A phase Ⅰ study of Hemay022, an irreversible dual EGFR/HER2 tyrosine kinase inhibitor in Chinese patients with HER2-positive advanced breast cancer

Objective: Hemay022 is a novel small-molecule and an irreversible tyrosine kinase inhibitor with the target of epidermal growth factor receptor(EGFR)/human epidermal growth factor receptor 2(HER2), which demonstrated anti-tumor activity in preclinical studies. This first-in-human study evaluated the safety, pharmacokinetics,tolerability and preliminary anti-tumor activity of Hemay022 in HER2-positive advanced breast cancer patients.Methods: Heavily pretreated patients with HER2-positive advanced breast cancer were assigned to eight dose cohorts in a 3+3 dose-escalation pattern at doses of 50-600 mg QD and 300 mg BID. Eligible patients were given a single dose of Hemay022 on d 1 in week 0, followed by once daily continuous doses for four weeks in 28-day cycles.Pharmacokinetic samples were obtained on d 1 and d 28. Clinical responses were assessed every eight weeks.Results: Twenty-eight patients with advanced breast cancer were treated with Hemay022. The most frequently reported drug-related adverse events were diarrhoea(85.7%), vomiting(28.6%), nausea(25.0%) and decreased appetite(17.9%). No grade 4 drug-related adverse events were reported. At 50-600 mg doses, steady state areas under the concentration-time curve and peak concentrations increased with doses. One patient achieved complete response(CR), and three achieved partial response(PR). The objective response rate(ORR) and disease control rate(DCR) were 14.3% and 46.4% in 28 patients, respectively. The median progression-free survival(PFS) was3.98 months.Conclusions: Hemay022 at the dose of 500 mg once daily was well tolerated. The pharmacokinetic properties and encouraging anti-tumor activities of Hemay022 in advanced breast cancer patients warranted further evaluation of Hemay022 for treating breast cancer patients in the current phase Ⅲ trial(No. NCT05122494).

Combined chemo-endocrine therapy as a potential new option for HR+/HER2−advanced breast cancer:a prospective study of fulvestrant plus oral vinorelbine

Objective:Endocrine therapy with fulvestrant has shown synergistic antitumor effects with some chemotherapy drugs in vitro.This study evaluated the efficacy and safety of fulvestrant with vinorelbine in patients with hormone receptor positive(HR+)/human epidermal growth factor receptor-2-negative(HER2−)recurrent or metastatic breast cancer.Methods:Patients were intramuscularly administered fulvestrant 500 mg(day 1 per cycle for 28 days)and oral vinorelbine(60 mg/m2 on days 1,8,and 15 of each cycle).The primary endpoint was progression-free survival(PFS).Secondary endpoints included overall survival,objective response rate,disease control rate,duration of response,and safety.Results:A total of 38 patients with HR+/HER2−advanced breast cancer included in the study were followed up for a median time of 25.1 months.The overall median PFS was 9.86 months[95%confidence interval(CI)7.2-23.13],and the median PFS of the first-line and the second-line treatment population was 20.73 months(95%CI 9.82 to NR)and 4.27 months(95%CI 3.68 to NR),respectively.Most adverse events reported were of grade 1/2,and none were of grade 4/5.Conclusions:This is the first exploratory study of a fulvestrant and oral vinorelbine regimen in the treatment of HR+/HER2−recurrent and metastatic breast cancer.The combination chemo-endocrine therapy was efficacious,safe,and promising for patients with HR+/HER2−advanced breast cancer.

热休克蛋白-90α在乳腺癌诊断和疗效监测及复发预测中的临床价值

目的:探讨乳腺癌及其他恶性肿瘤患者血浆中的热休克蛋白-90α(heat shock protein-90α,HSP-90α)表达水平差异,及在乳腺癌诊断、监测疗效、预测复发中的临床价值。方法:选取2016年6月至2016年9月就诊于中国医学科学院肿瘤医院615例女性患者的临床病理资料,分为试验组399例和对照组216例。试验组均为乳腺癌患者,再分为静态组289例和动态组110例,静态组根据TNM分期、组织学类型和分子分型等进行分类分析,动态组用于动态疗效分析;对照组包括健康对照人群103例,乳腺良性肿瘤患者51例及非乳腺系统恶性肿瘤患者62例。采用酶联免疫法检测HSP-90α表达水平。利用ROC曲线分析确定血浆中HSP-90α表达水平作为乳腺癌诊断、复发的截断值,采用Wilcoxon符号秩检验及Kruskal-Wallis检验分析各因素与HSP-90α表达水平的相关性。结果:乳腺癌患者血浆中的HSP-90α表达水平显著升高(P<0.001),且乳腺癌不同分子亚型患者血浆中的HSP-90α表达水平无显著性差异(P>0.05)。选取HSP-90α表达水平为59.7 ng/m L与43.22 ng/m L作为诊断乳腺癌和预测肿瘤复发的临界值时,其曲线下面积(area under curve,AUC)分别为0.834与0.877,灵敏度和特异度分别为90.3%和78.6%与95.7%和74.5%。新辅助治疗有效者及手术前后患者血浆中的HSP-90α表达水平明显下降(P<0.05),结论:乳腺癌患者血浆中的HSP-90α表达水平显著升高,对乳腺癌诊断、疗效判断及复发预测具有一定的价值。

Trastuzumab plus adjuvant chemotherapy for human epidermal growth factor receptor 2(HER2)-positive early-stage breast cancer: A real-world retrospective study in Chinese patients

Objective: To assess the long-term effectiveness and safety of trastuzumab in adjuvant therapy for Chinese patients with early-stage human epidermal growth factor 2(HER2)-positive breast cancer in a real-world setting.Methods: This retrospective observational study analyzed the medical records of HER2-positive breast cancer patients between 2000 and 2012 at the Chinese Academy of Medical Sciences. Patients who received adjuvant chemotherapy alone or adjuvant chemotherapy followed by/combined with trastuzumab were included. The Kaplan-Meier method was used to estimate disease-free survival(DFS) and overall survival(OS). Hazard ratios(HR) and 95% confidence intervals(95% CI) were calculated using the Cox regression model.Results: Of the 1,348 patients analyzed, 909 received chemotherapy alone and 439 received chemotherapy plus trastuzumab. The 3-year, 5-year and 10-year DFS rates were 83.70%, 76.38% and 68.94%, respectively, in the chemotherapy-alone cohort, and 90.21%, 86.19% and 83.45% in the chemotherapy plus trastuzumab cohort. The3-year, 5-year and 10-year OS rates were 96.10%, 91.40% and 81.88% in the chemotherapy-alone cohort, and98.17%, 94.91% and 90.01% in the chemotherapy plus trastuzumab cohort. The chemotherapy plus trastuzumab group had a significantly lower risk of disease recurrence and death than the chemotherapy-alone group(DFS:HR=0.50, 95% CI, 0.37-0.68;P<0.001;OS: HR=0.53, 95% CI, 0.34-0.81;P=0.004) after adjusting for covariates.In the 439 patients treated with trastuzumab, multivariate analysis suggested that lymph node positivity, higher T stages, and hormone receptor-negative status were significantly associated with higher risks of disease recurrence,and lymph node positivity and hormone receptor-negative status were significantly associated with higher risks of death. Grade 3/4 adverse events(incidence ≥1%) were more common in patients receiving trastuzumab(54.44% vs.15.73%).Conclusions: Early-stage HER2-positive breast cancer patients treated with trastuzumab plus adjuvant chemotherapy have a significant survival benefit compared with chemotherapy-alone in real-world settings. Lymph node positivity, hormone receptor-negative status, and higher T stages may be associated with higher risks of recurrence, and effective therapy for patients with these factors is required.

Intelligent modelling of clay compressibility using hybrid meta-heuristic and machine learning algorithms

Compression index Ccis an essential parameter in geotechnical design for which the effectiveness of correlation is still a challenge.This paper suggests a novel modelling approach using machine learning(ML)technique.The performance of five commonly used machine learning(ML)algorithms,i.e.back-propagation neural network(BPNN),extreme learning machine(ELM),support vector machine(SVM),random forest(RF)and evolutionary polynomial regression(EPR)in predicting Cc is comprehensively investigated.A database with a total number of 311 datasets including three input variables,i.e.initial void ratio e0,liquid limit water content wL,plasticity index Ip,and one output variable Cc is first established.Genetic algorithm(GA)is used to optimize the hyper-parameters in five ML algorithms,and the average prediction error for the 10-fold cross-validation(CV)sets is set as thefitness function in the GA for enhancing the robustness of ML models.The results indicate that ML models outperform empirical prediction formulations with lower prediction error.RF yields the lowest error followed by BPNN,ELM,EPR and SVM.If the ranges of input variables in the database are large enough,BPNN and RF models are recommended to predict Cc.Furthermore,if the distribution of input variables is continuous,RF model is the best one.Otherwise,EPR model is recommended if the ranges of input variables are small.The predicted correlations between input and output variables using five ML models show great agreement with the physical explanation.

Anorectal functional outcome after repeated transanal endoscopic microsurgery

AIM： TO evaluate the status of anorectal function after repeated transanal endoscopic microsurgery （TEN）. METHODS： Twenty-one patients undergoing subtotal colectomy with ileorectal anastomosis were included. There were more than 5 large （〉 1 cm） polyps in the remaining rectum （range： 6-20 cm from the anal edge）. All patients, 19 with villous adenomas and 2 with low-grade adenocarcinomas, underwent TEM with submucosal endoscopic excision at least twice between 2005 and 2011. Anorectal manometry and a question- naire about incontinence were carried out at week 1 before operation, and at weeks 2 and 3 and 6 mo after the last operation. Anal resting pressure, maxi- mum squeeze pressure, maximum tolerable volume （MTV） and rectoanal inhibitory reflexes （RAIR） were recorded. The integrity and thickness of the internal anal sphincter （IAS） and external anal sphincter （EAS） were also evaluated by endoanal ultrasonography. We determined the physical and mental health status with SF-36 score to assess the effect of multiple TEM on patient quality of life （QoL）. RESULTS： All patients answered the questionnaire. Apart from negative RAIR in 4 patients, all of the anorectal manometric values in the 21 patients were normal before operation. Mean anal resting pressure decreased from 38±5 mmHg to 19±3 mmHg （38±5 mmHg vs 19±3 mmHg, P = 0.000） and MTV from 165± 19mLto60± 11mL（165± 19mLvs60± 11 mL, P = 0.000） at month 3 after surgery. Anal resting pressure and MTV were 37 ± 5 mmHg （38 ± 5 mmHg vs 37 ± 5 mmHg, P = 0.057） and 159 ± 19 mL （165 ± 19 mL vs 159 ± 19 mL, P = 0.071）, respectively, at month 6 after TEM. Maximal squeeze pressure de- creased from 171 ± 19 mmHg to 62 ± 12 mmHg （171 ± 19 mmHg vs 62 ± 12 mmHg, P = 0.000） at week 2 after operation, and returned to normal values by postoperative month 3 （171 ± 19 vs 166 ± 18, P = 0.051）. RAIR were absent in 4 patients preoperatively and in 12 （χ2 = 4.947, P = 0.026） patients at month 3 after surgery. PAIR was absent only in 5 patients at postoperative month 6 （χ2 = 0.141, P = 0.707）. Endo- sonography demonstrated that IAS disruption occurred in 8 patients, and 6 patients had temporary inconti- nence to flatus that was normalized by postoperative month 3. IAS thickness decreased from 1.9 ± 0.6 mm preoperatively to 1.3 ± 0.4 mm （1.9 ± 0.6 mm vs 1.3 ± 0.4 mm, P = 0.000） at postoperative month 3 and increased to 1.8 ± 0.5 mm （1.9 ± 0.6 mm vs 1.8 ± 0.5 mm, P = 0.239） at postoperative month 6. EAS thickness decreased from 3.7 ± 0.6 mm preoperatively to 3.5 ± 0.3 mm （3.7 ± 0.6 mm vs 3.5 ± 0.3 mm, P = 0.510） at month 3 and then increased to 3.6 ± 0.4 mm （3.7 ± 0.6 mm vs 3.6 ± 0.4 mm, P = 0.123） at month 6 after operation. Most patients had frequent stools per day and relatively high Wexner scores in a short time period. While actual fecal incontinence was exceptional, episodes of soiling were reported by 3 pa- tients. With regard to the QoL, the physical and mental health status scores （SF-36） were 56.1 and 46.2 （50 in the general population）, respectively.CONCLUSION： The anorectal function after repeated TEM is preserved. Multiple TEM procedures are useful for resection of multi-polyps in the remaining rectum.

Phase Ⅱ study of apatinib in combination with oral vinorelbine in heavily pretreated HER2-negative metastatic breast cancer and clinical implications of monitoring ctDNA

Objective:Apatinib is an oral TKI targeting VEGFR-2.Single-agent apatinib treatment has been shown to produce an objective response in patients with pretreated m BC.Oral vinorelbine also holds promise as a treatment of choice in patients with m BC.This study aimed to investigate the efficacy and safety of the oral vinorelbine-apatinib combination in patients with pretreated m BC.In addition,we detected gene variants in ct DNA to explore the therapeutic implications.Methods:This study enrolled patients with HER2-negative m BC who were pretreated with anthracycline/taxanes.Patients were treated with apatinib at 500 mg/425 mg daily plus oral vinorelbine 60 mg/m2 on days 1,8,and 15 of every cycle(3 weeks).The primary endpoint was PFS.The secondary endpoints were ORR,CBR,OS,and safety.Patients eligible for ct DNA detection were evaluated before and during treatment.Results:Forty patients were enrolled.The median PFS was 5.2 months(95%CI,3.4–7.0 months),and the median OS was 17.4 months(95%CI,8.0–27.0 months).The ORR was 17.1%(6/35),and the CBR was 45.7%(16/35).The most common AEs included gastrointestinal reaction,myelosuppression,and hypertension.In 20 patients,ct DNA was detected at baseline and during treatment.A significant difference was found in PFS for undetected vs.detected baseline ct DNA(13.9 months vs.3.6 months,P=0.018).Conclusions:All-oral therapy with apatinib plus vinorelbine displayed objective efficacy in patients with heavily pretreated HER2-negative m BC,with acceptable and manageable toxicity profiles.Patients with no gene variant detected and lower variant allele frequencies in ct DNA at baseline showed longer PFS.

Dose-dense paclitaxel plus carboplatin vs.epirubicin and cyclophosphamide with paclitaxel as adjuvant chemotherapy for high-risk triple-negative breast cancer

Objective:The objective of this open-label,randomized study was to compare dose-dense paclitaxel plus carboplatin(PCdd)with dose-dense epirubicin and cyclophosphamide followed by paclitaxel(ECdd-P)as an adjuvant chemotherapy for early triple-negative breast cancer(TNBC).Methods:We included Chinese patients with high recurrence risk TNBC who underwent primary breast cancer surgery.They were randomly assigned to receive PCdd[paclitaxel 150 mg/m2 on d 1 and carboplatin,the area under the curve,(AUC)=3 on d 2]or ECdd-P(epirubicin 80 mg/m2 divided in 2 d and cyclophosphamide 600 mg/m2 on d 1 for 4 cycles followed by paclitaxel 175 mg/m2 on d 1 for 4 cycles)every 2 weeks with granulocyte colony-stimulating factor(G-CSF)support.The primary endpoint was 3-year disease-free survival(DFS);the secondary endpoints were overall survival(OS)and safety.Results:The intent-to-treat population included 143 patients(70 in the PCdd arm and 73 in the ECdd-P arm).Compared with the ECdd-P arm,the PCdd arm had significantly higher 3-year DFS[93.9%vs.79.1%;hazard ratio(HR)=0.310;95%confidence interval(95%CI),0.137-0.704;log-rank,P=0.005]and OS(98.5%vs.92.9%;HR=0.142;95%CI,0.060-0.825;log-rank,P=0.028).Worse neutropenia(grade 3/4)was found in the ECdd-P than the PCdd arm(47.9%V5.21.4%,P=0.001).Conclusions:PCdd was superior to ECdd-P as an adjuvant chemotherapy for early TNBC with respect to improving the 3-year DFS and OS.PCdd also yielded lower hematological toxicity.Thus,PCdd might be a preferred regimen for early TNBC patients with a high recurrence risk.

MTHFR和TYMS的多态性预测转移性乳腺癌患者因卡培他滨诱发的手足综合征

背景与目的乳腺癌是一个全球性问题,每年都会诊断出大量的新发病例。卡培他滨对转移性乳腺癌(metastatic breast cancer,MBC)患者有效。手足综合征(hand-foot syndrome,HFS)是卡培他滨的常见不良反应。在本文中,我们研究了卡培他滨代谢通路相关基因中的单核苷酸多态性(single nucleotide polymorphisms,SNPs)与卡培他滨诱导的中国MBC患者HFS之间的相关性,以确定一些具有预测性的生物标志物基因。方法我们选择了3个参与卡培他滨代谢的基因,并筛选了这些靶基因的遗传变体。我们对342例接受卡培他滨化疗的MBC患者的胸苷酸合酶基因(thymidylate synthase gene,TYMS)、亚甲基四氢叶酸还原酶基因(methylene tetrahydrofolate reductase gene,MTHFR)和核糖核苷酸还原酶M1基因(ribonucleotide reductaseM1gene,RRM1)中的22个SNPs进行了基因分型。使用Pearson’sχ2检验评估患有和不患有HFS的患者中每个SNP的基因型分布,并使用logistic回归分析确定HFS与SNP的基因型之间的相关性。使用血液表达数量定量性状基因座(expression quantitative trait loci,e QTL)Browser在线工具分析了SNP及其对应基因表达之间的相关性。结果我们在TYMS和MTHFR基因中发现了4个HFS阳性位点:TYMS rs2606241(P=0.022)、TYMS rs2853741(P=0.019)、MTHFR rs3737964(P=0.029)和MTHFR rs4846048(P=0.030)。Logistic回归分析显示,MTHFR rs3737964[比值比(odds ratio,OR)=0.54,95%置信区间(confidence interval,CI):0.3–0.97,P=0.038]和MTHFRrs4846048(OR=0.54,95%CI:0.30–0.98,P=0.042)的基因型AG是HFS的保护因素,而TYMS rs2853741的基因型CT(OR=2.25,95%CI:1.31–3.87,P=0.012)增加了HFS的风险。TYMSrs2606241的基因型GT(OR=1.27,95%CI:0.73–2.23,P=0.012)与HFS之间的相关性尚不确定。进一步的e QTL分析证实,rs3737964和rs4846048的等位基因影响顺式MTHFR的基因表达水平。结论我们已经确定了4个潜在有效的药物遗传学标记,TYMS rs2606241、TYMS rs2853741、MTHFR rs3737964和MTHFR rs4846048可以预测卡培他滨诱导的MBC患者的HFS。

基于上皮–间质转化标志物的循环肿瘤细胞表型检测对HER2阴性转移性乳腺癌一线化疗的预后意义

背景与目的上皮–间质转化(epithelia-mesenchymal,EMT)参与肿瘤细胞的转移,并且对基于上皮细胞黏附分子的循环肿瘤细胞(circulating tumor cells,CTCs)检测技术提出了挑战,CTCs已被证实是转移性乳腺癌的预后指标。虽然有证据表明基于EMT标志物的CTCs异质性与疾病进展相关,但在临床应用方面尚无统一的参考标准。本研究旨在评估基于EMT的动态CTCs检测对转移性乳腺癌患者的预后意义。方法我们从CAMELLIA III期前瞻性研究中招募了108例人表皮生长因子受体2阴性转移性乳腺癌患者,并应用CanPatrol CTC富集技术检测外周血中不同亚型的CTCs(包括上皮型CTCs、混合型上皮/间质CTCs和间质型CTCs)。应用1年无进展生存(progression-free survival,PFS)率作为界值分别寻找CTC总数和间质CTCs比例的受试者工作曲线来确定最佳阈值,并采用Kaplan-Meier分析和Cox比例风险回归分析验证综合考虑CTC总数和间质型CTCs比例制定的诊断标准的预后价值。结果CTC总数的最佳阈值为9.5[曲线下面积(area under the curve,AUC)=0.538,95%置信区间(confidence interval,CI=0.418–0.657)]及间质CTCs比例为10.7%(AUC=0.581,95%CI:0.463–0.699)作为预测1年PFS率的界值。我们采用CTC总数≥10/5 mL且间质CTCs比例>10.7%的联合标准预测PFS。符合联合标准的患者的中位PFS显著短于不符合标准的患者(6.2个月vs.9.9个月,P=0.010)。根据该标准和显著的临床病理学特征绘制列线图,C指数为0.613(P=0.010)。结论CTC总数和间质CTCs比例的联合标准可用于监测转移性乳腺癌患者的治疗耐药性和预测患者预后。

Newly Identified Silicate Carbon Stars from IRAS Low-Resolution Spectra

The discovery of silicate carbon star poses a challenge to the theory of stellar evolution in the late stage, hence it is important to look for more silicate carbon stars. To this end we have carried out cross-identifications between the new IRAS Low-Resolution Spectrum （LRS） database and the new carbon star catalog, CGCS3. We have found nine new silicate carbon stars with silicate features around 10μm and/or 18 μm. These newly identified stars are located in the Regions Ilia and VII in the IRAS two-color diagram, which means they indeed have typical far infrared colors of silicate carbon stars. The infrared properties of each of these sources are discussed.

An infrared study of Be stars based on ISO SWS01 spectra

The Infrared Space Observatory （ISO） Short-Wavelength Spectrometer （SWS） spectra of 10 Be stars are presented. It can be seen that the Be stars show a diversity in their ISO SWS01 spectral classifications by Kraemer et al., from naked stars, stars associated with dust, stars with warm dust shells, stars with cool dust shells to very red sources. In addition, the Brα/HI（14-6） line flux ratio derived for the sample stars is compared with that of P Cyg, and it is found that the line ratio of Be stars which were investigated show not only lower values as suggested by Waters et al., but also larger values. Therefore, the line ratio cannot be used to judge whether a star is a Be star or not.

高黎贡山外来植物入侵现状及管控建议

高黎贡山是中国生物多样性的关键地区,也是西南地区重要的生态安全屏障。在气候变化和人类活动等影响下,高黎贡山正面临越来越多的外来植物入侵,其生物生态安全遭受严重威胁。本研究通过系统野外调查并结合文献数据分析,揭示高黎贡山外来植物入侵现状,根据分布范围、记录频次、分布状态以及危害性划分入侵植物的入侵等级,并提出相应管控建议。结果显示,高黎贡山现有外来植物共225种,其中入侵植物214种、外来栽培植物11种;入侵植物分散于50个科,其中菊科占比最高,达到17.29%,其次是豆科(14.02%)、大戟科(7.01%)和苋科(6.54%);从地理来源看,美洲物种占比最高,达到67.76%(145种),其次是亚洲来源物种(17.76%)。根据入侵现状评估结果,1级(恶性入侵植物)和2级(严重入侵植物)入侵物种分别有15种和27种,另外还有一些物种虽然目前尚未形成明显危害,但具有较高的入侵风险。高黎贡山外来入侵植物类群组成和原产地来源复杂多样,入侵等级分布具有地域特点,应实施分类管理措施以提高管控成效。以上结果可以为更好地管理高黎贡山地区外来植物、推动高黎贡山国家公园建设提供重要参考。

Pyrotinib plus capecitabine could significantly improve overall survival in HER2-positive metastatic breast cancer

Dear Editor,The irreversible pan-ErbB tyrosine kinase inhibitors(TKIs),including neratinib and pyrotinib,demonstrated more complete inhibition towards ErbB-family and promising antitumor activity compared to lapatinib,a reversible TKI.1 In the phase III NALA study for HER2-positive metastatic breast cancer(MBC)who were progressed after two lines of HER2-targeted regimens,2 significant improvement was observed in progression-free survival(PFS)in patients receiving neratinib combined with capecitabine when compared to lapatinib plus capecitabine(L+C)group.However,the 2.2-month PFS improvement in neratinib plus capecitabine cohort failed to translate to a significant benefit in the overall survival(OS,24.0 vs 22.2 months,P=0.2086).2 While another irreversible TKI,pyrotinib combined with capecitabine(P+C)achieved clinically and statistically significant improvement in the PFS and a trend of benefits in the OS when compared to the L+C group,based on the interim analysis(with the cutoff of March 31,2019)of the phase III PHOEBE study.3 Generally speaking,current evidence was still limited regarding the survival data of irreversible TKIs.

Management and outcomes of gastric leak after sleeve gastrectomy:results from the 2010-2020 national registry

Background:Management of gastric leak after sleeve gastrectomy(SG)is challenging due to its unpredictable outcomes.We aimed to summarize the characteristics of SG leaks and analyze interventions and corresponding outcomes in a real-world setting.Methods:To retrospectively review of 15,721 SG procedures from 2010 to 2020 based on a national registry.A cumulative sum analysis was used to identify a fitting curve of gastric leak rate.The Kaplan-Meier method and log-rank tests were performed to calculate and compare the probabilities of relevant outcomes.The logistic regression analysis was conducted to determine the predictors of acute leaks.Results:A total of 78 cases of SG leaks were collected with an incidence of 0.5%(78/15,721)from this registry(6 patients who had the primary SG in non-participating centers).After accumulating 260 cases in a bariatric surgery center,the leak rate decreased to a stably low value of under 1.17%.The significant differences presented in sex,waist circumference,and the proportion of hypoproteinemia and type 2 diabetes at baseline between patients with SG leak and the whole registry population(P=0.005,=0.026,<0.001,and=0.001,respectively).Moreover,83.1%(59/71)of the leakage was near the esophagogastric junction region.Leakage healed in 64(88.9%,64/72)patients.The median healing time of acute and non-acute leaks was 5.93 months and 8.12 months,respectively.Acute leak(38/72,52.8%)was the predominant type with a cumulative reoperation rate>50%,whereas the cumulative healing probability in the patients who required surgical treatment was significantly lower than those requring non-surgical treatment(P=0.013).Precise dissection in the His angle area was independently associated with a lower acute leak rate,whereas preservation≥2 cm distance from the His angle area was an independent risk factor.Conclusions:Male sex,elevated waist circumference,hypoproteinaemia,and type 2 diabetes are risk factors of gastric leaks after SG.Optimizing surgical techniques,including precise dissection of His angle area and preservation of smaller gastric fundus,should be suggested to prevent acute leaks.

Prediction of shield tunneling-induced ground settlement using machine learning techniques

Predicting the tunneling-induced maximum ground surface settlement is a complex problem since the settlement depends on plenty of intrinsic and extrinsic factors.This study investigates the efficiency and feasibility of six machine learning(ML)algorithms,namely,back-propagation neural network,wavelet neural network,general regression neural network(GRNN),extreme learning machine,support vector machine and random forest(RF),to predict tunneling?induced settlement.Field data sets including geological conditions,shield operational parameters,and tunnel geometry collected from four sections of tunnel with a total of 3.93 km are used to build models.Three indicators,mean absolute error,root mean absolute error,and coefficient of determination the(7?2)are used to demonstrate the performance of each computational model.The results indicated that ML algorithms have great potential to predict tunneling-induced settlement,compared with the traditional multivariate linear regression method.GRNN and RF algorithms show the best performance among six ML algorithms,which accurately recognize the evolution of tunneling-induced settlement.The correlation between the input variables and settlement is also investigated by Pearson correlation coefficient.

The prognostic and therapeutic implications of circulating tumor cell phenotype detection based on epithelial-mesenchymal transition markers in the first-line chemotherapy of HER2-negative metastatic breast cancer

Background:Epithelial-mesenchymal transition(EMT)is implicated in the metastatic process and presents a chal-lenge to epithelial cell adhesion molecule-based detection of circulating tumor cells(CTCs),which have been demon-strated to be a prognostic indicator in metastatic breast cancer.Although evidence has indicated that heterogeneity of CTCs based on EMT markers is associated with disease progression,no standard recommendations have been established for clinical practice.This study aimed to evaluate the prognostic significance of dynamic CTC detection based on EMT for metastatic breast cancer patients.Methods:We enrolled 108 human epidermal growth factor receptor 2-negative metastatic breast cancer patients from the prospective phase III CAMELLIA study and applied the CanPatrol CTC enrichment technique to identify CTC phenotypes(including epithelial CTCs,biphenotypic epithelial/mesenchymal CTCs,and mesenchymal CTCs)in peripheral blood samples.Receiver operating characteristic curve analyses of total CTC count and the proportion of mesenchymal CTCs for predicting the 1-year progression-free survival(PFS)rate were conducted to determine the optimal cut-off values,and Kaplan-Meier analysis and Cox proportional hazards regression analysis were performed to investigate the prognostic value of the cut-off values of both total CTC count and the proportion of mesenchymal CTCs in combination.Results:For predicting the 1-year PFS rate,the optimal cut-off value of total CTC count was 9.5(Area under the curve[AUC]=0.538,95%confidence interval[CI]=0.418-0.657),and that of the proportion of mesenchymal CTCs was 10.7%(AUC=0.581,95%CI=0.463-0.699).We used the two cut-off values in combination to forecast PFS in which the total CTC count was equaled to or exceeded 10/5 mL with the proportion of mesenchymal CTCs surpassed 10.7%.Patients who met the combined criteria had significantly shorter median PFS than did those who did not meet the criteria(6.2 vs.9.9 months,P=0.010).A nomogram was constructed based on the criteria and significant clinicopatho-logical characteristics with a C-index of 0.613(P=0.010).Conclusions: The criteria, which combine the total CTC count and the proportion of mesenchymal CTCs, may be used to monitor therapeutic resistance and predict prognosis in patients with metastatic breast cancer.

Polymorphisms of MTHFR and TYMS predict capecitabine-induced hand-foot syndrome in patients with metastatic breast cancer

Background:Breast cancer is a global problem,and a large number of new cases are diagnosed every year.Capecit-abine is effective in patients with metastatic breast cancer(MBC).Hand-foot syndrome(HFS)is a common adverse effect of capecitabine.In this study,we investigated the association between single nucleotide polymorphisms(SNPs)in genes involved in capecitabine metabolism pathways and capecitabine-induced HFS in Chinese patients with MBC to identify some predictive genetic biomarkers.Methods:We selected 3 genes involved in capecitabine metabolism and screened genetic variants in these target genes.We genotyped a total of 22 SNPs in the thymidylate synthase gene(TYMS),the methylene tetrahydrofolate reductase gene(MTHFR),and the ribonucleotide reductase M1 gene(RRM1)in 342 MBC patients treated with capecit-abine-based chemotherapy.The genotype distributions of each SNP in patients with and without HFS were assessed using Pearson’sχ^(2)test,and the relationship between HFS and genotypes of SNPs was determined using logistic regression analysis.The association between SNPs and their corresponding gene expression was analyzed using the Blood expression quantitative trait loci(eQTL)browser online tools.Results:We found 4 positive sites for HFS in the TYMS and MTHFR genes:TYMS rs2606241(P=0.022),TYMS rs2853741(P=0.019),MTHFR rs3737964(P=0.029),and MTHFR rs4846048(P=0.030).Logistic regression analyses showed that the genotype AG of MTHFR rs3737964[odds ratio(OR)=0.54,95%confidence interval(CI)0.31-0.97,P=0.038]and MTHFR rs4846048(OR=0.54,95%CI 0.30-0.98,P=0.042)were protective factors of HFS,whereas the genotype CT of TYMS rs2853741(OR=2.25,95%CI 1.31-3.87,P=0.012)increased the risk of HFS.The association between the genotype GT of TYMS rs2606241(OR=1.27,95%CI 0.73-2.23,P=0.012)and HFS was uncertain.Further eQTL analyses confirmed that the alleles of rs3737964 and rs4846048 affected the gene expression levels of MTHFR in cis.Conclusions:We have identified four potentially useful pharmacogenetic markers,TYMS rs2606241,TYMS rs2853741,MTHFR rs3737964,and MTHFR rs4846048 to predict capecitabine-induced HFS in MBC patients.

Association of hypomethylation of LINE-1 repetitive element in blood leukocyte DNA with an increased risk of hepatocellular carcinoma

Global DNA hypomethylation has been associated with increased risk for cancers of the colorectum,bladder,breast,head and neck,and testicular germ cells.The aim of this study was to examine whether global hypomethylation in blood leukocyte DNA is associated with the risk of hepatocellular carcinoma (HCC).A total of 315 HCC cases and 356 age-,sex-and HBsAg status-matched controls were included.Global methylation in blood leukocyte DNA was estimated by analyzing long interspersed element-1 (LINE-1) repeats using bisulfite-polymerase chain reaction (PCR) and pyrosequencing.We observed that the median methylation level in HCC cases (percentage of 5-methylcytosine (5mC)=77.7%) was significantly lower than that in controls (79.5% 5mC) (P=0.004,Wilcoxon rank-sum test).The odds ratios (ORs) of HCC for individuals in the third,second,and first (lowest) quartiles of LINE-1 methylation were 1.1 (95% confidence interval (CI) 0.7-1.8),1.4 (95% CI 0.8-2.2),and 2.6 (95% CI 1.7-4.1) (P for trend <0.001),respectively,compared to individuals in the fourth (highest) quartile.A 1.9-fold (95% CI 1.4-2.6) increased risk of HCC was observed among individuals with LINE-1 methylation below the median compared to individuals with higher (>median) LINE-1 methylation.Our results demonstrate for the first time that individuals with global hypomethylation measured in LINE-1 repeats in blood leukocyte DNA have an increased risk for HCC.Our data provide the evidence that global hypomethylation detected in the easily obtainable DNA source of blood leukocytes may help identify individuals at risk of HCC.

Genetic polymorphisms of autophagy-related gene 5 (ATG5) rs473543 predict different disease-free survivals of triple-negative breast cancer patients receiving anthracycline- and/or taxane-based adjuvant chemotherapy

Background:Autophagy plays a crucial role in chemotherapy resistance of triple-negative breast cancer(TNBC).Hence,autophagy-related gene 5(ATG5),an essential molecule involved in autophagy regulation,is presumably associated with recurrence of TNBC.This study was aimed to investigate the potential influence of single-nucleotide polymorphisms in ATG5 on the disease-free survival(DFS)of early-stage TNBC patients treated with anthracycline-and/or taxane-based chemotherapy.Methods:We genotyped ATG5 SNP rs473543 in a cohort of 316 TNBC patients treated with anthracycline-and/or taxane-based chemotherapy using the sequenom’s MassARRAY system.Kaplan-Meier survival analysis and Cox proportional hazard regression analysis were used to analyze the association between ATG5 rs473543 genotypes and the clinical outcome of TNBC patients.Results:Three genotypes,AA,GA,and GG,were detected in the rs473543 of ATG5 gene.The distribution of ATG5 rs473543 genotypes was significantly different between patients with and without recurrence(P=0.024).Kaplan-Meier survival analysis showed that patients carrying A allele of ATG5 rs473543 had an increased risk of recurrence and shorter DFS compared with those carrying the variant genotype GG in rs473543(P=0.034).In addition,after adjust-ing for clinical factors,multivariate Cox regression analyses revealed that the AA/GA genotype of rs473543 was an independent predictor for DFS(hazard risk[HR],1.73;95%confidence interval[CI],1.04-2.87;P=0.034).In addition,DFS was shorter in node-negative patients with the presence of A allele(AA/GA)than in those with the absence of A allele(P=0.027).Conclusion:ATG5 rs473543 genotypes may serve as a potential marker for predicting recurrence of early-stage TNBC patients who received anthracycline-and/or taxane-based regimens as adjuvant chemotherapy.