Pub Date : 2024-08-09DOI: 10.3389/fonc.2024.1447807
E. Zanini, N. Forster-Gross, F. Bachmann, Adrian Brüngger, P. Mcsheehy, K. Litherland, K. Burger, Anna C. Groner, M. Roceri, Luc Bury, Martin Stieger, N. Willemsen-Seegers, J. de Man, D. Vu-Pham, Helma W. E. van Riel, G. Zaman, R. Buijsman, L. Kellenberger, Heidi A. Lane
Threonine tyrosine kinase (TTK) and polo-like kinase 1 (PLK1) are common essential kinases that collaborate in activating the spindle assembly checkpoint (SAC) at the kinetochore, ensuring appropriate chromosome alignment and segregation prior to mitotic exit. Targeting of either TTK or PLK1 has been clinically evaluated in cancer patients; however, dual inhibitors have not yet been pursued. Here we present the in vitro and in vivo characterization of a first in class, dual TTK/PLK1 inhibitor (BAL0891).Mechanism of action studies utilized biochemical kinase and proteomics-based target-engagement assays. Cellular end-point assays included immunoblot- and flow cytometry-based cell cycle analyses and SAC integrity evaluation using immunoprecipitation and immunofluorescence approaches. Anticancer activity was assessed in vitro using cell growth assays and efficacy was evaluated, alone and in combination with paclitaxel and carboplatin, using mouse models of triple negative breast cancer (TNBC).BAL0891 elicits a prolonged effect on TTK, with a transient activity on PLK1. This unique profile potentiates SAC disruption, forcing tumor cells to aberrantly exit mitosis with faster kinetics than observed with a TTK-specific inhibitor. Broad anti-proliferative activity was demonstrated across solid tumor cell lines in vitro. Moreover, intermittent intravenous single-agent BAL0891 treatment of the MDA-MB-231 mouse model of TNBC induced profound tumor regressions associated with prolonged TTK and transient PLK1 in-tumor target occupancy. Furthermore, differential tumor responses across a panel of thirteen TNBC patient-derived xenograft models indicated profound anticancer activity in a subset (~40%). Using a flexible dosing approach, pathologically confirmed cures were observed in combination with paclitaxel, whereas synergy with carboplatin was schedule dependent.Dual TTK/PLK1 inhibition represents a novel approach for the treatment of human cancer, including TNBC patients, with a potential for potent anticancer activity and a favorable therapeutic index. Moreover, combination approaches may provide an avenue to expand responsive patient populations.
{"title":"Dual TTK/PLK1 inhibition has potent anticancer activity in TNBC as monotherapy and in combination","authors":"E. Zanini, N. Forster-Gross, F. Bachmann, Adrian Brüngger, P. Mcsheehy, K. Litherland, K. Burger, Anna C. Groner, M. Roceri, Luc Bury, Martin Stieger, N. Willemsen-Seegers, J. de Man, D. Vu-Pham, Helma W. E. van Riel, G. Zaman, R. Buijsman, L. Kellenberger, Heidi A. Lane","doi":"10.3389/fonc.2024.1447807","DOIUrl":"https://doi.org/10.3389/fonc.2024.1447807","url":null,"abstract":"Threonine tyrosine kinase (TTK) and polo-like kinase 1 (PLK1) are common essential kinases that collaborate in activating the spindle assembly checkpoint (SAC) at the kinetochore, ensuring appropriate chromosome alignment and segregation prior to mitotic exit. Targeting of either TTK or PLK1 has been clinically evaluated in cancer patients; however, dual inhibitors have not yet been pursued. Here we present the in vitro and in vivo characterization of a first in class, dual TTK/PLK1 inhibitor (BAL0891).Mechanism of action studies utilized biochemical kinase and proteomics-based target-engagement assays. Cellular end-point assays included immunoblot- and flow cytometry-based cell cycle analyses and SAC integrity evaluation using immunoprecipitation and immunofluorescence approaches. Anticancer activity was assessed in vitro using cell growth assays and efficacy was evaluated, alone and in combination with paclitaxel and carboplatin, using mouse models of triple negative breast cancer (TNBC).BAL0891 elicits a prolonged effect on TTK, with a transient activity on PLK1. This unique profile potentiates SAC disruption, forcing tumor cells to aberrantly exit mitosis with faster kinetics than observed with a TTK-specific inhibitor. Broad anti-proliferative activity was demonstrated across solid tumor cell lines in vitro. Moreover, intermittent intravenous single-agent BAL0891 treatment of the MDA-MB-231 mouse model of TNBC induced profound tumor regressions associated with prolonged TTK and transient PLK1 in-tumor target occupancy. Furthermore, differential tumor responses across a panel of thirteen TNBC patient-derived xenograft models indicated profound anticancer activity in a subset (~40%). Using a flexible dosing approach, pathologically confirmed cures were observed in combination with paclitaxel, whereas synergy with carboplatin was schedule dependent.Dual TTK/PLK1 inhibition represents a novel approach for the treatment of human cancer, including TNBC patients, with a potential for potent anticancer activity and a favorable therapeutic index. Moreover, combination approaches may provide an avenue to expand responsive patient populations.","PeriodicalId":507440,"journal":{"name":"Frontiers in Oncology","volume":"35 2","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-08-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141923021","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
To construct deep learning-assisted diagnosis models based on automatic segmentation of ultrasound images to facilitate radiologists in differentiating benign and malignant parotid tumors.A total of 582 patients histopathologically diagnosed with PGTs were retrospectively recruited from 4 centers, and their data were collected for analysis. The radiomics features of six deep learning models (ResNet18, Inception_v3 etc) were analyzed based on the ultrasound images that were obtained under the best automatic segmentation model (Deeplabv3, UNet++, and UNet). The performance of three physicians was compared when the optimal model was used and not. The Net Reclassification Index (NRI) and Integrated Discrimination Improvement (IDI) were utilized to evaluate the clinical benefit of the optimal model.The Deeplabv3 model performed optimally in terms of automatic segmentation. The ResNet18 deep learning model had the best prediction performance, with an area under the receiver-operating characteristic curve of 0.808 (0.694−0.923), 0.809 (0.712−0.906), and 0.812 (0.680−0.944) in the internal test set and external test sets 1 and 2, respectively. Meanwhile, the optimal model-assisted clinical and overall benefits were markedly enhanced for two out of three radiologists (in internal validation set, NRI: 0.259 and 0.213 [p = 0.002 and 0.017], IDI: 0.284 and 0.201 [p = 0.005 and 0.043], respectively; in external test set 1, NRI: 0.183 and 0.161 [p = 0.019 and 0.008], IDI: 0.205 and 0.184 [p = 0.031 and 0.045], respectively; in external test set 2, NRI: 0.297 and 0.297 [p = 0.038 and 0.047], IDI: 0.332 and 0.294 [p = 0.031 and 0.041], respectively).The deep learning model constructed for automatic segmentation of ultrasound images can improve the diagnostic performance of radiologists for PGTs.
{"title":"Deep learning-assisted diagnosis of benign and malignant parotid gland tumors based on automatic segmentation of ultrasound images: a multicenter retrospective study","authors":"Wei Wei, Jingya Xu, Fei Xia, Jun Liu, Zekai Zhang, Jing Wu, Tianjun Wei, Huijun Feng, Qiang Ma, Feng Jiang, Xiangming Zhu, Xia Zhang","doi":"10.3389/fonc.2024.1417330","DOIUrl":"https://doi.org/10.3389/fonc.2024.1417330","url":null,"abstract":"To construct deep learning-assisted diagnosis models based on automatic segmentation of ultrasound images to facilitate radiologists in differentiating benign and malignant parotid tumors.A total of 582 patients histopathologically diagnosed with PGTs were retrospectively recruited from 4 centers, and their data were collected for analysis. The radiomics features of six deep learning models (ResNet18, Inception_v3 etc) were analyzed based on the ultrasound images that were obtained under the best automatic segmentation model (Deeplabv3, UNet++, and UNet). The performance of three physicians was compared when the optimal model was used and not. The Net Reclassification Index (NRI) and Integrated Discrimination Improvement (IDI) were utilized to evaluate the clinical benefit of the optimal model.The Deeplabv3 model performed optimally in terms of automatic segmentation. The ResNet18 deep learning model had the best prediction performance, with an area under the receiver-operating characteristic curve of 0.808 (0.694−0.923), 0.809 (0.712−0.906), and 0.812 (0.680−0.944) in the internal test set and external test sets 1 and 2, respectively. Meanwhile, the optimal model-assisted clinical and overall benefits were markedly enhanced for two out of three radiologists (in internal validation set, NRI: 0.259 and 0.213 [p = 0.002 and 0.017], IDI: 0.284 and 0.201 [p = 0.005 and 0.043], respectively; in external test set 1, NRI: 0.183 and 0.161 [p = 0.019 and 0.008], IDI: 0.205 and 0.184 [p = 0.031 and 0.045], respectively; in external test set 2, NRI: 0.297 and 0.297 [p = 0.038 and 0.047], IDI: 0.332 and 0.294 [p = 0.031 and 0.041], respectively).The deep learning model constructed for automatic segmentation of ultrasound images can improve the diagnostic performance of radiologists for PGTs.","PeriodicalId":507440,"journal":{"name":"Frontiers in Oncology","volume":"4 2","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-08-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141923184","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Gliomas are primary tumors that originate in the central nervous system. The conventional treatment options for gliomas typically encompass surgical resection and temozolomide (TMZ) chemotherapy. However, despite aggressive interventions, the median survival for glioma patients is merely about 14.6 months. Consequently, there is an urgent necessity to explore innovative therapeutic strategies for treating glioma. The foundational study of regulated cell death (RCD) can be traced back to Karl Vogt’s seminal observations of cellular demise in toads, which were documented in 1842. In the past decade, the Nomenclature Committee on Cell Death (NCCD) has systematically classified and delineated various forms and mechanisms of cell death, synthesizing morphological, biochemical, and functional characteristics. Cell death primarily manifests in two forms: accidental cell death (ACD), which is caused by external factors such as physical, chemical, or mechanical disruptions; and RCD, a gene-directed intrinsic process that coordinates an orderly cellular demise in response to both physiological and pathological cues. Advancements in our understanding of RCD have shed light on the manipulation of cell death modulation - either through induction or suppression - as a potentially groundbreaking approach in oncology, holding significant promise. However, obstacles persist at the interface of research and clinical application, with significant impediments encountered in translating to therapeutic modalities. It is increasingly apparent that an integrative examination of the molecular underpinnings of cell death is imperative for advancing the field, particularly within the framework of inter-pathway functional synergy. In this review, we provide an overview of various forms of RCD, including autophagy-dependent cell death, anoikis, ferroptosis, cuproptosis, pyroptosis and immunogenic cell death. We summarize the latest advancements in understanding the molecular mechanisms that regulate RCD in glioma and explore the interconnections between different cell death processes. By comprehending these connections and developing targeted strategies, we have the potential to enhance glioma therapy through manipulation of RCD.
{"title":"Revisiting the potential of regulated cell death in glioma treatment: a focus on autophagy-dependent cell death, anoikis, ferroptosis, cuproptosis, pyroptosis, immunogenic cell death, and the crosstalk between them","authors":"Maowen Luo, X. Luan, Chaoge Yang, Xiaofan Chen, Suxin Yuan, Youlin Cao, Jing Zhang, Jiaying Xie, Qinglian Luo, Ligang Chen, Shenjie Li, Wei Xiang, Jie Zhou","doi":"10.3389/fonc.2024.1397863","DOIUrl":"https://doi.org/10.3389/fonc.2024.1397863","url":null,"abstract":"Gliomas are primary tumors that originate in the central nervous system. The conventional treatment options for gliomas typically encompass surgical resection and temozolomide (TMZ) chemotherapy. However, despite aggressive interventions, the median survival for glioma patients is merely about 14.6 months. Consequently, there is an urgent necessity to explore innovative therapeutic strategies for treating glioma. The foundational study of regulated cell death (RCD) can be traced back to Karl Vogt’s seminal observations of cellular demise in toads, which were documented in 1842. In the past decade, the Nomenclature Committee on Cell Death (NCCD) has systematically classified and delineated various forms and mechanisms of cell death, synthesizing morphological, biochemical, and functional characteristics. Cell death primarily manifests in two forms: accidental cell death (ACD), which is caused by external factors such as physical, chemical, or mechanical disruptions; and RCD, a gene-directed intrinsic process that coordinates an orderly cellular demise in response to both physiological and pathological cues. Advancements in our understanding of RCD have shed light on the manipulation of cell death modulation - either through induction or suppression - as a potentially groundbreaking approach in oncology, holding significant promise. However, obstacles persist at the interface of research and clinical application, with significant impediments encountered in translating to therapeutic modalities. It is increasingly apparent that an integrative examination of the molecular underpinnings of cell death is imperative for advancing the field, particularly within the framework of inter-pathway functional synergy. In this review, we provide an overview of various forms of RCD, including autophagy-dependent cell death, anoikis, ferroptosis, cuproptosis, pyroptosis and immunogenic cell death. We summarize the latest advancements in understanding the molecular mechanisms that regulate RCD in glioma and explore the interconnections between different cell death processes. By comprehending these connections and developing targeted strategies, we have the potential to enhance glioma therapy through manipulation of RCD.","PeriodicalId":507440,"journal":{"name":"Frontiers in Oncology","volume":"31 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-08-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141924714","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-09DOI: 10.3389/fonc.2024.1441227
William S. Ferris, Benjamin George, Kristin A. Plichta, Joseph M. Caster, D. Hyer, Blake R. Smith, J. St-Aubin
This work presents a method to treat stereotactic body radiation therapy (SBRT) for pancreatic cancer on a magnetic resonance-guided linear accelerator (MR-linac) using daily adaptation, real-time motion monitoring, and abdominal compression.The motion management and treatment planning process involves a magnetic resonance imaging (MRI) simulation with cine and 3D images, a computed tomography (CT) simulation with a breath-hold CT and a 4DCT, pre-treatment verification and planning MRI, and intrafraction MRI cine images.The results from 26 patients were included in this work. Our motion management process results in consistent motion analysis on the CT simulation, MRI simulation, and each treatment fraction. The liver dome was found to be an overestimate of tumor superior/inferior (SI) motion for most patients. Adding compression reduced SI liver dome motion by 6.2 mm on average. Clinical outcomes are similar to those observed in the literature.In this work, we demonstrate how pancreatic SBRT can be successfully treated on an MR-linac using abdominal compression. This allows for an increased duty cycle compared to gating and/or breath-hold techniques.
这项研究提出了一种在磁共振引导直线加速器（MR-linac）上对胰腺癌进行立体定向体放射治疗（SBRT）的方法，该方法采用了日常适应、实时运动监测和腹部加压等技术。运动管理和治疗计划过程包括磁共振成像（MRI）模拟（含 cine 和 3D 图像）、计算机断层扫描（CT）模拟（含屏气 CT 和 4DCT）、治疗前验证和计划磁共振成像以及分量内磁共振成像 cine 图像。我们的运动管理流程可对 CT 模拟、MRI 模拟和每个治疗分段进行一致的运动分析。研究发现，大多数患者的肝脏穹顶都高估了肿瘤的上/下（SI）运动。加压平均减少了 6.2 毫米的 SI 肝穹运动。临床结果与文献中观察到的结果相似。在这项工作中，我们展示了如何通过腹部加压在磁共振直视机上成功进行胰腺 SBRT 治疗。与门控和/或屏气技术相比，这可以增加占空比。
{"title":"Clinical experience with adaptive MRI-guided pancreatic SBRT and the use of abdominal compression to reduce treatment volume","authors":"William S. Ferris, Benjamin George, Kristin A. Plichta, Joseph M. Caster, D. Hyer, Blake R. Smith, J. St-Aubin","doi":"10.3389/fonc.2024.1441227","DOIUrl":"https://doi.org/10.3389/fonc.2024.1441227","url":null,"abstract":"This work presents a method to treat stereotactic body radiation therapy (SBRT) for pancreatic cancer on a magnetic resonance-guided linear accelerator (MR-linac) using daily adaptation, real-time motion monitoring, and abdominal compression.The motion management and treatment planning process involves a magnetic resonance imaging (MRI) simulation with cine and 3D images, a computed tomography (CT) simulation with a breath-hold CT and a 4DCT, pre-treatment verification and planning MRI, and intrafraction MRI cine images.The results from 26 patients were included in this work. Our motion management process results in consistent motion analysis on the CT simulation, MRI simulation, and each treatment fraction. The liver dome was found to be an overestimate of tumor superior/inferior (SI) motion for most patients. Adding compression reduced SI liver dome motion by 6.2 mm on average. Clinical outcomes are similar to those observed in the literature.In this work, we demonstrate how pancreatic SBRT can be successfully treated on an MR-linac using abdominal compression. This allows for an increased duty cycle compared to gating and/or breath-hold techniques.","PeriodicalId":507440,"journal":{"name":"Frontiers in Oncology","volume":"3 10","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-08-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141921197","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-09DOI: 10.3389/fonc.2024.1407919
M. Berretta, Daniele Garozzo, Calogero Foti, Mario Roselli, M. Materazzo, Giulia Vita, Ferdinando Iellamo, Marco Scordari, Giordana Di Mauro, Giovanna Spatari, Alessandro Ottaiano, A. Noce, Marco Pelicciaro, Alessia Bignucolo, Gianluca Vanni, O. Buonomo
Improving prognosis of BC patients has drawn the attention of health care professionals on disease related long-term side effects and on the multiple treatments BC patients must undergo. Despite advances in procedures, surgery still has multiple detrimental effects, including pain, edema, and limited mobility. For this reason, fostering adapted physical activity (APA) and healthy lifestyle (including a balanced diet and weight management) should become an everyday purpose of healthcare professionals. Fencing may be a well-suited activity to counteract fatigue, pain, and limited arm mobility.The FENICE study is a mono-center, randomized clinical trial targeting women with BC stages I-III within four weeks from BC surgery. Participants in the control arm will receive the usual recommendations based on the good clinical practice guidelines. In the study arm, participants will be treated with the usual clinical and therapeutic recommendations together with APA and correct lifestyle suggestions.The primary objective of the study is to compare whether implementation of APA and healthy lifestyle in BC patient after surgery will result in an overall improvement of physical and mental status.Fencing and its early application in postoperative period may represent a feasible strategy to be implemented in the rehabilitation journey of BC patients.The study protocol FENICE has been approved by an Italian Ethics Committee on May 2023 (R.S 100.23 5th May 2023).
BC 患者预后的改善引起了医护人员对与疾病相关的长期副作用以及 BC 患者必须接受的多种治疗的关注。尽管手术程序不断进步，但手术仍会产生多种不利影响，包括疼痛、水肿和活动受限。因此，促进适应性体育活动（APA）和健康的生活方式（包括均衡饮食和体重管理）应成为医护人员的日常目标。FENICE 研究是一项单中心、随机临床试验，对象是 BC 手术后四周内的 BC I-III 期女性患者。对照组的参与者将接受基于良好临床实践指南的常规建议。该研究的主要目的是比较在 BC 患者术后实施 APA 和健康生活方式是否会全面改善其身体和精神状态。剑术及其在术后的早期应用可能是在 BC 患者康复过程中实施的一种可行策略。FENICE 研究方案已于 2023 年 5 月获得意大利伦理委员会批准（R.S 100.23，2023 年 5 月 5 日）。
{"title":"Implementing fencing as adapted physical activity in non-metastatic breast cancer patients: design and early rehabilitation strategy of the FENICE study protocol","authors":"M. Berretta, Daniele Garozzo, Calogero Foti, Mario Roselli, M. Materazzo, Giulia Vita, Ferdinando Iellamo, Marco Scordari, Giordana Di Mauro, Giovanna Spatari, Alessandro Ottaiano, A. Noce, Marco Pelicciaro, Alessia Bignucolo, Gianluca Vanni, O. Buonomo","doi":"10.3389/fonc.2024.1407919","DOIUrl":"https://doi.org/10.3389/fonc.2024.1407919","url":null,"abstract":"Improving prognosis of BC patients has drawn the attention of health care professionals on disease related long-term side effects and on the multiple treatments BC patients must undergo. Despite advances in procedures, surgery still has multiple detrimental effects, including pain, edema, and limited mobility. For this reason, fostering adapted physical activity (APA) and healthy lifestyle (including a balanced diet and weight management) should become an everyday purpose of healthcare professionals. Fencing may be a well-suited activity to counteract fatigue, pain, and limited arm mobility.The FENICE study is a mono-center, randomized clinical trial targeting women with BC stages I-III within four weeks from BC surgery. Participants in the control arm will receive the usual recommendations based on the good clinical practice guidelines. In the study arm, participants will be treated with the usual clinical and therapeutic recommendations together with APA and correct lifestyle suggestions.The primary objective of the study is to compare whether implementation of APA and healthy lifestyle in BC patient after surgery will result in an overall improvement of physical and mental status.Fencing and its early application in postoperative period may represent a feasible strategy to be implemented in the rehabilitation journey of BC patients.The study protocol FENICE has been approved by an Italian Ethics Committee on May 2023 (R.S 100.23 5th May 2023).","PeriodicalId":507440,"journal":{"name":"Frontiers in Oncology","volume":"3 5","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-08-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141925628","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-08DOI: 10.3389/fonc.2024.1455464
Issam S. Hamadeh, Reed Friend, S. Mailankody, S. Atrash
Although multiple myeloma is an incurable disease, the past decade has witnessed significant improvement in patient outcomes. This was brought about by the development of T-cell redirection therapies such as chimeric antigen receptor (CAR) T-cells, which can leverage the natural ability of the immune system to fight myeloma cells. The approval of the B-cell maturation antigen (BCMA)-directed CAR T, idecabtagene vicleucel (ide-cel), and ciltacabtagene autoleucel (cilta-cel) has resulted in a paradigm shift in the treatment of relapsed/refractory multiple myeloma. Overall response rates ranging from 73 to 97% are currently achievable. However, the limitations of KarMMa-1 and CARTITUDE-1 studies spurred the generation of real-world data to provide some insights into the effectiveness of ide-cel and cilta-cel among patients who were excluded from clinical trials, particularly those who received prior BCMA-targeted or other T-cell redirection therapies. Despite their unprecedented clinical efficacy in heavily pretreated patients, responses to CAR T remain non-durable. Although the underlying mechanisms of resistance to these agents haven’t been fully elucidated, studies have suggested that resistance patterns could be multifaceted, implicating T-cell exhaustion and tumor intrinsic mechanisms such as BCMA target loss, upregulation of gamma-secretase, and others. Herein, we provide a succinct overview of the development of CAR T-cells, manufacturing process, and associated toxicities/complications. In this review, we also recapitulate the existing literature pertaining MM CAR-T as well as emerging data from some of the ongoing clinical trials designed to mitigate the shortcomings of these agents, and improve the clinical efficacy of CAR T, especially in the relapsed/refractory setting.
虽然多发性骨髓瘤是一种无法治愈的疾病，但在过去十年中，患者的治疗效果得到了显著改善。这得益于嵌合抗原受体（CAR）T 细胞等 T 细胞重定向疗法的发展，这种疗法可以利用免疫系统的天然能力来对抗骨髓瘤细胞。以 B 细胞成熟抗原（BCMA）为导向的 CAR T、idecabtagene vicleucel（ide-cel）和 ciltacabtagene autoleucel（cilta-cel）获得批准后，复发性/难治性多发性骨髓瘤的治疗模式发生了转变。目前的总体反应率从 73% 到 97% 不等。然而，KarMMa-1 和 CARTITUDE-1 研究的局限性促使人们产生了真实世界的数据，以便深入了解 ide-cel 和 cilta-cel 在被排除在临床试验之外的患者中的疗效，尤其是那些之前接受过 BCMA 靶向疗法或其他 T 细胞重定向疗法的患者。尽管 CAR T 在接受过大量预处理的患者中取得了前所未有的临床疗效，但其反应仍不持久。虽然对这些药物产生耐药性的根本机制尚未完全阐明，但研究表明耐药性模式可能是多方面的，涉及T细胞衰竭和肿瘤内在机制，如BCMA靶点缺失、γ-分泌酶上调等。在此，我们将简明扼要地概述 CAR T 细胞的开发、制造过程和相关毒性/并发症。在这篇综述中，我们还回顾了有关 MM CAR-T 的现有文献以及一些正在进行的临床试验的新数据，这些临床试验旨在减轻这些药物的缺点，提高 CAR T 的临床疗效，尤其是在复发/难治性病例中的疗效。
{"title":"Chimeric antigen receptor T-cells: a review on current status and future directions for relapsed/refractory multiple myeloma","authors":"Issam S. Hamadeh, Reed Friend, S. Mailankody, S. Atrash","doi":"10.3389/fonc.2024.1455464","DOIUrl":"https://doi.org/10.3389/fonc.2024.1455464","url":null,"abstract":"Although multiple myeloma is an incurable disease, the past decade has witnessed significant improvement in patient outcomes. This was brought about by the development of T-cell redirection therapies such as chimeric antigen receptor (CAR) T-cells, which can leverage the natural ability of the immune system to fight myeloma cells. The approval of the B-cell maturation antigen (BCMA)-directed CAR T, idecabtagene vicleucel (ide-cel), and ciltacabtagene autoleucel (cilta-cel) has resulted in a paradigm shift in the treatment of relapsed/refractory multiple myeloma. Overall response rates ranging from 73 to 97% are currently achievable. However, the limitations of KarMMa-1 and CARTITUDE-1 studies spurred the generation of real-world data to provide some insights into the effectiveness of ide-cel and cilta-cel among patients who were excluded from clinical trials, particularly those who received prior BCMA-targeted or other T-cell redirection therapies. Despite their unprecedented clinical efficacy in heavily pretreated patients, responses to CAR T remain non-durable. Although the underlying mechanisms of resistance to these agents haven’t been fully elucidated, studies have suggested that resistance patterns could be multifaceted, implicating T-cell exhaustion and tumor intrinsic mechanisms such as BCMA target loss, upregulation of gamma-secretase, and others. Herein, we provide a succinct overview of the development of CAR T-cells, manufacturing process, and associated toxicities/complications. In this review, we also recapitulate the existing literature pertaining MM CAR-T as well as emerging data from some of the ongoing clinical trials designed to mitigate the shortcomings of these agents, and improve the clinical efficacy of CAR T, especially in the relapsed/refractory setting.","PeriodicalId":507440,"journal":{"name":"Frontiers in Oncology","volume":"35 23","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-08-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141928667","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
With the widespread use of computed tomography (CT), the detection rate of pulmonary nodules in children has gradually increased. Due to the lack of epidemiological evidence and clinical guideline on pulmonary nodule treatment in children, we aimed to provide a reference for the clinical diagnosis and management of pediatirc pulmonary nodules.This retrospective study collected consecutive cases from April 2012 to July 2021 in the Shanghai Children’s Medical Center. The sample included children with pulmonary nodules on chest CT scans and met the inclusion criteria. All patients were categorized into tumor and non-tumor groups by pre-CT clinical diagnosis. Nodule characteristics between groups were analyzed. To establish a clinical assessment model for the benign versus malignant pulmonary nodules, patients who have been followed-up for three months were detected and a decision tree model for nodule malignancy prediction was constructed and validated.The sample comprised 1341 patients with an average age of 7.2 ± 4.6 years. More than half of them (51.7%) were diagnosed with malignancies before CT scan. 48.3% were diagnosed with non-tumor diseases or healthy. Compared to non-tumor group, children with tumor were more likely to have multiple nodules in both lungs, with larger size and often be accompanied by osteolytic or mass lesions. Based on the decision tree model, patients’ history of malignancies, nodules diameter size≥5mm, and specific nodule distribution (multiple in both lungs, multiple in the right lung or solitary in the upper or middle right lobe) were important potential predictors for malignity. In the validation set, sensitivity, specificity and AUC were 0.855, 0.833 and 0.828 (95%CI: 0.712-0.909), respectively.This study conducted a clinical assessment model to differentiate benignity and malignancy of pediatric pulmonary nodules. We suggested that a nodule’s diameter, distribution and patient’s history of malignancies are predictable factors in benign or malignant determination.
{"title":"Imaging features and clinical evaluation of pulmonary nodules in children","authors":"Muheremu Dilimulati, Shuhua Yuan, Hejun Jiang, Yahua Wang, Hui Ma, Shiyu Shen, Jilei Lin, Jiande Chen, Yong Yin","doi":"10.3389/fonc.2024.1385600","DOIUrl":"https://doi.org/10.3389/fonc.2024.1385600","url":null,"abstract":"With the widespread use of computed tomography (CT), the detection rate of pulmonary nodules in children has gradually increased. Due to the lack of epidemiological evidence and clinical guideline on pulmonary nodule treatment in children, we aimed to provide a reference for the clinical diagnosis and management of pediatirc pulmonary nodules.This retrospective study collected consecutive cases from April 2012 to July 2021 in the Shanghai Children’s Medical Center. The sample included children with pulmonary nodules on chest CT scans and met the inclusion criteria. All patients were categorized into tumor and non-tumor groups by pre-CT clinical diagnosis. Nodule characteristics between groups were analyzed. To establish a clinical assessment model for the benign versus malignant pulmonary nodules, patients who have been followed-up for three months were detected and a decision tree model for nodule malignancy prediction was constructed and validated.The sample comprised 1341 patients with an average age of 7.2 ± 4.6 years. More than half of them (51.7%) were diagnosed with malignancies before CT scan. 48.3% were diagnosed with non-tumor diseases or healthy. Compared to non-tumor group, children with tumor were more likely to have multiple nodules in both lungs, with larger size and often be accompanied by osteolytic or mass lesions. Based on the decision tree model, patients’ history of malignancies, nodules diameter size≥5mm, and specific nodule distribution (multiple in both lungs, multiple in the right lung or solitary in the upper or middle right lobe) were important potential predictors for malignity. In the validation set, sensitivity, specificity and AUC were 0.855, 0.833 and 0.828 (95%CI: 0.712-0.909), respectively.This study conducted a clinical assessment model to differentiate benignity and malignancy of pediatric pulmonary nodules. We suggested that a nodule’s diameter, distribution and patient’s history of malignancies are predictable factors in benign or malignant determination.","PeriodicalId":507440,"journal":{"name":"Frontiers in Oncology","volume":"54 39","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-08-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141929036","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-08DOI: 10.3389/fonc.2024.1392540
Yixiao He, Pengchen He, Anqun Wang, Yuzhu Ji, Gang Xie, Lili Zou
Solitary fibrous tumor (SFT) is a type of fibroblastic neoplasm that can occur in various parts of the body, with SFT of the pineal gland being exceedingly rare. We report the case of a 58-year-old male presenting with recurrent hiccups, acid reflux, and headache. Magnetic resonance imaging revealed an occupying lesion in the pineal region, suggestive of a neoplastic process. Intraoperatively, the lesion was located in the pineal region, exhibiting a grayish-red color, and was largely resected. Pathological examination confirmed the diagnosis of solitary fibrous tumor (CNS WHO Grade 1). Postoperatively, the patient was supplemented with radiotherapy, and long-term follow-up showed no signs of recurrence or metastasis.
孤立性纤维瘤（SFT）是一种纤维肿瘤，可发生在身体的各个部位，松果体的孤立性纤维瘤则极为罕见。我们报告了一例 58 岁男性的病例，患者反复出现打嗝、反酸和头痛。磁共振成像显示松果体区域有占位性病变，提示为肿瘤过程。术中，病灶位于松果体区域，呈灰红色，大部分被切除。病理检查确诊为单发纤维瘤（中枢神经系统 WHO 1 级）。术后，患者接受了辅助放疗，长期随访显示无复发或转移迹象。
{"title":"Solitary fibrous tumor of the pineal gland: a case report and review of the literature","authors":"Yixiao He, Pengchen He, Anqun Wang, Yuzhu Ji, Gang Xie, Lili Zou","doi":"10.3389/fonc.2024.1392540","DOIUrl":"https://doi.org/10.3389/fonc.2024.1392540","url":null,"abstract":"Solitary fibrous tumor (SFT) is a type of fibroblastic neoplasm that can occur in various parts of the body, with SFT of the pineal gland being exceedingly rare. We report the case of a 58-year-old male presenting with recurrent hiccups, acid reflux, and headache. Magnetic resonance imaging revealed an occupying lesion in the pineal region, suggestive of a neoplastic process. Intraoperatively, the lesion was located in the pineal region, exhibiting a grayish-red color, and was largely resected. Pathological examination confirmed the diagnosis of solitary fibrous tumor (CNS WHO Grade 1). Postoperatively, the patient was supplemented with radiotherapy, and long-term follow-up showed no signs of recurrence or metastasis.","PeriodicalId":507440,"journal":{"name":"Frontiers in Oncology","volume":"17 18","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-08-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141927401","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-08DOI: 10.3389/fonc.2024.1436942
Munazza Khan, Grace L Wong, Chuling Zhuang, Mariana K. Najjar, Hui-Wen Lo
Breast cancer is the most frequent malignancy in women, constituting 15.2% of all new cancers diagnosed in the United States. Distant breast cancer metastasis accounts for the majority of breast cancer-related deaths; brain metastasis is the third most common site for metastatic breast cancer but is associated with worst prognosis of approximately eight months of survival. Current treatment options for breast cancer brain metastasis (BCBM) are limited and ineffective. To help identify new and effective therapies for BCBM, it is important to investigate the mechanisms by which breast cancer cells metastasize to the brain and thrive in the brain microenvironment. To this end, studies have reported that primary breast tumor cells can prime brain microenvironmental cells, including, astrocytes and microglia, to promote the formation of BCBM through the release of extracellular vesicle-microRNAs (miRNAs). Breast tumor-derived miRNAs can also promote breast cancer cell invasion through the blood-brain barrier by disrupting the integrity of the brain microvascular endothelial cells. In this review, we summarize current literature on breast cancer-derived BCBM-promoting miRNAs, cover their roles in the complex steps of BCBM particularly their interactions with microenvironmental cells within the brain metastatic niche, and finally discuss their therapeutic applications in the management of BCBM.
{"title":"Crosstalk between breast cancer-derived microRNAs and brain microenvironmental cells in breast cancer brain metastasis","authors":"Munazza Khan, Grace L Wong, Chuling Zhuang, Mariana K. Najjar, Hui-Wen Lo","doi":"10.3389/fonc.2024.1436942","DOIUrl":"https://doi.org/10.3389/fonc.2024.1436942","url":null,"abstract":"Breast cancer is the most frequent malignancy in women, constituting 15.2% of all new cancers diagnosed in the United States. Distant breast cancer metastasis accounts for the majority of breast cancer-related deaths; brain metastasis is the third most common site for metastatic breast cancer but is associated with worst prognosis of approximately eight months of survival. Current treatment options for breast cancer brain metastasis (BCBM) are limited and ineffective. To help identify new and effective therapies for BCBM, it is important to investigate the mechanisms by which breast cancer cells metastasize to the brain and thrive in the brain microenvironment. To this end, studies have reported that primary breast tumor cells can prime brain microenvironmental cells, including, astrocytes and microglia, to promote the formation of BCBM through the release of extracellular vesicle-microRNAs (miRNAs). Breast tumor-derived miRNAs can also promote breast cancer cell invasion through the blood-brain barrier by disrupting the integrity of the brain microvascular endothelial cells. In this review, we summarize current literature on breast cancer-derived BCBM-promoting miRNAs, cover their roles in the complex steps of BCBM particularly their interactions with microenvironmental cells within the brain metastatic niche, and finally discuss their therapeutic applications in the management of BCBM.","PeriodicalId":507440,"journal":{"name":"Frontiers in Oncology","volume":"45 24","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-08-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141928279","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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