Molecular mechanism of radiation tolerance in lung adenocarcinoma cells using single-cell RNA sequencing.

The efficacy of radiotherapy, a cornerstone in the treatment of lung adenocarcinoma (LUAD), is profoundly undermined by radiotolerance. This resistance not only poses a significant clinical challenge but also compromises patient survival rates. Therefore, it is important to explore this mechanism for the treatment of LUAD. Multiple public databases were used for single-cell RNA sequencing (scRNA-seq) data. We filtered, normalized and downscaled scRNA-seq data based on the Seurat package to obtain different cell subpopulations. Subsequently, the ssGSEA algorithm was used to assess the enrichment scores of the different cell subpopulations, and thus screen the cell subpopulations that are most relevant to radiotherapy tolerance based on the Pearson method. Finally, pseudotime analysis was performed, and a preliminary exploration of gene mutations in different cell subpopulations was performed. We identified HIST1H1D+ A549 and PIF1+ A549 as the cell subpopulations related to radiotolerance. The expression levels of cell cycle-related genes and pathway enrichment scores of these two cell subpopulations increased gradually with the extension of radiation treatment time. Finally, we found that the proportion of TP53 mutations in patients who had received radiotherapy was significantly higher than that in patients who had not received radiotherapy. We identified two cellular subpopulations associated with radiotherapy tolerance, which may shed light on the molecular mechanisms of radiotherapy tolerance in LUAD and provide new clinical perspectives.

DLL3-guided therapies in small-cell lung cancer: from antibody-drug conjugate to precision immunotherapy and radioimmunotherapy.

DLL3 acts as an inhibitory ligand that downregulates Notch signaling and is upregulated by ASCL1, a transcription factor prevalent in the small-cell lung cancer (SCLC) subtype SCLC-A. Currently, the therapeutic strategies targeting DLL3 are varied, including antibody-drug conjugates (ADCs), bispecific T-cell engagers (BiTEs), and chimeric antigen receptor (CAR) T-cell therapies. Although rovalpituzumab tesirine (Rova-T) showed promise in a phase II study, it failed to produce favorable results in subsequent phase III trials, leading to the cessation of its development. Conversely, DLL3-targeted BiTEs have garnered significant clinical interest. Tarlatamab, for instance, demonstrated enhanced response rates and progression-free survival compared to the standard of care in a phase II trial; its biologics license application (BLA) is currently under US Food and Drug Administration (FDA) review. Numerous ongoing phase III studies aim to further evaluate tarlatamab's clinical efficacy, alongside the development of novel DLL3-targeted T-cell engagers, both bispecific and trispecific. CAR-T cell therapies targeting DLL3 have recently emerged and are undergoing various preclinical and early-phase clinical studies. Additionally, preclinical studies have shown promising efficacy for DLL3-targeted radiotherapy, which employs ß-particle-emitting therapeutic radioisotopes conjugated to DLL3-targeting antibodies. DLL3-targeted therapies hold substantial potential for SCLC management. Future clinical trials will be crucial for comparing treatment outcomes among various approaches and exploring combination therapies to improve patient survival outcomes.

Risk and prognosis of secondary lung cancer after radiation therapy for thoracic malignancies.

OBJECTIVE: Radiation therapy (RT) may increase the risk of second cancer. This study aimed to determine the association between exposure to radiotherapy for the treatment of thoracic cancer (TC) and subsequent secondary lung cancer (SLC). MATERIALS AND METHODS: The Surveillance, Epidemiology, and End Results (SEER) database (from 1975 to 2015) was queried for TC. Univariate Cox regression analyses and multiple primary standardized incidence ratios (SIRs) were used to assess the risk of SLC. Subgroup analyses of patients stratified by latency time since TC diagnosis, age at TC diagnosis, and calendar year of TC diagnosis stage were also performed. Overall survival and SLC-related death were compared among the RT and no radiation therapy (NRT) groups by using Kaplan-Meier analysis and competitive risk analysis. RESULTS: In a total of 329 129 observations, 147 847 of whom had been treated with RT. And 6799 patients developed SLC. Receiving radiotherapy was related to a higher risk of developing SLC for TC patients (adjusted HR, 1.25; 95% CI, 1.19-1.32; P < 0.001). The cumulative incidence of developing SLC in TC patients with RT (3.8%) was higher than the cumulative incidence (2.9%) in TC patients with NRT(P). The incidence risk of SLC in TC patients who received radiotherapy was significantly higher than the US general population (SIR, 1.19; 95% CI, 1.14-1.23; P < 0.050). CONCLUSIONS: Radiotherapy for TC was associated with higher risks of developing SLC compared with patients unexposed to radiotherapy.

Experimental evidence that carbon-ion radiotherapy utilizes cytotoxic T lymphocyte-mediated anti-tumor immunity for shrinking tumors compared to X-ray therapy.

The therapeutic efficacy of radiotherapy (RT) is primarily driven by two factors: biophysical DNA damage in cancer cells and radiation-induced anti-tumor immunity. However, Anti-tumor immune responses between X-ray RT (XRT) and carbon-ion RT (CIRT) remain unclear. In this study, we, employed mouse models to assess the immunological contribution, especially cytotoxic T-lymphocyte (CTL)-mediated immunity, to the therapeutic effectiveness of XRT and CIRT in shrinking tumors. We irradiated mouse intradermal tumors of B16F10-ovalbumin (OVA) mouse melanoma cells and 3LL-OVA mouse lung cancer cells with carbon-ion beams or X-rays in the presence or absence of CTLs. CTL removal was performed by administration of anti-CD8 monoclonal antibody (mAb) in mice. Based on tumor growth delay, we determined the tumor growth and regression curves. The enhancement ratio (ER) of the slope of regression lines in the presence of CTLs, relative to the absence of CTLs, indicates the dependency of RT on CTLs for shrinking mouse tumors, and the biological effectiveness (RBE) of CIRT relative to XRT were calculated. Tumor growth curves revealed that the elimination of CD8+ CTLs by administrating anti-CD8 mAb accelerated tumor growth compared to the presence of CTLs in both RTs. The ERs were larger in CIRT compared to XRT in the B16F10-OVA tumor models, but not in the 3LL-OVA models, suggesting a greater contribution of CTL-mediated anti-tumor immunity to tumor reduction in CIRT compared to XRT in the B16F10-OVA tumor model. In addition, the RBE values for both models were larger in the presence of CTLs compared to models without CTLs, suggesting that CIRT may utilize CTL-mediated anti-tumor immunity more than X-ray. The findings from this study suggest that although immunological contribution to therapeutic efficacy may vary depending on the type of tumor cell, CIRT utilizes CTL-mediated immunity to a greater extent compared to XRT.

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.

Experimental validation of the accuracy of robotic-assisted radioactive seed implantation for tumor treatment.

An experimental validation of a robotic system for radioactive iodine-125 seed implantation (RISI) in tumor treatment was conducted using customized phantom models and animal models simulating liver and lung lesions. The robotic system, consisting of planning, navigation, and implantation modules, was employed to implant dummy radioactive seeds into the models. Fiducial markers were used for target localization. In phantom experiments across 40 cases, the mean errors between planned and actual seed positions were 0.98 ± 1.05 mm, 1.14 ± 0.62 mm, and 0.90 ± 1.05 mm in the x, y, and z directions, respectively. The x, y, and z directions correspond to the left-right, anterior-posterior, and superior-inferior anatomical planes. Silicone phantoms exhibiting significantly smaller x-axis errors compared to liver and lung phantoms (p < 0.05). Template assistance significantly reduced errors in all axes (p < 0.05). No significant dosimetric deviations were observed in parameters such as D90, V100, and V150 between plans and post-implant doses (p > 0.05). In animal experiments across 23 liver and lung cases, the mean implantation errors were 1.28 ± 0.77 mm, 1.66 ± 0.69 mm, and 1.86 ± 0.93 mm in the x, y, and z directions, slightly higher than in phantoms (p < 0.05), with no significant differences between liver and lung models. The dosimetric results closely matched planned values, confirming the accuracy of the robotic system for RISI, offering new possibilities in clinical tumor treatment.

Deep-Learning Model Prediction of Radiation Pneumonitis Using Pretreatment Chest Computed Tomography and Clinical Factors.

Objectives: This study aimed to build a comprehensive deep-learning model for the prediction of radiation pneumonitis using chest computed tomography (CT), clinical, dosimetric, and laboratory data. Introduction: Radiation therapy is an effective tool for treating patients with lung cancer. Despite its effectiveness, the risk of radiation pneumonitis limits its application. Although several studies have demonstrated models to predict radiation pneumonitis, no reliable model has been developed yet. Herein, we developed prediction models using pretreatment chest CT and various clinical data to assess the likelihood of radiation pneumonitis in lung cancer patients. Methods: This retrospective study analyzed 3-dimensional (3D) lung volume data from chest CT scans and 27 features including dosimetric, clinical, and laboratory data from 548 patients who were treated at our institution between 2010 and 2021. We developed a neural network, named MergeNet, which processes lung 3D CT, clinical, dosimetric, and laboratory data. The MergeNet integrates a convolutional neural network with subsequent fully connected layers. A support vector machine (SVM) and light gradient boosting machine (LGBM) model were also implemented for comparison. For comparison, the convolution-only neural network was implemented as well. Three-dimensional Resnet-10 network and 4-fold cross-validation were used. Results: Classification performance was quantified by using the area under the receiver operative characteristic curve (AUC) metrics. MergeNet showed the AUC of 0.689. SVM, LGBM, and convolution-only networks showed AUCs of 0.525, 0.541, and 0.550, respectively. Application of DeLong test to pairs of receiver operating characteristic curves respectively yielded P values of .001 for the MergeNet-SVM pair and 0.001 for the MergeNet-LGBM pair. Conclusion: The MergeNet model, which incorporates chest CT, clinical, dosimetric, and laboratory data, demonstrated superior performance compared to other models. However, since its prediction performance has not yet reached an efficient level for clinical application, further research is required. Contribution: This study showed that MergeNet may be an effective means to predict radiation pneumonitis. Various predictive factors can be used together for the radiation pneumonitis prediction task via the MergeNet.

[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.

First in vitro measurement of VHEE relative biological effectiveness (RBE) in lung and prostate cancer cells using the ARES linac at DESY.

Very high energy electrons (VHEE) are a potential candidate for radiotherapy applications. This includes tumours in inhomogeneous regions such as lung and prostate cancers, due to the insensitivity of VHEE to inhomogeneities. This study explores how electrons in the VHEE range can be used to perform successful in vitro radiobiological studies. The ARES (accelerator research experiment at SINBAD) facility at DESY, Hamburg, Germany was used to deliver 154 MeV electrons to both prostate (PC3) and lung (A549) cancer cells in suspension. Dose was delivered to samples with repeatability and uniformity, quantified with Gafchromic film. Cell survival in response to VHEE was measured using the clonogenic assay to determine the biological effectiveness of VHEE in cancer cells for the first time using this method. Equivalent experiments were performed using 300 kVp X-rays, to enable VHEE irradiated cells to be compared with conventional photons. VHEE irradiated cancer cell survival was fitted to the linear quadratic (LQ) model (R2 = 0.96-0.97). The damage from VHEE and X-ray irradiated cells at doses between 1.41 and 6.33 Gy are comparable, suggesting similar relative biological effectiveness (RBE) between the two modalities. This suggests VHEE is as damaging as photon radiotherapy and therefore could be used to successfully damage cancer cells during radiotherapy. The RBE of VHEE was quantified as the relative doses required for 50% (D0.5) and 10% (D0.1) cell survival. Using these values, VHEE RBE was measured as 0.93 (D0.5) and 0.99 (D0.1) for A549 and 0.74 (D0.5) and 0.93 (D0.1) for PC3 cell lines respectively. For the first time, this study has shown that 154 MeV electrons can be used to effectively kill lung and prostate cancer cells, suggesting that VHEE would be a viable radiotherapy modality. Several studies have shown that VHEE has characteristics that would offer significant improvements over conventional photon radiotherapy for example, electrons are relatively easy to steer and can be used to deliver dose rapidly and with high efficiency. Studies have shown improved dose distribution with VHEE in treatment plans, in comparison to VMAT, indicating that VHEE can offer improved and safer treatment plans with reduced side effects. The biological response of cancer cells to VHEE has not been sufficiently studied as of yet, however this initial study provides some initial insights into cell damage. VHEE offers significant benefits over photon radiotherapy and therefore more studies are required to fully understand the biological effectiveness of VHEE.

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.

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.

Radiomics-based discriminant analysis of principal components to stratify the treatment response of lung metastases following stereotactic body radiation therapy.

PURPOSE: Discriminant analysis of principal components (DAPC) was introduced to describe the clusters of genetically related individuals focusing on the variation between the groups of individuals. Borrowing this approach, we evaluated the potential of DAPC for the evaluation of clusters in terms of treatment response to SBRT of lung lesions using radiomics analysis on pre-treatment CT images. MATERIALS AND METHODS: 80 pulmonary metastases from 56 patients treated with SBRT were analyzed. Treatment response was stratified as complete, incomplete and null responses. For each lesion, 107 radiomics features were extracted using the PyRadiomics software. The concordance correlation coefficients (CCC) between the radiomics features obtained by two segmentations were calculated. DAPC analysis was performed to infer the structure of "radiomically" related lesions for treatment response assessment. The DAPC was performed using the "adegenet" package for the R software. RESULTS: The overall mean CCC was 0.97 ± 0.14. The analysis yields 14 dimensions in order to explain 95 % of the variance. DAPC was able to group the 80 lesions into the 3 different clusters based on treatment response depending on the radiomics features characteristics. The first Linear Discriminant achieved the best discrimination of individuals into the three pre-defined groups. The greater radiomics loadings who contributed the most to the treatment response differentiation were associated with the "sphericity", "correlation" and "maximal correlation coefficient" features. CONCLUSION: This study demonstrates that a DAPC analysis based on radiomics features obtained from pretreatment CT is able to provide a reliable stratification of complete, incomplete or null response of lung metastases following SBRT.

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.

Predictors of radioiodine (RAI)-avidity restoration for NTRK fusion-positive RAI-resistant metastatic thyroid cancers.

Context: Two-thirds of metastatic differentiated thyroid cancer (DTC) patients have radioiodine (RAI)-resistant disease, resulting in poor prognosis and high mortality. For rare NTRK and RET fusion-positive metastatic, RAI-resistant thyroid cancers, variable success of re-induction of RAI avidity during treatment with NTRK or RET inhibitors has been reported. Case presentation and results: We report two cases with RAI-resistant lung metastases treated with larotrectinib: an 83-year-old male presenting with an ETV6::NTRK3 fusion-positive tumor with the TERT promoter mutation c.-124C>T, and a 31-year-old female presenting with a TPR::NTRK1 fusion-positive tumor (and negative for TERT promoter mutation). Post larotrectinib treatment, diagnostic I-123 whole body scan revealed unsuccessful RAI-uptake re-induction in the TERT-positive tumor, with a thyroid differentiation score (TDS) of -0.287. In contrast, the TERT-negative tumor exhibited successful I-131 reuptake with a TDS of -0.060. Conclusion: As observed for RAI-resistance associated with concurrent TERT and BRAF mutations, the co-occurrence of TERT mutations and NTRK fusions may also contribute to re-sensitization failure.

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.

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.

Spatially modulated ablation driven by chaotic attractors in human lung epithelial cancer cells.

A significant modification in photoinduced energy transfer in cancer cells is reported by the assistance of a dynamic modulation of the beam size of laser irradiation. Human lung epithelial cancer cells in monolayer form were studied. In contrast to the quantum and thermal ablation effect promoted by a standard focused Gaussian beam, a spatially modulated beam can caused around 15% of decrease in the ablation threshold and formation of a ring-shaped distribution of the photothermal transfer effect. Optical irradiation was conducted in A549 cells by a 532 nm single-beam emerging from a Nd:YVO4 system. Ablation effects derived from spatially modulated convergent waves were controlled by an electrically focus-tunable lens. The proposed chaotic behavior of the spatial modulation followed an Arneodo chaotic oscillator. Fractional dynamic thermal transport was analyzed in order to describe photoenergy in propagation through the samples. Immediate applications of chaos theory for developing phototechnology devices driving biological functions or phototherapy treatments can be considered.

Six versus four or five cycles of first-line etoposide and platinum-based chemotherapy combined with thoracic radiotherapy in patients with limited-stage small-cell lung cancer: A propensity score-matched analysis of a prospective randomized trial.

OBJECTIVES: The recommended treatment for limited-stage small-cell lung cancer (LS-SCLC) is a combination of thoracic radiotherapy (TRT) and etoposide plus cisplatin (EP) chemotherapy, typically administered over 4-6 cycles. Nonetheless, the optimal duration of chemotherapy is still not determined. This study aimed to compare the outcomes of patients with LS-SCLC who received either 6 cycles or 4-5 cycles of EP chemotherapy combined with TRT. MATERIALS AND METHODS: In this retrospective analysis, we utilized data from our prior prospective trial to analyze the outcomes of 265 LS-SCLC patients who received 4-6 courses of EP combined with concurrent accelerated hyperfractionated TRT between 2002 and 2017. Patients were categorized into two groups depending on their number of chemotherapy cycles: 6 or 4-5 cycles. To assess overall survival (OS) and progression-free survival (PFS), we employed the Kaplan-Meier method after conducting propensity score matching (PSM). RESULTS: Among the 265 LS-SCLC patients, 60 (22.6%) received 6 cycles of EP chemotherapy, while 205 (77.4%) underwent 4-5 cycles. Following PSM (53 patients for each group), the patients in the 6 cycles group exhibited a significant improvement in OS and PFS in comparison to those in the 4-5 cycles group [median OS: 29.8 months (95% confidence interval [CI], 23.6-53.1 months) vs. 22.7 months (95% CI, 20.8-29.1 months), respectively, p = 0.019; median PFS: 17.9 months (95% CI, 13.7-30.5 months) vs. 12.0 months (95% CI, 9.8-14.2 months), respectively, p = 0.006]. The two-year and five-year OS rates were 60.38% and 29.87% in the 6 cycles group, whereas 47.17% and 15.72% in the 4-5 cycles group, respectively. CONCLUSION: Patients diagnosed with LS-SCLC who were treated with EP regimen chemotherapy combined with TRT exhibited notably enhanced survival when administered 6 cycles of chemotherapy, as compared to those who underwent only 4-5 cycles.