Faculty Profiles - HATTORI Norifumi

Expression of sushi domain containing two reflects the malignant potential of gastric cancer International journal

Umeda Shinichi, Kanda Mitsuro, Miwa Takashi, Tanaka Haruyoshi, Tanaka Chie, Kobayashi Daisuke, Suenaga Masaya, Hattori Norifumi, Hayashi Masamichi, Yamada Suguru, Nakayama Goro, Fujiwara Michitaka, Kodera Yasuhiro

CANCER MEDICINE Vol. 7 ( 10 ) page： 5194 - 5204 2018.10

Language：English 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

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：English 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

Pattern-Specific Transcriptomics Identifies <i>ASGR2</i> as a Predictor of Hematogenous Recurrence of Gastric Cancer. Reviewed International journal

Tanaka H, Kanda M, Miwa T, Tanaka C, Kobayashi D, Umeda S, Shibata M, Suenaga M, Hattori N, Hayashi M, Iwata N, Yamada S, Nakayama G, Fujiwara M, Kodera Y

Molecular cancer research : MCR Vol. 16 ( 9 ) page： 1420 - 1429 2018.9

Language：English 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

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：English 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

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：English 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 N, Yamada S, Sonohara F, Suenaga M, Hayashi M, Takami H, Niwa Y, Hattori N, Iwata N, Kanda M, Tanaka C, Kobayashi D, Nakayama G, Koike M, Fujiwara M, Fujii T, Kodera Y

Scientific reports Vol. 8 ( 1 ) page： 9846 2018.6

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：English 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

IDENTIFICATION OF MOLECULES DRIVING HEPATIC METASTASIS FORMATION OF GASTRIC CANCER CELLS

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

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：English 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

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

Effect of Plasma-Activated Lactated Ringer’s Solution on Pancreatic Cancer Cells In Vitro and In Vivo Reviewed

Clinical implication of nutrition for neoadjuvant therapy and impact of nutritional support in pancreatic cancer.

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 ) page： . 2018.2

Yusuke Sato, Suguru Yamada, Shigeomi Takeda, Norifumi Hattori, Kae Nakamura, Hiromasa Tanaka, Masaaki Mizuno, Masaru Hori, Yasuhiro Kodera

Annals of Surgical Oncology Vol. 25 ( 1 ) page： 299 - 307 2018.1

Language：English Publishing type：Research paper (scientific journal) Publisher：Springer New York LLC

Background: The medical applications of nonequilibrium atmospheric pressure plasma in cancer therapy have attracted attention. We previously reported on the antitumor effect of plasma-activated medium. However, this approach requires plasma-activated liquids that are administrable to the human body. In this study, we produced plasma-activated lactated Ringer’s solution (PAL) and evaluated its antitumor effect and mechanism. Furthermore, we evaluated the effect of the intraperitoneal administration of PAL using a peritoneal dissemination mouse tumor model. Methods: The antitumor effect of PAL on pancreatic cancer cell lines was evaluated using proliferation and apoptosis assays. In addition, cellular reactive oxygen species (ROS) generation was examined. The role of ROS was assessed using a proliferation assay with N-acetyl cysteine (NAC). An adhesion assay was performed to evaluate the effect of PAL on cell adhesion. Finally, pancreatic cancer cells stably expressing luciferase (AsPC-1/CMV-Luc) were injected intraperitoneally into mice, followed by intraperitoneal injection of PAL. Peritoneal dissemination was monitored using in vivo bioluminescent imaging. Results: The antitumor effect of PAL was shown in all cell lines in vitro. The TUNEL assay showed that PAL induced apoptosis. ROS uptake was observed in PAL-treated cells, and the antitumor effect was inhibited by NAC. Cell adhesion also was suppressed by PAL. The intraperitoneal administration of PAL suppressed the formation of peritoneal nodules in vivo. Conclusions: Our study demonstrated the antitumor effects of PAL in vitro and in vivo. Intraperitoneal administration of PAL may be a novel therapeutic option for peritoneal metastases.

DOI： 10.1245/s10434-017-6239-y

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：English 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

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：English 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

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：English 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