A nomogram to predict the cumulative risk for brain metastases in patients with limited-stage small cell lung cancer without prophylactic cranial irradiation.

OBJECTIVE: Patients with small cell lung cancer (SCLC) have a high risk of developing brain metastases (BM). Prophylactic cranial irradiation (PCI) is a standard therapy for limited-stage SCLC (LS-SCLC) patients who achieved complete or partial response after thoracic chemoradiotherapy (Chemo-RT). Recent studies have indicated that a subgroup of patients with a lower risk of BM can avoid PCI, and the present study therefore tries to construct a nomogram to predict the cumulative risk of development of BM in LS-SCLC patients without PCI. METHODS: After screening of 2298 SCLC patients who were treated at the Zhejiang Cancer Hospital from December 2009 to April 2016, a total of 167 consecutive patients with LS-SCLC who received thoracic Chemo-RT without PCI were retrospectively analyzed. The paper analyzed clinical and laboratory factors that may be correlated with BM, such as response to treatment, pretreatment serum neuron-specific enolase (NSE) and lactate dehydrogenase (LDH) levels, and TNM stage. Thereafter, a nomogram was constructed to predict 3­ and 5­year intracranial progression-free survival (IPFS). RESULTS: Of 167 patients with LS-SCLC, 50 developed subsequent BM. Univariate analysis showed that pretreatment LDH (pre-LDH) ≥ 200 IU/L, an incomplete response to initial chemoradiation, and UICC stage III were positively correlated to a higher risk of BM (p < 0.05). Multivariate analysis identified pretreatment LDH level (hazard ratio [HR] 1.90, 95% confidence interval [CI] 1.08-3.34, p = 0.026), response to chemoradiation (HR 1.87, 95% CI 1.04-3.34, p = 0.035), and UICC stage (HR 6.67, 95% CI 1.03-49.15, p = 0.043) as independent predictors for the development of BM. A nomogram model was then established, and areas under the curve of 3­year and 5­year IPFS were 0.72 and 0.67, respectively. CONCLUSION: The present study has developed an innovative tool that is able to predict the individual cumulative risk for development of BM in LS-SCLC patients without PCI, which is beneficial for providing personalized risk estimates and facilitating the decision to perform PCI.

Circ_0001955 promotes non-small cell lung cancer cell proliferation and invasion by regulating MiR-29a-3p/NKIRAS2 axis to activate the nuclear factor-κB pathway.

Non-small cell lung cancer (NSCLC) is one of the most common malignant tumors worldwide. Circular RNAs (circRNAs) have been widely reported to play a role in the pathogenesis of various tumors. Nevertheless, the function of circ_0001955 in NSCLC progression has not been explored yet. This study aims to explore the functions of circ_0001955 in NSCLC and investigate its regulatory molecular mechanism. First, we determined that circ_0001955 was upregulated in NSCLC cells. Subsequently, we demonstrated that knockdown of circ_0001955 restrained cell proliferation and invasion. In vivo experiments further proved the suppressive effect of circ_0001955 silence on tumor growth. Mechanism assays revealed that circ_0001955 enhanced nuclear factor-κB (NF-κB) inhibitor interacting Ras-like protein 2 (NKIRAS2) expression by sponging microRNA-29a-3p (miR-29a-3p). Upregulation of NKIRAS2 led to the deceased level of IκBß but increased levels of nuclear p65, thus activating the NF-κB signaling pathway. In conclusion, Circ_0001955 activates the NF-κB pathway to promote NSCLC cell proliferation and invasion by regulating miR-29a-3p/NKIRAS2 axis.

Serum lactate dehydrogenase predicts brain metastasis and survival in limited-stage small cell lung cancer patients treated with thoracic radiotherapy and prophylactic cranial irradiation.

BACKGROUND: Small cell lung cancer (SCLC) is characterized by a high risk of brain metastasis and poor survival. This study aims to assess the prognostic role of lactate dehydrogenase (LDH) in limited-stage small cell lung cancer (LS-SCLC) treated with thoracic radiotherapy (TRT) and prophylactic cranial irradiation (PCI). METHODS: This study retrospectively evaluated 197 consecutive patients who underwent TRT and PCI for LS-SCLC between November 2005 and October 2017. Both pretreatment and maximal serum LDH levels (mLDH) during treatment were checked, and an increased LDH level was defined as more than 240 IU/ml. Clinical factors were tested for associations with intracranial progression-free survival (IPFS) and overall survival (OS) after PCI. The Kaplan-Meier method was used to calculate survival rates, and multivariate Cox regression analyses were carried out to identify variables associated with survival. RESULTS: Of the total patients, 28 had higher pretreatment LDH levels and mLDH levels were increased in 95 patients during treatment. In patients in the normal and elevated mLDH groups, the 1­, 2­, and 5­year IPFS rates were 96.7% vs. 90.1%, 91.7% vs. 73.8%, and 87.8% vs. 61.0% (P < 0.01), respectively. Compared to those with normal LDH levels, patients with increased mLDH levels had a higher cumulative risk of intracranial metastasis (hazard ratio [HR] 3.87; 95% confidence interval [CI] 1.73-8.63; P < 0.01) and worse overall survival (HR 2.59; 95% CI 1.67-4.04; P < 0.01). The factors LDH level at baseline or changes between pretreatment level and maximum level during treatment failed to predict brain metastases or OS with statistical significance. In the multivariate analyses, both mLDH during treatment (HR 3.53; 95% CI 1.57-7.92; P = 0.002) and patient age ≥ 60 (HR 2.46; 95% CI 1.22-4.94; P = 0.012) were independently associated with worse IPFS. Factors significantly associated with worse OS included mLDH during treatment (HR 2.45; 95% CI 1.56-3.86; P < 0.001), IIIB stage (HR 1.75; 95% CI 1.06-2.88; P = 0.029), and conventional radiotherapy applied in TRT (HR 1.66; 95% CI 1.04-2.65; P = 0.034). CONCLUSION: The mLDH level during treatment predicts brain metastasis and survival in LS-SCLC patients treated with TRT and PCI, which may provide valuable information for identifying patients with poor survival outcomes and possible candidates for treatment intensification.

Targeting lactate dehydrogenase a improves radiotherapy efficacy in non-small cell lung cancer: from bedside to bench.

BACKGROUND: Lactate dehydrogenase A (LDHA) is overexpressed and associated with poor prognosis in many kinds of cancer. In the current study, we evaluated the prognostic value of LDHA expression in non-small cell lung cancer (NSCLC), and tested whether LDHA inhibition might improve radiotherapy efficacy in NSCLC. METHODS: LDHA expression was investigated in NSCLC patients, using online database and further verified by immunohistochemistry. The prognostic value of LDHA was evaluated using Kaplan-Meier plotter database. In vitro, two NSCLC cell lines were pretreated with oxamate, an inhibitor of LDHA, and colony formation method was performed to determine cellular radiosensitivity. Comet assay was used to detect DNA damage after irradiation. Flow cytometry was applied to test cell cycle progression and apoptosis, and monodansylcadaverine (MDC) staining was used to examine cell autophagy. RESULTS: Both mRNA and protein levels of LDHA expression were up-regulated in NSCLC tissues. High LDHA expression was a poor prognostic factor and associated with radioresistance in NSCLC patients. LDHA inhibition by oxamate remarkably increased radiosensitivity in both A549 and H1975 cancer cells, and enhanced ionizing radiation (IR)-induced apoptosis and autophagy, accompanied by cell cycle distribution alternations. Furthermore, LDHA inhibition induced reactive oxygen species (ROS) accumulation and cellular ATP depletion, which might increase DNA injury and hinder DNA repair activity. CONCLUSIONS: Our study suggests that inhibition of LDHA may be a potential strategy to improve radiotherapy efficacy in NSCLC patients, which needs to be further tested by clinical trials.

Elevated platelet count is a strong predictor of poor prognosis in stage I non-small cell lung cancer patients.

Stage I non-small cell lung cancer (NSCLC) show a highly variable biological behavior which cannot be accurately predicted by the current available prognostic markers. Platelet plays a significant role in cancer cell growth, progression and metastasis. This study aimed to investigate whether preoperative platelet count correlate with clinical prognosis in localized NSCLC. A retrospective clinical analysis was designed for a total of 234 stage I NSCLC patients in our hospital between October 2006 and December 2009. Pre-operative platelet count was measured. The association of platelet count with clinical pathological factors and patient outcome was evaluated. A significant correlation was detected between platelet count and tumor cell differentiation and T stage. Patients with elevated platelet count had an elevated risk of disease progression and death compared to patients with normal platelet count. The hazard ratio was 5.314 (95% confidence interval [CI] 2.750-10.269) for disease progression and 3.139 (95% CI 1.227-8.034) for death. The trend linking increasing platelet count with risk was also statistically significant for both the outcomes (p < 0.05). These finding demonstrate that preoperative platelet count is a useful predictor of high risk progression and poor prognosis in stage I NSCLC patients.

Comprehensive characterization of pyroptosis phenotypes with distinct tumor immune profiles in gastric cancer to aid immunotherapy.

OBJECTIVE: Pyroptosis is a form of programmed cell death that is essential for immunity. Herein, this study was conducted to uncover the implication of pyroptosis in immunomodulation and tumor microenvironment (TME) in gastric cancer. METHODS: Prognostic pyroptosis-related genes were extracted to identify different pyroptosis phenotypes and pyroptosis genomic phenotypes via unsupervised clustering analysis in the gastric cancer meta-cohort cohort (GSE15459, GSE62254, GSE84437, GSE26253 and TCGA-STAD). The activation of hallmark gene sets was quantified by GSVA and immune cell infiltration was estimated via ssGSEA and CIBERSORT. Through PCA algorithm, pyroptosis score was conducted. The predictors of immune response (TMB and IPS) and genetic mutations were evaluated. The efficacy of pyroptosis score in predicting immune response was verified in two anti-PD-1 therapy cohorts. RESULTS: Three different pyroptosis phenotypes with different prognosis, biological pathways and tumor immune microenvironment were established among 1275 gastric cancer patients, corresponding to three immune phenotypes: immune-inflamed, immune-desert, and immune-excluded. According to the pyroptosis score, patients were separated into high and low pyroptosis score groups. Low pyroptosis score indicated favorable survival outcomes, enhanced immune responses, and increased mutation frequency. Moreover, low pyroptosis score patients displayed more clinical benefits from anti-PD-1 and prolonged survival time. CONCLUSION: Our findings uncovered a nonnegligible role of pyroptosis in immunomodulation and TME multiformity and complicacy in gastric cancer. Quantifying the pyroptosis score in individual tumors may tailor more effective immunotherapeutic strategies.

Genomic and Transcriptomic Remodeling by Neoadjuvant Chemoradiotherapy (nCRT) and the Indicative Role of Acquired INDEL Percentage for nCRT Efficacy in Esophageal Squamous Cell Carcinoma.

PURPOSE: The effect of genomic factors on the response of patients with esophageal squamous cell carcinoma (ESCC) to neoadjuvant chemoradiotherapy (nCRT), as well as how nCRT influences the genome and transcriptome of ESCC, remain largely unknown. METHODS AND MATERIALS: In total, 137 samples from 57 patients with ESCC undergoing nCRT were collected and subjected to whole-exome sequencing and RNA sequencing analysis. Genetic and clinicopathologic factors were compared between the patients achieving pathologic complete response and patients not achieving pathologic complete response. Genomic and transcriptomic profiles before and after nCRT were analyzed. RESULTS: Codeficiency of the DNA damage repair and HIPPO pathways synergistically sensitized ESCC to nCRT. nCRT induced small INDELs and focal chromosomal loss concurrently. Acquired INDEL% exhibited a decreasing trend with the increase of tumor regression grade (P = .06, Jonckheere's test). Multivariable Cox analysis indicated that higher acquired INDEL% was associated with better survival (adjusted hazard ratio [aHR], 0.93; 95% CI, 0.86-1.01; P = .067 for recurrence-free survival [RFS]; aHR, 0.86; 95% CI, 0.76-0.98; P = .028 for overall survival [OS], with 1% of acquired INDEL% as unit). The prognostic value of acquired INDEL% was confirmed by the Glioma Longitudinal AnalySiS data set (aHR, 0.95; 95% CI, 0.902-0.997; P = .037 for RFS; aHR, 0.96; 95% CI, 0.917-1.004; P = .076 for OS). Additionally, clonal expansion degree was negatively associated with patient survival (aHR, 5.87; 95% CI, 1.10-31.39; P = .038 for RFS; aHR, 9.09; 95% CI, 1.10-75.36; P = .041 for OS, with low clonal expression group as reference) and also negatively correlated with acquired INDEL% (Spearman ρ = -0.45; P = .02). The expression profile was changed after nCRT. The DNA replication gene set was downregulated, while the cell adhesion gene set was upregulated after nCRT. Acquired INDEL% was negatively correlated with the enrichment of the DNA replication gene set (Spearman ρ = -0.56; P = .003) but was positively correlated with the enrichment of the cell adhesion gene set (Spearman ρ = 0.40; P = .05) in posttreatment samples. CONCLUSIONS: nCRT remodels the genome and transcriptome of ESCC. Acquired INDEL% is a potential biomarker to indicate the effectiveness of nCRT and radiation sensitivity.

Treatment Patterns and Outcomes of Elderly Patients With Potentially Curable Esophageal Cancer.

OBJECTIVES: The proportion of elderly patients with esophageal cancer (EC) is increasing due to prolonged life expectancy and aging process. The aim of the study is to explore the optimal treatment strategy for elderly patients (aged ≥70 years) with locally advanced EC. METHODS: Eligible patients with cT2-4aNxM0 EC were identified in the Surveillance, Epidemiology, and End Results database from 2010 to 2016. Treatment patterns were divided into six groups: surgical resection (S), chemoradiotherapy (CRT), trimodality therapy (CRT+S), radiotherapy (RT), chemotherapy (CT), or observation with no treatment (Obs). Survival between groups was compared using the log-rank test, and the Cox proportional hazards model was used to identify factors associated with overall survival (OS). RESULTS: A total of 2917 patients with potentially curable EC were identified. Of all the patients included, 6.7%, 51.8%, 18.0%, 9.4% and 3.6%received S, CRT, CRT+S, RT, and CT, respectively, whereas 10.6% underwent Obs. The 3-year OS estimates were 30.2% (95% confidence interval [CI]: 23.5-38.9%), 25.4% (95% CI: 22.8-28.3%),44.3% (95% CI: 39.3-49.9%), 11.4% (95% CI: 7.7-17.0%), 16.1% (95% CI: 9.1-28.3%), and 5.6% (95% CI: 3.2-9.8%) for S, CRT, CRT+S RT, CT, and Obs (p<0.001), respectively. Overall, patents underwent CRT+S had the longest OS, compared to other treatment patterns, and the survival difference was not significant between patients receiving CRT and S (p=0.12) in the elderly population. However, the survival benefits of trimodality therapy over CRT gradually weakened with the increase in age, and became statistically non-significant for EC patients aged ≥80 years (p=0.35). Multivariate analysis showed that treatment patterns, age, sex, tumor grade, T stage, N stage, and marital status were significantly associated with OS. CONCLUSION: Generally, the use of trimodality therapy was associated with the longest OS, the survival benefits were comparable between CRT and S alone, and CRT was superior to RT or CT alone in elderly patients with curable EC. For patients intolerable to surgery or aged ≥80 years, definitive CRT should be considered as a preferable option.

A Novel Exosome-Relevant Molecular Classification Uncovers Distinct Immune Escape Mechanisms and Genomic Alterations in Gastric Cancer.

Objective: Gastric cancer (GC) is a highly heterogeneous malignant carcinoma. This study aimed to conduct an exosome-based classification for assisting personalized therapy for GC. Methods: Based on the expression profiling of prognostic exosome-related genes, GC patients in The Cancer Genome Atlas (TCGA) cohort were classified using the unsupervised consensus clustering approach, and the reproducibility of this classification was confirmed in the GSE84437 cohort. An exosome-based gene signature was developed via Least Absolute Shrinkage and Selection Operator (LASSO) regression analysis. Immunological features, responses to immune checkpoint inhibitors, and genetic alterations were evaluated via computational methods. Results: Two exosome-relevant phenotypes (A and B) were clustered, and this classification was independent of immune subtypes and TCGA subtypes. Exosome-relevant phenotype B had a poorer prognosis and an inflamed tumor microenvironment (TME) relative to phenotype A. Patients with phenotype B presented higher responses to the anti-CTLA4 inhibitor. Moreover, phenotype B occurred at a higher frequency of genetic mutation than phenotype A. The exosome-based gene signature (GPX3, RGS2, MATN3, SLC7A2, and SNCG) could independently and accurately predict GC prognosis, which was linked to stromal activation and immunosuppression. Conclusion: Our findings offer a conceptual frame to further comprehend the roles of exosomes in immune escape mechanisms and genomic alterations of GC. More work is required to evaluate the reference value of exosome-relevant phenotypes for designing immunotherapeutic regimens.

A Phase III Multicenter Randomized Clinical Trial of 60 Gy versus 50 Gy Radiation Dose in Concurrent Chemoradiotherapy for Inoperable Esophageal Squamous Cell Carcinoma.

PURPOSE: In this multicenter phase 3 trial, the efficacy and safety of 60 Gy and 50 Gy doses delivered with modern radiotherapy technology for definitive concurrent chemoradiotherapy (CCRT) in patients with inoperable esophageal squamous cell carcinoma (ESCC) were evaluated. PATIENTS AND METHODS: Patients with pathologically confirmed stage IIA‒IVA ESCC were randomized 1:1 to receive conventional fractionated 60 Gy or 50 Gy to the tumor and regional lymph nodes. Concurrent weekly chemotherapy (docetaxel 25 mg/m2; cisplatin 25 mg/m2) and two cycles of consolidation chemotherapy (docetaxel 70 mg/m2; cisplatin 25 mg/m2 days 1‒3) were administered. RESULTS: A total of 319 patients were analyzed for survival, and the median follow-up was 34.0 months. The 1- and 3-year locoregional progression-free survival (PFS) rates for the 60 Gy group were 75.6% and 49.5% versus 72.1% and 48.4%, respectively, for the 50 Gy group [HR, 1.00; 95% confidence interval (CI), 0.75‒1.35; P = 0.98]. The overall survival rates were 83.7% and 53.1% versus 84.8% and 52.7%, respectively (HR, 0.99; 95% CI, 0.73‒1.35; P = 0.96), whereas the PFS rates were 71.2% and 46.4% versus 65.2% and 46.1%, respectively (HR, 0.97; 95% CI, 0.73‒1.30; P = 0.86). The incidence of grade 3+ radiotherapy pneumonitis was higher in the 60 Gy group (nominal P = 0.03) than in the 50 Gy group. CONCLUSIONS: The 60 Gy arm had similar survival endpoints but a higher severe pneumonitis rate compared with the 50 Gy arm. Fifty Gy should be considered as the recommended dose in CCRT for ESCC.

NCK1-AS1 promotes the progression of lung squamous cell carcinoma through transcriptionally upregulating NCK1 via interacting with MYC.

Lung squamous cell carcinoma (LUSC) is a prevalent subtype of nonsmall cell lung cancer (NSCLC). Dysregulated long noncoding RNAs (lncRNAs) are increasingly identified as pivotal modulators in cancer progression. NCK1 divergent transcript (NCK1-AS1) is a lncRNA that has been proven to be oncogenic in different types of human cancers. However, whether it exerts similar functions in LUSC remains to be elusive. The present study focused on investigating the influence of NCK1-AS1 on the cellular process in LUSC and exploring its underlying mechanism. Through online bioinformatics analysis, we obtained a high NCK1-AS1 level in LUSC tissues. Meanwhile, we confirmed that NCK1-AS1 was upregulated in LUSC cells. Gain- or loss-of-function assays suggested that NCK1-AS1 prompted cell proliferation and migration, whilst impeded cell apoptosis in LUSC. Mechanistically, we revealed that NCK1-AS1 induced the upregulation of its nearby gene NCK adaptor protein 1 (NCK1) at the transcriptional level by interacting with the transcription factor MYC proto-oncogene (MYC). Rescue assays indicated that NCK1 participated in the regulation of NCK1-AS1 on LUSC progression. In conclusion, we firstly demonstrated the oncogenic role of NCK1-AS1 in LUSC and illustrated its downstream molecular mechanism.

Omeprazole improves chemosensitivity of gastric cancer cells by m6A demethylase FTO-mediated activation of mTORC1 and DDIT3 up-regulation.

The curative effect for patients with advanced gastric cancer is still unsatisfactory. Proton pump inhibitors could be a promising treatment strategy that could sensitize gastric cancer cells to antitumor drugs further; however, the underlying molecular mechanism remains to be further elucidated. In this research, it was found that omeprazole pretreatment could enhance the inhibitory effect of 5-Fu, DDP and TAX on gastric cancer cells. Interestingly, omeprazole pretreatment enhanced the total m6A level of cells due to the decreased FTO. TCGA analysis showed that FTO expression is up-regulated in GC tissues and is negatively correlated with disease-free survival of GC patients. It was also found that FTO inhibition induced by omeprazole enhanced the activation of mTORC1 signal pathway that inhibited the prosurvival autophagy so as to improve the antitumor efficiency of chemotherapeutic drugs on GC cells. Meanwhile, transcript level of DDIT3, which is an apoptosis-related tumor suppressor gene downstream of mTORC1, was regulated by omeprazole-induced FTO silence through an m6A-dependent mechanism. The present study, for the first time, found that m6A modification and its eraser FTO may play a role in the improvement of chemosensitivity mediated by proton pump inhibitor omeprazole.

Impact of Radiation Dose on Survival for Esophageal Squamous Cell Carcinoma Treated With Neoadjuvant Chemoradiotherapy.

Purpose: Radiation dose used in the neoadjuvant chemoradiotherapy (NCRT) for patients with locally advanced esophageal squamous cell carcinoma (ESCC) varies in different trials and clinical practice. Methods and Materials: Data from patients diagnosed with ESCC receiving NCRT followed by esophagectomy were retrospectively collected from February 2013 to December 2017. Lower dose (LD) radiotherapy was defined as ≤45 Gy, and >45 Gy was considered as higher dose (HD). Survival rates were calculated by the Kaplan-Meier method and compared with long-rank test. Multivariate Cox regression analyses were performed to identify variables associated with survival. Results: A total of 118 patients treated with NCRT were included in our analysis: 62 patients received LD radiotherapy, and 56 patients received HD radiotherapy. The median follow-up time was 24.3 months (0.67-65.3 m). Two-years overall survival (OS) rates were 75.0 and 79.0% in HD and LD group, respectively (P = 0.360), and complete pathological remission (pCR) rates in two groups were 42.9 and 30.6%, respectively (P = 0.17). The incidences of toxic effects including post-operative complications were not significantly different between two groups. Multivariate analysis showed that tumor T stage, M1a disease, smoking history, and pCR rate were significantly associated with OS. Conclusions: In ESCC patients treated with NCRT followed by surgery, higher radiation dose was not significantly associated with a higher pCR rate and longer survival. Lower radiation dose might be a preferable time-dose fraction scheme. Our finding needs to be further validated by randomized trials.

Role of Perioperative Chemotherapy in Lymph Node-negative Esophageal Cancer After Resection: A Population-based Study With Propensity Score-matched Analysis.

BACKGROUND: Multimodality treatment is increasingly accepted and becoming the standard care for local advanced esophageal cancer (EC) patients. However, for early stage lymph node-negative EC patients, surgery alone is still the primary treatment approach, and the role of perioperative chemotherapy remains unclear. METHODS: Patients with lymph node-negative EC were identified from the Surveillance, Epidemiology, and End Results (SEER) database from 2004 to 2013. Survival was compared by the log-rank test. Cox proportional hazards analysis was used to identify covariates associated with overall survival (OS). Propensity score-matched analysis was also performed to control for confounding. RESULTS: A total of 3071 patients (T1-4N0M0) were identified, 1363 (44.4%) of which received perioperative chemotherapy. The effect of chemotherapy on OS was remarkably dependent on the T stage. For stage T1 patients, chemotherapy was inversely associated with OS (hazard ratio [HR]=1.54; 95% confidence interval [CI], 1.27-1.86), and no impact of chemotherapy on OS was found for T2 patients (HR=0.92; 95% CI, 0.712-1.18), whereas a significant improvement in OS was observed with the addition of chemotherapy for patients with stages T3 (HR=0.52; 95% CI, 0.43-0.62) and T4 (HR=0.60; 95% CI, 0.36-0.98) disease. Multivariable analysis with demonstrated that chemotherapy usage, age, sex, tumor grade, and T stage (P<0.05) were significantly associated with OS in T3-T4 patients. The results were similar in subgroup analyses stratified by confounding covariates, and the propensity score-matched analysis. CONCLUSIONS: This population-based study indicates perioperative chemotherapy is associated with improved survival in stage T3-4N0M0 patients with EC, which needs to be further validated by randomized trials.

Association of Twice-Daily Radiotherapy With Subsequent Brain Metastases in Adults With Small Cell Lung Cancer.

Importance: Although thoracic twice-daily radiotherapy (TDRT) is one of the standards of care for small cell lung cancer, its association with brain metastases remains unknown. Objective: To investigate the association of TDRT vs once-daily radiotherapy (ODRT) with brain metastases after prophylactic cranial irradiation in patients with small cell lung cancer. Design, Setting, and Participants: In this multicenter cohort study, data on 778 consecutive patients with small cell lung cancer who had undergone thoracic radiotherapy (609 received ODRT and 169 received TDRT), chemotherapy, and prophylactic cranial irradiation were retrieved from the databases of 8 hospitals in China between July 1, 2003, and June 30, 2016. A 1:1 propensity score matching approach was used to control for confounding between the ODRT and TDRT groups. Confounding covariates included 8 demographic variables and 8 treatment-related covariates. Data analysis was conducted from November 1, 2017, to May 31, 2018, and reanalyzed for revision. Exposures: The ODRT group received 50 to 66 Gy given in 25 to 33 fractions. The TDRT group received 45 Gy given in 30 fractions. Main Outcomes and Measures: The primary end point was brain metastases. Secondary end points included progression-free survival and overall survival. Results: Of the 778 patients (median age, 55 years [interquartile range, 48-61 years]), 204 were women and 574 were men. At a median follow-up of 23.6 months (interquartile range, 14.2-38.2 months), 131 patients (16.8%) experienced brain metastases. The rate of brain metastasis at 3 years in the TDRT group was significantly higher than in the ODRT group (26.0% vs 16.9%; hazard ratio, 1.55; 95% CI, 1.06-2.26; P = .03). Of the 338 matched patients (169 in the ODRT group vs 169 in the TDRT group), 60 (17.8%) experienced brain metastases, with a rate at 3 years of 14.9% in the ODRT group vs 26.0% in the TDRT group (hazard ratio, 1.71; 95% CI, 1.02-2.88; P = .04). Progression-free survival was similar in both the whole cohort and the matched cohort. Median overall survival in the ODRT group tended to be significantly longer than in the TDRT group after matching (47.2 vs 32.8 months; hazard ratio, 1.41; 95% CI, 0.99-2.01; P = .06). Conclusions and Relevance: In this study, patients with small cell lung cancer who received thoracic TDRT appeared to have a higher risk of brain metastases than those who received ODRT, which supports the need for further prospective randomized clinical trials, especially in China and other parts of Asia.

Crizotinib induces apoptosis of lung cancer cells through JAK-STAT pathway.

Effect of crizotinib on apoptosis of lung cancer cells was investigated. Human non-small cell lung adenocarcinoma H2228 cells were cultured in the presence of 0, 20, 40, 80, 160 and 320 nmol/l of crizotinib for 3 days, respectively. The inhibition rate of cell proliferation was measured by MTT assay, and half maximal inhibitory concentration (IC50) was calculated. Cell apoptosis was detected by flow cytometry. Transwell assay was performed to detect cell migration. Expression of Janus protein tyrosine kinase (JAK) and signal transducer and activator of transcription (STAT) proteins was detected by western blot analysis. Crizotinib significantly inhibited the proliferation of human lung cancer H2228 cells, and the inhibitory effect was enhanced with the increase of the concentration of crizotinib (p<0.01). The IC50 value was 311.26 nnol/l. According to IC50 value, concentration of crizotinib at 300 nmol/l was selected for the study. It was found that crizotinib at 300 nmol/l significantly promoted cell apoptosis (p<0.01) and inhibited cell migration (p<0.01). Compared with pretreatment levels, crizotinib downregulated the expression of JAK and STAT (p<0.01) on the 1st day of treatment, but with the prolongation of time, no further significant difference was observed on the 1st, 2nd or 3rd day in the level of JAK protein (p=0.47); there were no statistically significant differences in the level of STAT protein (p=0.91). Crizotinib can inhibit the migration and promote cell apoptosis of human lung cancer cell line H2228 by regulating the expression of JAK and STAT proteins in JAK-STAT signaling pathway.

Prophylactic cranial irradiation in resected small cell lung cancer: A systematic review with meta-analysis.

Background: The use of PCI in early operable patients with small cell lung cancer (SCLC) is still controversial. Therefore, we conducted a systematic review with meta-analysis to investigate the effects of PCI in resected SCLC patients. Methods: Relevant studies were identified from PubMed and EMBASE databases, the pooled hazard risks were obtained by the random-effects model. We also analyzed the brain metastasis (BM) risk in p-stage I patients without PCI. Results: Five retrospective studies were identified and a total of 1691 patients were included in our analysis, 315 of them received PCI. For all the resected patients, PCI was associated with improved overall survival (HR: 0.52, 95% CI: 0.33-0.82), and reduced brain metastasis risk (RR: 0.50, 95%CI: 0.32-0.78). However, with regard to p-stage I patients, no survival benefit was brought by PCI (HR: 0.87, 95% CI: 0.34-2.24). Moreover, the pooled analysis of 7 studies found that the 5-year brain metastasis risk was relatively low (12%, 95% CI: 8%-17%) for p-stage I patients without PCI. Conclusions: PCI might be associated with a favorable survival advantage and reduced BM risk in complete resected SCLC patients, except for p-stage I patients.

The prognostic role of nutrition risk score (NRS) in patients with metastatic or recurrent esophageal squamous cell carcinoma (ESCC).

The purpose of this study was to elucidate the prognostic value of nutritional risk score (NRS) in patients with metastatic or recurrent ESCC. A total of 187 patients who undergoing S1 based or paclitaxel based salvage chemotherapy were enrolled in this retrospective study. Nutritional status was evaluated by NRS. The relationship between NRS and clinicopathological variables and post-treatment outcomes were assessed by univariate and multivariate analysis. NRS was significantly associated with weight loss (P<0.001), BMI (P<0.001), chemotherapy regimens (P=0.038) and treatment response (P=0.013). The Kaplan-Meier survival curves indicated that patients with NRS ≥ 3 had worse overall survival (OS) compared to patients with NRS < 3 (P<0.001). Multivariable regression revealed that weight loss, NRS and treatment response were three prognostic factors (P<0.05). These results suggest that NRS is a promising indicator of poor prognosis in patients with metastatic or recurrent ESCC who received S1 based or paclitaxel based salvage chemotherapy.

Effects of icotinib with and without radiation therapy on patients with EGFR mutant non-small cell lung cancer and brain metastases.

EGFR-TKIs and radiation therapy (RT) are the principal treatment for patients with brain metastases (BM) and EGFR mutant NSCLC. However, the optimal use of brain RT for patients with asymptomatic BM remains undefined. A total of 152 patients were identified. 58 patients were excluded. Of the remaining 97 patients, 56 patients received upfront RT followed by icotinib, including WBRT or SRS. 41 patients received icotinib therapy alone. The mOS from diagnosis of BM was 27.0 months for the whole cohort (95% CI, 23.9-30.1 months). There was no difference in OS between the RT followed by icotinib group and the icotinib alone group (31.9 vs. 27.9 months, P = 0.237), and similar results were found in the SRS subgroup (35.5 vs. 27.9 months, P = 0.12). Patients with the EGFR Del19 mutation had a longer OS than patients with the exon 21 L858R mutation (32.7 vs. 27.4, P = 0.037). Intracranial progression-free survival (PFS) was improved in the patients who received RT followed by icotinib compared to those receiving icotinib alone (22.4 vs. 13.9 months, P = 0.043). Patients with EGFR-mutant adenocarcinoma and BM treated with icotinib exhibited prolonged survival. A longer duration of intracranial control was observed with brain RT.

Prophylactic cranial irradiation in 399 patients with limited-stage small cell lung cancer.

The benefit of prophylactic cranial irradiation (PCI) in limited-stage small-cell lung cancer (LS-SCLC) was established in a meta-analysis performed in 1999. Since then, considerable progress has been made in the diagnosis, staging and treatment of LS-SCLC, including chemotherapy and radiotherapy, which led to a longer survival time in patients. Therefore, the magnitude of the benefit of PCI should be re-evaluated. Furthermore, the optimum timing of PCI for LS-SCLC treatment has not been established and more data is required to demonstrate this. In the present retrospective study, the cases of patients that were diagnosed with LS-SCLC between March 2005 and December 2010 were reviewed. The main eligibility criteria of patients were a diagnosis of LS-SCLC and the achievement of a complete response (CR) or near CR subsequent to receiving ≥3 cycles of cisplatin-based chemotherapy, with or without advanced thoracic radiotherapy. Early and late PCI groups were separated using the median time interval between the start of primary chemotherapy and the start of PCI. In total, 80 patients were excluded from the analysis, including 9 patients that developed brain metastases, 2 during primary chemotherapy and 7 during radiotherapy. The remaining 399 patients were deemed eligible. PCI was administered to 185 patients; 92 patients were in the early PCI group and 93 were in the late PCI group. PCI significantly decreased the incidence of brain metastases [P<0.001; HR, 0.24; 95% confidence interval (CI), 0.15-0.39] and improved the overall survival time of the patients (median survival time, 21.5-38.8 months; P<0.001; HR, 0.60; 95% CI, 0.45-0.79). However, no significant difference was identified between the early and late PCI groups, either in the incidence of brain metastases (P=0.875) or the overall survival time (P=0.361). Multivariate analysis revealed that PCI (P=0.004) and thoracic radiotherapy (P=0.023) were the only 2 independent favorable prognostic factors of overall survival time. The present study demonstrates that PCI may be of considerable benefit to increase the survival rate and time of patients, and early PCI is as effective as late PCI. However, the present study recommends that PCI should be offered as soon as primary chemotherapy is completed, since there is a greater risk of developing brain metastases during thoracic radiotherapy.