Whole exome analysis reveals the genomic profiling related to chemo-resistance in Chinese population with limited-disease small cell lung cancer.

PURPOSE: The mechanism of chemo-resistance in small cell lung cancer (SCLC) is unclear. This study aims to explore the resistance-related genomic profiles of residual tumors after neo-adjuvant chemotherapy (NAC) in SCLC through the whole-exome sequencing (WES). EXPERIMENTAL DESIGN: A total of 416 limited diseases (LD) SCLC patients underwent surgery were retrospectively analyzed, of which 40 patients received NAC. Then we selected 29 patients undergoing NAC (n = 19) and chemotherapy naïve (CTN, n = 10) to perform WES sequence with formalin-fixed paraffin-embedded samples including tumor and paired para-tumor. RESULTS: In total, single nucleotide variation and mutation rate were similar between NAC and CTN groups. The mutation signatures were significantly discrepant between NAC and CTN groups, as well as among patients with partial response (PR), stable disease (SD), and progressive disease. There were more copy number variation deletions in NAC group compared with CTN group. The inactivation of TP53 and RB1 were the most significantly events in both NAC and CTN groups. RB1 nonsense mutations were recurrent in NAC group (9/19 vs. 0/9, 47.4% vs. 0%) with favorable survival, while the frame-shift deletions were frequent in CTN group (3/9 vs. 3/19, 33.3% vs.15.8%). Integrated function enrichment revealed that the frequently mutant genes were involved in cell cycle, metabolic reprogramming, and oncogenic signaling pathways in NAC group, such as BTG2 pathway, glycolysis in senescence and P53 pathway. A total of 27 genes presented frequently mutant in NAC group and might played a positive role in drug resistance. Multiple genes including BRINP3, MYH6, ST18, and PCHD15, which were associated with prognosis, occurred mutant frequently in PR and SD groups. CONCLUSION: Residual tumors after neo-adjuvant therapy exhibited different mutation signature spectrum. Multiple genes including RB1 nonsense mutations, BRINP3, MYH6, ST18, and PCHD15 were with frequent mutation in residual tumors, which might participate chemo-resistance and influenced the prognosis in patients with limited disease SCLC.

Quality control indices for standardized diagnosis and treatment of esophageal cancer in China (2022 edition).

Esophageal cancer (EC) is particularly common in China. With the continuing progress of multi-disciplinary therapy including early screening, minimally invasive techniques, radiotherapy and chemotherapy, the 5-year survival of EC has been improved in China. However, there are considerable disparities in the diagnosis and treatment quality among different regions. The Esophageal Cancer Expert Committee of the National Cancer Quality Control Center (NCQCC) considers a set of authoritative quality control standards as an opportunity to eliminate the disparities and improve the overall survival and quality of life of EC. To further promote the quality control for standardized diagnosis and treatment of EC, the National Cancer Center commissioned the Esophageal Cancer Quality Control Expert Committee to draft and formulate the Chinese Quality Control Indices for Standardized Diagnosis and Treatment of Esophageal Cancer (2022 edition). The Indices includes 21 items that cover all key areas in the diagnosis and treatment of esophageal cancer, such as medical oncology, radiation oncology, endoscopy, and pathology.

Effect of Adjuvant Radiation Dose on Survival in Patients with Esophageal Squamous Cell Carcinoma.

Background: For patients with esophageal squamous cell carcinoma (ESCC) treated with surgery alone, the incidence of local-regional recurrence remains unfavorable. Postoperative radiotherapy (PORT) has been associated with increased local-regional recurrence-free survival (LRFS), although its application is limited by concerns of PORT-related toxicities. Methods: Among 3591 patients with ESCC analyzed in this study, 2765 patients with T3-4N0 and T1-4N1-3 lesions and specific local-regional status information were analyzed in a subsequent analysis of adjuvant radiation dose (aRTD) effect. Application of the restricted cubic spline regression model revealed a non-linear relationship between aRTD and survival/radiotoxicity. Linear regression analysis (LRA) was performed to evaluate correlations between LRFS and overall survival (OS)/ disease-free survival (DFS). Results: For patients staged T1−2N0, T1−2N1−3, T3−4N0, and T3−4N1−3, 5-year OS in PORT and non-PORT groups were 77.38% vs. 72.91%, p = 0.919, 52.35% vs. 46.60%, p = 0.032, 73.41% vs. 61.19%, p = 0.005 and 38.30% vs. 25.97%, p < 0.001. With aRTD escalation, hazard ratios (HRs) of OS/DFS declined until aRTD exceeded 50Gy, then increased, whereas that of LRFS declined until aRTD exceeded 50 Gy, then remained steady. HR of treatment-related mortality was stable until aRTD exceeded 50 Gy, then increased. LRA revealed strong correlations between LRFS and OS/DFS (r = 0.984 and r = 0.952, respectively). An absolute 1% advancement in LRFS resulted in 0.32% and 0.34% improvements in OS and DFS. Conclusions: An aRTD of 50Gy was well-tolerated, with favorable survival resulting from PORT-related LRFS improvement in patients staged T3−4N0 or T1-4N1−3. Further stratification analyses based on tumor burden would help determine potential PORT-beneficiaries.

Progression-free survival as surrogate endpoint of overall survival in esophageal squamous cell carcinoma: a real-world data and literature-based analysis.

Background: The surrogacy of progression-free survival (PFS) for overall survival (OS) in esophageal squamous cell carcinoma (ESCC) remains unelucidated. This study aimed to determine the validity of PFS as a surrogate endpoint for OS in ESCC patients treated with definitive radiotherapy or definitive chemoradiotherapy (dRT/dCRT), as well as characterize the prognostic factors and survival of such patients. Methods: A total of 3662 patients from 10 cancer centers were enrolled. One-, 2-, and 3-year PFS (PFS12, PFS24, and PSF36, respectively) were used as time points for analysis. At each time point, ESCC-specific mortality and OS were characterized using competing risk and conditional survival models, while correlation between PFS and OS was evaluated by linear regression. Results: At PFS12, PFS24, and PFS36, a progressive decrease in 5-year ESCC-specific mortality (35.2%-13.4%) and increase in 5-year OS (46.6%-62.9%) were observed. Regardless, the OS of patients remained markedly lower than those of the age- and sex-matched Chinese general population. TNM stage remained a significant prognostic factor at PFS36. Strong correlation was found between 3-year PFS and 5-year OS, which was further externally validated. Conclusions: Three-year PFS may act as a potential surrogate endpoint for 5-year OS. TNM stage was considered a significant prognostic factor for OS, and may represent the optimal prognostic tool to guide clinical decision-making and post-treatment follow-up.

Survival benefit of surgery in patients with clinical T4 esophageal cancer who achieved complete or partial response after neoadjuvant chemoradiotherapy or radiotherapy.

Objective: This study aimed to determine the long-term survival of patients with cT4 esophageal cancer (EC) and whether neoadjuvant chemoradiotherapy/radiotherapy plus surgery (nCRT/RT + S) is superior to definitive CRT(dCRT)/RT in terms of survival in cT4 EC downstaged after nCRT/RT. Summary background data: Treatment options for cT4 EC include dCRT/RT and nCRT/RT + S, but it is not clear whether the latter provides survival benefit in patients downstaged after nCRT/RT. Methods: From 2002 to 2017, 726 patients with cT4 esophageal squamous cell carcinoma (ESCC) were retrospectively analyzed. Patients achieving clinical complete response (cCR) or partial response (PR) after 4-week RT (median dose, 40.7 Gy) and considered fit for surgery were offered esophagectomy. Of the 726 patients, 308 (42.4%) achieved cCR/PR, while 74 patients received subsequent surgery (nCRT/RT + S group), 234 patients received dCRT/RT. Results: Median follow-up was 58 months. The 3-year overall survival (OS) and progression-free survival (PFS) rates for all patients were 33.3% and 35.6%, respectively. The corresponding OS and PFS rates were 54.8% and 48.5% in the nCRT/RT + S group versus 30.0% and 22.1% in the dCRT/RT group (both p < 0.0001). After adjusting the confounding variables with inverse probability of treatment weighting, the adjusted 3-year OS rates were 50.4% in the nCRT/RT + S group versus 50.8% in the dCRT/RT group (p = 0.15). However, the adjusted 3-year PFS rates were significantly different between the two groups (49.0% and versus 38.3%, p = 0.004). Postoperative complications occurred in 18 (24.3%) patients. Conclusion: The long-term survival of cT4 ESCC was improved after the use of three-dimensional CRT. In cT4, EC responded to nCRT/RT, surgery improves PFS but not OS.

Upregulation of OATP1A2 in human oesophageal squamous cell carcinoma cells via the HDAC6-GCN5/PCAF-H3K9Ac axis.

1. OATP1A2 overexpressed is involved in chemotherapy disposition, indicating its role in tumour development and progression.2. CHIP and siRNA were used to evaluate the status of histone acetylation at the OATP1A2 promoter. The role of OATP1A2 was analysed by gene-set enrichment and overall survival analysis.3. OATP1A2 expression levels in ESCC was notably higher than that in para-cancer tissues. OATP1A2 high expression are associated with bile salt metabolic pathway and poor prognosis. Furthermore, HDAC6 was repressed in ESCC, increasing the levels of H3K9Ac catalysed by GCN5/PCAF at the OATP1A2 promoter region.4. Abnormal histone hyperacetylation mediated by the HDAC6-GCN5/PCAF-H3K9Ac axis resulted in increased OATP1A2 expression in ESCC, and OATP1A2 may serve as a promising prognostic biomarker for ESCC.5. In conclusion, this study indicated that suppression of OATP1A2 would inhibit the progression and prognosis in ESCC.

The status of medical physics in radiotherapy in China.

PURPOSE: To present an overview of the status of medical physics in radiotherapy in China, including facilities and devices, occupation, education, research, etc. MATERIALS AND METHODS: The information about medical physics in clinics was obtained from the 9-th nationwide survey conducted by the China Society for Radiation Oncology in 2019. The data of medical physics in education and research was collected from the publications of the official and professional organizations. RESULTS: By 2019, there were 1463 hospitals or institutes registered to practice radiotherapy and the number of accelerators per million population was 1.5. There were 4172 medical physicists working in clinics of radiation oncology. The ratio between the numbers of radiation oncologists and medical physicists is 3.51. Approximately, 95% of medical physicists have an undergraduate or graduate degrees in nuclear physics and biomedical engineering. 86% of medical physicists have certificates issued by the Chinese Society of Medical Physics. There has been a fast growth of publications by authors from mainland of China in the top international medical physics and radiotherapy journals since 2018. CONCLUSIONS: Demand for medical physicists in radiotherapy increased quickly in the past decade. The distribution of radiotherapy facilities in China became more balanced. High quality continuing education and training programs for medical physicists are deficient in most areas. The role of medical physicists in the clinic has not been clearly defined and their contributions have not been fully recognized by the community.

Clinical practice and outcome of radiotherapy for advanced esophageal squamous cell carcinoma between 2002 and 2018 in China: the multi-center 3JECROG Survey.

PURPOSE: To determine the survival and prognostic factors of esophageal squamous cell carcinoma (ESCC) patients undergoing radical (chemo)radiotherapy in the era of three-dimensional conformal radiotherapy (3DCRT) and intensity modulated radiotherapy (IMRT) in China. MATERIAL AND METHODS: The Jing-Jin-Ji Esophageal and Esophagogastric Cancer Radiotherapy Oncology Group (3JECROG) conducted the first nationwide survey of nine institutions. Detailed information was accumulated on 5185 patients with ESCC who received definitive 3DCRT/IMRT between 2002 and 2018. Relevant prognostic factors were evaluated to assess their influence on overall and progression-free survivals. RESULTS: After a median follow-up time of 47.0 (0.9-157.4) months, the 1-year, 2-year, 3-year and 5-year overall survival rates of the whole group were 69.8%, 46.6%, 37.9% and 30.1%. The 1-year, 2-year, 3-year, and 5-year progression-free survival rates were 54.1%, 36.6%, 30.5% and 24.9%. Multivariate analysis demonstrated that sex, clinical stage, treatment modality and radiation dose were prognostic factors for OS. The survival of patients who received concurrent chemoradiotherapy (CCRT) was better than that of patients who received radiotherapy alone or sequential chemoradiotherapy. Patients receiving adjuvant chemotherapy after CCRT had a better OS than patients receiving CCRT alone. Patients receiving higher radiation dose had a better OS than those patients receiving low-dose radiotherapy. CONCLUSIONS: The survival of ESCC patients undergoing radical (chemo)radiotherapy was relatively satisfactory in the era of 3DCRTand IMRT. As the largest-scale multicenter research on esophageal cancer radiotherapy conducted in China, this study establishes national benchmarks and helps to provide references for subsequent related researches.

Recurrence risk stratification based on a competing-risks nomogram to identify patients with esophageal cancer who may benefit from postoperative radiotherapy.

BACKGROUND: A reliable model is needed to estimate the risk of postoperative recurrence and the benefits of postoperative radiotherapy (PORT) in patients with thoracic esophageal squamous cell cancer (TESCC). METHODS: The study retrospectively reviewed 3652 TESCC patients in stage IB-IVA after radical esophagectomy, with or without PORT. In one institution as the training cohort (n = 1620), independent risk factors associated with locoregional recurrence (LRR), identified by the competing-risks regression, were used to establish a predicting nomogram, which was validated in an external cohort (n = 1048). Area under curve (AUC) values of receiver operating characteristic curves were calculated to evaluate discrimination. Risk stratification was conducted using a decision tree analysis based on the cumulative point score of the LRR nomogram. After balancing the baseline of characteristics between treatment groups by inverse probability of treatment weighting, the effect of PORT was evaluated in each risk group. RESULTS: Sex, age, tumor location, tumor grade, and N category were identified as independent risk factors for LRR and added into the nomogram. The AUC values were 0.638 and 0.706 in the training and validation cohorts, respectively. Three risk groups were established. For patients in the intermediate- and high-risk groups, PORT significantly improved the 5-year overall survival by 10.2% and 9.4%, respectively (p < 0.05). Although PORT was significantly associated with reduced LRR in the low-risk group, overall survival was not improved. CONCLUSION: The nomogram can effectively estimate the individual risk of LRR, and patients in the intermediate- and high-risk groups are highly recommended to undergo PORT.

Chemoradiotherapy with extended nodal irradiation and/or erlotinib in locally advanced oesophageal squamous cell cancer: long-term update of a randomised phase 3 trial.

BACKGROUND: To report the long-term outcomes of a phase III trial designed to test two hypotheses: (1) elective nodal irradiation (ENI) is superior to conventional field irradiation (CFI), and (2) chemoradiotherapy plus erlotinib is superior to chemoradiotherapy in locally advanced oesophageal squamous cell cancer (ESCC). METHODS: Patients with locally advanced ESCC were randomly assigned (1:1:1:1 ratio) to one of the four groups: A: radiotherapy adoption of ENI with two cycles of concurrent TP chemotherapy (paclitaxel and cisplatin) plus erlotinib; B: radiotherapy adoption of ENI with two cycles of concurrent TP; C: radiotherapy adoption of CFI with two cycles of concurrent TP plus erlotinib and D: radiotherapy adoption of CFI with two cycles of concurrent TP. A total of 60 Gy of radiation doses was delivered over 30 fractions. We explored the impact of epidermal growth factor receptor (EGFR) expression on the efficacy of erlotinib plus chemoradiotherapy. RESULTS: A total of 352 patients (88 assigned to each treatment group) were enrolled. The 5-year survival rates were 44.9%, 34.8%, 33.8% and 19.6% in groups A, B, C and D, respectively (P = 0.013). ENI significantly improved OS compared with standard CFI (median, 38.5 vs 22.6 months; HR, 0.74; P = 0.018). The addition of erlotinib significantly improved OS (median, 39.4 vs 27.4 months; HR, 0.75; P = 0.025). Patients with overexpressing EGFR treated with erlotinib had a better OS and PFS than those without erlotinib. CONCLUSIONS: Concurrent chemoradiotherapy with ENI and/or erlotinib improved long-term survival in locally advanced ESCC. CLINICAL TRIAL REGISTRATION: Trial registration: NCT00686114.

Dosiomics: Extracting 3D Spatial Features From Dose Distribution to Predict Incidence of Radiation Pneumonitis.

Radiation pneumonitis (RP) is one of the major toxicities of thoracic radiation therapy. RP incidence has been proven to be closely associated with the dosimetric factors and normal tissue control possibility (NTCP) factors. However, because these factors only utilize limited information of the dose distribution, the prediction abilities of these factors are modest. We adopted the dosiomics method for RP prediction. The dosiomics method first extracts spatial features of the dose distribution within ipsilateral, contralateral, and total lungs, and then uses these extracted features to construct prediction model via univariate and multivariate logistic regression (LR). The dosiomics method is validated using 70 non-small cell lung cancer (NSCLC) patients treated with volumetric modulated arc therapy (VMAT) radiotherapy. Dosimetric and NTCP factors based prediction models are also constructed to compare with the dosiomics features based prediction model. For the dosimetric, NTCP and dosiomics factors/features, the most significant single factors/features are the mean dose, parallel/serial (PS) NTCP and gray level co-occurrence matrix (GLCM) contrast of ipsilateral lung, respectively. And the area under curve (AUC) of univariate LR is 0.665, 0.710 and 0.709, respectively. The second significant factors are V5 of contralateral lung, equivalent uniform dose (EUD) derived from PS NTCP of contralateral lung and the low gray level run emphasis of gray level run length matrix (GLRLM) of total lungs. The AUC of multivariate LR is improved to 0.676, 0.744, and 0.782, respectively. The results demonstrate that the univariate LR of dosiomics features has approximate predictive ability with NTCP factors, and the multivariate LR outperforms both the dosimetric and NTCP factors. In conclusion, the spatial features of dose distribution extracted by the dosiomics method effectively improves the prediction ability.

Hypoxia-inducible factor-1α and nuclear factor-κB play important roles in regulating programmed cell death ligand 1 expression by epidermal growth factor receptor mutants in non-small-cell lung cancer cells.

Some driver gene mutations, including epidermal growth factor receptor (EGFR), have been reported to be involved in expression regulation of the immunosuppressive checkpoint protein programmed cell death ligand 1 (PD-L1), but the underlying mechanism remains obscure. We investigated the potential role and precise mechanism of EGFR mutants in PD-L1 expression regulation in non-small-cell lung cancer (NSCLC) cells. Examination of pivotal EGFR signaling effectors in 8 NSCLC cell lines indicated apparent associations between PD-L1 overexpression and phosphorylation of AKT and ERK, especially with increased protein levels of phospho-IκBα (p-IκBα) and hypoxia-inducible factor-1α (HIF-1α). Flow cytometry results showed stronger membrane co-expression of EGFR and PD-L1 in NSCLC cells with EGFR mutants compared with cells carrying WT EGFR. Additionally, ectopic expression or depletion of EGFR mutants and treatment with EGFR pathway inhibitors targeting MEK/ERK, PI3K/AKT, mTOR/S6, IκBα, and HIF-1α indicated strong accordance among protein levels of PD-L1, p-IκBα, and HIF-1α in NSCLC cells. Further treatment with pathway inhibitors significantly inhibited xenograft tumor growth and p-IκBα, HIF-1α, and PD-L1 expression of NSCLC cells carrying EGFR mutant in nude mice. Moreover, immunohistochemical analysis revealed obviously increased protein levels of p-IκBα, HIF-1α, and PD-L1 in NSCLC tissues with EGFR mutants compared with tissues carrying WT EGFR. Non-small-cell lung cancer tissues with either p-IκBα or HIF-1α positive staining were more likely to possess elevated PD-L1 expression compared with tissues scored negative for both p-IκBα and HIF-1α. Our findings showed important roles of phosphorylation activation of AKT and ERK and potential interplay and cooperation between NF-κB and HIF-1α in PD-L1 expression regulation by EGFR mutants in NSCLC.

Impact of thoracic radiation therapy after chemotherapy on survival in extensive-stage small cell lung cancer: A propensity score-matched analysis.

BACKGROUND: The role of thoracic radiation therapy (TRT) after chemotherapy (CHT) in extensive-stage small cell lung cancer (ES-SCLC) has not been well defined. We investigated whether intensity-modulated radiotherapy (IMRT) improves outcomes in ES-SCLC after CHT compared to CHT alone. METHODS: A total of 292 patients who reached a complete response (CR), partial response (PR), or stable disease (SD) after CHT were assigned into groups: CHT + TRT and CHT alone. Propensity score matching was used to balance patient groups (n = 72 each). RESULTS: The five-year overall survival (OS: 12.3% vs. 3.6%; P < 0.001) and progression-free survival (PFS: 3.2% vs. 1.7%; P = 0.006) rates were significantly higher in the CHT + TRT group. This data was confirmed in the matched samples (5-year OS: 10.5% vs. 1.6%, P < 0.001; PFS: 4.3% vs. 0.0%, P = 0.023). The overall (P = 0.002) and locoregional (P < 0.001) recurrence rates in the CHT + TRT group were significantly lower than in the CHT group. Univariate analysis showed that response evaluation after CHT and TRT were significant prognostic factors of OS. Multivariate analyses revealed that N Stage 0-1 (P = 0.02), > 6 cycles of CHT (P = 0.042), CR + PR after CHT (P < 0.001), and TRT (P < 0.001) were independently associated with longer OS compared to CHT alone. CONCLUSION: TRT using IMRT is strongly correlated with improved OS and PFS in ES-SCLC patients reaching CR, PR or SD after CHT. A multicenter, randomized phase III clinical trial is needed to confirm these findings.

Prediction of Radiation Pneumonitis With Dose Distribution: A Convolutional Neural Network (CNN) Based Model.

Radiation pneumonitis (RP) is one of the major side effects of thoracic radiotherapy. The aim of this study is to build a dose distribution based prediction model, and investigate the correlation of RP incidence and high-order features of dose distribution. A convolution 3D (C3D) neural network was used to construct the prediction model. The C3D network was pre-trained for action recognition. The dose distribution was used as input of the prediction model. With the C3D network, the convolution operation was performed in 3D space. The guided gradient-weighted class activation map (grad-CAM) was utilized to locate the regions of dose distribution which were strongly correlated with grade≥2 and grade<2 RP cases, respectively. The features learned by the convolution filters were generated with gradient ascend to understand the deep network. The performance of the C3D prediction model was evaluated by comparing with three multivariate logistic regression (LR) prediction models, which used the dosimetric, normal tissue complication probability (NTCP) or dosiomics factors as input, respectively. All the prediction models were validated using 70 non-small cell lung cancer (NSCLC) patients treated with volumetric modulated arc therapy (VMAT). The area under curve (AUC) of C3D prediction model was 0.842. While the AUC of the three LR models were 0.676, 0.744 and 0.782, respectively. The guided grad-CAM indicated that the low-dose region of contralateral lung and high-dose region of ipsilateral lung were strongly correlated with the grade≥2 and grade<2 RP cases, respectively. The features learned by shallow filters were simple and globally consistent, and of monotonous color. The features of deeper filters displayed more complicated pattern, which was hard or impossible to give strict mathematical definition. In conclusion, we built a C3D model for thoracic radiotherapy toxicity prediction. The results demonstrate its performance is superior over the classical LR models. In addition, CNN also offers a new perspective to further understand RP incidence.

Improved Virtual Gyroscope Technology Based on the ARMA Model.

In view of the large output noise and low precision of the Micro-electro-mechanical Systems (MEMS) gyroscope, the virtual gyroscope technology was used to fuse the data of the MEMS gyroscope to improve its output precision. Random error model in the conventional virtual gyroscopes contained an angular rate random walk and angle random walk ignoring other noise items and the virtual gyroscope technology can not compensate all random errors of MEMS gyroscope. So, the improved virtual gyroscope technology based on the autoregressive moving average (ARMA) model was proposed. First, the conventional virtual gyroscope technology was used to model the random error of three MEMS gyroscopes, and the data fusion was carried out by a Kalman filter to get the output of the virtual gyroscope. After that, the ARMA model was used to model the output of the virtual gyroscope, the random error model was improved with the ARMA model, and the Kalman filter was designed based on the improved random error model for data fusion of the MEMS gyroscopes. The experimental results showed that the 1σ standard deviation of the output of the virtual gyroscope based on the ARMA model was 1.4 times lower than that of the conventional virtual gyroscope output.

Random Error Analysis of MEMS Gyroscope Based on an Improved DAVAR Algorithm.

In view that traditional dynamic Allan variance (DAVAR) method is difficult to make a good balance between dynamic tracking capabilities and the confidence of the estimation. And the reason is the use of a rectangular window with the fixed window length to intercept the original signal. So an improved dynamic Allan variance method was proposed. Compared with the traditional Allan variance method, this method can adjust the window length of the rectangular window adaptively. The data in the beginning and terminal interval was extended with the inverted mirror extension method to improve the utilization rate of the interval data. And the sliding kurtosis contribution coefficient and kurtosis were introduced to adjust the length of the rectangular window by sensing the content of shock signal in terminal interval. The method analyzed the window length change factor in different stable conditions and adjusted the rectangular window's window length according to the kurtosis, sliding kurtosis contribution coefficient. The test results show that the more the kurtosis stability threshold was close to 3, the stronger the dynamic tracking ability of DAVAR would be. But the kurtosis stability threshold was too close to 3, there was a misjudgement in kurtosis analysis of signal stability, resulting in distortion of DAVAR analysis results. When using the improved DAVAR method, the kurtosis stability threshold can be close to 3 to improve the tracking ability and the estimation confidence in stable interval. Therefore, it solved the problem that the dynamic Allan variance tracking ability and confidence level were difficult to take into account, and also solved the problem of misjudgement in the stability analysis of kurtosis.

MicroRNA-886-3P functions as a tumor suppressor in small cell lung cancer.

Small cell lung cancer (SCLC) is a highly aggressive disease and miRNAs may play an important role in modulating SCLC progression. We have previously screened 924 miRNAs and found that miR-886-3P was negatively associated with SCLC survival. In the current study, we further investigated the role of miR-886-3P mimic in regulating SCLC cell phenotypic alteration in vitro and xenograft tumor formation in vivo. We found that transfection of miR-886-3P mimic significantly inhibited SCLC cell proliferation, migration, and colony formation, and induced mesenchymal-epithelial transition (MET) by suppressing TGF-ß1 synthesis in vitro. Furthermore, intra-tumor injection of miR-886-3P mimic lead to necrosis and suppression of tumor invasion to the surrounding tissue in the subcutaneous xenograft tumor, and intra-vein injection of miR-886-3P mimic suppressed xenograft lung cancer growth in vivo. These findings suggested that miR-886-3P functions as a tumor suppressor in SCLC and thus, it might be a potential therapeutic molecule in the treatment of lung cancer.

Randomised phase III trial of concurrent chemoradiotherapy with extended nodal irradiation and erlotinib in patients with inoperable oesophageal squamous cell cancer.

BACKGROUND: This randomised phase III study was conducted to investigate the efficacy of extended nodal irradiation (ENI) and/or erlotinib in inoperable oesophageal squamous cell cancer (ESCC). PATIENTS AND METHODS: Patients with histologically confirmed locally advanced ESCC or medically inoperable disease were randomly assigned (ratio 1:1:1:1) to one of four treatment groups: group A, radiotherapy adoption of ENI with two cycles of concurrent TP chemotherapy (paclitaxel 135 mg/m2 day 1 and cisplatin 20 mg/m2 days 1-3, every 4 weeks) plus erlotinib (150 mg per day during chemoradiotherapy); group B, radiotherapy adoption of ENI with two cycles of concurrent TP; group C, radiotherapy adoption of conventional field irradiation (CFI) with two cycles of concurrent TP plus erlotinib; group D, radiotherapy adoption of CFI with two cycles of concurrent TP. RESULTS: A total of 352 patients (88 assigned to each treatment group) were enrolled. The 2-year overall survival rates of group A, B, C and D were 57.8%, 49.9%, 44.9% and 38.7%, respectively (P = 0.015). Group A significantly improved 2-year overall survival compared with group D. The ENI significantly improved overall survival in patients with inoperable ESCC (P = 0.014). The addition of erlotinib significantly decreased loco-regional recurrence (P = 0.042). Aside from rash and radiation oesophagitis, the incidence of grade 3 or greater toxicities did not differ among 4 groups. CONCLUSION: Chemoradiotherapy with ENI and erlotinib might represent a substantial improvement on the standard of care for inoperable ESCC. ENI alone should be adopted in concurrent chemoradiotherapy for ESCC patients.

Development of a Data-Independent Targeted Metabolomics Method for Relative Quantification Using Liquid Chromatography Coupled with Tandem Mass Spectrometry.

Quantitative metabolomics approaches can significantly improve the repeatability and reliability of metabolomics investigations but face critical technical challenges, owing to the vast number of unknown endogenous metabolites and the lack of authentic standards. The present study contributes to the development of a novel method known as "data-independent targeted quantitative metabolomics" (DITQM), which was used to investigate the label-free quantitative metabolomics of multiple known and unknown metabolites in biofluid samples. This approach initially involved the acquisition of MS/MS data for all metabolites in biosamples using a sequentially stepped targeted MS/MS (sst-MS/MS) method, in which multiple product ion scans were performed by selecting all ions in the targeted mass ranges as the precursor ions. Subsequently, scheduled multiple reaction monitoring (MRM) by LC-MS/MS of the metabolome was established for 1658 characteristic ion pairs of 1324 metabolites. For sensitive and accurate quantification of these metabolites, mixed calibration curves were generated using sequentially diluted standard reference plasma samples using established MRM methods. Relative concentrations of all metabolites in each sample were calculated without using individual authentic standards. To evaluate the reliability and applicability of this new method, the performance of DITQM was validated by comparison to absolute quantification of 12 acylcarnitines using authentic standards and traditional metabolomics analysis for lung cancer. The results proved that the DITQM protocol is more reliable and can significantly improve clustering effects and repeatability in biomarker discovery. In this study, we established a novel methodology to standardize and quantify large-scale metabolome, providing a new choice for metabolomics research and its clinical applications.

DCE-MRI Perfusion and Permeability Parameters as predictors of tumor response to CCRT in Patients with locally advanced NSCLC.

In this prospective study, 36 patients with stage III non-small cell lung cancers (NSCLC), who underwent dynamic contrast-enhanced MRI (DCE-MRI) before concurrent chemo-radiotherapy (CCRT) were enrolled. Pharmacokinetic analysis was carried out after non-rigid motion registration. The perfusion parameters [including Blood Flow (BF), Blood Volume (BV), Mean Transit Time (MTT)] and permeability parameters [including endothelial transfer constant (Ktrans), reflux rate (Kep), fractional extravascular extracellular space volume (Ve), fractional plasma volume (Vp)] were calculated, and their relationship with tumor regression was evaluated. The value of these parameters on predicting responders were calculated by receiver operating characteristic (ROC) curve. Multivariate logistic regression analysis was conducted to find the independent variables. Tumor regression rate is negatively correlated with Ve and its standard variation Ve_SD and positively correlated with Ktrans and Kep. Significant differences between responders and non-responders existed in Ktrans, Kep, Ve, Ve_SD, MTT, BV_SD and MTT_SD (P < 0.05). ROC indicated that Ve < 0.24 gave the largest area under curve of 0.865 to predict responders. Multivariate logistic regression analysis also showed Ve was a significant predictor. Baseline perfusion and permeability parameters calculated from DCE-MRI were seen to be a viable tool for predicting the early treatment response after CCRT of NSCLC.