.71, and 0.76, respectively). In addition, survival analysis revealed that all three models were significantly associated with HCC prognosis. PALBI (grade 1 vs. 2, 3): recurrence-free survival (RFS): median survival time (MST), 34 vs. 17 months, 0.007; overall survival (OS): MST, 115 vs. 68, 0.02. FIB-4 (grade 1, 2 vs. 3): RFS: MST, 34 vs. 22, 0.004, OS: MST, 120 vs. 63, 0.0001. APRI (grade 1, 2 vs. 3), RFS: MST, 30 vs. 20, 0.0005; OS: MST, 107 vs. 55, 0.0003. Among three scoring systems, only PALBI grade was significantly associated with both operative time (median, 303 vs. 340 min, 0.01) and intraoperative blood loss (median, 581 vs. 859 mL, 0.03). CONCLUSIONS: This study showed robust performances of selected liver reserve and fibrosis models to predict HCC prognosis. Of them, PALBI might be used for assessing perioperative risks for hepatectomy for HCC.

DOI： 10.1111/hepr.13400

Expression, Function, and Prognostic Value of MAGE-D4 Protein in Esophageal Squamous Cell Carcinoma. Reviewed International journal

Uno Y, Kanda M, Sato Y, Shimizu D, Umeda S, Hattori N, Hayashi M, Tanaka C, Kobayashi D, Yamada S, Nakayama G, Motoyama S, Koike M, Kodera Y

Anticancer research Vol. 39 ( 11 ) page： 6015 - 6023 2019.11

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

BACKGROUND/AIM: We previously reported that expression of melanoma-associated antigen (MAGE)-D4 mRNA was a prognostic factor for esophageal squamous cell carcinoma (ESCC). The aim of this study was to validate the expression of MAGE-D4 in two additional patient cohorts, and to investigate its biological functions. MATERIALS AND METHODS: The role of MAGE-D4 in cell proliferation, adhesion, and migration was determined by gene knockdown experiments in the KYSE590 cell line. MAGE-D4 protein expression was analyzed in ESCC tissues by immunohistochemistry. A second validation cohort consisted of an ESCC mRNA dataset from The Cancer Genome Atlas. RESULTS: Knockdown of MAGE-D4 significantly decreased cell proliferation and migration. Expression of MAGE-D4 protein was significantly associated with disease-free survival. In the second validation cohort, high MAGE-D4 mRNA expression was associated with significantly shorter overall survival and disease-free survival. CONCLUSION: MAGE-D4 plays an important role in the malignant behavior of ESCC. MAGE-D4 was validated as a prognostic indicator in two independent ESCC patient cohorts.

DOI： 10.21873/anticanres.13807

PRAME Expression as a Potential Biomarker for Hematogenous Recurrence of Esophageal Squamous Cell Carcinoma. Reviewed International journal

Hayato Baba, Mitsuro Kanda, Koichi Sawaki, Dai Shimizu, Shinichi Umeda, Masahiko Koike, Yasuhiro Kodera, Tsutomu Fujii

Anticancer research Vol. 39 ( 11 ) page： 5943 - 5951 2019.11

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

BACKGROUND/AIM: To investigate the function of preferentially expressed antigen of melanoma (PRAME) in esophageal squamous cell carcinoma (ESCC). MATERIALS AND METHODS: mRNA expression levels of PRAME were analyzed in resected esophageal tissues of 150 ESCC patients and correlated with clinicopathological parameters. We also investigated the potential function of PRAME by analyzing coordinately expressed genes in 13 ESCC cell lines. RESULTS: RT-qPCR analysis of clinical samples revealed aberrantly high PRAME expression in tumors compared with normal esophageal tissues. High PRAME expression was significantly associated with shorter disease-specific survival and hematogenous recurrence, but not with overall recurrence. The cumulative incidence of hematogenous recurrence was significantly greater for patients with high compared to those with low PRAME expression. In vitro, PCR array analysis revealed that PRAME was coordinately expressed with EGFR, ITGB, and TCF3. CONCLUSION: PRAME is overexpressed in ESCC tissues and may serve as a novel biomarker for predicting hematogenous recurrence.

DOI： 10.21873/anticanres.13799

The levels of SYT13 and CEA mRNAs in peritoneal lavages predict the peritoneal recurrence of gastric cancer. Reviewed

Nakanishi K, Kanda M, Umeda S, Tanaka C, Kobayashi D, Hayashi M, Yamada S, Kodera Y

Gastric cancer : official journal of the International Gastric Cancer Association and the Japanese Gastric Cancer Association Vol. 22 ( 6 ) page： 1143 - 1152 2019.11

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

BACKGROUND: Although peritoneal lavage cytology often serves as a sensitive method to detect free cancer cells in the abdominal cavity, some patients experience peritoneal recurrence despite negative cytology. The aim of this study was to evaluate mRNAs in peritoneal lavage fluid as potential markers for predicting the peritoneal recurrence of gastric cancer (GC). METHODS: Peritoneal lavage fluid samples were obtained during surgery conducted on 187 patients with GC and from 30 patients with non-malignant disease (controls). The mRNA levels of nine candidate markers were quantified, and analysis of a receiver-operating characteristic curve compared their accuracies. The cutoff was defined as the highest value of the controls. RESULTS: Synaptotagmin XIII (SYT13) and carcinoembryonic antigen (CEA) mRNA levels were analyzed further. SYT13 levels were significantly associated with shorter peritoneal recurrence-free survival (PRFS) and overall survival. Among patients with negative peritoneal lavage cytology, those positive for either SYT13 or CEA mRNA experienced significantly shorter peritoneal recurrence-free survival compared with those with negative fluid (hazards ratio [HR] 4.21, P = 0.0114; HR 3.53; P = 0.0426, respectively). Univariate analysis revealed that SYT13 and CEA mRNA levels were significant predictors of peritoneal recurrence. Positive levels of both SYT13 and CEA mRNA demonstrated the highest HR for peritoneal recurrence (HR 12.27, P = 0.0064). Multivariable analysis revealed that SYT13 positivity was a significant independent prognostic factor (HR 3.69; 95% confidence interval, 1.18-12.74; P = 0.0246). CONCLUSIONS: Combined measurement of SYT13 and CEA mRNA levels in peritoneal lavage fluid could serve as a promising approach to predict peritoneal recurrence of GC.

DOI： 10.1007/s10120-019-00967-3

Delay in initiation of postoperative adjuvant chemotherapy with S-1 monotherapy and prognosis for gastric cancer patients: analysis of a multi-institutional dataset. Reviewed

Nakanishi K, Kanda M, Ito S, Mochizuki Y, Teramoto H, Ishigure K, Murai T, Asada T, Ishiyama A, Matsushita H, Tanaka C, Kobayashi D, Fujiwara M, Murotani K, Kodera Y

Gastric cancer : official journal of the International Gastric Cancer Association and the Japanese Gastric Cancer Association Vol. 22 ( 6 ) page： 1215 - 1225 2019.11

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

BACKGROUND: This study aimed to evaluate whether the timing of initiating postoperative chemotherapy with S-1 monotherapy affects gastric cancer patients' prognosis. METHODS: A multi-institution dataset identified patients with pStage II or III gastric cancer who received S-1 monotherapy for over 6 months after curative resection between 2010 and 2014. Patients were divided into three groups based on the timing of S-1 monotherapy initiation. Prognostic factors for relapse-free survival (RFS) were investigated. RESULTS: We classified 401 patients into groups as follows: S-1 administered within 6 weeks (n = 247), between 6 and 8 weeks (n = 95), and after 8 weeks (n = 59). The RFS times were not significantly different in the within 6 weeks group and the between 6 and 8 weeks group, but the after 8 weeks group had a shorter RFS time compared with the other two groups (within 6 weeks group vs. after 8 weeks group; P = 0.0044). By disease stage, this trend was the same. The multivariable analysis showed that a larger tumor size (≥ 50 mm), pStage III, and the after 8 weeks group were independent prognostic factors for RFS (after 8 weeks group: hazard ratio, 2.05; P = 0.0069). The prevalence of hematogenous metastasis as the initial recurrence site increased by delayed initiation of S-1. A forest plot revealed that delayed administration after 8 weeks was associated with a greater risk of recurrence in most subgroups. CONCLUSIONS: Postoperative chemotherapy with S-1 monotherapy for gastric cancer is recommended to begin within 8 weeks after surgery.

DOI： 10.1007/s10120-019-00961-9

Level of Melanotransferrin in Tissue and Sera Serves as a Prognostic Marker of Gastric Cancer. Reviewed International journal

Sawaki K, Kanda M, Umeda S, Miwa T, Tanaka C, Kobayashi D, Hayashi M, Yamada S, Nakayama G, Omae K, Koike M, Kodera Y

Anticancer research Vol. 39 ( 11 ) page： 6125 - 6133 2019.11

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

AIM: The aim of the study was to identify novel biomarkers that are vital for improving management of patients with gastric cancer (GC). MATERIALS AND METHODS: An RNA-sequencing analysis was conducted using gastric tissue from patients with metastatic GC. In vitro cell functions were evaluated by siRNA-mediated knockdown assays. A total of 230 pairs of gastric tissue were subjected to expression analysis of mRNA and protein in situ. The serum levels of the candidate biomarker were determined by ELISA. RESULTS: MELTF was identified as a candidate biomarker. Inhibition of MELTF expression suppressed the invasion ability of GC cells. Increased tissue MELTF mRNA expression was associated with shorter survival. Furthermore, staining intensity of tissue MELTF protein was linked to recurrence rates. Serum MELTF levels gradually were increased from healthy controls to advanced GC. Patients with high serum MELTF levels had poor prognosis. CONCLUSION: Both tissue and serum MELTF levels may serve as biomarkers of GC progression.

DOI： 10.21873/anticanres.13820

Tissue Expression of Melanoma-associated Antigen A6 and Clinical Characteristics of Gastric Cancer. Reviewed International journal

Endo M, Kanda M, Sawaki K, Shimizu D, Tanaka C, Kobayashi D, Hattori N, Hayashi M, Yamada S, Koike M, Omae K, Kodera Y

Anticancer research Vol. 39 ( 11 ) page： 5903 - 5910 2019.11

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

BACKGROUND: Gastric cancer (GC) exhibits heterogeneous clinical and molecular features, requiring the development of new biomarkers to further understand this disease. Our transcriptomic analysis detected overexpression of melanoma-associated antigen A6 (MAGEA6) in metastatic GC, leading us to determine the clinical significance of MAGEA6 in GC. MATERIALS AND METHODS: Fourteen GC cell lines and 230 pairs of surgically resected gastric tissues were subjected to mRNA expression analysis. Polymerase chain reaction array analysis was performed to identify coordinately expressed cancer-related genes, and immunohistochemistry (IHC) was used to detected MAGEA6 expression in situ. RESULTS: MAGEA6 mRNA levels were positively correlated with the expression of matrix metallopeptidase 9 mRNA. MAGEA6 mRNA levels were higher in GC tissues compared with those in normal adjacent tissues. Patients with high MAGEA6 expression had significantly worse prognosis. MAGEA6 protein levels in primary lesions predicted the likelihood of recurrence. CONCLUSION: Overexpression of MAGEA6 in GC tissues represents a promising biomarker for assessing the malignant phenotype of GC.

DOI： 10.21873/anticanres.13794

妊娠を契機に急速増大を来したMCNと術前診断した膵リンパ管腫の一切除例 Reviewed

加藤吉康, 山田豪, 高見秀樹, 園原史訓, 猪川祥邦, 林真路, 服部憲史, 神田光郎, 小林大介, 田中千恵, 中山吾郎, 小池聖彦, 藤原道隆, 小寺泰弘

日本消化器病学会東海支部例会プログラム抄録集 Vol. 131回 page： 75 - 75 2019.11

胃原発mixed adenoneuroendocrine carcinomaの1例 Reviewed

荘加道太, 清水大, 栗本景介, 園原史訓, 猪川祥邦, 高見秀樹, 服部憲史, 林真路, 神田光郎, 田中千恵, 小林大介, 山田豪, 中山吾郎, 小池聖彦, 小寺泰弘

日本消化器病学会東海支部例会プログラム抄録集 Vol. 131回 page： 59 - 59 2019.11

分子生物学的手法を応用した微小腹腔内遊離胃癌細胞検出法 Reviewed

中西香企, 神田光郎, 梅田晋一, 田中千恵, 小林大介, 林真路, 服部憲史, 高見秀樹, 園原史訓, 山田豪, 中山吾郎, 小池聖彦, 藤原道隆, 小寺泰弘

日本消化器外科学会雑誌 Vol. 52 ( Suppl.2 ) page： 102 - 102 2019.11

Feasibility of subtotal esophagectomy with systematic lymphadenectomy in selected elderly patients with esophageal cancer; a propensity score matching analysis. Reviewed International journal

Kanda M, Koike M, Tanaka C, Kobayashi D, Hayashi M, Yamada S, Nakayama G, Omae K, Kodera Y

BMC surgery Vol. 19 ( 1 ) page： 143 - 143 2019.10

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

BACKGROUND: The global increase in elderly populations is accompanied by an increasing number of candidates for esophagectomy. Here we aimed to determine the postoperative outcomes after subtotal esophagectomy in elderly patients with esophageal cancer. METHODS: Patients (n = 432) with who underwent curative-intent transthoracic subtotal esophagectomy with 2- or 3-field lymphadenectomies for thoracic esophageal cancer were classified as follows: non-elderly (age < 75 years, n = 373) and elderly (age ≥ 75 years, n = 59) and groups. To balance the essential variables including neoadjuvant treatment and stage of progression, we conducted propensity score analysis, and clinical characteristics, perioperative course and prognosis were compared. RESULTS: After two-to-one propensity score matching, 100 and 50 patients were classified in the non-elderly and elderly groups. The elderly group had more comorbidities and lower preoperative cholinesterase activities and prognostic nutrition indexes. Although incidences of postoperative pneumonia, arrhythmia and delirium were slightly increased in the elderly group, no significant differences were observed in overall incidence of postoperative complications, rates of repeat surgery and death caused by surgery, and length of postoperative hospital stay between the two groups. There were no significant differences in disease-free and disease-specific survival as well as overall survival between the two groups. CONCLUSION: Older age (≥75 years) had limited impact on morbidity, disease recurrence, and survival after subtotal esophagectomy. Therefore, age should not prevent older patients from benefitting from surgery.

DOI： 10.1186/s12893-019-0617-2

Novel implications of combined arterial resection for locally advanced pancreatic cancer in the era of newer chemo-regimens. Reviewed International journal

Sonohara F, Yamada S, Takami H, Hayashi M, Kanda M, Tanaka C, Kobayashi D, Nakayama G, Koike M, Fujiwara M, Fujii T, Kodera Y

European journal of surgical oncology : the journal of the European Society of Surgical Oncology and the British Association of Surgical Oncology Vol. 45 ( 10 ) page： 1895 - 1900 2019.10

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

INTRODUCTION: In this study, we assessed the prognostic efficacy and feasibility of combined arterial resection (AR) for locally advanced pancreatic cancer (LAPC), and aimed to identify significant prognostic factors for patients who underwent combined AR. METHODS: Between 1981 and 2018, 733 consecutive patients who underwent pancreatic surgery for PC were identified. The 730 cases with detailed information were enrolled in the analysis. RESULTS: Among 730 resected PC patients, 44 (6%) underwent AR including 21 hepatic (48%), 12 celiac (27%), five splenic (12%), four superior mesenteric (9%), and two other arteries (4%). The combined AR surgery showed significantly longer operative time (median, 608 vs 451 min, P < 0.0001), and the incidence of intraoperative blood transfusion was significantly higher in AR than surgery without AR (P = 0.0002), whereas there was no significant difference in the intraoperative blood loss (970 vs 1200 mL, P = 0.2) and occurrence of major complications (P = 0.5). In prognostic analysis of AR cases, multivariate Cox proportional hazard models revealed preoperative and postoperative therapy were the independent factors for both recurrence-free survival (RFS) and overall survival (OS) (preoperative therapy: RFS, HR = 0.21, P = 0.007; OS, HR = 0.18, P = 0.01; postoperative therapy: RFS, HR = 0.31, P = 0.003; OS, HR = 0.19, P = 0.002). CONCLUSION: This study showed the feasibility of combined AR for LAPC and robust association of pre- and postoperative therapy and survival after AR surgery. Preoperative therapy following combined AR surgery is potentially powerful strategy for LAPC.

DOI： 10.1016/j.ejso.2019.05.019

Risk Prediction of Postoperative Pneumonia After Subtotal Esophagectomy Based on Preoperative Serum Cholinesterase Concentrations. Reviewed International journal

Kanda M, Koike M, Tanaka C, Kobayashi D, Hayashi M, Yamada S, Omae K, Kodera Y

Annals of surgical oncology Vol. 26 ( 11 ) page： 3718 - 3726 2019.10

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

BACKGROUND: Patients undergoing subtotal esophagectomy for esophageal cancer frequently experience postoperative pneumonia. Development of preoperatively determined predictors for postoperative pneumonia will facilitate identifying high-risk patients and will assist with informing patients about their risk of postoperative pneumonia, enabling physicians to estimate with greater accuracy, will result in tailoring perioperative management. METHODS: Postoperative pneumonia was defined according to the revised Uniform Pneumonia Score. We analyzed the data for 355 patients to compare 32 potential predictive variables associated with postoperative pneumonia after subtotal esophagectomy. RESULTS: Forty-one patients (11.5%) had postoperative pneumonia. Preoperative cholinesterase (ChE) concentrations demonstrated the greatest area under the curve value (0.662) to predict postoperative pneumonia (optimal cutoff value = 217 IU/l). Univariate analysis identified a continuous value of preoperative ChE concentration as a significant risk factor for postoperative pneumonia (P = 0.0014). Multivariable analysis using factors potentially relevant to pneumonia revealed that preoperative ChE concentration was one of independent risk factors for pneumonia after esophagectomy (P = 0.008). Patients with low ChE concentrations were at increased risk of postoperative pneumonia in most patient subgroups. Moreover, the odds ratios of low ChE concentrations were highest in patients undergoing neoadjuvant treatment. A combination of preoperative serum ChE concentrations and Brinkman index stratified patients into low, intermediate, and high risk of postoperative pneumonia. CONCLUSIONS: Our findings indicate that preoperative ChE concentrations, particularly in combination with Brinkman index, may serve simply as a determined predictor of pneumonia after subtotal esophagectomy and may facilitate physicians' efforts to reduce the incidence of postoperative pneumonia.

DOI： 10.1245/s10434-019-07512-7

Conversion Surgery施行例の予後因子から検討した切除不能胃癌に対する集学的治療戦略 Reviewed

小林大介, 神田光郎, 田中千恵, 清水大, 園原史訓, 猪川祥邦, 高見秀樹, 服部憲史, 林真路, 山田豪, 中山吾郎, 小池聖彦, 藤原道隆, 小寺泰弘

日本癌治療学会学術集会抄録集 Vol. 57回 page： RT21 - 5 2019.10

DNAJC12の胃癌における役割についての検討 Reviewed

宇野泰朗, 神田光郎, 清水大, 田中千恵, 小林大介, 園原史訓, 服部憲史, 高見秀樹, 林真路, 山田豪, 中山吾郎, 小池聖彦, 藤原道隆, 小寺泰弘

日本癌治療学会学術集会抄録集 Vol. 57回 page： O7 - 4 2019.10

トランスレーショナルリサーチについて考える:臨床現場のアイデアをどう生かすか消化器外科医ならではの創薬シーズを求めて Reviewed

神田光郎, 清水大, 田中千恵, 小林大介, 園原史訓, 猪川祥邦, 高見秀樹, 服部憲史, 林真路, 山田豪, 中山吾郎, 小池聖彦, 藤原道隆, 小寺泰弘

日本臨床外科学会雑誌 Vol. 80 ( 増刊 ) page： 360 - 360 2019.10

胃癌におけるETNK2のアポトーシスへの関与と肝転移形成の関連性 Reviewed

三輪高嗣, 神田光郎, 田中千恵, 小林大介, 園原史訓, 高見秀樹, 清水大, 服部憲史, 林真路, 山田豪, 中山吾郎, 小池聖彦, 藤原道隆, 小寺泰弘

日本癌治療学会学術集会抄録集 Vol. 57回 page： O8 - 3 2019.10

日本のAYA世代のがん対策の方向性を読み解く Reviewed

栗本景介, 堀部敬三, 園原史訓, 猪川祥邦, 高見秀樹, 林真路, 神田光郎, 小林大介, 田中千恵, 山田豪, 中山吾郎, 小池聖彦, 清水千佳子, 高橋義行, 小寺泰弘

日本癌治療学会学術集会抄録集 Vol. 57回 page： P166 - 5 2019.10

切除不能進行再発胃癌に対するnivolumab療法における好中球/リンパ球比の臨床的意義 Reviewed

小林大介, 清水大, 神田光郎, 田中千恵, 園原史訓, 猪川祥邦, 高見秀樹, 服部憲史, 林真路, 山田豪, 中山吾郎, 小池聖彦, 藤原道隆, 小寺泰弘

日本臨床外科学会雑誌 Vol. 80 ( 増刊 ) page： 506 - 506 2019.10

胃癌のおけるS-1術後補助化学療法開始時期と予後との関係多施設統合データベース Reviewed

中西香企, 神田光郎, 伊藤誠二, 望月能成, 寺本仁, 石榑清, 村井俊文, 浅田崇洋, 石山聡治, 松下英信, 田中千恵, 小林大介, 藤原道隆, 小寺泰弘

日本癌治療学会学術集会抄録集 Vol. 57回 page： O56 - 1 2019.10

開腹・開胸手術のメリット・デメリットについて考える開胸アプローチを活用する食道癌治療戦略開胸のメリットは再建にあり? Reviewed

小池聖彦, 佐藤雄介, 園原史訓, 清水大, 高見秀樹, 猪川祥邦, 服部憲史, 林真路, 神田光郎, 小林大介, 田中千恵, 山田豪, 中山吾郎, 藤原道隆, 小寺泰弘

日本臨床外科学会雑誌 Vol. 80 ( 増刊 ) page： 351 - 351 2019.10

長期予後が得られた症例1(上部消化管) HER2陽性切除不能進行胃癌に対するtrastuzumab療法とconversion surgeryによる集学的治療 Reviewed

佐藤敏, 小林大介, 清水大, 神田光郎, 田中千恵, 園原史訓, 猪川祥邦, 高見秀樹, 服部憲史, 林真路, 山田豪, 中山吾郎, 小池聖彦, 藤原道隆, 小寺泰弘

日本臨床外科学会雑誌 Vol. 80 ( 増刊 ) page： 404 - 404 2019.10

英文論文について考える:方法論・重要性を中心に臨床外科医が英文論文を書く際の最初のハードルを越える定型化と剽窃回避 Reviewed

神田光郎, 清水大, 田中千恵, 小林大介, 園原史訓, 猪川祥邦, 高見秀樹, 服部憲史, 林真路, 山田豪, 中山吾郎, 小池聖彦, 藤原道隆, 小寺泰弘

日本臨床外科学会雑誌 Vol. 80 ( 増刊 ) page： 346 - 346 2019.10

腹腔鏡下胃切除術におけるIndocyanine Green蛍光法を用いた病変位置同定方法 Reviewed

田中千恵, 神田光郎, 林真路, 服部憲史, 小林大介, 山田豪, 中山吾郎, 小池聖彦, 藤原道隆, 小寺泰弘

日本臨床外科学会雑誌 Vol. 80 ( 増刊 ) page： 472 - 472 2019.10

胃癌根治切除術後S-1補助化学療法の忍容性予測因子の検討 Reviewed

三輪高嗣, 神田光郎, 田中千恵, 小林大介, 園原史訓, 高見秀樹, 服部憲史, 猪川祥邦, 林真路, 山田豪, 中山吾郎, 小池聖彦, 藤原道隆, 小寺泰弘

日本臨床外科学会雑誌 Vol. 80 ( 増刊 ) page： 570 - 570 2019.10

Incorporating molecular biomarkers into clinical practice for gastric cancer. Reviewed International journal

Shunsuke Nakamura, Mitsuro Kanda, Yasuhiro Kodera

Expert review of anticancer therapy Vol. 19 ( 9 ) page： 757 - 771 2019.9

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

Introduction: Gastric cancer is one of the most common causes of cancer-related mortality worldwide. To improve clinical outcomes, it is critical to develop appropriate approaches to diagnosis and treatment. Biomarkers have numerous potential clinical applications, including screening, assessing risk, determining prognosis, monitoring recurrence, and predicting response to treatment. Furthermore, biomarkers may contribute to the development of effective therapies. Areas covered: Here we review recent progress in exploiting GC-specific biomarkers such as protein-coding genes, microRNAs, long noncoding RNAs, and methylated gene promoters. Expert opinion: The development of biomarkers for diagnosing and monitoring gastric cancer and for individualizing therapeutic targets shows great promise for improving gastric cancer management.

DOI： 10.1080/14737140.2019.1659136

Biological and conditional factors should be included when defining criteria for resectability for patients with pancreatic cancer. International journal

Kato Y, Yamada S, Tashiro M, Sonohara F, Takami H, Hayashi M, Kanda M, Kobayashi D, Tanaka C, Nakayama G, Koike M, Fujiwara M, Kodera Y

HPB : the official journal of the International Hepato Pancreato Biliary Association Vol. 21 ( 9 ) page： 1211 - 1218 2019.9

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

BACKGROUND: This study aimed to evaluate novel resectability criteria for pancreatic ductal adenocarcinoma (PDAC) proposed by the International Association of Pancreatology (IAP) by comparing them with the National Comprehensive Cancer Network (NCCN) guidelines. METHODS: 369 patients who underwent upfront surgery for PDAC were retrospectively analyzed. Overall survival (OS) of each group as defined by either of the guidelines were compared and preoperative prognostic factors for OS were identified. RESULTS: Based on the IAP-criteria, 157 patients were classified as resectable (R), 192 as borderline resectable (BR) and 20 as unresectable (UR), with the median survival time (MST) of 40 months, 17 and 11, respectively. In contrast to the NCCN-criteria, BR demonstrated significantly better OS than UR (P = 0.023) under the IAP-criteria. Performance status ≥2 (hazard ratio [HR]: 2.47, P = 0.014) and lymph node metastasis suspected by imaging (HR: 1.55, P = 0.003) were identified as independent prognostic factors by the multivariate analysis along with portal or arterial invasion, while carbohydrate antigen 19-9 ≥ 500 U/ml was not (HR: 1.23, P = 0.190). CONCLUSION: The IAP-criteria, which includes biological and conditional factors, resulted in superior separation of survival curves stratified by the resectablity when compared with the NCCN-criteria.

DOI： 10.1016/j.hpb.2019.01.012

Multi-institutional analysis of the prognostic significance of postoperative complications after curative resection for gastric cancer. Reviewed International journal

Mitsuro Kanda, Seiji Ito, Yoshinari Mochizuki, Hitoshi Teramoto, Kiyoshi Ishigure, Toshifumi Murai, Takahiro Asada, Akiharu Ishiyama, Hidenobu Matsushita, Chie Tanaka, Daisuke Kobayashi, Michitaka Fujiwara, Kenta Murotani, Yasuhiro Kodera

Cancer medicine Vol. 8 ( 11 ) page： 5194 - 5201 2019.9

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

BACKGROUND: Insufficient data are available on the prognostic significance of complications after resection of gastric cancer. Therefore, we aimed to assess this gap in our knowledge by studying patients with resectable gastric cancer. METHODS: A multi-institutional retrospective database comprising clinical information of 3575 patients who received resection of gastric cancer from 2010 to 2014 at nine institutions. Grades 2 or greater complications of the Clavien-Dindo classification were judged as clinically relevant postoperative complications, and their associations with postoperative survival were assessed. We assessed the effect of complications on times of initiation and continuation of postoperative adjuvant chemotherapy by S-1. RESULTS: A total of 2954 patients were included in the analysis. Clinically relevant postoperative complications occurred in 664 (23%) patients. Patients' recurrence-free survival rate incrementally decreased as the grade of complications became greater. Patients with abdominal complications (eg, leakage of pancreatic fluids, intra-abdominal abscess, and anastomotic leakage) and those with nonabdominal complications (eg, pneumonia) experienced worse recurrence-free survival compared to those without complications. Patients who had complications were generally at greater risk of disease recurrence, except for those who underwent laparoscopic surgery and those with pathological stage I. Delayed initiation and shorter continuation of adjuvant S-1 chemotherapy was experienced by patients with postoperative complications. CONCLUSIONS: Postoperative complications adversely affected the prognosis in patients with resectable gastric cancer.

DOI： 10.1002/cam4.2439

Recent advances in molecular biomarkers for patients with hepatocellular carcinoma. Reviewed International journal

Shinichi Umeda, Mitsuro Kanda, Yasuhiro Kodera

Expert review of molecular diagnostics Vol. 19 ( 8 ) page： 725 - 738 2019.8

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

Introduction: Hepatocellular carcinoma (HCC) is a leading cause of cancer death worldwide and recurrence rate after curative resection remains high. To improve HCC prognosis, novel sensitive biomarkers and targeted molecular therapies are needed. Accumulation of multiple genetic aberrations caused by pathologically derived liver damage results in HCC carcinogenesis. Elucidating the genes associated with tumorigenesis and progression of HCC may lead to the development of early detection and prognosis markers and to the identification of therapeutic targets. Areas covered: We review recently reported (January 2017-March 2019) HCC-associated molecules, including protein-coding genes, microRNAs, long non-coding RNAs, and methylated gene promoters. Expert opinion: The molecules reviewed have the potential to be clinical biomarkers and therapeutic targets for HCC. The accumulation and understanding of genetic and epigenetic data are essential to improve the management of HCC patients.

DOI： 10.1080/14737159.2019.1638254

Proposal of a Scoring Scale to Estimate Risk of the Discontinuation of S-1 Adjuvant Monotherapy in Patients with Stage II to III Gastric Cancer: A Multi-Institutional Dataset Analysis. International journal

Iizuka A, Kanda M, Ito S, Mochizuki Y, Teramoto H, Ishigure K, Murai T, Asada T, Ishiyama A, Matsushita H, Tanaka C, Kobayashi D, Fujiwara M, Murotani K, Kodera Y

World journal of surgery Vol. 43 ( 8 ) page： 2016 - 2024 2019.8

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

BACKGROUND: Discontinuation of postoperative S-1 adjuvant monotherapy is a frequent problem in the management of patients with gastric cancer. METHODS: A total of 355 stage II/III gastric cancer patients who underwent gastrectomy and adjuvant S-1 were retrospectively analyzed using a multicenter dataset. We randomly assigned patients into either discovery or validation cohort in a 2:1 ratio. In the discovery cohort, 29 parameters were assessed as candidate factors to predict discontinuation of S-1 adjuvant within 6 months. A scoring system was designed using independent risk factors identified by the multivariate analysis. Reproducibility was tested in the validation cohort. RESULTS: Overall, 92 patients (25.9%) discontinued the treatment within 6 months because of adverse effects. Age, preoperative urea nitrogen (UN) and the preoperative albumin-to-bilirubin index (ALBI) showed the highest area under the curve (AUC) for the discontinuation of S-1 adjuvant within 6 months in each category: body status, blood tests and indices. In the multivariate analysis, age ≥ 64 years, preoperative UN ≥ 15.2 mg/dl and preoperative ALBI ≥ -0.265 were identified as independent risk factors. A scoring scale consisting of these three factors was developed for the prediction of drug discontinuation and demonstrated a greater AUC (0.728) than that of each of the three constituents. The time to treatment discontinuation decreased incrementally as the risk score increased. The reproducible findings were confirmed in the validation cohort. CONCLUSIONS: We identified risk factors and developed a scoring scale to predict S-1 adjuvant monotherapy discontinuation in patients with stage II/III gastric cancer.

DOI： 10.1007/s00268-019-04942-y

Risk factors for paraaortic lymph-node recurrence in colorectal cancer

Mayanagi Shuhei, Kashiwabara Kosuke, Honda Michitaka, Oba Koji, Aoyama Toru, Kanda Mitsuro, Maeda Hiromichi, Hamada Chikuma, Sadahiro Sotaro, Sakamoto Junichi, Maehara Yoshihiko, Yoshikawa Takaki

Annals of Cancer Research and Therapy Vol. 27 ( 2 ) page： 52 - 56 2019.7

Language：English Publishing type：Research paper (scientific journal) Publisher：The Japanese Society of Strategies for Cancer Research and Therapy

Background: The paraaortic lymph-node (PALN) is a relatively uncommon metastasis as a first site of recurrence following colorectal cancer (CRC) surgery. Localized and resectable PALN recurrence has the potential of long-term survival by curative resection. We evaluated the risk factors for the recurrence of PALN following curative surgery in patients with CRC in a pooled analysis of two large randomised control studies.

Patients and Methods: Individual patient data from the Japanese Foundation for Multidisciplinary Treatment of Cancer clinical Trials 7 and 15 were pooled for this analysis. We included total 4459 patients who had stage I-III colorectal cancer and underwent curative resection with over D2 lymph node dissection.

Results: Recurrent PALN occurred in 0.7% of all patients (30/4459). Of the 30 patients with recurrent PALN, 19 had PALN alone, whereas 11 had a recurrence in at least one other organ in addition to PALN. PALN recurrence occurred after the 3-year postoperative period in 10 patients (33%). In multivariate analysis, lymph node involvement was the only independent predictor of recurrent PALN (hazard ratio, 2.670; p = 0.0106).

Conclusions: Our findings clarify the risk factors for PALN recurrence in stage I–III CRC who undergo curative resection. These results will be useful to identify optimal subgroups for high risk of PLAN recurrence.

DOI： 10.4993/acrt.27.52

Other Link： https://search.jamas.or.jp/link/ui/2020287179

Number of retrieved lymph nodes is an independent prognostic factor after total gastrectomy for patients with stage III gastric cancer: propensity score matching analysis of a multi-institution dataset.

Hayashi S, Kanda M, Ito S, Mochizuki Y, Teramoto H, Ishigure K, Murai T, Asada T, Ishiyama A, Matsushita H, Tanaka C, Kobayashi D, Fujiwara M, Murotani K, Kodera Y

Gastric cancer : official journal of the International Gastric Cancer Association and the Japanese Gastric Cancer Association Vol. 22 ( 4 ) page： 853 - 863 2019.7

Functions of FRAS1 as a driver gene of liver metastasis from gastric cancer analyzed by the genome editing technology Reviewed

Umeda Shinichi, Kanda Mitsuro, Tanaka Haruyoshi, Sonohara Fuminori, Takami Hideki, Hattori Norifumi, Hayashi Masamichi, Tanaka Chie, Kobayashi Daisuke, Yamada Suguru, Nakayama Goro, Koike Masahiko, Fujiwara Michitaka, Kodera Yasuhiro

CANCER RESEARCH Vol. 79 ( 13 ) 2019.7

Genomewide expression profiling identifies a novel miRNA-based signature for the detection of peritoneal metastasis in gastric cancer Reviewed

Shimura Tadanobu, Toden Shusuke, Kandimalla Raju, Toiyama Yuji, Okugawa Yoshinaga, Kanda Mitsuro, Baba Hideo, Kodera Yasuhiro, Kusunoki Masato, Hori Hiroki, Goel Ajay

CANCER RESEARCH Vol. 79 ( 13 ) 2019.7

切除不能胃癌に対するConversion Surgeryの適応と予後因子の検討 Reviewed

小林大介, 神田光郎, 田中千恵, 服部憲史, 林真路, 山田豪, 中山吾郎, 小池聖彦, 藤原道隆, 小寺泰弘

日本消化器外科学会総会 Vol. 74回 page： P33 - 1 2019.7

胃癌に対するS-1術後補助化学療法の開始時期と予後に関する検討 Reviewed

中西香企, 神田光郎, 伊藤誠二, 望月能成, 寺本仁, 石榑清, 村井俊文, 浅田崇洋, 石山聡治, 小寺泰弘

日本消化器外科学会総会 Vol. 74回 page： P75 - 3 2019.7

Long-lasting discussion: Adverse effects of intraoperative blood loss and allogeneic transfusion on prognosis of patients with gastric cancer. Reviewed International journal

Nakanishi K, Kanda M, Kodera Y

World journal of gastroenterology Vol. 25 ( 22 ) page： 2743 - 2751 2019.6

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

Gastrectomy with radical lymph node dissection is the most promising treatment avenue for patients with gastric cancer. However, this procedure sometimes induces excessive intraoperative blood loss and requires perioperative allogeneic blood transfusion. There are lasting discussions and controversies about whether intraoperative blood loss or perioperative blood transfusion has adverse effects on the prognosis in patients with gastric cancer. We reviewed laboratory and clinical evidence of these associations in patients with gastric cancer. A large amount of clinical evidence supports the correlation between excessive intraoperative blood loss and adverse effects on the prognosis. The laboratory evidence revealed three possible causes of such adverse effects: anti-tumor immunosuppression, unfavorable postoperative conditions, and peritoneal recurrence by spillage of cancer cells into the pelvis. Several systematic reviews and meta-analyses have suggested the adverse effects of perioperative blood transfusions on prognostic parameters such as all-cause mortality, recurrence, and postoperative complications. There are two possible causes of adverse effects of blood transfusions on the prognosis: Anti-tumor immunosuppression and patient-related confounding factors (e.g., preoperative anemia). These factors are associated with a worse prognosis and higher requirement for perioperative blood transfusions. Surgeons should make efforts to minimize intraoperative blood loss and transfusions during gastric cancer surgery to improve patients' prognosis.

DOI： 10.3748/wjg.v25.i22.2743

Albumin-Bilirubin Score Predicts Tolerability to Adjuvant S-1 Monotherapy after Curative Gastrectomy. Reviewed International journal

Miwa T, Kanda M, Tanaka C, Kobayashi D, Hayashi M, Yamada S, Nakayama G, Koike M, Kodera Y

Journal of gastric cancer Vol. 19 ( 2 ) page： 183 - 192 2019.6

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

PURPOSE: Due to adverse events, dose reduction or withdrawal of adjuvant chemotherapy is required for some patients. To identify the predictive factors for tolerability to postoperative adjuvant S-1 monotherapy in gastric cancer (GC) patients, we evaluated the predictive values of blood indicators. MATERIALS AND METHODS: We analyzed 98 patients with pStage II/III GC who underwent postoperative adjuvant S-1 monotherapy. We retrospectively analyzed correlations between 14 parameters obtained from perioperative routine blood tests to assess their influence on the withdrawal of postoperative adjuvant S-1 monotherapy, within 6 months after discontinuation. RESULTS: Postoperative adjuvant chemotherapy was discontinued in 21 patients (21.4%) within 6 months. Univariable analysis revealed that high preoperative albumin-bilirubin (ALBI) scores had the highest odds ratio (OR) for predicting the failure of adjuvant S-1 chemotherapy (OR, 6.47; 95% confidence interval [CI], 2.08-20.1; cutoff value, -2.696). The high ALBI group had a significantly shorter time to failure of postoperative adjuvant S-1monotherapy (hazard ratio, 3.48; 95% CI, 1.69-7.25; P=0.001). Multivariable analysis identified high preoperative ALBI score as an independent prognostic factor for tolerability (OR, 10.3; 95% CI, 2.33-45.8; P=0.002). CONCLUSIONS: Preoperative ALBI shows promise as an indicator associated with the tolerability of adjuvant S-1 monotherapy in patients with pStage II/III GC.

DOI： 10.5230/jgc.2019.19.e15

Genome-wide Discovery of a Novel Gene-expression Signature for the Identification of Lymph Node Metastasis in Esophageal Squamous Cell Carcinoma. Reviewed International journal

Fuminori Sonohara, Feng Gao, Naoki Iwata, Mitsuro Kanda, Masahiko Koike, Naoki Takahashi, Yasuhide Yamada, Yasuhiro Kodera, Xin Wang, Ajay Goel

Annals of surgery Vol. 269 ( 5 ) page： 879 - 886 2019.5

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

OBJECTIVE: This study aimed to develop a gene-expression signature for identification of lymph node (LN) metastasis in esophageal squamous cell carcinoma (ESCC) patients. SUMMARY OF BACKGROUND DATA: LN metastasis is recognized as the most important independent risk factor for therapeutic decision-making of ESCC patients. METHODS: A bioinformatic approach was used to analyze RNA sequencing profiles of ESCC patients, and to develop a gene-expression signature for identifying LN metastasis. The robustness of this panel was assessed in 2 independent patient cohorts (n = 56 and 224). RESULTS: We initially prioritized a 16-gene signature out of the total 20,531 mRNAs. The model estimated by these 16 genes discriminated LN status with an area under the curve (AUC) of 0.77 [95% confidence interval (95% CI), 0.68-0.87, 5-fold cross-validation]. Subsequently, a reduced and optimized 5-gene panel was trained in a clinical cohort, which effectively distinguished ESCC patients with LN metastasis (cohort-1: AUC, 0.74; 95% CI, 0.58-0.89; cohort-2, T1-T2: AUC, 0.74; 95% CI, 0.63-0.86), and was significantly superior to preoperative computed tomography (AUC, 0.61; 95% CI, 0.50-0.72). Furthermore, a combination signature comprising of the 5-gene panel together with the lymphatic vessel invasion (LVI) and venous invasion (VI) demonstrated a significantly improved diagnostic performance compared with individual clinical variables, in both cohorts (cohort-1: AUC, 0.87; 95% CI, 0.78-0.96; cohort-2: AUC, 0.76; 95% CI, 0.65-0.88). CONCLUSION: Our novel 5-gene panel is a robust diagnostic tool for LN metastasis, especially in early-T stage ESCC patients, with a promising clinical potential.

DOI： 10.1097/SLA.0000000000002622

Homeobox C10 Influences on the Malignant Phenotype of Gastric Cancer Cell Lines and its Elevated Expression Positively Correlates with Recurrence and Poor Survival. International journal

Miwa T, Kanda M, Umeda S, Tanaka H, Tanaka C, Kobayashi D, Suenaga M, Hayashi M, Yamada S, Nakayama G, Koike M, Kodera Y

Annals of surgical oncology Vol. 26 ( 5 ) page： 1535 - 1543 2019.5

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

BACKGROUND: The detection of molecules and mechanisms affecting the malignant phenotype of gastric cancer cells may contribute to the identification of biomarkers for metastasis and recurrence, and such molecules may serve as targets of therapy. For this purpose, in this study transcriptome analysis was performed using surgically resected specimens from patients with gastric cancer with synchronous metastasis. We identified homeobox C10 (HOXC10) as the most highly expressed gene in gastric cancer tissues compared with the adjacent noncancerous gastric mucosa. METHODS: Polymerase chain reaction (PCR) array analysis was performed to identify genes coordinately expressed with HOXC10. The effects of inhibiting HOXC10 on malignant phenotype was evaluated using HOXC10 knockout gastric cancer cell lines, and antibody array analysis was performed to assess the effect of HOXC10 knockout on intracellular signaling. We used a mouse subcutaneous xenograft model to evaluate the tumorigenicity. HOXC10 expression was determined in gastric cancer tissues acquired from 300 patients with gastric cancer. RESULTS: PCR array analysis revealed that the levels of HOXC10 messenger RNA positively correlated with those of FGFBP1 and SOX10. The phosphorylation of ERK1/2 was decreased in HOXC10 knockout cells. HOXC10 knockout significantly suppressed proliferation by increasing apoptosis and reducing the migration and invasiveness of gastric cancer cells. Mouse xenograft models revealed that the tumorigenicity of HOXC10 knockout cells was attenuated compared with the parental cells. The relatively high expression levels of HOXC10 in gastric cancer tissues were significantly associated with hepatic and peritoneal recurrence, as well as worse prognosis. CONCLUSIONS: Our results indicated that HOXC10 enhances the malignant phenotype of gastric cancer cells. The expression levels of HOXC10 may therefore serve as a prognostic biomarker and the products of HOXC10 may provide targets of therapy.

DOI： 10.1245/s10434-019-07166-5

Long-term quality of life and nutrition status of the aboral pouch reconstruction after total gastrectomy for gastric cancer: a prospective multicenter observational study (CCOG1505).

Tanaka C, Kanda M, Murotani K, Yoshikawa T, Cho H, Ito Y, Matsui T, Nakayama H, Yamada T, Kobayashi D, Fujiwara M, Kodera Y

Gastric cancer : official journal of the International Gastric Cancer Association and the Japanese Gastric Cancer Association Vol. 22 ( 3 ) page： 607 - 616 2019.5

Increased Expression of DNAJC12 is Associated with Aggressive Phenotype of Gastric Cancer. International journal

Uno Y, Kanda M, Miwa T, Umeda S, Tanaka H, Tanaka C, Kobayashi D, Suenaga M, Hattori N, Hayashi M, Yamada S, Nakayama G, Fujiwara M, Kodera Y

Annals of surgical oncology Vol. 26 ( 3 ) page： 836 - 844 2019.3

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

BACKGROUND: Identification of gastric cancer-related molecules is necessary to elucidate the pathological mechanisms of this heterogeneous disease. The purpose of this study was to identify novel genes associated with aggressive phenotypes of gastric cancer. METHODS: Global expression profiling was conducted using tissues from four patients with metastatic gastric cancer to identify genes overexpressed in gastric cancer. Fifteen gastric cell lines and 262 pairs of surgically resected gastric tissues were subjected to mRNA expression analysis. The contribution of the candidate gene on gastric cancer cell proliferation, invasion, adhesion, and migration were evaluated using small interfering RNA. RESULTS: DnaJ heat shock protein family (Hsp40) member C12 (DNAJC12) was identified as a candidate gene by transcriptome analysis. In clinical samples, DNAJC12 mRNA levels were higher in gastric cancer tissues compared with normal adjacent tissues. Patients with high DNAJC12 expression showed significantly shorter overall survival in our cohort and in the extra-validation cohort analyzed by a published microarray dataset. High DNAJC12 expression in gastric cancer tissues was significantly associated with lymphatic involvement, infiltrative growth type, lymph node metastasis, and advanced stage and was identified as an independent prognostic factor for overall survival in multivariable analysis. Increased expression of DNAJC12 was found in 12 of 14 examined gastric cancer cell lines. Knockdown of DNAJC12 expression significantly decreased the proliferation and invasion abilities of gastric cancer cells. CONCLUSIONS: Our findings support DNAJC12 as a candidate gene associated with aggressive phenotypes of gastric cancer.

DOI： 10.1245/s10434-018-07149-y

Intraoperative Blood Loss is Associated with Shortened Postoperative Survival of Patients with Stage II/III Gastric Cancer: Analysis of a Multi-institutional Dataset.

Ito Y, Kanda M, Ito S, Mochizuki Y, Teramoto H, Ishigure K, Murai T, Asada T, Ishiyama A, Matsushita H, Tanaka C, Kobayashi D, Fujiwara M, Murotani K, Kodera Y

World journal of surgery Vol. 43 ( 3 ) page： 870 - 877 2019.3

A genomewide transcriptomic approach identifies a novel gene expression signature for the detection of lymph node metastasis in patients with early stage gastric cancer Reviewed International journal

D. Izumi, F. Gao, S. Toden, F. Sonohara, M. Kanda, T. Ishimoto, Y. Kodera, X. Wang, H. Baba, A. Goel

EBioMedicine Vol. 41 page： 268 - 275 2019.3

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

BACKGROUND: Although identification of lymph node (LN) metastasis is a well-recognized strategy for improving outcomes in patients with gastric cancer (GC), currently there is lack of availability of adequate molecular biomarkers that can identify such metastasis. Herein we have developed a robust gene-expression signature for detecting LN metastasis in early stage GC by using a transcriptome-wide biomarker discovery and subsequent validation in multiple clinical cohorts. METHODS: A total of 532 patients with pathological T1 and T2 GC from 4 different cohorts were analyzed. Two independent datasets (n = 96, and n = 188) were used to establish a gene signature for the identification of LN metastasis in GC patients. The diagnostic performance of our gene-expression signature was subsequently assessed in two independent clinical cohorts using qRT-PCR assays (n = 101, and n = 147), and subsequently compared against conventional tumor markers and image-based diagnostics. FINDINGS: We established a 15-gene signature by analyzing multiple high throughput datasets, which robustly distinguished LN status in both training (AUC = 0.765, 95% CI 0.667-0.863) and validation cohorts (AUC = 0.742, 95% CI 0.630-0.852). Notably, the 15-gene signature was significantly superior compared to the conventional tumor markers, CEA (P = .04) and CA19-9 (P = .005), as well as computed tomography-based imaging (P = .04). INTERPRETATION: We have established and validated a 15-gene signature for detecting LN metastasis in GC patients, which offers a robust diagnostic tool for potentially improving treatment outcomes in gastric cancer patients. FUND: NIH: CA72851, CA181572, CA14792, CA202797, CA187956; CPRIT: RP140784: Baylor Sammons Cancer Center polot grants (AG), VPRT: 9610337, CityU 21101115, 11102317, 11103718; JCYJ20170307091256048 (XW).

DOI： 10.1016/j.ebiom.2019.01.057

Prediction of peritoneal recurrences of gastric cancer by qPCR analysis of peritoneal lavage fluids. Reviewed

Nakanishi Koki, Kanda Mitsuro, Umeda Shinichi, Tanaka Chie, Kobayashi Daisuke, Hayashi Masamichi, Yamada Suguru, Nakayama Goro, Koike Masahiko, Fujiwara Michitaka, Kodera Yasuhiro

JOURNAL OF CLINICAL ONCOLOGY Vol. 37 ( 4 ) 2019.2

The Controlling Nutritional Status Score Serves as a Predictor of Short- and Long-Term Outcomes for Patients with Stage 2 or 3 Gastric Cancer: Analysis of a Multi-institutional Data Set.

Ryo S, Kanda M, Ito S, Mochizuki Y, Teramoto H, Ishigure K, Murai T, Asada T, Ishiyama A, Matsushita H, Tanaka C, Kobayashi D, Fujiwara M, Murotani K, Kodera Y

Annals of surgical oncology Vol. 26 ( 2 ) page： 456 - 464 2019.2

胃癌におけるMelanotransferrin発現と臨床的意義の検討 Reviewed

澤木康一, 神田光郎, 田中千恵, 小林大介, 園原史訓, 服部憲史, 末永雅也, 高見秀樹, 林真路, 山田豪, 中山吾郎, 小池聖彦, 藤原道隆, 小寺泰弘

日本胃癌学会総会記事 Vol. 91回 page： 490 - 490 2019.2

Prognostic significance of perioperative tumor marker levels in stage II/III gastric cancer. International journal

Suenaga Y, Kanda M, Ito S, Mochizuki Y, Teramoto H, Ishigure K, Murai T, Asada T, Ishiyama A, Matsushita H, Tanaka C, Kobayashi D, Fujiwara M, Murotani K, Kodera Y

World journal of gastrointestinal oncology Vol. 11 ( 1 ) page： 17 - 27 2019.1

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

AIM: To evaluate the prognostic significance of perioperative carcinoembryonic antigen (CEA) and carbohydrate antigen 19-9 (CA19-9) levels in stage II/III gastric cancer. METHODS: From a multi-institutional retrospective database compiled by integrating clinical data from nine institutions, data of 998 patients who underwent curative resection for stage II/III gastric cancer between 2010 and 2014 were retrieved and analyzed. The prognostic impact of the preoperative and postoperative levels and chronological changes in CEA, CA19-9 and their combination were evaluated. To test whether postoperative adjuvant chemotherapy alters the prognostic impact of perioperative CEA and CA19-9 levels, the hazard ratios for mortality were compared between patients who underwent surgery alone and patients who underwent surgery followed by adjuvant chemotherapy. RESULTS: The prognostic impact of postoperative CEA and CA19-9 was superior to that of the preoperative levels. Multivariable analysis identified high postoperative CEA and CA19-9 levels as independent prognostic factors for overall survival. Disease-free survival rates clearly decreased in a stepwise manner in association with postoperative CEA and CA19-9 levels, and patients with high levels of both markers showed significantly poorer prognosis than other patient groups. When we analyzed perioperative changes in serum CEA and CA19-9 levels, patients with high levels before and after surgery had the worst disease-free survival rates among all patient groups. Patients with normalized CEA levels after surgery had a significantly lower disease-free survival rate than those with normal perioperative levels, whereas patients with normalized CA19-9 levels after surgery had equivalent survival to those with normal perioperative levels. The prognostic impact of high CEA levels was observably smaller in patients who underwent adjuvant chemotherapy than in patients who underwent surgery alone, whereas that of high CA19-9 was greater in patients who underwent adjuvant chemotherapy. High postoperative CEA levels were significantly associated with an increased prevalence of liver, lung and bone recurrences, and high postoperative CA19-9 levels were significantly associated with increased frequencies of lymph node and liver recurrences. CONCLUSION: The evaluation of serum CEA and CA 19-9 levels both before and after surgery provides useful information for precise risk stratification after curative gastrectomy.

DOI： 10.4251/wjgo.v11.i1.17

Identification of a serum-based miRNA signature for response of esophageal squamous cell carcinoma to neoadjuvant chemotherapy

Niwa Yukiko, Yamada Suguru, Sonohara Fuminori, Kurimoto Keisuke, Hayashi Masamichi, Tashiro Mitsuru, Iwata Naoki, Kanda Mitsuro, Tanaka Chie, Kobayashi Daisuke, Nakayama Goro, Koike Masahiko, Fujiwara Michitaka, Kodera Yasuhiro

JOURNAL OF TRANSLATIONAL MEDICINE Vol. 17 ( 1 ) page： 1 2019.1

Optical trocar access for initial trocar placement in laparoscopic gastrointestinal surgery: A propensity score-matching analysis. Reviewed

Chie Tanaka, Michitaka Fujiwara, Mitsuro Kanda, Kenta Murotani, Naoki Iwata, Masamichi Hayashi, Daisuke Kobayashi, Suguru Yamada, Yasuhiro Kodera

Asian journal of endoscopic surgery Vol. 12 ( 1 ) page： 37 - 42 2019.1

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

INTRODUCTION: Optical trocar access is a technique to place the initial trocar in laparoscopic surgery. With optical trocar access, each tissue layer can be visualized before insertion, which can help prevent organ injury, and air leaks at the trocar site can be minimized even in obese patients. The aim of this study was to compare the time needed for trocar insertion using optical trocar access and an open method in patients who underwent laparoscopic gastrointestinal surgery. METHODS: We reviewed our prospectively collected database and identified 384 patients who underwent laparoscopic gastrointestinal surgery involving initial trocar insertion near the umbilicus by either the optical trocar access or the open method. Before the two methods were compared, propensity score matching was used to adjust for essential variables between the optical trocar access and open groups. RESULTS: Patients categorized in the optical trocar access and open groups were matched one-to-one by propensity score matching, and 137 pairs of patients were generated. The time needed for trocar insertion was significantly shorter in the optical trocar access group than in the open group (36.6 vs 209.8 s, P < 0.01). The multivariable analysis identified an inexperienced surgeon as the only independent risk factor for prolonged time for initial trocar insertion using the optical trocar access. CONCLUSIONS: This study indicated that optical trocar access may be recommended for inserting the initial trocar in laparoscopic gastrointestinal surgery.

DOI： 10.1111/ases.12484

Perioperative and prognostic implication of albumin-bilirubin-TNM score in Child-Pugh class A hepatocellular carcinoma.

Sonohara F, Yamada S, Tanaka N, Suenaga M, Takami H, Hayashi M, Niwa Y, Sugimoto H, Hattori N, Kanda M, Tanaka C, Kobayashi D, Nakayama G, Koike M, Fujiwara M, Kodera Y

Annals of gastroenterological surgery Vol. 3 ( 1 ) page： 65 - 74 2019.1

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

BACKGROUND AND AIM: A reliable classification for predicting postoperative prognosis and perioperative risk of hepatocellular carcinoma (HCC) patients is required to make a precise decision for HCC treatment. In the present study, we assessed the perioperative and prognostic importance of indocyanine green (ICG) testing, tumor-node-metastasis (TNM) stage, albumin-bilirubin (ALBI) grade, and ALBI-TNM (ALBI-T) score using consecutive resected HCC cases. METHODS: Between 1998 and 2011, 273 consecutive patients who underwent primary and curative hepatectomy for HCC were identified. Among these 273 cases, 235 Child-Pugh class A patients were enrolled in the present study. RESULTS: Correlation analysis showed that the value of linear predictor for ALBI grade was significantly correlated with ICG 15-minute retention rates (r = 0.51, P < 0.0001). Survival analysis for both recurrence-free survival (RFS) and overall survival (OS) showed there were significant differences between the two groups stratified by stage or ALBI-T score (stage, RFS: P = 0.01, OS: P = 0.003; ALBI-T, RFS: P < 0.0001, OS: P < 0.0001). In addition, Cox proportional hazard model identified ALBI-T score was a significant predictor for both RFS and OS (RFS, P = 0.001; OS, P = 0.004). Furthermore, ALBI-T score could predict perioperative risk in hepatectomy such as longer operation time and excessive intraoperative blood loss. CONCLUSIONS: This study showed a robust association of ALBI-T score with postoperative HCC patient survival and perioperative risk in hepatectomy. ALBI-T score can be used as a simple and powerful tool for assessing HCC patients with further study.

DOI： 10.1002/ags3.12212

Establishment of Peritoneal and Hepatic Metastasis Mouse Xenograft Models Using Gastric Cancer Cell Lines. Reviewed

Miwa T, Kanda M, Umeda S, Tanaka H, Shimizu D, Tanaka C, Kobayashi D, Hayashi M, Yamada S, Nakayama G, Koike M, Kodera Y

In vivo (Athens, Greece) Vol. 33 ( 6 ) page： 1785 - 1792 2019

Peritoneal Lavage Tumor DNA as a Novel Biomarker for Predicting Peritoneal Recurrence in Pancreatic Ductal Adenocarcinoma Reviewed

Suenaga M., Fujii T., Yamada S., Hayashi M., Shinjo K., Takami H., Niwa Y., Sonohara F., Shimizu D., Kanda M., Kobayashi D., Tanaka C., Nakayama G., Koike M., Fujiwara M., Kondo Y., Kodera Y.

PANCREAS Vol. 48 ( 10 ) page： 1528 - 1528 2019

A case of renal salt-wasting syndrome induced by cisplatin and 5-FU during treatment of esophageal squamous cell carcinoma Reviewed

Dai Shimizu, Mitsuro Kanda, Masahiko Koike, Shinichi Umeda, Fuminori Sonohara, Hideki Takami, Yoshikuni Inokawa, Norifumi Hattori, Masamichi Hayashi, Chie Tanaka, Daisuke Kobayashi, Suguru Yamada, Goro Nakayama, Michitaka Fujiwara, Yasuhiro Kodera

Annals of Cancer Research and Therapy Vol. 27 ( 2 ) page： 64 - 66 2019

Language：English Publishing type：Research paper (scientific journal) Publisher：PJD Publications Ltd

The combination regimen of cisplatin (CDDP) and fluorouracil (5-FU) (FP) is a standard regimen for definitive chemora-diotherapy, neoadjuvant chemotherapy, and for treatment of unresectable or recurrent esophageal squamous cell carcinoma (ESCC). Here, we report a patient with FP-induced renal salt-wasting syndrome (RSWS) who presented with severe hyponatremia with disturbance of consciousness and was admitted to the intensive care unit (ICU). A 66-year-old man with recurrent ESCC was admitted and started on chemotherapy with FP. From day 3 of the first course of FP, he presented with anorexia and vomiting (grade 3). At day 6, he experienced disturbance of consciousness and blood test showed severe hyponatremia (sodium (Na): 119 mmol/L) accompanied with excessive urinary excretion of Na (181 mmol/L). He was diagnosed with RSWS because of CDDP and was transferred to the ICU. Through intensive monitoring and 3% NaCl infusion, serum Na level and symptoms recovered with no sequelae and he was discharged from the ICU after a 4-day stay. RSWS is sometimes difficult to diagnose because of its low recognition and is misdiagnosed as the syndrome of inappropriate secretion of antidiuretic hormone. During chemotherapy with platinum-based agents, RSWS should be kept in mind as a disorder that causes hyponatremia.

DOI： 10.4993/acrt.27.64

ASO Author Reflections: Troponin I2-A Specific Biomarker for Detection and Prediction of Peritoneal Metastasis in Gastric Cancer. Reviewed

Sawaki K, Kanda M

Annals of surgical oncology Vol. 25 ( Suppl 3 ) page： 709 - 710 2018.12

RASEF expression correlates with hormone receptor status in breast cancer International journal

Shibata Masahiro, Kanda Mitsuro, Shimizu Dai, Tanaka Haruyoshi, Umeda Shinichi, Miwa Takashi, Hayashi Masamichi, Inaishi Takahiro, Miyajima Noriyuki, Adachi Yayoi, Takano Yuko, Nakanishi Kenichi, Takeuchi Dai, Noda Sumiyo, Kodera Yasuhiro, Kikumori Toyone

ONCOLOGY LETTERS Vol. 16 ( 6 ) page： 7223 - 7230 2018.12

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

Breast cancer (BC) is the most frequently diagnosed malignant tumor in women worldwide, and the development of new molecules associated with BC is essential for the management of this disease. RAS and EF-hand domain-containing (RASEF) encodes the GTPase enzyme that belongs to the Rab family. Although the effects of this gene have been reported in several malignant tumor types, the role of RASEF in BC has not been completely elucidated. The aim of the present study was to investigate the importance of RASEF expression in BC. RASEF mRNA expression levels were evaluated in BC and non-cancerous mammary cell lines. The association between RASEF mRNA expression levels and clinicopathological factors in 167 patients with BC were then determined. Among the 13 examined BC cell lines, ER-negative/HER2-negative cell lines expressed lower RASEF mRNA levels, when compared with the other examined cell lines (P=0.014). Of the 167 patients examined, patients with negative hormone receptor status exhibited significantly lower RASEF mRNA expression levels (P<0.001). In addition low RASEF expression in BC tissues was associated with negative estrogen receptor status (P<0.001), negative progesterone receptor status (P<0.001), and triple-negative status (P<0.001). Additionally, although the differences were not statistically significant, patients with low RASEF expression levels exhibited poorer disease-free survival (P=0.123) and overall survival (P=0.086) than other patients. The results of the present study indicate that RASEF mRNA expression levels are associated with hormone receptor status in BC.

DOI： 10.3892/ol.2018.9542

Pathological tumor infiltrative pattern and sites of initial recurrence in stage II/III gastric cancer: Propensity score matching analysis of a multi-institutional dataset. International journal

Nakagawa N, Kanda M, Ito S, Mochizuki Y, Teramoto H, Ishigure K, Murai T, Asada T, Ishiyama A, Matsushita H, Tanaka C, Kobayashi D, Fujiwara M, Murotani K, Kodera Y

Cancer medicine Vol. 7 ( 12 ) page： 6020 - 6029 2018.12

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

BACKGROUND: Advanced gastric cancer frequently recurs even after radical resection followed by adjuvant chemotherapy. The aim of this study was to evaluate the relationship between pathological infiltrative pattern (INF) and initial recurrence patterns in patients with stage II/III gastric cancer using a large multicenter database. METHODS: We retrospectively analyzed 1098 eligible patients who underwent curative gastrectomy for stage II/III gastric cancer at nine institutions between 2010 and 2014. Patients were categorized into the INF-a/b and INF-c groups and adjusted using propensity score matching. RESULTS: After propensity score matching, 686 patients (343 for each) were classified in the INF-a/b and INF-c groups. There were no significant differences in overall and disease-free survival between the two groups. In the INF-a/b group, frequencies of recurrence at the peritoneum, lymph node, and liver were equivalent. In contrast, the peritoneum was the most frequent site and accounted for 60% of the total recurrences in the INF-c group. The cumulative peritoneal recurrence rate was significantly higher in the INF-c group than in the INF-a/b group (hazard ratio 2.47). INF-c was a significant risk factor for peritoneal recurrences in most subgroups including age, sex, macroscopic type, tumor differentiation, and disease stage, and whether the postoperative treatment was given. Multivariate analysis identified INF-c as an independent risk factor for peritoneal recurrences. The cumulative liver recurrence rate was significantly higher in the INF-a/b group than in the INF-c group (hazard ratio 3.44). CONCLUSIONS: INF may represent an important predictor of recurrence patterns after curative resection of stage II/III gastric cancer.

DOI： 10.1002/cam4.1868

Homeobox C10 correlates with the malignant phenotype of gastric cancer and its recurrence and poor survival Reviewed

Miwa Takashi, Kanda Mitsuro, Tanaka Chie, Yamada Suguru, Koike Masahiko, Fujiwara Michitaka, Kodera Yasuhiro

CANCER SCIENCE Vol. 109 page： 1127-1127 2018.12

FRAS1 expression reflects the malignancy potential of gastric cancer Reviewed

Umeda Shinichi, Kanda Mitsuro, Tanaka Chie, Yamada Suguru, Nakayama Goro, Koike Masahiko, Fujiwara Michitaka, Kodera Yasuhiro

CANCER SCIENCE Vol. 109 page： 1128-1128 2018.12

Copine 5 expression predicts prognosis following curative resection of esophageal squamous cell carcinoma International journal

Umeda Shinichi, Kanda Mitsuro, Koike Masahiko, Tanaka Haruyoshi, Miwa Takashi, Tanaka Chie, Kobayashi Daisuke, Suenaga Masaya, Hayashi Masamichi, Yamada Suguru, Nakayama Goro, Kodera Yasuhiro

ONCOLOGY REPORTS Vol. 40 ( 6 ) page： 3772 - 3780 2018.12

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

Patients with esophageal squamous cell carcinoma (ESCC) have a poor prognosis. Identification of biomarkers to accurately predict the risk of recurrence and survival following curative esophageal resection is required to improve patient outcomes. The copine 5 (CPNE5) gene encodes a calcium‑dependent lipid‑binding intracellular protein. Copine proteins interact with diverse target proteins that are components of pathways that aberrantly regulate the phenotypes of malignant cells. However, limited information is available on the role of CPNE5 in cancer. The present study investigated whether CPNE5 may serve as a predictive marker of the prognosis of patients with ESCC following curative resection. CPNE5 mRNA expression levels and the methylation status of the CPNE5 promotor region were measured in 11 ESCC cell lines. CPNE5 mRNA expression levels in 106 pairs of surgically resected specimens were measured, and their associations with clinicopathological characteristics were analyzed. The CPNE5 mRNA expression levels in 9 ESCC cell lines were decreased compared with those of the non-tumorigenic esophageal mucosa cell line Het‑1A. Bisulfite sequencing detected the methylation of the CPNE5 promotor region in all cell lines tested, including Het‑1A. Furthermore, analysis of tissues revealed that CPNE5 mRNA expression was significantly lower in ESCC cells compared with cognate non-cancerous adjacent mucosal cells. Kaplan‑Meier analysis revealed that patients with low CPNE5 expression experienced significantly shorter overall survival. Multivariable analysis identified low CPNE5 expression to be an independent prognostic factor of OS. Analysis of recurrence patterns revealed that significantly more patients with local recurrence expressed lower levels of CPNE5 mRNA. These findings indicated that CPNE5 expression in ESCC tissues may serve as an informative biomarker for predicting ESCC recurrence, particularly in patients with local recurrence, and may help to ensure that patients receive optimal treatment and follow‑up.

DOI： 10.3892/or.2018.6742

Biological significance of ArfGAP with GTPase domain, ankyrin repeat and PH domain 3 (AGAP3) in colorectal cancer (CRC) Reviewed

Shimizu Dai, Sato Kuniaki, Masuda Takaaki, Otsu Hajime, Kuroda Yousuke, Eguchi Hidetoshi, Kanda Mitsuro, Kodera Yasuhiro, Mimori Koshi

CANCER SCIENCE Vol. 109 page： 1235-1235 2018.12

A New Biomarker for Peritoneal Lavage Using Digital PCR in Patients with Pancreatic Ductal Adenocarcinoma Reviewed

Suenaga Masaya, Yamada Suguru, Hayashi Masamichi, Kanda Mitsuro, Tanaka Chie, Nakayama Goro, Koike Masahiko, Fujiwara Michitaka, Kodera Yasuhiro

CANCER SCIENCE Vol. 109 page： 650-650 2018.12

Integrated multigene expression panel to prognosticate patients with gastric cancer Reviewed

Kanda Mitsuro, Miwa Takashi, Umeda Shinichi, Tanaka Chie, Hayashi Masamichi, Suenaga Masaya, Yamada Suguru, Nakayama Goro, Koike Masahiko, Fujiwara Michitaka, Kodera Yasuhiro

CANCER SCIENCE Vol. 109 page： 769 - 769 2018.12

Pattern-specific Transcriptomics Identifies ASGR2 as a Predictor of Hematogenous Recurrence of Gastric Cancer Reviewed

Tanaka Haruyoshi, Kanda Mitsuro, Suenaga Masaya, Hayashi Masamichi, Tanaka Chie, Yamada Suguru, Nakayama Goro, Koike Masahiko, Fujiwara Michitaka, Kodera Yasuhiro

CANCER SCIENCE Vol. 109 page： 1128 - 1128 2018.12

Troponin I2 as a specific biomarker for prediction of peritoneal metastasis in gastric cancer Reviewed

Sawaki Koichi, Kanda Mitsuro, Suenaga Masaya, Hayashi Masamichi, Tanaka Chie, Yamada Suguru, Nakayama Goro, Koike Masahiko, Fujiwara Michitaka, Kodera Yasuhiro

CANCER SCIENCE Vol. 109 page： 765 - 765 2018.12

A New Biomarker for Peritoneal Lavage Using Digital PCR in Patients with Pancreatic Ductal Adenocarcinoma

Suenaga Masaya, Yamada Suguru, Hayashi Masamichi, Kanda Mitsuro, Tanaka Chie, Nakayama Goro, Koike Masahiko, Fujiwara Michitaka, Kodera Yasuhiro

CANCER SCIENCE Vol. 109 page： 650-650 2018.12

FRAS1 expression reflects the malignancy potential of gastric cancer

Umeda Shinichi, Kanda Mitsuro, Tanaka Chie, Yamada Suguru, Nakayama Goro, Koike Masahiko, Fujiwara Michitaka, Kodera Yasuhiro

CANCER SCIENCE Vol. 109 page： 1128-1128 2018.12

Pattern-specific Transcriptomics Identifies ASGR2 as a Predictor of Hematogenous Recurrence of Gastric Cancer Reviewed

Tanaka Haruyoshi, Kanda Mitsuro, Suenaga Masaya, Hayashi Masamichi, Tanaka Chie, Yamada Suguru, Nakayama Goro, Koike Masahiko, Fujiwara Michitaka, Kodera Yasuhiro

CANCER SCIENCE Vol. 109 page： 1128-1128 2018.12

Homeobox C10 correlates with the malignant phenotype of gastric cancer and its recurrence and poor survival

Miwa Takashi, Kanda Mitsuro, Tanaka Chie, Yamada Suguru, Koike Masahiko, Fujiwara Michitaka, Kodera Yasuhiro

CANCER SCIENCE Vol. 109 page： 1127-1127 2018.12

Cutting-edge evidence of adjuvant treatments for gastric cancer

Shimizu Dai, Kanda Mitsuro, Kodera Yasuhiro, Sakamoto Junichi

EXPERT REVIEW OF GASTROENTEROLOGY & HEPATOLOGY Vol. 12 ( 11 ) page： 1109 - 1122 2018.11

A randomized phase II multicenter trial to explore efficacy of weekly intraperitoneal in comparison with intravenous paclitaxel administered immediately after gastrectomy to the patients with high risk of peritoneal recurrence: final results of the INPACT trial Reviewed

Naoto Takahashi, Mitsuro Kanda, Takaki Yoshikawa, Nobuhiro Takiguchi, Kazumasa Fujitani, Katsufumi Miyamoto, Yuichi Ito, Osamu Takayama, Motohiro Imano, Norio Mitsumori, Junichi Sakamoto, Satoshi Morita, Yasuhiro Kodera

Gastric Cancer Vol. 21 ( 6 ) page： 1014 - 1023 2018.11

Language：Japanese Publishing type：Research paper (scientific journal) Publisher：Springer Tokyo

Background: Intraperitoneal administration of paclitaxel had been considered a promising option to treat peritoneal metastasis, the most frequent pattern of recurrence in gastric cancer after D2 gastrectomy, but its safety and efficacy after gastrectomy had not been fully explored. Methods: A phase II randomized comparison of postoperative intraperitoneal (IP) vs. intravenous (IV) paclitaxel was conducted. Patients with resectable gastric linitis plastica, cancer with minimal amount of peritoneal deposits (P1), or cancer positive for the peritoneal washing cytology (CY1) were eligible. After intraoperative confirmation of the above disease status and of resectability, patients were randomized to be treated either by the IP therapy (paclitaxel 60 mg/m2 delivered intraperitoneally on days 0, 14, 21, 28, 42, 49, and 56) or the IV therapy (80 mg/m2 administered intravenously using the identical schedule) before receiving further treatments with evidence-based systemic chemotherapy. The primary endpoint was 2-year survival rate. Results: Of the 86 patients who were randomized intraoperatively, 83 who actually started the protocol treatment were eligible for analysis (n = 39, IP group
n = 44, IV group). The 2-year survival rate of the IP and IV groups was 64.1% (95% CI 47.9–76.9) and 72.3% (95% CI 56.3–83.2%), respectively (p = 0.5731). The IP treatment did not confer significant overall or progression-free survival benefits, and was associated with particularly poor performance in patients with residual disease, including the CY1 P0 population. Conclusions: We were unable to prove superiority of the IP paclitaxel over IV paclitaxel delivered after surgery to control advanced gastric cancer with high risk of peritoneal recurrence.

DOI： 10.1007/s10120-018-0817-y

Treatment strategy of intraperitoneal and systemic chemotherapy combined with gastrectomy for gastric cancer with peritoneal metastasis Reviewed

Kobayashi Daisuke, Kanda Mitsuro, Tanaka Chie, Sonohara Fuminori, Suenaga Masaya, Takami Hideki, Hattori Norifumi, Niwa Yukiko, Hayashi Masamichi, Yamada Suguru, Nakayama Goro, Koike Masahiko, Fujiwara Michitaka, Kodera Yasuhiro

JOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY Vol. 33 page： 98-98 2018.11

Treatment strategy of intraperitoneal and systemic chemotherapy combined with gastrectomy for gastric cancer with peritoneal metastasis

JOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY Vol. 33 page： 98-98 2018.11

結腸癌における腫瘍局在の臨床病理学的意義の検討 3つの第三相試験の統合解析結果 Reviewed

青山徹, 大庭幸治, 本多通孝, 貞廣荘太郎, 眞柳修平, 神田光郎, 前田広道, 柏原康佑, 坂本純一, 前原喜彦, 吉川貴己

日本消化器外科学会雑誌 Vol. 51 ( Suppl.2 ) page： 294 - 294 2018.11

Expression of sushi domain containing two reflects the malignant potential of gastric cancer. Reviewed International journal

Umeda S, Kanda M, Miwa T, Tanaka H, Tanaka C, Kobayashi D, Suenaga M, Hattori N, Hayashi M, Yamada S, Nakayama G, Fujiwara M, Kodera Y

Cancer medicine Vol. 7 ( 10 ) page： 5194 - 5204 2018.10

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

Hepatic recurrence of gastric cancer (GC) is uncontrollable. Discovery of causative oncogenes and the development of sensitive biomarkers to predict hepatic recurrence are required to improve patients' outcomes. In this study, recurrence pattern-specific transcriptome analysis of 57 749 genes was conducted to identify mRNAs specifically associated with hepatic metastasis of patients with stage III GC who underwent curative resection. GC cell lines were subjected to mRNA expression analysis, PCR array analysis, and siRNA-mediated knockdown. The expression levels of primary cancer tissues from 154 patients with resectable GC were determined and correlated with clinicopathological variables. Among 21 genes significantly overexpressed specifically in patients with hepatic recurrence, Sushi domain containing 2 (SUSD2) was selected as a promising target. PCR array analysis revealed that SUSD2 mRNA levels positively correlated with those of FZD7, CDH2, TGFB1, SPARC, ITGA5, and ZEB1. Functional analysis revealed that knockdown of SUSD2 significantly reduced the proliferation, migration, and invasiveness GC cell lines. Patients with high SUSD2 expression were more likely to experience shorter disease-free and overall survival. Analysis of the relation between disease recurrence pattern and SUSD2 levels revealed that significantly more patients with hepatic metastases expressed higher levels of SUSD2 mRNA. The cumulative incidence of hepatic recurrence was greater in patients with high SUSD2 expression. In conclusion, SUSD2 likely contributes to the malignant potential of GC and may serve as a novel biomarker that predicts hepatic recurrence after curative resection.

DOI： 10.1002/cam4.1793

Significance of Preoperative Systemic Inflammation Score in Short-Term and Long-Term Outcomes of Patients with Pathological T2-4 Gastric Cancer After Radical Gastrectomy. Reviewed International journal

Bin Sato, Mitsuro Kanda, Chie Tanaka, Daisuke Kobayashi, Naoki Iwata, Norifumi Hattori, Masaya Suenaga, Masamichi Hayashi, Suguru Yamada, Kenta Murotani, Michitaka Fujiwara, Yasuhiro Kodera

World journal of surgery Vol. 42 ( 10 ) page： 3277 - 3285 2018.10

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

BACKGROUND: Surgical resection is the mainstay of treatment for patients with gastric cancer (GC). Development of a simple, high-performance, integrated scoring system is needed to provide appropriate management. This study aimed to evaluate predictive values of the systemic inflammation score (SIS) for short- and long-term outcomes of patients who underwent surgery for GC. METHODS: A total of 187 patients who underwent gastrectomy for pT2-4 GC without preoperative treatment were analyzed. SIS was formulated based on serum albumin level and lymphocyte-monocyte ratio, and graded into SIS 0, 1, and 2. RESULTS: Preoperative SIS was significantly associated with incidence of postoperative complications, showing a stepwise increased incidence in proportion to SIS in the entire cohort and all subgroups according to operative procedure and disease stage. Overall and disease-free survival times of patients in SIS 0, 1, and 2 shortened in a stepwise fashion. SIS was linked to prevalence of hematogenous metastasis as initial recurrence site. Survival differences between patients with SIS 2 and the others were particularly large in patients who underwent adjuvant chemotherapy. The continuation rate of adjuvant S-1 was lower in the SIS 2 group. CONCLUSION: SIS represents a simple predictor for incidence of postoperative complications and survival in patients with pT2-4 GC.

DOI： 10.1007/s00268-018-4597-7

SYT7 acts as a driver of hepatic metastasis formation of gastric cancer cells Reviewed

Mitsuro Kanda, Haruyoshi Tanaka, Dai Shimizu, Takashi Miwa, Shinichi Umeda, Chie Tanaka, Daisuke Kobayashi, Norifumi Hattori, Masaya Suenaga, Masamichi Hayashi, Naoki Iwata, Suguru Yamada, Michitaka Fujiwara, Yasuhiro Kodera

Oncogene Vol. 37 ( 39 ) page： 5355 - 5366 2018.9

Language：Japanese Publishing type：Research paper (scientific journal) Publisher：Nature Publishing Group

Liver metastasis remains a serious problem in the management of gastric cancer (GC). Our aims were to identify through transcriptome analysis a molecule that mediates hepatic metastasis in GC, and to evaluate its potential as a diagnostic marker and a therapeutic target. The effects of knocking out a relevant molecule using genome editing were evaluated in vitro experiments and in mouse xenograft models. Expression levels of candidate molecule in 300 pairs of gastric tissues were determined to assess whether differentially expressed genes predicted hepatic recurrence, metastasis, or both. Transcriptome data identified the overexpression of synaptotagmin VII (SYT7) in GC tissues with hepatic metastasis. Its expression in the GC cell lines was high, particularly in those that exhibited a differentiated phenotype, and positively correlated with the expression of SNAI1 and TGFB3, and inversely with RGS2. SYT7 knockout inhibited the proliferation of GC cells, indicated by increased apoptosis with activated caspase and loss of mitochondria membrane potential, G2/M cell-cycle arrest and attenuated cell migration, invasion, and adhesion. The tumorigenicity of SYT7-knockout cells was moderately reduced in a mouse model of subcutaneous metastasis in which the levels of BCL2 and HIF1A were decreased and was more strikingly attenuated in a model of hepatic metastasis. The SYT7 levels in the primary GC tissues were significantly associated with hepatic recurrence, metastasis, and adverse prognosis. SYT7 represents a tool for prediction and monitoring of hepatic metastasis from GC as well as being a promising therapeutic target.

DOI： 10.1038/s41388-018-0335-8

Comparison of the Survival Outcomes of Pancreatic Cancer and Intraductal Papillary Mucinous Neoplasms. Reviewed

Yamada S, Fujii T, Hirakawa A, Takami H, Suenaga M, Hayashi M, Niwa Y, Hattori N, Iwata N, Kanda M, Tanaka C, Kobayashi D, Nakayama G, Koike M, Fujiwara M, Kodera Y

Pancreas Vol. 47 ( 8 ) page： 974 - 979 2018.9

Synaptotagmin XIII expression and peritoneal metastasis in gastric cancer Reviewed

Kanda M, Shimizu D, Tanaka H, Tanaka C, Kobayashi D, Hayashi M, Takami H, Niwa Y, Yamada S, Fujii T, Sugimoto H, Kodera Y

BRITISH JOURNAL OF SURGERY Vol. 105 ( 10 ) page： 1349 - 1358 2018.9

Pattern-Specific Transcriptomics Identifies ASGR2 as a Predictor of Hematogenous Recurrence of Gastric Cancer Reviewed International journal

Tanaka Haruyoshi, Kanda Mitsuro, Miwa Takashi, Tanaka Chie, Kobayashi Daisuke, Umeda Shinichi, Shibata Masahiro, Suenaga Masaya, Hattori Norifumi, Hayashi Masamichi, Iwata Naoki, Yamada Suguru, Nakayama Goro, Fujiwara Michitaka, Kodera Yasuhiro

MOLECULAR CANCER RESEARCH Vol. 16 ( 9 ) page： 1420 - 1429 2018.9

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

Hematogenous recurrence is a challenging clinical finding that often leads to fatalities of patients with gastric cancer. Therefore, the identification of specific biomarkers and potential therapeutic target molecules for hematogenous recurrence is required to improve the outcomes of these patients. Here, transcriptome and bioinformatics analyses were conducted to uncover candidate molecules differentially expressed in patients with hematogenous recurrence of gastric cancer. One potential candidate identified was asialoglycoprotein receptor 2 (ASGR2), and siRNA experiments were conducted to determine the effect of manipulating ASGR2 expression has on cell phenotypes. ASGR2 mRNA expression analysis using quantitative real-time reverse-transcription PCR was conducted with stage II/III gastric cancer clinical specimens (n = 95). Transcript levels were increased in gastric cancer cells as compared with a control nontumorigenic epithelial cell line. Knockdown of ASGR2 decreased the adhesion and migration potential. Thus, although gastric cancer cell-invasive activity was significantly decreased by knockdown, forced expression of ASGR2 promoted invasive activity. Using a mouse hepatic metastasis model, knockdown of ASGR2 resulted in the absence of hepatic metastasis formation. High ASGR2 expression in primary gastric cancer tissues was an independent predictor of shorter disease-free and overall survival. Finally, patients with high ASGR2 expression were more likely to have a high cumulative rate of hematogenous recurrence but not peritoneal or nodal recurrence.Implications:ASGR2 expression is associated with the malignant phenotypes in gastric cancer and represents a specific biomarker of hematogenous recurrences after curative resection for gastric cancer. Mol Cancer Res; 16(9); 1420-9. ©2018 AACR.

DOI： 10.1158/1541-7786.MCR-17-0467

大腸癌におけるAGAP3の分子生物学的意義の検討(Biological significance of ArfGAP with GTPase domain, ankyrin repeat and PH domain 3(AGAP3) in colorectal cancer(CRC)) Reviewed

清水大, 佐藤晋彰, 増田隆明, 大津甫, 黒田陽介, 江口英利, 神田光郎, 小寺泰弘, 三森功士

日本癌学会総会記事 Vol. 77回 page： 2066 - 2066 2018.9

＜Editors' Choice＞ Efficacy of enteral nutrients containing β-hydroxy-β-methylbutyrate, glutamine, and arginine for the patients with anastomotic leakage after gastrectomy: study protocol of a multicenter phase II clinical trial. Reviewed

Mitsuro Kanda, Chie Tanaka, Kenta Murotani, Daisuke Kobayashi, Seiji Ito, Yoshinari Mochizuki, Kiyoshi Ishigure, Akiharu Ishiyama, Hitoshi Teramoto, Toshifumi Murai, Takahiro Asada, Hidenobu Matsushita, Michitaka Fujiwara, Yasuhiro Kodera

Nagoya journal of medical science Vol. 80 ( 3 ) page： 351 - 355 2018.8

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

Anastomotic leakage is a major cause of prolonged hospitalization after gastrectomy and sometimes leads to fatal complications, such as abdominal abscess and sepsis. Arginine, glutamine, and β-hydroxy-β-methylbutyrate (HMB) are indispensable for biosynthesis of collagen, which plays an important role in the process of wound healing. However, treatment effects of amino acid supplements containing HMB on the healing process of anastomotic leakage after gastrectomy remain unclear. We designed an open-label, multicenter, phase II clinical trial to evaluate the therapeutic efficacy of an enteral amino acid supplement consisting of arginine, glutamine, and HMB (Abound, Abbott Japan Co., Ltd., Tokyo, Japan) in patients with anastomotic leakage after gastrectomy. Patients who are diagnosed with anastomotic leakage within 14 days after gastrectomy are eligible for this trial and the target sample size is 20. A pack of Abound is administered twice a day for 2 weeks. The primary objective of this clinical trial is to determine the length of time between diagnosis and cure of anastomotic leakage. The secondary endpoints include the safety of Abound, duration of drainage placement and fasting, postoperative hospital stay, surgical procedure, and blood test data. Variables are compared between enrolled patients and a historical control consisting of 20 patients who underwent gastrectomy between 2004 and 2016 at Nagoya University Hospital. We herein describe the study design and the concept in this protocol paper.

DOI： 10.18999/nagjms.80.3.351

Randomized Phase II Trial of CapOX plus Bevacizumab and CapIRI plus Bevacizumab as First-Line Treatment for Japanese Patients with Metastatic Colorectal Cancer (CCOG-1201 Study). Reviewed International journal

Goro Nakayama, Ayako Mitsuma, Yuki Sunagawa, Kiyoshi Ishigure, Hiroyuki Yokoyama, Takanori Matsui, Hiroshi Nakayama, Kazuhiko Nakata, Akiharu Ishiyama, Takahiro Asada, Shinichi Umeda, Kazuhiro Ezaka, Norifumi Hattori, Hideki Takami, Daisuke Kobayashi, Chie Tanaka, Mitsuro Kanda, Suguru Yamada, Masahiko Koike, Michitaka Fujiwara, Tsutomu Fujii, Kenta Murotani, Yuichi Ando, Yasuhiro Kodera

The oncologist Vol. 23 ( 8 ) page： 919 - 927 2018.8

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

PURPOSE: The aim of this randomized, multicenter, noncomparative, phase II trial was to investigate the efficacy and safety of two potential first-line treatments, capecitabine and oxaliplatin (CapOX) plus bevacizumab (BEV) and capecitabine and irinotecan (CapIRI) plus bevacizumab, in Japanese patients with metastatic colorectal cancer (mCRC). PATIENTS AND METHODS: Patients with untreated mCRC were randomly assigned to receive either CapOX plus bevacizumab (CapOX/BEV arm: bevacizumab 7.5 mg/kg and oxaliplatin 130 mg/m2 on day 1 and oral capecitabine 2,000 mg/m2 on days 1-14, every 3 weeks) or CapIRI plus bevacizumab (CapIRI/BEV arm: bevacizumab 7.5 mg/kg and irinotecan 200 mg/m2 on day 1 and capecitabine 1,600 mg/m2 on days 1-14, every 3 weeks). The primary endpoint was overall response rate (ORR), and the secondary endpoints included progression-free survival (PFS), overall survival (OS), and safety. RESULTS: A total of 107 patients were enrolled. The intent-to-treat population comprised 54 patients in the CapOX/BEV arm and 53 patients in the CapIRI/BEV arm. The median follow-up period was 35.5 months. ORR was 56% in the CapOX/BEV arm and 55% in the CapIRI/BEV arm. Median PFS and OS were 12.4 and 26.7 months in the CapOX/BEV arm and 11.5 and 28.7 months in the CapIRI/BEV arm, respectively. The frequencies of hematological and nonhematological adverse events above grade 3 were 13% and 30% in the CapOX/BEV arm and 25% and 23% in the CapIRI/BEV arm, respectively. CONCLUSION: CapOX plus bevacizumab and CapIRI plus bevacizumab are equally effective and feasible as the first-line treatments in Japanese patients with mCRC. IMPLICATIONS FOR PRACTICE: The CCOG-1201 study was designed to evaluate the efficacy and safety of capecitabine and oxaliplatin plus bevacizumab and capecitabine and irinotecan plus bevacizumab as a first-line treatment in Japanese patients with metastatic colorectal cancer. This article reports on the trial and efforts to define the role of these regimens, including the effect of KRAS status and UGT1A1 polymorphisms in metastatic colorectal cancer.

DOI： 10.1634/theoncologist.2017-0640

Impact of the Controlling Nutritional Status Score on the Prognosis After Curative Resection of Pancreatic Ductal Adenocarcinoma Reviewed

Kato Yoshiyasu, Yamada Suguru, Suenaga Masaya, Takami Hideki, Niwa Yukiko, Hayashi Masamichi, Iwata Naoki, Kanda Mitsuro, Tanaka Chie, Nakayama Goro, Koike Masahiko, Fujiwara Michitaka, Kodera Yasuhiro

PANCREAS Vol. 47 ( 7 ) page： 823 - 829 2018.8

Risk Factors for Peritoneal Recurrence in Stage II to III Colon Cancer. Reviewed International journal

Shuhei Mayanagi, Kosuke Kashiwabara, Michitaka Honda, Koji Oba, Toru Aoyama, Mitsuro Kanda, Hiromichi Maeda, Chikuma Hamada, Sotaro Sadahiro, Junichi Sakamoto, Shigetoyo Saji, Takaki Yoshikawa

Diseases of the colon and rectum Vol. 61 ( 7 ) page： 803 - 808 2018.7

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

BACKGROUND: Most previous reports to analyze risk factors for peritoneal recurrence in patients with colon cancer have been observational studies of a population-based cohort. OBJECTIVE: This study aimed to determine the risk factors for peritoneal recurrence in patients with stage II to III colon cancer who underwent curative resection. DESIGN: This was a pooled analysis using a combined database obtained from 3 large phase III randomized trials (N = 3714). SETTINGS: Individual patient data were collected from the Japanese Foundation for Multidisciplinary Treatment of Cancer clinical trials 7, 15, and 33, which evaluated the benefits of postoperative 5-fluorouracil-based adjuvant therapies in patients with locally advanced colorectal cancer. PATIENTS: We included patients who had stage II to III colon cancer and underwent curative resection with over D2 lymph node dissection. MAIN OUTCOME MEASURES: Main outcomes measured were risk factors for peritoneal recurrence without other organ metastasis after curative surgery. RESULTS: Peritoneal recurrence occurred in 2.3% (86/3714) of all patients undergoing curative resection. Mean duration from operation to peritoneal recurrence was 17.0 ± 10.3 months. Of these patients with peritoneal recurrence, 29 patients (34%) had recurrence in ≥1 other organ. Multivariate analysis showed that age (≥60 y: HR = 0.531; p = 0.0182), pathological T4 (HR = 3.802; p < 0.0001), lymph node involvement (HR = 3.491; p = 0.0002), and lymphadenectomy (D2: HR = 1.801; p = 0.0356) were independent predictors of peritoneal recurrence. The overall survival was lower in patients who developed peritoneal recurrence than in those with other recurrence (HR = 1.594; p = 0.002). LIMITATIONS: The regimens of adjuvant chemotherapy were limited to oral 5-fluorouracil. CONCLUSIONS: Our findings clarified the risk factors for peritoneal recurrence in patients who underwent curative resection for colon cancer. See Video Abstract at http://links.lww.com/DCR/A609.

DOI： 10.1097/DCR.0000000000001002

Troponin I2 as a Specific Biomarker for Prediction of Peritoneal Metastasis in Gastric Cancer Reviewed

Koichi Sawaki, Mitsuro Kanda, Takashi Miwa, Shinichi Umeda, Haruyoshi Tanaka, Chie Tanaka, Daisuke Kobayashi, Masaya Suenaga, Norifumi Hattori, Masamichi Hayashi, Suguru Yamada, Goro Nakayama, Michitaka Fujiwara, Yasuhiro Kodera

Annals of Surgical Oncology Vol. 25 ( 7 ) page： 2083 - 2090 2018.7

Language：Japanese Publishing type：Research paper (scientific journal) Publisher：Springer New York LLC

Background: Although peritoneal metastasis is a serious concern in patients with gastric cancer, no acceptable and specific biomarker is available. We aimed to identify a candidate biomarker to predict peritoneal metastasis of gastric cancer. Methods: Metastatic pathway-specific transcriptome analysis was conducted by comparison of patient groups with no recurrence and with peritoneal, hepatic, and nodal recurrence. Fifteen cell lines and 262 pairs of surgically resected gastric tissues were subjected to messenger RNA (mRNA) expression analysis. Polymerase chain reaction array analysis was performed to explore coordinately expressed cancer-related genes. To evaluate the in situ protein localization and expression patterns, immunohistochemical staining was performed. Results: From transcriptome data, troponin I2 (TNNI2) was identified as a candidate molecule specifically overexpressed in gastric cancer prone to peritoneal metastasis. TNNI2 mRNA was expressed at differential levels, independent of differentiated phenotype of cell lines. Epithelial to mesenchymal transition-related genes, tumor inhibitor of metalloproteinase 1 (TIMP1), and vacuolar protein sorting 13 homolog A (VPS13A) were expressed with TNNI2 at correlation coefficient &gt
0.7. The optimal cutoff of TNNI2 expression was determined as 0.00017. High TNNI2 expression was significantly and specifically associated with peritoneal metastasis and served as an independent risk marker for peritoneal recurrence after curative gastrectomy. Prevalence of peritoneal recurrence increased in parallel with staining intensity of TNNI2. Conclusions: TNNI2 expression in gastric tissues may serve as a specific biomarker for prediction of peritoneal metastasis of gastric cancer and contribute to improvement of patient management.

DOI： 10.1245/s10434-018-6480-z

Clinical Implications of Lysyl Oxidase-Like Protein 2 Expression in Pancreatic Cancer Reviewed

Tanaka Nobutake, Yamada Suguru, Sonohara Fuminori, Suenaga Masaya, Hayashi Masamichi, Takami Hideki, Niwa Yukiko, Hattori Norifumi, Iwata Naoki, Kanda Mitsuro, Tanaka Chie, Kobayashi Daisuke, Nakayama Goro, Koike Masahiko, Fujiwara Michitaka, Fujii Tsutomu, Kodera Yasuhiro

SCIENTIFIC REPORTS Vol. 8 ( 1 ) page： 9846 2018.6

Emerging evidence of the molecular landscape specific for hematogenous metastasis from gastric cancer Reviewed

Dai Shimizu, Mitsuro Kanda, Yasuhiro Kodera

World Journal of Gastrointestinal Oncology Vol. 10 ( 6 ) page： 124 - 136 2018.6

Language：Japanese Publishing type：Research paper (scientific journal) Publisher：Baishideng Publishing Group Co

Gastric cancer (GC) is one of the most frequently diagnosed cancers in the world. Most GC patients are diagnosed when the cancer is in an advanced stage, and consequently, some develop metastatic lesions that generally cause cancer-related death. Metastasis establishment is affected by various conditions, such as tumor location, hemodynamics and organotropism. While digestive cancers may share a primary site, certain cases develop hematogenous metastasis with the absence of peritoneal metastasis, and vice versa. Numerous studies have revealed the clinicopathological risk factors for hematogenous metastasis from GC, such as vascular invasion, advanced age, differentiation, Borrmann type 1 or 2 and expansive growth. Recently, molecular mechanisms that contribute to metastatic site determination have been elucidated by advanced molecular biological techniques. Investigating the molecules that specifically participate in metastasis establishment in distinct secondary organs will lead to the development of novel biomarkers for patient stratification according to their metastatic risk and strategies for preventing and treating distinct metastases. We reviewed articles related to the molecular landscape of hematogenous metastasis from GC.

DOI： 10.4251/wjgo.v10.i6.124

A novel dual-marker expression panel for easy and accurate risk stratification of patients with gastric cancer. Reviewed International journal

Mitsuro Kanda, Kenta Murotani, Haruyoshi Tanaka, Takashi Miwa, Shinichi Umeda, Chie Tanaka, Daisuke Kobayashi, Masamichi Hayashi, Norifumi Hattori, Masaya Suenaga, Suguru Yamada, Goro Nakayama, Michitaka Fujiwara, Yasuhiro Kodera

Cancer medicine Vol. 7 ( 6 ) page： 2463 - 2471 2018.6

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

Development of specific biomarkers is necessary for individualized management of patients with gastric cancer. The aim of this study was to design a simple expression panel comprising novel molecular markers for precise risk stratification. Patients (n = 200) who underwent gastrectomy for gastric cancer were randomly assigned into learning and validation sets. Tissue mRNA expression levels of 15 candidate molecular markers were determined using quantitative PCR analysis. A dual-marker expression panel was created according to concordance index (C-index) values of overall survival for all 105 combinations of two markers in the learning set. The reproducibility and clinical significance of the dual-marker expression panel were evaluated in the validation set. The patient characteristics of the learning and validation sets were well balanced. The C-index values of combinations were significantly higher compared with those of single markers. The panel with the highest C-index (0.718) of the learning set comprised SYT8 and MAGED2, which clearly stratified patients into low-, intermediate-, and high-risk groups. The reproducibility of the panel was demonstrated in the validation set. High expression scores were significantly associated with larger tumor size, vascular invasion, lymph node metastasis, peritoneal metastasis, and advanced disease. The dual-marker expression panel provides a simple tool that clearly stratifies patients with gastric cancer into low-, intermediate-, and high risk after gastrectomy.

DOI： 10.1002/cam4.1522

IDENTIFICATION OF MOLECULES DRIVING HEPATIC METASTASIS FORMATION OF GASTRIC CANCER CELLS Reviewed

Kanda Mitsuro, Tanaka Chie, Kobayashi Daisuke, Suenaga Masaya, Takami Hideki, Hattori Norifumi, Niwa Yukiko, Hayashi Masamichi, Yamada Suguru, Nakayama Goro, Koike Masahiko, Fujiwara Michitaka, Kodera Yasuhiro

GUT Vol. 67 page： A5 - A5 2018.6

Significance of Lysyl oxidase-like 2 gene expression on the epithelial-mesenchymal status of hepatocellular carcinoma Reviewed

Go Ninomiya, Suguru Yamada, Masamichi Hayashi, Shigeomi Takeda, Masaya Suenaga, Hideki Takami, Mitsuro Kanda, Naoki Iwata, Yukiko Niwa, Chie Tanaka, Daisuke Kobayashi, Tsutomu Fujii, Goro Nakayama, Hiroyuki Sugimoto, Masahiko Koike, Michitaka Fujiwara, Yasuhiro Kodera

Oncology Reports Vol. 39 ( 6 ) page： 2664 - 2672 2018.6

Language：Japanese Publishing type：Research paper (scientific journal) Publisher：Spandidos Publications

In the present study, we investigated the role of lysyl oxidase-like 2 (LOXL2), the correlation between LOXL2 and epithelial to mesenchymal transition (EMT) and the effects of using β-aminopropionitrile (BAPN) to inhibit LOXL2 with the aim of reducing tumor progression in hepatocellular carcinoma (HCC). The expression level of LOXL2 was evaluated in HCC and adjacent non-cancerous tissues using quantitative reverse transcription polymerase chain reaction and clinicopathological analyses. The effects of BAPN on cell proliferation, migration and invasion were investigated in vitro. Additionally, LOXL2 expression was assessed in the culture supernatants of HCC cell lines. Our results revealed that LOXL2 expression was higher in HCC cell lines and tissues. There was a significant correlation between EMT status and LOXL2 levels (P=0.004). BAPN reduced migration and invasion in HCC cells. HCC patients with high levels of LOXL2 expression had relatively shorter disease-free survival (P=0.009) and overall survival (P=0.035). The expression level of LOXL2 was similar between cell supernatants and HCC cell lines. A multivariate analysis demonstrated that portal vein invasion (P=0.015), venous invasion (P=0.026), serum AFP (α-fetoprotein) levels (P=0.019) and LOXL2 expression (P=0.009) were independent prognostic factors. Our results indicated that a higher level of LOXL2 may contribute to tumor progression, indicating that LOXL2 has clinical value as a therapeutic target in HCC.

DOI： 10.3892/or.2018.6349

Postoperative adalimumab maintenance therapy for Japanese patients with Crohn’s disease: a single-center, single-arm phase II trial (CCOG-1107 study) Reviewed

Takahiro Asada, Goro Nakayama, Chie Tanaka, Daisuke Kobayashi, Kazuhiro Ezaka, Norifumi Hattori, Mitsuro Kanda, Suguru Yamada, Masahiko Koike, Yasuhiro Kodera

Surgery Today Vol. 48 ( 6 ) page： 609 - 617 2018.6

Language：Japanese Publishing type：Research paper (scientific journal) Publisher：Springer Tokyo

Purpose: To investigate the efficacy and safety of planned postoperative adalimumab (ADA) therapy for Japanese patients with Crohn’s disease (CD). Methods: The subjects of this study were 26 patients who underwent bowel resection for CD. All patients received subcutaneous injections of ADA 160/80 mg at the time of surgery and 2 weeks later, followed by 40 mg every 2 weeks thereafter. The primary endpoint of this study was the incidence of endoscopic recurrence, defined by Rutgeerts endoscopic recurrence scale ≥ i2, 1 year after surgery. Results: After the median follow-up period of 41.3 months, the median number of treatments with ADA was 56 and the median time-to-treatment failure was 25.6 months. Endoscopic recurrence was observed in 34.6% of the patients 1 year after surgery. Univariate analyses showed that preoperative ADA therapy was significantly associated with endoscopic recurrence. Clinical recurrence developed in 16.7% of the patients within 1 year after surgery. Secondary surgery for recurrence was not required. Although adverse events (≥ grade 3) were experienced by 15.4% of patients, none was withdrawn from this study. Conclusion: Planned postoperative ADA therapy reduced the incidence of endoscopic and clinical recurrence after bowel resection in Japanese patients with CD. Trial registration: This trial is registered with the University Hospital Medical Information Network (UMIN000007514).

DOI： 10.1007/s00595-018-1634-y

A phase II trial to evaluate the efficacy of panitumumab combined with fluorouracil-based chemotherapy for metastatic colorectal cancer: the PF trial. Reviewed International journal

Yoshinori Munemoto, Mitsuro Kanda, Koji Oba, Ho Min Kim, Hiroyoshi Takemoto, Tadamichi Denda, Naoki Nagata, Nao Takano, Mutsumi Fukunaga, Masato Kataoka, Yukihiko Tokunaga, Junichi Sakamoto, Hideyuki Mishima

Cancer chemotherapy and pharmacology Vol. 81 ( 5 ) page： 829 - 838 2018.5

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

PURPOSE: Fluorouracil monotherapy, instead of the FOLFOX or FOLFIRI regimen, is administered to patients intolerant to oxaliplatin or irinotecan because of their adverse effects. A prospective clinical trial was designed to evaluate the efficacy and safety of fluorouracil monotherapy combined with panitumumab administered to patients with KRAS wild-type (WT) metastatic colorectal cancer (mCRC) intolerant to oxaliplatin and irinotecan. Screening for potential serum biomarkers to predict early therapeutic responses was conducted. METHODS: This single-arm, open-label multicenter phase II trial recruited patients with KRAS WT mCRC from 16 institutes between January 2012 and October 2014. Panitumumab (6 mg/kg) was intravenously administered every 2 weeks, combined with fluorouracil monotherapy, in 2-week cycles. The primary objective was overall response rate, and secondary endpoints included disease-control rate, progression-free survival, overall survival, toxicity, and blood-test data. RESULTS: Forty patients (male, 65.0%; median age, 74 years; colon cancer, 72.5%) met eligibility criteria and received 7 cycles (median) of fluorouracil chemotherapy combined with panitumumab. There were no treatment-related deaths. Median time to treatment failure was 3.2 months. 23 (57.5%) patients experienced at least one adverse effect ≥ grade 3. The response rate was 10.0% (95% confidence interval 2.8-23.7%). Median progression-free survival and overall survival were 4.3 and 11.3 months, respectively. Total lactase dehydrogenase (LDH) levels and those of LDH-4 and LDH-5, quickly changed with disease reduction or progression. CONCLUSIONS: Fluorouracil monotherapy combined with panitumumab was safely administered to patients with KRAS WT mCRC intolerant to oxaliplatin and irinotecan. Serum LDH levels may predict early responses.

DOI： 10.1007/s00280-018-3556-1

Integrated multigene expression panel to prognosticate patients with gastric cancer. Reviewed International journal

Oncotarget Vol. 9 ( 27 ) page： 18775 - 18785 2018.4

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

Most of the proposed individual markers had limited clinical utility due to the inherent biological and genetic heterogeneity of gastric cancer. We aimed to build a new molecular-based model to predict prognosis in patients with gastric cancer. A total of 200 patients who underwent gastric resection for gastric cancer were divided into learning and validation cohorts using a table of random numbers in a 1:1 ratio. In the learning cohort, mRNA expression levels of 15 molecular markers in gastric tissues were analyzed and concordance index (C-index) values of all single and combinations of the 15 candidate markers for overall survival were calculated. The multigene expression panel was designed according to C-index values and the subpopulation index. Expression scores were determined with weighting according to the coefficient of each constituent. The reproducibility of the panel was evaluated in the validation cohort. C-index values of the 15 single candidate markers ranged from 0.506-0.653. Among 32,767 combinations, the optimal and balanced expression panel comprised four constituents (MAGED2, SYT8, BTG1, and FAM46) and the C-index value was 0.793. Using this panel, patients were provisionally categorized with scores of 1-3, and clearly stratified into favorable, intermediate, and poor overall survival groups. In the validation cohort, both overall and disease-free survival rates decreased incrementally with increasing expression scores. Multivariate analysis revealed that the expression score was an independent prognostic factor for overall survival after curative gastrectomy. We developed an integrated multigene expression panel that simply and accurately stratified risk of patients with gastric cancer.

DOI： 10.18632/oncotarget.24661

Emerging evidence of molecular biomarkers in hepatocellular carcinoma Reviewed

Shinichi Umeda, Mitsuro Kanda, Yasuhiro Kodera

Histology and Histopathology Vol. 33 ( 4 ) page： 343 - 355 2018.4

Language：Japanese Publishing type：Research paper (scientific journal) Publisher：Histology and Histopathology

Hepatocellular carcinoma (HCC) is the third most common cause of cancer-related death worldwide. Patients with HCC generally present at an advanced stage resulting in death within 6-20 months. Therefore, novel treatment modalities and sensitive prognostic markers that can decrease the mortality rate of HCC are required. HCC is a complex and heterogeneous tumor with multiple genetic aberrations. It has been well described that accumulation of genetic and epigenetic changes leads to the clonal selection of cancer cells harboring aggressive tumor behavior. Aberrant expression of cancer-related genes is one of the hallmarks of cancer cells and plays a role in hepatocarcinogenesis. Epigenetic alterations, such as the alteration of DNA methylation and histone modification in cancer cells, can also induce the activation and inactivation of cancer-related genes. Studies have shed light on the link between HCC-related genes and molecules, and a better understanding of the mechanisms of HCC pathogenesis could be translated into clinical biomarker tools. Moreover, analyses of genetic and epigenetic alterations have identified potential biomarkers that might be targeted therapeutically. In this review, we update the current knowledge of biomarkers in HCC, examine recently published literature, and introduce some representative molecules in each category.

DOI： 10.14670/HH-11-936

Clinical Signatures of Mucinous and Poorly Differentiated Subtypes of Colorectal Adenocarcinomas by a Propensity Score Analysis of an Independent Patient Database from Three Phase III Trials. Reviewed International journal

Mitsuro Kanda, Koji Oba, Toru Aoyama, Kosuke Kashiwabara, Shuhei Mayanagi, Hiromichi Maeda, Michitaka Honda, Chikuma Hamada, Sotaro Sadahiro, Junichi Sakamoto, Shigetoyo Saji, Takaki Yoshikawa

Diseases of the colon and rectum Vol. 61 ( 4 ) page： 461 - 471 2018.4

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

BACKGROUND: Although colorectal cancer comprises several histological subtypes, the influences of histological subtypes on disease progression and treatment responses remain controversial. OBJECTIVE: We sought to evaluate the prognostic relevance of mucinous and poorly differentiated histological subtypes of colorectal cancer by the propensity score weighting analysis of prospectively collected data from multi-institute phase III trials. DESIGN: Independent patient data analysis of a pooled database from 3 phase III trials was performed. SETTINGS: An integrated database of 3 multicenter prospective clinical trials (the Japanese Foundation for Multidisciplinary Treatment of Cancer 7, 15, and 33) was the source of study data. INTERVENTIONS: Surgery alone or postoperative adjuvant chemotherapy was offered in patients with resectable colorectal cancer. MAIN OUTCOME MEASURES: To balance essential variables more strictly for the comparison analyses, propensity score weighting was conducted with the use of a multinomial logistic regression model. We evaluated the clinical signatures of mucinous and poorly differentiated subtypes with regard to postoperative survival, recurrence, and chemosensitivity. RESULTS: Of 5489 patients, 136 (2.5%) and 155 (2.8%) were pathologically diagnosed with poorly differentiated and mucinous subtypes. The poorly differentiated subtypes were associated with a poorer prognosis than the "others" group (HR, 1.69; 95% CI, 1.00-2.87; p = 0.051), particularly in the patient subgroup of adjuvant chemotherapy (HR, 2.16). Although the mucinous subtype had a marginal prognostic impact among patients with stage I to III colorectal cancer (HR, 1.33; 95% CI, 0.90-1.96), it was found to be an independent prognostic factor in the subpopulation of patients with stage II disease, being associated with a higher prevalence of peritoneal recurrence. LIMITATIONS: The treatment regimens of postoperative chemotherapy are now somewhat outdated. CONCLUSIONS: Both mucinous and poorly differentiated subtypes have distinct clinical characteristics. Patients with the mucinous subtype require special attention during follow-up, even for stage II disease, because of the risk of peritoneal or local recurrence. See Video Abstract at http://links.lww.com/DCR/A531.

DOI： 10.1097/DCR.0000000000001022

門脈合併切除膵癌における脾静脈再建-するvsしない- しない Reviewed

藤井努, 服部正嗣, 山田豪, 猪川祥邦, 神田光郎, 高見秀樹, 吉岡伊作, 渋谷和人, 奥村知之, 中尾昭公, 小寺泰弘

日本外科学会定期学術集会抄録集 Vol. 118回 page： 743 - 743 2018.4

Significance of SYT8 For the Detection, Prediction, and Treatment of Peritoneal Metastasis From Gastric Cancer. Reviewed International journal

Mitsuro Kanda, Dai Shimizu, Haruyoshi Tanaka, Chie Tanaka, Daisuke Kobayashi, Masamichi Hayashi, Naoki Iwata, Yukiko Niwa, Suguru Yamada, Tsutomu Fujii, Hiroyuki Sugimoto, Kenta Murotani, Michitaka Fujiwara, Yasuhiro Kodera

Annals of surgery Vol. 267 ( 3 ) page： 495 - 503 2018.3

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

OBJECTIVE: To develop novel diagnostic and therapeutic targets specific for peritoneal metastasis of gastric cancer (GC). BACKGROUND: Advanced GC frequently recurs because of undetected micrometastases even after curative resection. Peritoneal metastasis has been the most frequent recurrent pattern after gastrectomy and is incurable. METHODS: We conducted a recurrence pattern-specific transcriptome analysis in an independent cohort of 16 patients with stage III GC who underwent curative gastrectomy and adjuvant S-1 for screening candidate molecules specific for peritoneal metastasis of GC. Next, another 340 patients were allocated to discovery and validation sets (1:2) to evaluate the diagnostic and predictive value of the candidate molecule. The results of quantitative reverse-transcription PCR and immunohistochemical analysis were correlated with clinical characteristics and survival. The effects of siRNA-mediated knockdown on phenotype and fluorouracil sensitivity of GC cells were evaluated in vitro, and the therapeutic effects of siRNAs were evaluated using a mouse xenograft model. RESULTS: Synaptotagmin VIII (SYT8) was identified as a candidate biomarker specific to peritoneal metastasis. In the discovery set, the optimal cut-off of SYT8 expression was established as 0.005. Expression levels of SYT8 mRNA in GC tissues were elevated in the validation set comprising patients with peritoneal recurrence or metastasis. SYT8 levels above the cut-off value were significantly and specifically associated with peritoneal metastasis, and served as an independent prognostic marker for peritoneal recurrence-free survival of patients with stage II/III GC. The survival difference between patients with SYT8 levels above and below the cut-off was associated with patients who received adjuvant chemotherapy. Inhibition of SYT8 expression by GC cells correlated with decreased invasion, migration, and fluorouracil resistance. Intraperitoneal administration of SYT8-siRNA inhibited the growth of peritoneal nodules and prolonged survival of mice engrafted with GC cells. CONCLUSIONS: SYT8 represents a promising target for the detection, prediction, and treatment of peritoneal metastasis of GC.

DOI： 10.1097/SLA.0000000000002096

Preoperative Albumin-Bilirubin Grade Predicts Recurrences After Radical Gastrectomy in Patients with pT2-4 Gastric Cancer. Reviewed International journal

Mitsuro Kanda, Chie Tanaka, Daisuke Kobayashi, Hiroaki Uda, Kenichi Inaoka, Yuri Tanaka, Masamichi Hayashi, Naoki Iwata, Suguru Yamada, Tsutomu Fujii, Hiroyuki Sugimoto, Kenta Murotani, Michitaka Fujiwara, Yasuhiro Kodera

World journal of surgery Vol. 42 ( 3 ) page： 773 - 781 2018.3

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

BACKGROUND: The albumin-bilirubin (ALBI) score was initially developed for assessing liver dysfunction severity and was suggested to have prognostic value in patients with hepatocellular carcinoma. We aimed to evaluate the prognostic impact of ALBI grade in patients with advanced gastric cancer (GC) after radical gastrectomy. METHODS: This study included 283 patients who underwent radical gastrectomy for pT2-4 GC without preoperative treatment. ALBI was calculated as follows: (log10 bilirubin (μmol/L) × 0.66) + (albumin (g/L) × -0.0852) and categorized into grades 1 (≤-2.60), 2 (-2.60<, ≤-1.39) and 3 (-1.39<). RESULTS: The median ALBI score was -2.96, and a number of patients in ALBI grades 1, 2 and 3 were 228, 55 and 0, respectively. Patients with ALBI grade 2 had a lower administration rate of adjuvant chemotherapy than those with ALBI grade 1, whereas no significant differences were found in morbidity rate and disease stage. The ALBI grade 2 group was more likely to have shorter disease-specific and disease-free survival compared with the ALBI grade 1 group. Multivariable analysis identified ALBI grade 2 as an independent prognostic factor for disease-free survival (hazard ratio 1.97, 95% confidence interval 1.10-3.47, p = 0.0242). Survival differences between ALBI grade 1 and 2 groups were increased in the patient subset that received adjuvant chemotherapy. ALBI grade 2 was correlated with a shortened duration of administration of postoperative S-1 adjuvant. CONCLUSIONS: ALBI grade serves as a simple and promising predictive factor for disease-free and disease-specific survival in patients with pT2-4 GC after radical gastrectomy.

DOI： 10.1007/s00268-017-4234-x

Identification of a novel molecule target for the diagnosis, prediction, and treatment of hepatic metastasis of gastric cancer. Reviewed

Kanda Mitsuro, Tanaka Haruyoshi, Miwa Takashi, Kobayashi Daisuke, Tanaka Chie, Takami Hideki, Hayashi Masamichi, Iwata Naoki, Niwa Yukiko, Yamada Suguru, Nakayama Goro, Sugimoto Hiroyuki, Koike Masahiko, Fujiwara Michitaka, Kodera Yasuhiro

JOURNAL OF CLINICAL ONCOLOGY Vol. 36 ( 4 ) page： . 2018.2

Phase I study of chemoradiotherapy using gemcitabine plus nab-paclitaxel for unresectable locally advanced pancreatic cancer. Reviewed

Yamada Suguru, Fujii Tsutomu, Takano Nao, Takami Hideki, Suenaga Masaya, Niwa Yukiko, Hayashi Masamichi, Iwata Naoki, Kanda Mitsuro, Kobayashi Daisuke, Tanaka Chie, Nakayama Goro, Sugimoto Hiroyuki, Koike Masahiko, Fujiwara Michitaka, Kodera Yasuhiro

JOURNAL OF CLINICAL ONCOLOGY Vol. 36 ( 4 ) page： . 2018.2

Clinical implication of nutrition for neoadjuvant therapy and impact of nutritional support in pancreatic cancer. Reviewed

Tashiro Mitsuru, Yamada Suguru, Fujii Tsutomu, Hattori Norifumi, Takami Hideki, Suenaga Masaya, Niwa Yukiko, Hayashi Masamichi, Iwata Naoki, Kanda Mitsuro, Tanaka Chie, Kobayashi Daisuke, Nakayama Goro, Sugimoto Hiroyuki, Koike Masahiko, Fujiwara Michitaka, Kodera Yasuhiro

JOURNAL OF CLINICAL ONCOLOGY Vol. 36 ( 4 ) 2018.2

Clinical implication of nutrition for neoadjuvant therapy and impact of nutritional support in pancreatic cancer.

JOURNAL OF CLINICAL ONCOLOGY Vol. 36 ( 4 ) page： . 2018.2

Identification of a novel molecule target for the diagnosis, prediction, and treatment of hepatic metastasis of gastric cancer.

JOURNAL OF CLINICAL ONCOLOGY Vol. 36 ( 4 ) page： . 2018.2

Phase I study of chemoradiotherapy using gemcitabine plus nab-paclitaxel for unresectable locally advanced pancreatic cancer.

JOURNAL OF CLINICAL ONCOLOGY Vol. 36 ( 4 ) page： . 2018.2

Review of recent molecular landscape knowledge of gastric cancer Reviewed

Dai Shimizu, Mitsuro Kanda, Yasuhiro Kodera

HISTOLOGY AND HISTOPATHOLOGY Vol. 33 ( 1 ) page： 11 - 26 2018.1

Language：Japanese Publishing type：Research paper (scientific journal) Publisher：F HERNANDEZ

Gastric cancer (GC) is one of the most frequently diagnosed cancers worldwide and its prognosis remains dismal. One reason for poor outcomes of GC patients is that most are diagnosed when the cancer has already advanced. Novel biomarkers with high sensitivity and specificity are needed to diagnose GC in the early stage. In addition, to improve the outcome of patients with GC, patient stratification according to prognostic factors and sensitivity to chemo(radio) therapy are necessary. Appropriate follow-up criteria and individualized treatment will contribute to improvement in prognosis. Over the past decades, development of microarray and sequencing technology have coalesced to increase reports regarding epigenetic alterations that affect the character of malignancies including GC. These advances help our understanding of gastric carcinogenesis and have the possibility of improving the prognosis of GC by contributing to the optimization of therapeutic strategies. Further development of biomarkers for diagnosis and prognosis are desperately needed. Here, we enumerate and describe some GC-related molecules reported over the past few years that may be useful biomarkers.

DOI： 10.14670/HH-11-898

Effectiveness of plasma activated lactated Ringer's solution on pancreatic cancer cells in vitro and in vivo

Sato Yusuke, Yamada Suguru, Takeda Shigeomi, Kanda Mitsuo, Nakayama Goro, Koike Masahiko, Fujiwara Michitaka, Kodera Yasuhiro

CANCER SCIENCE Vol. 109 page： 707-707 2018.1

Oncogenic function of miR-23b-3p in hepatocellular carcinoma

Masamichi Hayashi, Yamada Suguru, Kanda Mitsuro, Tanaka Chie, Fujiwara Michitaka, Kodera Yasuhiro

CANCER SCIENCE Vol. 109 page： 1123-1123 2018.1

Nutritional Recovery after Open and Laparoscopic Distal Gastrectomy for Early Gastric Cancer: A Prospective Multicenter Comparative Trial (CCOG1204) Reviewed

Hidenobu Matsushita, Chie Tanaka, Kenta Murotani, Kazunari Misawa, Seiji Ito, Yuichi Ito, Mitsuro Kanda, Yoshinari Mochizuki, Kiyoshi Ishigure, Toyohisa Yaguchi, Jin Teramoto, Hiroshi Nakayama, Yoshihisa Kawase, Michitaka Fujiwara, Yasuhiro Kodera

DIGESTIVE SURGERY Vol. 35 ( 1 ) page： 11 - 18 2018

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

Background: Little information from prospective clinical trials is available on the influences of surgical approaches on postoperative body compositions and nutritional status. We designed a prospective non-randomized trial to compare postoperative chronological changes in body composition and nutritional status between laparoscopic and open distal gastrectomy for stage I gastric cancer (GC). Methods: Body compositions and nutritional indicators in blood tests were measured at the baseline and at the 1st, 3rd, 6th, and 12th postoperative months (POM). The primary end point was the decrease relative to the baseline in the body muscle mass at POM 6. Results: Ninety-six patients for the laparoscopic group and 52 for the open group were eligible for data analysis. No significant differences were found in any baseline demographics, body compositions, and nutritional indicators between the groups. The changes of body muscle mass at POM 6 were similar in both groups. Overall, no significant differences between the groups were observed in any of the body composition and nutritional indicators during the first year after surgery. Conclusions: Postoperative body compositions and nutritional status were not affected by surgical approaches during the first 12 months after surgery in patients who underwent distal gastrectomy for stage I GC. (c) 2017 S. Karger AG, Basel

DOI： 10.1159/000458714

Perioperative Serum Carcinoembryonic Antigen Levels Predict Recurrence and Survival of Patients with Pathological T2-4 Gastric Cancer Treated with Curative Gastrectomy Reviewed

Hiroaki Uda, Mitsuro Kanda, Chie Tanaka, Daisuke Kobayashi, Kenichi Inaoka, Yuri Tanaka, Masamichi Hayashi, Naoki Iwata, Suguru Yamada, Tsutomu Fujii, Hiroyuki Sugimoto, Kenta Murotani, Michitaka Fujiwara, Yasuhiro Kodera

DIGESTIVE SURGERY Vol. 35 ( 1 ) page： 55 - 63 2018

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

Background/Aims: Do serum carcinoembryonic antigen (CEA) and carbohydrate antigen (CA) 19-9 levels serve as prognostic indicators in patients with gastric cancer (GC)? This is a question that has long been disputed. The aim of this study was to evaluate the significance of perioperative serum levels of CEA and CA19-9 for predicting the recurrence and long-term survival after patients with pT2-4 GC undergo curative gastrectomy. Methods: This study included 251 patients with radically resected pT2-4 GC without preoperative treatment. Associations between the preoperative and postoperative serum levels of CEA or CA19-9 and postoperative long-term outcomes and recurrence patterns were evaluated. Results: Preoperative CEA > 5.0 ng/mL was an independent prognostic factor of overall survival. Elevation of both preoperative CEA and CA19-9 levels showed no synergistic adverse effects on prognosis. Preoperative levels of these markers achieved superior predictive performance compared with the postoperative values. Adverse prognosis is significantly associated with persistent elevation of CEA levels before and after gastrectomy. Elevation of CEA levels, particularly at postoperative measurement, was significantly associated with hematogenous recurrence. Conclusion: Determination of perioperative CEA levels facilitated predictions of recurrence patterns and prognosis among patients with pT2-4 GC who underwent curative gastrectomy. (c) 2017 S. Karger AG, Basel

DOI： 10.1159/000471931

Review of recent efforts to discover biomarkers for early detection, monitoring, prognosis, and prediction of treatment responses of patients with gastric cancer Reviewed

Sawaki Koichi, Kanda Mitsuro, Kodera Yasuhiro

EXPERT REVIEW OF GASTROENTEROLOGY & HEPATOLOGY Vol. 12 ( 7 ) page： 657 - 670 2018

Prognostic Impact of Portal System Invasion in Pancreatic Cancer Based on Image Classification

Morimoto Daishi, Yamada Suguru, Murotani Kenta, Sonohara Fuminori, Takami Hideki, Suenaga Masaya, Hayashi Masamichi, Niwa Yukiko, Tashiro Mitsuru, Hattori Norifumi, Iwata Naoki, Kanda Mitsuro, Tanaka Chie, Kobayashi Daisuke, Nakayama Goro, Koike Masahiko, Fujiwara Michitaka, Fujii Tsutomu, Kodera Yasuhiro

PANCREAS Vol. 47 ( 10 ) page： 1350 - 1356 2018

Randomized phase II study of daily and alternate-day administration of S-1 for advanced gastric cancer (JFMC43-1003) Reviewed

Hiroaki Tanaka, Mitsuro Kanda, Satoshi Morita, Masataka Taguri, Kazuhiro Nishikawa, Mitsuo Shimada, Kazuya Muguruma, Keisuke Koeda, Masazumi Takahashi, Mikihito Nakamori, Hiroyuki Konno, Akihito Tsuji, Yoshinori Hosoya, Tetsuhiko Shirasaka, Susumu Yamamitsu, Michio Sowa, Masaki Kitajima, Masazumi Okajima, Michiya Kobayashi, Junichi Sakamoto, Shigetoyo Saji, Kosei Hirakawa

INTERNATIONAL JOURNAL OF CLINICAL ONCOLOGY Vol. 22 ( 6 ) page： 1052 - 1059 2017.12

Language：Japanese Publishing type：Research paper (scientific journal) Publisher：SPRINGER JAPAN KK

Purpose Although S-1 based chemotherapy for patients with advanced gastric cancer has generally been accepted in Japan, discontinuations of treatment have been reported due to grade 3 or more adverse events. The present randomized phase II study was conducted to test whether alternate-day administration of S-1 would be comparably efficient and reduce adverse events compared with conventional daily administration in the first-line chemotherapy for advanced gastric cancer.
Methods 132 patients with advanced gastric cancer were randomly assigned to 1:2 ratios to receive treatment with daily at a standard dose of 80 mg/m(2)/day or alternate-day administration group received S-1 on 4 days a week. The primary end point was progression-free survival (PFS), and the secondary end points were safety, overall survival, time to treatment failure (TTF), disease control rate, and response rate.
Results The 6-month PFS rate of the alternate-day administration group was 20.9% and failed to show significant difference from the pre-specified threshold at 15% (p = 0.117), whereas that of the daily administration group was 39.1% and significantly higher than the threshold (p = 0.001). The hazard ratio of the alternate-day administration group compared with the daily administration group was 1.753 (95% confidence interval (CI) 1.15-2.68, p = 0.010). With regard to OS, the hazard ratio of the alternate-day administration group compared with the daily administration group was 1.487 (95% CI 0.97-2.29, p = 0.072). The median TTF were 4.2 and 2.8 months in the daily and alternate-day administration group, respectively (p = 0.007).
Conclusion The alternate-day administration of S-1 was not recommended as the first-line therapy for patients with advanced gastric cancer.

DOI： 10.1007/s10147-017-1157-3

Prevalence of Helicobacter pylori infection in dyspeptic patients in Andkhoy Afghanistan Reviewed

Mohammad Hussain Hamrah, Mohammad Shoaib Hamrah, Mohammad Hassan Hamrah, Mitsuro Kanda, Ahmad Edris Hamrah, Ahmad Elias Dahi, Farhat Homayoun, Mohammad Hashem Hamrah, Akbar Fotouhi, Junichi Sakamoto

Asian Pacific Journal of Cancer Prevention Vol. 18 ( 11 ) page： 3123 - 3127 2017.11

Language：English Publishing type：Research paper (scientific journal) Publisher：Asian Pacific Organization for Cancer Prevention

Background: The prevalence of Helicobacter pylori (H. pylori) infection is reported to be more than 50% worldwide. It has been associated with peptic ulcer disease, gastric carcinoma, and mucosal-associated lymphoid tissue lymphoma. The seroprevalence of H. pylori varies greatly among societies and geographical locations. The objective of this study was to determine the seroprevalence and factors associated with H. pylori infection among dyspeptic patients in Afghanistan. Materials and Methods: This cross-sectional study was designed to determine the seroprevalence of H. pylori among dyspeptic patients in an outpatient clinic in Andkhoy, Afghanistan from January 2017 to April 2017. Data were obtained from patients using a questionnaire, including socio-demographic data and history of smoking and dyspeptic symptoms. Serum samples were also collected from the patients and tested for H. pylori antibodies using the enzyme-linked immunosorbent assay. Results: A total of 152 patients with dyspepsia were included in the analysis
59 were men (40.0%), and 93 were women (60.0%). The overall seroprevalence of H. pylori was 75.6%. The predictor of seroprevalence of H. pylori was found to be illiteracy (odds ratio [OR] 4.99, 95% confidence interval [CI] 1.03-24.17), epigastric pain (OR 12.01, 95% CI 3.56- 40.52), and rural population (OR 9.66, 95% CI 3.36- 27.82). There was an inverse association between employed status and seroprevalence of H. pylori (OR 0.08, 95% CI 0.01- 0.52). Conclusions: The seroprevalence of H. pylori was high among patient with dyspepsia in an outpatient clinic in Afghanistan. Illiteracy, unemployment and rural populations, and epigastric pain were significantly associated with H. pylori infection.

DOI： 10.22034/APJCP.2017.18.11.3123

Development and validation of a prognostic nomogram for colorectal cancer after radical resection based on individual patient data from three large-scale phase III trials. Reviewed International journal

Michitaka Honda, Koji Oba, Takashi Akiyoshi, Hiromichi Maeda, Kosuke Kashiwabara, Mitsuro Kanda, Shuhei Mayanagi, Toru Aoyama, Chikuma Hamada, Sotaro Sadahiro, Yosuke Fukunaga, Masashi Ueno, Junichi Sakamoto, Shigetoyo Saji, Takaki Yoshikawa

Oncotarget Vol. 8 ( 58 ) page： 99150 - 99160 2017.11

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

Background: Few prediction models have so far been developed and assessed for the prognosis of patients who undergo curative resection for colorectal cancer (CRC). Materials and Methods: We prepared a clinical dataset including 5,530 patients who participated in three major randomized controlled trials as a training dataset and 2,263 consecutive patients who were treated at a cancer-specialized hospital as a validation dataset. All subjects underwent radical resection for CRC which was histologically diagnosed to be adenocarcinoma. The main outcomes that were predicted were the overall survival (OS) and disease free survival (DFS). The identification of the variables in this nomogram was based on a Cox regression analysis and the model performance was evaluated by Harrell's c-index. The calibration plot and its slope were also studied. For the external validation assessment, risk group stratification was employed. Results: The multivariate Cox model identified variables; sex, age, pathological T and N factor, tumor location, size, lymphnode dissection, postoperative complications and adjuvant chemotherapy. The c-index was 0.72 (95% confidence interval [CI] 0.66-0.77) for the OS and 0.74 (95% CI 0.69-0.78) for the DFS. The proposed stratification in the risk groups demonstrated a significant distinction between the Kaplan-Meier curves for OS and DFS in the external validation dataset. Conclusions: We established a clinically reliable nomogram to predict the OS and DFS in patients with CRC using large scale and reliable independent patient data from phase III randomized controlled trials. The external validity was also confirmed on the practical dataset.

DOI： 10.18632/oncotarget.21845

FBXO50 Enhances the Malignant Behavior of Gastric Cancer Cells Reviewed

Takashi Miwa, Mitsuro Kanda, Haruyoshi Tanaka, Chie Tanaka, Daisuke Kobayashi, Shinichi Umeda, Naoki Iwata, Masamichi Hayashi, Suguru Yamada, Tsutomu Fujii, Michitaka Fujiwara, Yasuhiro Kodera

ANNALS OF SURGICAL ONCOLOGY Vol. 24 ( 12 ) page： 3771 - 3779 2017.11

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

Challenges to our understanding the molecular mechanisms of the progression of gastric cancer (GC) must be overcome to facilitate the identification of novel biomarkers and therapeutic targets. In this article, we analyzed the expression of the gene encoding F-box-only 50 (FBXO50) and determined whether it contributes to the malignant phenotype of GC.
FBXO50 messenger RNA (mRNA) levels and copy numbers of the FBXO50 locus were determined in 10 GC cell lines and a nontumorigenic epithelial cell line. Polymerase chain reaction array analysis was performed to identify genes coordinately expressed with FBXO50. The effects of inhibiting FBXO50 on GC cell proliferation, adhesion, invasiveness, and migration were evaluated using a small interfering RNA targeted to FBXO50 mRNA. To evaluate the clinical significance of FBXO50 expression, we determined the levels of FBXO50 mRNA in tissues acquired from 200 patients with GC.
The levels of FBXO50 mRNA were increased in five GC cell lines and positively correlated with those of ITGA5, ITGB1, MMP2, MSN, COL5A2, GNG11, and WNT5A. Copy number gain of the FBXO50 locus was detected in four GC cell lines. Inhibition of FBXO50 expression significantly decreased the proliferation, adhesion, migration, and invasiveness of GC cell lines. In clinical samples, high FBXO50 expression correlated with increased pT4, invasive growth, lymph node metastasis, and positive peritoneal lavage cytology. Patients with high FBXO50 expression had a significantly higher prevalence of recurrence after curative gastrectomy and were more likely to experience shorter overall survival.
FBXO50 may represent a biomarker for GC phenotypes and as a target for therapy.

DOI： 10.1245/s10434-017-5882-7

Clinical impact of postoperative surgical complications on the colorectal cancer survival and recurrence: Analyses of pooled individual patients' data from three large phase III randomized trials

Aoyama T., Oba K., Honda M., Sadahiro S., Hamada C., Mayanagi S., Kanda M., Maeda H., Sakamoto J., Saji S., Yoshikawa T.

ANNALS OF ONCOLOGY Vol. 28 page： . 2017.11

Clinical impact of tumor location on the colon cancer survival and recurrence: analyses of pooled data from three large phase III randomized clinical trials. Reviewed International journal

Toru Aoyama, Kosuke Kashiwabara, Koji Oba, Michitaka Honda, Sotaro Sadahiro, Chikuma Hamada, Hiromichi Maeda, Shuhei Mayanagi, Mitsuro Kanda, Junichi Sakamoto, Shigetoyo Saji, Takaki Yoshikawa

Cancer medicine Vol. 6 ( 11 ) page： 2523 - 2530 2017.11

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

The aim of the present study was to determine whether or not the overall survival (OS) and disease-free survival (DFS) were affected by the tumor location in patients who underwent curative resection for colon cancer in a pooled analysis of three large phase III studies performed in Japan. In total, 4029 patients were included in the present study. Patients were classified as having right-side colon cancer (RC) if the primary tumor was located in the cecum, ascending colon, hepatic flexure or transverse colon, and left-side colon cancer (LCC) if the tumor site was within the splenic flexure, descending colon, sigmoid colon or recto sigmoid junction. The risk factors for the OS and DFS were analyzed. In the present study, 1449 patients were RC, and 2580 were LCC. The OS rates at 3 and 5 years after surgery were 87.6% and 81.6% in the RC group and 91.5% and 84.5% in the LCC group, respectively. Uni- and multivariate analyses showed that RRC increased the risk of death by 19.7% (adjusted hazard ratio = 1.197; 95% confidence interval, 1.020-1.408; P = 0.0272). In contrast, the DFS was similar between the two locations. The present study confirmed that the tumor location was a risk factor for the OS in patients who underwent curative treatment for colon cancer. Tumor location may, therefore, need to be considered a stratification factor in future phase III trials of colon cancer.

DOI： 10.1002/cam4.1208

FAM46C Serves as a Predictor of Hepatic Recurrence in Patients with Resectable Gastric Cancer Reviewed

Haruyoshi Tanaka, Mitsuro Kanda, Dai Shimizu, Chie Tanaka, Daisuke Kobayashi, Masamichi Hayashi, Naoki Iwata, Suguru Yamada, Tsutomu Fujii, Goro Nakayama, Hiroyuki Sugimoto, Michitaka Fujiwara, Yukiko Niwa, Yasuhiro Kodera

ANNALS OF SURGICAL ONCOLOGY Vol. 24 ( 11 ) page： 3438 - 3445 2017.10

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

Gastric cancer (GC) relapse can occur even if curative resection is achieved. Biomarkers predicting recurrence are needed to provide appropriate postoperative surveillance and perioperative therapeutic strategy.
A global expression profiling was performed using tissues from GC patients with synchronous liver-confined metastasis. Family with sequence similarity 46, member C (FAM46C), was identified as a candidate biomarker. mRNA expression analysis, direct nucleotide sequencing, bisulfite sequencing and copy number assays for FAM46C were performed with eleven GC cell lines. Expression levels of FAM46C in primary GC tissues from 129 patients who underwent curative GC resection were determined and correlated with clinicopathological factors, including postoperative outcome.
Levels of FAM46C mRNA differed among GC cell lines. Point mutations in FAM46C were detected in five GC cell lines accompanied with reduced FAM46C transcription. No hypermethylation was found in the promoter region of FAM46C. Copy number alterations were found in six GC cell lines with differing FAM46C transcription levels. Reduced FAM46C mRNA expression levels were detected in 117 (91 %) GC specimens compared with adjacent noncancerous tissues. Low FAM46C expression levels were significantly associated with larger macroscopic GC tumor sizes. The low FAM46C expression group was likely to have shorter disease-free survival than the high group and low FAM46C level was identified as an independent risk factor for recurrence after curative resection. FAM46C expression levels were low in all cases that were later found to have hepatic recurrence.
Reduced GC expression of FAM46C is a potential biomarker to predict hepatic recurrence after curative gastrectomy.

DOI： 10.1245/s10434-016-5636-y

Identification of NCCRP1 as an epigenetically regulated tumor suppressor and biomarker for malignant phenotypes of squamous cell carcinoma of the esophagus Reviewed

Takashi Miwa, Mitsuro Kanda, Masahiko Koike, Naoki Iwata, Haruyoshi Tanaka, Shinichi Umeda, Chie Tanaka, Daisuke Kobayashi, Masamichi Hayashi, Suguru Yamada, Tsutomu Fujii, Michitaka Fujiwara, Yasuhiro Kodera

ONCOLOGY LETTERS Vol. 14 ( 4 ) page： 4822 - 4828 2017.10

Language：Japanese Publishing type：Research paper (scientific journal) Publisher：SPANDIDOS PUBL LTD

The poor prognosis and increasing incidence of esophageal squamous cell carcinoma (ESCC) highlight the need for identification of novel ESCC-associated molecular events to improve the diagnosis, and treatment of this disease. Non-specific cytotoxic cell receptor protein 1 (NCCRP1) was reported to be abundantly expressed in human squamous epithelium and to be involved in cell proliferation; however, the role of NCCRP1 in ESCC remains unclear. To elucidate the oncological roles of NCCRP1 in ESCC, NCCRP1 expression, DNA methylation, and copy numbers were analyzed in ESCC cell lines. Nine ESCC cell lines demonstrated different NCCRP1 mRNA expression levels and all exhibited hypermethylation of the NCCRP1 promoter, but no copy number loss. Additionally, NCCRP1 expression was determined in 213 surgically resected esophageal tissue samples. NCCRP1 mRNA expression levels were reduced in ESCC tissues compared with corresponding non-cancerous adjacent tissues in 204 (95.8%) patients. Patients in the low NCCRP1 expression group tended to have a higher recurrence rate and a shorter overall survival time compared with those in the high NCCRP1 expression group. Additionally, multivariate analysis revealed that low NCCRP1 expression was an independent prognostic factor (hazard ratio, 1.75; 95% confidence interval, 1.08-2.87; P=0.022). The findings of the current study indicate that NCCRP1 acts as a putative tumor suppressor that is inactivated through promoter hypermethylation, and serves as a promising biomarker to predict postoperative prognosis in ESCC.

DOI： 10.3892/ol.2017.6753

Evaluation and proposal of novel resectability criteria for pancreatic cancer established by the Japan Pancreas Society Reviewed

Suguru Yamada, Tsutomu Fujii, Hideki Takami, Masamichi Hayashi, Naoki Iwata, Mitsuro Kanda, Chie Tanaka, Hiroyuki Sugimoto, Goro Nakayama, Masahiko Koike, Michitaka Fujiwara, Yasuhiro Kodera

SURGERY Vol. 162 ( 4 ) page： 784 - 791 2017.10

Language：Japanese Publishing type：Research paper (scientific journal) Publisher：MOSBY-ELSEVIER

Background. The guidelines for the classification of the resectability of pancreatic cancer established by the National Comprehensive Cancer Network can be difficult to utilize in clinical practice. We evaluated novel criteria proposed by the Japan Pancreas Society.
Methods. We analyzed 382 patients with pancreatic cancer between 2001 and 2015 for survival differences among subgroups classified according to the Japan Pancreas Society classification. Overall survival and disease-free survival were expressed as median values and compared with data based on the National Comprehensive Cancer Network classification, and differences in initial patterns of recurrence were analyzed.
Results. Overall survival times according to the Japan Pancreas Society criteria were 34.2, 29.7, 17.3, 14.3, and 15.8 months for the groups defined as resectable, resectable with portal vein invasion, borderline resectable with portal vein invasion, borderline resectable with arterial invasion, and unresectable by locally advanced disease respectively. The overall survival of the resectable group was better than those of the borderline resectable with portal vein invasion or borderline resectable with arterial invasion groups (P <.0001); however, the borderline resectable with portal vein invasion, borderline resectable with arterial invasion, and unresectable by locally advanced groups showed no differences in overall survival. The resectable group showed a tendency toward better survival than the resectable with portal vein invasion group (P=.058). The median overall survival times according to the classic 2012 National Comprehensive Cancer Network criteria were 30.5, 20.5, 15.8, and 13.8 months for the resectable, portal invasion, common hepatic artery and superior mesenteric artery invasion groups, respectively. Each survival curve was clearly separate. The borderline resectable with arterial invasion and unresectable by locally advanced groups exhibited high local recurrence rates (42.0% and 44. 8 %, respectively).
Conclusion. The Japan Pancreas Society criteria, which are simpler, predicted survival differences between the resectable group and the other subgroups. Our data suggest that cancer patients with borderline resectable pancreatic cancer (borderline resectable with portal vein invasion and borderline resectable with arterial invasion) can be managed as a single subset.

DOI： 10.1016/j.surg.2017.04.023

An integrated multigene expression panel to predict long-term survival after curative hepatectomy in patients with hepatocellular carcinoma Reviewed

Mitsuro Kanda, Kenta Murotani, Hiroyuki Sugimoto, Takashi Miwa, Shinichi Umeda, Masaya Suenaga, Masamichi Hayashi, Norifumi Hattori, Chie Tanaka, Daisuke Kobayashi, Suguru Yamada, Michitaka Fujiwara, Yasuhiro Kodera

ONCOTARGET Vol. 8 ( 41 ) page： 71070 - 71079 2017.9

Language：Japanese Publishing type：Research paper (scientific journal) Publisher：IMPACT JOURNALS LLC

Hepatocellular carcinoma (HCC) frequently recurs even after curative hepatectomy. To develop an integrated multigene expression panel, 144 patients were randomly assigned to either discovery or validation set in a 1: 2 ratio. Using surgically resected HCC specimens, expression levels of 12 candidate molecular markers were determined using quantitative reverse-transcriptase PCR. In the discovery set, an expression panel was developed according to the concordance index (C-index) values for overall survival from all 4095 combinations of the 12 candidate molecular markers. Expression scores was determined with weighting according to the coefficient in a Cox regression, and patients were classified into grade 1, 2 and 3. Reproducibility was then tested in the validation set. A panel consisting of four markers, PRMT5, MAGED4, DPYSL3 and AJAP1 was selected as the optimal and most well-balanced set with a C-index value of 0.707. Patient prognosis was clearly stratified by the expression grade using this panel. In the validation set, both overall and disease-free survival rates decreased incrementally with as the grade increased. Higher grades were significantly associated with tumor multiplicity and vessel invasion. The prevalence of extrahepatic recurrences was increased in grade 3 patients. The integrated multigene expression panel clearly stratified HCC patients into low, intermediate and high risk.

DOI： 10.18632/oncotarget.20369

Downregulation of GPR155 as a prognostic factor after curative resection of hepatocellular carcinoma Reviewed

Shinichi Umeda, Mitsuro Kanda, Hiroyuki Sugimoto, Haruyoshi Tanaka, Masamichi Hayashi, Suguru Yamada, Tsutomu Fujii, Hideki Takami, Yukiko Niwa, Naoki Iwata, Chie Tanaka, Daisuke Kobayashi, Michitaka Fujiwara, Yasuhiro Kodera

BMC CANCER Vol. 17 ( 1 ) page： 610 2017.9

Language：Japanese Publishing type：Research paper (scientific journal) Publisher：BIOMED CENTRAL LTD

Background: Molecular biomarkers capable of predicting recurrence patterns and prognosis are helpful for risk stratification and providing appropriate treatment to patients with hepatocellular carcinoma (HCC). In this study, we focused on G protein-coupled receptor 155 (GPR155), a cell surface signaling protein, as a candidate biomarker.
Methods: We analyzed GPR155 expression, DNA methylation, and copy number in HCC cell lines. The clinical significance of GPR155 expression was evaluated using 144 pairs of surgically resected liver and normal tissues with subgroup analysis based on hepatitis virus infection.
Results: GPR155 mRNA expression levels were differential and were decreased in 89% of HCC cell lines. No DNA methylation was detected, whereas copy number alterations were present in five (56%) HCC cell lines. GPR155 mRNA expression level was independent of background liver status and significantly lower in HCC tissues than corresponding normal liver tissues. The expression patterns of GPR155 protein by immunohistochemical staining were significantly associated with those of GPR155 mRNA. Downregulation of GPR155 was significantly associated with more aggressive HCC phenotypes including high preoperative alpha-fetoprotein, poor differentiation, serosal infiltration, vascular invasion, and advanced disease stage. Patients with downregulation of GPR155 were more likely to have worse prognosis after curative resection irrespective of hepatitis virus infection. Patients who experienced extrahepatic (distant) recurrences had significantly lower GPR155 expression than those with intrahepatic (liver confined) recurrences.
Conclusions: Downregulation of GPR155 may serve as a prognosticator that also predicts initial recurrence sites independent of hepatitis virus infection.

DOI： 10.1186/s12885-017-3629-2

Overexpression of Derlin 3 is associated with malignant phenotype of breast cancer cells Reviewed

Masahiro Shibata, Mitsuro Kanda, Haruyoshi Tanaka, Shinichi Umeda, Takashi Miwa, Dai Shimizu, Masamichi Hayashi, Takahiro Inaishi, Noriyuki Miyajima, Yayoi Adachi, Yuko Takano, Kenichi Nakanishi, Dai Takeuchi, Sumiyo Noda, Yasuhiro Kodera, Toyone Kikumori

ONCOLOGY REPORTS Vol. 38 ( 3 ) page： 1760 - 1766 2017.9

Language：Japanese Publishing type：Research paper (scientific journal) Publisher：SPANDIDOS PUBL LTD

Breast cancer (BC) is the most common malignant tumor among women worldwide. Development of novel molecular targets is important to improve prognosis of BC patients. Derlin 3 (DERL3) gene is a member of derlin family, and its coding protein is critical to the endoplasmic reticulum-associated degradation mechanism. However, its oncological role in breast cancer remains unclear. This study evaluated DERL3 expression and function in BC. We analyzed DERL3 mRNA in 13 BC and two non-cancerous cell lines, and explored effects of DERL3 knockdown on BC proliferation, invasion and migration. We also evaluated correlation of DERL3 mRNA expression levels with clinicopathological factors and prognosis in 167 BC patients. DERL3 mRNA expression was detected in five (38%) BC cell lines. Inhibiting DERL3 expression significantly decreased proliferation and invasion in BC cells. Specimens from patients with lymph node metastasis had higher DERL3 mRNA expression than those without (P=0.030). Patients in the highest quartile for DERL3 mRNA expression (n=42) were more likely to experience shorter overall survival than other patients (P=0.032). These findings indicate that DERL3 promotes malignant phenotype in BC cells. DERL3 may serve as a potential prognostic marker and therapeutic target for BC.

DOI： 10.3892/or.2017.5800

Involvement of the immunoregulator MZB1 in progression of gastric cancer Reviewed

Tanaka Y., Kanda M., Tanaka C., Kobayashi D., Tanaka H., Takami H., Hayashi M., Iwata N., Niwa Y., Yamada S., Nakayama G., Sugimoto H., Koike M., Fujiwara M., Kodera Y.

ANNALS OF ONCOLOGY Vol. 28 page： . 2017.9

Nutritional recovery after open and laparoscopic distal gastrectomy for early gastric cancer: A prospective multicenter comparative trial (CCOG1204) Reviewed

Tanaka C., Kanda M., Misawa K., Ito S., Ito Y., Mochizuki Y., Ishigure K., Yaguchi T., Teramoto J., Nakayama H., Kawase Y., Fujiwara M., Kodera Y.

ANNALS OF ONCOLOGY Vol. 28 page： . 2017.9

Usefulness of preoperative estimated glomerular filtration rate to predict complications after curative gastrectomy in patients with clinical T2-4 gastric cancer Reviewed

Yuri Tanaka, Mitsuro Kanda, Chie Tanaka, Daisuke Kobayashi, Akira Mizuno, Naoki Iwata, Masamichi Hayashi, Yukiko Niwa, Hideki Takami, Suguru Yamada, Tsutomu Fujii, Goro Nakayama, Hiroyuki Sugimoto, Michitaka Fujiwara, Yasuhiro Kodera

GASTRIC CANCER Vol. 20 ( 4 ) page： 736 - 743 2017.7

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

Gastrectomy with systemic lymphadenectomy is the standard of care for resectable gastric cancer (GC), but it is sometimes associated with postoperative morbidity. Predicting complications is therefore an essential part of risk management in clinical practice. The renal function is routinely evaluated before surgery by blood examinations to determine dose of medication and infusion. However, the value of various parameters of renal function in prediction of postoperative complications remain unclear.
We included 315 patients who underwent curative D2 gastrectomy for clinical T2-T4 GC without preoperative treatment, and evaluated the correlation between the incidence of postoperative complications and the indicators of renal function.
Forty-three patients experienced clinically relevant postoperative complications. Estimated glomerular filtration rate (eGFR) showed a higher area under the curve for predicting complications compared with urea nitrogen, creatinine, and creatinine clearance. The optimal eGFR cutoff value was 63.2 ml/min/1.73 m(2), and eGFR < 63.2 was an independent risk factor for postoperative complications in multivariable analysis (odds ratio 4.67; 95 % confidence interval 2.16-10.5; p < 0.001). Particularly, the incidence of anastomotic leakage was significantly higher in patients with eGFR < 63.2 than those with eGFR >63.2 (9.4 % vs. 3.5 %). eGFR < 63.2 was also associated with a higher incidence of postoperative complications independent of age, body mass index, operative procedure, and clinical disease stage. Postoperative hospital stay was significantly longer in the eGFR < 63.2 group.
Preoperative eGFR is a simple and useful predictor for complications after gastrectomy in patients with GC and may improve clinical care and the process of obtaining informed consent.

DOI： 10.1007/s10120-016-0657-6

Impact of postoperative complications on the colorectal cancer survival and recurrence: analyses of pooled individual patients' data from three large phase III randomized trials. Reviewed International journal

Toru Aoyama, Koji Oba, Michitaka Honda, Sotaro Sadahiro, Chikuma Hamada, Shuhei Mayanagi, Mitsuro Kanda, Hiromichi Maeda, Kosuke Kashiwabara, Junichi Sakamoto, Shigetoyo Saji, Takaki Yoshikawa

Cancer medicine Vol. 6 ( 7 ) page： 1573 - 1580 2017.7

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

This study assessed the impact of postoperative complications on the colorectal cancer survival and recurrence after curative surgery using pooled individual patients' data from three large phase III randomized trials. In total, 5530 patients were included in this study. The patients were classified as those with postoperative complications (C group) and those without postoperative complications (NC group). The risk factors for the overall survival (OS) and the disease-free survival (DFS) were analyzed. Postoperative complications were found in 861 (15.6%) of the 5530 patients. The OS and DFS rates at 5 years after surgery were 68.9% and 74.8%, respectively, in the C group and 75.8% and 82.2%, respectively, in the NC group, values that were significantly different between the two groups (P < 0.001). The multivariate analysis demonstrated that postoperative complications were a significant independent risk factor for the OS and DFS. Postoperative complications can worsen the colorectal cancer survival and risk of recurrence. Surgical morbidity must be considered as a stratification factor in future phase III trials evaluating the effects of adjuvant chemotherapy on colorectal cancer.

DOI： 10.1002/cam4.1126

Expression of regulatory factor X1 can predict the prognosis of breast cancer Reviewed

Masahiro Shibata, Mitsuro Kanda, Dai Shimizu, Haruyoshi Tanaka, Shinichi Umeda, Masamichi Hayashi, Takahiro Inaishi, Noriyuki Miyajima, Yayoi Adachi, Yuko Takano, Kenichi Nakanishi, Dai Takeuchi, Sumiyo Noda, Yasuhiro Kodera, Toyone Kikumori

ONCOLOGY LETTERS Vol. 13 ( 6 ) page： 4334 - 4340 2017.6

Language：Japanese Publishing type：Research paper (scientific journal) Publisher：SPANDIDOS PUBL LTD

Breast cancer (BC) is the most common malignancy among women. Identifying novel biomarkers to predict prognosis accurately is important in managing this disease. The regulatory factor X1 (RFX1) gene is a member of the regulatory factor X gene family. Its protein reportedly downregulates the proto-oncogene c-myc, but its role in BC has been unclear. In this study, expression and methylation status of RFX1 were determined in BC cell lines. We then evaluated RFX1 mRNA expression levels with regard to clinicopathological factors including postoperative prognosis in 167 patients with BC. Expression of RFX1 was heterogeneous among cell lines, and we found no DNA methylation at the RFX1 promoter region. Patients were categorized into groups with high or low RFX1 expression, based on ratio of RFX1 mRNA expression in BC and adjacent non-cancerous tissues. The high RFX1 group was significantly associated with low T factor (P=0.028), earlier disease stage (P=0.015), positive expression of estrogen receptor (P=0.005) and progesterone receptor (P=0.011), negative expression of human epidermal growth factor receptor 2 (P=0.001). The high RFX1 group experienced more favorable disease-free survival (P=0.007) and overall survival (P=0.013). In multivariate analysis, RFX1 expression was an independent prognostic factor for disease-free survival. Our findings indicate that RFX1 may serve as a prognostic marker for BC.

DOI： 10.3892/ol.2017.6005

Stapling an extracorporeal Billroth-I anastomosis by the complete double stapling technique after laparoscopy-assisted distal gastrectomy. Reviewed

Chie Tanaka, Michitaka Fujiwara, Mitsuro Kanda, Kenta Murotani, Naoki Iwata, Masamichi Hayashi, Daisuke Kobayashi, Suguru Yamada, Goro Nakayama, Hiroyuki Sugimoto, Masahiko Koike, Tsutomu Fujii, Yasuhiro Kodera

Asian journal of endoscopic surgery Vol. 10 ( 2 ) page： 137 - 142 2017.5

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

INTRODUCTION: Laparoscopy-assisted distal gastrectomy is one of the major treatments for early stage gastric cancer, particularly in the East Asia. In this method, extracorporeal anastomosis is performed via a small laparotomy wound, but excessive tissue traction may be encountered during the anastomotic procedure. Therefore, we developed an original procedure for extracorporeal Billroth-I reconstruction: end-to-end stapling gastroduodenostomy with complete double stapling technique. This procedure aims to reduce the problems related to maneuvers through a small laparotomy. METHODS: An end-to-end anastomosis is constructed on the transection line using a circular stapler inserted from the distal end of the greater curvature of the remnant stomach. Short-term outcomes were reviewed in 218 consecutive patients who underwent complete double stapling technique reconstruction after laparoscopy-assisted distal gastrectomy between 2002 and 2012. Findings from GI endoscopy were reviewed in 110 patients. RESULTS: The mean operative time was 216 min, and mean blood loss was 163 mL. There was no conversion to the open surgery and no operative death. Eight patients (3.6%) had anastomosis-related postoperative complications. In follow-up endoscopic examinations 1 year after surgery, grade 3 or higher residual food was seen in 17.2% of patients. Gastritis extending to the entire remnant stomach was observed in 8.2% of patients, and grade 3 gastritis was seen in 2.7%. Los Angeles classification grade A or higher reflux esophagitis was found in 10.9%. CONCLUSIONS: Billroth-I reconstruction by the complete double stapling technique is a safe and feasible procedure. This method provides satisfactory short-term outcomes, including the incidence of reflex remnant gastritis and esophagitis.

DOI： 10.1111/ases.12357

Intraperitoneal Administration of Plasma-Activated Medium: Proposal of a Novel Treatment Option for Peritoneal Metastasis From Gastric Cancer Reviewed

Shigeomi Takeda, Suguru Yamada, Norifumi Hattori, Kae Nakamura, Hiromasa Tanaka, Hiroaki Kajiyama, Mitsuro Kanda, Daisuke Kobayashi, Chie Tanaka, Tsutomu Fujii, Michitaka Fujiwara, Masaaki Mizuno, Masaru Hori, Yasuhiro Kodera

ANNALS OF SURGICAL ONCOLOGY Vol. 24 ( 5 ) page： 1188 - 1194 2017.5

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

The administration of fluid irradiated with non-equilibrium atmospheric pressure plasma (NEAPP) has attracted much interest as a novel therapeutic method for cancer. The authors previously reported on the efficacy of plasma-activated medium (PAM) for treating cancer cell lines through the induction of apoptosis. In this study, the therapeutic effect of PAM was evaluated in vivo using a peritoneal metastasis mouse model.
Two gastric cancer cell lines were used in proliferation assays performed to optimize the production of PAM by changing the distance between the plasma source and the medium surface and by altering the volume of irradiated medium. Wound-healing and adhesion assays were conducted to determine the effect of PAM therapy on cell migration and adhesion capacity in vitro. Finally, a mouse model established by the intraperitoneal injection of enhanced green fluorescent protein-tagged gastric cancer cells was used to explore the efficacy of PAM administered intraperitoneally in inhibiting peritoneal metastasis formation.
Shorter distances between the plasma source and the medium surface and smaller volumes of treated medium increased the anti-tumor effect of PAM. The PAM treatment attenuated gastric cancer cell migration and adhesion in vitro. The intraperitoneal administration of PAM decreased the formation of peritoneal metastatic nodules by 60% in the mouse model, and no adverse events were observed.
Plasma-activated liquids may represent a novel therapeutic method for the treatment of peritoneal metastases in gastric cancer.

DOI： 10.1245/s10434-016-5759-1

Clinical utility of the platelet-lymphocyte ratio as a predictor of postoperative complications after radical gastrectomy for clinical T2-4 gastric cancer Reviewed

Kenichi Inaoka, Mitsuro Kanda, Hiroaki Uda, Yuri Tanaka, Chie Tanaka, Daisuke Kobayashi, Hideki Takami, Naoki Iwata, Masamichi Hayashi, Yukiko Niwa, Suguru Yamada, Tsutomu Fujii, Hiroyuki Sugimoto, Kenta Murotani, Michitaka Fujiwara, Yasuhiro Kodera

WORLD JOURNAL OF GASTROENTEROLOGY Vol. 23 ( 14 ) page： 2519 - 2526 2017.4

Language：Japanese Publishing type：Research paper (scientific journal) Publisher：BAISHIDENG PUBLISHING GROUP INC

AIM
To identify simple and sensitive markers for postoperative complications after gastrectomy, the predictive values were compared among candidate preoperative factors.
METHODS
Three-hundred and twelve patients with previously untreated clinical T2-4 gastric cancer who underwent a D2 standard gastrectomy (distal gastrectomy or total gastrectomy) were included in the analysis. Correlations between 21 parameters that can be determined by preoperative routine blood tests and clinically relevant postoperative complications (grade. or higher according to the Clavien-Dindo classification) were evaluated. The optimal cutoff values and clinical significance of the selected markers were further evaluated by subgroup analyses according to age, body mass index, operative procedure and clinical disease stage.
RESULTS
Sixty-six patients (21.1%) experienced grade. or higher postoperative complications. The plateletl-ymphocyte ratio (PLR, total lymphocyte count/platelet count x 100) exhibited the highest area under the curve value (0.639) for predicting postoperative complications among the 21 parameters, and the optimal cutoff value was determined to be 0.71 (sensitivity = 70%, specificity = 56%). In the univariate analysis, the odds ratio of a low PLR for the occurrence of postoperative complications was 2.94 (95% CI: 1.66-5.35, P < 0.001), and a multivariate binomial logistic analysis involving other potential risk factors identified a low PLR as an independent risk factor for postoperative complications (OR = 3.32, 95% CI: 1.82-6.25, P < 0.001). In subgroups classified according to age, body mass index, operative procedure and clinical disease stage, the low PLR group exhibited an increased incidence of postoperative complications.
CONCLUSION
The preoperative PLR is a simple and useful predictor of complications after curative gastrectomy in patients with clinical T2-4 gastric cancer.

DOI： 10.3748/wjg.v23.i14.2519

The efficacy and safety of CapeOX plus bevacizumab therapy followed by capecitabine plus bevacizumab maintenance therapy in patients with metastatic colorectal cancer: a multi-center, single-arm, phase II study (CCOG-0902) Reviewed

Goro Nakayama, Kiyoshi Ishigure, Hiroyuki Yokoyama, Keisuke Uehara, Hiroshi Kojima, Akiharu Ishiyama, Naomi Hayashi, Nao Takano, Norifumi Hattori, Daisuke Kobayashi, Chie Tanaka, Masamichi Hayashi, Mitsuro Kanda, Suguru Yamada, Hiroyuki Sugimoto, Masahiko Koike, Michitaka Fujiwara, Tsutomu Fujii, Kenta Murotani, Yuichi Ando, Yasuhiro Kodera

BMC CANCER Vol. 17 ( 1 ) page： 243 2017.4

Language：Japanese Publishing type：Research paper (scientific journal) Publisher：BIOMED CENTRAL LTD

Background: The aim of this study was to evaluate the efficacy and safety of CapeOX plus bevacizumab with a planned oxaliplatin stop-and-go strategy in Japanese patients with metastatic colorectal cancer (mCRC).
Methods: Patients with untreated mCRC were treated with 4 cycles of CapeOX plus bevacizumab therapy, followed by capecitabine plus bevacizumab maintenance therapy. Reintroduction of oxaliplatin was scheduled after 8 cycles of maintenance therapy or upon tumor progression. The primary endpoint was progression-free survival (PFS), and secondary end points included overall survival (OS), objective response rate to each treatment, reintroduction rate of oxaliplatin, frequency of peripheral sensory neuropathy (PSN), and safety.
Results: The 52 patients who received the protocol treatment were included in the evaluation of efficacy and safety. Median PFS and OS were 12.4 months (95% confidence interval [CI], 10.0-14.8) and 30.6 months (95% CI, 27. 6-33.5), respectively. The objective response rates were 55.8% for the initial CapeOX plus bevacizumab therapy, 17. 8% for capecitabine plus bevacizumab maintenance therapy, and 31.0% for reintroduced CapeOX plus bevacizumab therapy. The frequency of PSN was 63.5%, including 3.8% of patients with grade 3 PSN. No patients required treatment discontinuation because of PSN during the induction or maintenance therapy.
Conclusions: CapeOX plus bevacizumab therapy with a planned oxaliplatin stop-and-go strategy is a feasible first-line treatment for Japanese patients with mCRC.

DOI： 10.1186/s12885-017-3245-1

Clinical impact of sarcopenia on prognosis in pancreatic ductal adenocarcinoma: A retrospective cohort study Reviewed

Go Ninomiya, Tsutomu Fujii, Suguru Yamada, Norimitsu Yabusaki, Kojiro Suzuki, Naoki Iwata, Mitsuro Kanda, Masamichi Hayashi, Chie Tanaka, Goro Nakayama, Hiroyuki Sugimoto, Masahiko Koike, Michitaka Fujiwara, Yasuhiro Kodera

INTERNATIONAL JOURNAL OF SURGERY Vol. 39 page： 45 - 51 2017.3

Language：Japanese Publishing type：Research paper (scientific journal) Publisher：ELSEVIER SCIENCE BV

Objectives: To investigate the impact of the body composition such as skeletal muscle, visceral fat and body mass index (BMI) on patients with resected pancreatic ductal adenocarcinoma (PDAC).
Methods: A total of 265 patients who underwent curative surgery for PDAC were examined in this study. The total skeletal muscle and fat tissue areas were evaluated in a single image obtained at the third lumber vertebra during a preoperative computed tomography (CT) scan. The patients were assigned to either the sarcopenia or non-sarcopenia group based on their skeletal muscle index (SMI) and classified into high visceral fat area (H-VFA) or low VFA (L-VFA) groups. The association of clinicopathological features and prognosis with the body composition were statistically analyzed.
Results: There were 170 patients (64.2%) with sarcopenia. The median survival time (MST) was 23.7 months for sarcopenia patients and 25.8 months for patients without sarcopenia. The MST was 24.4 months for H-VFA patients and 25.8 months for L-VFA patients. However, sarcopenia patients with BMI >= 22 exhibited significantly poorer survival than patients without sarcopenia (MST: 19.2 vs. 35.4 months, P - 0.025). There was a significant difference between patients with and without sarcopenia who did not receive chemotherapy (5-year survival rate: 0% vs. 68.3%, P = 0.003). The multivariate analysis revealed that tumor size, positive dissected peripancreatic tissue margin, and sarcopenia were independent prognostic factors.
Conclusions: Sarcopenia is an independent prognostic factor in PDAC patients with a BMI >= 22. Therefore, evaluating skeletal muscle mass may be a simple and useful approach for predicting patient prognosis. (C) 2017 IJS Publishing Group Ltd. Published by Elsevier Ltd. All rights reserved.

DOI： 10.1016/j.ijsu.2017.01.075

GPR155 Serves as a Predictive Biomarker for Hematogenous Metastasis in Patients with Gastric Cancer Reviewed

Dai Shimizu, Mitsuro Kanda, Haruyoshi Tanaka, Daisuke Kobayashi, Chie Tanaka, Masamichi Hayashi, Naoki Iwata, Yukiko Niwa, Hideki Takami, Suguru Yamada, Tsutomu Fujii, Goro Nakayama, Michitaka Fujiwara, Yasuhiro Kodera

SCIENTIFIC REPORTS Vol. 7 page： 42089 2017.2

Language：Japanese Publishing type：Research paper (scientific journal) Publisher：NATURE PUBLISHING GROUP

The prognosis of patients with gastric cancer (GC) with hematogenous metastasis is dismal. Identification of biomarkers specific for hematogenous metastasis is required to develop personalized treatments that improve patients' outcomes. Global expression profiling of GC tissues with synchronous hepatic metastasis without metastasis to the peritoneal cavity or distant lymph nodes was conducted using next-generation sequencing and identified the G protein-coupled receptor 155 (GPR155) as a candidate biomarker. GPR155 transcription was suppressed in GC cell lines compared with a nontumorigenic cell line. DNA methylation of the GPR155 promoter region was not detected, albeit 20% of GC cell lines harbored copy number loss at GPR155 locus. The expression levels of GPR155 mRNA correlated inversely with those of TWIST1 and WNT5B. Inhibition of GPR155 expression increased the levels of p-ERK1/2 and p-STAT1, significantly increased cell proliferation, and increased the invasiveness of a GC cell lines. GPR155 mRNA levels in GC clinical samples correlated with hematogenous metastasis and recurrence. Multivariate analysis revealed that reduced expression of GPR155 mRNA was an independent predictive marker of hematogenous metastasis. GPR155 may represent a biomarker for diagnosing and predicting hematogenous metastasis of GC.

DOI： 10.1038/srep42089

Esophageal cancer and associated factors among Uzbek-Turkmen and other ethnic groups in the northern part of Afghanistan Reviewed

Mohammad Hassan Hamrah, Mohammad Shoaib Hamrah, Mitsuro Kanda, Junichi Sakamoto, Mohammad Hussain Hamrah, Asif Hami, Ahmad Edris Hamrah, Ahmad Elias Dahi, Mohammad Hashem Hamrah

Asian Pacific Journal of Cancer Prevention Vol. 18 ( 2 ) page： 333 - 337 2017.2

Language：English Publishing type：Research paper (scientific journal) Publisher：Asian Pacific Organization for Cancer Prevention

Background: A high incidence rate of esophageal cancer has been observed in the Northern part of Afghanistan, particularly among those of Uzbek-Turkmen ethnicity. However, there is a paucity of published data from which to compare the prevalence of environmental risk factors for esophageal cancer between Uzbek-Turkmen and other ethnic groups. Thus, we investigated the prevalence of environmental risk factors associated with esophageal cancer in the Northern part of Afghanistan, focusing on ethnicity differences. Methods: This retrospective study covered 168 patients diagnosed with esophageal cancer based on endoscopic findings when attending an outpatient clinic from October 2013 to April 2016. Demographic data and burden of relevant environmental risk factors were compared between Uzbek-Turkmen and other ethnic groups. Results: In the total of 168 patients (108 Uzbek-Turkmen and 60 other ethnicities), males had significantly higher rates of opium use, chewing nass (a mixture of tobacco, ash and lime), and smoking than female patients. The mean age of the Uzbek-Turkmen group was 62.9 years, while that of the other ethnic group cases was 59.1. The prevalence of opium use, chewing nass and hot tea consumption was significantly higher in the Uzbek-Turkmen group. Conclusions: This study showed that there were significant differences in prevalence of opium, nass, and hot tea consumption between Uzbek-Turkmen and the other ethnic group patients with esophageal cancer in the northern part of Afghanistan.

DOI： 10.22034/APJCP.2017.18.2.333

Clinical impact of sarcopenia on prognosis in pancreatic ductal adenocarcinoma. Reviewed

Ninomiya Go, Fujii Tsutomu, Yamada Suguru, Asano Tomonari, Takano Nao, Takami Hideki, Iwata Naoki, Kanda Mitsuro, Niwa Yukiko, Hayashi Masamichi, Kobayashi Daisuke, Tanaka Chie, Nakayama Goro, Sugimoto Hiroyuki, Fujiwara Michitaka, Koike Masahiko, Kodera Yasuhiro

JOURNAL OF CLINICAL ONCOLOGY Vol. 35 ( 4 ) 2017.2

Conversion surgery for unresectable gastric cancer following complete response of distant metastasis by systemic chemotherapy. Reviewed

Kobayashi Daisuke, Kanda Mitsuro, Tanaka Chie, Iwata Naoki, Hayashi Masamichi, Yamada Suguru, Nakayama Goro, Sugimoto Hiroyuki, Koike Masahiko, Fujii Tsutomu, Fujiwara Michitaka, Kodera Yasuhiro

JOURNAL OF CLINICAL ONCOLOGY Vol. 35 ( 4 ) 2017.2

Clinical implication of inflammation-based prognostic score and perioperative nutrition control in pancreatic cancer. Reviewed

Takano Nao, Yamada Suguru, Fujii Tsutomu, Tashiro Mitsuru, Tanaka Nobutake, Morimoto Daishi, Ninomiya Go, Niwa Yukiko, Takami Hideki, Iwata Naoki, Hayashi Masamichi, Kanda Mitsuro, Tanaka Chie, Kobayashi Daisuke, Nakayama Goro, Sugimoto Hiroyuki, Koike Masahiko, Fujiwara Michitaka, Kodera Yasuhiro

JOURNAL OF CLINICAL ONCOLOGY Vol. 35 ( 4 ) 2017.2

Tumor infiltrative pattern predicts sites of recurrence after curative gastrectomy for gastric cancer.

Kanda Mitsuro, Kobayashi Daisuke, Tanaka Chie, Yamada Suguru, Fujii Tsutomu, Nakayama Goro, Sugimoto Hiroyuki, Koike Masahiko, Fujiwara Michitaka, Kodera Yasuhiro

JOURNAL OF CLINICAL ONCOLOGY Vol. 35 ( 4 ) 2017.2

Inverse probability of treatment weighting analysis of upfront surgery versus neoadjuvant chemoradiotherapy followed by surgery for pancreatic adenocarcinoma with arterial abutment. Reviewed

Fujii Tsutomu, Yamada Suguru, Murotani Kenta, Takami Hideki, Hayashi Masamichi, Kanda Mitsuro, Nakayama Goro, Sugimoto Hiroyuki, Koike Masahiko, Fujiwara Michitaka, Kodera Yasuhiro

JOURNAL OF CLINICAL ONCOLOGY Vol. 35 ( 4 ) 2017.2

The efficacy and safety of CapeOX plus bevacizumab therapy with a planned oxaliplatin stop-and-go strategy in patients with metastatic colorectal cancer: A multicenter, single-arm, phase II study (CCOG-0902 study). Reviewed

Sunakawa Yuuki, Nakayama Goro, Ishigure Kiyoshi, Yokoyama Hiroyuki, Uehara Keisuke, Kanda Mitsuro, Murotani Kenta, Fujii Tsutomu, Kodera Yasuhiro

JOURNAL OF CLINICAL ONCOLOGY Vol. 35 ( 4 ) 2017.2

Clinical impact of sarcopenia on prognosis in pancreatic ductal adenocarcinoma.

JOURNAL OF CLINICAL ONCOLOGY Vol. 35 ( 4 ) page： . 2017.2

Conversion surgery for unresectable gastric cancer following complete response of distant metastasis by systemic chemotherapy.

Kobayashi Daisuke, Kanda Mitsuro, Tanaka Chie, Iwata Naoki, Hayashi Masamichi, Yamada Suguru, Nakayama Goro, Sugimoto Hiroyuki, Koike Masahiko, Fujii Tsutomu, Fujiwara Michitaka, Kodera Yasuhiro

JOURNAL OF CLINICAL ONCOLOGY Vol. 35 ( 4 ) page： . 2017.2

The COMET Open-label Phase II Study of Neoadjuvant FOLFOX or XELOX Treatment Combined with Molecular Targeting Monoclonal Antibodies in Patients with Resectable Liver Metastasis of Colorectal Cancer. Reviewed International journal

Masato Kataoka, Mitsuro Kanda, Kiyoshi Ishigure, Hiroshi Matsuoka, Yusuke Sato, Takao Takahashi, Chihiro Tanaka, Tomohiro Deguchi, Yoshihisa Shibata, Mikinori Sato, Hitoshi Inagaki, Takanori Matsui, Akinobu Kondo, Nao Takano, Haruyoshi Tanaka, Junichi Sakamoto, Koji Oba, Ken Kondo

Annals of surgical oncology Vol. 24 ( 2 ) page： 546 - 553 2017.2

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

BACKGROUND: Advantages of neoadjuvant chemotherapy combined with monoclonal antibodies for treating patients with resectable colorectal cancer liver metastasis (CLM) have not been established. The purpose of this study was to evaluate the efficacy and safety of oxaliplatin-based regimen (FOLFOX or XELOX) plus monoclonal antibodies (cetuximab or bevacizumab) treatment in patients with resectable CLM. METHODS: A single-arm, open-label, multicenter, phase II trial was conducted for patients aged ≥ 20 years with resectable and untreated CLM. Patients received preoperative FOLFOX (6 cycles) or XELOX (4 cycles). Cetuximab or bevacizumab was administered to patients with wild-type or mutated KRAS codons 12 and 13, respectively. The primary endpoint was progression-free survival (PFS). RESULTS: Between January 2010 and June 2012, 47 patients were enrolled from 12 institutions. Wild-type or mutant KRAS sequences were examined in 32 and 15 patients, respectively. Twenty-one (45 %) patients experienced Grades 3/4 adverse events, and 55 % of all patients responded to therapy. The sizes of tumors of patients in the wild-type KRAS group were significantly reduced compared with those of the mutant KRAS group. The overall rates of liver resection and postoperative morbidity were 83 and 14 %, respectively, and the median PFS was 15.6 months. The median PFS times of the KRAS wild-type and mutant groups were 22.5 months and 10.5 months, respectively. CONCLUSIONS: Neoadjuvant therapy using FOLFOX/XELOX combined with monoclonal antibodies did not improve PFS, although it was administered safely and had less adverse effects after liver resection.

DOI： 10.1245/s10434-016-5557-9

Proposal of the Coagulation Score as a Predictor for Short-Term and Long-Term Outcomes of Patients with Resectable Gastric Cancer Reviewed

Mitsuro Kanda, Chie Tanaka, Daisuke Kobayashi, Akira Mizuno, Yuri Tanaka, Hideki Takami, Naoki Iwata, Masamichi Hayashi, Yukiko Niwa, Suguru Yamada, Tsutomu Fujii, Hiroyuki Sugimoto, Kenta Murotani, Michitaka Fujiwara, Yasuhiro Kodera

ANNALS OF SURGICAL ONCOLOGY Vol. 24 ( 2 ) page： 502 - 509 2017.2

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

Systemic hemostasis and thrombosis activation has been implicated in tumor progression and metastasis. This study aimed to investigate the use of coagulation factors as a novel prediction method for postoperative outcomes after curative gastrectomy in patients with stage II/III gastric cancer (GC).
Overall, 126 patients with stage II/III GC who underwent gastrectomy between May 2003 and February 2016 were eligible for inclusion in the study. We retrospectively evaluated the predictive value of preoperative platelet count and plasma fibrinogen and d-dimer levels, and coagulation score (0: fibrinogen and d-dimer both below upper limits; 1: either fibrinogen or d-dimer over upper limits; 2: both fibrinogen and d-dimer over upper limits) for short- and long-term outcomes.
Postoperative complications were significantly more frequent in patients with elevated preoperative d-dimer levels compared with those with normal d-dimer levels (26 vs. 10 %; p = 0.032). The prevalence of postoperative complications showed a stepwise increase in proportion to the coagulation score. Patients with a coagulation score of 2 had significantly larger tumors (p = 0.013) and significantly greater intraoperative blood loss (p = 0.004) than those who scored 0 or 1. Coagulation score showed the highest values distinguished high-risk patients in overall and disease-free survival, and a coagulation score of 2 was an independent prognostic factor for recurrence. Patients with a coagulation score of 2 experienced a significantly higher prevalence of liver metastasis as an initial recurrence than those who scored 0 or 1 (p = 0.019).
The coagulation score is a simple and promising predictor for postoperative complications and recurrence after gastrectomy in stage II/III GC patients.

DOI： 10.1245/s10434-016-5544-1

The protein arginine methyltransferase 5 promotes malignant phenotype of hepatocellular carcinoma cells and is associated with adverse patient outcomes after curative hepatectomy Reviewed

Dai Shimizu, Mitsuro Kanda, Hiroyuki Sugimoto, Masahiro Shibata, Haruyoshi Tanaka, Hideki Takami, Naoki Iwata, Masamichi Hayashi, Chie Tanaka, Daisuke Kobayashi, Suguru Yamada, Goro Nakayama, Masahiko Koike, Michitaka Fujiwara, Tsutomu Fujii, Yasuhiro Kodera

INTERNATIONAL JOURNAL OF ONCOLOGY Vol. 50 ( 2 ) page： 381 - 386 2017.2

Language：Japanese Publishing type：Research paper (scientific journal) Publisher：SPANDIDOS PUBL LTD

The prognosis of advanced hepatocellular carcinoma (HCC) is dismal. Novel molecular targets for diagnosis and therapy is urgently required. This study evaluated expression and functions of the protein arginine methyltransferase 5 (PRMT5) in HCC. Using HCC cell lines, the expression levels of PRMT5 mRNA were determined using the quantitative real-time reverse-transcription polymerase chain reaction, and the effect of a small interfering PRMT5-siRNA on cell phenotype was evaluated. Further, PRMT5 expression was determined in 144 pairs of resected liver tissues to evaluate its clinical significance. Regardless of their differentiated phenotypes, nine HCC cell lines expressed different levels of PRMT5 mRNA. Inhibition of PRMT5 expression significantly decreased the proliferation, invasion, and migration of HCC cell lines. Although the level of PRMT5 mRNA was not influenced by patient's background liver status, it was significantly higher in HCC tissues than in the corresponding noncancerous tissues. High levels of PRMT5 mRNA in HCC tissues were significantly associated with advanced disease stage and adverse prognosis. In conclusion, our results indicate that PRMT5 may act as a putative oncogene in HCC and that the levels of PRMT5 mRNA represent a promising prognostic marker and a potential target of molecular therapy for HCC.

DOI： 10.3892/ijo.2017.3833

Association of Inflammasome Components in Background Liver with Poor Prognosis After Curatively-resected Hepatocellular Carcinoma Reviewed

Fuminori Sonohara, Yoshikuni Inokawa, Mitsuro Kanda, Yoko Nishikawa, Suguru Yamada, Tsutomu Fujii, Hiroyuki Sugimoto, Yasuhiro Kodera, Shuji Nomoto

ANTICANCER RESEARCH Vol. 37 ( 1 ) page： 293 - 300 2017.1

Language：Japanese Publishing type：Research paper (scientific journal) Publisher：INT INST ANTICANCER RESEARCH

Background/Aim: Inflammasomes are multiprotein complexes that evoke key inflammatory cascades. The present study evaluated the influence of inflammasome component expression in non-tumorous tissue on postsurgical hepatocellular carcinoma (HCC) prognosis. Materials and Methods: The expressions of candidate genes were investigated using real-time quantitative reverse-transcription polymerase chain reaction in resected HCC cases. In order to identify potential prognostic factors, statistical analyses were performed for each gene. Results: The expression of nod-like receptor family, pyrin domain containing 3 (NLRP3), nod-like receptor family, CARD domain containing 4 (NLRC4), and absent in melanoma 2 (AIM2) was significantly higher in corresponding normal tissue (CN) compared to those in HCC. High expression of NLRP3, NLRC4, and caspase 1 (CASP1) in CN was significantly correlated with worse overall survival. Furthermore, multivariate analysis revealed that NLRP3 expression in CN greater than the median was an independent prognostic factor for poorer overall survival. Conclusion: High expression of NLRP3, NLRC4, and CASP1 in background non-tumorous liver is significantly correlated with poor prognosis of patients after resection of HCC.

DOI： 10.21873/anticanres.11320

Clinical benefits of neoadjuvant chemoradiotherapy for adenocarcinoma of the pancreatic head: an observational study using inverse probability of treatment weighting Reviewed

Tsutomu Fujii, Sohei Satoi, Suguru Yamada, Kenta Murotani, Hiroaki Yanagimoto, Hideki Takami, Tomohisa Yamamoto, Mitsuro Kanda, So Yamaki, Satoshi Hirooka, Masanori Kon, Yasuhiro Kodera

JOURNAL OF GASTROENTEROLOGY Vol. 52 ( 1 ) page： 81 - 93 2017.1

Language：Japanese Publishing type：Research paper (scientific journal) Publisher：SPRINGER JAPAN KK

The efficacy of neoadjuvant chemoradiotherapy (NACRT) and subset of pancreatic ductal adenocarcinoma (PDAC) patients who are most likely to benefit from this strategy remain elusive. The aim of this study was to investigate the effects of NACRT in patients with resectable (R) or borderline resectable (BR) adenocarcinoma of the pancreatic head. BR diseases were classified into two groups: lesions involving exclusively the portal vein system (BR-PV) and those abutting the major artery (BR-A).
A total of 504 patients treated with curative intent for PDAC were analyzed (R, n = 273; BR-PV, n = 129; BR-A, n = 102). Patients who underwent upfront surgery and those who underwent NACRT followed by surgery were compared using propensity score-matched and inverse probability of treatment-weighted analyses (UMIN000019719).
No significant differences were noted in the incidences of curative resection among the three categories (R, BR-PV and BR-A). Propensity score-weighted logistic regression analysis revealed that the incidence of pathologically positive resection margins was reduced by NACRT only for BR patients. Among the propensity score-matched patients, NACRT rather than upfront surgery significantly prolonged the median survival time of BR-PV patients (28.4 vs. 20.1 months; P = 0.044) but not that of R-PDAC patients (28.6 vs. 33.7 months; P = 0.960). NACRT prolonged the median survival time of BR-A patients (18.1 vs. 10.0 months; P = 0.046), but the results remained unsatisfactory.
These findings suggest that NACRT improves R0 rates and increases the survival of patients with BR-PV adenocarcinoma of the pancreatic head but not that of patients with R-PDAC.

DOI： 10.1007/s00535-016-1217-x

PAX5 gene as a novel methylation marker that predicts both clinical outcome and cisplatin sensitivity in esophageal squamous cell carcinoma Reviewed

Keisuke Kurimoto, Masamichi Hayashi, Rafael Guerrero-Preston, Masahiko Koike, Mitsuro Kanda, Sho Hirabayashi, Hiroshi Tanabe, Nao Takano, Naoki Iwata, Yukiko Niwa, Hideki Takami, Daisuke Kobayashi, Chie Tanaka, Suguru Yamada, Goro Nakayama, Hiroyuki Sugimoto, Tsutomu Fujii, Michitaka Fujiwara, Yasuhiro Kodera

EPIGENETICS Vol. 12 ( 10 ) page： 865 - 874 2017

Language：Japanese Publishing type：Research paper (scientific journal) Publisher：TAYLOR & FRANCIS INC

Therapeutic strategies for esophageal cancer largely depend on histopathological assessment. To select appropriate treatments of individual patients, we examined the background molecular characteristics of tumor malignancy and sensitivity to multidisciplinary therapy. Seventy-eight surgically-resected esophageal squamous cell carcinoma (ESCC) cases during 2001-2013 were examined. PAX5, a novel gene methylation marker in ESCC, was evaluated in the specimens, as methylation of this gene was identified as an extremely tumor-specific event in squamous cell carcinogenesis of head and neck. PAX5 methylation status was evaluated by quantitative MSP (QMSP) assays. Mean QMSP value was 15.7 (0-136.3) in ESCCs and 0.3 (0-8.6) in adjacent normal tissues (P < 0.001). The 78 cases were divided into high QMSP value (high QMSP, n D 26) and low QMSP value (low QMSP, n D 52). High QMSP cases were significantly associated with downregulated PAX5 expression (P D 0.040), and showed significantly poor recurrencefree survival [Hazard Ratio (HR) D 2.84; P D 0.005; 95% Confidence Interval (CI): 1.39-5.81] and overall survival (HR D 3.23; P D 0.002; 95% CI: 1.52-7.01) in multivariable analyses with histopathological factors. PAX5-knockdown cells exhibited significantly increased cell proliferation and cisplatin resistance. PAX5 gene methylation can predict poor survival outcomes and cisplatin sensitivity in ESCCs and could be a useful diagnostic tool for cancer therapy selection.

DOI： 10.1080/15592294.2017.1365207

Hazard rate of tumor recurrence over time in patients with colon cancer: implications for postoperative surveillance from three Japanese Foundation for Multidisciplinary Treatment of Cancer (JFMC) clinical trials. Reviewed International journal

Hiromichi Maeda, Kosuke Kashiwabara, Toru Aoyama, Koji Oba, Michitaka Honda, Shuhei Mayanagi, Mitsuro Kanda, Chikuma Hamada, Sotaro Sadahiro, Junichi Sakamoto, Shigetoyo Saji, Takaki Yoshikawa

Journal of Cancer Vol. 8 ( 19 ) page： 4057 - 4064 2017

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

Purpose: Reliable risk estimates of recurrence are necessary to establish optimal postoperative surveillance strategies. The purpose of the present study was to clarify changes in the hazard rate (HR) for tumor recurrence over time in Japanese patients with colon cancer. Methods: Data for 3984 patients from three clinical trials evaluating the benefit of adjuvant chemotherapy for colon cancer were analyzed. Estimated HRs were plotted over time for the entire cohort, as well as for node-positive and node-negative patients separately. The changes in risk were further analyzed according to eight clinical variables, and factors predictive of early (<3 years) and late (>3 years) recurrence were explored using Cox's regression analysis. Results: In node-positive patients, there was a prominent HR peak 0.6 years after surgery, whereas HR remained at consistently low levels in node-negative patients. In node-positive patients, HR decreased steadily until 3 years, after which the decline in HR plateaued. Those with T4 tumors had a prominent HR peak around 1 year, including node-negative patients. The HR for T1/T2 Stage III colon cancers showed a similar pattern as that for T1-T3 node-negative colon cancers. Cox regression analysis revealed that a lack of adjuvant chemotherapy, positive node status, T3/T4 factors, and male gender predict early recurrence, whereas patients with lymph node metastasis, T4 tumors, and a lesser extent of lymph node removal have a higher risk of recurrence 3-4 years after surgery (P<0.05). Conclusion: The present study supports the concept of intensive surveillance during the first 3 years after curative resection. However, a reduction in surveillance intensity may be acceptable for patients with T3 Stage II and T1/T2 Stage III colon cancer.

DOI： 10.7150/jca.21365