Papers - MATSUZAKI Juntaro

A novel combination of serum microRNAs for the detection of early gastric cancer

S Abe, J Matsuzaki, K Sudo, I Oda, H Katai, K Kato, S Takizawa, ...

Gastric Cancer, 1-9 (Gastric Cancer)  24 ( 4 ) 835 - 843 2021.03

Research paper (scientific journal), Joint Work, Lead author, Accepted,  ISSN  1436-3291

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Background: The aim of this study was to identify serum miRNAs that discriminate early gastric cancer (EGC) samples from non-cancer controls using a large cohort. Methods: This retrospective case–control study included 1417 serum samples from patients with EGC (seen at the National Cancer Center Hospital in Tokyo between 2008 and 2012) and 1417 age- and gender-matched non-cancer controls. The samples were randomly assigned to discovery and validation sets and the miRNA expression profiles of whole serum samples were comprehensively evaluated using a highly sensitive DNA chip (3D-Gene ) designed to detect 2565 miRNA sequences. Diagnostic models were constructed using the levels of several miRNAs in the discovery set, and the diagnostic performance of the model was evaluated in the validation set. Results: The discovery set consisted of 708 samples from EGC patients and 709 samples from non-cancer controls, and the validation set consisted of 709 samples from EGC patients and 708 samples from non-cancer controls. The diagnostic EGC index was constructed using four miRNAs (miR-4257, miR-6785-5p, miR-187-5p, and miR-5739). In the discovery set, a receiver operating characteristic curve analysis of the EGC index revealed that the area under the curve (AUC) was 0.996 with a sensitivity of 0.983 and a specificity of 0.977. In the validation set, the AUC for the EGC index was 0.998 with a sensitivity of 0.996 and a specificity of 0.953. Conclusions: A novel combination of four serum miRNAs could be a useful non-invasive diagnostic biomarker to detect EGC with high accuracy. A multicenter prospective study is ongoing to confirm the present observations. ®

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Precision medicine approaches to prevent gastric cancer

J Matsuzaki, H Tsugawa, H Suzuki

Gut and Liver 15 (1), 3 (Gut and Liver)  15 ( 1 ) 3 - 12 2021.01

Research paper (scientific journal), Accepted

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© Gut and Liver. Gastric cancer remains one of the most common causes of cancer-related death worldwide, although the incidence is declining gradually. The primary risk factor for gastric cancer is Helicobacter pylori infection. The Kyoto global consensus report recommends eradication of H. pylori in all infected patients. However, because it is difficult to stratify the risk of carcinogenesis among patients with a history of H. pylori infection, annual endoscopic surveillance is performed for everyone after eradication. This review summarizes the current approaches used to screen for novel molecules that could assist in the diagnosis of gastric cancer and reduce mortality. Most well-studied molecules are tissue protein biomarkers expressed by the gastric epithelium and associated with metaplasia-dysplasia-carcinoma sequences. Other strategies focus on the origin of cancer stem cell-related markers, such as CD44, and immune reaction-related markers, such as matrix metallopeptidases. Noninvasive methods such as blood-based approaches are more attractive. Serum pepsinogen levels predict the severity of gastric mucosal atrophy before H. pylori eradication, whereas plasma ghrelin levels are associated with atrophy even after eradication. Cell-free DNAs and RNAs are attractive tools for the early detection of cancer. These ideas could lead to the development of more personalized strategies for cancer prevention based on cutting-edge technologies.

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【大腸癌診療におけるprecision medicine】大腸癌患者の血清miRNAを用いた術前リンパ節転移予測診断能の意義について

森谷 弘乃介, 松崎 潤太郎, 高見澤 康之, 坂本 良平, 塚本 俊輔, 志田 大, 金光 幸秀

癌の臨床 ((株)篠原出版新社)  65 ( 4 ) 345 - 351 2021.01

Joint Work,  ISSN  0021-4949

Development of diagnostic models for solid cancers using circulating microRNAs

J Matsuzaki

CANCER SCIENCE 112, 203-203  2021

Research paper (international conference proceedings)

Su252 SUPERIORITY OF URGENT VS. EARLY ENDOSCOPIC HEMOSTASIS IN PATIENTS WITH UPPER GASTROINTESTINAL BLEEDING

M Horibe, E Iwasaki, J Matsuzaki, F Bazerbachi, T Kaneko, K Minami, ...

Gastroenterology 160 (6), S-655  2021

Research paper (international conference proceedings)

Comprehensive serum and tissue microRNA profiling in dedifferentiated liposarcoma

I Kohama, N Asano, J Matsuzaki, Y Yamamoto, T Yamamoto, ...

Oncology Letters 22 (2), 1-8 (Oncology Letters)  22 ( 2 ) 623 2021

Research paper (scientific journal), Accepted

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Sarcoma is a rare cancer with several subtypes; therefore, our understanding of the pathogenesis of sarcoma is limited, and designing effective treatments is difficult. Circulating microRNAs (miRNAs), including exosomal miRNAs, have attracted attention as biomarkers in cancer. However, the roles of miRNAs and exosomes in sarcoma remain unclear. The present analysis of tissue and serum miRNA expression in osteosarcoma, Ewing's sarcoma and dedifferentiated liposarcoma (DDLPS) identified miR-1246, -4532, -4454, -619-5p and -6126 as biomarkers for DDLPS. These miRNAs were highly expressed in human DDLPS cell lines and exosomes, suggesting that they are secreted from DDLPS tissues. The present results suggested that specific miRNAs may be used as biomarkers for early diagnosis or treatment targets in DDLPS.

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Machine learning-based multiple cancer detections with circulating miRNA profiles in the blood.

J Matsuzaki, Y Yamamoto, O Yi, S Ayyar, R Miyajima, Y Takeda, T Nolan, ...

Journal of Clinical Oncology 39 (15_suppl), 3037-3037  2021

Research paper (international conference proceedings)

Superiority of urgent vs early endoscopic hemostasis in patients with upper gastrointestinal bleeding with high-risk stigmata

M Horibe, E Iwasaki, J Matsuzaki, F Bazerbachi, T Kaneko, K Minami, ...

Gastroenterology Report 9 ( 6 ) 543 - 551 2021

Research paper (scientific journal), Joint Work, Accepted,  ISSN  2052-0034

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Circulating microRNAs: Next-generation Cancer Detection

J Matsuzaki, T Ochiya

The Keio journal of medicine 69 (4), 88-96 (Keio Journal of Medicine)  69 ( 4 ) 88 - 96 2020.12

Research paper (bulletin of university, research institution), Lead author, Corresponding author, Accepted

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© 2020 by The Keio Journal of Medicine. Early detection of cancer is crucial for its ultimate control and the prevention of malignant progression. In Japan, a nationwide project was conducted between 2014 and 2019 to develop novel cancer detection tools using serum microRNAs (miRNAs). Using the National Cancer Center Biobank, we collected more than 10,000 serum samples from patients with malignant diseases, including rare cancers such as ovarian cancer, gliomas, and sarcomas. Subsequently, comprehensive miRNA microarray analyses were performed for all samples. This serum miRNA database provides insights regarding miRNA bio-marker candidates for each cancer type. Here, we summarize the major achievements of this national project. Notably, although circulating miRNAs packaged in extracellular vesicles are thought to be a cell-to-cell communication tool, the functional characteristics of the miRNAs listed in the project are still unknown. We hope that our findings will help elucidate the biological functions of circulating miR-NAs.

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Extracellular miRNAs for the Management of Barrett’s Esophagus and Esophageal Adenocarcinoma: A Systematic Review

K Inokuchi, T Ochiya, J Matsuzaki

Journal of Clinical Medicine 10 (1), 117 (Journal of Clinical Medicine)  10 ( 1 ) 1 - 16 2020.12

Research paper (scientific journal), Joint Work, Accepted,  ISSN  2077-0383

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Esophageal adenocarcinoma (EAC), the major histologic type of esophageal cancer (EC) in Western countries, is a disease with a poor prognosis, primarily due to usual diagnosis at an advanced stage. The prevalence of EAC has increased in recent years, both in Western countries and in Asia. Barrett’s esophagus (BE) is a precursor lesion of EAC. Therefore, early detection and proper management of BE and EAC is important to improve prognosis. Here, we systematically summarize current knowledge about the potential utility of extracellular microRNAs (miRNAs), which are thought to be non-invasive biomarkers for many diseases, for these purposes. A search of the PubMed and Embase databases identified 22 papers about extracellular miRNAs that have potential utility for management of EAC. Among them, 19 were EAC-related and ten were BE-related; some of these dealt with both conditions. The articles included studies reporting diagnosis, prognosis, and treatment responses. Multiple papers report dysregulation of miR-194-5p in BE and miR-21-5p, -25-3p, and -93-5p in EAC. Although it will take time to utilize these miRNAs in clinical practice, they are likely to be useful non-invasive markers in the future.

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Horibe GI bleeding prediction score: a simple score for triage decision-making in patients with suspected upper GI bleeding

M Horibe, E Iwasaki, F Bazerbachi, T Kaneko, J Matsuzaki, K Minami, ...

Gastrointestinal endoscopy 92 (3), 578-588. e4 (Gastrointestinal Endoscopy)  92 ( 3 ) 578 - 588.e4 2020.09

Research paper (scientific journal), Accepted

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© 2020 American Society for Gastrointestinal Endoscopy Background and Aims: Although upper GI bleeding (UGIB) is a significant cause of inpatient admissions, no scoring method has proven to be accurate and simple as a standard for triage purposes. Therefore, we compared a previously described 3-variable score (1 point each for absence of daily proton pump inhibitor use in the week before the index presentation, shock index [heart rate/systolic blood pressure] ≥1, and blood urea nitrogen/creatinine ≥30 [urea/creatinine≥140]), the Horibe gAstRointestinal BleedING scoRe (HARBINGER), with the 8-variable Glasgow-Blatchford Score (GBS) and 5-variable AIMS65 to evaluate and validate the accuracy in predicting high-risk features that warrant admission and urgent endoscopy. Methods: Consecutive patients presenting with suspected UGIB between 2012 and 2015 were prospectively enrolled in 3 acute care Japanese hospitals. On presentation to the emergency setting, an endoscopy was performed in a timely fashion. The primary outcome was the prediction of high-risk endoscopic stigmata. Results: Of 1486 enrolled patients, 637 (43%) harbored high-risk endoscopic stigmata according to international consensus statements. The area under the receiver operating characteristic curve (AUC) for the HARBINGER was.76 (95% confidence interval [CI],.72-.79), which was significantly superior to both the GBS (AUC,.68; 95% CI,.64-.71; P <.001) and the AIMS65 (AUC,.54; 95% CI,.50-.58; P <.001). When the HARBINGER cutoff value was set at 1 to rule out patients who needed admission and urgent endoscopy, its sensitivity and specificity was 98.8% (95% CI, 97.9-99.6) and 15.5% (95% CI, 13.1-18.0), respectively. Conclusions: The HARBINGER, a simple 3-variable score, provides a more accurate method for triage of patients with suspected UGIB than both the GBS and AIMS65.

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【癌早期発見・早期診断のNew Era】血中マイクロRNAを用いた癌早期診断法の開発と展望

松崎 潤太郎, 落谷 孝広

消化器・肝臓内科 ((有)科学評論社)  8 ( 2 ) 132 - 136 2020.08

Joint Work,  ISSN  2432-3446

【Helicobacter Topics!-「旬のHelicobacter」を知り、驚き、理解を深め、楽しむ-】Helicobacter pylori関連ディスペプシアの病態

松崎 潤太郎

Helicobacter Research ((株)先端医学社)  24 ( 1 ) 83 - 85 2020.05

Joint Work,  ISSN  1342-4319

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慢性的に持続するディスペプシア症状のなかで、とくにHelicobacter pylori除菌治療によって改善するものをH.pylori関連ディスペプシアとよぶ。現在、世界中の主要なガイドラインにおいてディスペプシア診療の最も最初にH.pylori感染診断が推奨されている。H.pylori感染に伴うグレリン分泌の低下とディスペプシア症状との関連は以前より指摘されているが、胃粘膜萎縮の程度と除菌後の症状改善頻度には明確な関連性はない。最近、われわれの研究グループは、H.pyloriにおける好中球活性化因子NapAの多型によってディスペプシア症状の惹起頻度が異なることを見出し、スナネズミ感染モデルにおいて実際に胃排出遅延が生じることなどから、H.pylori関連ディスペプシアの有力な機序であることを報告した。(著者抄録)

Highly sensitive circulating microRNA panel for accurate detection of hepatocellular carcinoma in patients with liver disease

Y Yamamoto, S Kondo, J Matsuzaki, M Esaki, T Okusaka, K Shimada, ...

Hepatology communications 4 (2), 284-297 (Hepatology Communications)  4 ( 2 ) 284 - 297 2020.02

Research paper (scientific journal), Joint Work, Lead author, Accepted,  ISSN  2471254X

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Hepatocellular carcinoma (HCC) is the fourth leading cause of cancer deaths worldwide. The high mortality rate in HCC is largely due to the difficulty of early detection. In this study, to improve patient outcomes, serum samples from 345 patients with HCC, 46 patients with chronic hepatitis (CH), 93 patients with liver cirrhosis (LC), and 1,033 healthy individuals were analyzed with microRNA (miRNA) microarrays. We investigated the diagnostic potential of circulating miRNAs in serum and developed a detection model of HCC, including early stage. A diagnostic model was constructed based on the expression levels of a combination of miRNAs in a discovery set. We selected 52 miRNAs that had altered expressions according to disease progression status, established the diagnostic model with a combination of eight miRNAs in the discovery set, and tested the model in a validation set. The diagnostic values for discriminating cancer from HCC at-risk control samples were as follows: area under the curve, 0.99; sensitivity, 97.7%; specificity, 94.7%. With this model, 98% of stage I HCC cases were detected; these results were much better than those observed from conventional methods. Conclusion: Circulating miRNAs could serve as biomarkers for the accurate detection of HCC. Because the diagnostic accuracy was maintained even in stage I, this may represent an accurate detection method even for early stage HCC.

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Identification of serum microRNAs predicting the response of esophageal squamous-cell carcinoma to nivolumab

K Sudo, K Kato, J Matsuzaki, S Takizawa, Y Aoki, H Shoji, S Iwasa, ...

Japanese journal of clinical oncology 50 (2), 114-121 50 ( 2 ) 114 - 121 2020

Research paper (scientific journal), Joint Work, Accepted,  ISSN  0368-2811

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A miRNA-based diagnostic model predicts resectable lung cancer in humans with high accuracy

K Asakura, T Kadota, J Matsuzaki, Y Yoshida, Y Yamamoto, K Nakagawa, ...

Communications biology 3 (1), 1-9 (Communications Biology)  3 ( 1 ) 134 2020

Research paper (scientific journal), Accepted

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© 2020, The Author(s). Lung cancer, the leading cause of cancer death worldwide, is most frequently detected through imaging tests. In this study, we investigated serum microRNAs (miRNAs) as a possible early screening tool for resectable lung cancer. First, we used serum samples from participants with and without lung cancer to comprehensively create 2588 miRNAs profiles; next, we established a diagnostic model based on the combined expression levels of two miRNAs (miR-1268b and miR-6075) in the discovery set (208 lung cancer patients and 208 non-cancer participants). The model displayed a sensitivity of 99% and specificity of 99% in the validation set (1358 patients and 1970 non-cancer participants) and exhibited high sensitivity regardless of histological type and pathological TNM stage of the cancer. Moreover, the diagnostic index markedly decreased after lung cancer resection. Thus, the model we developed has the potential to markedly improve screening for resectable lung cancer.

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Adenosine leakage from perforin-burst extracellular vesicles inhibits perforin secretion by cytotoxic T-lymphocytes

H Tadokoro, A Hirayama, R Kudo, M Hasebe, Y Yoshioka, J Matsuzaki, ...

PloS one 15 (4), e0231430 (PLoS ONE)  15 ( 4 ) e0231430 2020

Research paper (scientific journal), Accepted

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© 2020 Tadokoro et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Extracellular vesicles (EVs) in the tumor microenvironment facilitate intercellular communication. Cancer cell-derived EVs act as an immunosuppressor by transporting cargos and presenting transmembrane proteins. By contrast, CD8+ cytotoxic T-lymphocytes (CTLs) exert anti-cancer cytotoxicity via the pore-forming protein perforin. Here, we hypothesize that although EVs are destroyed by perforin, cancer cell-derived EVs might possess mechanisms that enable them to avoid this destruction. We used a breast cancer cell line, MDA-MB-231luc-D3H2LN (D3H2LN), to generate EVs. Destruction of the EVs by perforin was demonstrated visually using atomic force microscopy. To investigate immunosuppressive metabolites within cancer cell-derived EVs, we performed metabolomic profiling of EVs from D3H2LN cells cultured for 48 h with or without IFN-γ, which induces metabolic changes in the cells. We found that both types of EV from IFN-γ treated D3H2LN cells and non-treated D3H2LN cells contained adenosine, which has immunosuppressive effects. When we exposed cancer cell-derived EVs to CTLs, perforin secretion by CTLs fell significantly. In addition, the decreases in perforin secretion were ameliorated by treatment with adenosine deaminase, which degrades extracellular adenosine. Taken together, these results suggest that after perforin secreted by CTLs disrupts the membrane of EVs, adenosine released from the EVs acts as an immunosuppressive metabolite by binding to the adenosine receptor on the CTL membrane. This mechanism provides a novel survival strategy using cancer cell-derived EVs.

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Efficacy and safety of immediate oral intake in patients with mild acute pancreatitis: A randomized controlled trial

M Horibe, E Iwasaki, A Nakagawa, J Matsuzaki, K Minami, Y Machida, ...

Nutrition 74, 110724 (Nutrition)  74   110724 2020

Research paper (scientific journal), Accepted

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© 2020 Objectives: Early enteral nutrition is recommended for patients with severe acute pancreatitis (AP); however, nutritional management strategies for patients with mild AP have not been established. The aim of this study was to evaluate the benefits and safety of immediate oral intake of low-fat solid food in patients with mild AP who were allowed to take opioid analgesics. Methods: In this single-center randomized study, the immediate feeding (IMF) group was permitted immediate oral intake of low-fat (15 g/d) solid food. In the standard food (STF) group, patients received gradually increasing amounts of dietary fat. Twenty-six patients were randomized, with 13 allocated to each group. The primary outcome was the period between diagnosis and recovery from AP. The cost and rate of progression to severe disease were evaluated as secondary outcomes. Results: The IMF group (mean recovery days: 2 ± 1) recovered significantly earlier (mean difference in recovery days: 6.3; 95% confidence interval [CI], 4.8–7.9; P < 0.001) than the STF group (mean recovery days: 8.3 ± 2.3), with a lower overall treatment cost (mean difference in costs: −$460; 95% CI, −$880 to –$40; P = 0.034). The IMF group showed a lower rate of progression to severe AP (IMF, 0%; STF, 15.3%; P = 0.48). Conclusion: The initial treatment strategy for mild AP should be altered from the gradual introduction of oral feeding upon the absence of pain to immediate oral nutrition with opioid analgesics, to improve treatment efficacy and reduce treatment cost.

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Transcriptomic dissection of hepatocyte heterogeneity: linking ploidy, zonation, and stem/progenitor cell characteristics

T Katsuda, K Hosaka, J Matsuzaki, W Usuba, M Prieto-Vila, T Yamaguchi, ...

Cellular and molecular gastroenterology and hepatology 9 (1), 161-183 (Cellular and Molecular Gastroenterology and Hepatology)  9 ( 1 ) 161 - 183 2020

Research paper (scientific journal), Accepted

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© 2019 The Authors Background & Aims: There is a long-standing debate regarding the biological significance of polyploidy in hepatocytes. Recent studies have provided increasing evidence that hepatocytes with different ploidy statuses behave differently in a context-dependent manner (eg, susceptibility to oncogenesis, regenerative ability after injury, and in vitro proliferative capacity). However, their overall transcriptomic differences in a physiological context is not known. Methods: By using microarray transcriptome analysis, we investigated the heterogeneity of hepatocyte populations with different ploidy statuses. Moreover, by using single-cell quantitative reverse-transcription polymerase chain reaction (scPCR) analysis, we investigated the intrapopulational transcriptome heterogeneity of 2c and 4c hepatocytes. Results: Microarray analysis showed that cell cycle–related genes were enriched in 8c hepatocytes, which is in line with the established notion that polyploidy is formed via cell division failure. Surprisingly, in contrast to the general consensus that 2c hepatocytes reside in the periportal region, in our bulk transcriptome and scPCR analyses, the 2c hepatocytes consistently showed pericentral hepatocyte-enriched characteristics. In addition, scPCR analysis identified a subpopulation within the 2c hepatocytes that co-express the liver progenitor cell markers Axin2, Prom1, and Lgr5, implying the potential biological relevance of this subpopulation. Conclusions: This study provides new insights into hepatocyte heterogeneity, namely 2c hepatocytes are preferentially localized to the pericentral region, and a subpopulation of 2c hepatocytes show liver progenitor cell–like features in terms of liver progenitor cell marker expression (Axin2, Prom1, and Lgr5).

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Su1391 EFFICACY AND SAFETY OF VONOPRAZAN, SITAFLOXACIN AND METRONIDAZOLE CONTAINING REGIMEN FOR HELICOBACTER PYLORI ERADICATION IN PATIENTS WITH PENICILLIN ALLERGY

T Masaoka, H Mori, H Suzuki, J Matsuzaki, A Okazawa, M Yoshioka, ...

Gastroenterology 158 (6), S-574  2020

Research paper (international conference proceedings)