Faculty Profiles - KANDA Mitsuro

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