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A Phase I, First-In-Human Study of CBA-1205, an Anti-DLK1 Monoclonal Antibody, in Patients With Advanced Solid Tumors. 抗dlk1单克隆抗体CBA-1205在晚期实体瘤患者中的I期首次人体研究
IF 5.7 2区 医学 Q1 Medicine Pub Date : 2025-01-20 DOI: 10.1111/cas.16454
Yuki Katsuya, Masafumi Ikeda, Takafumi Koyama, Jun Sato, Mao Okada, Nobuaki Matsubara, Chihiro Kondoh, Toru Mukohara, Kazuo Watanabe, Daisuke Kotani, Yoshimi Ogawa, Shose Taoka, Noboru Yamamoto

CBA-1205 is a novel humanized antibody targeting delta-like 1 homolog (DLK1) that enhances antibody-dependent cellular cytotoxicity activity. DLK1 overexpression has been reported in various cancer types, such as hepatocellular carcinoma and neuroblastoma. CBA-1205 demonstrates potent antitumor activity in multiple tumor models, making it a potential treatment option for DLK1-expressing cancers. This first-in-human, open-label Phase I study includes three parts. Part 1, the dose-escalation phase, primarily evaluates the safety profile, tolerability, and maximum tolerated dose of CBA-1205. The drug is administered intravenously every 2 weeks in a 28-day cycle. A standard 3 + 3 dose-escalation design was used across seven cohorts. In a cohort of 22 Japanese patients, over 80% had undergone three or more prior treatments. CBA-1205 was well tolerated, with no dose-limiting toxicity observed at doses ranging from 0.1 to 30 mg/kg, the planned highest dose. There were no treatment-related serious adverse events or trial-related deaths. CBA-1205 exposure, as measured by Cmax, AUC0-14, and AUC0-∞, increased in a dose-dependent manner. No serum anti-CBA-1205 antibodies were detected. Serum DLK1 concentrations were found in 6 out of 22 patients. Stable disease for over 6 months was observed in six patients, with progression-free survival ranging from 29 to 144 weeks. CBA-1205 was well tolerated, showing no severe toxicity in patients with advanced or recurrent solid tumors. The favorable safety profile and indications of potential activity support further investigation in Parts 2 and 3 of this Phase I study to evaluate the safety, tolerability, and preliminary efficacy of CBA-1205.

CBA-1205是一种新的人源化抗体,靶向delta-样1同源物(DLK1),可增强抗体依赖性细胞毒性活性。DLK1过表达已被报道在各种类型的癌症中,如肝细胞癌和神经母细胞瘤。CBA-1205在多种肿瘤模型中显示出强大的抗肿瘤活性,使其成为表达dlk1的癌症的潜在治疗选择。这项首次在人体中进行的开放标签I期研究包括三个部分。第一部分,剂量递增阶段,主要评估CBA-1205的安全性、耐受性和最大耐受剂量。该药每2周静脉注射一次,周期为28天。在7个队列中采用标准的3 + 3剂量递增设计。在一组22名日本患者中,超过80%的患者之前接受过三次或更多的治疗。CBA-1205耐受性良好,在计划最高剂量0.1至30 mg/kg的剂量范围内未观察到剂量限制性毒性。没有与治疗相关的严重不良事件或与试验相关的死亡。Cmax、AUC0-14和AUC0-∞测量的CBA-1205暴露量呈剂量依赖性增加。血清未检出抗cba -1205抗体。22例患者中有6例发现血清DLK1浓度。6例患者病情稳定超过6个月,无进展生存期为29至144周。CBA-1205耐受性良好,对晚期或复发性实体瘤患者无严重毒性。良好的安全性和潜在活性适应症支持在本I期研究的第2部分和第3部分进行进一步研究,以评估CBA-1205的安全性、耐受性和初步疗效。
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引用次数: 0
Highly hypofractionated biaxially rotational dynamic radiation therapy (BROAD-RT) for high-risk prostate cancer. 高度低分割双轴旋转动态放疗(BROAD-RT)治疗高危前列腺癌。
IF 5.7 2区 医学 Q1 Medicine Pub Date : 2025-01-20 DOI: 10.1111/cas.16429
Rihito Aizawa, Takashi Ogata, Takayuki Goto, Kiyonao Nakamura, Kenji Takayama, Ryo Ashida, Yuki Kita, Takayuki Sumiyoshi, Kaoru Murakami, Kei Mizuno, Takashi Kobayashi, Takashi Mizowaki

To report clinical outcomes following highly hypofractionated biaxially rotational dynamic radiation therapy (BROAD-RT), a unique radiation therapy method that facilitates non-coplanar volumetric-modulated arc therapy (VMAT) without the need to rotate the couch or reposition the patient, for high-risk prostate cancer (PCa) with simultaneous integrated boost (SIB) for intra-prostatic dominant lesions (IPDLs), we performed a single-center prospective pilot study. In this study, patients with high-risk PCa according to the D'Amico classification or those with cT3aN0M0 PCa were eligible. VMAT was performed using BROAD-RT, and a dose of 54 Gy in 15 fractions was prescribed for the prostate in combination with SIB for IPDLs at a dose of 57 Gy in 15 fractions. Short-term neoadjuvant androgen-deprivation therapy (median: 6.9 months) was conducted. Neither adjuvant androgen-deprivation therapy nor fiducial marker implantation to the prostate was applied for any patient. In total, 26 patients were registered in this study between August 2018 and November 2020. Their median age was 73 years at the initiation of RT. The median follow-up period was 49.7 months. The 4-year cumulative incidence rates of grade 2 late GU and GI toxicities were 15.4 and 3.8%, respectively. No grade 3 or higher acute or late toxicities were observed. The 4-year biochemical failure-free survival rates were 87.7%. In conclusion, highly hypofractionated RT using BROAD-RT for high-risk PCa with SIB for IPDLs was feasible and facilitated favorable oncological outcomes. Therefore, this approach is considered a promising method to achieve safe dose escalation and shorten the treatment duration.

为了报告高度低分割双轴旋转动态放射治疗(BROAD-RT)的临床结果,我们进行了一项单中心前瞻性试验研究,这是一种独特的放射治疗方法,可促进非共面体积调制弧线治疗(VMAT),而无需旋转长椅或重新定位患者,用于同时集成增强(SIB)前列腺内显性病变(ipdl)的高风险前列腺癌(PCa)。在本研究中,符合D'Amico分类的高危PCa患者或cT3aN0M0 PCa患者均入选。VMAT使用BROAD-RT进行,并为前列腺开出了15份54 Gy的剂量,同时为ipdl开出了15份57 Gy的SIB剂量。短期新辅助雄激素剥夺治疗(中位:6.9个月)。所有患者均未接受辅助雄激素剥夺治疗或前列腺基础标志物植入。在2018年8月至2020年11月期间,共有26名患者在该研究中登记。研究开始时的中位年龄为73岁,中位随访时间为49.7个月。2级晚期GU和GI毒性的4年累积发生率分别为15.4%和3.8%。未观察到3级或以上急性或晚期毒性。4年无生化失败生存率为87.7%。综上所述,使用BROAD-RT对高风险PCa进行高分割放疗并对ipdl进行SIB是可行的,并促进了良好的肿瘤预后。因此,这种方法被认为是一种有希望实现安全剂量递增和缩短治疗时间的方法。
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引用次数: 0
Multiple Kinase Small Molecule Inhibitor Tinengotinib (TT-00420) Alone or With Chemotherapy Inhibit the Growth of SCLC. 多激酶小分子抑制剂Tinengotinib (TT-00420)单独或联合化疗抑制SCLC的生长。
IF 5.7 2区 医学 Q1 Medicine Pub Date : 2025-01-16 DOI: 10.1111/cas.16450
Hui Li, Chenchen Tang, Peiyan Zhao, Rui Zhong, Yuanhua Lu, Yan Liu, Rixin Li, Shaowei Lan, Chunjiao Wu, Xiaoyan Qiang, Peng Peng, Frank Wu, Ying Cheng, Ying Liu

There is an urgent need to develop new targeted treatment agents for small cell lung cancer (SCLC). Tinengotinib (TT-00420) is a novel, multi-targeted, and spectrally selective small-molecule kinase inhibitor that has shown significant inhibitory effects on certain solid tumors in preclinical studies. However, its role and mechanism of action in SCLC remain unclear. In this study, we demonstrated that tinengotinib effectively inhibited SCLC cell proliferation, especially highly expressing NeuroD1 (SCLC-N), in the SCLC cell line-derived xenograft (CDX) model and the malignant pleural effusion cell model of patients with SCLC. When combined with etoposide/cisplatin, it synergistically inhibited SCLC growth. Tinengotinib regulates proliferation, apoptosis, migration, cell cycle and angiogenesis in SCLC cells. Mechanistic studies revealed that c-Myc expression may be a key factor influencing the effect of tinengotinib in SCLC-N. This study provides reliable preclinical data and a new direction for tinengotinib as a promising therapy for SCLC, either alone or in combination with chemotherapy.

目前迫切需要开发新的靶向治疗小细胞肺癌的药物。Tinengotinib (TT-00420)是一种新型的、多靶点的、光谱选择性的小分子激酶抑制剂,在临床前研究中对某些实体肿瘤显示出显著的抑制作用。然而,其在SCLC中的作用和作用机制尚不清楚。在这项研究中,我们证明了在SCLC细胞系来源的异种移植(CDX)模型和SCLC患者的恶性胸腔积液细胞模型中,tinengotinib有效地抑制了SCLC细胞的增殖,特别是高表达的NeuroD1 (SCLC- n)。当与依托泊苷/顺铂联合使用时,它协同抑制SCLC的生长。Tinengotinib调节SCLC细胞的增殖、凋亡、迁移、细胞周期和血管生成。机制研究显示,c-Myc表达可能是影响丁丁哥替尼治疗SCLC-N疗效的关键因素。该研究提供了可靠的临床前数据,并为tinengotinib作为一种有希望的SCLC治疗方法提供了新的方向,无论是单独使用还是联合化疗。
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引用次数: 0
Mutation Analysis of TMB-High Colorectal Cancer: Insights Into Molecular Pathways and Clinical Implications. tmb -高结直肠癌的突变分析:分子途径和临床意义。
IF 5.7 2区 医学 Q1 Medicine Pub Date : 2025-01-16 DOI: 10.1111/cas.16455
Yuko Chikaishi, Hiroshi Matsuoka, Eiji Sugihara, Mayu Takeda, Makoto Sumitomo, Seiji Yamada, Gaku Inaguma, Yusuke Omura, Yeongcheol Cheong, Yosuke Kobayashi, Masaya Nakauchi, Junichiro Hiro, Koji Masumori, Koki Otsuka, Hiroshi Nishihara, Koichi Suda, Hideyuki Saya, Tetsuya Takimoto

Colorectal cancer (CRC) is well characterized in terms of genetic mutations and the mechanisms by which they contribute to carcinogenesis. Mutations in APC, TP53, and KRAS are common in CRC, indicating key roles for these genes in tumor development and progression. However, for certain tumors with low frequencies of these mutations that are defined by tumor location and molecular phenotypes, a carcinogenic mechanism dependent on BRAF mutations has been proposed. We here analyzed targeted sequence data linked to clinical information for CRC, focusing on tumors with a high tumor mutation burden (TMB) in order to identify the characteristics of associated mutations, their relations to clinical features, and the mechanisms of carcinogenesis in tumors lacking the major driver oncogenes. Analysis of overall mutation frequencies confirmed that APC, TP53, and KRAS mutations were the most prevalent in our cohort. Compared with other tumors, TMB-high tumors were more frequent on the right side of the colon, had lower KRAS and higher BRAF mutation frequencies as well as a higher microsatellite instability (MSI) score, and showed a greater contribution of a mutational signature associated with MSI. Ranking of variant allele frequencies to identify genes that play a role early in carcinogenesis suggested that mutations in genes related to the DNA damage response (such as ATM and POLE) and to MSI (such as MSH2 and MSH6) may precede BRAF mutations associated with activation of the serrated pathway in TMB-high tumors. Our results thus indicate that TMB-high tumors suggest that mutations of genes related to mismatch repair and the DNA damage response may contribute to activation of the serrated pathway in CRC.

结直肠癌(CRC)在基因突变及其致癌机制方面具有很好的特征。APC、TP53和KRAS突变在结直肠癌中很常见,表明这些基因在肿瘤发生和进展中起关键作用。然而,对于某些由肿瘤位置和分子表型定义的这些突变频率较低的肿瘤,已经提出了依赖于BRAF突变的致癌机制。我们在此分析了与CRC临床信息相关的靶向序列数据,重点关注具有高肿瘤突变负担(TMB)的肿瘤,以确定相关突变的特征,它们与临床特征的关系,以及缺乏主要驱动癌基因的肿瘤的致癌机制。总体突变频率分析证实,APC、TP53和KRAS突变在我们的队列中最为普遍。与其他肿瘤相比,tmb -高肿瘤多发于结肠右侧,KRAS较低,BRAF突变频率较高,微卫星不稳定性(microsatellite instability, MSI)评分较高,与MSI相关的突变特征贡献更大。对变异等位基因频率进行排序,以确定在癌变早期发挥作用的基因,这表明与DNA损伤反应相关的基因(如ATM和POLE)和与MSI相关的基因(如MSH2和MSH6)的突变可能先于与tmb高肿瘤中锯齿状通路激活相关的BRAF突变。因此,我们的研究结果表明,高tmb肿瘤表明,与错配修复和DNA损伤反应相关的基因突变可能有助于CRC中锯齿状通路的激活。
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引用次数: 0
A 37-Year Retrospective Analysis Reveals a High Rate of Cutaneous Angiosarcoma of the Scalp in Okinawa, Japan. 一项37年的回顾性分析显示,日本冲绳地区头皮皮肤血管肉瘤的发病率很高。
IF 5.7 2区 医学 Q1 Medicine Pub Date : 2025-01-16 DOI: 10.1111/cas.16453
Aoi Ohira, Daisuke Utsumi, Ryoko Awazawa, Nobutake Yagi, Tsuyoshi Awazawa, Sayaka Yamaguchi, Teruki Yanagi, Kenzo Takahashi

Angiosarcoma (AS) is a rare, aggressive malignancy originating from vascular or lymphatic endothelial cells. Despite its severity, little is known about its epidemiology, and no geographical regions have previously been identified as having an exceptionally high incidence. We retrospectively analyzed medical records spanning 37 years (1987-2023) in Okinawa, Japan, identifying 135 cases of AS that were used to calculate its incidence. This incidence was compared to global data to highlight significant regional differences. Factors related to patients' survival were also assessed. The age-adjusted incidence of AS of the scalp in Okinawa was 4.1 per million per year (mpy; 2015 Japanese model population) or 2.0 per mpy (2000 US standard population), significantly higher than the global data, including in the United States (about eightfold higher) and mainland Japan (about fourfold higher). The estimated five-year survival for patients with AS of the scalp in Okinawa was 9.2%. Multivariate analysis identified surgery, chemotherapy, and radiotherapy as significant factors associated with patient survival. This study provides the first evidence of a significantly higher incidence rate of AS of the scalp in Okinawa. Given its rarity, further research is crucial to uncover the epidemiological, genetic, and environmental factors driving this cancer.

血管肉瘤(AS)是一种罕见的、侵袭性的恶性肿瘤,起源于血管或淋巴内皮细胞。尽管其严重程度,但对其流行病学知之甚少,而且以前没有确定任何地理区域具有异常高的发病率。我们回顾性分析了日本冲绳37年(1987-2023)的医疗记录,确定了135例AS病例,并用于计算其发病率。将这一发生率与全球数据进行比较,以突出显著的区域差异。与患者生存相关的因素也被评估。冲绳县经年龄调整的头皮AS发病率为4.1 /百万人/年(mpy;2015年日本模型人口)或每年2.0人(2000年美国标准人口),显著高于全球数据,包括美国(约高出8倍)和日本大陆(约高出4倍)。冲绳头皮AS患者的5年生存率估计为9.2%。多变量分析确定手术、化疗和放疗是与患者生存相关的重要因素。这项研究首次提供了冲绳地区头皮AS发病率明显较高的证据。鉴于其罕见性,进一步的研究对于揭示导致这种癌症的流行病学、遗传和环境因素至关重要。
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引用次数: 0
IGF2BP3 Triggers STAT3 Pathway by Stabilizing SRC RNA in an m6A-Dependent Manner to Promote Lymphatic Metastasis in LUAD. IGF2BP3通过m6a依赖性方式稳定SRC RNA触发STAT3通路,促进LUAD的淋巴转移。
IF 5.7 2区 医学 Q1 Medicine Pub Date : 2025-01-13 DOI: 10.1111/cas.16451
Jiapei Ding, Xuequan Wang, Haihua Yang, Lele Zhang, Yongquan Ying, Wenhu Pi, Guozhong Deng, Yaqun Zhu

Lymph node metastasis significantly affects the NSCLC patients' staging, treatment strategy, and prognosis. Studies have shown that IGF2BP3, an oncofetal protein and an m6A reader, overexpresses and correlates to lymph node metastasis and worse overall survival in histopathological studies including NSCLC, but its mechanism needs further study. This study explored IGF2BP3's function and mechanism in LUAD lymphatic metastasis using public databases, a human LUAD tissue microarray, human LUAD cells, and a lymphatic metastasis model in male BALB/c nude mice. Firstly, we proved that IGF2BP3 overexpression was positively correlated to patients' lymph node metastasis and worse overall survival in bioinformatics and a human LUAD tissue microarray analysis. IGF2BP3 was knocked out or overexpressed in human LUAD cell lines. Functionally, IGF2BP3 facilitated NCI-H1299, NCI-H358, and A549 cell growth, migration, invasion, and EMT in vitro, and promoted tumorigenesis, lymphangiogenesis, and lymphatic metastasis of NCI-H1299 cells in BALB/c nude mice. Mechanically, RIP, RNA pull-down assay, MeRIP, mRNA stability assays, rescue experiments, and immunohistochemical assays were conducted. IGF2BP3 was demonstrated to bind to the m6A site of the 3'UTR region of SRC, stabilizing its mRNA and activating the downstream STAT3 signaling pathway and lymphatic growth factors such as VEGF-C, therefore affecting lymphatic metastasis. The cell migration and EMT function of IGF2BP3 were partially rescued by utilizing SRC siRNA or AZD0530, an SRC inhibitor. This study demonstrated that IGF2BP3 promotes lymphatic metastasis in LUAD via activating the m6A-SRC-STAT3-VEGFC signaling axis, indicating that IGF2BP3 is a potential therapeutic target to overcome metastasis in LUAD patients.

淋巴结转移严重影响 NSCLC 患者的分期、治疗策略和预后。研究表明,在包括NSCLC在内的组织病理学研究中,IGF2BP3作为一种胎盘上蛋白和m6A阅读器,其过表达与淋巴结转移和较差的总生存率相关,但其机制有待进一步研究。本研究利用公共数据库、人LUAD组织芯片、人LUAD细胞和雄性BALB/c裸鼠淋巴转移模型,探讨了IGF2BP3在LUAD淋巴转移中的功能和机制。首先,我们在生物信息学和人LUAD组织芯片分析中证明了IGF2BP3过表达与患者淋巴结转移和总生存期恶化呈正相关。IGF2BP3在人LUAD细胞系中被敲除或过表达。从功能上看,IGF2BP3在体外促进了NCI-H1299、NCI-H358和A549细胞的生长、迁移、侵袭和EMT,并在BALB/c裸鼠体内促进了NCI-H1299细胞的肿瘤发生、淋巴管生成和淋巴转移。研究人员对IGF2BP3进行了机理分析、RIP分析、RNA牵引分析、MeRIP分析、mRNA稳定性分析、挽救实验和免疫组化分析。结果表明,IGF2BP3能与SRC 3'UTR区的m6A位点结合,稳定其mRNA,激活下游STAT3信号通路和VEGF-C等淋巴生长因子,从而影响淋巴转移。利用SRC siRNA或SRC抑制剂AZD0530可部分挽救IGF2BP3的细胞迁移和EMT功能。这项研究表明,IGF2BP3通过激活m6A-SRC-STAT3-VEGFC信号轴促进了LUAD的淋巴转移,表明IGF2BP3是克服LUAD患者转移的潜在治疗靶点。
{"title":"IGF2BP3 Triggers STAT3 Pathway by Stabilizing SRC RNA in an m6A-Dependent Manner to Promote Lymphatic Metastasis in LUAD.","authors":"Jiapei Ding, Xuequan Wang, Haihua Yang, Lele Zhang, Yongquan Ying, Wenhu Pi, Guozhong Deng, Yaqun Zhu","doi":"10.1111/cas.16451","DOIUrl":"https://doi.org/10.1111/cas.16451","url":null,"abstract":"<p><p>Lymph node metastasis significantly affects the NSCLC patients' staging, treatment strategy, and prognosis. Studies have shown that IGF2BP3, an oncofetal protein and an m6A reader, overexpresses and correlates to lymph node metastasis and worse overall survival in histopathological studies including NSCLC, but its mechanism needs further study. This study explored IGF2BP3's function and mechanism in LUAD lymphatic metastasis using public databases, a human LUAD tissue microarray, human LUAD cells, and a lymphatic metastasis model in male BALB/c nude mice. Firstly, we proved that IGF2BP3 overexpression was positively correlated to patients' lymph node metastasis and worse overall survival in bioinformatics and a human LUAD tissue microarray analysis. IGF2BP3 was knocked out or overexpressed in human LUAD cell lines. Functionally, IGF2BP3 facilitated NCI-H1299, NCI-H358, and A549 cell growth, migration, invasion, and EMT in vitro, and promoted tumorigenesis, lymphangiogenesis, and lymphatic metastasis of NCI-H1299 cells in BALB/c nude mice. Mechanically, RIP, RNA pull-down assay, MeRIP, mRNA stability assays, rescue experiments, and immunohistochemical assays were conducted. IGF2BP3 was demonstrated to bind to the m6A site of the 3'UTR region of SRC, stabilizing its mRNA and activating the downstream STAT3 signaling pathway and lymphatic growth factors such as VEGF-C, therefore affecting lymphatic metastasis. The cell migration and EMT function of IGF2BP3 were partially rescued by utilizing SRC siRNA or AZD0530, an SRC inhibitor. This study demonstrated that IGF2BP3 promotes lymphatic metastasis in LUAD via activating the m6A-SRC-STAT3-VEGFC signaling axis, indicating that IGF2BP3 is a potential therapeutic target to overcome metastasis in LUAD patients.</p>","PeriodicalId":48943,"journal":{"name":"Cancer Science","volume":" ","pages":""},"PeriodicalIF":5.7,"publicationDate":"2025-01-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142980209","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Comparison of 11C-Acetate and 18F-FDG PET/CT for Immune Infiltration and Prognosis in Hepatocellular Carcinoma. 11C-Acetate与18F-FDG PET/CT对肝细胞癌免疫浸润及预后的比较
IF 5.7 2区 医学 Q1 Medicine Pub Date : 2025-01-11 DOI: 10.1111/cas.16449
Hao Xu, Hao Wang, Dong-Lang Jiang, Yan-Fei Wu, Sun-Zhe Xie, Ying-Han Su, Yi-Hui Guan, Fang Xie, Wen-Wei Zhu, Lun-Xiu Qin

Immunotherapy has revolutionized cancer treatment, making it a challenge to noninvasively monitor immune infiltration. Metabolic reprogramming in cancers, including hepatocellular carcinoma (HCC), is closely linked to immune status. In this study, we aimed to evaluate the ability of carbon-11 acetate (11C-acetate) and fluorine-18 fluorodeoxyglucose (18F-FDG) PET/CT findings in predicting overall survival (OS) and immune infiltration in HCC patients. Totally 32 patients who underwent preoperative 18F-FDG and 11C-acetate PET/CT, followed by liver resection for HCC, were prospectively enrolled at authors' institute between January 2019 and October 2021. Tracer uptake was qualified. Densities of CD3+, CD8+, and granzyme B+ CD8+ immune cells were assessed and the Immunoscore was defined by combining the densities of CD3+ and CD8+ in tumor interior (TI) and invasion margin (IM). Patients with avid HCCs in 11C-acetate PET/CT demonstrated a longer OS. Those with only 11C-acetate-avid HCCs exhibited a longer OS compared to those with only 18F-FDG uptake. In contrast to 18F-FDG uptake, 11C-acetate uptake was positively associated with CD3+, CD8+, and granzyme B+ CD8+ cell infiltration. Patients with a higher Immunoscore exhibited a longer OS and an increased uptake of 11C-acetate rather than 18F-FDG. The sensitivity of 11C-acetate PET/CT in the detection of patients with immune infiltration was superior to that of 18F-FDG PET/CT (88% [21 of 24] vs. 58% [14 of 24]). These data show that preoperative 11C-acetate PET/CT may be a promising approach for the evaluation of immune status and postoperative outcome of HCCs.

免疫疗法已经彻底改变了癌症治疗,使其成为无创监测免疫浸润的挑战。包括肝细胞癌(HCC)在内的癌症的代谢重编程与免疫状态密切相关。在这项研究中,我们旨在评估碳-11醋酸酯(11c -醋酸酯)和氟-18氟脱氧葡萄糖(18F-FDG) PET/CT结果预测HCC患者总生存期(OS)和免疫浸润的能力。在2019年1月至2021年10月期间,共有32名患者接受了术前18F-FDG和11C-acetate PET/CT检查,随后进行肝切除术。示踪剂摄取合格。评估CD3+、CD8+和颗粒酶B+ CD8+免疫细胞的密度,并结合肿瘤内部(TI)和侵袭边缘(IM)的CD3+和CD8+密度定义免疫评分。11c -乙酸酯PET/CT显示急性hcc患者的生存期较长。与仅摄取18F-FDG的hcc相比,仅摄取11c -醋酸酯的hcc表现出更长的OS。与18F-FDG摄取相反,11C-acetate摄取与CD3+、CD8+和颗粒酶B+ CD8+细胞浸润呈正相关。免疫评分较高的患者表现出更长的生存期,11c -醋酸酯的摄取比18F-FDG增加。11C-acetate PET/CT检测免疫浸润患者的敏感性优于18F-FDG PET/CT(88%[21 / 24]对58%[14 / 24])。这些数据表明,术前11C-acetate PET/CT可能是评估hcc免疫状态和术后预后的一种有前景的方法。
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引用次数: 0
Identification of clinicopathological-specific driver gene and genetic subtyping of colorectal cancer. 结直肠癌临床病理特异性驱动基因的鉴定及遗传分型。
IF 5.7 2区 医学 Q1 Medicine Pub Date : 2025-01-11 DOI: 10.1111/cas.16432
Jianjiong Li, Chunnian Wang, Changshun Yang, Hua Bao, Ningyou Li, Xianqiang Huang, Wei Gong, Xinyue Hong, Jiani C Yin, Jiaohui Pang, Meifu Gan, Danping Yuan

This study analyzed targeted sequencing data from 6530 tissue samples from patients with metastatic Chinese colorectal cancer (CRC) to identify low mutation frequency and subgroup-specific driver genes, using three algorithms for overall CRC as well as across different clinicopathological subgroups. We analyzed 425 cancer-related genes, identifying 101 potential driver genes, including 36 novel to CRC. Notably, some genes demonstrated subgroup specificity; for instance, ERBB4 was found as a male-specific driver gene and mutations of ERBB4 only influenced the prognosis of male patients with CRC. This sex disparity of ERBB4 was validated in an independent large-scale Memorial Sloan Kettering Cancer Center CRC cohort with 2444 samples. Furthermore, using network-based stratification based on protein-protein interaction, we classified the microsatellite stable (MSS) and unstable (MSI) CRCs into six and three major subtypes, respectively, each showing unique phenotypes and prognoses. In MSS CRC, cluster 5 (APCAMER1-KRAS) and cluster 2 (RNF43-BRAF-PIK3CA) were predominant, and cluster 5 showed a superior overall survival compared with cluster 2. This extensive heterogeneity in driver gene mutations underscores the complexity of CRC and suggests significant implications for treatment and prognostic assessments.

本研究分析了来自中国转移性结直肠癌(CRC)患者的6530个组织样本的靶向测序数据,以确定低突变频率和亚组特异性驱动基因,使用三种算法用于总体CRC以及不同临床病理亚组。我们分析了425个癌症相关基因,确定了101个潜在的驱动基因,其中36个是CRC的新基因。值得注意的是,一些基因表现出亚群特异性;例如,ERBB4被发现是男性特有的驱动基因,ERBB4的突变仅影响男性结直肠癌患者的预后。ERBB4的这种性别差异在一个独立的大型纪念斯隆凯特琳癌症中心CRC队列中得到了验证,该队列有2444个样本。此外,利用基于蛋白-蛋白相互作用的网络分层,我们将微卫星稳定型(MSS)和不稳定型(MSI) crc分别分为6个和3个主要亚型,每个亚型都表现出独特的表型和预后。在MSS CRC中,簇5 (APCAMER1-KRAS)和簇2 (RNF43-BRAF-PIK3CA)占主导地位,簇5的总生存率高于簇2。驱动基因突变的广泛异质性强调了结直肠癌的复杂性,并对治疗和预后评估具有重要意义。
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引用次数: 0
LHPP-P38 MAPK/ERK-ETS1 Axis Negative Feedback Signaling Restrains Progression in Breast Cancer. LHPP-P38 MAPK/ERK-ETS1轴负反馈信号抑制乳腺癌进展
IF 5.7 2区 医学 Q1 Medicine Pub Date : 2025-01-10 DOI: 10.1111/cas.16448
Xu Liu, Deyang Yu, Zhen Yu, Sisi Su, Meixia Jiang, Chunbo Zhao

Invasion and metastasis are major causes of mortality in breast cancer (BRCA) patients. LHPP, known for its tumor-suppressive effects, has an undefined role in BRCA. We found reduced LHPP protein in BRCA tissues, with lower levels correlating with poor patient outcomes. In vitro studies show LHPP inhibits BRCA cell proliferation, migration, invasion, and stemness. In vivo xenograft models support LHPP's role in curbing tumorigenesis and lung metastasis. Mechanistically, LHPP interacts with ERK and P38 MAPK, leading to their dephosphorylation and suppression of the MAPK pathway. We also reveal ETS1, a MAPK effector, repressing LHPP mRNA transcription, suggesting a LHPP-P38 MAPK/ERK-ETS1 negative feedback loop as a key regulatory mechanism in controlling BRCA invasion and metastasis.

侵袭和转移是乳腺癌(BRCA)患者死亡的主要原因。LHPP以其肿瘤抑制作用而闻名,但在BRCA中的作用尚不明确。我们发现BRCA组织中LHPP蛋白减少,低水平与患者预后差相关。体外研究表明,LHPP抑制BRCA细胞的增殖、迁移、侵袭和干性。体内异种移植模型支持LHPP在抑制肿瘤发生和肺转移中的作用。在机制上,LHPP与ERK和P38 MAPK相互作用,导致它们的去磷酸化和抑制MAPK通路。我们还发现MAPK效应物ETS1抑制LHPP mRNA转录,表明LHPP- p38 MAPK/ERK-ETS1负反馈回路是控制BRCA侵袭和转移的关键调控机制。
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引用次数: 0
AURKA/PLK1/CDC25C Axis as a Novel Therapeutic Target in INI1-Deficient Epithelioid Sarcoma. AURKA/PLK1/CDC25C轴作为ini1缺陷上皮样肉瘤的新治疗靶点
IF 5.7 2区 医学 Q1 Medicine Pub Date : 2025-01-09 DOI: 10.1111/cas.16438
Akitomo Inoue, Hidetatsu Outani, Yoshinori Imura, Sho Nakai, Haruna Takami, Yuki Kotani, Hirokazu Mae, Seiji Okada

Effective therapeutic strategies for epithelioid sarcoma (EpS), a high-grade soft tissue sarcoma characterized by loss of integrase interactor 1 (INI1), have not yet been developed. The present study therefore investigated the association between INI1 loss and upregulation of the aurora kinase A (AURKA)/polo-like kinase 1 (PLK1)/cell division cycle 25C (CDC25C) axis, as well as the therapeutic relevance of this axis in EpS. Notably, our findings showed that the reintroduction of INI1 in VA-ES-BJ cells significantly reduced proliferation, mitigated tumorigenicity, and negatively regulated the expression of AURKA and its downstream effectors, as well as the activation of PLK1 and CDC25C. These results suggest that INI1 deficiency enhanced EpS growth by upregulating the AURKA/PLK1/CDC25C axis. AURKA silencing using siRNAs inhibited VA-ES-BJ and Asra-EPS cell proliferation by inactivating PLK1 and CDC25C. Alisertib, a selective AURKA inhibitor, exerted markedly greater antiproliferative effects on EpS cells than on normal human dermal fibroblasts, and these effects were dependent on INI1 deficiency. Inhibition of AURKA activity by alisertib induced G2/M cell cycle arrest and apoptosis via the inactivation of AURKA downstream effectors in EpS cells. Alisertib also significantly decreased VA-ES-BJ xenograft tumor growth. Taken together, our findings revealed that INI1 loss in EpS cells enhances the expression of AURKA and its downstream effectors and persistently activates PLK1 and CDC25C mediated by AURKA, making the cells reliant on the AURKA/PLK1/CDC25C axis. Therefore, the AURKA/PLK1/CDC25C axis activated by INI1 deficiency could serve as a novel therapeutic target for this devastating disease.

上皮样肉瘤(EpS)是一种以整合酶相互作用因子1 (INI1)缺失为特征的高级软组织肉瘤,目前尚未发现有效的治疗策略。因此,本研究调查了INI1缺失与极光激酶A (AURKA)/polo样激酶1 (PLK1)/细胞分裂周期25C (CDC25C)轴上调之间的关系,以及该轴在EpS中的治疗相关性。值得注意的是,我们的研究结果表明,在VA-ES-BJ细胞中重新引入INI1可显著降低增殖,减轻致瘤性,并负向调节AURKA及其下游效应物的表达,以及PLK1和CDC25C的激活。这些结果表明,INI1缺乏通过上调AURKA/PLK1/CDC25C轴来促进EpS的生长。使用sirna沉默AURKA通过灭活PLK1和CDC25C来抑制VA-ES-BJ和Asra-EPS细胞的增殖。Alisertib是一种选择性AURKA抑制剂,对EpS细胞的抗增殖作用明显大于对正常人真皮成纤维细胞的抗增殖作用,这些作用依赖于INI1缺乏。alisertib抑制AURKA活性通过使EpS细胞中AURKA下游效应物失活,诱导G2/M细胞周期阻滞和凋亡。Alisertib也显著降低VA-ES-BJ异种移植瘤的生长。综上所述,我们的研究结果表明,INI1在EpS细胞中的缺失增强了AURKA及其下游效应物的表达,并持续激活由AURKA介导的PLK1和CDC25C,使细胞依赖于AURKA/PLK1/CDC25C轴。因此,INI1缺乏激活的AURKA/PLK1/CDC25C轴可以作为这种毁灭性疾病的新治疗靶点。
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Cancer Science
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