Brachial plexopathy following stereotactic body radiation therapy in apical lung malignancies: A dosimetric pooled analysis of individual patient data.

BACKGROUND AND OBJECTIVES: The aim of this study is to establish dosimetric constraints for the brachial plexus at risk of developing grade ≥ 2 brachial plexopathy in the context of stereotactic body radiation therapy (SBRT). PATIENTS AND METHODS: Individual patient data from 349 patients with 356 apical lung malignancies who underwent SBRT were extracted from 5 articles. The anatomical brachial plexus was delineated following the guidelines provided in the atlases developed by Hall, et al. and Kong, et al.. Patient characteristics, pertinent SBRT dosimetric parameters, and brachial plexopathy grades (according to CTCAE 4.0 or 5.0) were obtained. Normal tissue complication probability (NTCP) models were used to estimate the risk of developing grade ≥ 2 brachial plexopathy through maximum likelihood parameter fitting. RESULTS: The prescription dose/fractionation schedules for SBRT ranged from 27 to 60 Gy in 1 to 8 fractions. During a follow-up period spanning from 6 to 113 months, 22 patients (6.3 %) developed grade ≥2 brachial plexopathy (4.3 % grade 2, 2.0 % grade 3); the median time to symptoms onset after SBRT was 8 months (ranged, 3-54 months). NTCP models estimated a 10 % risk of grade ≥2 brachial plexopathy with an anatomic brachial plexus maximum dose (Dmax) of 20.7 Gy, 34.2 Gy, and 42.7 Gy in one, three, and five fractions, respectively. Similarly, the NTCP model estimates the risks of grade ≥2 brachial plexopathy as 10 % for BED Dmax at 192.3 Gy and EQD2 Dmax at 115.4 Gy with an α/ß ratio of 3, respectively. Symptom persisted after treatment in nearly half of patients diagnosed with grade ≥2 brachial plexopathy (11/22, 50 %). CONCLUSIONS: This study establishes dosimetric constraints ranging from 20.7 to 42.7 Gy across 1-5 fractions, aimed at mitigating the risk of developing grade ≥2 brachial plexopathy following SBRT. These findings provide valuable guidance for future ablative SBRT in apical lung malignancies.

Short-peptide-based enteral nutrition affects rats MDP translocation and protects against gut-lung injury via the PepT1-NOD2-beclin-1 pathway in vivo.

BACKGROUND: Peptide transporter 1 (PepT1) transports bacterial oligopeptide products and induces inflammation of the bowel. Nutritional peptides compete for the binding of intestinal bacterial products to PepT1. We investigated the mechanism of short-peptide-based enteral nutrition (SPEN) on the damage to the gut caused by the bacterial oligopeptide product muramyl dipeptide (MDP), which is transported by PepT1. The gut-lung axis is a shared mucosal immune system, and immune responses and disorders can affect the gut-respiratory relationship. METHODS AND RESULTS: Sprague-Dawley rats were gavaged with solutions containing MDP, MDP + SPEN, MDP + intact-protein-based enteral nutrition (IPEN), glucose as a control, or glucose with GSK669 (a NOD2 antagonist). Inflammation, mitochondrial damage, autophagy, and apoptosis were explored to determine the role of the PepT1-nucleotide-binding oligomerization domain-containing protein 2 (NOD2)-beclin-1 signaling pathway in the small intestinal mucosa. MDP and proinflammatory factors of lung tissue were explored to determine that MDP can migrate to lung tissue and cause inflammation. Induction of proinflammatory cell accumulation and intestinal damage in MDP gavage rats was associated with increased NOD2 and Beclin-1 mRNA expression. IL-6 and TNF-α expression and apoptosis were increased, and mitochondrial damage was severe, as indicated by increased mtDNA in the MDP group compared with controls. MDP levels and expression of proinflammatory factors in lung tissue increased in the MDP group compared with the control group. SPEN, but not IPEN, eliminated these impacts. CONCLUSIONS: Gavage of MDP to rats resulted in damage to the gut-lung axis. SPEN reverses the adverse effects of MDP. The PepT1-NOD2-beclin-1 pathway plays a role in small intestinal inflammation, mitochondrial damage, autophagy, and apoptosis.

Causal association between tea consumption and head and neck cancer: a Mendelian randomization study.

Although evidence supports an observational association between tea consumption and susceptibility to head and neck cancer, the causal nature of this association remains unclear. We performed a two-sample Mendelian randomization (MR) analysis to determine the causal effects of tea consumption on head and neck cancer. We employed a fixed-effects inverse variance-weighted model for the MR analysis. Genome-wide association study (GWAS) summary data for tea consumption were obtained from the UK Biobank Consortium, and GWAS data for head and neck cancer were derived from two data sources and were used as the outcomes. Our MR analysis revealed limited evidence for a causal relationship between various types of tea intake and head and neck cancer. After adjustment for smoking and alcohol consumption, there was no causal relationship between tea consumption and head and neck cancer. Further experimental studies are required to confirm its potential role in these malignancies.

Phenothiazine-based fluorescent probes for the detection of hydrazine in environment and living cells.

As an important chemical raw material, hydrazine brings convenience to people's lives and provides opportunities for human development. However, the misuse or leakage of hydrazine has brought pollution to the environment, including water, soil and living organisms. At the same time, hydrazine poses a potential threat to human health as a carcinogen. Despite the enormous challenges, it is crucial to develop an effective method to detect hydrazine in environmental samples. In this work, we have synthesized a series of probes based on phenothiazine fluorophore by the introduction of different substituents and developed a novel probe for the detection of hydrazine. The probe is capable of detecting hydrazine in aqueous solutions with high sensitivity and selectivity, and can be easily fabricated into paper test strips for use in in situ samples. In addition, the probe is effective in detecting hydrazine in water, soil, cells, and zebrafish, providing an excellent tool for detecting hydrazine in the environment.

Dosimetric analysis of brachial plexopathy after stereotactic body radiotherapy: Significance of organ delineation.

OBJECTIVES: Examine the significance of contouring the brachial plexus (BP) for toxicity estimation and select metrics for predicting radiation-induced brachial plexopathy (RIBP) after stereotactic body radiotherapy. MATERIALS AND METHODS: Patients with planning target volume (PTV) ≤ 2 cm from the BP were eligible. The BP was contoured primarily according to the RTOG 1106 atlas, while subclavian-axillary veins (SAV) were contoured according to RTOG 0236. Apical PTVs were classified as anterior (PTV-A) or posterior (PTV-B) PTVs. Variables predicting grade 2 or higher RIBP (RIBP2) were selected through least absolute shrinkage and selection operator regression and logistic regression. RESULTS: Among 137 patients with 140 BPs (median follow-up, 32.1 months), 11 experienced RIBP2. For patients with RIBP2, the maximum physical dose to the BP (BP-Dmax) was 46.5 Gy (median; range, 35.7 to 60.7 Gy). Of these patients, 54.5 % (6/11) satisfied the RTOG limits when using SAV delineation; among them, 83.3 % (5/6) had PTV-B. For patients with PTV-B, the maximum physical dose to SAV (SAV-Dmax) was 11.2 Gy (median) lower than BP-Dmax. Maximum and 0.3 cc biologically effective doses to the BP based on the linear-quadratic-linear model (BP-BEDmax LQL and BP-BED0.3cc LQL, α/ß = 3) were selected as predictive variables with thresholds of 118 and 73 Gy, respectively. CONCLUSION: Contouring SAV may significantly underestimate the RIBP2 risk in dosimetry, especially for patients with PTV-B. BP contouring indicated BP-BED0.3cc LQL and BP-BEDmax LQL as potential predictors of RIBP2.

Protective effect of vitamin B6 against doxorubicin-induced cardiotoxicity by modulating NHE1 expression.

Doxorubicin (DOX) has been used to treat various types of cancer, but its application is limited due to its heart toxicity as well as other drawbacks. Chronic inhibition of Na+ /H+ exchanger (NHE1) reduces heart failure and reduces the production of reactive oxygen species (ROS); vitamin B6 (VitB6 ) has been demonstrated to have a crucial role in antioxidant mechanism. So, this study was designed to explore the effect of VitB6 supplement on the DOX-induced cardiotoxicity and to imply whether NHE1 is involved. Ultrasonic cardiogram analysis revealed that VitB6 supplement could alleviate DOX-induced cardiotoxicity; hematoxylin and eosin (HE) and Masson's staining further confirmed this effect. Furthermore, VitB6 supplement exhibited significant antioxidative stress and antiapoptosis effect, which was evidenced by decreased serum malondialdehyde (MDA) content and increased serum superoxide dismutase (SOD) content, and decreased Bcl-2-associated X protein/B-cell lymphoma-2 ratio, respectively. Collectively, VitB6 supplement may exert antioxidative and antiapoptosis effects to improve cardiac function by decreasing NHE1 expression and improve DOX-induced cardiotoxicity.

Reirradiation with stereotactic body radiotherapy for primary or secondary lung malignancies: Tumor control probability and safety analyses.

BACKGROUND: Reirradiation with stereotactic body radiotherapy (SBRT) for patients with primary or secondary lung malignancies represents an appealing definitive approach, but its feasibility and safety are not well defined. The purpose of this study was to investigate the tumor control probability (TCP) and toxicity for patients receiving reirradiation with SBRT. PATIENTS AND METHODS: Eligible patients with recurrence of primary or secondary lung malignancies from our hospital were subjected to reirradiation with SBRT, and PubMed- and Embase-indexed articles were reviewed. The patient characteristics, pertinent SBRT dosimetric details, local tumor control, and toxicities were extracted. The logistic dose-response models were compared for TCP and overall survival (OS) in terms of the physical dose and three-, four-, and five-fraction equivalent doses. RESULTS: The data of 17 patients from our hospital and 195 patients extracted from 12 articles were summarized. Reirradiation with SBRT yielded 2-year estimates of 80% TCP for doses of 50.10 Gy, 55.85 Gy, and 60.54 Gy in three, four, and five fractions, respectively. The estimated TCP with common fractionation schemes were 50%, 60%, and 70% for 42.04 Gy, 47.44 Gy, and 53.32 Gy in five fractions, respectively. Similarly, the 2-year estimated OS was 50%, 60%, and 70% for 41.62 Gy, 46.88 Gy, and 52.55 Gy in five fractions, respectively. Central tumor localization may be associated with severe toxicity. CONCLUSIONS: Reirradiation with SBRT doses of 50-60 Gy in 3-5 fractions is feasible for appropriately selected patients with recurrence of peripheral primary or secondary lung malignancies, but should be carefully considered for centrally-located tumors due to potentially severe toxicity. Further studies are warranted for optimal dose/fractionation schedules and more accurate selection of patients suitable for reirradiation with SBRT.

Association between Serum Cystatin C levels and long-term cardiovascular outcomes and all-cause mortality in older patients with obstructive sleep apnea.

Background and Aims: To investigate the association between obstructive sleep apnea (OSA) severity and baseline serum cystatin C (Cys-C) concentration and to explore the association between baseline serum Cys-C and long-term cardiovascular outcomes and mortality in older patients with OSA. Methods: Between January 2015 and October 2017, a total of 1107 consecutive eligible older patients (≥60 years) with OSA were included in this multicenter, prospective cohort study, and baseline demographics, clinical characteristics, sleep parameters, and follow-up outcomes were collected. Participants were divided into different groups based on baseline serum Cys-C levels. The primary end point was major adverse cardiovascular events (MACE) and the secondary end point was all-cause mortality. The correlation between OSA severity and baseline serum Cys-C was evaluated by Spearman correlation analysis. Multivariate Cox regression was used to analyze the association between Cys-C and the incidence of MACE and mortality. Results: Participants included 672 men and 435 women, with a median age of 66 (range, 60-96) years. At baseline, apnea-hypopnea index (AHI) (r = 0.128, p < 0.05), oxygen desaturation index (ODI) (r = 0.116, p < 0.05), and the lowest pulse oxygen saturation (LSpO2) (r = -0.097, p < 0.05) were correlated with serum Cys-C concentration. During the median follow-up period of 42 months, 97 patients (8.8%) experienced MACE and 40 patients (3.6%) experienced death. The association between serum Cys-C levels and the risk of MACE and all-cause mortality was slow rising shaped. The multivariable Cox regression analysis showed patients with a serum Cys-C concentration of ≥1.14 mg/L had higher risks of MACE (HR = 5.30, 95% CI: 2.28-12.30, p < 0.05) and all-cause mortality (HR = 9.66, 95% CI: 2.09-44.72, p < 0.05) compared with patients with serum Cys-C of ≤0.81 mg/L in older patients with OSA. The receiver-operating characteristic curve showed baseline serum Cys-C levels exhibited moderately capable of identifying patients with a long-term risk of clinical adverse events (MACE and mortality). Conclusion: OSA severity was positively correlated with serum Cys-C concentration. High levels of Cys-C were independently associated with increased risks of MACE and all-cause mortality in older patients with OSA, suggesting that lowering Cys-C levels should be considered as a therapeutic target, and monitoring serum Cys-C may be beneficial to the favorable prognosis of older patients with OSA.

Risk-adapted stereotactic body radiotherapy for patients with cervical spinal metastases.

Owing to the complex anatomical structure and biomechanics, the current standard palliative treatments for cervical spinal metastases are associated with a high risk of recurrence and complications. Stereotactic body radiotherapy (SBRT) can provide radical dose to tumors while protecting normal organs to the maximum extent. However, the efficacy and safety of SBRT for cervical spinal metastases is not well characterized. Data from 71 patients with cervical spine metastases who were treated with SBRT using CyberKnife between 2006 and 2021 were obtained from our prospectively maintained database. Primary endpoint was pain response at 12 weeks following SBRT completion; secondary endpoints included local control (LC), overall survival (OS), and adverse events. Standard-risk patients were planned to receive 30 Gy (range 21-36) with median fractions of 3 (range 1-3) and high-risk patients 35 Gy (range 24-50) with median fractions of 5 (range 4-5) according to the spinal cord and esophagus dose constraints. The median follow-up time was 17.07 months (range 3.1-118.9). After 12 weeks of SBRT completion, 54 (98.2%) of 55 patients with baseline pain achieved pain response and 46 (83.6%) achieved complete pain response. LC rates were 93.1% and 90% at 1 year and 2 year, respectively. The 1-year and 2-year OS rates were 66.2% and 37.4%, respectively. Eight patients experienced grades 1-4 adverse events (six vertebral compression fracture [VCF], five of them had VCF before SBRT; and two hemiparesis). No grade 5 adverse events were observed. Therefore, risk-adapted SBRT for cervical spine metastases achieved high pain control and LC rates with acceptable adverse events.

Anti-diabetic Role of Adropin in Streptozotocin Induced Diabetic Rats via Alteration of PI3K/Akt and Insulin Signaling Pathway.

Diabetes mellitus (DM) is a hyperglycemia-related multifactorial condition with an elevated risk of microvascular and microvascular complications associated with this disease. The current experimental study was to examine the antidiabetic activity of streptozotocin (STZ)-induced adropin against diabetic rats by altering the PI3K/Akt and insulin signaling pathways. STZ (60 mg/kg) was used for the induction of DM and rats were divided into different groups and received the adropin (20, 40 and 80 mg/kg) and glibenclamide (10 mg/kg) till 28 days. Body weight, plasma insulin, blood glucose and food intake were estimated, respectively. Biochemical enzymes, carbohydrate enzymes, lipid parameters, AMPK and insulin signalling pathway parameters were estimated. GLUT4 and PPARγ expression were also estimated. Oral administration of adropin significantly (p < 0.001) increased the glycogen, glucose-6-phosphatase dehydrogenase, insulin, hexokinase and belittled the blood glucose level, fructose 1-6-biphosphatase, glucose-6-phosphatase at dose dependent manner. Adropin significantly (p < 0.001) reduced the level of triglyceride, cholesterol, low density lipoprotein, very low density lipoprotein and increased the level of high density lipoprotein at dose dependent manner. Adropin significantly (p < 0.001) activated the Akt, IRS-2, IRS-1, IR, p-AKT and PI3k, which are the key modulator molecules of PI3K/Akt, AMPK and insulin signalling pathway in DM rats. The current experimental study confirms the anti-diabetic effect of adropin on DM rats induced by AMPK and insulin signalling pathway against STZ.

The dorsal and the ventral side of hypoglossal motor nucleus showed different response to chronic intermittent hypoxia in rats.

PURPOSE: To study neurochemical reactions to chronic intermittent hypoxia (CIH) in the hypoglossal nucleus (HN) of rats. METHODS: Adult male Sprague-Dawley rats (n = 12) were randomly divided into two groups (the CIH and the control group). The CIH rats were housed in a hypoxic chamber with the fraction of oxygen volume alternating between 21% and 5% by providing air for 60 s and then providing nitrogen for 60 s from 8:30 am to 16:30 pm each day for 35 days. The control group was housed in a cabin with normal oxygen levels. We studied the expression of c-fos protein, 5-hydroxytryptamine (5-HT) positive terminals, and its 2A receptors in hypoglossal nuclei by immunohistochemistry. RESULTS: The expression of c-fos, 5-HT positive terminals, and accordingly 5-HT 2A receptors in the CIH group were significantly higher than that in the controls (p < 0.05). The ventral side of the HN showed a clearly higher expression of 5-HT and its 2A receptors than the dorsal side (p < 0.05). CONCLUSION: There were 2 responses of the HN to CIH. First, CIH induced a higher expression of 5-HT positive terminals and its 2A receptors, and second, this reaction was much more evident in ventral side than in the dorsal side. We postulate that these responses may serve to be a protective and compensatory mechanism for CIH.

Differential Diagnosis, Clinical Characteristics, and Interventions of Braid-Like Coronary Artery: Case Series Analysis Based on Optical Coherence Tomography.

AIM: Based on optical coherence tomography (OCT), we aimed to determine the diagnosis, clinical characteristics, and interventions of braid-like coronary arteries, which are rare and tend to be diagnosed as a woven coronary artery (WCA) anomaly. METHODS AND RESULTS: We identified braid-like lesions on coronary angiography (CAG) in 7 patients (6 men; median age 47 years; age range 26 to 57 years). All patients were heavy smokers. Four patients were diagnosed with an old myocardial infarction and the other 3 with unstable angina. The braid-like lesions were located in the left anterior descending arteries in 2 patients and in the right coronary arteries in the other 5. TIMI grade 2 flow was observed in all involved vessels. OCT findings of all lesions were consistent with recanalization of organized thrombi, which consisted of septa that divided the lumen into multiple small cavities communicating with each other. No separate three-layered structure could be defined. Based on the significance of the stenosis and its related symptoms, drug-eluting stents were implanted in all of the lesions. All patients experienced symptomatic improvement after the intervention and were followed up event-free for 12 months. CONCLUSIONS: Braid-like coronary arteries are likely to undergo recanalization of organized thrombi rather than WCA according to our OCT findings. The majority of cases affect men who smoke heavily. Percutaneous stent implantation may be beneficial in selected patients when feasible.

Combined toxicity of outdoor air pollution on kidney function among adult women in Mianyang City, southwest China.

Environmental pollution is a risk factor for kidney dysfunction. However, the combined toxicity of air pollutants on kidney function is scarce. We estimated the relationship between combined toxicity of air pollutants and kidney function among adult women (n = 7071, 18-65 years old) in Mianyang City, Southwest China. We measured serum concentrations of uric acid, urea, creatinine, and cystatin C, and we calculated the individual estimated glomerular filtration rate (eGFR) using a cystatin C-based equation developed specifically for Chinese patients with CKD equation. Air pollution data were collected to calculate the individual average daily dose (ADD) of pollutants based on the air quality complex index (AQCI). Mean AQCI was higher in winter and lower in summer, and followed the monthly and seasonal trends of air pollutants. Concomitantly, individual ADD was also higher in winter and lower in summer, and the seasonal differences were reflected in the levels of kidney biomarkers (including uric acid, urea, creatinine, cystatin C, and eGFR). With an interquartile range (IQR: 1.04-1.50 m3/day/kg) increases of ADD, the serum concentrations of uric acid, urea, creatinine, and cystatin C increase [B (95%CI): 1.774 (0.318, 3.231) umol/L, 0.218 (0.1888, 0.247) mmol/L, 1.501 (1.016, 1.986) umol/L, and 0.006 (0.003, 0.009) mg/L, respectively], whereas eGFR decreases [B (95%CI): -0.776 (-1.106, -0.446) mL/min/1.73 m2]. Totally, the relationship between combined toxicity of air pollutants and kidney function in Chinese adult women suggests that the toxicity of combined air pollutants inversely affects kidney function, which might accelerate the risk of CKD.

Risk-adapted stereotactic body radiation therapy for central and ultra-central early-stage inoperable non-small cell lung cancer.

To determine the therapeutic efficacy and safety of risk-adapted stereotactic body radiation therapy (SBRT) schedules for patients with early-stage central and ultra-central inoperable non-small cell lung cancer. From 2006 to 2015, 80 inoperable T1-2N0M0 NSCLC patients were treated with two median dose levels: 60 Gy in six fractions (range, 48-60 Gy in 4-8 fractions) prescribed to the 74% isodose line (range, 58%-79%) for central lesions (ie within 2 cm of, but not abutting, the proximal bronchial tree; n = 43), and 56 Gy in seven fractions (range, 48-60 Gy in 5-10 fractions) prescribed to the 74% isodose line (range, 60%-80%) for ultra-central lesions (ie abutting the proximal bronchial tree; n = 37) on consecutive days. Primary endpoint was overall survival (OS); secondary endpoints included progression-free survival (PFS), tumor local control rate (LC), and toxicity. Median OS and PFS were 64.47 and 32.10 months (respectively) for ultra-central patients, and not reached for central patients. Median time to local failure, regional failure, and any distant failures for central versus ultra-central lesions were: 27.37 versus 26.07 months, 20.90 versus 12.53 months, and 20.85 versus 15.53 months, respectively, all P < .05. Multivariate analyses showed that tumor categorization (ultra-central) and planning target volume ≥52.76 mL were poor prognostic factors of OS, PFS, and LC, respectively (all P < .05). There was one grade 5 toxicity; all other toxicities were grade 1-2. Our results showed that ultra-central tumors have a poor OS, PFS, and LC compared with central patients because of the use of risk-adapted SBRT schedules that allow for equal and favorable toxicity profiles.

The synthesis and application of nano doxorubicin- indocyanine green matrix metalloproteinase-responsive hydrogel in chemophototherapy for head and neck squamous cell carcinoma.

BACKGROUND: Head and neck squamous cell carcinoma (HNSCC) is one of the most common malignancies, with high rates of mortality and morbidity worldwide. Owing to the special anatomical location of this tumor, an effective, minimally invasive treatment with low systemic toxicity is highly desirable. Hydrogels have shown great potential for tumor-targeting therapy, with excellent performance. However, there have been few reports on co-loading photosensitizers and chemotherapeutic drugs into hydrogels. In this study, we synthesized a nano doxorubicin-indocyanine green matrix metalloproteinase (MMP)-responsive hydrogel (denoted as NDIMH), combining chemotherapy and phototherapy, to achieve superior antitumor efficacy. METHODS: First, NDIMH was synthesized and characterized by scanning electron microscopy and drug-release assays. Second, the photosensitivity properties and antitumor efficiency of this drug delivery system were studied in vivo and in vitro. Last, the imaging and biodistribution of NDIMH were monitored using the Maestro EX in vivo imaging system. RESULTS: The nanodrugs loaded into the smart hydrogel exhibited uniform size distribution, excellent size stability, and a sustained release in the presence of MMP-2. NDIMH showed ideal photosensitivity characteristics under light. NDIMH with 808 nm near-infrared (NIR) irradiation effectively inhibited the viability, invasion, and metastasis of SCC-15 in vitro. After intratumoral injection of NDIMH with 808 nm NIR illumination, the hydrogels exhibited favorable synergistic antitumor efficacy and acceptable biosafety. Additionally, fluorescence imaging showed that NDIMH could significantly improve the retention of nanodrugs at the tumor site. CONCLUSION: The intratumoral injection of NDIMH with 808 nm NIR irradiation could be a promising chemophototherapy alternative for HNSCC.

Ablative Hypofractionated Radiation Therapy Enhances Non-Small Cell Lung Cancer Cell Killing via Preferential Stimulation of Necroptosis In Vitro and In Vivo.

PURPOSE: To investigate how necroptosis (ie, programmed necrosis) is involved in killing of non-small cell lung cancer (NSCLC) after ablative hypofractionated radiation therapy (HFRT). METHODS AND MATERIALS: Deoxyribonucleic acid damage, DNA repair, and the death form of NSCLC cells were assessed after radiation therapy. The overexpression and silencing of receptor-interacting protein kinases 3 (RIP3, a key protein involved activation of necroptosis)-stable NSCLC cell lines were successfully constructed. The form of cell death, the number and area of colonies, and the regulatory proteins of necroptosis were characterized after radiation therapy in vitro. Finally, NSCLC xenografts and patient specimens were used to examine involvement of necroptosis after ablative HFRT in vivo. RESULTS: Radiation therapy induced expected DNA damage and repair of NSCLC cell lines, but ablative HFRT at ≥10 Gy per fraction preferentially stimulated necroptosis in NSCLC cells and xenografts with high RIP3 expression, as characterized by induction and activation of RIP3 and mixed-lineage kinase domain-like protein and release of immune-activating chemokine high-mobility group box 1. In contrast, RNA interference of RIP3 attenuated ablative HFRT-induced necroptosis and activation of its regulatory proteins. Among central early-stage NSCLC patients receiving stereotactic body radiation therapy, high expression of RIP3 was associated with improved local control and progression-free survival (all P < .05). CONCLUSIONS: Ablative HFRT at ≥10 Gy per fraction enhances killing of NSCLC with high RIP3 expression via preferential stimulation of necroptosis. RIP3 may serve as a useful biomarker to predict favorable response to stereotactic body radiation therapy.

Early postoperative radiotherapy is associated with improved outcomes over late postoperative radiotherapy in the management of completely resected (R0) Stage IIIA-N2 non-small cell lung cancer.

AIMS: The aim of this study was to evaluate the ideal timing of PORT in the management of completely resected (R0) Stage IIIA-N2 NSCLC. PATIENTS AND METHODS: Between January 2008 and December 2015, patients with known histologies of pathologic Stage IIIA-N2 NSCLC who underwent R0 resection and received PORT concurrent with or prior to two sequential cycles of chemotherapy ("early PORT") or with PORT administered after two cycles of chemotherapy ("late PORT") at multiple hospitals. The primary endpoint was OS; secondary end points included pattern of the first failure, LRRFS, and DMFS. Kaplan-Meier OS, LRRFS, and DMFS curves were compared with the log-rank test. Cox regression analysis was used to determine prognosticators for OS, LRRFS, and DMFS. RESULTS: Of 112 included patients, 41 (36.6%) and 71 (63.4%) patients received early PORT and late PORT, respectively. The median OS, LRRFS, and DMFS were longer for those who received early PORT than for those who received late PORT at the median follow-up of 29.6 months (all p < 0.05). Uni- and multi-variate analyses showed that number of POCT cycles and the combination schedule of PORT and POCT were independent prognostic factors for OS, LRRFS, and DMFS. CONCLUSIONS: Early PORT is associated with improved outcomes in pathologic Stage IIIA-N2 R0 NSCLC patients.

Association of α2A-Adrenergic Receptor Genetic Variants with Platelet Reactivity in Chinese Patients on Dual Antiplatelet Therapy Undergoing Percutaneous Coronary Intervention.

OBJECTIVE: The alpha 2A-adrenergic receptor gene (ADRA2A) polymorphism in individuals modifies the antiplatelet response to sympathetic stimulation. The aim of this study was to investigate the effect of ADRA2A variants on platelet reactivity in Chinese patients on dual antiplatelet therapy (DAPT) after undergoing percutaneous coronary intervention (PCI). METHODS: From March 2011 to March 2013, 1,024 patients were enrolled in this prospective, single-center, observational study in China. Four single nucleotide polymorphisms (SNPs) of ADRA2A gene (rs11195419, rs3750625, rs13306146, and rs553668) and CYP2C19*2 were detected by ligase detection reaction (LDR), and adenosine diphosphate (ADP) inhibition was detected by thromboelastography (TEG®). RESULTS: The minor allele frequencies of ADRA2A SNPs were common. Platelet ADP inhibition was significantly different among patients carrying rs11195419 (adjusted P = 0.022) and rs3750625 (adjusted P = 0.016). The homozygous allele carriers had the lowest ADP inhibition. However, ADP inhibition was not significantly different in rs553668 and rs13306146. At the multivariate analysis, rs11195419 (P = 0.033), rs3750625 (P = 0.020) and CYP2C19*2 (P = 0.002) were independent predictors of ADP inhibition. Subgroups analysis based on sex showed rs11195419 (P = 0.003) and rs3750625 (P = 0.002) were significantly associated with ADP inhibition in males, but not in females. CONCLUSION: ADRA2A genetic variations were associated with ADP-induced platelet aggregation during DAPT in Chinese patients undergoing PCI, and the effect was particularly more pronounced in males.

Sublobar resection is associated with improved outcomes over radiotherapy in the management of high-risk elderly patients with Stage I non-small cell lung cancer: a systematic review and meta-analysis.

BACKGROUND AND AIM: A matched-pair comparison was performed to compare the efficacy and safety of sublobar resection versus radiotherapy for high-risk elderly patients with Stage I non-small cell lung cancer (NSCLC). PATIENTS AND METHODS: We searched the Cochrane Library, MEDLINE, CENTRAL, EMBASE and manual searches. The meta-analysis was performed to compare overall survival, pattern of failure, and toxicity among the homogeneous studies. Subdivided analyses were also performed. RESULTS: Sixteen studies containing 11540 patients were included in the meta-analysis. Among these studies, 9 were propensity-score matched (PSM) cohort studies, and 7 were cohort studies. Sublobar resection, compared with radiotherapy (either conventional fraction radiation therapy or stereotactic body radiation therapy), significantly improved the overall survival regardless in both PSM and non-PSM analyses (all p < 0.05). However, the difference in the pattern of failure and toxicity were not significant (all p > 0.05). CONCLUSIONS: Sublobar resection was associated with improved outcomes in high-risk elderly patients with Stage I NSCLC, which supports the need to compare both treatments in large prospective, randomized, controlled clinical trials.

Stereotactic body radiation therapy for patients with recurrent pancreatic adenocarcinoma at the abdominal lymph nodes or postoperative stump including pancreatic stump and other stump.

BACKGROUND AND AIM: The aim of this study is to evaluate the efficacy and safety of stereotactic body radiation therapy (SBRT) using CyberKnife in the treatment of patients with recurrent pancreatic adenocarcinoma at the abdominal lymph node or stump after surgery. PATIENTS AND METHODS: Between October 1, 2006 and May 1, 2015, patients with recurrent pancreatic adenocarcinoma at the abdominal lymph node or stump after surgery were enrolled and treated with SBRT at our hospital. The primary end point was local control rate after SBRT. Secondary end points were overall survival, time to symptom alleviation, and toxicity, assessed using the Common Terminology Criteria for Adverse Events version 4.0. RESULTS: Twenty-four patients with 24 lesions (17 abdominal lymph nodes and seven stumps) were treated with SBRT, of which five patients presented with abdominal lymph nodes and synchronous metastases in the liver and lung. The 6-, 12-, and 24-month actuarial local control rates were 95.2%, 83.8%, and 62.1%, respectively. For the entire cohort, the median overall survival from diagnosis and SBRT was 28.9 and 12.2 months, respectively. Symptom alleviation was observed in eleven of 14 patients (78.6%) within a median of 8 days (range, 1-14 days) after SBRT. Nine patients (37.5%) experienced Common Terminology Criteria for Adverse Events version 4.0 grade 1-2 acute toxicities; one patient experienced grade 3 acute toxicity due to thrombocytopenia. CONCLUSION: SBRT is a safe and effective treatment for patients with recurrent pancreatic adenocarcinoma at the abdominal lymph node or stump after surgery. Further studies are needed before SBRT can be recommended routinely.