Prognostic factors of refractory NSCLC patients receiving anlotinib hydrochloride as the third-or further-line treatment

Objective:Anlotinib hydrochloride is a multitarget tyrosine kinase inhibitor that targets vascular endothelial growth factor receptor,fibroblast growth factor receptor,platelet-derived growth factor receptor,c-Kit,and c-MET;therefore,it exhibits both antitumor and anti-angiogenetic activities.A phase III trial has shown that anlotinib improved progression-free survival(PFS)and overall survival(OS)in patients with advanced non-small cell lung cancer(NSCLC),who presented with progressive disease or intolerance after standard chemotherapy.This study aimed to analyze the characteristics of patients receiving anlotinib treatment to determine the dominant populations who are fit for the treatment.Methods:Data were collected from March 2015 to January 2017 from a randomized,double-blind,placebo-controlled,multicenter,phase III trial of anlotinib(ALTER0303).A total of 437 patients were enrolled and randomly allocated(2:1)to the anlotinib and placebo groups.Kaplan–Meier analysis and log-rank test were performed to compare PFS and OS.Cox proportional hazards model was adopted for multivariate prognostic analysis.Results:Multivariate analysis indicated that high post-therapeutic peripheral blood granulocyte/lymphocyte ratio and elevated alkaline phosphatase levels were independent risk factors for PFS.Meanwhile,elevated thyroid-stimulating hormone,blood glucose,and triglyceride levels;hypertension;and hand–foot syndrome were independent protective factors of PFS.High posttherapeutic peripheral blood granulocyte/lymphocyte ratio,an Eastern Cooperative Oncology Group(ECOG)score≥2,and the sum of the maximal target lesion length at baseline were independent risk factors of OS,and hypertriglyceridemia was an independent protective factor of OS.Conclusions:This study preliminarily explored the possible factors that affected PFS and OS after anlotinib treatment in patients with advanced refractory NSCLC,and the baseline characteristics of the therapeutically dominant populations were then identified.

Equivalent efficacy study of QL1101 and bevacizumab on untreated advanced non-squamous non-small cell lung cancer patients: a phase 3 randomized, double-blind clinical trial

Objective:This phase 3 study aimed to test equivalence in efficacy and safety for QL1101,a bevacizumab analogue in Chinese patients with untreated locally advanced non-squamous non-small cell lung cancer(NSCLC).Methods:Eligible patients were randomly assigned 1:1 to receive carboplatin and paclitaxel in combination with either QL1101 or bevacizumab,15 mg/kg every 3-week for 6 cycles.This was followed by maintenance treatment with single agent QL1101 every 3-week.The primary end-point was objective response rate(ORR),with secondary end-points being progression-free survival(PFS),overall survival(OS),disease control rate(DCR),and adverse events(AEs).Results:Of 675 patients,535 eligible patients were randomized to the QL1101 group(n=269)and bevacizumab group(n=266).ORRs were 52.8%and 56.8%,respectively,for the QL1101 and bevacizumab groups,with an ORR hazard ratio 0.93(95%confidence interval:0.8-0131.1).The PFS,OS,DCR,and AEs were comparable between the 2 groups,which remained the same after stratification according to epidermal growth factor receptor mutation or smoking history.Conclusions:QL1101 showed similar efficacy and safety profiles as compared to bevacizumab among Chinese patients with untreated locally advanced non-squamous NSCLC.

Activated conduction by small incision and moderate stimulation for treatment of cerebral palsy in 182 cases

BACKGROUND： Intemationally, methods to treat cerebral palsy （CP） are basically the same, including correction of deformity with orthopaedic operation, selective posterior rhizotomy（SPR）, rehabilitation therapy and so on. Domestic methods to treat CP are basically close to the international methods. Traditional Chinese medical therapies, such as, acupuncture and moxibustion, acupoint injection, massage and so on, also have good curative effects. OBJECTIVE ： To observe the effect of activated conduction by small incision and moderate stimulation （ACSIMS） on limb function and living ability in patients with spastic CP at different degrees.DESIGN： Retrospective case analysis.SETTING： Department of Medical Education, Shanxi Medical College for Continuing Education.PARTICIPANTS ： A total of 182 patients with CP, including 97 males and 85 females, aged 3 to 23 years, who received treatment in Beijing Haidian District Diaoyutai Hospital during October 1996 to September 2005, were involved in this trial. The involved patients met the diagnostic criteria proposed in 2004 National Special Seminar of Cerebral Palsy. According to typing criteria of CP purposed in 1990 Brioni International Conference, the involved patients were typed： 117 with spastic CP, 14 with involuntary movement CP, 19 with defective coordination CP, 5 with hypotonia CP and 27 with mixed type CP. The guardians of underage patients and adult patients themselves were all informed of the therapeutic regimens. METHODS： ①According to CP typing assessment quantitative criteria of Li, the involved patients were assigned from limb position, daily living and movement 3 aspects： mild 23, moderate 75, severe 62 and extremely severe 22. ② Operation methods： The lower limb of moderate spastic CP patient was taken as an example. A median incision or paramedian incision was made between L2 and S1, and it was also the first incision in lower limb. The second incision was made at the center of buttock or at the midpoint of the line of sciatic tuber and greater trochanter. The third incision was determined according to the posture of shank of patients. The located region was locally anesthetized, then in which a small incision was made. Moderate stimulation was performed by a smooth mental instrument in muscular layer from different angles. Surgical catgut-embedding therapy was used after stimulation in CP patients who had hyperexplexia and obvious muscular atrophy. Anti-inflammatory was taken orally 3 to 5 days; physical treatment was daily conducted 10 to 15 minutes within 5 to 7 days, one course of treatment. Operation was needed once or twice in mild CP patients, twice or three times in moderate CP patients, three or four times in severe CP patients and three to five times in extremely severe CP patients. ③Assessment criteria of therapeutic effect of CP： cured, significantly effective, effective and non-effective based on a favorable tum in the limb position, daily living and movement 3 aspects. ④Chi-square test was used for difference comparison of enumeration data. MAIN OUTCOME MEASURES ： Comparison of therapeutic effect of patients with CP at different degrees after ACSIMS treatment.RESULTS ： Totally 182 CP patients were involved in the result analysis. ① Effective rate： ACSIMS had remarkably therapeutic effect in treatment of spastic CP. The effective rate of mild, moderate, severe and extremely severe CP was 100.0%, 97.3%, 95.2%, and 90.9%, respectively. The total effective rate reached 96.2%. The effective rate of CP at different degrees was close after treatment （P 〉 0.05）. ② Operation frequency： The mild patients began to recover within one to three days after one or two operations and moderate patients within one week to one month after two or three operations. After one to three times of treatments, the function of lower limbs of patients with mild or moderate CP was close to normal; After three to five times of operations, patients with severe or extremely severe CP began to recover within one week to three months, and their muscular tensions were decreased by one or two degrees, and walking was obviously improved as compared with preoperation. CONCLUSION ： ACSIMS has different therapeutic effects in treatment of spastic CP at different degrees. It can improve the limb function and daily living ability of CP patients. It needs fewer operations and has rapid response to treat mild CP with ACSIMS; on the contrary, it needs more operations and has slow response to treat severe CP with ACSMS.

A review on flexible solar cells

With the gradual progression of the carbon neutrality target,the future of our electricity supply will experience a massive increase in solar generation,and approximately 50%of the global electricity generation will come from solar generation by 2050.This provides the opportunity for researchers to diversify the applications of photovoltaics(PVs)and integrate for daily use in the future.Flexible solar cell technology is the next frontier in solar PV and is the key way to achieve CO_(2)neutrality.The integration of PV technology with other fields will greatly broaden the development areas for the PV industry,providing products with higher added value.In this paper,we reviewed the latest research progress on flexible solar cells(perovskite solar cells,organic solar cells,and flexible silicon solar cells),and proposed the future applications of flexible solar cell technology.

装配式带悬臂梁段嵌入式加强型节点抗震性能分析

为深入分析带悬臂梁段嵌入式加强型节点抗震性能,以及节点构件参数变化对节点抗震性能的影响,对带悬臂梁段嵌入式加强型节点进行拟静力分析,计算结果可为该类型节点设计提供优化方案。分别改变节点的螺栓数目、悬臂梁段外伸翼缘厚度、外伸翼缘宽度以及悬臂梁长度4个主要构件参数,获取一系列节点有限元数值计算模型,通过计算分析节点的滞回性能、破坏形态、耗能能力、承载力、刚度退化及应力路径等,将各系列节点的数值计算结果进行对比,分析节点的螺栓数目、悬臂梁段外伸翼缘厚度、外伸翼缘宽度以及悬臂梁长度对节点力学性能的影响。分析结果表明:翼缘螺栓的数目对节点的力学性能影响较小,在等强设计法设计的节点基础上增加翼缘螺栓数目,对节点的力学性能无明显影响,而减少翼缘螺栓数目会降低节点的整体性,节点会提前发生失稳破坏,但节点的承载能力和刚度下降并不明显。增加外伸翼缘的厚度和悬臂梁段翼缘的宽度可以明显提高节点的耗能能力、承载力和刚度,但当外伸翼缘厚度和外伸翼缘宽度达到一定程度后,耗能能力提高不明显,承载力退化较快,节点在弹塑性阶段的刚度退化加快,节点破坏形态也发生改变,但应力集中现象得到缓解,当外伸翼缘宽度过宽时,节点的耗能能力反而开始降低。悬臂梁段的长度对节点的力学性能有一定影响,增加悬臂梁段长度可提高节点的滞回性能、承载能力和刚度,总体上提高效果没有改变外伸翼缘的宽度和厚度提高的效果明显。由于悬臂梁段外伸翼缘厚度和悬臂梁段翼缘宽度对节点的力学性能影响较大,节点设计时建议外伸翼缘厚度和宽度的选取通过截面控制,外伸梁截面面积与中间梁段翼缘的横截面积比值建议在1.10~1.29范围之内。适当增大悬臂梁段外伸翼缘的截面可明显提高节点的耗能能力、承载能力和刚度,但当悬臂梁段外伸翼缘的截面过大时,破坏形态会发生改变,力学性能略有提高,但会加快节点承载力和刚度的退化速度。

Efficacy,safety and pharmacokinetics of Unecritinib(TQ-B3101)for patients with ROS1 positive advanced non-small cell lung cancer:a Phase I/II Trial

This phase I/II trial characterized the tolerability,safety,and antitumor activities of unecritinib,a novel derivative of crizotinib and a multi-tyrosine kinase inhibitor targeting ROS1,ALK,and c-MET,in advanced tumors and ROS1 inhibitor-naive advanced or metastatic non-small cell lung cancer(NSCLC)harboring ROS1 rearrangements.Eligible patients received unecritinib 100,200.

Third-line or above anlotinib in relapsed and refractory small cell lung cancer patients with brain metastases:A post hoc analysis of ALTER1202,a randomized,double-blind phase 2 study

Background:The prognosis of patients with small cell lung cancer(SCLC)and brain metastases(BM)was poor.This study aimed to explore the efficacy and safety of anlotinib as third-line or above treatment in SCLC with BM.Methods:This was a subgroup analysis of the ALTER1202 trial,which was a randomized,placebo-controlled trial aimed to evaluate the role of anlotinib as third-line treatment or above in patients with SCLC.This study included patients with BM at baseline.The efficacy and safety outcomes included progression-free survival(PFS),overall survival(OS),central nervous system(CNS),objective response rate(ORR),CNS disease control rate(DCR),time to CNS progression,and adverse events(AEs).Results:Twenty-one and nine patients with BM were included in the anlotinib and placebo groups,respectively.The median PFS and OS were 3.8 months(95%confidence interval[CI]:1.8-6.1)and 6.1 months(95%CI:4.1-8.0)in the anlotinib group.Anlotinib was associated with a significant improvement in PFS(hazard ratio[HR]=0.15,95%CI:0.04-0.51,p=0.0005)and OS(HR=0.26,95%CI:0.09-0.73,p=0.0061)than placebo.Anlotinib significantly prolonged the time to CNS progression(p<0.0001).The anlotinib group had a higher CNS DCR than placebo(95.2%vs.22.2%,p=0.0001).The most common grade 3 or higher AEs were increased lipase(19.0%),hypertension(14.3%),and hyponatremia(14.3%)in the anlotinib group.Conclusions:Anlotinib proved to have potential CNS activity and a manageable toxicity profile in patients with SCLC and BM,significantly delaying CNS progression.

Sintilimab versus docetaxel as second-line treatment in advanced or metastatic squamous non-small-cell lung cancer:an open-label,randomized controlled phase 3 trial(ORIENT-3)

Background:Treatment options for Chinese patients with locally advanced or metastatic squamous-cell non-small-cell lung cancer(sqNSCLC)after failure of first-line chemotherapy are limited.This study(ORIENT-3)aimed to evaluate the efficacy and safety of sintilimab versus docetaxel as second-line treatment in patients with locally advanced or metastatic sqNSCLC.Methods:ORIENT-3 was an open-label,multicenter,randomized controlled phase 3 trial that recruited patients with stage IIIB/IIIC/IV sqNSCLC after failure with first-line platinum-based chemotherapy.Patients were randomized in a 1:1 ratio to receive either 200 mg of sintilimab or 75 mg/m^(2) of docetaxel intravenously every 3 weeks,stratified by the Eastern Cooperative Oncology Group performance status.The primary endpoint was overall survival(OS)in the full analysis set(FAS).Secondary endpoints included progression-free survival(PFS),objective response rate(ORR),disease control rate(DCR),duration of response(DoR)and safety.Results:Between August 25,2017,and November 7,2018,290 patients were randomized.For FAS,10 patients fromthe docetaxel armwere excluded.Themedian OS was 11.79(n=145;95%confidence interval[CI],10.28-15.57)months with sintilimab versus 8.25(n=135;95%CI,6.47-9.82)months with docetaxel(hazard ratio[HR]:0.74;95%CI,0.56-0.96;P=0.025).Sintilimab treatment significantly prolonged PFS(median 4.30 vs.2.79 months;HR:0.52;95%CI,0.39-0.68;P<0.001)and showed higher ORR(25.50%vs.2.20%,P<0.001)and DCR(65.50%vs.37.80%,P<0.001)than the docetaxel arm.The median DoRwas 12.45(95%CI,4.86-25.33)months in the sintilimab arm and 4.14(95%CI,1.41-7.23)months in the docetaxel arm(P=0.045).Treatment-related adverse events of grade≥3were reported in 26(18.1%)patients in the sintilimab arm and 47(36.2%)patients in the docetaxel arm.Exploratory biomarker analysis showed potential predictive values of expression levels of two transcription factors,including OVOL2(HR:0.35;P<0.001)and CTCF(HR:3.50;P<0.001),for sintilimab treatment.Conclusions:Compared with docetaxel,sintilimab significantly improved the OS,PFS,and ORR of Chinese patients with previously treated locally advanced or metastatic sqNSCLC.

Bevacizumab biosimilar LY01008 compared with bevacizumab(Avastin)as first-line treatment for Chinese patients with unresectable,metastatic,or recurrent non-squamous non-small-cell lung cancer:A multicenter,randomized,double-blinded,phase Ⅲ trial

Background:Previous studies have demonstrated the preclinical pharmacological and toxicological consistency,and clinical pharmacokinetic equivalence of bevacizumab biosimilar LY01008 with reference bevacizumab(Avastin).This randomized controlled trial aimed to compare the efficacy and safety of LY01008 with Avastin in first-line treatment of Chinese patients with advanced or recurrent non-squamous non-small cell lung cancer(NSCLC).Methods:StageⅢB-ⅣNSCLC patients with evaluable lesions,good physical status,and adequate organ functions from 67 centers across China were randomized in a ratio of 1:1 to receive LY01008 or Avastin 15 mg/kg intravenously in combination with paclitaxel/carboplatin(combined treatment)for 4-6 cycles,followed by maintenance monotherapy with LY01008 until disease progression,intolerable toxicity,or death.The primary endpoint was objective response rate(ORR)in accordance with Response Evaluation Criteria in Solid Tumors(RECIST)version 1.1 confirmed by independent radiological review committees(IRRC).Secondary endpoints included disease control rate(DCR),duration of response(DoR),progression-free survival(PFS),overall survival(OS),and safety.This study was registered in Clinical Trials.gov(NCT03533127).Results:Between December 15^(th),2017,and May 15^(th),2019,a total of 649 patients were randomized to the LY01008(n=324)or Avastin(n=325)group.As of September 25th,2019 for primary endpoint analysis,589 patients received ORR evaluation,with a median number of combined treatment cycles of 5(range 1-6)andmedian duration of treatment of 3.0(range 0.0-5.1)months.ORRof responseevaluable patients in the LY01008 and Avastin groups were 48.5% and 53.0%,respectively.The stratified ORR ratio was 0.91(90%CI 0.80-1.04,within the prespecified equivalence margin of 0.75-1.33).Up to May 15^(th),2020,with a median follow-up of 13.6(range 0.8-28.4)months,no notable differences in DCR,median DoR,median PFS,median OS,and 1-year OS rate were observed between the LY01008 and Avastin groups.There were no clinically meaningful differences in safety and immunogenicity across treatment groups.Conclusions:LY01008 demonstrated similarity to Avastin in terms of efficacy and safety in Chinese patients with advanced or recurrent non-squamous NSCLC.LY01008 combined with paclitaxel/carboplatin is expected to become a new treatment option for unresectable,metastatic,LY01008 and Avastin groups.There were no clinically meaningful differences in safety and immunogenicity across treatment groups.Conclusions:LY01008 demonstrated similarity to Avastin in terms of efficacy and safety in Chinese patients with advanced or recurrent non-squamous NSCLC.LY01008 combined with paclitaxel/carboplatin is expected to become a new treatment option for unresectable,metastatic,or recurrent non-squamous NSCLC patients in the first-line setting.

Anlotinib as third- or further-line therapy for short-term relapsed small-cell lung cancer: subgroup analysis of a randomized phase 2 study (ALTER1202)

Patients with small-cell lung cancer (SCLC) relapse within months after completing previous therapies. This study aimed to investigate the efficacy and safety of anlotinib as third- or further-line therapy in patients with short-term relapsed SCLC from ALTER1202. Patients with short-term relapsed SCLC (disease progression within 3 months after completing ≥ two lines of chemotherapy) in the anlotinib (n = 67) and placebo (n = 34) groups were analyzed. The primary endpoint was progression-free survival (PFS). The secondary endpoints included overall survival, objective response rate (ORR), disease control rate, and safety. Anlotinib significantly improved median PFS/OS (4.0 vs. 0.7 months, P < 0.0001)/(7.3 vs. 4.4 months, P = 0.006) compared with placebo. The ORR was 4.5%/2.9% in the anlotinib/placebo group (P = 1.000). The DCR in the anlotinib group was higher than that in the placebo group (73.1% vs. 11.8%, P < 0.001). The most common adverse events (AEs) were hypertension (38.8%), loss of appetite (28.4%), and fatigue (22.4%) in the anlotinib group and gamma-glutamyl transpeptidase elevation (20.6%) in the placebo group. No grade 5 AEs occurred. For patients with short-term relapsed SCLC, third- or further-line anlotinib treatment was associated with improved survival benefit. Further studies are warranted in this regard.

High-quality industrial n-type silicon wafers with an efficiency of over 23% for Si heterojunction solar cells

n-type CZ-Si wafers featuring longer minority carrier lifetime and higher tolerance of certain metal contamination can offer one of the best Si-based solar cells. In this study, Si heterojuction （SHJ） solar cells which was fabricated with different wafers in the top, middle and tail positions of the ingot, exhibited a stable high efficiency of〉 22% in spite of the various profiles of the resistivity and lifetime, which demonstrated the high material utilization of n-type ingot. In addition, for effectively converting the sunlight into electrical power, the pyramid size, pyramid density and roughness of surface of the Cz-Si wafer were investigated by scanning electron microscope （SEM） and transmission electron microscope （TEM）. Furthermore, the dependence of SHJ solar cell open- circuit voltage on the surface topography was discussed, which indicated that the uniformity of surface pyramid helps to improve the open-circuit voltage and conversion efficiency. Moreover, the simulation revealed that the highest efficiency of the SHJ solar cell could be achieved by the wafer with a thickness of 100 μm. Fortunately, over 23% of the conversion efficiency of the SHJ solar cell with a wafer thickness of 100 μm was obtained based on the systematic optimization of cell fabrication process in the pilot production line. Evidently, the large availability of both n-type ingot and thinner wafer strongly supported the lower cost fabrication of high efficiency SHJ solar cell.

Multiplexed imaging of tumor immune microenvironmental markers in locally advanced or metastatic non-small-cell lung cancer characterizes the features of response to PD-1 blockade plus chemotherapy

Background:Although programmed cell death 1(PD-1)blockade plus chemotherapy can significantly prolong the progression-free survival(PFS)and overall survival(OS)in first-line settings in patients with driver-negative advanced non-small-cell lung cancer(NSCLC),the predictive biomarkers remain undetermined.Here,we investigated the predictive value of tumor immune microenvironmental marker expression to characterize the response features to PD-1 blockade plus chemotherapy.Methods:Tumor tissue samples at baseline were prospectively collected from 144 locally advanced or metastatic NSCLC patients without driver gene alterations who received camrelizumab plus chemotherapy or chemotherapy alone.Tumor immune microenvironmental markers,including PD-1 ligand(PDL1),CD8,CD68,CD4 and forkhead box P3,were assessed using multiplex immunofluorescence(mIF)assays.Kaplan-Meier curveswere used to determine treatment outcome differences according to their expression status.Mutational profiles were compared between tumors with distinct expression levels of these markers and their combinations.Results:Responders had significantly higher CD8/PD-L1(P=0.015)or CD68/PD-L1 co-expression levels(P=0.021)than non-responders in the camrelizumab plus chemotherapy group,while no difference was observed in the chemotherapy group.Patients with high CD8/PD-L1 or CD68/PD-L1 co-expression level was associated with significantly longer PFS(P=0.002,P=0.024;respectively)and OS(P=0.006,P=0.026;respectively)than those with low co-expression in camrelizumab plus chemotherapy group.When comparing survival in the camrelizumab plus chemotherapy with chemotherapy by CD8/PD-L1 co-expression stratification,significantly better PFS(P=0.003)and OS(P=0.032)were observed in high co-expression subgroups.The predictive value of CD8/PD-L1 and CD68/PD-L1 co-expression remained statistically significant for PFS and OS when adjusting clinicopathological features.Although the prevalence of TP53 or KRAS mutations was similar between patients with and without CD8/PD-L1 or CD68/PD-L1 co-expression,the positive groups had a significantly higher proportion of TP53/KRAS co-mutations than the negative groups(both 13.0%vs.0.0%,P=0.023).Notably,enriched PI3K(P=0.012)and cell cycle pathway(P=0.021)were found in the CD8/PD-L1 co-expression group.Conclusion:Tumor immune microenvironmental marker expression,especially CD8/PD-L1 or CD68/PD-L1 co-expression,was associated with the efficacy of PD-1 blockade plus chemotherapy as first-line treatment in patients with advanced NSCLC.

Cross-linked hole transport layers for high-efficiency perovskite tandem solar cells

Perovskite tandem solar cells have recently received extensive attention due to their promise of achieving power conversion efficiency(PCE)beyond the limits of single-junction cells.However,their performance is still largely constrained by the widebandgap perovskite solar cells which show considerable open-circuit voltage(VOC)losses.Here,we increase the VOCand PCE of wide-bandgap perovskite solar cells by changing the hole transport layer(HTL)from commonly used poly(bis(4-phenyl)(2,4,6-trimethylphenyl)amine)(PTAA)to in-situ cross-linked small molecule N_(4),N_(4)′-di(naphthalen-1-yl)-N_(4),N_(4)′-bis(4-vinylphenyl)biphenyl-4,4′-diamine(VNPB).The stronger interaction and lower trap density at the VNPB/perovskite interface improve the PCE and stability of wide-bandgap perovskite solar cells.By using the cross-linked HTL for front wide-bandgap subcells,PCEs of 24.9%and 25.4%have been achieved in perovskite/perovskite and perovskite/silicon tandem solar cells,respectively.The results demonstrate that cross-linkable small molecules are promising for high-efficiency and cost-effective perovskite tandem photovoltaic devices.