Cancer pathogenesis and therapy最新文献

英文中文

Dostarlimab in the treatment of mismatch repair deficient recurrent or advanced endometrial cancer 多司他林单抗治疗错配修复缺陷复发性或晚期子宫内膜癌

Cancer pathogenesis and therapy

Pub Date : 2024-07-01 DOI: 10.1016/j.cpt.2023.10.003

Siddhant Shukla , Harsh Patel , Shuzhen Chen , Rainie Sun , Liuya Wei , Zhe-Sheng Chen

Dostarlimab, a programmed death receptor-1 (PD-1)-blocking IgG4 humanized monoclonal antibody, gained accelerated approval from the US Food and Drug Administration (FDA) in April 2021, and received a full approval in February 2023. Dostarlimab was approved for treating adult patients with mismatch repair deficient (dMMR) recurrent or advanced endometrial cancer (EC) that progressed during or after prior treatment who have no other suitable treatment options. Herein, we review the structure-based mechanism of action of dostarlimab and the results of a clinical study (GARNET; NCT02715284) to comprehensively clarify the efficacy and toxicity of the drug. The efficacy and safety of dostarlimab as monotherapy was assessed in a non-randomized, multicenter, open-label, multi-cohort trial that included 209 patients with dMMR recurrent or advanced solid tumors after receiving systemic therapy. Patients received 500 mg of dostarlimab intravenously every three weeks until they were given four doses. Then, patients received 1000 mg dostarlimab intravenously every six weeks until disease progression or unacceptable toxicity. The overall response rate, as determined by shrinkage in tumor size, was 41.6% (95% confidence interval [CI]; 34.9, 48.6), with 34.7 months as the median response duration. In conclusion, dostarlimab is an immunotherapy-based drug that has shown promising results in adult patients with recurrent or advanced dMMR EC. However, its efficacy in other cancer subtypes, the development of resistance to monotherapy, and efficacy and safety in combination with other immunotherapeutic drugs have not yet been studied.

Dostarlimab是一种程序性死亡受体-1（PD-1）阻断IgG4人源化单克隆抗体，于2021年4月获得美国食品药品管理局（FDA）的加速批准，并于2023年2月获得全面批准。多斯他利单抗被批准用于治疗错配修复缺陷（dMMR）复发性或晚期子宫内膜癌（EC）成年患者，这些患者在之前的治疗过程中或治疗后病情进展，且没有其他合适的治疗方案。在此，我们回顾了多司他利单抗基于结构的作用机制以及一项临床研究（GARNET；NCT02715284）的结果，以全面阐明该药物的疗效和毒性。在一项非随机、多中心、开放标签、多队列试验中评估了多司他利单抗作为单药疗法的疗效和安全性，该试验纳入了209名接受过全身治疗后复发或晚期实体瘤的dMMR患者。患者每三周静脉注射一次500毫克多斯他利单抗，直到注射四次为止。然后，患者每六周静脉注射1000毫克多斯他利单抗，直到疾病进展或出现不可接受的毒性。根据肿瘤缩小程度确定的总体反应率为41.6%（95%置信区间[CI]；34.9，48.6），中位反应持续时间为34.7个月。总之，多司他林单抗是一种基于免疫疗法的药物，在复发性或晚期dMMR EC成人患者中显示出良好的疗效。然而，该药物对其他癌症亚型的疗效、单药治疗耐药性的产生以及与其他免疫治疗药物联合使用的疗效和安全性尚未得到研究。

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引用次数: 0

Gene mutations in newly diagnosed multiple myeloma patients detected by next-generation sequencing technology 利用新一代测序技术检测新诊断多发性骨髓瘤患者的基因突变

Cancer pathogenesis and therapy

Pub Date : 2024-07-01 DOI: 10.1016/j.cpt.2023.12.004

Yutong Wang, Mengzhen Wang, Bin Chu, Minqiu Lu, Lei Shi, Shan Gao, Yuan Chen, Qin Yan, Na Ji, Li Bao

Background

Multiple myeloma (MM) is a heterogeneous plasma-derived hematopoietic malignancy with complex genetic mutation contributing to the pathogenesis. Though gene sequencing has been applied in MM, genetic features from Chinese MM patients are reported less. We investigated the genetic mutation of newly diagnosed multiple myeloma (NDMM) patients and explore its correlation with cytogenetic abnormalities detected by fluorescence in situ hybridization (FISH).

Methods

A total of 206 patients with NDMM were enrolled. After enriching plasma cells with CD138 magnetic beads, 92 MM-related target gene mutations were detected by the Illumina sequencing platform, and six common genetic abnormalities were detected by FISH.

Results

162 cases (78.6%) had at least one gene mutation detected by NDMM. The top 5 mutated genes were KRAS, NRAS, TRAF3, BRAF, and TP53. Cytogenetic abnormalities detected by FISH have a certain correlation with gene mutations, t(11;14) translocations are often accompanied by CCND1 and TP53 mutations, KLHL6 in t(4;14), SP140, CDKN1B and PRKD2 in t(14;16) and t(14;20) translocations. The mutation ratio was higher for EGR1, while lower of CCND1 in patients with gain 1q21. The TP53 mutation was more likely in patients with 17p deletion. The gene mutation affects the pathway of the RNA process is more frequently occurring in males and age less than 70 years patients. The International Staging System (ISS) Stage III correlated with gene mutations in the NK-κB pathway while Revised ISS (R-ISS) Stage III correlated with the DNA damage repair pathway.

Conclusions

There are various gene mutations in NDMM patients, mainly RAS/MAPK and NF-κB pathway gene pathways.

背景多发性骨髓瘤（MM）是一种异质性血浆源性造血恶性肿瘤，其发病机制与复杂的基因突变有关。虽然基因测序已应用于多发性骨髓瘤，但中国多发性骨髓瘤患者的基因特征报道较少。我们研究了新诊断多发性骨髓瘤（NDMM）患者的基因突变，并探讨了其与荧光原位杂交（FISH）检测到的细胞遗传学异常的相关性。用CD138磁珠富集浆细胞后，用Illumina测序平台检测了92个与MM相关的靶基因突变，并用FISH检测了6种常见的基因异常。前五位突变基因分别是 KRAS、NRAS、TRAF3、BRAF 和 TP53。FISH检测到的细胞遗传学异常与基因突变有一定的相关性，t（11;14）易位常伴有CCND1和TP53突变，t（4;14）易位伴有KLHL6突变，t（14;16）和t（14;20）易位伴有SP140、CDKN1B和PRKD2突变。在1q21增益的患者中，EGR1的突变率较高，而CCND1的突变率较低。影响 RNA 过程途径的基因突变更多发生在男性和年龄小于 70 岁的患者身上。国际分期系统（ISS）III期与NK-κB通路的基因突变相关，而修订版ISS（R-ISS）III期与DNA损伤修复通路相关。

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引用次数: 0

Overlap in oncogenic and pro-inflammatory pathways associated with areca nut and nicotine exposure 与亚麻仁和尼古丁接触相关的致癌和促炎途径的重叠

Cancer pathogenesis and therapy

Pub Date : 2024-07-01 DOI: 10.1016/j.cpt.2023.09.003

Krati Garg , Anuj Kumar , Vidisha Kizhakkethil , Pramod Kumar , Shalini Singh

Background

Betel nut/areca nut/Areca catechu is one of the most commonly used psychoactive substance, and is also a major preventable cause of cancer. Unlike other psychoactive substances, such as nicotine, the mechanisms underlying addiction to areca nuts and related oncogenesis remain elusive. Recent reports suggest a possible overlap in the mechanisms of action of nicotine and areca nuts in the human body. Thus, this study aimed to investigate the interactome of human proteins associated with areca nut exposure and the intricate similarities and differences in the effects of the two psychoactive substances on humans.

Methods

A list of proteins associated with areca nut use was obtained from the available literature using terms from Medical Subject Headings (MeSH). Protein-protein interaction (PPI) networks and functional enrichment were analyzed. The results obtained for both psychoactive substances were compared.

Results

Given the limited number of common proteins (36/226, 16%) in the two sets, a substantial overlap (612/1176 nodes, 52%) was observed in the PPI networks, as well as in Gene Ontology. Areca nuts mainly affect signaling pathways through three hub proteins (alpha serine/threonine-protein kinase, tumor protein 53, and interleukin-6), which are common to both psychoactive substances, as well as two unique hub proteins (epidermal growth factor receptor and master regulator of cell cycle entry and proliferative metabolism). Areca nut-related proteins are associated with unique pathways, such as extracellular matrix organization, lipid storage, and metabolism, which are not found in nicotine-associated proteins.

Conclusions

Areca nuts affect regulatory mechanisms, leading to systemic toxicity and oncogenesis. Areca nuts also affect unique pathways that can be studied as potential markers of exposure, as well as targets for anticancer therapeutic agents.

背景甜菜/夏威夷果/儿茶是最常用的精神活性物质之一，也是可预防癌症的主要原因。与尼古丁等其他精神活性物质不同的是，人们对甜叶菊果实上瘾及相关致癌机制仍难以捉摸。最近的报告表明，尼古丁和亚麻仁在人体内的作用机制可能存在重叠。因此，本研究旨在调查与接触亚麻仁相关的人体蛋白质相互作用组，以及这两种精神活性物质对人体影响的复杂异同。对蛋白质-蛋白质相互作用（PPI）网络和功能富集进行了分析。结果鉴于两组共同蛋白质的数量有限（36/226，16%），在 PPI 网络和基因本体论中观察到大量重叠（612/1176 个节点，52%）。阿雷卡坚果主要通过三种枢纽蛋白（α 丝氨酸/苏氨酸蛋白激酶、肿瘤蛋白 53 和白细胞介素-6）影响信号传导通路，这三种枢纽蛋白是两种精神活性物质所共有的，另外还有两种独特的枢纽蛋白（表皮生长因子受体和细胞周期进入及增殖代谢主调节因子）。阿雷卡坚果相关蛋白与细胞外基质组织、脂质储存和新陈代谢等独特途径有关，而尼古丁相关蛋白中没有这些途径。阿月浑子果还会影响一些独特的途径，这些途径可作为潜在的暴露标记以及抗癌治疗药物的靶点进行研究。

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引用次数: 0

Relationship between visceral obesity and prognosis in patients with stage IVB cervical cancer receiving radiotherapy and chemotherapy 接受放疗和化疗的 IVB 期宫颈癌患者内脏肥胖与预后的关系

Cancer pathogenesis and therapy

Pub Date : 2024-07-01 DOI: 10.1016/j.cpt.2023.09.002

Chao Ji, Silin Liu, Che Wang, Jie Chen, Jin Wang, Xinyue Zhang, Jinlu Ma, Mengjiao Cai

Background

Concurrent chemoradiotherapy is the preferred treatment for stage IVB cervical cancer; however, some patients experience a poor prognosis. The prognostic significance of body composition indicators, including visceral obesity, has been extensively investigated in patients with cancer. This study aimed to assess the impact of body composition indicators, specifically pretreatment fat content, on the survival outcomes of patients with stage IVB cervical cancer.

Methods

We retrospectively analyzed clinical information from patients diagnosed with stage IVB cervical cancer between 2010 and 2018. We measured visceral obesity (visceral-to-subcutaneous adipose tissue area ratio [VSR]) and skeletal muscle index (SMI) on pretreatment computed tomography (CT) images. We evaluated the impact of these body composition parameters on the prognosis of patients with cervical cancer.

Results

Overall, 116 patients were included, 81 of whom had complete clinical and imaging information. Based on the cut-off values from X-tile analysis, we categorized patients into high and low VSR and SMI groups. The overall survival (OS) rate of patients with a high VSR was significantly higher than that of patients with a low VSR (P = 0.022). Multivariate Cox regression analysis showed that a low VSR was an independent risk factor for the prognosis of patients with stage IVB cervical cancer.

Conclusion

Visceral obesity before radiotherapy and chemotherapy has a protective effect on the prognosis of patients with stage IVB cervical cancer, while low muscle index and VSR are associated with poor prognosis.

背景同期放化疗是 IVB 期宫颈癌的首选治疗方法，但有些患者的预后较差。包括内脏肥胖在内的身体成分指标对癌症患者预后的影响已被广泛研究。本研究旨在评估身体成分指标，特别是治疗前脂肪含量，对 IVB 期宫颈癌患者生存结果的影响。方法我们回顾性分析了 2010 年至 2018 年期间确诊为 IVB 期宫颈癌患者的临床信息。我们测量了治疗前计算机断层扫描（CT）图像上的内脏肥胖（内脏与皮下脂肪组织面积比[VSR]）和骨骼肌指数（SMI）。我们评估了这些身体成分参数对宫颈癌患者预后的影响。结果共纳入 116 例患者，其中 81 例有完整的临床和影像学信息。根据 X-tile 分析的临界值，我们将患者分为高、低 VSR 组和 SMI 组。高VSR患者的总生存率（OS）明显高于低VSR患者（P = 0.022）。结论放化疗前内脏肥胖对 IVB 期宫颈癌患者的预后有保护作用，而低肌肉指数和 VSR 与不良预后相关。

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引用次数: 0

Enhancing post-treatment outcomes in patients with oral cancer: Integrating interventions and psychosocial support 提高口腔癌患者的治疗后效果：整合干预措施和社会心理支持

Cancer pathogenesis and therapy

Pub Date : 2024-06-21 DOI: 10.1016/j.cpt.2024.06.005

Ponnambalam Ragini Yaashikaa

引用次数: 0

New insights into digestive tract tumors 对消化道肿瘤的新认识

Cancer pathogenesis and therapy

Pub Date : 2024-06-20 DOI: 10.1016/j.cpt.2024.06.002

Zhidong Gao, Zhanlong Shen, Shuo Wang, Yingjiang Ye

引用次数: 0

Incidence rate and risk factors of second primary neoplasms among older patients with hematological malignancies: Insights from a Chinese single-center experience (1997–2021) 老年血液恶性肿瘤患者二次原发肿瘤的发病率和风险因素：中国单中心经验的启示（1997-2021 年）

Cancer pathogenesis and therapy

Pub Date : 2024-06-08 DOI: 10.1016/j.cpt.2024.06.001

Background

Patients with hematological malignancies face an increased risk of developing second primary neoplasms due to various factors, including immune system compromise and chemotherapy-related effects. However, the incidence and associated risk factors in older patients remain poorly understood. This study aimed to assess the incidence, identify risk factors, and evaluate their impact on survival outcomes among older patients with hematological malignancies.

Methods

This retrospective single-center study analyzed data from 163 patients, focusing on the occurrence of second primary neoplasms. Cumulative incidence rates were calculated, and risk factor analysis was conducted using a competing risk model.

Results

Among 124 eligible patients with a total follow-up duration of 572.57 person-years, the incidence rate of second primary neoplasms was 15.72/1000 person-years. The standardized incidence ratio (SIR) was 0.81 (95% confidence interval [CI] [0.39–1.48], P = 0.518). History of radiotherapy emerged as a significant risk factor (sub-distribution hazard ratio [SHR] = 21.61 [2.81–166.14], P = 0.003), whereas regular natural killer (NK) cell infusion was associated with reduced risk (SHR = 3.25 e−8 [9.81 e−9–1.08 e−7], P ＜ 0.001).

Conclusions

These findings underscore the importance of informing older patients with hematological malignancies about the long-term risks of second primary neoplasms. Healthcare providers should carefully weigh risk factors when formulating treatment strategies. The results are valuable for investigating the fundamental principles underlying the occurrence and progression of second primary neoplasms.

背景由于免疫系统受损和化疗相关影响等各种因素，血液恶性肿瘤患者罹患第二原发性肿瘤的风险增加。然而，人们对老年患者的发病率和相关风险因素仍然知之甚少。这项研究旨在评估老年血液恶性肿瘤患者的发病率、确定风险因素并评估其对生存结果的影响。方法这项回顾性单中心研究分析了 163 名患者的数据，重点关注二次原发肿瘤的发生情况。结果在总随访时间为 572.57 人年的 124 名符合条件的患者中，二次原发肿瘤的发病率为 15.72/1000 人年。标准化发病率比（SIR）为 0.81（95% 置信区间 [CI] [0.39-1.48]，P = 0.518）。放疗史是一个重要的风险因素（亚分布危险比 [SHR] = 21.61 [2.81-166.14]，P = 0.003），而定期输注自然杀伤（NK）细胞可降低风险（SHR = 3.25 e-8 [9.81 e-9-1.08 e-7]，P ＜ 0.001）。医疗服务提供者在制定治疗策略时应仔细权衡风险因素。这些结果对研究二次原发肿瘤发生和发展的基本原理很有价值。

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