論文 - 松崎　潤太郎

Circulating microRNAs: Challenges with their use as liquid biopsy biomarkers.

Takizawa S, Matsuzaki J, Ochiya T

Cancer biomarkers : section A of Disease markers 35 （ 1 ） 1 - 9 2022年06月

研究論文（学術雑誌）, 共著, 査読有り,  ISSN  1574-0153

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Efficacy and safety of low-dose rifabutin-based 7-day triple therapy as a third- or later-line Helicobacter pylori eradication regimen.

Inokuchi K, Mori H, Matsuzaki J, Hirata K, Harada Y, Saito Y, Suzuki H, Kanai T, Masaoka T

Helicobacter 27 （ 4 ） e12900 2022年05月

研究論文（学術雑誌）, 共著, 査読有り,  ISSN  1083-4389

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Identification of circulating microRNAs as potential biomarkers for hepatic necroinflammation in patients with autoimmune hepatitis.

Saeki C, Matsuzaki J, Kuroda M, Fujita K, Ichikawa M, Takizawa S, Takano K, Oikawa T, Nakanuma Y, Saruta M, Ochiya T, Tsubota A

BMJ open gastroenterology 9 （ 1 ）  2022年04月

研究論文（学術雑誌）, 共著, 筆頭著者, 査読有り,  ISSN  2054-4774

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Serum microRNA as liquid biopsy biomarker for the prediction of oncological outcomes in patients with bladder cancer.

Urabe F, Matsuzaki J, Ito K, Takamori H, Tsuzuki S, Miki J, Kimura T, Egawa S, Nakamura E, Matsui Y, Fujimoto H, Yamamoto Y, Ochiya T

International journal of urology : official journal of the Japanese Urological Association 29 （ 9 ） 968 - 976 2022年03月

研究論文（学術雑誌）, 共著, 査読有り,  ISSN  0919-8172

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Development of plasma ghrelin level as a novel marker for gastric mucosal atrophy after Helicobacter pylori eradication

H Mori, H Suzuki, J Matsuzaki, K Kameyama, K Igarashi, T Masaoka, ...

Annals of Medicine 54 (1), 170-180 （Annals of Medicine）  54 （ 1 ） 170 - 180 2022年

研究論文（学術雑誌）, 共著, 査読有り

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Background and aim: The severity of atrophic gastritis is significantly associated with the risk of gastric cancer. Although the current gold standard for assessing the gastric cancer risk is esophagogastroduodenoscopy with a pathological examination, the development of less-invasive biomarkers is warranted for efficient risk stratification of gastric cancer. Serum pepsinogens (PGs) are biomarkers used to predict the extent of gastric mucosal atrophy; however, they are not an accurate reflection of gastric mucosal atrophy after Helicobacter pylori eradication. The present study was conducted to investigate the usefulness of plasma ghrelin levels as a marker for gastric mucosal atrophy, and as a risk stratification marker for gastric cancer, even after H. pylori eradication. Methods: Patients who received H. pylori eradication treatment were enrolled in the study. The severity of gastric mucosal atrophy was evaluated both endoscopically and histologically. Serum pepsinogen and plasma ghrelin levels were measured before and at 1, 12, 24, and 48 weeks after treatment. The study was approved by the Research Ethics Committee of the Keio University School of Medicine (no. 20140102; 8 July 2014). Results: Eighteen patients completed the study protocol. Total and acyl plasma ghrelin levels demonstrated no significant change from before treatment to 48 weeks after eradication; however, there was a significant difference between open-type and closed-type atrophic gastritis. The PG I/II ratio increased significantly from 48 weeks after H. pylori eradication. The severity of the histological intestinal metaplasia scores correlated inversely with plasma total ghrelin levels from before to 48 weeks after H. pylori eradication. Conclusion: Plasma levels of ghrelin correlate well with the level of gastric mucosal atrophy, even after H. pylori eradication.KEY MESSAGES Ghrelin plasma levels are associated with the progression of endoscopic atrophic gastritis, even at 48 weeks after H. pylori eradication. Ghrelin plasma levels are also associated with increased severity of histological intestinal metaplasia 48 weeks after H. pylori eradication. Pepsinogen I/II ratios increased immediately after H. pylori eradication and are inappropriate for assessing atrophic gastritis after H. pylori eradication.

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Extracellular microRNA profiling for prognostic prediction in patients with high‐grade serous ovarian carcinoma

Kosuke Yoshida and Akira Yokoi and Juntaro Matsuzaki and Tomoyasu Kato and Takahiro Ochiya and Hiroaki Kajiyama and Yusuke Yamamoto

Cancer Science （Wiley）  112 （ 12 ） 4977 - 4986 2021年10月

研究論文（学術雑誌）, 共著, 査読有り

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High-grade serous ovarian carcinoma is a leading cause of death in female patients worldwide. MicroRNAs (miRNAs) are stable noncoding RNAs in the peripheral blood that reflect a patient’s condition, and therefore, they have received substantial attention as noninvasive biomarkers in various diseases. We previously reported the usefulness of serum miRNAs as diagnostic biomarkers. Here, we investigated the prognostic impact of the serum miRNA profile. We used the GSE106817 dataset, which included preoperative miRNA profiles of patients with ovarian malignancies. Excluding patients with other malignancy or insufficient prognostic information, we included 175 patients with high-grade serous ovarian carcinoma. All patients except four underwent surgery and received chemotherapy as initial treatment. The median follow-up period was 54.6 months (range, 3.5-144.1 months). Univariate Cox regression analysis revealed that higher levels of miR-187-5p and miR-6870-5p were associated with both poorer progression-free survival (PFS) and overall survival (OS), and miR-1908-5p, miR-6727-5p, and miR-6850-5p were poor prognostic indicators of PFS. The OS and PFS prognostic indices were then calculated using the expression values of three prognostic miRNAs. Multivariate Cox regression analysis showed that both indices were significantly independent poor prognostic factors (hazard ratio for OS and PFS, 2.343 [P =.015] and 2.357 [P =.005], respectively). In conclusion, circulating miRNA profiles can potentially provide information to predict the prognosis of patients with high-grade serous ovarian carcinoma. Therefore, there is a strong demand for early clinical application of circulating miRNAs as noninvasive biomarkers.

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Challenges for Better Diagnosis and Management of Pancreatic and Biliary Tract Cancers Focusing on Blood Biomarkers: A Systematic Review

Tominaga H, Matsuzaki J, Oikawa C, Toyoshima K, Manabe H, Ozawa E, Shimamura A, Yokoyama R, Serizawa Y, Ochiya T, Saito Y

Cancers （Cancers）  13 （ 16 ）  2021年08月

研究論文（学術雑誌）, 共著, 責任著者, 査読有り,  ISSN  2072-6694

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Background: pancreatic cancer (PCa) and biliary tract cancer (BTC) are cancers with a poor prognosis and few effective treatments. One of the reasons for this is late detection. Many researchers are tackling to develop non-invasive biomarkers for cancer, but few are specific for PCa or BTC. In addition, genetic abnormalities occur in cancer tissues, which ultimately affect the expression of various molecules. Therefore, it is important to identify molecules that are altered in PCa and BTC. For this systematic review, a systematic review of Medline and Embase to select biomarker studies of PCa and BTC patients was conducted. Results: after reviewing 72 studies, 79 biomarker candidates were identified, including 22 nucleic acids, 43 proteins, and 14 immune cell types. Of the 72 studies, 61 examined PCa, and 11 examined BTC. Conclusion: PCa and BTC are characterized by nucleic acid, protein, and immune cell profiles that are markedly different from those of healthy subjects. These altered molecules and cell subsets may serve as cancer-specific biomarkers, particularly in blood. Further studies are needed to better understand the diagnosis and prognosis of PCa and BTC.

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Early prediction of COVID-19 severity using extracellular vesicle COPB2.

Fujita Y, Hoshina T, Matsuzaki J, Yoshioka Y, Kadota T, Hosaka Y, Fujimoto S, Kawamoto H, Watanabe N, Sawaki K, Sakamoto Y, Miyajima M, Lee K, Nakaharai K, Horino T, Nakagawa R, Araya J, Miyato M, Yoshida M, Kuwano K, Ochiya T

Journal of extracellular vesicles （Journal of Extracellular Vesicles）  10 （ 8 ） e12092 2021年06月

研究論文（学術雑誌）, 共著, 筆頭著者, 査読有り,  ISSN  2001-3078

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The clinical manifestations of COVID-19 vary broadly, ranging from asymptomatic infection to acute respiratory failure and death. But the predictive biomarkers for characterizing the variability are still lacking. Since emerging evidence indicates that extracellular vesicles (EVs) and extracellular RNAs (exRNAs) are functionally involved in a number of pathological processes, we hypothesize that these extracellular components may be key determinants and/or predictors of COVID-19 severity. To test our hypothesis, we collected serum samples from 31 patients with mild COVID-19 symptoms at the time of their admission for discovery cohort. After symptomatic treatment without corticosteroids, 9 of the 31 patients developed severe/critical COVID-19 symptoms. We analyzed EV protein and exRNA profiles to look for correlations between these profiles and COVID-19 severity. Strikingly, we identified three distinct groups of markers (antiviral response-related EV proteins, coagulation-related markers, and liver damage-related exRNAs) with the potential to serve as early predictive biomarkers for COVID-19 severity. As the best predictive marker, EV COPB2 protein, a subunit of the Golgi coatomer complex, exhibited significantly higher abundance in patients remained mild than developed severe/critical COVID-19 and healthy controls in discovery cohort (AUC 1.00 (95% CI: 1.00-1.00)). The validation set included 40 COVID-19 patients and 39 healthy controls, and showed exactly the same trend between the three groups with excellent predictive value (AUC 0.85 (95% CI: 0.73-0.97)). These findings highlight the potential of EV COPB2 expression for patient stratification and for making early clinical decisions about strategies for COVID-19 therapy.

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

Abe S, Matsuzaki J, Sudo K, Oda I, Katai H, Kato K, Takizawa S, Sakamoto H, Takeshita F, Niida S, Saito Y, Ochiya T

Gastric cancer : official journal of the International Gastric Cancer Association and the Japanese Gastric Cancer Association （Gastric Cancer）  24 （ 4 ） 835 - 843 2021年03月

研究論文（学術雑誌）, 共著, 筆頭著者, 査読有り,  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

Matsuzaki J, Tsugawa H, Suzuki H

Gut and Liver （Gut and Liver）  15 （ 1 ） 3 - 12 2021年01月

研究論文（学術雑誌）, 査読有り

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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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Development of diagnostic models for solid cancers using circulating microRNAs

J Matsuzaki

CANCER SCIENCE 112, 203-203 2021年

研究論文（国際会議プロシーディングス）

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年

研究論文（国際会議プロシーディングス）

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年

研究論文（学術雑誌）, 査読有り

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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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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年

研究論文（学術雑誌）, 共著, 査読有り,  ISSN  2052-0034

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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年

研究論文（国際会議プロシーディングス）

Circulating microRNAs: Next-generation Cancer Detection.

Matsuzaki J, Ochiya T

The Keio journal of medicine （Keio Journal of Medicine）  69 （ 4 ） 88 - 96 2020年12月

研究論文（大学，研究機関等紀要）, 筆頭著者, 責任著者, 査読有り

　概要を見る

© 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

Inokuchi K, Ochiya T, Matsuzaki J

Journal of Clinical Medicine （Journal of Clinical Medicine）  10 （ 1 ） 1 - 16 2020年12月

研究論文（学術雑誌）, 共著, 査読有り,  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.

Horibe M, Iwasaki E, Bazerbachi F, Kaneko T, Matsuzaki J, Minami K, Masaoka T, Hosoe N, Ogura Y, Namiki S, Hosoda Y, Ogata H, Chan AT, Kanai T

Gastrointestinal endoscopy （Gastrointestinal Endoscopy）  92 （ 3 ） 578 - 588.e4 2020年09月

研究論文（学術雑誌）, 査読有り

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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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Highly Sensitive Circulating MicroRNA Panel for Accurate Detection of Hepatocellular Carcinoma in Patients With Liver Disease.

Yamamoto Y, Kondo S, Matsuzaki J, Esaki M, Okusaka T, Shimada K, Murakami Y, Enomoto M, Tamori A, Kato K, Aoki Y, Takizawa S, Sakamoto H, Niida S, Takeshita F, Ochiya T

Hepatology communications （Hepatology Communications）  4 （ 2 ） 284 - 297 2020年02月

研究論文（学術雑誌）, 共著, 筆頭著者, 査読有り,  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年

研究論文（学術雑誌）, 共著, 査読有り,  ISSN  0368-2811

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