Induction immunochemotherapy followed by definitive chemoradiotherapy for unresectable locally advanced non-small cell lung cancer: a multi-institutional retrospective cohort study.

This study aimed to evaluate the efficacy and safety of induction immunochemotherapy followed by definitive chemoradiotherapy (CRT) for unresectable locally advanced non-small cell lung cancer (LA-NSCLC). We identified unresectable stage III NSCLC patients who received induction immunochemotherapy. Overall survival (OS) and progression-free survival (PFS) were the primary endpoints. From February 2019 to August 2022, 158 patients were enrolled. Following the completion of induction immunochemotherapy, the objective response rate (ORR) and disease control rate (DCR) were 52.5% and 83.5%, respectively. The ORR of CRT was 73.5%, representing 68.4% of the total cohort. The median PFS was 17.8 months, and the median OS was 41.9 months, significantly higher than in patients who received CRT alone (p < 0.001). Patients with concurrent CRT demonstrated markedly improved PFS (p = 0.012) and OS (p = 0.017) than those undergoing sequential CRT. Additionally, those with a programmed-death ligand 1 (PD-L1) expression of 50% or higher showed significantly elevated ORRs (72.2% vs. 47.2%, p = 0.011) and superior OS (median 44.8 vs. 28.6 months, p = 0.004) compared to patients with PD-L1 expression below 50%. Hematologic toxicities were the primary severe adverse events (grade ≥ 3) encountered, with no unforeseen treatment-related toxicities. Thus, induction immunochemotherapy followed by definitive CRT demonstrated encouraging efficacy and tolerable toxicities for unresectable LA-NSCLC.

Superior component compositions and antioxidant activity of Volvariella volvacea oil compared to those of Agrocybe cylindracea and two Lentinula edodes oils.

The biological activity of an oil not only depends on its fatty acid composition but also the lipid composition and trace components. In this paper, to select the optimal mushroom oil, the component compositions (fatty acids, lipids, polyphenols, flavones, tocopherols, and unsaponifiable matters) and antioxidant activities in vitro of four mushroom oils (Agrocybe cylindracea, two Lentinula edodes, and Volvariella volvacea) were investigated and compared. The results showed that the four tested oils had the same fatty acid composition in different amounts, but the lipid component, minor components, and free radical scavenging activity in the tested oils varied widely depending on the type of mushroom. Overall, Volvariella volvacea oil was considered superior to the other three tested oils, as it had the largest contents of polar lipids, diglycerides, polyunsaturated fatty acids (74.38%), unsaponifiable matter (319.09 mg/kg), total phenols (124.08 mg/100 g), tocopherols (139.86 mg/100 g), as well as the highest ABTS and FRAP values (349.45 and 3801.70 µmol Trolox/100 g). This finding suggests that Volvariella volvacea oil is a promising resource that should be further researched.

The interaction of peptide inhibitors and Aß protein: Binding mode analysis, inhibition of the formation of Aß aggregates, and then exert neuroprotective effects.

Introduction: The misfolding and aggregation of ß-amyloid (Aß) easily form Aß fibers, which are continuously deposited in the brain, leading to the massive generation of amyloid plaques, severely destroying neuronal connections, and promoting Alzheimer's disease (AD) The occurrence and development of AD is one of the pathogenesis of AD. There is an urgent need to develop inhibitors against Aß aggregation, which is hopefully a potential way to treat AD. Methods: In this study, we first found the crystal structure of the Aß1-42 receptor protein from the RCSB PDB protein structure database and used the SYBYL X2.0 software for molecular docking, and then used the Peptide Ranker, Innovagen, DPL, and ToxinPred online websites to perform peptides. Predict the activity score, toxicity and water solubility, and then calculate the affinity constant KD value of polypeptide and Aß through Surface Plasmon Resonance (SPR) experiment. Subsequently, the CCK-8 kit method was used to determine the toxicity of different concentrations of peptides (3.125, 6.25, 12.5, 25, 50, 100, 200 µM) to PC12 cells, and then the peptides and Aß according to different concentration ratios (1:4, 1:2, 1:1, 1:0.5, 1:0.25, 0:4), this method is also used to detect the effect of peptides on Aß-induced neurotoxicity. The thioflavin T (ThT) fluorescence method was used to detect the effects of peptides (50 µM) on Aß (25 µM) aggregation inhibitory effect. Results: The results showed that the CScore of YVRHLKYVRHLK peptide molecule docking was 10.0608, the predicted activity score was 0.20, and the KD value was 5.385 × 10-5. The ThT and CCK-8 kit method found that the peptide itself is less toxic to PC12 cells at a concentration of 50 µM, and it has a significant inhibitory effect on the formation of Aß1-42 aggregates when incubated with Aß1-42 at a ratio of 1:1 (p < 0.05) and can significantly reduce the PC12 cytotoxicity induced by Aß1-42 (p < 0.05). Conclusion: In conclusion, the polypeptide YVRHLKYVRHLK designed in this study has a neuroprotective effect on PC12 cytotoxicity induced by Aß1-42. Graphical Abstract.

TRPV1: A promising therapeutic target for skin aging and inflammatory skin diseases.

TRPV1 is a non-selective channel receptor widely expressed in skin tissues, including keratinocytes, peripheral sensory nerve fibers and immune cells. It is activated by a variety of exogenous or endogenous inflammatory mediators, triggering neuropeptide release and neurogenic inflammatory response. Previous studies have shown that TRPV1 is closely related to the occurrence and/or development of skin aging and various chronic inflammatory skin diseases, such as psoriasis, atopic dermatitis, rosacea, herpes zoster, allergic contact dermatitis and prurigo nodularis. This review summarizes the structure of the TRPV1 channel and discusses the expression of TRPV1 in the skin as well as its role of TRPV1 in skin aging and inflammatory skin diseases.

Butyrate ameliorates colorectal cancer through regulating intestinal microecological disorders.

The occurrence and progression of colorectal cancer (CRC) are closely related to intestinal microecological disorders. Butyrate, the representative of short chain fatty acids, possess anti-inflammatory and antioxidant effects, and its antitumor effect has been gradually paid attention to. In this study, azoxymethane/dextran sodium sulfate induced mouse CRC model was used to explore the role and mechanism of butyrate in regulating colon cancer and its intestinal microecological balance. Outcomes exhibited that butyrate alleviated weight loss, disease activity index, and survival in CRC mice and inhibited tumor number and progression. Further research revealed that butyrate restrained the aggregation of harmful while promoting the colonization of beneficial flora, such as Actinobacteriota, Bifidobacteriales and Muribaculacea through 16S rDNA sequence analysis. This study confirmed that butyrate can ameliorate CRC by repairing intestinal microecology, providing ideas and evidence for chemical prophylactic agents, such as butyrate to remedy tumors and regulate tumor microbiota.

Effects of Weaning Modes on the Intestinal pH, Activity of Digestive Enzymes, and Intestinal Morphology of Piglets.

The present study investigated the effects of weaning modes on the intestinal pH, digestive enzyme activities, and intestinal morphology of piglets. A total of 27 litters of "Duroc boars × Landrace × Large White" piglets were selected and randomly divided into three groups. Those groups were the conventional weaning group (C), the odorant spray group (S), and the weaning-after-mixing group (M), with three repeats in each group and three litters in each repeat. The experiment began seven days before weaning, and ended seven days after weaning. The piglets were euthanized on the eighth day after weaning, and the jejunum and ileum tissues and contents were sampled. The pH and enzyme activities of the intestinal contents were determined, and the intestinal morphologies were revealed using H&E staining. It was concluded that a 2% glutaraldehyde spray on the body surfaces of piglets after weaning could increase average weight after nursery, lower intestinal pH, increase the activities of digestive enzymes, improve intestinal morphology, and relieve weaning stress. It was also found that weaning after mixing could increase the average weight after nursery, lower intestinal pH, improve intestinal morphology, and reduce weaning stress.

The efficacy and safety of Zengxiao Jiandu decoction combined with definitive concurrent chemoradiotherapy for unresectable locally advanced non-small cell lung cancer: a randomized, double-blind, placebo-controlled clinical trial.

Background: Traditional Chinese medicine (TCM) makes a synergistic and attenuative effect when combined with chemoradiotherapy. However, strong evidence-based studies are lacking. The study sought to investigate whether Zengxiao Jiandu decoction as an adjunctive therapy is superior to definitive concurrent chemoradiotherapy (DCCRT) alone in unresectable, locally advanced (LA), stage III non-small cell lung cancer (NSCLC). Methods: Patients with unresectable LA-NSCLC were randomly assigned to receive DCCRT either combined with Zengxiao Jiandu decoction (TCM arm) or placebo therapy (Control arm), by computer-generated random assignment lists using a central randomization system. The patients were routinely followed-up every 3 months for the first 2 years after the therapy, and every 6 months for the subsequent 3 years, or earlier if clinically indicated. The primary endpoint was grade ≥3 chemoradiotherapy-related toxicities, while secondary endpoints included the completion rate of chemoradiotherapy, the clinical objective response rate (ORR), and survival. The placebo achieved full consistency in color, aroma, taste and appearance with the Zengxiao Jiandu decoction. Results: From February 2019 to December 2020, 163 patients were randomly allocated to TCM arm (n=82) or Control arm (n=81). Fifty-nine (72.0%) patients in TCM arm finished chemoradiotherapy per protocol and 79 (96.3%) received protocol-specified Zengxiao Jiandu decoction. Forty-two patients in Control arm finished chemoradiotherapy per protocol. The incidence of grade ≥3 chemoradiotherapy-related toxicities was higher in Control arm than TCM arm (44.4% vs. 31.7%, P=0.094). Grade ≥3 radiation pneumonitis occurred more frequently in Control arm than TCM arm (13.6% vs. 3.7%, P=0.024). The completion rate of the protocol-specified chemotherapy was significantly higher in TCM arm than Control arm (79.3% vs. 64.2%, P=0.033), but the completion rates of the definitive-dose radiotherapy were similar. There were no significant differences in ORR between the 2 arms. The progression-free survival (PFS) of TCM arm was significantly better than Control arm (median PFS, 12.0 vs. 9.0 months, P=0.035). However, Zengxiao Jiandu decoction was not found to produce any significant benefit in overall survival. Conclusions: The Zengxiao Jiandu decoction adjunctive therapy, as compared to DCCRT alone, reduced grade ≥3 radiation pneumonitis, improved the completion rate of DCCRT, and prolonged PFS for unresectable LA-NSCLC. Trial Registration: Chinese Clinical Trial Registry ChiCTR2000031667.

Transient Receptor Potential Vanilloid1 (TRPV1) Channel Opens Sesame of T Cell Responses and T Cell-Mediated Inflammatory Diseases.

Transient receptor potential vanilloid1 (TRPV1) was primarily expressed in sensory neurons, and could be activated by various physical and chemical factors, resulting in the flow of extracellular Ca2+ into cells. Accumulating data suggest that the TRPV1 is expressed in some immune cells and is a novel regulator of the immune system. In this review, we highlight the structure and biological features of TRPV1 channel. We also summarize recent findings on its role in modulating T cell activation and differentiation as well as its protective effect in T cell-mediated inflammatory diseases and potential mechanisms.

Self-administration of complex decongestive therapy facilitated by the mobile application WeChat improves lymphedema and quality of life in breast cancer survivors: an observational study.

Background: Lymphedema is the most common complication of breast cancer patients. Complex decongestive therapy (CDT) is often recommended but the efficacy varies due to the complexity of management. This study investigated a novel model of CDT based on a mobile application with the aim of improving the management of lymphedema in China. Methods: We developed a novel model of CDT for breast cancer survivors with lymphedema, including 5 days of CDT therapy with training provided by medical staff in the outpatient clinic and 3 weeks of self-administrated CDT with daily online instructions during phase I, and a life-long maintenance treatment with online instructions once a week for phase II, which delivered by WeChat public accounts. The breast cancer and lymphedema symptom experience index (BCLE-SEI) and the Short-Form Health Survey (SF-36) were used to assess lymphatic symptoms and quality of life. Arm volume and lymphatic symptoms were assessed at baseline, and at 5 days, 1 month, and 3 months post-treatment. The quality of life was assessed at baseline and at 3 months post-treatment. Results: A total of 88 patients with lymphedema were recruited, of whom, 61 followed the protocols and were further analyzed for this study. The mean relative excess arm volume (EAV) was reduced from a baseline value of 30.72% to 22.05%, 18.46%, and 16.67% at 5 days, 1 month, and 3 months post-therapy, respectively (P=0.000). The BCLE-SEI scores of lymphatic pain, heaviness, and impaired limb mobility were all significantly improved after 3 months of treatment (P<0.05). Moreover, according to the subscale of SF-36, the general health and vitality were significantly improved after 3 months of therapy (56.64 vs. 62.93, P=0.008; and 64.26 vs. 70.08, P=0.024, respectively). Conclusions: The proposed model of CDT based on the mobile application WeChat achieved promising outcomes. The volume of the affected arm, the lymphedema symptoms, and the quality of life were all significantly improved.

Comparison of stereotactic body radiotherapy and radiofrequency ablation for early-stage non-small cell lung cancer: a systematic review and meta-analysis.

Background: Stereotactic body radiation therapy (SBRT) and radiofrequency ablation (RFA) are recommended for patients with inoperable early-stage non-small cell lung cancer (NSCLC), with both offering promising results. However, it is largely unknown which of these two treatment modalities provides superior benefits for patients. Therefore, this systematic review and meta-analysis compared clinical outcomes and safety between SBRT and RFA in patients with inoperable early-stage NSCLC. Methods: Eligible studies published between 2001 and 2020 were obtained through a comprehensive search of the PubMed, Medline, Embase, and Cochrane Library databases. Original English-language studies on the treatment of early-stage NSCLC with SBRT or RFA were included. Local control (LC) rates, overall survival (OS) rates, and adverse events were obtained by pooled analyses. Results: Eighty-seven SBRT studies (12,811 patients) and 18 RFA studies (1,535 patients) met the eligibility criteria. For SBRT, the LC rates (with 95% confidence intervals) at 1, 2, 3, and 5 years were 98% (97-98%), 95% (95-96%), 92% (91-93%), and 92% (91-93%), respectively, which were significantly higher than those for RFA [75% (69-82%), 31% (22-39%), 67% (58-76%), and 41% (30-52%), respectively] (P<0.01). There were no significant differences in short-term OS between SBRT and RFA [1-year OS rate: 87% (86-88%) versus 89% (88-91%), P=0.07; 2-year OS rate: 71% (69-72%) versus 69% (64-74%), P=0.42]. Regarding long-term OS, the 3- and 5-year OS rates for SBRT were 58% (56-59%) and 39% (37-40%), respectively, which were significantly (P<0.01) superior to those for RFA [48% (45-51%) and 21% (19-23%), respectively]. The most common complication of SBRT was radiation pneumonitis (grade ≥2), making up 9.1% of patients treated with SBRT, while pneumothorax was the most common complication of RFA, making up 27.2% of patients treated with RFA. Discussion: Compared with RFA, SBRT has superior LC and long-term OS rates but similar short-term OS rates. Prospective randomized trials with large sample sizes comparing the efficacy of SBRT and RFA are warranted.

Postoperative radiotherapy improves survival of patients with ypN2 non-small cell lung cancer after neoadjuvant chemotherapy followed by surgery - A propensity score matching study of the Surveillance, Epidemiology, and End Results database.

BACKGROUND: For patients with ypN2 non-small cell lung cancer (NSCLC) after neoadjuvant chemotherapy followed by surgery (NCS), the role of postoperative radiotherapy (PORT) is unclear. The aim of our study was to evaluate the effect of PORT on survival of ypN2 NSCLC patients after NCS. METHODS: Between 2004 and 2015, patients with ypN2 NSCLC after NCS were filtrated from the Surveillance, Epidemiology, and End Results (SEER) database. Propensity score matching (PSM) was used to balance the baseline characteristics of the PORT and non-PORT groups. Kaplan-Meier method and Cox proportional hazards models were adopted to estimate overall survival (OS) and cancer-specific survival (CSS). RESULTS: A total of 257 patients who met the criteria were included in the study. After PSM, 115 patients remained in each group. The survival of patients in the PORT group was significantly better than those in the non-PORT group. Median OS was 36 months vs. 26 months, and 5-year OS rate was 40.5% vs. 21.0% (p = 0.002). The median CSS was 38 months vs. 27 months, and the 5-year CSS rate was 43.7% vs. 22.1% (p < 0.001). Multivariable analysis showed that PORT was an independent prognostic factor for OS (HR = 0.59, 95% CI: 0.43-0.82, p = 0.001) and CSS (HR = 0.56, 95% CI: 0.41-0.78, p = 0.001). Subgroup analysis showed that patients in the following subgroups could benefit from PORT: age ≤ 70, diagnosed in the later period (2010-2015), white race, squamous cell carcinoma, grade III-IV, lobectomy, stage T3-4, or with positive regional nodes ≤3 or > 3. CONCLUSIONS: For patients with ypN2 NSCLC after NCS, PORT significantly improves OS and CSS. These results need to be confirmed by further randomized studies.

A Nomogram for Predicting Brain Metastasis in IIIA-N2 Non-Small Cell Lung Cancer After Complete Resection: A Competing Risk Analysis.

BACKGROUND: Brain metastasis (BM) is one of the most common failure patterns of pIIIA-N2 non-small cell lung cancer (NSCLC) after complete resection. Prophylactic cranial irradiation (PCI) can improve intracranial control but not overall survival. Thus, it is particularly important to identify the risk factors that are associated with BM and subsequently provide instructions for selecting patients who will optimally benefit from PCI. METHODS AND MATERIALS: Between 2011 and 2014, patients with pIIIA-N2 NSCLC who underwent complete resection in our institution were reviewed and enrolled in the study. Clinical characteristics, pathological parameters, treatment mode, BM time, and overall survival were analyzed. A nomogram was built based on the corresponding parameters by Fine and Gray's competing risk analysis to predict the 1-, 3-, and 5-year probabilities of BM. Receiver operating characteristic curves and calibration curves were chosen for validation. A statistically significant difference was set as P <0.05. RESULTS: A total of 517 patients were enrolled in our retrospective study. The median follow-up time for surviving patients was 53.2 months (range, 0.50-123.17 months). The median age was 57 (range, 25-80) years. Of the 517 patients, 122 (23.6%) had squamous cell carcinoma, 391 (75.6%) received adjuvant chemotherapy, and 144 (27.3%) received post-operative radiotherapy. The 1-, 3-, and 5-year survival rates were 94.0, 72.9, and 66.0%, respectively. The 1-, 3-, and 5-year BM rates were 5.4, 15.7, and 22.2%, respectively. According to the univariate analysis, female, non-smokers, patients with non-squamous cell carcinoma, bronchial invasion, perineural invasion, and patients who received adjuvant chemotherapy were more likely to develop BM. In a multivariate analysis, non-squamous cell carcinoma (subdistribution hazard ratios, SHR: 3.968; 95% confidence interval, CI: 1.743-9.040; P = 0.0010), bronchial invasion (SHR: 2.039, 95% CI: 1.325-3.139; P = 0.0012), perineural invasion (SHR: 2.514, 95% CI: 1.058-5.976; P = 0.0370), and adjuvant chemotherapy (SHR: 2.821, 95% CI: 1.424-5.589; P = 0.0030) were independent risk factors for BM. A nomogram model was established based on the final multivariable analysis result. The area under the curve was 0.767 (95% CI, 0.758-0.777). CONCLUSIONS: For patients with IIIA-N2 NSCLC after complete resection, a nomogram was established based on clinicopathological factors and treatment patterns for predicting the BM. Based on this nomogram, patients with a high risk of BM who may benefit from PCI can be screened.

Additional Radiotherapy With or Without Chemotherapy Following Endoscopic Resection for Stage I Esophageal Carcinoma: A Pilot Study.

Objective: To evaluate the safety and efficacy of additional radiotherapy after endoscopic resection (ER) for stage I esophageal carcinoma (EC) with high-risk factors. Materials and methods: Patients with stage cT1N0M0 EC who underwent ER and additional radiotherapy between January 2010 and August 2019 at our institution were retrospectively included. Overall survival (OS), disease-free survival (DFS), cancer-specific survival (CSS), local control rate, regional control rate, common acute toxicities, esophageal stricture, and dysphagia were analyzed. Results: Thirty-one consecutive patients were included in the study. The median age was 62 years (range, 49-78). Thirty patients (96.8%) had squamous cell carcinoma, and one patient (3.2%) had adenosquamous cell carcinoma. Twenty-six patients (83.9%) had submucosal invasion, 15 patients (48.4%) had lymphovascular invasion, and one patient (3.2%) had a venous invasion. The 1-, 3-, and 5-year OS rates were 100.0%, 86.9%, and 68.5%, respectively. The corresponding DFS rates were 100.0%, 85.2%, and 75.8%, respectively. The corresponding CSS rates were 100.0%, 89.8%, and 78.6%, respectively. The local and regional control rates were 100.0% and 93.5%, respectively. No grade 4-5 acute toxicities were observed. Fifteen patients (48.4%) were endoscopically diagnosed with esophageal strictures after ER. At the last follow-up, 28 patients (90.5%) were able to eat a regular diet, one patient (3.2%) could eat a soft diet, one needed a semifluid diet, and only one (3.2%) had to eat a fluid diet. Conclusions: For patients with stage I EC, additional radiotherapy following ER is safe and effective, with the swallowing function well-preserved. Nevertheless, prospective studies are needed to verify these results.

A Propensity-Matched Analysis of Survival of Clinically Diagnosed Early-Stage Lung Cancer and Biopsy-Proven Early-Stage Non-Small Cell Lung Cancer Following Stereotactic Ablative Radiotherapy.

PURPOSE: Stereotactic body radiotherapy (SBRT) has been increasingly regarded as a reasonable option for early-stage lung cancer patients without pretreatment pathologic results, but the efficacy and safety in a Chinese population remains unclear. The aim of this study was to compare survival outcomes and toxicities between patients with clinically diagnosed early-stage lung cancer or biopsy-proven early-stage non-small cell lung cancer and to demonstrate the rationality of this treatment. MATERIAL AND METHODS: From May 2012 to December 2018, 56 patients with clinically diagnosed early-stage lung cancer and 60 patients with early-stage biopsy-proven were selected into non-pathological group and pathological group, respectively. Propensity score matching (PSM) was performed to reduce patient selection bias. Survival analysis with log-rank test was used to assess the differences of treatment outcomes, which included local control (LC), progression-free survival (PFS), and overall survival (OS). RESULTS: The median age was 76 (range 47-93) years, and the median follow-up time was 58.3 (range 4.3-95.1) months in the cohort without pathologic results. The median age was 74 (range 57-88) years, and the median follow-up time was 56.3 (range 2.6-94) months in the cohort with pathologic results. 45 matched-pair were analyzed. The 5-year LC, PFS, and OS rates in matched-pair patients with or without pathologic biopsy were 85.5% and 89.8%, 40.6% and 70.9%, and 63.2% and 76.1%, respectively. On Kaplan-Meier survival analysis after PSM analysis, there was no significant difference between patients with pathologic results versus patients with no pathologic results in terms of LC (P= 0.498) and OS (P=0.141). Of the matched-pair patients treated with SBRT, only 1 patient experienced grade 3 or above radiation pneumonitis. CONCLUSION: For early-stage lung cancer patients with medically inoperable or not suitable for invasive diagnosis, SBRT may be a good local treatment.

The association between the ERCC1/2 polymorphisms and radiotherapy efficacy in 87 patients with non-small cell lung cancer.

BACKGROUND: This study sought to investigate the association between the ERCC1/2 single-nucleotide polymorphisms (SNPs) and the efficacy of radiotherapy and prognosis in patients with non-small cell lung cancer (NSCLC). METHODS: We examined 6 SNPs in the ERCC1 and ERCC2 genes in 87 consecutive patients with NSCLC who were treated with definitive radiotherapy. The objective remission rates (ORR), overall survival (OS), and progressive-free survival (PFS) were assessed. A Cox regression analysis was conducted to analyze the independent factors related to death and recurrence. RESULT: Patients with the G allele had better OS than patients with the A allele, and there was a statistical difference between the two groups (30.9 vs. 16.2 months; P=0.003). Patients with the AA genotype had significantly worse OS than patients with the AG or GG genotypes (6.8 vs. 19.8 vs. 30.9 months, respectively; P=0.000). The median PFS of the G allele was 18.9 months, which was significantly better than that of the A allele (P=0.040). The median PFS of patients with the GG genotype, the AG genotype, and the AA genotype was 18.9, 11.3, and 5.1 months, respectively; the difference among the three groups was statistically significant (P=0.019). Patients with the G allele also had better PFS than those with the A allele (18.9 vs. 11.3 months, P=0.040). The multivariate cox proportional hazard analysis showed that the ERCC1 gene rs11615 was an independent survival indicator [HR: 1.623, 95% confidence interval (CI): 1.018-2.591, P=0.042] but not an independent recurrence indicator (HR: 1.497, 95% CI: 0.932-2.404, P=0.095). CONCLUSIONS: The ERCC1 rs11615 SNP may be a potential biomarker for predicting survival prognosis in Chinese NSCLC patients who have undergone definitive radiotherapy. Patients with the G allele had better OS than those with the A allele.

Effect of Postoperative Radiotherapy for Patients With pIIIA-N2 Non-Small Cell Lung Cancer After Complete Resection and Adjuvant Chemotherapy: The Phase 3 PORT-C Randomized Clinical Trial.

IMPORTANCE: The role of postoperative radiotherapy (PORT) has not been well defined in resected pIIIA-N2 non-small cell lung cancer (NSCLC). OBJECTIVE: To evaluate the effect of PORT using modern techniques on survival and safety in patients with pIIIA-N2 NSCLC after complete resection and adjuvant chemotherapy. DESIGN, SETTING, AND PARTICIPANTS: The PORT-C randomized clinical trial was conducted in 394 patients with pIIIA-N2 NSCLC treated with complete resection and 4 cycles of platinum-based chemotherapy between January 2009 and December 2017. Data were analyzed between March 2019 and December 2020. INTERVENTIONS: Patients were randomized equally into the PORT arm (n = 202) or the observation arm (n = 192). The total dose of PORT was 50 Gy. MAIN OUTCOMES AND MEASURES: The primary end point was disease-free survival (DFS). Secondary end points included overall survival (OS), locoregional recurrence-free survival (LRFS), distant metastasis-free survival, and toxic effects. RESULTS: In total, 394 patients were enrolled and 364 were eligible, with a median (range) age of 55 (25-70) years. There were 202 (55.5%) male and 162 (44.5%) female patients. The median follow-up was 46.0 (95% CI, 41.9-51.4) months, and 230 DFS events were reported. There were 184 patients in the PORT arm and 180 patients in the observation arm. The 3-year DFS rates were 40.5% with PORT vs 32.7% with observation (median, 22.1 vs 18.6 months), and the difference in DFS was not statistically significant without adjustment (hazard ratio [HR], 0.84; 95% CI, 0.65-1.09; P = .20), though it was significant with preplanned yet exploratory analysis (stratified analysis by the number of detected lymph nodes and positive lymph nodes, HR, 0.75; log-rank P = .04). The 3-year OS rates were 78.3% vs 82.8% (HR, 1.02; P = .93), and LRFS was 66.5% vs 59.7% (HR, 0.71; 95% CI, 0.51-0.97; P = .03), respectively. For 310 per-protocol patients (140 with PORT and 170 with observation), PORT significantly improved DFS (42.8% vs 30.6%; HR, 0.75; 95% CI, 0.57-1.00; P = .05) but not OS (HR, 0.83; 95% CI, 0.53-1.30; P = .41). The 3-year local recurrence only rates were 9.5% and 18.3% in the 2 arms, respectively (Fine-Gray HR, 0.55; Gray test P = .04). No radiotherapy-related grade 4 or 5 adverse event was observed. CONCLUSIONS AND RELEVANCE: In this phase 3 randomized clinical trial of patients with pIIIA-N2 NSCLC after complete resection and adjuvant chemotherapy, PORT did not improve DFS. Further studies exploring patients who might best benefit from PORT are needed. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT00880971.

mtROS-mediated Akt/AMPK/mTOR pathway was involved in Copper-induced autophagy and it attenuates Copper-induced apoptosis in RAW264.7 mouse monocytes.

Copper (Cu) is a trace element necessary in animals as well as human beings. However, excessive Cu is toxic to immunocytes, but the precise mechanism is largely unclear so far. This work was conducted aiming to examine the Cu-mediated autophagy mechanism together with its role in Cu toxicology in RAW264.7 cells. Here, we demonstrated that CuSO4 reduced the cell viability depending on its dose. CuSO4 could obviously increase autophagy in RAW264.7 cells. According to the obtained results, CuSO4 induced autophagy through Akt/AMPK/mTOR pathway which characterized by down regulation of p-Akt (Ser473)/Akt, p-mTOR/mTOR, p-ULK1(Ser757)/ULK1 and subsequent up-regulation of p-AMPKα/AMPKα and p-ULK1(Ser555)/ULK1. Furthermore, CuSO4 significantly induced the production of mitochondrial reactive oxygen species (mtROS). In addition, CuSO4-mediated apoptosis and autophagy might be suppressed through suppressing mtROS generation by exposure to Mito-TEMPO. Intriguingly, autophagy promotion with rapamycin could decrease the apoptosis and the inhibition of autophagy with knock down Atg5 could enhance the apoptosis induced by CuSO4. Moreover, our results suggested that mtROS is the original cause in CuSO4-induced apoptosis and autophagy. Additionally, CuSO4 induced autophagy through mtROS-dependent Akt/AMPK/mTOR signalling pathwayin RAW264.7 cells. Moreover, autophagy activation might potentially generate a protection mechanism for improving CuSO4-induced RAW264.7 cell apoptosis.

Postoperative radiotherapy for pathological stage IIIA-N2 non-small cell lung cancer with positive surgical margins.

BACKGROUND: The aim of this study was to evaluate the efficacy of postoperative radiotherapy (PORT) in stage pIIIA-N2 non-small cell lung cancer (NSCLC) patients with positive surgical margins. METHODS: Between January 2003 and December 2015, patients who had undergone lobectomy or pneumonectomy plus mediastinal lymph node dissection or systematic sampling in our single institution were retrospectively reviewed. Those with pIIIA-N2 NSCLC and positive surgical margins were enrolled into the study. The Kaplan-Meier method was used for survival analysis, and the log-rank test was used to analyze differences between the groups. Univariate and multivariate analyses using Cox proportional hazards regression models were performed to evaluate potential prognostic factors for OS. Statistically significant difference was set as P < 0.05. RESULTS: Of all the 1547 patients with pIIIA-N2 NSCLC reviewed, 113 patients had positive surgical margins, including 76 patients with R1 resection and 37 with R2 resection. The median overall survival (OS) was 28.3 months in the PORT group and 22.6 months in the non-PORT group (P = 0.568). Subset analysis showed that for patients with R1 resection, the median OS was 52.4 months in the PORT group which was nonsignificantly longer than that of 22.6 months in the non-PORT group (P = 0.127), whereas PORT combined with chemotherapy could significantly improve OS, with a median OS of 52.4 months versus 17.2 months (P = 0.027). For patients with R2 resection, PORT made no significant difference in OS (17.6 vs. 63.8 months, P = 0.529). CONCLUSIONS: For pIIIA-N2 NSCLC patients with positive surgical margins, PORT did not improve OS, but OS was improved in those patients who underwent R1 resection combined with chemotherapy. KEY POINTS: SIGNIFICANT FINDINGS OF THE STUDY: Significant findings of the study: Postoperative radiotherapy (PORT) has been recommended to treat patients with positive surgical margins. However, the existing evidence is controversial and high-level evidence is lacking. WHAT THIS STUDY ADDS: What this study adds: The PORT group had markedly, but not statistically significant, longer median OS compared with the non-PORT group in patients with R1 resection. OS was significantly longer in the patients with R1 resection receiving adjuvant CRT than the surgery alone group.

High vs. Low Radiation Dose of Concurrent Chemoradiotherapy for Esophageal Carcinoma With Modern Radiotherapy Techniques: A Meta-Analysis.

Purpose: The aim of this study was to evaluate the clinical benefit of different radiation doses in concurrent chemoradiotherapy (CCRT) for esophageal carcinoma using modern radiotherapy techniques. Methods: A systematic review was conducted by screening PubMed, EMBASE, Cochrane Central Register of Controlled Trials, SCOPUS, Wanfang, and Chinese National Knowledge Infrastructure (CNKI) databases with prespecified searching strategy. Studies which compared high radiation dose group with low-dose radiation group using modern radiotherapy techniques for esophageal cancer patients in CCRT were identified. The hazard ratios (HR) for overall survival (OS) and the odds ratios (OR) for local-regional failure (LRF), distant metastasis (DM), and toxicities were considered as the outcomes of interest. R 3.6.2 software was used for statistical analysis. Results: Twelve studies involving 10,896 patients were included for analyses. The results showed that the high-dose group had better OS (HR = 0.79, 95% CI = 0.70-0.90, P = 0.0004) and the local-regional control (OR = 0.59, 95% CI = 0.46-0.76, P < 0.0001), especially for patients who were diagnosed with squamous cell carcinoma (SCC). The subgroup analyses further indicated that ≥ circa 60 Gy can significantly improve the OS (HR = 0.73, 95% CI = 0.68-0.80, P < 0.0001) as well as the local-regional control (OR = 0.54, 95% CI = 0.40-0.74, P < 0.0001) as compared with < circa 60 Gy. Another subgroup analysis comparing ≤ 50.4 Gy with > 50.4 Gy showed no substantial difference in OS (HR = 0.98, 95% CI = 0.93-1.03, P = 0.43). In addition, there are no significant differences between the two groups in grade 3-5 radiation pneumonitis (OR = 1.05, 95% CI = 0.54-2.05, P = 0.89), grade 3-5 radiation esophagitis (OR = 1.40, 95% CI = 0.93-2.11, P = 0.11), treatment-related death (OR = 1.60, 95% CI = 0.70-3.66, P = 0.27), and DM (OR = 1.21, 95% CI = 0.92-1.59, P = 0.17). Conclusions: For esophageal carcinoma receiving CCRT with modern radiation techniques, evidence suggested that high-dose radiotherapy, especially ≥circa 60 Gy, had potentials to improve the OS and local-regional control without increase in severe toxicities when compared with low-dose radiotherapy. The result needs to be confirmed by randomized clinical trials.

Combined neat model for the prognosis of postoperative stage III-N2 non-small cell lung cancer.

BACKGROUND: Lung cancer serum tumor markers including carcinoembryonic antigen (CEA), cytokeratin 19 fragment (CYFRA21-1), and carbohydrate antigen 125(CA125) as prognostic predictors is controversial. Therefore, this study aimed to evaluate the association between these markers and the survival of patients with postoperative stage III-N2 non-small cell lung cancer (NSCLC). METHODS: We enrolled 1011 patients with pathologically confirmed stage III-N2 NSCLC who underwent resection and whose pretreatment serum tumor marker levels were available. Patients were categorized according to their serum levels into low-, medium-, and high-risk groups. Overall survival (OS), progression-free survival (PFS), local regional relapse-free survival (LRFS), and distant metastasis-free survival (DMFS) were calculated from the date of resection. Their association with each serum tumor marker was assessed using the log-rank test. RESULTS: Abnormal CEA levels were associated with worse five-year OS, PFS and DMFS; abnormal CYFRA21-1 levels were associated with worse five-year OS and LRFS; and abnormal CA125 levels were associated with worse five-year OS, PFS, LRFS and DMFS. Among the risk groups, there were significant differences in five-year OS, PFS, LRFS and DMFS (P = 0.000). In propensity score matching analysis, the model also achieved prognostic significance for all four survival classifications (P = 0.001-0.004) among the three risk groups. CONCLUSIONS: The combined model achieved prognostic significance for all survival outcome types. The serum tumor markers tested are useful prognostic predictors for postoperative NSCLC patients but not for all survival outcomes. The combination of the three indices is more reliable in predicting all four of the survival outcomes. KEY POINTS: SIGNIFICANT FINDINGS OF THE STUDY: Serum CEA, CYFRA21-1, and CA125 levels can be used as prognostic factors of postoperative N2 non-small cell lung cancer patients but not for all survival outcomes, suggesting that combinative detection of all three indices would be more reliable. WHAT THIS STUDY ADDS: Our model utilizes available technology, with conventional cutoff values, inexpensive costs, and simple mathematics methods and, thus, can be feasibly employed by clinicians or oncologists.