International Journal of Radiation Oncology Biology Physics最新文献_第9页

A Mechanistic Model of Brain Necrosis Progression Based on Vascular Heterogeneity 基于血管异质性的脑坏死进展机制模型。

IF 6.5 1区医学 Q1 ONCOLOGY

International Journal of Radiation Oncology Biology Physics

Pub Date : 2026-03-01 Epub Date: 2025-10-11 DOI: 10.1016/j.ijrobp.2025.09.059

Nicolò Cogno PhD , Keyur D. Shah PhD , Felix Ehret MD , Chris Beekman PhD , Heiko Enderling PhD , Robert J. Dawson MSc , Wesley E. Bolch PhD , Helen A. Shih MD , Harald Paganetti PhD , Ibrahim Chamseddine PhD

Purpose

Brain radionecrosis (RN) is a significant late toxicity of radiation therapy, yet its progression remains challenging to predict because of patient-specific factors. This study develops a mechanistic model to simulate RN expansion focusing on vascular heterogeneity.

Methods and Materials

A 3-dimensional cellular automaton (CA) model was developed to simulate RN progression, based on the assumption that vascular heterogeneity drives its spatial dynamics. Patient-specific vasculature maps were generated by registering a synthetic brain phantom to magnetic resonance imaging-derived segmentations. Microvessel length density (L_d) was estimated to account for regional vascular heterogeneity. The model parameters—RN progression rate (

k

) and necrotic neighborhood threshold (

ρ_{t}

)—were inferred using sequential Monte Carlo approximate Bayesian computation. Probability risk maps were validated against follow-up (FU) imaging from 3 independent cases, with voxelwise agreement assessed using receiver operating characteristic analysis.

Results

The model successfully predicted RN expansion patterns, achieving area under the curve values of 0.87 to 0.95 in validation cases. Simulated necrotic regions exhibited anisotropic expansion influenced by local vascular density, supporting the vascular hypothesis. Patient-specific posterior distributions for progression rate reflected wide interpatient variability, whereas the necrotic neighboring effect had a narrower range. The model consistently identified high-risk voxels, with predicted necrotic regions overlapping observed RN in FU imaging.

Conclusions

This study presents a mechanistic model that integrates vascular heterogeneity to predict RN progression, providing interpretable, patient-specific risk maps. It extends RN evolution modeling beyond dose-based metrics, potentially aiding in refining treatment planning and adaptive FU strategies to minimize radiation-induced toxicity.

目的：脑放射性坏死（RN）是一种重要的放射治疗晚期毒性，但由于患者特异性因素，其进展仍然具有挑战性。本研究建立了一个以血管异质性为重点的机制模型来模拟RN扩张。材料和方法：基于血管异质性驱动其空间动力学的假设，开发了三维元胞自动机（CA）模型来模拟RN的进展。通过将合成脑幻像与mri衍生的分割相匹配，生成患者特异性脉管系统图。微血管长度密度（Ld）估计可以解释区域血管的异质性。模型参数- rn进展率(k)和坏死邻域阈值(ρt)-使用顺序蒙特卡罗近似贝叶斯计算推断。根据三个独立病例的随访（FU）成像验证概率风险图，并使用接收者操作特征分析评估体素一致性。结果：该模型成功预测了RN的扩张模式，验证病例的曲线下面积为0.87 ~ 0.95。模拟坏死区域表现出受局部血管密度影响的各向异性扩张，支持血管假说。进展率的患者特异性后验分布反映了广泛的患者间变异性，而坏死邻近效应的范围较窄。该模型一致地识别出高危体素，预测的坏死区域与FU成像中观察到的RN重叠。结论：本研究提出了一个机制模型，整合血管异质性来预测RN进展，提供可解释的患者特异性风险图。它将RN演化模型扩展到基于剂量的指标之外，可能有助于改进治疗计划和适应性FU策略，以最大限度地减少辐射引起的毒性。

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引用次数: 0

Dose Mapping Using Image Registration for Reirradiation: A Systematic Review 使用图像配准进行再照射剂量定位：系统综述。

IF 6.5 1区医学 Q1 ONCOLOGY

International Journal of Radiation Oncology Biology Physics

Pub Date : 2026-03-01 Epub Date: 2025-10-11 DOI: 10.1016/j.ijrobp.2025.09.053

Chelmis Muthoni Thiong’o MPhil , Angela Davey PhD , Ane Appelt PhD , Madalyne Day BRT , Pauline Dupuis MSc , Serena Monti PhD , Jaime Perez-Alija MSc , Theodora Skopidou MSc , Stina Svensson PhD , Eliana Vasquez Osorio PhD

As reirradiation becomes increasingly common due to longer patient survival, accurately mapping previous radiation dose is essential to balance toxicity and tumour control. Image registration (IR) is widely used to align previous dose distributions with current anatomy. However, significant anatomic changes between treatment courses pose unique challenges, and it remains unclear how existing IR practices—largely developed for other contexts—translate to reirradiation. This systematic review aims to report on what is currently being done in the field regarding the use of IR for dose mapping in reirradiation scenarios, identify methodological gaps, and propose recommendations to improve reproducibility and clinical utility. We performed a Preferred Reporting Items for Systematic Reviews and Meta-Analysis-compliant search for full-length articles (PubMed and Scopus) and conference abstracts (ScienceDirect and American Association of Physicists in Medicine, AAPM) that explicitly referenced IR for dose mapping in reirradiation. Each article was reviewed by ≥2 independent reviewers, with key data extracted on IR approaches and evaluation strategies. As of mid-May 2025, 34 articles and 30 abstracts were selected. Most studies lacked comprehensive evaluation: about one-third reported geometric accuracy metrics, and few included dosimetric assessments or uncertainty estimation. Multimodal reirradiation, nonexternal beam techniques, and pediatric populations were notably underrepresented. Based on the synthesis of current literature and expert consensus, we propose 3 clinical and 10 research recommendations to support reproducible research and clinical practices. Clear and consistent reporting of registration methods, geometrical, and dosimetrical assessments are essential to improve the reliability of dose mapping and to support safer, evidence-based use of IR in the reirradiation setting.

背景：由于患者生存时间的延长，再照射变得越来越普遍，准确地绘制先前的辐射剂量对于平衡毒性和肿瘤控制至关重要。图像配准（IR）广泛用于将先前的剂量分布与当前解剖结构对齐。然而，治疗过程之间的重大解剖变化带来了独特的挑战，目前尚不清楚现有的IR实践（主要是为其他情况开发的）如何转化为再照射。本系统综述旨在报告目前在再照射情景中使用红外进行剂量测绘方面所做的工作，确定方法学上的差距，并提出建议以提高可重复性和临床实用性。方法：我们对明确引用IR进行再照射剂量测绘的全文（PubMed和Scopus）和会议摘要（ScienceDirect和AAPM）进行了符合prisma标准的检索。每篇文章至少由两名独立的审稿人审阅，并提取有关IR方法和评估策略的关键数据。结果：截至2025年5月中旬，共入选论文34篇，摘要30篇。大多数研究缺乏综合评价：大约三分之一的研究报告几何精度指标，很少包括剂量学评估或不确定度估计。多模态再照射、非外部光束技术和儿科人群的代表性明显不足。结论：在综合现有文献和专家共识的基础上，我们提出3项临床建议和10项研究建议，以支持可重复性研究和临床实践。明确和一致地报告配准方法、几何和剂量学评估对于提高剂量测绘的可靠性和支持在再照射环境中更安全、基于证据的图像配准使用至关重要。

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引用次数: 0

In Reply to Hannoun-Levi et al 在对hannounce - levi等人的答复中

IF 6.5 1区医学 Q1 ONCOLOGY

International Journal of Radiation Oncology Biology Physics

Pub Date : 2026-03-01 Epub Date: 2026-02-03 DOI: 10.1016/j.ijrobp.2025.11.020

Jehee Isabelle Choi MD, Danielle Rodin MD, Rima Patel MD, Joseph Sparano MD, Atif Khan MD, Naamit Gerber MD

引用次数: 0

In Reply to May et al 回复May等人

IF 6.5 1区医学 Q1 ONCOLOGY

International Journal of Radiation Oncology Biology Physics

Pub Date : 2026-03-01 Epub Date: 2026-02-03 DOI: 10.1016/j.ijrobp.2025.11.021

Kanta Ka MD, MPH, Abel Cordoba MD, Renaud Schiappa M.Sc, Nicolas Martz MD, Sophie Espenel MD, Alexandre Escande MD, PhD, Nicolas Demogeot MD, PhD, Jean Michel Hannoun-Levi MD, PhD, Cyrus Chargari MD, PhD

引用次数: 0

In Regard to Huang et al 关于黄等人

IF 6.5 1区医学 Q1 ONCOLOGY

International Journal of Radiation Oncology Biology Physics

Pub Date : 2026-03-01 Epub Date: 2026-02-03 DOI: 10.1016/j.ijrobp.2025.11.056

Michael Oertel MD, Fabian M. Troschel MD, Hans Theodor Eich MD, PhD

引用次数: 0

Timescale of FLASH Sparing Effect Determined by Varying Temporal Split of Dose Delivery in Mice 不同时间给药间隔对小鼠FLASH节约效应的影响。

IF 6.5 1区医学 Q1 ONCOLOGY

International Journal of Radiation Oncology Biology Physics

Pub Date : 2026-03-01 Epub Date: 2025-10-02 DOI: 10.1016/j.ijrobp.2025.09.052

Jacob P. Sunnerberg PhD , David I. Hunter MS , Austin M. Sloop MS , Armin D. Tavakkoli AB , Petr Bruza PhD , Rongxiao Zhang PhD , Jiang Gui PhD , Lesley A. Jarvis MD, PhD , Harold M. Swartz MD, PhD , David J. Gladstone ScD , P. Jack Hoopes DVM, PhD , Brian W. Pogue PhD

Purpose

To determine the timescale for ultra high dose rate (UHDR) radiation delivery that dictates FLASH normal tissue sparing and elucidate its relationship to in vivo oxygen dynamics. A split-dose experiment was used to determine the transition time below which the observation of the FLASH sparing effect is preserved.

Methods and Materials

A 25 Gy dose was split into 2 deliveries (12.5 Gy), with varied interruption times. Albino B6 mice received flank skin irradiation in 8 groups: single-beam UHDR (25 Gy at 415 Gy/s), single-beam conventional dose rate (CDR) (25 Gy at 0.15 Gy/s), or split-beam delivery with 2 lower-dose UHDR beams (12.5 Gy at 415 Gy/s) separated by 0.1, 1, 5, 15, 25, or 120 seconds. Skin damage was scored daily for 31 days, with mixed-effects analysis comparing damage progression across cohorts. Real-time tissue pO₂ was monitored using the phosphorescence-lifetime probe, Oxyphor PdG4. Radiolytic oxygen consumption per unit dose (g_O2) and reoxygenation rates were quantified.

Results

Single-beam UHDR significantly spared skin versus CDR. In split-dose groups, this sparing effect showed a transition at longer interbeam intervals. Damage progression remained significantly lower than CDR and comparable to single-beam UHDR (P > 0.16) for interruptions <15 seconds. Longer intervals progressively lost tissue sparing. Oximetry indicated an average tissue reoxygenation lifetime of 7.7 ± 1.1 seconds. At the delivery of the second beam, pO₂ remained lower when interbeam times were shorter than the reoxygenation period, but recovered fully for longer interruptions. The g_O2 values correlated with baseline tissue pO₂.

Conclusions

Observation of the FLASH sparing effect requires delivery within a critical temporal window that is similar to the timescale of tissue reoxygenation kinetics. The transition time for loss of the FLASH sparing effect in skin roughly corresponds to a diffusion timescale for oxygen, from capillaries to the cells. Although not conclusively demonstrating a mechanism, this unique finding supports the likelihood that local oxygen depletion or consumption underlies the FLASH tissue sparing effect observed in vivo, with important implications for clinical implementation and the timescale needed for multibeam FLASH radiation therapy.

目的：确定决定FLASH正常组织保留的超高剂量率（UHDR）辐射递送的时间尺度，并阐明其与体内氧动力学的关系。采用分剂量实验确定过渡时间，在过渡时间以下，可以保留观察到的FLASH保留效应。方法和材料：25 Gy剂量分两次给药（12.5 Gy），间断时间不同。白化病B6小鼠分别接受8组侧腹皮肤照射：单束UHDR （25 Gy, 415 Gy/s）、单束常规剂量率（25 Gy, 0.15 Gy/s）或两束低剂量UHDR (12.5 Gy, 415 Gy/s)，间隔0.1、1、5、15、25或120秒。在31天内每天对皮肤损伤进行评分，并用混合效应分析比较各组间的损伤进展。使用磷光寿命探针Oxyphor PdG4实时监测组织pO2。定量测定单位剂量放射解氧耗氧量（gO2）和再氧化速率。结果：与CDR相比，单束UHDR可显著保护皮肤。在分剂量组中，这种节约效应在较长的光束间隔中发生转变。损伤进展明显低于CDR，与单束UHDR （p>0.16）相比，中断时间< 15秒。较长的间隔逐渐失去组织保留。血氧测定结果显示，平均组织再氧化寿命为7.7±1.1 s。在第二束传输时，当束间时间短于再氧化时间时，pO2保持在较低水平，但当间隔时间较长时，pO2完全恢复。gO2值与基线组织pO2相关。结论：观察FLASH保留效果需要在临界时间窗内递送，该时间窗与组织再氧化动力学相似。皮肤中FLASH保留效应消失的过渡时间大致对应于氧气从毛细血管到细胞的扩散时间尺度。虽然没有最终证明机制，但这一独特的发现支持了局部氧气消耗或消耗是体内观察到的FLASH组织保留效应的可能性，这对临床实施和多束FLASH- rt所需的时间范围具有重要意义。

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引用次数: 0

Proton Therapy May Reduce the Risk of Cancer Progression During Immune Checkpoint Inhibitor Therapy: A Propensity Score-Matched Analysis of Intensity Modulated Proton Versus Photon Radiation Therapy 质子治疗可以降低免疫检查点抑制剂治疗期间癌症进展的风险：强度调制质子与光子放疗的倾向评分匹配分析。

IF 6.5 1区医学 Q1 ONCOLOGY

International Journal of Radiation Oncology Biology Physics

Pub Date : 2026-03-01 Epub Date: 2025-10-01 DOI: 10.1016/j.ijrobp.2025.09.042

Cong Bo MD , Zhenhuan Lv MPharm , Hong Zhang MMed , Xianmin Hou MMed , Yinxin Wang MBBS , Jing Liu MD , Xue Meng MD

Purpose

Intensity modulated proton therapy (IMPT) may preserve the immune response more effectively than intensity modulated photon radiation therapy (IMRT) owing to its dosimetric advantages, making it a potentially superior modality in immunotherapy. This study aimed to evaluate the clinical benefits of IMPT versus IMRT during immune checkpoint inhibitors (ICIs) treatment.

Methods and Materials

We retrospectively analyzed the data of 466 patients (IMPT group, n = 109; IMRT group, n = 357) who received radiation therapy (RT) during ICI therapy between July 2022 and September 2024. Propensity score matching was applied to balance clinical characteristics. The primary endpoint was the duration of response (DoR). Secondary endpoints included progression-free survival (PFS) and post-RT adverse events. Kaplan-Meier and Cox proportional hazards regression were used to calculate survival curves and identify independent prognostic factors. The threshold used to dichotomize post-RT lymphocyte count was 0.5 × 10⁹/L.

Results

Baseline clinical characteristics were balanced after propensity score matching. The IMPT group showed significantly longer median DoR (17.7 vs 5.7 months; P = .0001) and PFS (18.8 vs 6.8 months; P < .0001) than the IMRT group. Multivariable regression revealed IMPT to be an independent predictor of improved DoR (hazard ratio, 0.34; 95% CI, 0.21-0.55; P < .0001) and PFS (hazard ratio, 0.36; 95% CI, 0.25-0.52; P < .0001). Subgroup analyses suggested greater benefit of IMPT over IMRT in patients with a Charlson Comorbidity Index ≥4, lung cancer, advanced-stage disease, or those receiving palliative, thoracic, or abdominal/pelvic RT. Higher post-RT lymphocyte counts in the IMPT group showed potential correlation with improved DoR and PFS. Additionally, the IMPT group had fewer grade ≥2 post-RT adverse events (P = .012).

Conclusions

IMPT is linked to enhanced efficacy of ICIs, compared with IMRT, by improving DoR and PFS with tolerable adverse effects. Higher post-RT lymphocyte counts may be associated with improved survival in patients receiving IMPT during ICI therapy. These findings suggest that IMPT may be a preferable option for preserving immune function, thereby optimizing outcomes during immunotherapy.

目的：调强质子放射治疗（IMPT）由于其剂量学上的优势，可能比调强光子放射治疗（IMRT）更有效地保持免疫应答，使其成为一种潜在的优越的免疫治疗方式。本研究旨在评估免疫检查点抑制剂（ICIs）治疗期间IMPT与IMRT的临床益处。方法与材料：回顾性分析2022年7月至2024年9月期间在ICI治疗期间接受放疗（RT）的466例患者（IMPT组，n=109； IMRT组，n=357）的资料。倾向评分匹配（PSM）用于平衡临床特征。主要终点是反应持续时间（DoR）。次要终点包括无进展生存期（PFS）和放疗后不良事件。Kaplan-Meier和Cox比例风险回归用于计算生存曲线和确定独立预后因素。rt后淋巴细胞计数二分类阈值为0.5 × 109/L。结果：PSM后基线临床特征平衡。IMPT组显着延长了中位DoR（17.7个月vs 5.7个月，p=0.0001）和PFS（18.8个月vs 6.8个月）。结论：与IMRT相比，IMPT通过改善DoR和PFS以及可容忍的不良反应来增强ICIs的疗效。在ICI治疗期间接受IMPT的患者，较高的rt后淋巴细胞计数可能与生存率提高有关。这些发现表明IMPT可能是保存免疫功能的更好选择，从而优化免疫治疗期间的结果。

{"title":"Proton Therapy May Reduce the Risk of Cancer Progression During Immune Checkpoint Inhibitor Therapy: A Propensity Score-Matched Analysis of Intensity Modulated Proton Versus Photon Radiation Therapy","authors":"Cong Bo MD , Zhenhuan Lv MPharm , Hong Zhang MMed , Xianmin Hou MMed , Yinxin Wang MBBS , Jing Liu MD , Xue Meng MD","doi":"10.1016/j.ijrobp.2025.09.042","DOIUrl":"10.1016/j.ijrobp.2025.09.042","url":null,"abstract":"<div><h3>Purpose</h3><div>Intensity modulated proton therapy (IMPT) may preserve the immune response more effectively than intensity modulated photon radiation therapy (IMRT) owing to its dosimetric advantages, making it a potentially superior modality in immunotherapy. This study aimed to evaluate the clinical benefits of IMPT versus IMRT during immune checkpoint inhibitors (ICIs) treatment.</div></div><div><h3>Methods and Materials</h3><div>We retrospectively analyzed the data of 466 patients (IMPT group, n = 109; IMRT group, n = 357) who received radiation therapy (RT) during ICI therapy between July 2022 and September 2024. Propensity score matching was applied to balance clinical characteristics. The primary endpoint was the duration of response (DoR). Secondary endpoints included progression-free survival (PFS) and post-RT adverse events. Kaplan-Meier and Cox proportional hazards regression were used to calculate survival curves and identify independent prognostic factors. The threshold used to dichotomize post-RT lymphocyte count was 0.5 × 10<sup>9</sup>/L.</div></div><div><h3>Results</h3><div>Baseline clinical characteristics were balanced after propensity score matching. The IMPT group showed significantly longer median DoR (17.7 vs 5.7 months; <em>P</em> = .0001) and PFS (18.8 vs 6.8 months; <em>P</em> < .0001) than the IMRT group. Multivariable regression revealed IMPT to be an independent predictor of improved DoR (hazard ratio, 0.34; 95% CI, 0.21-0.55; <em>P</em> < .0001) and PFS (hazard ratio, 0.36; 95% CI, 0.25-0.52; <em>P</em> < .0001). Subgroup analyses suggested greater benefit of IMPT over IMRT in patients with a Charlson Comorbidity Index ≥4, lung cancer, advanced-stage disease, or those receiving palliative, thoracic, or abdominal/pelvic RT. Higher post-RT lymphocyte counts in the IMPT group showed potential correlation with improved DoR and PFS. Additionally, the IMPT group had fewer grade ≥2 post-RT adverse events (<em>P</em> = .012).</div></div><div><h3>Conclusions</h3><div>IMPT is linked to enhanced efficacy of ICIs, compared with IMRT, by improving DoR and PFS with tolerable adverse effects. Higher post-RT lymphocyte counts may be associated with improved survival in patients receiving IMPT during ICI therapy. These findings suggest that IMPT may be a preferable option for preserving immune function, thereby optimizing outcomes during immunotherapy.</div></div>","PeriodicalId":14215,"journal":{"name":"International Journal of Radiation Oncology Biology Physics","volume":"124 3","pages":"Pages 733-744"},"PeriodicalIF":6.5,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145225461","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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

Evolutionary Double-Bind Treatment Using Radiation Therapy and Natural Killer Cell-Based Immunotherapy in Prostate Cancer 放疗和NK细胞免疫治疗前列腺癌的进化双结合治疗。

IF 6.5 1区医学 Q1 ONCOLOGY

International Journal of Radiation Oncology Biology Physics

Pub Date : 2026-03-01 Epub Date: 2025-09-23 DOI: 10.1016/j.ijrobp.2025.09.034

Kimberly A. Luddy PhD , Jeffrey West PhD , Mark Robertson-Tessi PhD , Bina Desai PhD , Andrew Ojeda MS , Hannah Newman , Veronica Estrella MS , Taylor M. Bursell , Sarah Barrett PhD , Jacintha O’Sullivan PhD , Laure Marignol PhD , Robert A. Gatenby MD , Joel S. Brown PhD , Alexander R.A. Anderson PhD , Cliona O’Farrelly PhD

<div><h3>Purpose</h3><div>Evolution-informed therapies exploit evolutionary consequences of drug resistance to inhibit treatment resistance and prolong time to progression. One strategy, termed an evolutionary double-bind, uses an initial therapy to elicit a specific adaptive response by cancer cells, which is then selectively targeted by a follow-on therapy. Although the concept of an evolutionary double-bind has long been hypothesized in cancer, it has not been measured. Here, to our knowledge, we present the first example of a quantifiable double-bind: radiation therapy (RT) with natural killer (NK) cells. RT induces lethal double-strand DNA breaks, but cancer cells adapt. Although this increases resistance to DNA-damaging agents, it also enhances expression of NK cell ligands creating an obvious choice for a double-bind strategy.</div></div><div><h3>Methods and Materials</h3><div>We investigated this potential evolutionary double-bind through in vitro studies and evolution-based mathematical models. Using multiple prostate cancer cell lines, we evaluated surface and soluble NK ligand expression following RT. In vitro competition experiments were performed with an isogenic radiation-resistant cell line model. We introduced a two-population Lotka-Volterra competition model, consisting of radiation-sensitive and radiation-resistant populations modeling intrinsic growth rates with fixed carrying capacity and inter-specific competition terms.</div></div><div><h3>Results</h3><div>Alterations in NK cell ligands resulted in a twofold increase in sensitivity to NK cell-mediated killing with selective targeting of RT-resistant cells. These dynamics were framed mathematically to quantify the double bind. RT alone slowed overall growth but strongly selected for RT-resistant cells. NK cell therapy alone suppressed the RT-resistant population, but with a surviving population of radiation-sensitive cells. Model simulation predicted that optimal tumor control would be achieved through initial RT followed by NK cells. Subsequent experiments confirmed the model prediction.</div></div><div><h3>Conclusions</h3><div>We conclude that RT and NK cell-based immunotherapy produce an evolutionary double-bind. This multidimensional approach addresses the immediate challenge of treatment resistance and lays the groundwork for the development of personalized treatment regimens tailored to the evolving dynamics of individual tumors.</div></div><div><h3>Significance</h3><div>Clinical experience demonstrates that prostate cancer has a remarkable capacity to evolve resistance to all currently available treatments resulting in progression and, ultimately, patient death. Resistance mechanisms often come at a fitness cost placing cells in a bind when competing with surrounding cells. A carefully chosen secondary drug can introduce a double-bind targeting the adaptive resistance mechanism. This manuscript provides the first direct experimental evidence quantifying an “evolutionar

目的：进化知情疗法利用耐药性的进化后果来抑制治疗耐药性并延长进展时间。一种被称为进化双重约束的策略，使用初始治疗引起癌细胞的特定适应性反应，然后通过后续治疗选择性地靶向癌细胞。虽然进化的双重束缚概念长期以来一直被假设存在于癌症中，但它尚未被测量。在这里，我们提出了一个可量化的双重结合的第一个例子：放射治疗（RT）与NK细胞。RT诱导致命的双链DNA断裂，但癌细胞适应了。虽然这增加了对DNA损伤剂的抵抗力，但它也增强了NK细胞配体的表达，为双重结合策略创造了一个明显的选择。方法和材料：我们通过体外研究和基于进化的数学模型来研究这种潜在的进化双重束缚。使用多种前列腺癌细胞系，我们评估了rt后表面和可溶性NK配体的表达。在体外竞争实验中，我们用等基因抗辐射细胞系模型进行了竞争。我们引入了一个由辐射敏感种群和辐射抗性种群组成的两种群Lotka-Volterra竞争模型，该模型模拟了具有固定承载能力和种间竞争条件的内在增长率。结果：NK细胞配体的改变导致NK细胞介导杀伤的敏感性增加2倍，选择性靶向rt抗性细胞。这些动态是用数学的方式来量化双重约束的。单独放疗减缓了整体生长，但强烈选择了抗rt细胞。NK细胞治疗单独抑制抗rt细胞群，但与存活的辐射敏感细胞群。模型模拟预测，通过初始RT然后NK细胞可以达到最佳的肿瘤控制。随后的实验证实了模型的预测。结论：放疗和NK细胞免疫治疗产生了进化上的双重束缚。这种多维方法解决了治疗耐药性的直接挑战，并为开发针对个体肿瘤不断变化的动态量身定制的个性化治疗方案奠定了基础。意义：临床经验表明，前列腺癌具有对所有现有治疗方法产生耐药性的显著能力，从而导致病情进展，并最终导致患者死亡。抵抗机制通常以适应性为代价，使细胞在与周围细胞竞争时处于束缚状态。精心选择的次级药物可以引入针对适应性耐药机制的双重结合。这篇论文提供了第一个直接的实验证据，量化了前列腺癌的“进化双重束缚”，支持DNA损伤剂和基于NK细胞的免疫疗法在进化指导治疗设计中的结合。我们的工作在数学上是新颖的，因为它扩展了进化博弈论模型，并建立了一个实验数学框架，以量化适用于癌症类型和治疗方式的真正进化双结合。

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引用次数: 0

After Burnout: Reigniting the Flame 倦怠之后：重燃火焰

IF 6.5 1区医学 Q1 ONCOLOGY

International Journal of Radiation Oncology Biology Physics

Pub Date : 2026-03-01 Epub Date: 2026-02-03 DOI: 10.1016/j.ijrobp.2025.10.042

Daniel W. Golden MD, MHPE

引用次数: 0

Analysis of the Radiosensitivity Index in Paired Preneoadjuvant and Postneoadjuvant Therapy Triple-Negative Breast Cancer 配对新辅助治疗前后三阴性乳腺癌放射敏感性指数（RSI）分析。

IF 6.5 1区医学 Q1 ONCOLOGY

International Journal of Radiation Oncology Biology Physics

Pub Date : 2026-03-01 Epub Date: 2025-09-25 DOI: 10.1016/j.ijrobp.2025.09.038

Shane R. Stecklein MD, PhD , Roberto Salgado MD, PhD , Julia R. White MD , Bruce F. Kimler PhD , Rachel Yoder MS , Joshua M. Staley MS , Anne P. O’Dea MD , Lauren E. Nye MD , Deepti Satelli MD , Gregory J. Crane MD , Rashna Madan MD , Maura F. O’Neil MD , Andrew K. Godwin PhD , Harsh Pathak PhD , Qamar J. Khan MD , Joyce O’Shaughnessy MD , Priyanka Sharma MD

Purpose

The radiosensitivity index (RSI) is a validated gene expression-based biomarker that can predict intrinsic radiosensitivity and has been shown to be associated with local control in patients with triple-negative breast cancer (TNBC) treated with upfront surgery. Currently, most patients with TNBC receive neoadjuvant systemic therapy (NAST). Whether the RSI predicts response to NAST and how the RSI and predicted radiosensitivity are altered by exposure to NAST is unknown.

Methods and Materials

Total RNA was extracted from pretreatment core needle biopsy specimens from 197 patients with TNBC treated on the NeoSTOP (NCT02413320) and NeoPACT (NCT03639948) trials. Total RNA was also extracted from paired post-NAST (residual disease) tumor tissue in 58 patients. A published algorithm using 10 genes was used to compute the RSI for each tumor. Stromal tumor-infiltrating lymphocytes (sTILs) were scored on pretreatment and post-NAST samples by an expert breast pathologist according to international consensus guidelines. CIBERSORTx was used to impute leukocyte fractions in samples using RNA-sequencing data.

Results

Cluster analysis of RSI genes in pretreatment samples revealed immune-depleted and immune-enriched groups, and this classification was strongly associated with sTIL infiltration (P < .0001) and likelihood of achieving pathologic complete response (pCR) (P = .001). RSI showed associations (false discovery rate q < 0.01) with M0 and M1 macrophages, CD4+ memory resting, CD4+ memory activated, CD8+, and follicular helper T-cells, activated natural killer cells, naïve and memory B cells, and resting dendritic cells on CIBERSORTx leukocyte deconvolution. In the entire cohort, NAST-induced change in RSI was variable, but among initially RSI-immune-enriched tumors that did not achieve pCR, there was a significant decrease in predicted radiosensitivity between paired pretreatment and post-NAST samples. NAST-induced reduction in sTILs and naïve B cells may be associated with this decrease in radiosensitivity.

Conclusions

Pretreatment RSI cluster identity is associated with the degree of immune enrichment and response to NAST in TNBC. Initially immune-enriched TNBCs that do not achieve a pCR to NAST exhibit a decrease in predicted radiosensitivity compared with paired pretreatment tumors.

目的：放射敏感性指数（RSI）是一种经过验证的基于基因表达的生物标志物，可以预测内在的放射敏感性，并已被证明与接受前期手术治疗的三阴性乳腺癌（TNBC）患者的局部控制相关。目前，大多数TNBC患者接受新辅助全身治疗（NAST）。RSI是否能预测对NAST的反应，以及RSI和预测的放射敏感性如何因暴露于NAST而改变尚不清楚。方法：从***(***)和***(***)试验中治疗的197例TNBC患者的治疗前针芯活检标本中提取总RNA。我们还从58例患者的配对后残留瘤组织中提取了总RNA。使用已发表的使用10个基因的算法来计算每个肿瘤的RSI。由一位乳腺病理学专家根据国际共识指南对治疗前和治疗后的样品进行基质肿瘤浸润淋巴细胞（sTILs）评分。CIBERSORTx使用RNA测序数据对样品中的白细胞组分进行估算。结果：预处理样本RSI基因聚类分析显示免疫缺失（RSI- id）和免疫富集（RSI- ie）组，这种分类与sTIL浸润密切相关(p)结论：预处理RSI聚类身份与TNBC中免疫富集程度和对NAST的反应有关。与配对的治疗前肿瘤相比，最初免疫富集的tnbc未达到对NAST的病理完全反应，其预测的放射敏感性降低。

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引用次数: 0