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

DOI： 10.1038/s41586-020-2499-y

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DOI： 10.1038/s41586-020-2496-1

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DOI： 10.1158/0008-5472.CAN-18-3544

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

Single-cell transcriptomics of 20 mouse organs creates a Tabula Muris.

DOI： 10.1038/s41586-018-0590-4

Language：English  

DOI： 10.3892/or.2018.6464

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

DOI： 10.7554/eLife.01977

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DOI： 10.1016/j.yexcr.2011.07.022

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Effective monotherapy with amrubicin for a refractory extrapulmonary small-cell carcinoma of the liver.

DOI： 10.1155/2009/538081

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DOI： 10.1038/sj.bmt.1704750

Language：English   Publishing type：Research paper (scientific journal)   Publisher：Biochimica Et Biophysica Acta Molecular Basis of Disease  

BACKGROUND: Helicobacter pylori infection and subsequent atrophic gastritis (AG) and intestinal metaplasia (IM) are regarded as precursor conditions for gastric cancer (GC). Though diverse mechanisms of carcinogenesis from AG and IM have been clarified using mouse models, few studies using human models have been reported. Here, we describe in vitro modeling of IM, as well as in vivo modeling of the oncogenic transformation from AG using human gastric organoids. METHODS: Organoids derived from patients with AG were established and characterized by immunohistochemistry and in situ hybridization. Niche factor withdrawal and genetic engineering using CRISPR/Cas9 were conducted for modeling IM, and manipulated organoids were xenografted subcutaneously in mice to establish a GC model. RESULTS: AG organoids (AGOs) were maintained by Wnt niche factors; withdrawal of these factors led to differentiation toward foveolar cells. Knockout of Runt-related transcription factor 3 (RUNX3), or activation of bone morphogenetic protein (BMP) signaling, resulted in accumulation of the key IM markers caudal-type homeobox 2 (CDX2) and mucin 2 (MUC2) in AGOs; disruption of SMAD4 counteracted the induction of these markers. Organoids doubly deficient for TP53 and SMAD4 formed larger and more proliferative p21 -negative subcutaneous tumors than did RUNX3-deficient organoids, suggesting that induction of a senescent state is a key barrier in stepwise carcinogenesis from AG. CONCLUSIONS: Wnt signaling is essential for homeostasis of AG, and SMAD4-dependent activation of BMP signaling promotes intestinal differentiation. Combined disruption of TP53 and SMAD4 confers tumorigenic potential to AGOs by inhibiting p21 induction.

DOI： 10.1016/j.bbadis.2025.167843

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Language：English   Publisher：The Japanese Society of Internal Medicine  

<p>A 75-year-old man diagnosed with esophageal cancer and lung metastasis received a combination of fluorouracil, cisplatin, and pembrolizumab. During pembrolizumab maintenance therapy, lymphoproliferative lesions at the lips and mouth and multiple lymph node swellings appeared. Histologically, Epstein-Barr virus (EBV)-encoded RNA was positive, and EBV-DNA was detected in the blood. The patient was diagnosed with other iatrogenic immunodeficiency-associated lymph proliferative disorders (OIIA-LPDs) related to EBV activation induced by pembrolizumab. Rituximab was administered, resulting in the improvement of the OIIA-LPD. The emergence of an OIIA-LPD merits close attention in patients receiving immune checkpoint inhibitors. </p>

DOI： 10.2169/internalmedicine.3743-24

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DOI： 10.1007/s13691-025-00768-9

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Language：English   Publisher：Oxford University Press  

Language：English  

DOI： 10.1101/2025.01.22.633435

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Language：English   Publisher：ESMO Open  

Background: Pembrolizumab, an immune checkpoint inhibitor (ICI), shows significant survival benefits in patients with microsatellite instability-high (MSI-H) metastatic colorectal cancer (mCRC), but its efficacy in microsatellite-stable (MSS) mCRC is limited. Although ICIs are effective in tumor mutational burden-high (TMB-H) solid tumors, the impact on MSS-TMB-H mCRC, a rare subset within MSS mCRC, remains unclear. Materials and methods: We conducted a retrospective analysis using clinical and genomic data from the Center for Cancer Genomics and Advanced Therapeutics (C-CAT) repository in Japan. Patients with MSS-TMB-H mCRC who underwent tissue-based comprehensive genomic profiling and were treated with pembrolizumab or other later-line therapies were included. Pembrolizumab's efficacy was compared with that of trifluridine/tipiracil (FTD/TPI) and regorafenib. Genomic profiles of MSS-TMB-H, MSI-H-TMB-H, and MSS-TMB-low (TMB-L) CRCs were analyzed across 71 cancer-related genes. Results: Among 127 TMB-H mCRC cases treated with pembrolizumab in the C-CAT repository, 77 were MSS and 50 were MSI-H. Pembrolizumab showed significantly shorter time to treatment failure (TTF) and overall survival (OS) in patients with MSS-TMB-H mCRC compared with those with MSI-H-TMB-H mCRC [median TTF 2.0 versus 10.6 months; hazard ratio (HR) 4.79, 95% confidence interval (CI) 2.65-8.64, median OS 4.5 versus 33.6 months; HR 9.86, 95% CI 3.93-24.77, both P < 0.0001]. Among MSS-TMB-H mCRC patients, 19 received pembrolizumab, 73 received FTD/TPI (±bevacizumab), and 18 received regorafenib as their first later-line therapy. Pembrolizumab showed significantly shorter TTF and OS compared with FTD/TPI (median TTF 1.6 versus 4.1 months; HR 2.66, 95% CI 1.41-5.02, P = 0.0017, median OS 5.4 versus 13.8 months; HR 2.42, 95% CI, 1.09-5.38, P = 0.025). Genomic analysis of 6737 CRCs revealed that MSS-TMB-H CRCs harbored fewer pathogenic alterations than MSI-H-TMB-H CRCs but had a profile similar to MSS-TMB-L CRCs. Conclusions: Pembrolizumab may be less effective than FTD/TPI in later-line treatment of MSS-TMB-H mCRC, potentially due to genomic similarities between MSS-TMB-H and MSS-TMB-L CRC, suggesting the need for alternative therapeutic strategies in this subgroup.

DOI： 10.1016/j.esmoop.2024.104108

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Japanese Journal of Clinical Oncology  

BACKGROUND: Malignant primary cardiac tumors require multimodal approaches including surgery, chemotherapy and radiotherapy, but these treatments can be associated with cardiovascular complications. However, few reports have described the cardiovascular complications related to primary cardiac tumor treatment because of their rarity. METHODS: Clinical records of patients with primary cardiac tumors treated at Kyushu University Hospital from January 2010 to August 2021 were retrospectively examined. RESULTS: Of the 47 primary cardiac tumor patients, 13 (28%) were diagnosed with malignancy, including 5 angiosarcomas, 3 intimal sarcomas, 3 diffuse large B-cell lymphomas, 1 Ewing's sarcoma and 1 fibrosarcoma. Cardiovascular events were observed in 10 patients (77%), including cardiac dysfunction in 6 patients, arrhythmias in 5 patients, right heart failure in 2 patients, and excessively prolonged prothrombin time due to the combination of warfarin and chemotherapy in 1 patient. Two patients who showed notable cardiac complications are described. Case A involved a 69-year-old woman who underwent surgery for a left atrial intimal sarcoma, followed by postoperative chemotherapy with doxorubicin plus ifosfamide and radiotherapy. After three cycles of chemotherapy and sequential radiotherapy, her left ventricular ejection fraction decreased to 34%, and ongoing heart failure therapy was required. Case B involved a 66-year-old man who received chemotherapy for primary cardiac lymphoma, resulting in tumor shrinkage. However, due to tumor involvement of the intraventricular septum, atrioventricular block developed, requiring cardiac pacemaker implantation. CONCLUSION: High incidences of cardiac failure and arrhythmias were observed during multimodal treatments for malignant primary cardiac tumors. Proper management of complications may lead to a favorable prognosis in patients with malignant primary cardiac tumors.

DOI： 10.1093/jjco/hyae138

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Language：Others   Publishing type：Research paper (scientific journal)   Publisher：Springer Science and Business Media LLC  

Abstract

Background

Rhabdomyosarcoma is the most common soft tissue sarcoma in children, but rare in adults. Para-meningeal rhabdomyosarcoma in head and neck (PM-HNRMS) is less applicable for surgery due to the anatomic reason. PM-HNRMS has a poor prognosis in children. However, its clinical outcomes remain unclear in adults due to the rarity. Further, there is almost no detailed data about salvage therapy.

Methods

We retrospectively examined the adult patients with PM-HNRMS treated at institutions belonging to the Kyushu Medical Oncology Group from 2009 to 2022. We evaluated the overall survival (OS) and progression-free survival (PFS) of the patients who received a first-line therapy. We also reviewed the clinical outcomes of patients who progressed against a first-line therapy and received salvage therapy.

Results

Total 11 patients of PM-HNRMS received a first-line therapy. The characteristics were as follows: median age: 38 years (range 25 – 63 years), histology (alveolar/spindle): 10/1, and risk group (intermediate/high): 7/4. As a first-line therapy, VAC and ARST0431-based regimen was performed in 10 and 1 patients, respectively. During a first-line therapy, definitive radiation for all lesions were performed in seven patients. The median PFS was 14.2 months (95%CI: 6.0 – 25.8 months): 17.1 months (95%CI: 6.0 – not reached (NR)) for patients with stage I-III and 8.5 months (95%CI: 5.2 – 25.8 months) for patients with stage IV. The 1-year and 3-year PFS rates were 54.5% and 11.3% for all patients. Median OS in all patients was 40.8 months (95%CI: 12.1 months–NR): 40.8 months (95%CI: 12.1 – NR) for patients with stage I-III and NR for patients with stage IV. The 5-year OS rate was 48.5% for all patients. Among seven patients who received salvage therapy, three are still alive, two of whom remain disease-free for over 4 years after completion of the last therapy. Those two patients received multi-modal therapy including local therapy for all detected lesions.

Conclusion

The cure rate of adult PM-HNRMS is low in spite of a first-line therapy in this study. Salvage therapy might prolong the survival in patients who received the multi-modal therapy including local therapy for all detected lesions.

DOI： 10.1186/s12885-023-11528-4

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Other Link： https://link.springer.com/article/10.1186/s12885-023-11528-4/fulltext.html

Language：English   Publishing type：Research paper (scientific journal)   Publisher：Cancer Immunology, Immunotherapy  

Combined immune checkpoint blockade (ICB) is effective therapy for renal cell carcinoma (RCC). However, the dynamic changes in circulating B cells induced by combined ICB have not been clarified. The present study prospectively examined 22 patients scheduled to receive ICB for unresectable or metastatic RCC between March 2018 and August 2021. Eleven patients received combined therapy with anti-PD-1 (nivolumab) and anti-CTLA-4 (ipilimumab), and the other 11 patients received nivolumab monotherapy. Comprehensive phenotypes of circulating immune cells obtained prior to and after ICB therapy were analyzed by flow cytometry. Although the proportion of naïve B cells among total B cells was significantly decreased, that of switched memory B cells was significantly increased after combined therapy. In responders, the proportion of B cells among peripheral blood mononuclear cells was significantly higher prior to ICB therapy, and the proportion of switched memory B cells among total B cells tended to increase after ICB therapy. Of note, the proportion of plasmablasts among total B cells was significantly increased after ICB therapy in patients who developed severe immune-related adverse events (irAEs), and the proportion of B cells among peripheral blood decreased significantly. Furthermore, in four of five patients who developed immune-related hypophysitis following combined therapy, anti-pituitary antibody was detected in the serum. These results suggested that immune-related hypophysitis was closely related to the increase in circulating plasmablasts. Collectively, this study suggests that combined ICB promotes the differentiation of B cell populations, which is associated with efficient tumor suppression and development of irAEs.

DOI： 10.1007/s00262-023-03505-4

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Language：English   Publisher：John Wiley & Sons Australia, Ltd  

大腸癌幹細胞の中で増殖状態にあるものの特徴を決定するため、オルガノイドと大腸癌組織を材料に、それらのトランスクリプトミクスを解析した。その結果、CD44陽性を示す通常のヒト大腸癌幹細胞の分画の中に、ヒアルロン酸媒介運動性受容体(RHAMM)を発現している亜集団があることを発見した。細胞種の多様性を再構成することで腫瘍組織のミニチュア版としたオルガノイドを材料に、単一細胞トランスクリプトミクス解析を施行したところ、増殖性を示し、様々な細胞種の中にあって独特の特徴を示すRHAMM陽性細胞があることに注目された。ヒト大腸癌組織からRHAMM陽性CD44陽性の細胞を予期的に分離した結果、分離された同細胞は他の癌細胞と比較して高い増殖特性と自己新生能を現した。RHAMMを阻害するとin vitroでのオルガノイド形成は強く抑制され、in vivoでは腫瘍成長が阻害された。RHAMMは、通常の癌幹細胞分画内に含まれる増殖性の亜集団への特異的マーカーになりうると考えられた。

Language：English   Publisher：John Wiley & Sons Australia, Ltd  

クロイソカイメンから発見されたハリコンドリンBの誘導体である微小管標的薬エリブリン(Eri)に対する耐性のメカニズムについて検討した。Eri耐性大腸癌由来SW480細胞におけるインスリン様成長因子-1受容体(IGF-1R)/インスリン受容体(INSR)活性化に対するEri処理の影響を分析した。その結果、Eriへの曝露により、リン酸化されたIGF-1R/INSRとその下流エフェクターにおけるAktの蓄積量が増加し、IGFシグナルが活性化された。Eri処理はIGF-1Rの活性化とそれに続く核移行を誘導したが、IGF-1Rの活性化や核移行を阻害した場合、EriはDNA損傷を誘導し、G2/M停止を促進した。さらに、Eri耐性細胞株であるSW480を用いた異種移植マウスモデルにおいて、EriとIGF-1R阻害剤であるリンシチニブの併用は、いずれの単剤よりも腫瘍増殖を抑制した。以上より、EriとIGF-1R阻害剤の併用はEri耐性を克服することが示唆された。

Language：English   Publishing type：Research paper (scientific journal)   Publisher：Japanese journal of clinical oncology  

BACKGROUND: The incidence of venous thromboembolism has been reported as 20% in cancer patients. Anticoagulation therapy is the standard treatment for venous thromboembolism. On the other hand, bleeding should be carefully managed, because advanced cancer, particularly gastrointestinal cancer, carries a high risk of bleeding. However, the optimal management for cancer-associated thromboembolism remains to be clarified. METHODS: We retrospectively examined patients with advanced gastrointestinal cancer, including gastric cancer and colorectal cancer, who were treated with chemotherapy between 2014 and 2018 for the incidence and characteristics of venous thromboembolism and bleeding. RESULTS: In total, 194 patients (120 men, 74 women) were enrolled in this study. The underlying pathology was gastric cancer in 74 cases and colorectal cancer in 120 cases. Of the 194 patients, 40 patients (20.6%) were diagnosed with venous thromboembolism and 10 patients (5.2%) were diagnosed with concomitant pulmonary thromboembolism. Conversely, bleeding was observed in 29 patients (15%). The location of bleeding was the primary tumor in 17 cases, metastatic tumor in 9 and hemorrhagic gastric ulcer in 3. Within the venous thromboembolism group (n = 40), bleeding was observed in 10 patients (25%). Multivariate analysis showed that International Medical Prevention Registry on Venous Thromboembolism (IMPROVE) bleeding score ≥7 correlated significantly with major bleeding (P = 0.01). In patients with a low risk of bleeding, major bleeding was observed in only three patients. CONCLUSIONS: IMPROVE bleeding score may predict the risk for bleeding in gastrointestinal cancer patients with venous thromboembolism. Selecting patients with a low risk of bleeding using with IMPROVE bleeding score is expected to contribute to the safer management of anticoagulation therapy for cancer-associated thromboembolism.

DOI： 10.1093/jjco/hyac103

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Language：English   Publisher：シュプリンガー・ジャパン(株)  

E-カドヘリン欠損胃印環細胞癌(SRCC)における新規治療標的を同定することを目的とした。E-カドヘリンをコードするCDH1遺伝子をノックアウト(KO)したヒト胃オルガノイド(hGO)を用いて、in vitroのE-カドヘリン欠損胃癌モデルを作製し、新規治療標的を探索した。CDH1 KO hGO細胞は、SRCCに類似した特徴的な形態変化と高い細胞運動性を示した。RNA配列解析の結果、CDH1 KO hGO細胞では、野生型と比較して、マトリックスメタロプロテアーゼ(MMP)遺伝子の発現が増加していた。MMP阻害剤は、in vitroでCDH1 KO hGO細胞およびSRCC細胞株の細胞運動を抑制した。95例の臨床胃癌組織を用いた免疫蛍光分析により、MMP-3はE-カドヘリン異常のSRCCに特異的に多く存在することが示された。また、CDH1 KO後、CXCR4分子が細胞膜上に移行した。CXCR4のリガンドであるCXCL12を培養液に添加すると、CDH1 KO hGO細胞の細胞生存率が延長し、CXCR4アンタゴニストであるAMD3100によってその効果が消失した。SRCCの臨床サンプルでは、CXCL12を分泌する線維芽細胞が癌領域に著しく浸潤していることを確認した。以上より、MMPとCXCL12/CXCR4軸は、E-カドヘリン欠損SRCCの新規治療標的として有望な候補であると考えられた。

Language：English   Publisher：シュプリンガー・ジャパン(株)  

結腸癌組織8例(ヒト6例、マウス2例)から陰窩底部および陰窩頂部の上皮細胞を精製し、335個のmiRNA発現の差異を調べた。最終分化した頂部の上皮細胞で6個のmiRNA(miR-200a、miR-200b、miR-200c、miR-203、miR-210、miR-345)が最も上方制御されていた。ヒト大腸癌におけるこれらのmiRNA発現レベルは相互に正相関していた。相互の相関係数が高いmiRNA(miR-200a、miR-200b、miR-200c)の高発現は生存予後良好と関連した。最も上方制御された二つのmiRNA(miR-200c、miR-203)は、結腸上皮細胞において、幹細胞集団の自己複製の制御因子であるBMI1発現を相乗的に抑制し、増殖、オルガノイド形成および腫瘍形成性を阻害した。以上より、結腸上皮における最終分化ではmiR-200cとmiR-203が協調的に上方制御され、これらのmiRNAは協働してBMI1を抑制することにより上皮細胞の増殖を抑制すると考えられた。

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

Cancer-associated fibroblasts (CAFs) play an important role in cancer progression. However, the origin of CAFs remains unclear. This study shows that macrophages in malignant ascites and pleural effusions (cavity fluid-associated macrophages: CAMs) transdifferentiate into fibroblast-like cells. CAMs obtained from gastrointestinal cancer patients were sorted by flow cytometry and cultured in vitro. CD45+CD14+ CAMs transdifferentiated into CD45-CD90+ fibroblast-like cells that exhibited spindle shapes. Then, cDNA microarray analysis showed that the CD45-CD90+ fibroblast-like cells (macrophage-derived CAFs: MDCAFs) had a fibroblast-specific gene expression signature and produced growth factors for epithelial cell proliferation. Human colon cancer cells transplanted into immunodeficient mice with MDCAFs formed larger tumors than cancer cells alone. Gene ontology analyses showed the involvement of TGFβ signaling and cell-matrix adhesion in MDCAFs, and transdifferentiation of CAMs into MDCAFs was canceled by inhibiting TGFβ and cell adhesion. Furthermore, the acquired genetic alterations in hematopoietic stem cells (HSCs) were shared in CAMs and MDCAFs. Taken together, CAMs could be a source of CAFs and might originate from HSCs. We propose the transdifferentiation process of CAMs into MDCAFs as a new therapeutic target for fibrosis associated with gastrointestinal cancer.

DOI： 10.1016/j.canlet.2022.215597

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DOI： 10.3390/jcm10214972

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DOI： 10.1097/md.0000000000025773

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DOI： 10.1038/S41598-021-82448-1

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DOI： 10.1038/s41598-020-77898-y

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DOI： 10.1002/2211-5463.12765

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Organoid Culture of Human Cancer Stem Cells.

DOI： 10.1007/7651_2016_13

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DOI： 10.1007/s00280-015-2706-y

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DOI： 10.1007/s13691-012-0060-z

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DOI： 10.1016/j.yexcr.2012.04.011

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DOI： 10.1186/1752-1947-6-315

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DOI： 10.3892/ol_00000074

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DOI： 10.1097/CAD.0b013e3283218080

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DOI： 10.1002/eji.200737694

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DOI： 10.1016/j.annonc.2023.09.205

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

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