Objectives:Fluorine 18 (18F)-labeled fibroblast activation protein inhibitor-04 (denoted as FAPI-04) positron emission tomography/computed tomography (PET/CT) has showed excellent diagnostic performance for multiple solid tumors. However, its utility in characterizing myocardial injury has not yet been reported. In this study, the additional value of 18F-FAPI-04 PET/CT in assessing myocardial injury was evaluated in patients with cancer. Methods:Myocardial tracer uptake in 168 patients who underwent 18F-FAPI-04 PET/CT was analyzed retrospectively. Maximum and mean standard uptake values in the myocardium (SUVmax-myocardium and SUVmean-myocardium) and blood pool (SUVmax-BP and SUVmean-BP) were recorded. The ratio of SUVmax-myocardium to SUVmean-BP was denoted as the target-to-background ratio (TBR). Myocardial uptake higher than the background was visual uptake (n = 49), and uptake consistent with the background was no visual uptake (n = 119). Patients with abnormal uptake but without cardiovascular disease (CVD) were followed up. Results:Myocardial uptake higher than the background was visual uptake (n = 49), and uptake consistent with the background was no visual uptake (n = 119). The prevalence of hypertension, diabetes mellitus (DM), CVD, and levels of cardiac troponin T and pro-BNP were higher in the visual uptake group (all p<0.05). SUVmax-myocardium and TBR were significantly correlated with age and pro-BNP levels (p<0.05). Hypertension, DM, CVD, pro-BNP>125pg/mL, and prior chest radiotherapy were independent risk factors for abnormal uptake (p<0.05). The area under the curve (AUC) values of myocardial 18F-FAPI-04 uptake to predict myocardial injury were 0.79 and 0.87 for SUVmax-myocardium and TBR, respectively (p<0.001). Conclusion:18F-FAPI-04 PET/CT imaging identified features of myocardial injury in patients with cancer, providing complementary value beyond tumor staging.
As a core modality for local control of thoracic tumors, including lung and esophageal cancers, radiotherapy (RT) shows synergistic effects with immunotherapy, fundamentally reshaping the landscape of cancer treatment. Given the rapid advancements in immunotherapy, this review explores the critical role of precise delineation of radiotherapy targets in achieving synergistic effects between RT and immunotherapy. It elucidates the dual-edged nature of RT, which can both activate antitumor immune responses and suppress immune function. Notably, larger radiation target volumes often cause destruction of tumor-draining lymph nodes and reduce the number of peripheral blood lymphocytes, thereby impairing the efficacy of immunotherapy. To address this challenge, we discuss strategies tailored to thoracic tumors, including reducing target volumes, optimizing irradiation fields, and adjusting target positioning to protect key immune components. Furthermore, we highlight recent advancements in multimodal imaging, real-time dynamic tracking technologies, and deep learning-enabled automated segmentation methods that can increase the precision of target delineation. Additionally, emerging RT techniques, such as proton therapy and FLASH-RT, demonstrate unique advantages in minimizing irradiation of normal tissues and circulating immune cells while enhancing immunomodulatory effects and thereby facilitating precise RT. This review aims to provide a theoretical foundation and technical support for accurate target delineation in the era of immunotherapy, particularly for thoracic malignancies, to promote the deep integration of RT and immunotherapy and improve patient outcomes.
Purpose:The radiation-induced bystander effect (RIBE) refers to biological responses in non-irradiated cells exposed to signals from irradiated cells and may contribute to tumor control during radiotherapy. Periodic dose heterogeneity caused by the thread effect of helical tomotherapy (TOMO) may favor RIBE, but the underlying intercellular mechanisms remain unclear. This study investigated exosome-mediated bystander responses and their molecular and clinical relevance in cervical cancer. Methods:Thread effect and uniform TOMO irradiation plans were established, and their effects on cervical cancer cell viability, DNA damage, apoptosis, and cell-cycle progression were compared. Cell-mixture, conditioned-medium transfer, exosome-depletion, and xenograft models were used to characterize RIBE. Proteomic analysis and exosomal miRNA sequencing identified candidate regulators. Gain- and loss-of-function experiments evaluated the effects of hnRNPA1 on exosomal miRNA levels and bystander tumor suppression. Dual-luciferase and rescue assays validated the miR-27a-3p/HIPK2 relationship. Survival associations were assessed in 218 TOMO-treated patients and an independent TCGA-CESC cohort. Results:The thread plan produced growth-inhibitory effects consistent with a contribution of RIBE. Co‑culture with irradiated tumor cells significantly increased DNA damage and inhibited cell proliferation in non‑irradiated bystander cells. Exosome-depleted conditioned medium largely lost its growth-inhibitory activity, supporting exosomes as major mediators of this bystander response. Irradiation did not markedly alter exosome yield, size, morphology, or cellular uptake but reduced exosomal hnRNPA1 levels. hnRNPA1 overexpression attenuated exosome-mediated growth inhibition. Conversely, hnRNPA1 depletion decreased exosomal miR-27a-3p levels and enhanced tumor suppression. Target prediction and pathway enrichment prioritized miR-27a-3p for functional validation. miR-27a-3p directly targeted the HIPK2 3' untranslated region and promoted cervical cancer cell proliferation, while HIPK2 overexpression counteracted this effect. These findings support an hnRNPA1/miR-27a-3p/HIPK2 regulatory model in which radiation-induced loss of exosomal hnRNPA1 reduces exosomal miR-27a-3p, relieves HIPK2 repression, and enhances tumor-inhibitory bystander responses. High hnRNPA1 expression was associated with shorter OS and PFS in the TOMO-treated cohort and with adverse survival outcomes in the TCGA-CESC cohort. High HIPK2 expression was associated with longer OS and PFS in the TOMO-treated cohort. Conclusion:Tumor cell-derived exosomes are major mediators of cervical cancer RIBE. Radiation-induced reduction of exosomal hnRNPA1 may enhance tumor-inhibitory bystander responses through the miR-27a-3p/HIPK2 axis. This pathway represents a candidate target for modulating RIBE, while the prognostic utility of hnRNPA1 warrants validation in independent radiotherapy cohorts.
Brain metastasis (BM) is a common complication of advanced non-small cell lung cancer (NSCLC). Although immune checkpoint inhibitors (ICIs) have demonstrated efficacy in treating NSCLC-BM, their clinical benefits are often limited. The combination of radiotherapy (RT) and ICIs has emerged as a promising strategy for overcoming these challenges. This review summarizes the current knowledge regarding the immune landscape of NSCLC-BM as well as the clinical evidence supporting and challenging the RT-ICI combination, and it provides an expanded mechanistic framework detailing how RT reshapes the tumor immune microenvironment. RT can enhance the antitumor immune response by disrupting the blood-brain barrier, reprogramming the tumor microenvironment, and improving immune cell infiltration. Clinical studies have supported the synergistic potential of RT and ICIs against NSCLC-BM, showing improved survival and progression-free survival rates. However, challenges such as resistance and toxicity remain, and further investigation is required to refine treatment strategies. We further discuss optimal RT fractionation and sequencing strategies, toxicity mitigation, including practical approaches for managing radiation necrosis, and emerging biomarkers that may guide personalized treatment. A clearer understanding of these biological and clinical interactions is essential to refine treatment algorithms and maximize the therapeutic potential of radioimmunotherapy in NSCLC-BM.
Background and purpose:Deep inspiration breath hold (DIBH) is a respiratory control technique designed to minimize cardiopulmonary toxicity induced by adjuvant radiotherapy for left-sided breast cancer. This study aimed to evaluate the dosimetric effects of DIBH compared with those of free breathing (FB) in patients undergoing postoperative radiotherapy for left-sided breast cancer in order to assess differences in potential cardiopulmonary complications between the two approaches. Methods:Forty patients with left-sided breast cancer undergoing postoperative adjuvant radiotherapy were included. Of these, 20 patients received conventional radiotherapy (5000 cGy in 25 fractions), and the other 20 patients received hypofractionated radiotherapy (4005 cGy in 15 fractions, with a sequential boost to the tumor bed of 1000 cGy in 5 fractions). Treatment plans were performed on both FB and DIBH computed tomography images for each patient. Mean heart dose (MHD), mean left lung dose, and other cardiopulmonary parameters were recorded. The normal tissue complication probability (NTCP) model was applied to predict complications, including pericarditis/pericardial effusion, heart valvular dysfunction (RVD), coronary artery disease (CAD), and Radiation Therapy Oncology Group (RTOG) grade ≥ 2 radiation pneumonitis (RP). Clinical anatomical features, including the number of contact layers between the heart surface and the chest wall (defined as Contact_Heart) and the Haller index (HI), were also documented, followed by correlation analysis. Results:The DIBH technique significantly reduced MHD by 22% in both conventional radiotherapy (P = 0.004, 95% confidence interval [CI][14, 31]) and hypofractionated radiotherapy (P = 0.003, 95% CI[14, 30]). DIBH also reduced the mean left lung dose by 10% in conventional radiotherapy (P = 0.010, 95% CI[2, 15]) and by 7% in hypofractionated radiotherapy (P = 0.008, 95% CI[0, 14]). Using the NTCP model to predict the risk of toxicities, DIBH reduced the predicted occurrence rates of pericarditis/pericardial effusion, RVD, CAD, and RTOG grade ≥ 2 RP by 35-39%, 46-51%, 4-7%, and 4-6%, respectively, across both treatment modalities. Contact_Heart was positively correlated with MHD but only weakly correlated with HI. Conclusion:DIBH significantly reduces radiation exposure to the heart and lungs in patients with left-sided breast cancer undergoing radiotherapy, potentially decreasing the risk of cardiopulmonary toxicity.
Background:Volumetric modulated arc therapy (VMAT) for breast cancer with skin involvement requires a bolus to ensure adequate surface dose. Although both physical and virtual bolus methods are clinically established, their dosimetric robustness against interfraction anatomical variations remains underexplored. This study utilized deep learning-based synthetic CT (sCT) to evaluate the robustness of these two strategies. Methods:Ten patients with skin-involved breast cancer treated with VMAT were retrospectively analyzed. Two plans were generated for each patient: planpb (physical bolus during simulation) and planvb (virtual bolus optimization). To evaluate robustness, pretreatment cone beam CT images from fractions 1, 6, and 11 were converted to sCT using a registration-based generative adversarial network (RegGAN). Dose distributions were recalculated on these sCT to quantify deviations in the conformity index (CI), homogeneity index (HI), and volume percentage of the prescribed dose (Vpd). Results:Initial planning showed no statistically significant differences between the two methods in target coverage or organs at risk sparing. In the robustness analysis performed on sCT, the virtual bolus method (planvb) demonstrated statistically superior robustness for Vpd (P < 0.05), although the absolute magnitude of improvement was small (mean Vpd deviation: -0.8% vs -1.5%). The physical bolus method (planpb) showed better robustness for CI. Conclusions:Using a RegGAN-based evaluation framework, this study demonstrates that although both bolus strategies are dosimetrically comparable, the virtual bolus method provides marginally improved robustness in target dose coverage against daily anatomical variations.
Background:Medical image segmentation methods based on encoder-decoder architectures often achieve high accuracy but typically require substantial computational resources and contain redundant parameters. Purpose:This study aims to develop an efficient decoder-free segmentation framework that maintains competitive performance by strengthening the encoding process. Methods:We propose R3Net, an encoder-only segmentation architecture based on a recursive residual refinement (R3) mechanism. By recursively reusing encoder stages and progressively fusing multiscale features through residual pathways, R3Net reconstructs high-resolution features without requiring a dedicated decoder. Results:Experiments on three medical imaging modalities-cardiac MRI (Automated Cardiac Diagnosis Challenge), abdominal CT (Synapse), and thyroid ultrasound (Thyroid Nodule Multimodal Learning)-demonstrate that R3Net achieves segmentation performance comparable to representative encoder-decoder models while reducing the number of model parameters and computational complexity. Conclusion:R3Net provides an effective decoder-free alternative for medical image segmentation, suggesting that competitive dense prediction can be achieved through recursive refinement within the encoder.
Purpose: In our previous research, we found that the subcompartments formed by the cervical fascia in the supraclavicular region (levels IV, Vb, and lower VI) effectively define the boundaries of the nodal clinical target volume (CTV) for nasopharyngeal carcinoma (NPC). This study aimed to determine whether the same anatomical approach could be applied to the middle neck region (levels III, Va, and upper VI). Materials and Methods: We enrolled 100 patients with NPC who had positive lymph nodes throughout the neck, including the supraclavicular region. Their pretreatment images were systematically reviewed. We analyzed lymph node distribution patterns in relation to both the 2013 International Consensus node-level definitions and the cervical fascia-based subcompartments proposed in our previous study. Based on our findings, we recommend several modifications to the 2018 international CTV consensus guidelines. Results: Our analysis confirmed that the cervical fascial subcompartments effectively define nodal CTV borders. Based on the observed lymph node distribution patterns, we propose several specific optimizations for the middle neck. The lateral border of level Va can be retracted from the skin and platysma to the line connecting the posterior margin of the sternocleidomastoid muscle (SCM) and the anterior margin of the trapezius muscle (TM). Medially, the border can be safely retracted to an anterior-posterior line bisecting the center of the common carotid artery (CCA), as the space medial to this line is consistently devoid of nodes. In addition, the anterior boundary of the CTV may be defined by the lymph nodes located anterior to the carotid sheath; otherwise, the carotid sheath itself serves as the boundary. Conclusions: Cervical fascial anatomy provides valuable insight into the distribution patterns of lymph nodes in the middle neck region in patients with NPC. Based on these anatomical considerations, appropriate modifications to the nodal CTV defined by the 2018 consensus can be implemented for the middle neck region.
Hepatocellular carcinoma (HCC) remains a leading cause of mortality from cancer worldwide. Surgical resection is the main curative strategy for early-stage HCC; however, many advanced cases require multidisciplinary management, including radiotherapy and immunotherapy. Recent advances in radiation delivery have enabled precise tumor targeting while sparing healthy liver tissue, thereby expanding the role of radiotherapy beyond palliation. Moreover, the intricate effect of radiotherapy on the tumor microenvironment (TME) is being increasingly understood. In this review, we systematically examine the bidirectional immunomodulatory effects of radiotherapy on the TME and the biological rationale for combining radiotherapy with immunotherapy in HCC. We also summarize the preclinical and clinical evidence supporting radiotherapy-immunotherapy combinations in HCC and discuss future directions. Continued translational and clinical research is necessary to fully realize the therapeutic potential of this strategy in HCC management.
Objectives:To develop and validate a nomogram integrating radiomic features, white matter hyperintensity (WMH) grading, and clinical factors for predicting overall survival (OS) in patients with non-small cell lung cancer (NSCLC) and brain metastases (BMs) receiving whole-brain radiotherapy (WBRT). Methods:One hundred and forty-nine patients with BMs were enrolled. A radiomic score (Rad-score) was developed based on features identified by univariate Cox regression and least absolute shrinkage and selection operator Cox modeling. WMH was graded using the Fazekas scale, into mild- and extensive-burden groups. Cox proportional hazard models incorporating different combinations of these features were developed and compared. A nomogram was constructed by integrating the Rad-score, WMH grade, and independent clinical variables, and its performance was evaluated using receiver operating characteristic (ROC) analysis, decision curve analysis (DCA), and calibration plots. Results:Twelve radiomic features were identified. Both the Rad-score (hazard ratio (HR) = 1.072; P < 0.001) and WMH grade (HR = 2.420; P < 0.001) independently and significantly predicted OS. Significant improvements in model fit followed the inclusion of these variables (P < 0.01). The integrated nomogram outperformed the single-feature models, yielding area under the curves (AUCs) of 0.820, 0.900, and 0.889 for 1-, 2-, and 3-year OS, respectively, with a concordance index (C-index) of 0.706 (95% CI: 0.598-0.815). Calibration plots and DCA further supported the predictive accuracy and clinical utility. Conclusion:The radiomics- and WMH grading-based nomogram represents a potential prognostic tool for patients with NSCLC and BMs receiving WBRT.
