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.

Ononin promotes radiosensitivity in lung cancer by inhibiting HIF-1α/VEGF pathway.

BACKGROUND: In our previous study, we provided evidence that Astragalus mongholicus Bunge(AM) and its extracts possess a protective capability against radiation-induced damage, potentially mediated through the reduction of reactive oxygen species (ROS) and nitric oxide (NO). However, we were pleasantly surprised to discover during our experimentation that AM not only offers protection against radiation damage but also exhibits a radiation sensitization effect. This effect may be attributed to a specific small molecule present in AM known as ononin. Currently, radiation sensitizers are predominantly found in nitrazole drugs and nanomaterials, with no existing reports on the radiation sensitization properties of ononin, nor its underlying mechanism. PURPOSE: This study aims to investigate the sensitization effect of the small molecule ononin derived from AM on lung cancer radiotherapy, elucidating its specific molecular mechanism of action. Additionally, the safety profile of combining astragalus small molecule ononin with radiation therapy will be evaluated. METHODS: The effective concentration of ononin was determined through cell survival experiments, and the impact of ononin combined with varying doses of radiation on lung cancer cells was observed using CCK-8 and cell cloning experiments. The apoptotic effect of ononin combined with radiation on lung cancer cells was assessed using Hochester staining, flow cytometry, and WB assay. Additionally, WB and immunofluorescence analysis were conducted to investigate the influence of ononin on HIF-1α/VEGF pathway. Furthermore, Molecular Dynamics Simulation was employed to validate the targeted binding ability of ononin and HIF-1α. A lung cancer cell line was established to investigate the effects of knockdown and overexpression of HIF-1α. Subsequently, the experiment was repeated using tumor bearing nude mice and C57BL/6 mouse models in an in vivo study. Tumor volume was measured using a vernier caliper, while HE, immunohistochemistry, and immunofluorescence techniques were employed to observe the effects of ononin combined with radiation on tumor morphology, proliferation, and apoptosis. Additionally, Immunofluorescence was employed to examine the impact of ononin on HIF-1α/VEGF pathway in vivo, and its effect on liver function in mice was assessed through biochemistry analysis. RESULTS: At a concentration of 25 µM, ononin did not affect the proliferation of lung epithelial cells but inhibited the survival of lung cancer cells. In vitro experiments demonstrated that the combination of ononin and radiation could effectively inhibit the growth of lung cancer cells, induce apoptosis, and suppress the excessive activation of the Hypoxia inducible factor 1 alpha/Vascular endothelial growth factor pathway. In vivo experiments showed that the combination of ononin and radiation reduced the size and proliferation of lung cancer tumors, promoted cancer cell apoptosis, mitigated abnormal activation of the Hypoxia inducible factor 1 alpha pathway, and protected against liver function damage. CONCLUSION: This study provides evidence that the combination of AM and its small molecule ononin can enhance the sensitivity of lung cancer to radiation. Additionally, it has been observed that this combination can specifically target HIF-1α and exert its effects. Notably, ononin exhibits the unique ability to protect liver function from damage while simultaneously enhancing the tumor-killing effects of radiation, thereby demonstrating a synergistic and detoxifying role in tumor radiotherapy. These findings contribute to the establishment of a solid basis for the development of novel radiation sensitizers derived from traditional Chinese medicine.

A 4D-CBCT correction network based on contrastive learning for dose calculation in lung cancer.

OBJECTIVE: This study aimed to present a deep-learning network called contrastive learning-based cycle generative adversarial networks (CLCGAN) to mitigate streak artifacts and correct the CT value in four-dimensional cone beam computed tomography (4D-CBCT) for dose calculation in lung cancer patients. METHODS: 4D-CBCT and 4D computed tomography (CT) of 20 patients with locally advanced non-small cell lung cancer were used to paired train the deep-learning model. The lung tumors were located in the right upper lobe, right lower lobe, left upper lobe, and left lower lobe, or in the mediastinum. Additionally, five patients to create 4D synthetic computed tomography (sCT) for test. Using the 4D-CT as the ground truth, the quality of the 4D-sCT images was evaluated by quantitative and qualitative assessment methods. The correction of CT values was evaluated holistically and locally. To further validate the accuracy of the dose calculations, we compared the dose distributions and calculations of 4D-CBCT and 4D-sCT with those of 4D-CT. RESULTS: The structural similarity index measure (SSIM) and peak signal-to-noise ratio (PSNR) of the 4D-sCT increased from 87% and 22.31 dB to 98% and 29.15 dB, respectively. Compared with cycle consistent generative adversarial networks, CLCGAN enhanced SSIM and PSNR by 1.1% (p < 0.01) and 0.42% (p < 0.01). Furthermore, CLCGAN significantly decreased the absolute mean differences of CT value in lungs, bones, and soft tissues. The dose calculation results revealed a significant improvement in 4D-sCT compared to 4D-CBCT. CLCGAN was the most accurate in dose calculations for left lung (V5Gy), right lung (V5Gy), right lung (V20Gy), PTV (D98%), and spinal cord (D2%), with the relative dose difference were reduced by 6.84%, 3.84%, 1.46%, 0.86%, 3.32% compared to 4D-CBCT. CONCLUSIONS: Based on the satisfactory results obtained in terms of image quality, CT value measurement, it can be concluded that CLCGAN-based corrected 4D-CBCT can be utilized for dose calculation in lung cancer.

A Hybrid Nanoadjuvant Simultaneously Depresses PD-L1/TGF-ß1 and Activates cGAS-STING Pathway to Overcome Radio-Immunotherapy Resistance.

Currently, certain cancer patients exhibit resistance to radiotherapy due to reduced DNA damage under hypoxic conditions and acquired immune tolerance triggered by transforming growth factor-ß1 (TGF-ß1) and membrane-localized programmed death ligand-1 (PD-L1). Meanwhile, cytoplasm-distributed PD-L1 induces radiotherapy resistance through accelerating DNA damage repair (DDR). However, the disability of clinically used PD-L1 antibodies in inhibiting cytoplasm-distributed PD-L1 limits their effectiveness. Therefore, a nanoadjuvant is developed to sensitize cancer to radiotherapy via multi-level immunity activation through depressing PD-L1 and TGF-ß1 by triphenylphosphine-derived metformin, and activating the cGAS-STING pathway by generating Mn2+ from MnO2 and producing more dsDNA via reversing tumor hypoxia and impairing DDR. Thus, Tpp-Met@MnO2@Alb effectively enhances the efficiency of radiotherapy to inhibit the progression of irradiated local and abscopal tumors and tumor lung metastases, offering a long-term memory of antitumor immunity without discernible side effects. Overall, Tpp-Met@MnO2@Alb has the potential to be clinically applied for overcoming radio-immunotherapy resistance.

Pingxiao capsule inhibits lung metastasis of triple-negative breast cancer and sensitizes breast cancer to radiotherapy.

OBJECTIVES: To investigate the anticancer effect of Pingxiao capsule (, PXC) on the treatment of breast cancer and . METHODS: The inhibition of PXC on cell viability and proliferation was determined by cell counting kit-8, EdU assay and colony formation assay, respectively. The effect of PXC on cell apoptosis was detected by using flow cytometry. The suppression of PXC on cell migration and invasion was investigated by chamber assay. To investigate the underlying molecular mechanisms, the expression of proteins related to epithelial to mesenchymal transition (EMT) was analyzed by Western blotting in breast cancer cells and by immunohistochemistry in tumor tissues. The anticancer effect of PXC was evaluated by using MDA-MB-231 xenograft model and 4T1 metastatic breast cancer model. RESULTS: Our results indicated that triple-negative breast cancer (TNBC) cell lines MDA-MB-231 and MDA-MB-468 were sensitive to PXC. PXC potently inhibited the proliferation, colony formation, migration, and invasion of MDA-MB-231 and MDA-MB-468 cells . Then, MDA-MB-231 xenograft model depicted that PXC significantly reduced tumor size and weight compared with Control. 4T1 lung metastasis model showed that PXC significantly inhibited breast cancer cell spreading to lungs in mice. Mechanistically, PXC inhibited EMT process by reducing cadherin turnover in TNBC. Furthermore, PXC in combination with 8 Gy X-ray treatment obviously promoted the induction of apoptosis, and suppressed cell proliferation. CONCLUSION: PXC could inhibit the proliferation and invasion of TNBC both and , and exerted its anti-metastatic effect by regulating cadherin turnover, Furthermore, it sensitized the TNBC cells to radiotherapy. The data supported further development of PXC as an adjuvant-therapy agent for TNBC.

Suppressing epithelial-mesenchymal-transition blue light therapy for reducing macrophage-mediated cancerous pulmonary fibrosis: An in-vitro study.

Lung cancer is the leading killer among all types of cancer globally. As a key factor, epithelial-mesenchymal transition (EMT) plays a crucial role in pathological fibrosis and lung cancer metastasis. This study endeavors to investigate the effect of blue light at specific wavelengths of 405 nm and 415 nm (54 J/cm2 ) on EMT induced by TGF-ß1 in A549 cells. The results revealed that the blue light irradiation reduced the morphological characteristics of EMT in the A549 cells, and cell-to-cell connections were weakened significantly. Molecular analysis showed upregulation of epithelial marker E-cadherin and downregulation of EMT marker vimentin. Additionally, exposure to blue light irradiation at 405 nm and 415 nm significantly decelerated the ability of invasion and migration. Moreover, cell viability was also investigated. Based on these findings, blue light can serve as a useful therapeutic option for inhibiting EMT in cases of lung cancer and fibrotic lung disease.

Compound Kushen Injection Reduces Severe Toxicity and Symptom Burden Associated With Curative Radiotherapy in Patients With Lung Cancer.

BACKGROUND: Radiotherapy (RT) causes adverse events for which there are no effective treatments. This study investigated the clinical benefits of compound Kushen injection (CKI) in managing radiation injury in patients with lung cancer. METHODS: A multicenter, open-label, randomized clinical trial randomly assigned patients with lung cancer to receive either CKI (20 mL/d for at least 4 weeks) integrated with curative RT (RT + CKI group; n=130) or RT alone (control group; n=130). The primary outcome was the incidence of grade ≥2 radiation-induced lung injury (RILI) in the lungs, esophagus, or heart. Secondary outcomes included patient-reported symptoms, quality of life, objective response rate (ORR), and toxic effects. RESULTS: During the 16-week trial, the RT + CKI group had a significantly lower incidence of grade ≥2 RT-related injury than the control group (12.3% [n=16] vs 23.1% [n=30]; P=.02). Compared with the control group, the RT + CKI group experienced a significant decrease in moderate-to-severe symptoms of fatigue, cough, and pain (P<.001 for the treatment and time interaction term); significantly less physical symptom interference (P=.01); and significantly better quality of life by the end of the trial (P<.05). No statistically significant difference in ORR was found. Adverse reactions associated with CKI were rare. CONCLUSIONS: This study demonstrated low toxicity of CKI and its effectiveness in patients with lung cancer in reducing the incidence of grade ≥2 RILI and symptom burden, improving patients' quality of life.

A Cross-Talk about Radioresistance in Lung Cancer-How to Improve Radiosensitivity According to Chinese Medicine and Medicaments That Commonly Occur in Pharmacies.

Lung cancer is one of the most common cancers in the population and is characterized by non-specific symptoms that delay the diagnosis and reduce the effectiveness of oncological treatment. Due to the difficult placement of the tumor, one of the main methods of lung cancer treatment is radiotherapy, which damages the DNA of cancer cells, inducing their apoptosis. However, resistance to ionizing radiation may develop during radiotherapy cycles, leading to an increase in the number of DNA points of control that protect cells from apoptosis. Cancer stem cells are essential for radioresistance, and due to their ability to undergo epithelial-mesenchymal transition, they modify the phenotype, bypassing the genotoxic effect of radiotherapy. It is therefore necessary to search for new methods that could improve the cytotoxic effect of cells through new mechanisms of action. Chinese medicine, with several thousand years of tradition, offers a wide range of possibilities in the search for compounds that could be used in conventional medicine. This review introduces the potential candidates that may present a radiosensitizing effect on lung cancer cells, breaking their radioresistance. Additionally, it includes candidates taken from conventional medicine-drugs commonly available in pharmacies, which may also be significant candidates.

A Prospective Study of Nurse-Led Oral Mucositis Management: Impact on Health Outcomes of Patients Receiving Radiotherapy for Head and Neck Cancer and Lung Cancer.

OBJECTIVES: The study aimed to evaluate the impact of nurse-led mucositis management on the health outcomes of patients receiving radiotherapy for head and neck cancer and lung cancer. The study adopted a holistic approach that involved the patient in the care process by screening, providing education and counseling about mucositis management and integrating it into daily life by the radiotherapy nurse. DATA SOURCES: In this prospective, longitudinal cohort study, 27 patients were assessed and monitored through use of the WHO Oral Toxicity Scale and Oral Mucositis Follow-up Form and educated on mucositis during their radiotherapy through use of the Mucositis Prevention and Care Guide. At the end of radiotherapy, an evaluation of the radiotherapy process was performed. In this study, each patient was followed for 6 weeks from the start of radiotherapy. CONCLUSION: The worst clinical data for oral mucositis and its variables emerged at week 6 of treatment. While the Nutrition Risk Screening score increased over time, weight decreased was observed to decrease. The mean stress level was 4.74 ± 0.33 in the first week and 5.77 ± 0.35 in the last week. It was observed that 88.9% of the patients showed good compliance with the treatment. IMPLICATIONS FOR NURSING PRACTICE: Nurse-led mucositis management contributes to better patient outcomes during the radiotherapy process. Such an approach improves oral care management in patients receiving radiotherapy for head and neck and lung cancer, demonstrating its positive impact on additional patient-focused outcomes.

High-dose insulin and dexamethasone combined with radiotherapy in endometrial stromal sarcoma recurring with multiple metastases: A case report.

RATIONALE: Endometrial stromal sarcoma (ESS) is a rare malignant tumor. There is insufficient data supporting the efficiency of current treatments in multiple metastatic settings, and novel therapeutic options for ESS are considered an area of high unmet clinical need. PATIENT CONCERNS: We report the case of a 28-year-old woman who was diagnosed with ESS after undergoing total hysterectomy and left adnexectomy at another hospital. Two years later, the disease recurred, with multiple abdominal cavities and lung metastases. The patient was treated with a variety of chemotherapeutic drugs, including tyrosine kinase inhibitors, at the same hospital; however, none of them inhibited disease progression. DIAGNOSES: Computed tomography (CT) revealed multiple masses in the abdominal and pelvic cavities and multiple pulmonary nodules. Ultrasound-guided biopsy was performed and the tumor tissue was histologically confirmed after treatment. INTERVENTIONS: Insulin 300-400 IU was administrated by intravenous infusion in 10% glucose (500 mL) with disodium adenosine triphosphate 60 mg, coenzyme A 100 units, 10% potassium chloride 5 mL and 25% magnesium sulfate 5 mL. Dexamethasone (20-25 mg/d) was diluted with 10 mL of 2% lidocaine and then intraperitoneally injected after ascites draw. After 9 months, the patient was referred to another center for radiotherapy. OUTCOMES: CT images tomography showed recurrent pelvic masses, and multiple abdominal cavity and lung metastases gradually shrunk with treatment. Histological biopsy revealed growth arrest of tumor cells. The patient experienced for 3-years survival. LESSONS: High-dose insulin and dexamethasone combined with radiotherapy provides a novel and promising option for patients with multiple ESS metastases.

Prevalence of and Risk Factors for Emotional Distress in Patients Undergoing Radiotherapy for Lung Cancer.

BACKGROUND/AIM: Quality of life of patients with lung cancer can be impaired by psychological distress. This study evaluated prevalence of and risk factors for emotional distress in patients undergoing radiotherapy or chemoradiotherapy. PATIENTS AND METHODS: Fourteen potential risk factors were retrospectively investigated in 144 patients. Emotional distress was evaluated with the National Comprehensive Cancer Network Distress Thermometer. Values of p<0.0036 (Bonferroni correction) were considered significant. RESULTS: At least one emotional problem (worry, fear, sadness, depression, nervousness, loss of interest) was reported by the majority of patients (N=93, 65%). Prevalence of these problems was 37%, 38%, 31%, 15%, 32% and 23%, respectively. Physical problems were significantly associated with worry (p=0.0029), fear (p=0.0030), sadness (p<0.0001), depression (p=0.0008), nervousness (p<0.0001), and loss of interest (p<0.0001). Age ≤69 years was associated with worry (p=0.0003), and female sex with fear (p=0.0002) and sadness (p=0.0026). Trends were found for associations of age with sadness (p=0.045), female sex with nervousness (p=0.034), and chemoradiotherapy with worry (p=0.027). CONCLUSION: Many patients with lung cancer experience emotional distress. Early psycho-oncological assistance may be important, particularly for high-risk patients.

Evaluation of quality of life in lung cancer patients receiving radiation and Viscum album L.: a real-world data study.

BACKGROUND: Lung cancer (LC) is associated with high mortality and poor quality of life (QoL). The disease as well as oncological treatments such as radiation and chemotherapy with adverse effects can impair the QoL of patients. Add-on treatment with extracts of Viscum album L. (white-berry European mistletoe, VA) has been shown to be feasible and safe and to improve the QoL of cancer patients. The aim of this study was to analyze the changes in QoL of LC patients being treated with radiation according to oncological guidelines and add-on VA treatment in a real-world setting. METHODS: A real-world data study was conducted using registry data. Self-reported QoL was assessed by the evaluation of the European Organization of Research and Treatment Health-Related Quality of Life Core Questionnaire scale (EORTC QLQ-C30). Adjusted multivariate linear regression analyses were performed to analyze factors associated with changes in QoL at 12 months. RESULTS: A total of 112 primary LC patients (all stages, 92% non-small-cell lung cancer, median age 70 (ICR: 63-75)), answered the questionnaires at first diagnosis and 12 months later. Assessment of 12 months changes in QoL revealed significant improvement of 27 points for pain (p = 0.006) and 17 points for nausea/vomiting (p = 0.005) in patients who received combined radiation and VA. In addition, significant improvements of 15 to 21 points for role (p = 0.03), physical (p = 0.02), cognitive (p = 0.04), and social functioning (p = 0.04) were observed in guideline treated patients receiving no radiation but add-on VA. CONCLUSIONS: Add-on VA therapy reveals supportive effects for the QoL of LC patients. Particularly in combination with radiation a significant reduction in pain and nausea/ vomiting has been observed. Trial registration The study received ethics approval and was retrospectively registered (DRKS00013335 on 27/11/2017).

Review: Mechanisms and perspective treatment of radioresistance in non-small cell lung cancer.

Radiotherapy is the major treatment of non-small cell lung cancer (NSCLC). The radioresistance and toxicity are the main obstacles that leading to therapeutic failure and poor prognosis. Oncogenic mutation, cancer stem cells (CSCs), tumor hypoxia, DNA damage repair, epithelial-mesenchymal transition (EMT), and tumor microenvironment (TME) may dominate the occurrence of radioresistance at different stages of radiotherapy. Chemotherapy drugs, targeted drugs, and immune checkpoint inhibitors are combined with radiotherapy to treat NSCLC to improve the efficacy. This article reviews the potential mechanism of radioresistance in NSCLC, and discusses the current drug research to overcome radioresistance and the advantages of Traditional Chinese medicine (TCM) in improving the efficacy and reducing the toxicity of radiotherapy.

Lack of Adherence to Guideline-Based Imaging Before Subsequent Radiation in Patients with Non-Small Cell Lung Cancer: Impact on Patient Outcomes.

Lung cancer is the leading cause of cancer death within the United States, yet prior studies have shown a lack of adherence to imaging and treatment guidelines in patients with lung cancer. This study evaluated the use of 18F-FDG PET/CT imaging before subsequent radiation therapy (RT) in patients with non-small cell lung cancer (NSCLC), as recommended by National Comprehensive Cancer Network guidelines, and whether the use of this imaging modality impacts cancer-specific survival. Methods: This was a retrospective study of the National Cancer Institute's Surveillance, Epidemiology, and End Results program of Medicare-linked data in patients with NSCLC. Hazard ratios and 95% CIs for overall and cancer-specific survival were estimated for patients diagnosed between 2006 and 2015 who underwent either 18F-FDG PET/CT-based or CT-based imaging before subsequent RT. Results: Significant improvement in cancer-specific survival was found in patients who underwent 18F-FDG PET/CT imaging before subsequent RT, compared with those who underwent CT (hazard ratio, 1.43 [95% CI, 1.32-1.55; P < 0.0001]). Although the National Comprehensive Cancer Network recommends 18F-FDG PET/CT before subsequent RT, 43.6% of patients were imaged with CT alone. Conclusion: Many patients with NSCLC are not being imaged according to national guidelines before subsequent RT, and this omission is associated with a lower cancer-specific survival.

Efficacy of ω-3 Polyunsaturated Fatty Acids in Patients with Lung Cancer Undergoing Radiotherapy and Chemotherapy: A Meta-Analysis.

Background: Radiotherapy and chemotherapy in patients with lung cancer can lead to a series of problems such as malnutrition and inflammatory reaction. Some studies have shown that ω-3 polyunsaturated fatty acids (PUFAs) could improve malnutrition and regulate inflammatory reaction in these patients, but no relevant meta-analysis exists. Methods: We systematically searched randomized controlled trials of ω-3 PUFAs in the adjuvant treatment of lung cancer in the PubMed, EMBASE, Cochrane Library, Web of Science, Chinese Biomedical Literature Database (CBM), China National Knowledge Infrastructure (CNKI), and Wanfang databases. Relevant outcomes were extracted, and we pooled standardized mean differences (SMDs) using a random or fixed-effects model. The risk of bias was evaluated according to the Cochrane Handbook (version 15.1). The quality of evidence was assessed using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE). Results: A total of 7 studies were included. The SMDs (95% CI) of body weight change, albumin change, energy intake, and protein intake at the end of intervention were 1.15 (0.50, 1.80), 0.60 (0.11, 1.09), 0.39 (-0.10, 0.89), and 0.27 (-0.04, 0.58), respectively. The SMDs (95% CI) of CRP change and TNF-α change were -3.44 (-6.15, -0.73) and -1.63 (-2.53, -0.73), respectively. Conclusions: ω-3 PUFAs can improve nutritional status and regulate indicators of inflammation in patients with lung cancer undergoing radiotherapy and chemotherapy. This study was registered in the PROSPERO (registration number: CRD42022307699).

Adverse Events Following Limited Resection versus Stereotactic Body Radiation Therapy for Early Stage Lung Cancer.

Rationale: Approximately a quarter of patients with early stage lung cancer are not medically fit for lobectomy. Limited resection and stereotactic body radiation therapy (SBRT) have emerged as alternatives for these patients. Given the equipoise on the effectiveness of the two treatments, treatment-related adverse events (AEs) could have a significant impact on patients' decision-making and treatment outcomes. Objectives: To compare the AE profile between SBRT versus limited resection. Methods: Data were derived from a prospective cohort of patients with stage I-IIA non-small cell lung cancer who were deemed as high-risk for lobectomy recruited from five centers across the United States. Propensity scores and inverse probability weighting were used to compare the rates of 30- and 90-day AEs among patients treated with limited resection versus SBRT. Results: Overall, 65% of 252 patients underwent SBRT. After adjusting for propensity scores, there was no significant difference in developing at least one AE comparing SBRT to limited resection (odds ratio [OR]: 1.00; 95% confidence interval [CI]: 0.65-1.55 and OR: 1.27; 95% CI: 0.84-1.91 at 30 and 90 days, respectively). SBRT was associated with lower risk of infectious AEs than limited resection at 30 days (OR: 0.05; 95% CI: 0.01-0.39) and 90 days posttreatment (OR: 0.41; 95% CI: 0.17-0.98). Additionally, SBRT was associated with persistently elevated risk of fatigue (OR: 2.47; 95% CI: 1.34-4.54 at 30 days and OR: 2.69; 95% CI: 1.52-4.77 at 90 days, respectively), but significantly lower risks of respiratory AEs (OR: 0.36; 95% CI: 0.20-0.65 and OR: 0.51; 95% CI: 0.31-0.86 at 30 and 90 days, respectively). Conclusions: Though equivalent in developing at least one AE, we found that SBRT is associated with less toxicity than limited resection in terms of infectious and respiratory AEs but higher rates of fatigue that persisted up to 3 months posttreatment. This information, combined with data about oncologic effectiveness, can help patients' decision-making regarding these alternative therapies.

Secondary Infections After Diagnosis of Severe Radiation Pneumonitis (SRP) Among Patients With Non-Small Cell Lung Cancer: Pathogen Distributions, Choice of Empirical Antibiotics, and the Value of Empirical Antifungal Treatment.

PURPOSE: This study aimed to assess pathogen distributions and antimicrobial sensitivity characteristics in patients with non-small cell lung cancer (NSCLC) with severe radiation pneumonitis (SRP) and secondary infections. METHODS AND MATERIALS: Data from 1746 patients with NSCLC and SRP after thoracic radiation therapy from January 2009 to December 2020 were retrospectively analyzed. Pneumonia incidence, causative pathogens, and antibiotic resistance characteristics in patients with secondary lung infections were analyzed. Risk factors associated with mortality were identified through univariate and multivariate analyses. Antifungal drug efficacy and duration-related effects were assessed with Forest plots and receiver operating characteristic curves. RESULTS: Overall, 44.5% of patients with NSCLC and SRP (777 of 1746 patients) were diagnosed with secondary lung infections. In total, 899 bacterial strains were isolated from these patients, with Acinetobacter baumannii (n = 206; 27%), Klebsiella pneumonia (n = 200; 26.2%), and Pseudomonas aeruginosa (n = 104; 13.6%) being the most common. Carbapenem and cefoperazone-sulbactam resistance rates of 52.7% and 32.2%, 28.8% and 26.4%, and 23.7% and 20.2% were observed for these isolates, respectively. Infection-related deaths occurred in 22.4% of patients with SRP. Independent risk factors for infection-related death included poor performance status scores, inappropriate empirical antimicrobial treatment, bacteria/fungal coinfection, and lack of empirical antifungal treatment. Receiver operating characteristic curves showed that the cutoff value of empirical antifungal treatment duration was 9 (area under the curve: 0.819). CONCLUSIONS: For patients with SRP and secondary lung infections, appropriate empirical antimicrobial treatment could decrease infection-related mortality, and cefoperazone-sulbactam may be an appropriate antibacterial drug. Empirical antifungal treatment for a minimum of 9 days might contribute to better outcomes. Although this represents a promising treatment approach for patients with SRP and secondary lung infections before antibacterial susceptibility testing, further prospective validation is essential.

Chemoradiation treatment patterns among United States Veteran Health Administration patients with unresectable stage III non-small cell lung cancer.

BACKGROUND: The Veterans Health Administration (VHA) is the largest integrated health care system in the United States (US). Among VHA patients, the rate of use of concurrent chemoradiation therapy (CCRT) among those with unresectable, stage III non-small cell lung cancer (NSCLC) is unknown. The objective was to report recent CCRT treatment patterns in VHA patients and identify characteristics associated with receipt of CCRT. METHODS: Using Department of Veteran Affairs (VA) Cancer Registry System data linked to VA electronic medical records, we determined rates of CCRT, sequential CRT (SCRT), radiation therapy (RT) only, chemotherapy (CT) only, and neither treatment. RESULTS: Among 4054 VHA patients who met study criteria, CCRT rates slightly increased from 44 to 50% between 2013 and 2017. Factors associated with decreased odds of CCRT receipt compared to any other treatment included increasing age (adjusted odds ratio [aOR] per 10 years = 0.67; 95% CI: 0.60-0.76) and Charlson-Deyo comorbidity score (aOR = 0.94; 95% CI: 0.91-0.97). White race was associated with increased odds of CCRT receipt (aOR = 1.24; 95% CI: 1.004-1.53). In a chart review sample of 200 patients, less than half (n = 85) had a documented reason for not receiving CCRT. Among these, 29% declined treatment, and 71% did not receive CCRT due to "not being a candidate" for reasons related to frailty or lung nodules being too far apart for radiation therapy. CONCLUSIONS: CCRT rates among VHA patients with unresectable, stage III NSCLC slightly increased from 2013 to 2017; however in 2017, only half were receiving CCRT. Older patients and those with multiple comorbidities were less likely to receive CCRT and even when controlling for these factors, non-white patients were less likely to receive CCRT.

Phase II Trial of Flaxseed to Prevent Acute Complications After Chemoradiation for Lung Cancer.

Background: Thoracic radiotherapy is complicated by acute radiation-induced adverse events such as radiation pneumonitis (RP) and radiation esophagitis (RE). Based on preclinical work and a randomized pilot trial from our laboratory, this single-arm phase II trial investigated administering flaxseed as a radioprotector in patients receiving definitive chemoradiation for nonsmall cell lung cancer (NSCLC). Methods: Between June 2015 and February 2018, 33 patients with locally advanced or metastatic NSCLC with planned definitive chemoradiation were enrolled. Finely-ground Linum usitatissimum L. (Linaceae; flaxseed or linseed) in 40-g packets were provided for daily consumption in any patient-desired formulation 1 week before radiotherapy and throughout radiotherapy as tolerated. The primary outcomes were overall adverse events, with particular focus on Grade ≥3 RP, and flaxseed tolerability. Adverse events were graded according to CTCAE v4.0. Results: Of the 33 patients enrolled, 5 patients (15%) did not receive chemoradiation, 4 (12%) withdrew promptly after enrollment, 4 (12%) did not return a flaxseed consumption log, and 1 patient had irritable bowel syndrome (3%). The remaining 19 patients (57%) had chemoradiation and flaxseed ingestion with a mean completion and standard deviation of the intended flaxseed course of 62% ± 8.3%. Nine (50%) of these 19 patients reported difficulties with flaxseed consumption, citing nausea, constipation, odynophagia, or poor taste or texture. One patient (5%), with unverifiable flaxseed consumption, developed Grade 3 RP. There were no cases of Grade 2 RP. Six patients (32%) developed Grade 2 RE, but no patients developed Grade ≥3 RE. Median overall and progression-free survival were 31 and 12 months, respectively. Conclusions: Despite the low incidence of acute radiation-induced complications reported, significant treatment-related gastrointestinal toxicities and subsequently low flaxseed tolerability inhibit accurate determination of flaxseed effect in patients receiving concurrent thoracic chemoradiation. Thus, further investigations should focus on optimizing flaxseed formulation for improved tolerability and evaluation. ClinicalTrials.gov ID: NCT02475330.

Avasopasem manganese synergizes with hypofractionated radiation to ablate tumors through the generation of hydrogen peroxide.

Avasopasem manganese (AVA or GC4419), a selective superoxide dismutase mimetic, is in a phase 3 clinical trial (NCT03689712) as a mitigator of radiation-induced mucositis in head and neck cancer based on its superoxide scavenging activity. We tested whether AVA synergized with radiation via the generation of hydrogen peroxide, the product of superoxide dismutation, to target tumor cells in preclinical xenograft models of non-small cell lung cancer (NSCLC), head and neck squamous cell carcinoma, and pancreatic ductal adenocarcinoma. Treatment synergy with AVA and high dose per fraction radiation occurred when mice were given AVA once before tumor irradiation and further increased when AVA was given before and for 4 days after radiation, supporting a role for oxidative metabolism. This synergy was abrogated by conditional overexpression of catalase in the tumors. In addition, in vitro NSCLC and mammary adenocarcinoma models showed that AVA increased intracellular hydrogen peroxide concentrations and buthionine sulfoximine- and auranofin-induced inhibition of glutathione- and thioredoxin-dependent hydrogen peroxide metabolism selectively enhanced AVA-induced killing of cancer cells compared to normal cells. Gene expression in irradiated tumors treated with AVA suggested that increased inflammatory, TNFα, and apoptosis signaling also contributed to treatment synergy. These results support the hypothesis that AVA, although reducing radiotherapy damage to normal tissues, acts synergistically only with high dose per fraction radiation regimens analogous to stereotactic ablative body radiotherapy against tumors by a hydrogen peroxide-dependent mechanism. This tumoricidal synergy is now being tested in a phase I-II clinical trial in humans (NCT03340974).