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

The effect of the combination of atezolizumab and bevacizumab (Atez/Bev) for hepatocellular carcinoma (HCC) on pulmonary arterial hypertension (PAH) is unknown. Estimation of PAH by using computed tomography (CT) has recently been proposed. Thus, we aimed to estimate the effect of Atez/Bev on PAH using CT. Altogether, 113 patients who received Atez/Bev for HCC were enrolled. Probable PAH was defined as the diameter of the main pulmonary artery (mPA-D) ≥ 33 mm, whereas suspicious PAH was defined as mPA-D ≥ 29 mm or mPA-D/the diameter of the ascending aorta (aAo-D) ≥ 1.0. Before treatment, probable/suspicious PAH were diagnosed in 7 (6.7%)/22 (21.0%) patients, respectively. mPA-D and mPA-D/aAo-D significantly increased after induction of Atez/Bev. The increment of mPA-D was correlated with the occurrence of post-treatment respiratory/heart failure. In analysis of 55 patients who underwent CT at 3 months after the last dose of Atez/Bev, mPA-D and mPA-D/aAo-D significantly decreased. However, in the group with continuous treatment of other molecular-targeted drugs after Atez/Bev, mPA-D and mPA-D/aAo-D showed no significant change. In conclusion, PAH may not be a rare complication in patients with HCC and should be managed carefully because of the possible negative effect of Atez/Bev on PAH.

DOI： 10.1038/s41598-023-38377-2

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Language：Japanese   Publisher：(一社)日本肝臓学会  

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BACKGROUND: Hyperprogressive disease (HPD) is a phenomenon with greatly accelerated tumor growth and clinical deterioration rates compared to pre-therapy, in patients treated with immune checkpoint inhibitors (ICI). The aim of this study is to clarify the reality of HPD in patients with advanced hepatocellular carcinoma (HCC) who were treated with atezolizumab plus bevacizumab (Atez/Bev) using tumor dynamics. METHODS: Medical records of consecutive patients with advanced HCC who were treated with Atez/Bev were retrospectively reviewed. HPD was defined as a more than two- or fourfold increase in tumor growth rate (TGR) or tumor growth kinetics rate (TGKR) before and after treatment. Overall survival (OS) and baseline characteristics with or without HPD were analyzed. RESULTS: A total of 85 patients were included in the analysis. When HPD was defined as a twofold of TGR or TGKR, 8 patients (8/85, 9.4%) had HPD and 11 had PD without HPD. A total of 5 patients (5/85, 5.9%) were diagnosed with HPD and 14 with PD without HPD when HPD was defined as a fourfold of TGR or TGKR. No significant difference was observed in the baseline characteristics between HPD and non-HPD. CONCLUSION: The prevalence of HPD in patients with advanced HCC treated with Atez/Bev was lower than those treated with nivolumab monotherapy. The HPD mechanism in ICI combined with antibodies targeting vascular endothelial growth factor (VEGF) remains to be elucidated.

DOI： 10.1186/s12876-023-02731-5

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PURPOSE: Ramucirumab was shown to be effective as a second-line treatment after sorafenib in patients with advanced hepatocellular carcinoma (HCC) with alpha-fetoprotein levels > 400 ng/mL in a worldwide phase 3 trial. Ramucirumab is used in patients pretreated with various systemic therapies in clinical practice. We retrospectively examined the treatment outcomes of ramucirumab administered to advanced HCC patients after diverse systemic therapies. METHODS: Data were collected from patients with advanced HCC who received ramucirumab at three institutions in Japan. Radiological assessments were determined according to both Response Evaluation Criteria in Solid Tumours (RECIST) version 1.1 and modified RECIST and the Common Terminology Criteria for Adverse Events version 5.0 was used to assess adverse events. RESULTS: A total of 37 patients treated with ramucirumab between June 2019 and March 2021 were included in the study. Ramucirumab was administered as second, third, fourth, and fifth-line treatment in 13 (35.1%), 14 (37.8%), eight (21.6%), and two (5.4%) patients, respectively. Most patients (29.7%) who received ramucirumab as a second-line therapy were pretreated with lenvatinib. We found grade 3 or higher adverse events only in seven patients and no significant changes in the albumin-bilirubin score during ramucirumab treatment in the present cohort. The median progression-free survival of patients treated with ramucirumab was 2.7 months (95% confidence interval, 1.6-7.3). CONCLUSION: Although ramucirumab is used for various lines of treatment other than second-line immediately after sorafenib, its safety and effectiveness were not significantly different from the findings of the REACH-2 trial.

DOI： 10.1186/s12876-023-02674-x

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Language：Japanese   Publisher：(一財)日本消化器病学会  

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BACKGROUND/AIM: MHC-class I-related chain A (MICA) functions as a ligand for natural killer group D, an activating receptor on natural killer (NK) cells, and its expression correlates with the carcinogenesis and progression of hepatocellular carcinoma (HCC). Although membranous MICA (mMICA) activates NK cells, soluble forms of MICA (sMICA), shed by cleaving enzymes, such as A disintegrin and metalloprotease (ADAM) 9, suppress NK cells. Therefore, the prevention of MICA shedding through the inhibition of ADAM9 has the potential to activate cancer immunity. Although we have discovered several ADAM inhibitors, many did not sufficiently activate NK cells without being cytotoxic, and, thus, new ADAM9 inhibitor candidates are needed. MATERIALS AND METHODS: To identify possible compounds for drug development, chemical library screening (a total of 741 compounds) was conducted using a fluorescence assay. Compounds with reduced fluorescence intensity were used as hit compounds in a subsequent analysis. Their impact on sMICA and mMICA in HCC cell lines was assessed using ELISA and flow cytometry, respectively. The cytotoxicity of NK cells was also evaluated by co-culturing NK cells with HCC cells. RESULTS: CCL347, a symmetrical compound with five benzene rings, was identified as a hit compound. CCL347 significantly reduced sMICA levels in the culture medium supernatant with negligible cytotoxicity. Although mMICA was also reduced, CCL347 successfully enhanced NK cell cytotoxicity in co-cultures of NK cells and HCC cells. CONCLUSION: CCL347 has potential as a novel therapeutic drug for HCC.

DOI： 10.21873/anticanres.16249

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Combination therapy with anti-cytotoxic T lymphocyte-associated protein 4 (CTLA-4) and anti-programmed death-1 (PD-1) monoclonal antibodies (mAbs) has dramatically improved the prognosis of patients with multiple types of cancer, including renal cell carcinoma (RCC). However, more than half of RCC patients fail to respond to this therapy. Regulatory T cells (Treg cells) are a subset of highly immunosuppressive CD4+ T cells that promote the immune escape of tumors by suppressing effector T cells in the tumor microenvironment (TME) through various mechanisms. CTLA-4 is constitutively expressed in Treg cells and is regarded as a key molecule for Treg cell-mediated immunosuppressive functions, suppressing antigen-presenting cells by binding to CD80/CD86. Reducing Treg cells in the TME with an anti-CTLA-4 mAb with antibody-dependent cellular cytotoxicity (ADCC) activity is considered an essential mechanism to achieve tumor regression. In contrast, we demonstrated that only CTLA-4 blockade without ADCC activity enhanced CD28 costimulatory signaling pathways in Treg cells and promoted Treg-cell proliferation in mouse models. CTLA-4 blockade also augmented CTLA-4-independent immunosuppressive functions, including cytokine production, leading to insufficient antitumor effects. Similar results were also observed in human peripheral blood lymphocytes and tumor-infiltrating lymphocytes from patients with RCC. Our findings highlight the importance of Treg-cell depletion to achieve tumor regression in response to CTLA-4 blockade therapies.

DOI： 10.1111/cas.15756

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Authorship：Lead author   Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND: Identifying biomarkers to predict immune checkpoint inhibitor (ICI) efficacy is warranted. Considering that somatic mutation-derived neoantigens induce strong immune responses, patients with a high tumour mutational burden reportedly tend to respond to ICIs. However, there are several conflicting data. Therefore, we focused on the original function of neoantigenic mutations and their impact on the tumour microenvironment (TME). METHODS: We evaluated 88 high-frequency microsatellite instability (MSI-H) colorectal cancers and analysed the function of the identified neoantigenic mutations and their influence on programmed cell death 1 (PD-1) blockade efficacy. The results were validated using The Cancer Genome Atlas (TCGA) datasets. RESULTS: We identified frameshift mutations in RNF43 as a common neoantigenic gene mutation in MSI-H tumours. However, loss-of-function RNF43 mutations induced noninflamed TME by activating the WNT/β-catenin signalling pathway. In addition, loss of RNF43 function induced resistance to PD-1 blockade even in neoantigen-rich tumours. TCGA dataset analyses demonstrated that passenger rather than driver gene mutations were related to the inflamed TME in diverse cancer types. CONCLUSIONS: We propose a novel concept of "paradoxical neoantigenic mutations" that can induce noninflamed TME through their original gene functions, despite deriving neoantigens, suggesting the significance of qualities as well as quantities in neoantigenic mutations.

DOI： 10.1038/s41416-023-02165-6

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Transforming growth factor (TGF)-β/Smad pathway is implicated in the pathogenesis of liver fibrosis, a condition characterized by excessive deposition of extracellular matrix (ECM) proteins such as collagen in response to chronic inflammation. It has been reported that ceramide regulates collagen production through TGF-β/Smad pathway activation. In this study, we examined whether miglustat, an inhibitor of glucosylceramide synthase, can suppress liver fibrosis by reducing TGF-β/Smad pathway activity. Human hepatic stellate cells (HHSteCs) were cultured with TGF-β and multiple miglustat concentrations to examine dose-dependent effects on the expression levels of ECM-related genes and Smad proteins. To evaluate the efficacy of miglustat for fibrosis mitigation, C57BL/6 mice were treated with carbon tetrachloride (CCl4) for 4 weeks to induce liver fibrosis, followed by combined CCl4 plus miglustat for a further 2 weeks. To examine if miglustat can also prevent fibrosis, mice were treated with CCl4 for 2 weeks, followed by CCl4 plus miglustat for 2 weeks. Miglustat dose-dependently downregulated expression of α-smooth muscle actin and ECM components in TGF-β-treated HHSteCs. Both phosphorylation and nuclear translocation of Smad2 and Smad3 were also suppressed by miglustat treatment. Sirius-Red staining and hydroxyproline assays of model mouse liver samples revealed that miglustat reduced fibrosis, an effect accompanied by decreased expression of ECM. Our findings suggest that miglustat can both prevent and reverse liver fibrosis by inhibiting TGF-β/Smad pathway.

DOI： 10.1016/j.bbrc.2022.12.025

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

BACKGROUND: Although the efficacy of atezolizumab has been demonstrated in randomized controlled trials, its long-term efficacy and association with adverse events in real-world practice are unknown. This study was designed to shed light on these issues. METHODS: In this multicenter retrospective study, data were collected from patients with advanced hepatocellular carcinoma treated with atezolizumab plus bevacizumab in seven institutions in Japan. The authors focused on the efficacy and adverse events related to vascular endothelial growth factor (VEGF) inhibition. RESULTS: A total of 123 patients were enrolled in this study. The median progression-free survival (PFS) for the first-line treatment group was 8.0 months (95% confidence interval [CI], 6.1-9.9), whereas the median PFS for the second- or later-line treatment group was 4.1 months (95% CI, 2.6-5.7), which was significantly worse than that of the first-line treatment group (p = .005). Twenty-seven patients had interrupted bevacizumab treatment. Proteinuria accounted for the largest proportion of bevacizumab treatment interruptions. The cumulative incidence rate of bevacizumab interruption due to anti-VEGF-related adverse events was significantly higher in patients with hypertension and/or diabetes mellitus than in those without (p = .026). The landmark analysis showed that patients experienced bevacizumab interruption by 24 weeks from treatment initiation had poorer PFS than those who did not (p = .013). CONCLUSIONS: The PFS of atezolizumab plus bevacizumab as first-line treatment mostly replicates that of a global phase 3 trial. Interrupted bevacizumab treatment was more common in patients with hypertension and/or diabetes mellitus, which may be associated with worsening long-term PFS. PLAIN LANGUAGE SUMMARY: Atezolizumab plus bevacizumab has been the standard front line systemic therapy for advanced hepatocellular carcinoma. With the growing incidence of fatty liver due to metabolic syndrome as a background liver disease for hepatocellular carcinoma, the rate of comorbid hypertension and diabetes mellitus has been increasing accordingly. The present study demonstrated the cumulative incidence rate of bevacizumab interruption due to anti-VEGF-related adverse events was significantly higher in patients with hypertension and/or diabetes mellitus. The landmark analysis clarified that interruption of bevacizumab might be a risk of impaired efficacy of atezolizumab plus bevacizumab over the long term in patients with advanced hepatocellular carcinoma.

DOI： 10.1002/cncr.34559

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Other Link： https://onlinelibrary.wiley.com/doi/full-xml/10.1002/cncr.34559

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

Immune checkpoint inhibitors (ICIs) are effective for various types of cancer, and their application has led to paradigm shifts in cancer treatment. While many patients can obtain clinical benefits from ICI treatment, a large number of patients are primarily resistant to such treatment or acquire resistance after an initial response. Thus, elucidating the resistance mechanisms is warranted to improve the clinical outcomes of ICI treatment. ICIs exert their antitumor effects by activating T cells in the tumor microenvironment. There are various resistance mechanisms, such as insufficient antigen recognition by T cells, impaired T-cell migration and/or infiltration, and reduced T-cell cytotoxicity, most of which are related to the T-cell activation process. Thus, we classify them into three main mechanisms: resistance mechanisms related to antigen recognition, T-cell migration and/or infiltration, and effector functions of T cells. In this review, we summarize these mechanisms of resistance to ICIs related to the T-cell activation process and progress in the development of novel therapies that can overcome resistance.

DOI： 10.1111/cas.15497

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Language：Japanese   Publisher：(一社)日本肝臓学会  

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Language：English   Publisher：(一社)日本癌学会  

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Language：English   Publisher：(一社)日本癌学会  

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

BACKGROUND: With the evolution of personalized medicine in the field of oncology, which includes optimal treatment selection using next-generation sequencing-based companion diagnostic systems and tumor-agnostic treatments according to common biomarkers, a liver tumor biopsy technique that can obtain a sufficient specimen volume must be established. The current study aimed to evaluate the safety and availability of a liver tumor biopsy technique with multiple puncture sites made using a coaxial introducer needle and embolization with gelatin sponge particles. METHODS: Patients with primary or metastatic liver cancer who underwent liver tumor biopsies with puncture tract embolization using gelatin sponge (Spongel®) from October 2019 to September 2020 were included in the study. The complication and diagnostic rates were evaluated, and whether the specimen volume was sufficient for Foundation® CDx was investigated. RESULTS: In total, 96 patients were enrolled in this analysis. The median total number of puncture times per patient was 3 (range 1-8). The pathological diagnostic rate was 79.2%. Using the FoundationOne® CDx, specimens with a sufficient volume required for genomic medicine were collected in 84.9% of patients. The incidence rate of bleeding was 4.2% (n = 4), and only one patient presented with major bleeding requiring transfusion. CONCLUSIONS: Liver biopsy with puncture tract embolization using a gelatin sponge may be safe and effective for collecting specimens with a volume sufficient for modern cancer treatments.

DOI： 10.1007/s10147-022-02195-9

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

INTRODUCTION: Advanced hepatocellular carcinoma (HCC) with macrovascular invasion (MVI) has the worst prognosis among all phenotypes. This trial aims to evaluate whether treatment with durvalumab, alone or in combination with tremelimumab, plus particle therapy is a safe and synergistically effective treatment in patients with advanced HCC and MVI. METHODS AND ANALYSIS: This phase Ib, multicentre (two sites in Japan), open-label, single-arm, investigator-initiated clinical trial will assess durvalumab monotherapy in combination with particle therapy (cohort A) and that of durvalumab plus tremelimumab in combination with particle therapy (cohort B) for patients with advanced HCC with MVI. Cohort A will receive 1500 mg durvalumab every 4 weeks. Cohort B will receive 1500 mg durvalumab every 4 weeks in principle and 300 mg tremelimumab only on day 1 of the first cycle. Carbon-ion radiotherapy will be administered after day 8 of the first cycle. The primary endpoints are rates of any and severe adverse events, including dose-limiting toxicities (DLTs); secondary endpoints are overall survival, 6-month survival, objective response, 6-month progression-free survival and time to progression. Patients are initially enrolled into cohort A. If cohort A treatment is confirmed to be tolerated (ie, no DLT in three patients or one DLT in six patients), the trial proceeds to enrol more patients into cohort B. Similarly, if cohort B treatment is confirmed to be tolerated (ie, no DLT in three patients or one DLT in six patients), a total of 15 patients will be enrolled into cohort B. ETHICS AND DISSEMINATION: This study was approved by the ethics committees of the two participating institutions (Chiba University Hospital and National Institutes for Quantum (approval number: 2020040) and Radiological Science and Technology, QST Hospital (approval number: C20-001)). Participants will be required to provide written informed consent. Trial results will be reported in a peer-reviewed journal publication. TRIAL REGISTRATION NUMBER: jRCT2031210046.

DOI： 10.1136/bmjopen-2021-059779

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Language：Japanese   Publisher：(一社)日本門脈圧亢進症学会  

門脈血栓症は時として致死的な転機をたどる病態である。今回、高度の門脈圧亢進症を呈した亜急性門脈血栓症に対して経頸静脈的肝内門脈静脈短絡術(TIPS)が著効した1例を経験したので報告する。症例は56歳男性。腹痛を契機に近医を受診し、門脈本幹から肝内門脈右枝、上腸間膜静脈に至る広範囲の血栓を認め、当院紹介となった。前医で出血性十二指腸潰瘍の治療歴があったため、AT III製剤単独の投与を開始したが治療効果なく、胸腹水の増悪を認めた。そのため、経頸静脈的に肝内門脈から上腸間膜静脈にアプローチし血栓回収・ウロキナーゼ持続門注を開始した。門注後も血栓は溶解されず、下腸間膜静脈から右肝静脈へTIPSステントを留置した。その後、血流の求肝性変化、胸腹水の消失と低アルブミン血症の改善を認め、独歩での退院となった。血栓溶解療法に反応せず著明な門脈圧亢進症を呈している門脈血栓の症例においては、TIPSは治療選択肢に考慮するべきである。(著者抄録)

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BACKGROUND AND AIMS: The prognosis of patients with advanced hepatocellular carcinoma (HCC) is expected to improve as multiple molecular target agents (MTAs) are now available. However, the impact of the availability of sequential MTAs has not been fully verified yet. APPROACH AND RESULTS: We retrospectively collected the data on the whole clinical course of 877 patients who received any MTAs as first-line systemic therapy for advanced HCC between June 2009 and March 2019. The study population was divided into 3 groups according to the date of first-line MTA administration (period 1: 2009-2012, n = 267; period 2: 2013-2016, n = 352; period 3: 2017-2019, n = 258). Then, we compared the number of MTAs used, overall survival (OS), and MTA treatment duration among the 3 groups. Analysis was also performed separately for advanced-stage and nonadvanced-stage HCC. The proportion of patients who received multiple MTAs was remarkably increased over time (1.1%, 10.2%, and 42.6% in periods 1, 2, and 3, respectively, p < 0.001). The median OS times were prolonged to 10.4, 11.3, and 15.2 months in periods 1, 2, and 3, respectively (p = 0.016). Similarly, the MTA treatment durations were extended (2.7, 3.2, and 6.6 months in periods 1, 2, and 3, respectively; p < 0.001). We confirmed that the correlation between OS and MTA treatment duration was strengthened (period 1: 0.395, period 2: 0.505, and period 3: 0.667). All these trends were pronounced in the patients with advanced-stage HCC but limited in the patients with nonadvanced-stage HCC. CONCLUSIONS: The availability of multiple MTAs had steadily improved the prognosis of patients with advanced HCC patients, particularly advanced-stage HCC patients.

DOI： 10.1159/000519868

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

Atezolizumab plus bevacizumab (ATZ/BV) treatment is a combined immunotherapy consisting of immune checkpoint inhibitor (ICI) and anti-vascular endothelial growth factor monoclonal antibody, which has brought a major paradigm shift in the treatment of unresectable hepatocellular carcinoma (HCC). Gain-of-function mutation of CTNNB1 contributes to resistance of ICI monotherapy through the framework of non-T-cell-inflamed tumor microenvironment. However, whether CTNNB1 mutation renders resistance to ATZ/BV similar to ICI monotherapy remains to be elucidated. In this study, a liquid biopsy sample in plasma of 33 patients with HCC treated with ATZ/BV was subjected to droplet digital PCR for detecting hotspot mutations at the exon 3 of CTNNB1 locus. A total of eight patients (24.2%) exhibited at least one CTNNB1 mutation. The objective response rate (ORR) in patients with wild-type (WT) and mutant (MT) CTNNB1 was 8.0% and 12.5%, respectively, and the disease control rate (DCR) was 68.0% and 87.5%, respectively. No significant difference in both ORR and DCR has been observed between the two groups. The median progression-free survival in patients with WT and MT CTNNB1 was 6.6 and 7.6 months, respectively (not statistically significant). Similarly, no significant difference in overall survival has been observed between patients with WT and MT CTNNB1 (13.6 vs. 12.3 months). In conclusion, the treatment effect of ATZ/BV in patients with HCC with MT CTNNB1 was comparable to those patients with WT CTNNB1. These results implicate that BV added to ATZ might improve immunosuppressive tumor microenvironment caused by CTNNB1 mutation.

DOI： 10.7150/jca.71494

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Language：Japanese   Publisher：(一社)日本肝臓学会  

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Language：Japanese   Publisher：(一社)日本肝臓学会  

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

BACKGROUND AND AIM: Immune checkpoint inhibitors and their combination with other agents have recently been available in advanced hepatocellular carcinoma (HCC). Hence, a thorough understanding of the tumor microenvironment based on tumor samples is yet to be achieved. This study aimed to explore the tumor microenvironment in advanced HCC in terms of microsatellite instability-high (MSI-H) by using tumor samples from advanced HCC patients eligible for systemic therapy. METHODS: MSI-H was assessed by polymerase chain reaction, and the expression of mismatch repair proteins, PD-L1, CD8, VEGF, and HLA-class1 was evaluated by immunohistochemistry. Whole-exome sequencing was performed for MSI-H tumor samples. RESULTS: Of 50 patients, one (2.0%) was confirmed with MSI-H. In the MSI-H advanced HCC tumor, a high tumor mutation burden, infiltration of CD8+ lymphocytes, and low expression of VEGF were identified. Although PD-L1 expression was negative, there was shrinkage of tumor following pembrolizumab. However, another tumor nonresponsive to pembrolizumab was present simultaneously. Checking the Cancer Genome Atlas (TCGA) database, we found a similar case to this patient. The TCGA case had unique gene features of miR-21 and miR-155 overexpression and hypermethylation of the MSH2 gene. CONCLUSION: We identified a very small number of MSI-H cases in HCC using one tumor biopsy sample for each patient with advanced HCC. In addition, epigenetic aberrations possibly lead to MSI-H in HCC patients. Since different HCC clones might coexist in the liver, sampling from multiple tumors should be considered to clarify the true proportion of MSI-H in HCC and to analyze tumor microenvironments.

DOI： 10.1002/jgh3.12660

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Language：Japanese   Publisher：(有)科学評論社  

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Language：Japanese   Publisher：(株)アークメディア  

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Language：Japanese   Publisher：(一社)日本肝臓学会  

J-GLOBAL

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Language：Japanese   Publisher：(株)アークメディア  

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Language：Japanese   Publisher：日本分子腫瘍マーカー研究会  

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Language：Japanese   Publisher：(一社)日本肝臓学会  

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Language：Japanese   Publisher：医学図書出版(株)  

2020年9月、本邦においてアテゾリズマブ・ベバシズマブ併用療法が切除不能な肝細胞癌の一次治療薬として保険承認され、実臨床で用いられるようになった。本邦の実臨床で認められた有害事象は、第III相試験(IMbrave150試験)と同様の傾向があったものの、IMbrave150試験では経験しなかった免疫関連有害事象(irAE)も散見されている。irAEは、これまでの分子標的治療薬では経験のない有害事象が少なくなく、多種多様な有害事象が報告されている。免疫療法が先行して開発された他癌腫での経験から学び、複数の診療科の専門医、看護師、薬剤師などといった多職種との連携を構築しながら診療にあたる必要があるだろう。(著者抄録)

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Other Link： https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2021&ichushi_jid=J06599&link_issn=&doc_id=20211101360003&doc_link_id=%2Faa6kancd%2F2021%2F000701%2F004%2F0019b0024%26dl%3D3&url=https%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Faa6kancd%2F2021%2F000701%2F004%2F0019b0024%26dl%3D3&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_4.gif

Language：Japanese   Publisher：日本分子腫瘍マーカー研究会  

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Language：Japanese   Publisher：日本消化器病学会-関東支部  

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Language：Japanese   Publisher：千葉医学会  

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Language：Japanese   Publisher：(一財)日本消化器病学会  

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Language：Japanese   Publisher：日本消化器病学会-関東支部  

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Language：Japanese   Publisher：日本内科学会-関東地方会  

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