Cystine and theanine for chemoradiotherapy-induced esophagitis in non-small cell lung cancer: a prospective observational study.

PURPOSE: Although several potential radioprotectants have been explored, radiation esophagitis is still difficult to control. Further development of supportive therapies is required. Our purpose was to investigate the efficacy and safety of cystine and theanine for esophagitis in non-small cell lung cancer (NSCLC) patients undergoing chemoradiotherapy (CRT). METHODS: This study is a prospective observational study. The participants were recruited from unresectable locally advanced NSCLC who had scheduled to receive weekly paclitaxel or nab-paclitaxel/carboplatin plus radiation therapy (60 Gy in 30 fractions) for 6 weeks. They took an oral amino acid supplement containing 700 mg cystine and 280 mg theanine once daily regardless of CRT timing from the start of CRT until completion. The primary endpoint was the incidence of any grade esophagitis. The secondary endpoints were quality of life (QoL) and adverse events (AEs). RESULTS: A total of 26 patients were evaluated. All participants completed 60 Gy of RT in 30 fractions. The overall incidence of esophagitis was 73%; however, no ≥ grade 3 was reported. There were no AEs likely to be related to cystine and theanine. The mean EuroQoL 5-Dimension 5-Level health index score before and after chemoradiotherapy was 0.952 ± 0.0591 and 0.952 ± 0.0515 (P = 0.89), and the mean Visual Analogue Scale scores before and after treatment were 67.9 ± 15.4 and 79.4 ± 13.2 (P = 0.0047), respectively. CONCLUSION: Our study showed no severe esophagitis, any AEs, nor QoL decrease in NSCLC patients receiving CRT. Cystine and theanine are potentially effective to reduce severe CRT-induced esophagitis. TRIAL REGISTRATION: UMIN000052622, 26 October 2023, retrospectively registered.

Predicting treatment response in multicenter non-small cell lung cancer patients based on federated learning.

BACKGROUND: Multicenter non-small cell lung cancer (NSCLC) patient data is information-rich. However, its direct integration becomes exceptionally challenging due to constraints involving different healthcare organizations and regulations. Traditional centralized machine learning methods require centralizing these sensitive medical data for training, posing risks of patient privacy leakage and data security issues. In this context, federated learning (FL) has attracted much attention as a distributed machine learning framework. It effectively addresses this contradiction by preserving data locally, conducting local model training, and aggregating model parameters. This approach enables the utilization of multicenter data with maximum benefit while ensuring privacy safeguards. Based on pre-radiotherapy planning target volume images of NSCLC patients, a multicenter treatment response prediction model is designed by FL for predicting the probability of remission of NSCLC patients. This approach ensures medical data privacy, high prediction accuracy and computing efficiency, offering valuable insights for clinical decision-making. METHODS: We retrospectively collected CT images from 245 NSCLC patients undergoing chemotherapy and radiotherapy (CRT) in four Chinese hospitals. In a simulation environment, we compared the performance of the centralized deep learning (DL) model with that of the FL model using data from two sites. Additionally, due to the unavailability of data from one hospital, we established a real-world FL model using data from three sites. Assessments were conducted using measures such as accuracy, receiver operating characteristic curve, and confusion matrices. RESULTS: The model's prediction performance obtained using FL methods outperforms that of traditional centralized learning methods. In the comparative experiment, the DL model achieves an AUC of 0.718/0.695, while the FL model demonstrates an AUC of 0.725/0.689, with real-world FL model achieving an AUC of 0.698/0.672. CONCLUSIONS: We demonstrate that the performance of a FL predictive model, developed by combining convolutional neural networks (CNNs) with data from multiple medical centers, is comparable to that of a traditional DL model obtained through centralized training. It can efficiently predict CRT treatment response in NSCLC patients while preserving privacy.

[An investigation of the advantages of the adjustable angle stitch template compared with CT-guided 125I seeds free-hand implantation in the treatment of non-small cell lung carcinoma].

Objective: To investigate the advantages of adjustable angle needle path template compared with CT-guided 125I seeds free-hand implantation in the treatment of non-small cell lung carcinoma. Methods: This randomized controlled trial involved the retrospective analysis of the clinical data of 45 patients with non-small cell lung carcinoma who underwent 125I seeds implantation at the Shandong Cancer Hospital, Shaanxi Provincial Tumor Hospital and The Third Affiliated Hospital of Shandong First Medical University from May 2018 to January 2023. Patients were divided into the template (n=21) and free-hand (n=24) groups, according to the modality used. The template group comprised 16 males and 5 females, aged (66±12) years, while the free-hand group comprised 16 males and 8 females, aged (62±8) years. The dose distribution, implant quality, intraoperative computed tomography (CT) scan times, and 125I seed reseeding numbers after implantation were compared between the two groups to evaluate the potential advantages of adjustable angle needle path template-assisted implantation over free-hand 125I implantation. Results: Statistical comparison revealed no significant differences in age (t=1.16, P=0.253), tumor volume [(71±26) vs. (71±22) cm3, t=0.21, P=0.837), or any other baseline characteristics between the template and free-hand groups. Overall, 45 patients successfully completed the operation. In the template group, the mean values of the D90 (dose that was delivered to 90% of the target volume), V100 (the target volume receiving 100% of the prescription dose), coverage index (CI), relative dose homogeneity index (HI), and external volume index (EI) pre-and post-implantation were (131.0±2.1) vs. (131.1±5.5) Gy, 90.0%±0.4% vs. 91.0%±2.8%, 0.83±0.07 vs. 0.82±0.05, 41%±11% vs. 37%± 13%, and 4.3%(2.9%, 14.0%) vs.8.8%(5.2%,14.6%), respectively. None of these parameters showed any significant difference (all P>0.05). In the free-hand group, the mean value of D90 pre- and post-implantation was (131.4±2.9) vs.(128.6±8.6) Gy, showing no significant difference (P>0.05), the mean values of V100, CI, HI, and EI pre-and post-implantation were 90.0%±0.5% vs. 89.0%± 3.0%, 0.84±0.04 vs. 0.71±0.09, 41%±9% vs. 34%±10%, and 7.7% (4.9%,11.0%) vs.24.2% (14.3%, 35.3%), respectively, showing significant differences (all P<0.05). The number of reseeding seeds in the template group was lower than that in the free-hand group [2.0 (0,2.5) vs. 4.0 (2.0, 7.0), Z=-3.36, P=0.001], showing a statistically significant difference. Further, the number of CT scans in the template group was significantly less than that in the free-hand group (3.9±0.5 vs. 4.6±1.2, t=-2.54, P=0.016). The incidences of adverse reactions were 23.8% (5/21) and 33.3% (8/24) (χ2=12.86, P=0.002) in the template and free-hand groups, respectively, indicating a significant difference. Conclusion: Compared with free-hand implantation, use of the adjustable angle needle path template technique can shorten the operation time, reduce the number of scans, reduce the incidence of complications, and improve treatment efficacy to a certain extent.

Survival Predictive Nomograms for Non-Surgical Brain Metastases Patients From Non-Small Cell Lung Cancer Receiving Radiotherapy: A Population-Based Study.

OBJECTIVE: A high number of Non-Small Cell Lung Cancer (NSCLC) patients with brain metastasis who have not had surgery often have a negative outlook. Radiotherapy remains a most common and effective method. Nomograms were developed to forecast the cancer-specific survival (CSS) and overall survival (OS) in NSCLC individuals with nonoperative brain metastases who underwent radiotherapy. METHODS: Information was gathered from the Surveillance, Epidemiology, and End Results (SEER) database about patients diagnosed with NSCLC who had brain metastases not suitable for surgery. Nomograms were created and tested using multivariate Cox regression models to forecast CSS and OS at intervals of 1, 2, and 3 years. RESULTS: The research involved 3413 individuals diagnosed with NSCLC brain metastases who had undergone radiotherapy but had not experienced surgery. These participants were randomly divided into two categories. The analysis revealed that gender, age, ethnicity, marital status, tumor location, tumor laterality, tumor grade, histology, T stage, N stage, chemotherapy, tumor size, lung metastasis, bone metastasis, and liver metastasis were significant independent predictors for OS and CSS. The C-index for the training set for predicting OS was .709 (95% CI, .697-.721), and for the validation set, it was .705 (95% CI, .686-.723), respectively. The C-index for predicting CSS was .710 (95% CI, .697-.722) in the training set and .703 (95% CI, .684-.722) in the validation set, respectively. The nomograms model, as suggested by the impressive C-index, exhibits outstanding differentiation ability. Moreover, the ROC and calibration curves reveal its commendable precision and distinguishing potential. CONCLUSIONS: For the first time, highly accurate and reliable nomograms were developed to predict OS and CSS in NSCLC patients with non-surgical brain metastases, who have undergone radiotherapy treatment. The nomograms may assist in tailoring counseling strategies and choosing the most effective treatment method.

Preoperative CT-based radiomic prognostic index to predict the benefit of postoperative radiotherapy in patients with non-small cell lung cancer: a multicenter study.

BACKGROUND: The value of postoperative radiotherapy (PORT) for patients with non-small cell lung cancer (NSCLC) remains controversial. A subset of patients may benefit from PORT. We aimed to identify patients with NSCLC who could benefit from PORT. METHODS: Patients from cohorts 1 and 2 with pathological Tany N2 M0 NSCLC were included, as well as patients with non-metastatic NSCLC from cohorts 3 to 6. The radiomic prognostic index (RPI) was developed using radiomic texture features extracted from the primary lung nodule in preoperative chest CT scans in cohort 1 and validated in other cohorts. We employed a least absolute shrinkage and selection operator-Cox regularisation model for data dimension reduction, feature selection, and the construction of the RPI. We created a lymph-radiomic prognostic index (LRPI) by combining RPI and positive lymph node number (PLN). We compared the outcomes of patients who received PORT against those who did not in the subgroups determined by the LRPI. RESULTS: In total, 228, 1003, 144, 422, 19, and 21 patients were eligible in cohorts 1-6. RPI predicted overall survival (OS) in all six cohorts: cohort 1 (HR = 2.31, 95% CI: 1.18-4.52), cohort 2 (HR = 1.64, 95% CI: 1.26-2.14), cohort 3 (HR = 2.53, 95% CI: 1.45-4.3), cohort 4 (HR = 1.24, 95% CI: 1.01-1.52), cohort 5 (HR = 2.56, 95% CI: 0.73-9.02), cohort 6 (HR = 2.30, 95% CI: 0.53-10.03). LRPI predicted OS (C-index: 0.68, 95% CI: 0.60-0.75) better than the pT stage (C-index: 0.57, 95% CI: 0.50-0.63), pT + PLN (C-index: 0.58, 95% CI: 0.46-0.70), and RPI (C-index: 0.65, 95% CI: 0.54-0.75). The LRPI was used to categorize individuals into three risk groups; patients in the moderate-risk group benefited from PORT (HR = 0.60, 95% CI: 0.40-0.91; p = 0.02), while patients in the low-risk and high-risk groups did not. CONCLUSIONS: We developed preoperative CT-based radiomic and lymph-radiomic prognostic indexes capable of predicting OS and the benefits of PORT for patients with NSCLC.

The incidence of and risk factors for radiation pneumonitis in patients treated with simultaneous bevacizumab and thoracic radiotherapy.

BACKGROUND: First-line chemotherapy combined with bevacizumab is one of the standard treatment modes for patients with advanced non-small cell lung cancer (NSCLC). Thoracic radiotherapy (TRT) can provide significant local control and survival benefits to patients during the treatment of advanced NSCLC. However, the safety of adding TRT has always been controversial, especially because of the occurrence of radiation pneumonia (RP) during bevacizumab treatment. Therefore, in this study, we used an expanded sample size to evaluate the incidence of RP when using bevacizumab in combination with TRT. PATIENTS AND METHODS: Using an institutional query system, all medical records of patients with NSCLC who received TRT during first-line chemotherapy combined with bevacizumab from 2017 to 2020 at Shandong Cancer Hospital and Institute were reviewed. RP was diagnosed via computed tomography and was classified according to the RTOG toxicity scoring system. The risk factors for RP were identified using univariate and multivariate analyses. The Kaplan-Meier method was used to calculate progression-free survival (PFS) and overall survival (OS). RESULTS: Ultimately, 119 patients were included. Thirty-eight (31.9%) patients developed Grade ≥ 2 RP, of whom 27 (68.1%) had Grade 2 RP and 11 (9.2%) had Grade 3 RP. No patients developed Grade 4 or 5 RP. The median time for RP occurrence was 2.7 months (range 1.2-5.4 months). In univariate analysis, male, age, KPS score, V20 > 16.9%, V5 > 33.6%, PTV (planning target volume)-dose > 57.2 Gy, and PTV-volume > 183.85 cm3 were correlated with the occurrence of RP. In multivariate analysis, male, V20 > 16.9%, and PTV-volume > 183.85 cm3 were identified as independent predictors of RP occurrence. The mPFS of all patients was 14.27 (95% CI, 13.1-16.1) months. The one-year and two-year PFS rates were 64.9% and 20.1%, respectively. The mOS of all patients was 37.09 (95% CI, 33.8-42.0) months. The one-year survival rate of all patients was 95%, and the two-year survival rate was 71.4%. CONCLUSIONS: The incidence of Grade ≥ 2 RP in NSCLC patients who received both bevacizumab and TRT was 31.9%. Restricting factors such as V20 and PTV will help reduce the risk of RP in these patients. For patients who receive both bevacizumab and TRT, caution should be exercised when increasing TRT, and treatment strategies should be optimized to reduce the incidence of RP.

BIBR1532 combined with radiotherapy induces ferroptosis in NSCLC cells and activates cGAS-STING pathway to promote anti-tumor immunity.

BACKGROUND: Telomerase, by safeguarding damaged telomeres and bolstering DNA damage repair, has the capacity to heighten the radioresistance of tumour cells. Thus, in turn, can compromise the efficacy of radiotherapy (RT) and radioimmunotherapy. Our previous studies have revealed that the highly selective telomerase inhibitor, BIBR1532, possesses the potential to enhance the radiosensitivity of Non-small cell lung cancer (NSCLC). In this study, we delve further into the impact of BIBR1532 on the immune activation induced by RT and elucidate the underlying mechanisms. METHODS: Biological information analyses, immunofluorescence assays, western blot assays, flow cytometry analysis were conducted to elucidate the functions of the combination of BIBR1532 with radiotherapy in NSCLC. Intracellular levels of lipid peroxides, glutathione, malondialdehyde, and Fe2+ were measured as indicators of ferroptosis status. Both in vitro and in vivo studies were conducted to examine the antitumor effects. RESULTS: Our findings indicate that the confluence of BIBR1532 with RT significantly augments the activation of the cGAS-STING pathway in both in vivo and in vitro settings, thereby fostering an effective anti-tumoral immune response. The effects can be ascribed to two key processes. Firstly, ionizing radiation, in precipitating DNA double-strand breaks (DSBs), prompts the release of tumour-derived double-stranded DNA (dsDNA) into the cytoplasm. Subsequently, BIBR1532 amplifies the activation of antigen-presenting cells by dsDNA post-RT and instigates the cGAS-STING pathway. Secondly, BIBR1532 enhances the ferroptosis response in NSCLC following RT, thereby promoting unrestrained lipid peroxidation and elevated levels of reactive oxygen species (ROS) within tumour cells. This ultimately leads to mitochondrial stress and the release of endogenous mitochondrial DNA (mtDNA) into the cytoplasm, thus facilitating the activation of the STING pathway and the induction of a type I interferon (IFN)-linked adaptive immune response. CONCLUSION: This study underscores the potential of BIBR1532 as an efficacious and safe radiosensitizer and radioimmunotherapy synergist, providing robust preclinical research evidence for the treatment of NSCLC.

Prognostic value of neutrophil-to-lymphocyte ratio change in patients with locally advanced non-small cell lung cancer treated with thoracic radiotherapy.

In prior investigations, a correlation was established between patient outcomes in locally advanced non-small cell lung cancer (LA-NSCLC) following thoracic irradiation and parameters, such as pre/post-treatment neutrophil-to-lymphocyte ratio (NLR) and NLR change (ΔNLR). However, these parameters could potentially be influenced by radiation-related variables, such as gross tumor volume (GTV). The primary aim of this study was to elucidate the factors impacting post-treatment NLR and ΔNLR and to further assess their prognostic relevance. In this retrospective study, a cohort of 188 LA-NSCLC patients who underwent thoracic radiation between 2012 and 2017 was assessed. The calculation of pre/post-treatment NLR involved the use of absolute neutrophil and lymphocyte counts. ΔNLR was defined as the difference between post- and pre-treatment NLR values. To assess the relationships between various variables and overall survival (OS), local progression-free survival (LPFS), and distant metastasis-free survival (DMFS), the Kaplan-Meier technique and Cox proportional hazards regression were employed. Additionally, Spearman's rank correlation analysis was carried out to investigate correlations between the variables. The analysis revealed that both post-treatment NLR (r = 0.315, P < 0.001) and ΔNLR (r = 0.156, P = 0.032) were associated with GTV. However, OS, LPFS, and DMFS were not independently correlated with pre/post-treatment NLR. ΔNLR, on the other hand, exhibited independent associations with OS and DMFS (HR = 1.054, P = 0.020, and P = 0.046, respectively). Elevated ΔNLR values were linked to poorer OS (P = 0.023) and DMFS (P = 0.018) in the Kaplan-Meier analysis. Furthermore, when stratifying by GTV, a higher ΔNLR remained to be associated with worse OS and DMFS (P = 0.047 and P = 0.035, respectively) in the GTV ≤ 67.41 cm3 group, and in the GTV > 67.41 cm3 group (P = 0.028 and P = 0.042, respectively), highlighting ΔNLR as the sole independent predictive factor for survival and metastasis, irrespective of GTV.

Targeting the Hippo pathway to prevent radioresistance brain metastases from the lung (Review).

The prognosis for patients with non­small cell lung cancer (NSCLC), a cancer type which represents 85% of all lung cancers, is poor with a 5­year survival rate of 19%, mainly because NSCLC is diagnosed at an advanced and metastatic stage. Despite recent therapeutic advancements, ~50% of patients with NSCLC will develop brain metastases (BMs). Either surgical BM treatment alone for symptomatic patients and patients with single cerebral metastases, or in combination with stereotactic radiotherapy (RT) for patients who are not suitable for surgery or presenting with fewer than four cerebral lesions with a diameter range of 5­30 mm, or whole­brain RT for numerous or large BMs can be administered. However, radioresistance (RR) invariably prevents the action of RT. Several mechanisms of RR have been described including hypoxia, cellular stress, presence of cancer stem cells, dysregulation of apoptosis and/or autophagy, dysregulation of the cell cycle, changes in cellular metabolism, epithelial­to­mesenchymal transition, overexpression of programmed cell death­ligand 1 and activation several signaling pathways; however, the role of the Hippo signaling pathway in RR is unclear. Dysregulation of the Hippo pathway in NSCLC confers metastatic properties, and inhibitors targeting this pathway are currently in development. It is therefore essential to evaluate the effect of inhibiting the Hippo pathway, particularly the effector yes­associated protein­1, on cerebral metastases originating from lung cancer.

Exosome miR-101-3p derived from bone marrow mesenchymal stem cells promotes radiotherapy sensitivity in non-small cell lung cancer by regulating DNA damage repair and autophagy levels through EZH2.

BACKGROUND AND OBJECTIVE: The morbidity rate of non-small cell lung cancer (NSCLC) increases with age, highlighting that NSCLC is a serious threat to human health. The aim of this study was mainly to describe the role of exosomal miR-101-3p derived from bone marrow mesenchymal stem cells (BMSCs) in NSCLC. METHODS: A549 or NCI-H1703 cells (1×105/mouse) were injected into nude mice to establish an NSCLC animal model. RTqPCR, Western blotting and comet assays were used to assess the changes in gene expression, proteins and DNA damage repair. RESULTS: miR-101-3p and RAI2 were found to be expressed at low levels in NSCLC, while EZH2 was highly expressed. In terms of function, miR-101-3p downregulated EZH2. In addition, exosomal miR-101-3p derived from BMSCs promoted the expression of RAI2, inhibited DNA damage repair, and inhibited the activation of the PI3K/AKT/mTOR signaling pathway by inhibiting EZH2, thereby promoting autophagy and decreasing cell viability and finally enhancing the sensitivity of NSCLC to radiotherapy and inhibiting the malignant biological behavior of NSCLC. CONCLUSION: Exosomal miR-101-3p derived from BMSCs can inhibit DNA damage repair, promote autophagy, enhance the radiosensitivity of NSCLC, and inhibit the progression of NSCLC by inhibiting EZH2.

Survival analysis after stereotactic ablative radiotherapy for early stage non-small cell lung cancer: a single-institution cohort study.

BACKGROUND: Stereotactic ablative radiotherapy (SABR) is the standard treatment for medically inoperable early-stage non-small cell lung cancer (ES-NSCLC), but which patients benefit from stereotactic radiotherapy is unclear. The aim of this study was to analyze prognostic factors for early mortality. METHODS: From August 2010 to 2022, 617 patients with medically inoperable, peripheral or central ES-NSCLC were treated with SABR at our institution. We retrospectively evaluated the data from 172 consecutive patients treated from 2018 to 2020 to analyze the prognostic factors associated with overall survival (OS). The biological effective dose was > 100 Gy10 in all patients, and 60 Gy was applied in 3-5 fractions for a gross tumor volume (GTV) + 3 mm margin when the tumor diameter was < 1 cm; 30-33 Gy was delivered in one fraction. Real-time tumor tracking or an internal target volume approach was applied in 96% and 4% of cases, respectively. In uni- and multivariate analysis, a Cox model was used for the following variables: ventilation parameter FEV1, histology, age, T stage, central vs. peripheral site, gender, pretreatment PET, biologically effective dose (BED), and age-adjusted Charlson comorbidity index (AACCI). RESULTS: The median OS was 35.3 months. In univariate analysis, no correlation was found between OS and ventilation parameters, histology, PET, or centrality. Tumor diameter, biological effective dose, gender, and AACCI met the criteria for inclusion in the multivariate analysis. The multivariate model showed that males (HR 1.51, 95% CI 1.01-2.28; p = 0.05) and AACCI > 5 (HR 1.56, 95% CI 1.06-2.31; p = 0.026) were significant negative prognostic factors of OS. However, the analysis of OS showed that the significant effect of AACCI > 5 was achieved only after 3 years (3-year OS 37% vs. 56%, p = 0.021), whereas the OS in one year was similar (1-year OS 83% vs. 86%, p = 0.58). CONCLUSION: SABR of ES-NSCLC with precise image guidance is feasible for all medically inoperable patients with reasonable performance status. Early deaths were rare in our real-life cohort, and OS is clearly higher than would have been expected after best supportive care.

Identification of CT radiomic features robust to acquisition and segmentation variations for improved prediction of radiotherapy-treated lung cancer patient recurrence.

The primary objective of the present study was to identify a subset of radiomic features extracted from primary tumor imaged by computed tomography of early-stage non-small cell lung cancer patients, which remain unaffected by variations in segmentation quality and in computed tomography image acquisition protocol. The robustness of these features to segmentation variations was assessed by analyzing the correlation of feature values extracted from lesion volumes delineated by two annotators. The robustness to variations in acquisition protocol was evaluated by examining the correlation of features extracted from high-dose and low-dose computed tomography scans, both of which were acquired for each patient as part of the stereotactic body radiotherapy planning process. Among 106 radiomic features considered, 21 were identified as robust. An analysis including univariate and multivariate assessments was subsequently conducted to estimate the predictive performance of these robust features on the outcome of early-stage non-small cell lung cancer patients treated with stereotactic body radiation therapy. The univariate predictive analysis revealed that robust features demonstrated superior predictive potential compared to non-robust features. The multivariate analysis indicated that linear regression models built with robust features displayed greater generalization capabilities by outperforming other models in predicting the outcomes of an external validation dataset.

Novel Blood Biomarkers for Response Prediction and Monitoring of Stereotactic Ablative Radiotherapy and Immunotherapy in Metastatic Oligoprogressive Lung Cancer.

Up to 80% of patients under immune checkpoint inhibitors (ICI) face resistance. In this context, stereotactic ablative radiotherapy (SABR) can induce an immune or abscopal response. However, its molecular determinants remain unknown. We present early results of a translational study assessing biomarkers of response to combined ICI and SABR (I-SABR) in liquid biopsy from oligoprogressive patients in a prospective observational multicenter study. Cohort A includes metastatic patients in oligoprogression to ICI maintaining the same ICI due to clinical benefit and who receive concomitant SABR. B is a comparative group of oligometastatic patients receiving only SABR. Blood samples are extracted at baseline (T1), after the first (T2) and last (T3) fraction, two months post-SABR (T4) and at further progression (TP). Response is evaluated by iRECIST and defined by the objective response rate (ORR)-complete and partial responses. We assess peripheral blood mononuclear cells (PBMCs), circulating cell-free DNA (cfDNA) and small RNA from extracellular vesicles. Twenty-seven patients could be analyzed (cohort A: n = 19; B: n = 8). Most were males with non-small cell lung cancer and one progressing lesion. With a median follow-up of 6 months, the last ORR was 63% (26% complete and 37% partial response). A decrease in cfDNA from T2 to T3 correlated with a good response. At T2, CD8+PD1+ and CD8+PDL1+ cells were increased in non-responders and responders, respectively. At T2, 27 microRNAs were differentially expressed. These are potential biomarkers of response to I-SABR in oligoprogressive disease.

Prognostic utility of blood inflammation biomarkers before and after treatment on the survival of patients with locally advanced non-small cell lung cancer undergoing stereotactic body radiotherapy.

BACKGROUND AND OBJECTIVE: The neutrophil-lymphocyte ratio (NLR) and platelet-lymphocyte ratio (PLR) were significant and succinct indicators of systemic inflammation. We assessed the influence of stereotactic body radiotherapy (SBRT) on NLR and PLR in patients with locally advanced non-small cell lung cancer (LA-NSCLC). METHODS: We reviewed the medical data of patients with LA-NSCLC who underwent SBRT between 1 January 2013 and 31 December 2018. NLR and PLR values recorded at pre- and post-SBRT were examined. We assessed the correlation between pre/post-SBRT NLR and PLR and survival outcomes. The decision tree evaluation was conducted using Chi-square automatic detection. RESULTS: In total, 213 patients were included in the study with a median follow-up duration of 40.00 (ranging from 5.28 to 100.70) months. Upon dichotomization by a median, we identified that post-SBRT NLR > 5.5 and post-SBRT PLR > 382.0 were negatively associated with shorter overall survival (OS). In the multivariate assessment, post-SBRT PLR > 382.0 was the only factor. Based on post-SBRT PLR, tumor locations, and tumor stage, we categorized patients into low, medium, or high-risk groups. CONCLUSIONS: Post-SBRT PLR > 382.0 correlated with survival in patients undergoing SBRT. The decision tree model might play a role in future risk stratification to guide the clinical practice of individualized SBRT for LA-NSCLC.

Artificial Intelligence-suggested Predictive Model of Survival in Patients Treated With Stereotactic Radiotherapy for Early Lung Cancer.

BACKGROUND/AIM: Overall survival (OS)-predictive models to clinically stratify patients with stage I Non-Small Cell Lung Cancer (NSCLC) undergoing stereotactic body radiation therapy (SBRT) are still unavailable. The aim of this work was to build a predictive model of OS in this setting. PATIENTS AND METHODS: Clinical variables of patients treated in three Institutions with SBRT for stage I NSCLC were retrospectively collected into a reference cohort A (107 patients) and 2 comparative cohorts B1 (32 patients) and B2 (38 patients). A predictive model was built using Cox regression (CR) and artificial neural networks (ANN) on reference cohort A and then tested on comparative cohorts. RESULTS: Cohort B1 patients were older and with worse chronic obstructive pulmonary disease (COPD) than cohort A. Cohort B2 patients were heavier smokers but had lower Charlson Comorbidity Index (CCI). At CR analysis for cohort A, only ECOG Performance Status 0-1 and absence of previous neoplasms correlated with better OS. The model was enhanced combining ANN and CR findings. The reference cohort was divided into prognostic Group 1 (0-2 score) and Group 2 (3-9 score) to assess model's predictions on OS: grouping was close to statistical significance (p=0.081). One and 2-year OS resulted higher for Group 1, lower for Group 2. In comparative cohorts, the model successfully predicted two groups of patients with divergent OS trends: higher for Group 1 and lower for Group 2. CONCLUSION: The produced model is a relevant tool to clinically stratify SBRT candidates into prognostic groups, even when applied to different cohorts. ANN are a valuable resource, providing useful data to build a prognostic model that deserves to be validated prospectively.

Service Improvements and Workload Increases: Royal College of Radiologists (RCR) Re-Audit of Curative Intent Radiotherapy for Non-Small Cell Lung Cancer (NSCLC).

AIMS: The Royal College of Radiologists (RCR) audit of radical radiotherapy (RR) for patients with non-small cell lung cancer (NSCLC) in 2013 concluded that there was under-treatment compared to international comparators and marked variability between cancer networks. Elderly patients were less likely to receive guideline recommended treatments. Access to technological developments was low. Various national and local interventions have since taken place. This study aims to re-assess national practice. MATERIALS AND METHODS: Radiotherapy departments completed one questionnaire for each patient started on RR for 4 weeks in January 2023. RESULTS: Ninety-three percent of centres returned data on 295 patients. RR has increased 70% since 2013 but patients on average wait 20% longer to start treatment (p = 0.02). Staging investigations were often outside a desirable timeframe (79% of PET/CT scans). Advanced planning techniques are used more frequently: 4-dimensional planning increased from 33% to 90% (P < 0.001), cone beam imaging from 67% to 97% (p < 0.001) and colleague led peer review increased from 41% to 73% (P < 0.001). CONCLUSION: There have been significant improvements in care. There has been a considerable increase in clinical oncology workload with evidence of stress on the system that requires additional resourcing.

Modeling of the resensitization effect on carbon-ion radiotherapy for stage I non-small cell lung cancer.

Objective. To investigate the effect of redistribution and reoxygenation on the 3-year tumor control probability (TCP) of patients with stage I non-small cell lung cancer (NSCLC) treated with carbon-ion radiotherapy.Approach. A meta-analysis of published clinical data of 233 NSCLC patients treated by carbon-ion radiotherapy under 18-, 9-, 4-, and single-fraction schedules was conducted. The linear-quadratic (LQ)-based cell-survival model incorporating the radiobiological 5Rs, radiosensitivity, repopulation, repair, redistribution, and reoxygenation, was developed to reproduce the clinical TCP data. Redistribution and reoxygenation were regarded together as a single phenomenon and termed 'resensitization' in the model. The optimum interval time between fractions was investigated for each fraction schedule using the determined model parameters.Main results.The clinical TCP data for 18-, 9-, and 4-fraction schedules were reasonably reproduced by the model without the resensitization effect, whereas its incorporation was essential to reproduce the TCP data for all fraction schedules including the single fraction. The curative dose for the single-fraction schedule was estimated to be 49.0 Gy (RBE), which corresponds to the clinically adopted dose prescription of 50.0 Gy (RBE). For 18-, 9-, and 4-fraction schedules, a 2-to-3-day interval is required to maximize the resensitization effect during the time interval. In contrast, the single-fraction schedule cannot benefit from the resensitization effect, and the shorter treatment time is preferable to reduce the effect of sub-lethal damage repair during the treatment.Significance.The LQ-based cell-survival model incorporating the radiobiological 5Rs was developed and used to evaluate the effect of the resensitization on clinical results of NSCLC patients treated with hypo-fractionated carbon-ion radiotherapy. The incorporation of the resensitization into the cell-survival model improves the reproducibility to the clinical TCP data. A shorter treatment time is preferable in the single-fraction schedule, while a 2-to-3-day interval between fractions is preferable in the multi-fraction schedules for effective treatments.

NF-κB in the Radiation Response of A549 Non-Small Cell Lung Cancer Cells to X-rays and Carbon Ions under Hypoxia.

Cellular hypoxia, detectable in up to 80% of non-small cell lung carcinoma (NSCLC) tumors, is a known cause of radioresistance. High linear energy transfer (LET) particle radiation might be effective in the treatment of hypoxic solid tumors, including NSCLC. Cellular hypoxia can activate nuclear factor κB (NF-κB), which can modulate radioresistance by influencing cancer cell survival. The effect of high-LET radiation on NF-κB activation in hypoxic NSCLC cells is unclear. Therefore, we compared the effect of low (X-rays)- and high (12C)-LET radiation on NF-κB responsive genes' upregulation, as well as its target cytokines' synthesis in normoxic and hypoxic A549 NSCLC cells. The cells were incubated under normoxia (20% O2) or hypoxia (1% O2) for 48 h, followed by irradiation with 8 Gy X-rays or 12C ions, maintaining the oxygen conditions until fixation or lysis. Regulation of NF-κB responsive genes was evaluated by mRNA sequencing. Secretion of NF-κB target cytokines, IL-6 and IL-8, was quantified by ELISA. A greater fold change increase in expression of NF-κB target genes in A549 cells following exposure to 12C ions compared to X-rays was observed, regardless of oxygenation status. These genes regulate cell migration, cell cycle, and cell survival. A greater number of NF-κB target genes was activated under hypoxia, regardless of irradiation status. These genes regulate cell migration, survival, proliferation, and inflammation. X-ray exposure under hypoxia additionally upregulated NF-κB target genes modulating immunosurveillance and epithelial-mesenchymal transition (EMT). Increased IL-6 and IL-8 secretion under hypoxia confirmed NF-κB-mediated expression of pro-inflammatory genes. Therefore, radiotherapy, particularly with X-rays, may increase tumor invasiveness in surviving hypoxic A549 cells.

Federated Learning Survival Model and Potential Radiotherapy Decision Support Impact Assessment for Non-small Cell Lung Cancer Using Real-World Data.

AIMS: The objective of this study was to develop a two-year overall survival model for inoperable stage I-III non-small cell lung cancer (NSCLC) patients using routine radiation oncology data over a federated (distributed) learning network and evaluate the potential of decision support for curative versus palliative radiotherapy. METHODS: A federated infrastructure of data extraction, de-identification, standardisation, image analysis, and modelling was installed for seven clinics to obtain clinical and imaging features and survival information for patients treated in 2011-2019. A logistic regression model was trained for the 2011-2016 curative patient cohort and validated for the 2017-2019 cohort. Features were selected with univariate and model-based analysis and optimised using bootstrapping. System performance was assessed by the receiver operating characteristic (ROC) and corresponding area under curve (AUC), C-index, calibration metrics and Kaplan-Meier survival curves, with risk groups defined by model probability quartiles. Decision support was evaluated using a case-control analysis using propensity matching between treatment groups. RESULTS: 1655 patient datasets were included. The overall model AUC was 0.68. Fifty-eight percent of patients treated with palliative radiotherapy had a low-to-moderate risk prediction according to the model, with survival times not significantly different (p = 0.87 and 0.061) from patients treated with curative radiotherapy classified as high-risk by the model. When survival was simulated by risk group and model-indicated treatment, there was an estimated 11% increase in survival rate at two years (p < 0.01). CONCLUSION: Federated learning over multiple institution data can be used to develop and validate decision support systems for lung cancer while quantifying the potential impact of their use in practice. This paves the way for personalised medicine, where decisions can be based more closely on individual patient details from routine care.

DNA Repair Genetics and the Risk of Radiation Pneumonitis in Patients With Lung Cancer: A Systematic Review and Meta-analysis.

AIMS: ERCC1 rs11615 and ERCC2 rs238406 single nuclear polymorphism (SNPs) are known for their association with treatment outcome, likely related to radiosensitivity of both tumor and normal tissue in patients with non-small-cell lung cancer. This study aimed to review the effect of 1) these ERCC1/2 SNPs and 2) other SNPs of DNA repair genes on radiation pneumonitis (RP) in patients with lung cancer. MATERIALS AND METHODS: SNPs of our interest included ERCC1 rs11615 and ERCC2 rs238406 and other genes of DNA repair pathways that are functional and biologically active. DNA repair SNPs reported by at least two independent studies were pooled for meta-analysis. The study endpoint was radiation pneumonitis (RP) after radiotherapy. Recessive, dominant, homozygous, heterozygous, and allelic genotype models were used where appropriate. RESULTS: A total of 16 studies (3080 patients) were identified from the systematic review and 12 studies (2090 patients) on 11 SNPs were included in the meta-analysis. The SNPs were ATM rs189037, ATM rs373759, NEIL1 rs4462560, NEIL1 rs7402844, APE1 rs1130409, XRCC3 rs861539, ERCC1 rs11615, ERCC1 rs3212986, ERCC2 rs238406, ERCC2 rs13181, and XRCC1 rs25487. ERCC1 rs11615 (236 patients) and ERCC2 rs238406 (254 patients) were not significantly associated with RP. Using the allelic model, the G allele for NEIL1 gene was significantly associated with a reduced odds of developing symptomatic (grade ≥2) RP compared to the C allele for rs7402844 (OR 0.70, 95% CI: 0.49, 0.99, P = 0.04). Similarly, the T allele for APE1 gene was significantly associated with a reduced odds of developing symptomatic (grade ≥2) RP compared to the G allele for rs1130409 (OR 0.59, 95% CI: 0.43, 0.81, P = 0.001). CONCLUSION: Genetic variation in the DNA repair pathway genes may play a significant role in the risk of developing radiation pneumonitis in patients with lung cancer. Further studies are needed on genotypic features of DNA repair pathway genes and their association with treatment sensitivity, as such knowledge may guide personalized radiation dose prescription.