Biomarkers that predict neurologic death may allow for personalization of therapy for high-risk brain metastases patients. Patients with NSCLC who underwent comprehensive genomic profiling were identified in an institutional database. Neurologic death was determined by medical record review. Proportional hazards regression models considering non-neurologic death as a competing risk were used to identify mutations statistically associated with the occurrence of neurologic death (p < 0.1) and to create a risk scoring system for neurologic death. A competing risk proportional hazards regression model with non-neurologic death as a competing risk was used to assess the association between the risk score and neurologic death, and to calculate hazard ratios predicting neurologic death between risk groups. 307 patients were included in the primary analysis and 213 in a cohort of patients with brain metastases. Risk scores were constructed in both populations. Patients with higher risk scores had an increased risk of neurologic death when compared to those in the low-risk group, with respective HRs of 3.76 for the entire cohort and 2.87 for the brain metastasis cohort per unit increase in the risk score. When dividing the risk score into three groups, the cumulative incidence of neurologic death in high, moderate, and low risk groups was 49.0

BACKGROUND AND PURPOSE:Rib fracture is a recognized clinical complication in medically inoperable patients with non-small cell lung cancer (NSCLC) undergoing stereotactic body radiotherapy (SBRT), leading to diminished quality of life and delayed recovery. There remains an unmet need for reliable tools to predict rib fracture risk to support individualized prognosis. This study aimed to develop and validate a deep learning model for predicting post-SBRT rib fractures using time-series CT radiomics. MATERIAL AND METHODS:This retrospective study collected CT scans from three timepoints in 67 NSCLC patients, comprising over 1600 individual ribs. We proposed a novel Knowledge-aware Temporal Mixture of Experts (KA-TMoE) model that integrates longitudinal CT radiomics with radiomic grouping knowledge to estimate fracture risk at the rib level. Model performance and interpretability were evaluated. RESULTS:The KA-TMoE model demonstrated favorable predictive performance in the validation cohort, achieving an area under the receiver operating characteristic curve (AUC) of 0.792. Exploratory DeLong testing was generally consistent with the observed performance differences between KA-TMoE and the ablation variants, suggesting that both longitudinal information and radiomics-grouping knowledge contributed to model performance. Mann-Whitney U tests demonstrated significant differences in model output distributions across cohorts. Time-to-event analysis showed that the model-predicted high-risk group had a higher risk of fracture than the low-risk group (hazard ratio = 10.82; p < 0.001). Multivariable logistic analysis showed that the KA-TMoE output remained independently associated with fracture risk in the validation cohort (odds ratio = 12.05; p = 0.002). Decision curve analysis demonstrated potential net benefit across clinically relevant thresholds. Features from all three timepoints contributed to the model's decision-making, highlighting the importance of temporal information. CONCLUSION:KA-TMoE showed potential as a preliminary rib-level risk-stratification framework for predicting post-SBRT rib fractures in NSCLC patients. It may support earlier personalized risk stratification, closer surveillance, and timely supportive evaluation.

Abstract Background and purpose: Rib fracture is a recognized clinical complication in medically inoperable patients with non-small cell lung cancer (NSCLC) undergoing stereotactic body radiotherapy (SBRT), leading to diminished quality of life and delayed recovery. This study aimed to develop and validate a deep learning model for predicting post-radiotherapy rib fracture using time-series CT radiomics. Material and methods: This study retrospectively collected CT scans from 67 NSCLC patients, comprising 1,605 individual ribs as separate instances. We proposed a novel Knowledge-aware Temporal Mixture of Experts (KA-TMoE) model that integrates radiomics from sequential CT scans to estimate fracture risk for each rib. Model performance was evaluated using area under the curve (AUC), sensitivity, specificity, and F1 score. Model interpretability was achieved using SHapley Additive exPlanations analysis, which attributed predictive value to each input feature. Results: The KA-TMoE model demonstrated strong predictive performance, achieving favorable AUC in the validation cohort (0.792). The DeLong test confirmed statistically significant improvements over ablation variants, underscoring the importance of integrating temporal data and domain knowledge. High sensitivity (0.85) and specificity (0.78) reflected a well-balanced trade-off, surpassing alternative approaches. Whitney U tests further supported its robustness, which showed significant differences in output distributions across cohorts. Among the top 20 most influential features, half originated from three-month postoperative radiomics, emphasizing the critical role of temporal information. Conclusion: The KA-TMoE model provides a robust, accurate framework for predicting rib fractures after SBRT in NSCLC patients. Its predictive power enables personalized risk assessment, better patient management, and optimized clinical prognosis. Citation Format: Yijun Chen, Michael Farris, Ariel Choi, Nga Thi Thanh Nguyen, Amanda Goetz, Corbin A. Helis, Fei Xing, Liang Liu, Qing Lyu, Christopher T. Whitlow, Christina K. Cramer, Michael D. Chan, Dan Bourland, Michael T. Munley, Jeffrey S Willey, Yuming Jiang. Time-series deep learning radiomics for predicting post-radiotherapy rib fractures in non-small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 3732.

Background/Objectives: No prior studies have attempted to identify a biomarker for initial brain metastasis velocity (iBMV), with limited studies attempting to correlate genomic data with the development of brain metastases. Methods: Patients with non-small-cell lung cancer (NSCLC) who underwent next-generation sequencing (NGS) were identified in our departmental database. iBMV was calculated by dividing the number of BMs by the interval of time between primary cancer and BM diagnosis. Two-sample t-testing was used to identify mutations statistically associated with iBMV (p < 0.1). A value of +1 was assigned to each mutation with a positive association (“deleterious genes”), and a value of −1 to each with an inverse association (“protective genes”). The sum of these values was calculated to define iBMV risk scores of −1, 0 and 1. Pearson correlation test was used to determine the association between iBMV risk score and calculated iBMV, and a competing risk analysis assessed for death as a competing risk to the development of BMs. Results: A total of 312 patients were included in the analysis, 218 of whom (70%) developed brain metastases. “Deleterious genes” included ARID1A, BRAF, CDK4, GNAQ, MLH1, MSH6, PALB2, RAD51D, RB1 and TSC1; “protective genes” included ARAF, IDH1, MYC, and PTPN11. iBMV risk scores of 1, 0 and −1, predicted an 88%, 61% and 65% likelihood of developing a BM (p < 0.01). A competing risk analysis found a significant association between iBMV risk scores of 1 vs. 0 and 1 vs. −1, and the likelihood of developing a BM using death as a competing risk. Overall survival (OS) at 1 and 2 years for patients with iBMV risk scores of 1, 0 and −1 was 72% vs. 84% vs. 85% and 46% vs. 69% vs. 70% (p < 0.02). Conclusions: Development of a genomic signature for iBMV via non-invasive liquid biopsy appears feasible in NSCLC patients. Patients with a positive iBMV risk score were more likely to develop brain metastases. Validation of this signature could lead to a biomarker with the potential to guide treatment recommendations and surveillance schedules.

PURPOSE:The number of early-stage lung cancer survivors (LCS) is increasing, yet few survivorship programs address their specific needs. We developed a workflow to transition early-stage LCS to dedicated lung survivorship care and comprehensively identify and address their needs using electronic patient-reported outcomes (ePROs). METHODS:A lung cancer multidisciplinary team developed a workflow (eg, referrals, survivorship care plan delivery, documentation, orders, tracking, ePROs, and surveillance) for a survivorship clinic staffed by Advanced Practice Providers (APPs). ePROs included the NCCN Distress Thermometer, PROMIS-29, and investigator-developed patient satisfaction items. Patient characteristics, ePROs, and referrals are described; chi-square and t-tests examined ePRO completion by patient characteristics and compared PROMIS-29 domains by treatment modality and to a national sample. RESULTS:From January 2020-March 2023, 315 early-stage LCS completed a survivorship orientation visit. Patient satisfaction was high; 75% completed ePROs. Females were overall less likely to complete ePROs than males; male, age 65+, Black or other race, and rural patients were more likely to complete ePROs in clinic versus online. Patients reported lower symptom burden compared to a general population of early-stage LCS in the United States; scores were similar regardless of treatment modality. Rates of moderate-severe symptoms ranged from 6% (depression) to 42% (poor physical function); ≤ 20% had a referral placed. CONCLUSIONS:A referral-based, APP-staffed survivorship clinic model for early-stage LCS which includes ePROs to identify specific needs is acceptable to patients. Future work should include outreach to female LCS and increasing supportive care referrals and acceptability to further address early-stage LCS reported needs.

Purpose Small cell carcinoma of the lung (SCLC) often presents with brain metastases, with most patients developing them within a few years of diagnosis. Prophylactic cranial irradiation (PCI) is commonly recommended. Extrapulmonary small cell carcinoma (EPSCC) is rare, and its metastatic pattern is not well understood. This study reviews brain metastases in EPSCC patients at a single institution, focusing on management and overall survival (OS). Materials We identified EPSCC patients and analyzed their characteristics, treatment, and outcomes. Brain metastases were assessed through diagnostic imaging. Extracranial progression-free survival (ePFS) was defined as the time from diagnosis to progression outside the brain, while OS was defined as the time from diagnosis to death from any cause. Kaplan-Meier methods and log-rank tests were used for time-to-event analyses, and the cumulative incidence of brain metastasis was estimated with the competing risk of death. Statistical significance was set at p < 0.05. Results Of the 68 EPSCC patients with a median follow-up of 7.1 months, 66% were male with a median age of 68 years old. Common primary sites included genitourinary (32%) and gastrointestinal/hepatobiliary (22%). Brain metastases occurred in 12 patients (18%): five at diagnosis and seven during follow-up. The treatment of brain metastases varied, with four patients receiving whole-brain radiotherapy (WBRT), two receiving stereotactic radiosurgery (SRS), and one receiving both WBRT and SRS. The median OS was 10.0 months, with no significant survival difference between patients with (10.8 months) and without (9.4 months) brain metastases (p = 0.89). Conclusion EPSCC has a lower incidence of brain metastases than SCLC, and brain metastases do not significantly impact OS. Further research on brain imaging, PCI, and management strategies is warranted.

Importance Radiotherapy (RT) plan quality is an established predictive factor associated with cancer recurrence and survival outcomes. The addition of radiologists to the peer review (PR) process may increase RT plan quality. Objective To determine the rate of changes to the RT plan with and without radiology involvement in PR of radiation targets. Data Sources PubMed, Scopus, and Web of Science were queried for peer-reviewed articles published from inception up to March 6, 2024. Search terms included key words associated with PR of contoured targets for the purposes of RT planning with or without radiology involvement. Study Selection Studies reporting PR of contoured radiation targets with or without radiology involvement. Studies were excluded if they lacked full text, reported clinical trial-specific quality assurance, or reported PR without dedicated review of RT targets. Data Extraction and Synthesis Data were extracted according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Titles and abstracts were screened by 2 reviewers. In the case of discordance, discussion was used to reach consensus regarding inclusion for full-text review. RT plan changes were characterized as major when the change was expected to have a substantial clinical impact, as defined by the original study. Pooled outcomes were estimated using random-effects models. Main Outcomes and Measures Primary outcome was pooled rate of RT plan changes. Secondary outcomes included pooled rates of major and minor changes to RT targets or organs at risk. Results Of 4185 screened studies, 31 reporting 39 509 RT plans were included (390 with radiology and 39 119 without). The pooled rate of plan changes was 29.0% (95% CI, 20.7%-37.2%). Radiologist participation in PR was associated with significant increases in plan change rates (49.4% [95% CI, 28.6%-70.1%] vs 25.0% [95% CI, 17.0%-33.1%]; P = .02) and in clinically relevant major changes (47.0% [95% CI, 34.1%-59.8%] vs 10.2% [95% CI, 4.6%-15.8%]; P < .001). There was no difference in minor changes (15.2% [95% CI, 9.7%-20.6%] vs 13.8% [95% CI, 9.3%-18.3%]; P = .74). Subgroup analyses identified increases in the rates of changes to the gross tumor and planning target volumes with radiology-based PR. The highest rates of plan changes were observed in head and neck or lung cancer studies, studies performing PR prior to RT planning, and prospective studies. Conclusions and Relevance In this systematic review and meta-analysis of radiation oncology PR of contoured targets, radiologist involvement in peer review was associated with a significant increase in the rate of total and clinically meaningful changes to the RT targets with no change in minor change rates. These results support the value of interdisciplinary collaboration with radiology during RT planning.

Purpose/objective(s)Biomarkers for extracranial oligometastatic disease remain elusive and few studies have attempted to correlate genomic data to the presence of true oligometastatic disease.MethodsPatients with non-small cell lung cancer (NSCLC) and brain metastases were identified in our departmental database. Electronic medical records were used to identify patients for whom liquid biopsy-based comprehensive genomic profiling (Guardant Health) was available. Extracranial oligometastatic disease was defined as patients having ≤5 non-brain metastases without diffuse involvement of a single organ. Widespread disease was any spread beyond oligometastatic. Fisher’s exact tests were used to screen for mutations statistically associated (p<0.1) with either oligometastatic or widespread extracranial disease. A risk score for the likelihood of oligometastatic disease was generated and correlated to the likelihood of having oligometastatic disease vs widespread disease. For oligometastatic patients, a competing risk analysis was done to assess for cumulative incidence of oligometastatic progression. Cox regression was used to determine association between oligometastatic risk score and oligoprogression.Results130 patients met study criteria and were included in the analysis. 51 patients (39%) had extracranial oligometastatic disease. Genetic mutations included in the Guardant panel that were associated (p<0.1) with the presence of oligometastatic disease included ATM, JAK2, MAP2K2, and NTRK1, while ARID1A and CCNE1 were associated with widespread disease. Patients with a positive, neutral and negative risk score for oligometastatic disease had a 78%, 41% and 11.5% likelihood of having oligometastatic disease, respectively (p<0.0001). Overall survival for patients with positive, neutral and negative risk scores for oligometastatic disease was 86% vs 82% vs 64% at 6 months (p=0.2). Oligometastatic risk score was significantly associated with the likelihood of oligoprogression based on the Wald chi-square test. Patients with positive, neutral and negative risk scores for oligometastatic disease had a cumulative incidence of oligometastatic progression of 77% vs 35% vs 33% at 6 months (p=0.03).ConclusionsElucidation of a genomic signature for extracranial oligometastatic disease derived from non-invasive liquid biopsy appears feasible for NSCLC patients. Patients with this signature exhibited higher rates of early oligoprogression. External validation could lead to a biomarker that has the potential to direct local therapies in oligometastatic patients.

AIMS:During the COVID-19 public health emergency, we previously identified decreased rates of radiotherapy (RT) peer review (PR) discussion and plan changes in virtual versus in-person PR conferences. To expand on these findings, we continued to prospectively collect data on all PR conferences from 2021 to 2023 and performed a follow-up analysis before and after the transition back to in-person PR. MATERIALS AND METHODS:A prospectively maintained database of weekly PR cases was queried for consecutive cases reviewed before and after the transition from virtual to in-person conferences. Rates of PR discussion and change recommendations were summarized and compared between the virtual and in-person groups. A survey was developed and administered to assess participants' perceived levels of engagement, opinions on optimal PR format, and preferences for future meetings before and 3 months after the transition back to in-person PR. RESULTS:In total, 2,103 RT plans were reviewed: 1,590 virtually and 513 after the transition back to in-person. There was no difference in faculty attendance between groups. The proportion of cases with PR discussion increased from virtual (9.8%) to in-person (25.5%) format (p < 0.001). In the virtual group, 8.1% of cases had 1 topic and 1.7% had 2+ topics discussed. This increased to 15.8% and 9.7% during in-person PR, respectively (p < 0.001). The rate of change recommendation also increased from 1.5% (virtual) to 3.3% (in-person, p = 0.016). Among cases with at least 1 topic discussed, there was no difference in changes. Survey-reported distraction significantly decreased from virtual to in-person PR (p < 0.001). CONCLUSION:Upon returning to in-person PR conferences, peer discussion and plan change recommendations significantly increased and returned to pre-pandemic levels, and participants' perceived levels of distraction were reduced. In an increasingly virtual world, additional efforts to develop best practices that maximize PR discussion and minimize distraction outside virtual conferences are warranted.

Purpose/Objective(s) Current interstitial brachytherapy needles utilize radio-opaque markers that are expensive, largely MR incompatible, and/or create significant artifact on CT/MR imaging. Here, we developed a novel 3Dprinted radio-opaque marker composed of metal-infused polylactic acid (PLA) and evaluated its performance on CT and MR. Materials/Methods Novel radio-opaque markers were 3D-printed using PLA filament infused with either copper, bronze, or brass. Physical parameters were designed to match existing brachytherapy needles. Solid and hollow markers were designed, with hollow markers capable of containing viscous contrast media. Markers were inserted into a tissue-equivalent prostate phantom and images were acquired using CT and MR (1.5 and 3.0 T) techniques. Commercially available stainless steel and nitinol markers were imaged with the same modalities. Imaging artifact was quantified using ImageJ and a treatment planning system. CT metal artifact (CTMA) was quantified by computing standard deviation in the volume around each marker. Contrastto-noise ratios (CNR) were evaluated for both imaging modalities, demonstrating better marker visualization compared with commercially available. Artifact differences between each set of markers were compared using F-tests and CNRs were compared using bootstrap tests, with a P-value <0.05 considered significant. Results The average CNR for copper, brass, and bronze PLA markers were 33.6, 33.9, and 34.0, respectively, while the average CNR for the commercially available nitinol and wire markers was 28.1, and 7.7, respectively (P<0.001 for all pairwise comparisons). CTMA for copper, brass, and bronze PLA markers were 29.9 HU, 31.4 HU, and 34.5 HU, respectively, while the average artifact for the nitinol and wire markers was 42.7 and 193.5 HU, respectively (P<0.001). Conclusion When compared with commercially available steel or nitinol, 3D-printed markers have enhanced visibility, reduced imaging artifact, and superior CT- and MR contrast. These novel markers can help improve the accuracy of interstitial brachytherapy implants for treatment planning and facilitate MR only planning.

Stereotactic Body Radiation Therapy for lung tumors near the chest wall often causes significant chest wall pain (CWP), negatively impacting patients' quality of life. The mechanisms behind SBRT-induced CWP remain unclear and may involve multiple factors. We investigated the potential crosstalk between radiation-activated osteoclasts and sensory neurons, focusing on osteoclast-derived factors in CWP. Using the murine pre-osteoclast cell line Raw264.7, we induced differentiation with RANKL, followed by 10Gy gamma-irradiation. Conditioned media from these irradiated osteoclasts was used to treat sensory neuronal cultures from mouse dorsal root ganglia. Neuronal cultures were also directly exposed to 10Gy radiation, with and without osteoclast co-culture. Analysis of osteoclast markers and pain-associated neuropeptides was conducted using RT-qPCR and histochemical staining. Osteoclast differentiation and activity were inhibited using Osteoprotegerin and risedronate. Results showed that high-dose radiation significantly increased osteoclast size, resorption pit size, and activity biomarkers. Neurons treated with CM from irradiated osteoclasts showed increased expression of pain-associated neuropeptides CGRP and Substance P, which was mitigated by osteoprotegerin and risedronate. This study suggests that high-dose radiation enhances osteoclast activity, upregulating pain-associated neuropeptides in sensory neurons, and that inhibitors like osteoprotegerin and risedronate may offer therapeutic strategies for managing radiation-induced pain.

Abstract Metastatic disease is the main cause of cancer death, and the brain is one of the major sites of breast tumor metastasis. The median survival of breast cancer patients who developed brain metastases (BrM) is less than a year even with the advanced treatment such as stereotactic radiosurgery (SRS). Regardless of high clinical significance, the pathological mechanism of brain metastasis is still poorly understood. Previously, we found that loss of lncRNA XIST robustly promote metastasis and specially brain metastasis in breast cancer. However, the underlying molecular mechanism was not fully understood. In following study, we found that loss of XIST has significantly altered lipid metabolism of breast cancer cells specifically increasing lipid droplet amount and PUFA incorporation. Instead of de novo syntheses, XISTlow cancer cells acquire fatty acid by uptake from exogenous. We found that one X-linked gene, Acyl-CoA Synthetase Long Chain Family Member 4 (ACSL4) which are highly upregulated after loss of XIST is responsible for the altered lipid metabolism. ACSL4 activated the free polyunsaturated fatty acids (PUFAs) and lead to increased incorporation of PUFAs into phospholipids. On one hand, elevated ACLS4 expression leads to relative low PPAR pathway activation by decreasing the cellular free PUFA level which directly binds and activate PPAR. PPAR pathway is known to inhibit the expression of inflammatory cytokines which are important for cancer cells to establish brain metastasis. On the other hand, elevated ACSL4 expression enable cancer cells to metabolize the abundant PUFAs in the brain environment, thereby gaining survival advantage. However, increased PUFA incorporation into lipids especially phospholipids produce excess lipid ROS and sensitize cells to ferroptosis inducer such as RSL3. Our study has find out that brain microenvironment not only supports the outgrowth of XIST low cells by providing PUFAs for maintaining their metastatic properties but also sensitizes those cells to ferroptosis inducers, a potential therapy for treating this devastating disease. Citation Format: Yin Liu, Margaret R. Smith, Yuezhu Wang, Ralph D’Agostino, Jimmy Ruiz, Gregory L. Kucera, Lance D. Miller, Wencheng Li, Michael D. Chan, Michael Farris, Dawen Zhao, Fei Xing. Loss of lncRNA XIST promote brain metastasis by reshaping tumor lipid metabolism via upregulation of ACSL4 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1557.

High grade immune-related adverse events (irAEs) in vital organs are likely to cause permanent discontinuation of ICI therapy, greatly affecting the efficacy of ICI as well as patients' health conditions. This study analyzed the correlation between high-grade irAEs and tumor sequencing data from 430 nonsmall cell lung cancer (NSCLC) patients from 2015 to 2022. Our data suggest that specific gene mutations are associated with the occurrence of high-grade irAEs which offers novel insights of post-ICI monitoring. Objectives: Compared to low-grade irAEs, high-grade irAEs are more often dose-limiting and can alter the long-term treatment options for a patient. Predicting the incidence of high-grade irAEs would help with treatment selection and therapeutic drug monitoring. Materials and methods: We performed a retrospective study of 430 stage III and IV patients with non-small cell lung cancer (NSCLC) who received an immune checkpoint inhibitor (ICI), either with or without chemotherapy, at a single comprehensive cancer center from 2015 to 2022. The study team retrieved sequencing data and complete clinical information, including detailed irAEs medical records. Fisher's exact test was used to determine the association between mutations and the presence or absence of high-grade irAEs. Patients were analyzed separately based on tumor subtypes and sequencing platforms. Results: High-grade and low-grade irAEs occurred in 15.2% and 46.2% of patients, respectively. Respiratory and gastrointestinal irAEs were the 2 most common irAEs. The distribution of patients with or without irAEs was similar between ICI and ICI+chemotherapy-treated patients. By analyzing the mutation data, we identified 5 genes (MYC, TEK, FANCA, FAM123B, and MET) with mutations that were correlated with an increased risk of high-grade irAEs. For the adenocarcinoma subtype, mutations in TEK, MYC, FGF19, RET, and MET were associated with high-grade irAEs; while for the squamous subtype, ERBB2 mutations were associated with high-grade irAEs. Conclusion: This study is the first to demonstrate that specific tumor mutations correlate with the incidence of high-grade irAEs in patients with NSCLC treated with an ICI, providing molecular guidance for treatment selection and drug monitoring.

Abstract Radiation therapy (RT)-induced chest wall pain (CWP) is a severe complication after thoracic stereotactic body radiation therapy (SBRT) for lung tumors; with increased survivorship, ~30% of patients develop severe CWP. The causes of CWP are unknown, but could involve: 1] damage to intercostal peripheral nerves; 2] bone loss from affected osteoclast activity, or 3] both (secreted factors from activated osteoclasts can affect nerves). This study tested the potential for radiation to affect osteoclasts and/or sensory neurons to induce pain. Mature osteoclasts differentiated from RAW264.7 cells plated on Osteoassay surfaces were exposed to an acute 10 Gy Cs137 γ-rays and bone resorption was assessed. We collected conditioned media (CM) from these cells at 48h and applied to cultured primary mouse dorsal root ganglia neurons (irradiated and non-irradiated neuron), assessing neurite growth and pain-associated marker (CGRP, SP) expression through immunohistochemistry and RT-qPCR. Risedronate (50µM), an anti-resorptive agent, was administered pre-radiation to inhibit osteoclast activity. Unpaired t-tests were utilized for statistical analyses (α=0.05). Osteoclast resorption activity was increased by 48h after irradiation. These irradiated, activated osteoclasts exhibited increased mRNA expression of differentiation (RANK) and activity (CTSK, MMP9) markers. Neurons treated with CM from irradiated osteoclasts exhibited elevated levels of CGRP (+38.5%) and SP (+29.5%) compared to cells treated with CM from non-irradiated cells. Consistently, in co-cultures of osteoclasts and neurons exposed to radiation, irradiated neurons exhibited significantly increased neuropeptide levels. Risedronate not only reduced osteoclast activity but also inhibited neuropeptide expression in irradiated neurons within these co-cultures. Moreover, neuropeptide levels were similar between directly irradiated neurons and non-irradiated neurons. However, irradiated neurons exposed to CM from either irradiated or non-irradiated osteoclasts showed a marked 4-fold increase in neuropeptide levels vs neurons that were non-irradiated and then received osteoclast CM. Our findings indicate that radiation activates osteoclasts and leads to direct bone loss in vitro and signaling between irradiated osteoclasts and non-irradiated neurons increases pain responses. Importantly, this response is enhanced when neurons were also previously irradiated. During SBRT, intercostal nerves may be influenced by adjacent irradiated osteoclasts, increasing expression of pain-related neuropeptides as the osteoclasts break down bone, thus enhancing the risk of CWP as treatment progresses across time. Understanding these interactions could reveal potential targets for preventing CWP, allowing higher tumor radiation doses with less toxicity. Support: The Milton Raben Foundation. Citation Format: Sun Park, Megan Peters, Joseph Moore, Kaitlyn Reno, Michael Farris, Christopher Peters, Jeffery Willey. Osteoclast and neuronal cross-talk as a mechanism for chest-wall pain caused by thoracic radiosurgery for lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2886.

Treatment of non-small cell lung cancer (NSCLC) has drastically changed in recent years owing to the robust anticancer effects of immune checkpoint inhibitors (ICI). However, only 20% of the patients with NSCLC benefit from ICIs, highlighting the need to uncover the mechanisms mediating resistance. By analyzing the overall survival (OS) and mutational profiles of 424 patients with NSCLC who received ICI treatments between 2015 and 2021, we determined that patients carrying a loss-of-function mutation in neurotrophic tyrosine kinase receptor 1 (NTRK1) had a prolonged OS when compared with patients with wild-type NTRK1. Notably, suppression of the NTRK1 pathway by knockdown or entrectinib treatment significantly enhanced ICI efficacy in mouse NSCLC models. Comprehensive T-cell population analyses demonstrated that stem-like CD4+ T cells and effector CD4+ and CD8+ T cells were highly enriched in anti-PD-1-treated mice bearing tumors with decreased NTRK1 signaling. RNA sequencing revealed that suppression of NTRK1 signaling in tumor cells increased complement C3 expression, which enhanced the recruitment of T cells and myeloid cells and stimulated M1-like macrophage polarization in the tumor. Together, this study demonstrates a role for NTRK1 signaling in regulating cross-talk between tumor cells and immune cells in the tumor microenvironment and provides a potential therapeutic approach to overcome immunotherapy resistance in patients with NSCLC with NTRK1 wild-type. Significance: Inhibition of NTRK1 signaling confers sensitivity to immunotherapy by enhancing complement C3-mediated T-cell and macrophage functions, leading to improved responses to immune checkpoint inhibitors in patients with lung cancer with NTRK1 mutations.

ImportanceRadiotherapy (RT) plan quality is an established predictive factor associated with cancer recurrence and survival outcomes. The addition of radiologists to the peer review (PR) process may increase RT plan quality.ObjectiveTo determine the rate of changes to the RT plan with and without radiology involvement in PR of radiation targets.Data SourcesPubMed, Scopus, and Web of Science were queried for peer-reviewed articles published from inception up to March 6, 2024. Search terms included key words associated with PR of contoured targets for the purposes of RT planning with or without radiology involvement.Study SelectionStudies reporting PR of contoured radiation targets with or without radiology involvement. Studies were excluded if they lacked full text, reported clinical trial–specific quality assurance, or reported PR without dedicated review of RT targets.Data Extraction and SynthesisData were extracted according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Titles and abstracts were screened by 2 reviewers. In the case of discordance, discussion was used to reach consensus regarding inclusion for full-text review. RT plan changes were characterized as major when the change was expected to have a substantial clinical impact, as defined by the original study. Pooled outcomes were estimated using random-effects models.Main Outcomes and MeasuresPrimary outcome was pooled rate of RT plan changes. Secondary outcomes included pooled rates of major and minor changes to RT targets or organs at risk.ResultsOf 4185 screened studies, 31 reporting 39 509 RT plans were included (390 with radiology and 39 119 without). The pooled rate of plan changes was 29.0% (95% CI, 20.7%-37.2%). Radiologist participation in PR was associated with significant increases in plan change rates (49.4% [95% CI, 28.6%-70.1%] vs 25.0% [95% CI, 17.0%-33.1%]; P = .02) and in clinically relevant major changes (47.0% [95% CI, 34.1%-59.8%] vs 10.2% [95% CI, 4.6%-15.8%]; P < .001). There was no difference in minor changes (15.2% [95% CI, 9.7%-20.6%] vs 13.8% [95% CI, 9.3%-18.3%]; P = .74). Subgroup analyses identified increases in the rates of changes to the gross tumor and planning target volumes with radiology-based PR. The highest rates of plan changes were observed in head and neck or lung cancer studies, studies performing PR prior to RT planning, and prospective studies.Conclusions and RelevanceIn this systematic review and meta-analysis of radiation oncology PR of contoured targets, radiologist involvement in peer review was associated with a significant increase in the rate of total and clinically meaningful changes to the RT targets with no change in minor change rates. These results support the value of interdisciplinary collaboration with radiology during RT planning.