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Prostate Cancer Risk Stratification in NRG Oncology Phase III Randomized Trials Using Multimodal Deep Learning With Digital Histopathology. 利用数字组织病理学进行多模态深度学习,在 NRG 肿瘤学 III 期随机试验中进行前列腺癌风险分层。
IF 5.3 2区 医学 Q1 ONCOLOGY Pub Date : 2024-10-01 Epub Date: 2024-10-24 DOI: 10.1200/PO.24.00145
Jonathan David Tward, Huei-Chung Huang, Andre Esteva, Osama Mohamad, Douwe van der Wal, Jeffry P Simko, Sandy DeVries, Jingbin Zhang, Songwan Joun, Timothy N Showalter, Edward M Schaeffer, Todd M Morgan, Jedidiah M Monson, James A Wallace, Jean-Paul Bahary, Howard M Sandler, Daniel E Spratt, Joseph P Rodgers, Felix Y Feng, Phuoc T Tran

Purpose: Current clinical risk stratification methods for localized prostate cancer are suboptimal, leading to over- and undertreatment. Recently, machine learning approaches using digital histopathology have shown superior prognostic ability in phase III trials. This study aims to develop a clinically usable risk grouping system using multimodal artificial intelligence (MMAI) models that outperform current National Comprehensive Cancer Network (NCCN) risk groups.

Materials and methods: The cohort comprised 9,787 patients with localized prostate cancer from eight NRG Oncology randomized phase III trials, treated with radiation therapy, androgen deprivation therapy, and/or chemotherapy. Locked MMAI models, which used digital histopathology images and clinical data, were applied to each patient. Expert consensus on cut points defined low-, intermediate-, and high-risk groups on the basis of 10-year distant metastasis rates of 3% and 10%, respectively. The MMAI's reclassification and prognostic performance were compared with the three-tier NCCN risk groups.

Results: The median follow-up for censored patients was 7.9 years. According to NCCN risk categories, 30.4% of patients were low-risk, 25.5% intermediate-risk, and 44.1% high-risk. The MMAI risk classification identified 43.5% of patients as low-risk, 34.6% as intermediate-risk, and 21.8% as high-risk. MMAI reclassified 1,039 (42.0%) patients initially categorized by NCCN. Despite the MMAI low-risk group being larger than the NCCN low-risk group, the 10-year metastasis risks were comparable: 1.7% (95% CI, 0.2 to 3.2) for NCCN and 3.2% (95% CI, 1.7 to 4.7) for MMAI. The overall 10-year metastasis risk for NCCN high-risk patients was 16.6%, with MMAI further stratifying this group into low-, intermediate-, and high-risk, showing metastasis rates of 3.4%, 8.2%, and 26.3%, respectively.

Conclusion: The MMAI risk grouping system expands the population of men identified as having low metastatic risk and accurately pinpoints a high-risk subset with elevated metastasis rates. This approach aims to prevent both overtreatment and undertreatment in localized prostate cancer, facilitating shared decision making.

目的:目前针对局部前列腺癌的临床风险分层方法不够理想,导致过度治疗或治疗不足。最近,利用数字组织病理学的机器学习方法在 III 期试验中显示出了卓越的预后能力。本研究旨在利用多模态人工智能(MMAI)模型开发一种临床可用的风险分组系统,该系统优于当前的美国国家综合癌症网络(NCCN)风险分组:研究对象包括来自八项NRG肿瘤学随机III期试验的9787名局部前列腺癌患者,这些患者接受了放疗、雄激素剥夺疗法和/或化疗。锁定的 MMAI 模型使用数字组织病理学图像和临床数据,适用于每位患者。专家就切点达成共识,根据 10 年远处转移率分别为 3% 和 10% 的标准定义了低危、中危和高危组。MMAI的重新分类和预后效果与NCCN三级风险组进行了比较:筛查出的患者的中位随访时间为 7.9 年。根据 NCCN 风险分类,30.4% 的患者为低风险,25.5% 为中风险,44.1% 为高风险。MMAI风险分类将43.5%的患者确定为低风险,34.6%为中风险,21.8%为高风险。MMAI 对 1,039 名(42.0%)最初由 NCCN 分类的患者进行了重新分类。尽管 MMAI 低风险组的人数多于 NCCN 低风险组,但 10 年转移风险却相当:NCCN为1.7%(95% CI,0.2至3.2),MMAI为3.2%(95% CI,1.7至4.7)。NCCN高危患者的10年总体转移风险为16.6%,MMAI将这一群体进一步分为低危、中危和高危,转移率分别为3.4%、8.2%和26.3%:MMAI风险分组系统扩大了被确定为低转移风险的男性人群,并准确定位了转移率较高的高风险亚群。这种方法旨在防止局部前列腺癌的过度治疗和治疗不足,促进共同决策。
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引用次数: 0
Addressing the Intersection of Chemotherapy-Induced Peripheral Neuropathy and Fall Risk in Cancer Survivors: Insights and Future Directions. 解决化疗引起的周围神经病变与癌症幸存者跌倒风险的交叉问题:见解与未来方向。
IF 5.3 2区 医学 Q1 ONCOLOGY Pub Date : 2024-10-01 Epub Date: 2024-10-21 DOI: 10.1200/PO-24-00421
Emad Shash
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引用次数: 0
Toxicity Adaptive Lists Design: A Practical Design for Phase I Drug Combination Trials in Oncology. 毒性适应性列表设计:肿瘤学 I 期联合用药试验的实用设计。
IF 5.3 2区 医学 Q1 ONCOLOGY Pub Date : 2024-10-01 Epub Date: 2024-10-21 DOI: 10.1200/PO.24.00275
Massimiliano Russo, Francesco Mariani, James M Cleary, Geoffrey I Shapiro, Gregory M Coté, Lorenzo Trippa

Purpose: We introduce a novel algorithmic approach to design phase I trials for oncology drug combinations.

Methods: Our proposed Toxicity Adaptive Lists Design (TALE) is straightforward to implement, requiring the prespecification of a small number of parameters that define rules governing dose escalation, de-escalation, or reassessment of previously explored dose levels. These rules effectively regulate dose exploration and control the number of toxicities. A key feature of TALE is the possibility of simultaneous assignment of multiple-dose combinations that are deemed safe by previously accrued data.

Results: A numerical study shows that TALE shares comparable operative characteristics, in terms of identification of the maximum tolerated dose (MTD), to alternative approaches such as the Bayesian optimal interval design, the COPULA, the product of independent beta probabilities escalation, and the continual reassessment method for partial ordering designs while reducing the risk of overdosing patients.

Conclusion: The proposed TALE design provides a favorable balance between maintaining patient safety and accurately identifying the MTD. To facilitate the use of TALE, we provide a user-friendly R Shiny application and an R package for computing relevant operating characteristics, such as the risk of assigning highly toxic dose combinations.

目的:我们介绍了一种新的算法方法,用于设计肿瘤药物组合的 I 期试验:我们提出的毒性自适应列表设计(TALE)简单易行,只需预先设定少量参数,这些参数定义了剂量升级、降级或重新评估先前探索过的剂量水平的规则。这些规则可有效调节剂量探索并控制毒性反应的数量。TALE 的一个主要特点是可以同时分配先前积累的数据认为安全的多种剂量组合:一项数值研究表明,在确定最大耐受剂量(MTD)方面,TALE 与贝叶斯最优间隔设计、COPULA、独立贝塔概率升级乘积、部分排序设计的持续再评估法等替代方法具有相似的操作特性,同时降低了患者用药过量的风险:结论:建议的 TALE 设计在维护患者安全和准确确定 MTD 之间取得了良好的平衡。为了方便使用 TALE,我们提供了一个用户友好的 R Shiny 应用程序和一个 R 软件包,用于计算相关的运行特征,如分配高毒性剂量组合的风险。
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引用次数: 0
Using a Polygenic Risk Score to Improve the Risk Prediction of Non-Small Cell Lung Cancer in Taiwan. 使用多基因风险评分改进台湾非小细胞肺癌的风险预测。
IF 5.3 2区 医学 Q1 ONCOLOGY Pub Date : 2024-10-01 Epub Date: 2024-10-02 DOI: 10.1200/PO.24.00236
Po-Hsin Lee, I-Chieh Chen, Yi-Ming Chen, Tzu-Hung Hsiao, Jeng-Sen Tseng, Yen-Hsiang Huang, Kuo-Hsuan Hsu, Ho Lin, Tsung-Ying Yang, Yu-Hsuan Joni Shao

Purpose: Low-dose computed tomography (LDCT) can help reducing lung cancer mortality. In Taiwan, the existing screening criteria revolve around smoking habits and family history of lung cancer. The role of genetic variation in non-small cell lung cancer (NSCLC) development is increasingly recognized. In this study, we aimed to investigate the potential benefits of polygenic risk scores (PRSs) in predicting NSCLC and enhancing the effectiveness of screening programs.

Methods: We conducted a retrospective cohort study that included participants without prior diagnosis of lung cancer and later received LDCT for lung cancer screening. Genetic data for these participants were obtained from the project of Taiwan Precision Medicine Initiative. We adopted the model of genome-wide association study-derived PRS calculation using 19 susceptibility loci associated with the risk of NSCLC as reported by Dai et al.

Results: We studied a total of 2,287 participants (1,197 male, 1,090 female). More female participants developed NSCLC during the follow-up period (4.4% v 2.5%, P = .015). The only risk factor of NSCLC diagnosis among male participants was age. Among female participants, independent risk factors of NSCLC diagnosis were age (adjusted hazard ratio [aHR], 1.08 [95% CI, 1.04 to 1.11]), a family history of lung cancer (aHR, 3.21 [95% CI, 1.78 to 5.77]), and PRS fourth quartile (aHR, 2.97 [95% CI, 1.25 to 7.07]). We used the receiver operating characteristics to show an AUC value of 0.741 for the conventional model. With the further incorporation of PRS, the AUC rose to 0.778.

Conclusion: The evaluation of PRS for NSCLC prediction holds promise for enhancing the effectiveness of lung cancer screening in Taiwan especially in women. By incorporating genetic information, screening criteria can be tailored to identify individuals at higher risks of NSCLC.

目的:低剂量计算机断层扫描(LDCT)有助于降低肺癌死亡率。在台湾,现有的筛查标准主要围绕吸烟习惯和肺癌家族史。基因变异在非小细胞肺癌(NSCLC)发展中的作用日益得到认可。本研究旨在探讨多基因风险评分(PRS)在预测非小细胞肺癌和提高筛查计划有效性方面的潜在益处:我们进行了一项回顾性队列研究,研究对象包括既往未确诊肺癌、后来接受了 LDCT 肺癌筛查的参与者。这些参与者的基因数据来自台湾精准医疗计划项目。我们采用了 Dai 等人报告的全基因组关联研究得出的 PRS 计算模型,使用了 19 个与 NSCLC 风险相关的易感基因位点:我们共研究了 2,287 名参与者(男性 1,197 人,女性 1,090 人)。更多女性参与者在随访期间罹患了 NSCLC(4.4% 对 2.5%,P = .015)。男性参与者确诊 NSCLC 的唯一风险因素是年龄。在女性参与者中,确诊 NSCLC 的独立危险因素是年龄(调整后危险比 [aHR],1.08 [95% CI,1.04 至 1.11])、肺癌家族史(aHR,3.21 [95% CI,1.78 至 5.77])和 PRS 第四四分位数(aHR,2.97 [95% CI,1.25 至 7.07])。我们使用接收器操作特征显示,传统模型的 AUC 值为 0.741。在进一步纳入 PRS 后,AUC 上升到 0.778:对预测 NSCLC 的 PRS 进行评估,有望提高台湾肺癌筛查(尤其是女性肺癌筛查)的有效性。通过纳入基因信息,筛查标准可以量身定制,以识别罹患 NSCLC 风险较高的个体。
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引用次数: 0
Microsatellite Instability and Clinical Use in Sarcomas: Systematic Review and Illustrative Case Report. 微卫星不稳定性与肉瘤的临床应用:系统综述与说明性病例报告。
IF 5.3 2区 医学 Q1 ONCOLOGY Pub Date : 2024-10-01 Epub Date: 2024-10-21 DOI: 10.1200/PO.24.00047
Italo Fernandes, Douglas Dias E Silva, Vanderlei Segatelli, Renée Zon Filippi, Ana Carolina de Rezende, Paulo Campregher, Fernando Moura, Reynaldo Jesus-Garcia, Roberto Carmagnani Pestana

Sarcomas, a diverse group of malignancies, exhibit substantial heterogeneity in both biological behavior and microenvironment, influencing their response to immunotherapy. Although pembrolizumab is approved for deficient mismatch repair or microsatellite instability-high (dMMR/MSI-H) tumors regardless of histology, there is a paucity of data to support its effectiveness in dMMR/MSI-H sarcomas. This study presents a case of a metastatic undifferentiated pleomorphic sarcoma of the retroperitoneum with dMMR status demonstrating a sustained complete response to pembrolizumab. Our case revealed inconsistencies in identifying dMMR/MSI-H status through next-generation sequencing, immunohistochemistry, and polymerase chain reaction methods. Therefore, we conducted a systematic review to analyze various methods for assessing dMMR/MSI-H and to explore whether pembrolizumab's indications rely on this biomarker.

肉瘤是一种多种多样的恶性肿瘤,在生物学行为和微环境方面都表现出很大的异质性,从而影响了它们对免疫疗法的反应。尽管pembrolizumab已被批准用于错配修复缺陷或微卫星不稳定性高(dMMR/MSI-H)的肿瘤(无论组织学如何),但支持其对dMMR/MSI-H肉瘤有效的数据却很少。本研究介绍了一例具有dMMR状态的腹膜后转移性未分化多形性肉瘤对pembrolizumab的持续完全应答。我们的病例揭示了通过新一代测序、免疫组化和聚合酶链反应方法确定 dMMR/MSI-H 状态的不一致性。因此,我们进行了一项系统综述,分析评估 dMMR/MSI-H 的各种方法,并探讨 pembrolizumab 的适应症是否依赖于该生物标志物。
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引用次数: 0
New Molecular Targets in Prostate Cancer-The Emerging Role of ACP1 and Low Molecular Weight Protein Tyrosine Phosphatase. 前列腺癌的新分子靶点--ACP1 和低分子量蛋白酪氨酸磷酸酶的新作用
IF 5.3 2区 医学 Q1 ONCOLOGY Pub Date : 2024-10-01 Epub Date: 2024-11-20 DOI: 10.1200/PO-24-00682
Miguel Zugman, Alexander Chehrazi-Raffle, Oren Smaletz
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引用次数: 0
Evidenced-Based Prior for Estimating the Treatment Effect of Phase III Randomized Trials in Oncology. 估算肿瘤学 III 期随机试验治疗效果的循证先例。
IF 5.3 2区 医学 Q1 ONCOLOGY Pub Date : 2024-10-01 Epub Date: 2024-10-02 DOI: 10.1200/PO.24.00363
Alexander D Sherry, Pavlos Msaouel, Gabrielle S Kupferman, Timothy A Lin, Joseph Abi Jaoude, Ramez Kouzy, Zachary R McCaw, Ethan B Ludmir, Erik van Zwet

Purpose: The primary results of phase III oncology trials may be challenging to interpret, given that results are generally based on P value thresholds. The probability of whether a treatment is beneficial, although more intuitive, is not usually provided. Here, we developed and released a user-friendly tool that calculates the probability of treatment benefit using trial summary statistics.

Methods: We curated 415 phase III randomized trials enrolling 338,600 patients published between 2004 and 2020. A phase III prior probability distribution for the treatment effect was developed on the basis of a three-component zero-mean mixture distribution of the observed z-scores. Using this prior, we computed the probability of clinically meaningful benefit (hazard ratio [HR] <0.8). The distribution of signal-to-noise ratios and power of phase III oncology trials were compared with that of 23,551 randomized trials from the Cochrane Database.

Results: The signal-to-noise ratios of phase III oncology trials tended to be much larger than randomized trials from the Cochrane Database. Still, the median power of phase III oncology trials was only 49% (IQR, 14%-95%), and the power was <80% in 65% of trials. Using the phase III oncology-specific prior, only 53% of trials claiming superiority (114 of 216) had a ≥90% probability of clinically meaningful benefits. Conversely, the probability that the experimental arm was superior to the control arm (HR <1) exceeded 90% in 17% of trials interpreted as having no benefit (34 of 199).

Conclusion: By enabling computation of contextual probabilities for the treatment effect from summary statistics, our robust, highly practical tool, now posted on a user-friendly webpage, can aid the wider oncology community in the interpretation of phase III trials.

目的:III 期肿瘤试验的主要结果通常以 P 值阈值为基础,因此解释这些结果可能具有挑战性。治疗是否获益的概率虽然更直观,但通常不会提供。在此,我们开发并发布了一款用户友好型工具,可使用试验摘要统计计算治疗获益概率:我们整理了 2004 年至 2020 年间发表的 415 项 III 期随机试验,共招募了 338600 名患者。在观察到的 z 分数的三组零均值混合分布的基础上,我们建立了 III 期治疗效果的先验概率分布。利用该先验值,我们计算了有临床意义的获益概率(危险比 [HR] 结果):肿瘤学 III 期试验的信噪比往往比 Cochrane 数据库中的随机试验大得多。尽管如此,III 期肿瘤学试验的中位研究功率仅为 49%(IQR,14%-95%),研究功率为结论值:我们的工具功能强大、实用性强,目前已发布在用户友好型网页上,可帮助广大肿瘤学界解读III期试验。
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引用次数: 0
Molecular Subtypes Are Associated With Clinical Benefit in Cisplatin-Treated Metastatic Urothelial Cancer Patients. 分子亚型与顺铂治疗转移性尿路上皮癌患者的临床获益有关
IF 5.3 2区 医学 Q1 ONCOLOGY Pub Date : 2024-10-01 Epub Date: 2024-10-02 DOI: 10.1200/PO.24.00209
Karin Holmsten, Gottfrid Sjödahl, Johan Abrahamsson, Carina Bernardo, Pontus Eriksson, Mattias Höglund, Fredrik Liedberg, Anders Ullén

Purpose: Cisplatin-based combination chemotherapy (CHT) is standard of care in metastatic urothelial cancer (mUC); however, no predictive molecular biomarkers are available for clinical use. The aim of this study was to investigate the impact of molecular subtypes in relation to treatment response and survival in patients with mUC treated with first-line CHT.

Patients and methods: Molecular subtype classification according to the Lund Taxonomy (LundTax) was performed by tumor transcriptomic profiling and immunostaining in a retrospective cohort. Molecular subtypes were investigated in relation to the primary end point overall response rate (ORR) and secondary end points progression-free survival (PFS) and overall survival (OS). Differential gene expression and association to treatment response were explored.

Results: Ninety-five patients with mUC were classified into urothelial-like (Uro, 43%), genomically unstable (GU, 26%), basal squamous-like (Ba/Sq, 20%), mesenchymal-like (Mes-like, 8%), and small cell neuroendocrine-like (Sc/NE, 3%) subtypes. Patients with Mes-like tumors had lower ORR (14%) compared with Uro (70%), GU (77%), Ba/Sq (75%), and Sc/NE (67%; odds ratio, 0.06 [95% CI, 0.01 to 0.54], P = .012). Furthermore, patients with Mes-like tumors had significantly shorter PFS (hazard ratio [HR], 5.18 [95% CI, 2.28 to 11.76], P < .001) and OS (HR, 3.19 [95% CI, 1.45 to 7.03], P = .004). Patients with Uro and GU showed the longest survival. In responders, an enrichment of downregulated stromal- and immune-related genes was seen. Downregulation of interferon-induced transmembrane protein 2 was associated with increased ORR and improved OS.

Conclusion: This study identifies different CHT responses by LundTax molecular subtypes in patients with mUC, where the Mes-like subtype was associated with lower response rate and shorter survival.

目的:以顺铂为基础的联合化疗(CHT)是转移性尿路上皮癌(mUC)的标准治疗方法;然而,目前尚无可用于临床的预测性分子生物标记物。本研究旨在调查分子亚型对接受一线CHT治疗的mUC患者的治疗反应和生存期的影响:在一个回顾性队列中,通过肿瘤转录组学分析和免疫染色,根据隆德分类法(LundTax)进行分子亚型分类。研究了分子亚型与主要终点总反应率(ORR)及次要终点无进展生存期(PFS)和总生存期(OS)的关系。研究还探讨了基因表达的差异及其与治疗反应的关系:95名mUC患者被分为尿路上皮样(Uro,43%)、基因组不稳定(GU,26%)、基底鳞状细胞样(Ba/Sq,20%)、间质样(Mes,8%)和小细胞神经内分泌样(Sc/NE,3%)亚型。Mes样肿瘤患者的ORR(14%)低于Uro(70%)、GU(77%)、Ba/Sq(75%)和Sc/NE(67%;几率比为0.06 [95% CI, 0.01 to 0.54],P = .012)。此外,Mes 样肿瘤患者的 PFS(危险比 [HR],5.18 [95% CI,2.28 至 11.76],P < .001)和 OS(HR,3.19 [95% CI,1.45 至 7.03],P = .004)明显较短。泌尿系统和生殖系统疾病患者的生存期最长。在应答者中,基质和免疫相关基因的下调幅度较大。干扰素诱导跨膜蛋白2的下调与ORR增加和OS改善有关:这项研究发现了mUC患者中LundTax分子亚型的不同CHT反应,其中Mes样亚型与较低的反应率和较短的生存期相关。
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引用次数: 0
Erratum: A Targeted Methylation-Based Multicancer Early Detection Blood Test Preferentially Detects High-Grade Prostate Cancer While Minimizing Overdiagnosis of Indolent Disease. 勘误:一种基于目标甲基化的多癌早期检测血液检验能优先检测高级别前列腺癌,同时最大限度地减少对隐匿性疾病的过度诊断。
IF 5.3 2区 医学 Q1 ONCOLOGY Pub Date : 2024-10-01 Epub Date: 2024-10-16 DOI: 10.1200/PO-24-00637
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引用次数: 0
Poly (ADP-ribose) Polymerase Inhibitor Resistance Driven by Emergence of Polyclonal Mutations With Convergent Evolution: A Molecular Tumor Board Discussion. 多聚(ADP-核糖)聚合酶抑制剂耐药性由趋同进化的多克隆突变驱动:分子肿瘤委员会的讨论。
IF 5.3 2区 医学 Q1 ONCOLOGY Pub Date : 2024-10-01 Epub Date: 2024-10-11 DOI: 10.1200/PO.24.00254
Maria Fatteh, Jaime Wehr, Katerina Karaindrou, Rena R Xian, Christopher Gocke, Ming-Tseh Lin, Dana Petry, Kala Visvanathan, Rima Couzi, Cesar Santa Maria, Vered Stearns, Jessica J Tao, Valsamo Anagnostou, Jenna V Canzoniero

Polyclonal convergent evolution to PARPi resistance in a patient with metastatic breast cancer with gPALB2.

一名患有 gPALB2 的转移性乳腺癌患者对 PARPi 耐药性的多克隆趋同进化。
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引用次数: 0
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JCO precision oncology
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