结肠癌切除术患者预后列线图模型及危险分层系统构建与验证

目的:基于大样本量,构建个体化预测模型及危险分层系统。方法:从美国SEER临床数据库中,筛选结肠癌术后患者,进行模型构建,并筛选一组独立的中国人群,用于外部验证。经过单因素与多因素Cox回归分析,筛选出独立预后指标,并全部纳入用于构建列线图预测模型。通过计算一致性指数(C-index)及绘制校准曲线,检验模型准确性。结果:列线图模型共纳入11个独立预后因子,C-index在训练组、内部验证组及外部验证组分别为0.768,0.761和0.759,均>0.7,且优于第7版美国癌症联合委员会(AJCC)-TNM分期系统(0.729,0.720,0.735)。校准曲线显示,模型预测效果与实际生存相吻合,进一步验证了模型的区分及校准能力。通过决策树分析,依据模型预测个体风险评分,进行危险分层,模型的实际应用价值得到确定。结论:该列线图预测模型能够较准确预测结肠癌术后患者预后状态,并较传统TNM分期系统有所改善,基于预测模型的危险分层系统,能够更好地区分高危患者,并指导选择临床治疗措施。

The relationship between treatment-induced hypertension and efficacy of anlotinib in recurrent or metastatic esophageal squamous cell carcinoma

Objective:In this post-hoc analysis,we evaluated anlotinib treatment-induced hypertension as a potential predictive factor of efficacy in esophageal squamous cell carcinoma(ESCC)patients.Methods:A total of 109 patients enrolled in the anlotinib group in a phase 2 trial were included.The tumor response was assessed by computed tomography at week 3,week 6,and then every 6 weeks until progressive disease was observed.The primary endpoint of the study was progression free survival(PFS).The secondary endpoints included overall survival(OS)and objective response rate(ORR).Results:In all patients,the median PFS was 3.02 months[95%confidence interval(CI):2.63–3.65 months]and the OS was 6.11 months(95%CI:4.40–7.79 months).The ORR was 7.34%(95%CI:3.22%–13.95%).A total of 59(54%)patients were diagnosed with treatment-induced hypertension(Group A),and the remaining patients(n=50,46%)were in Group B.Baseline prognostic factors were similar between the 2 groups.Patients in Group A had a longer PFS and OS and higher ORR.When stratifying patients using a previously known history of hypertension,treatment-induced hypertension was a predictor only for patients without previous hypertension,who had longer PFS[hazard ratio(HR):0.40,95%CI:0.24–0.68]and OS(HR:0.37,95%CI:0.21–0.67).Conclusions:We showed,for the first time,a correlation between treatment-induced hypertension and better prognoses in recurrent or metastatic ESCC patients treated with anlotinib,without a previously known history of hypertension.Treatment-induced hypertension may be a simple and low cost predictor for anlotinib antitumor efficacy in these patients,which may also reflect the intended target inhibition.

Insulin-Enhanced Antitumor Effect of 5-Fluorouracil in vivo

OBJECTIVE To determine if insulin treatment can enhance the antitumor effect of 5-fluorouracil(5-FU),and to explore the mech- anism of the enhancement of insulin. METHODS S180 sarcoma,H22 liver cancer and human Eca-109 esophageal cancer cells were transplanted into nude mice to evaluate the inhibitory effect on tumor growth of insulin alone or in combination with 5-FU.The levels of serum insulin-like growth factor-I(IGF-I)and insulin-like growth factor binding protein-3 (IGFBP-3)were determined. RESULTS Compared with 5-FU treatment alone,the tumor weight of H22 liver cancer and S180 sarcoma was reduced further with high,medium and low-dose insulin(0.09,0.06,0.03 U/20 g) +5-FU treatment.When a high dosage of insulin+5-FU was ad- ministered,tumor weight was significantly reduced(P<0.05).The inhibitory rate of growth of S180 sarcoma and H22 liver cancer reached 50.2% and 51.4%,respectively,which was significantly higher than 24.9% and 27.9% in the group receiving 5-FU alone (P<0.05).High,medium and low-dose insulin combined with 5-FU significantly inhibited the growth of Eca-109 cancer cells (P<0.05).Compared with the control group,the level of serum IGF-1 decreased(P<0.05),whereas the level of serum IGFBP-3 slightly increased in the 5-FU±insulin groups(P>0.05).In mice with H22 liver cancer and S180 sarcoma the IGF-1 level with high- dose insulin+5-FU treatment was significantly lower compared to treatment with 5-FU alone(P<0.05),but the difference was not significant in mice transplanted with esophageal cancer cells. CONCLUSION Insulin can enhance the anti-tumor effect of 5-FU without significantly increasing 5-FU toxicity.Although changes in the serum IGF-1 or IGFBP-3 level do not explain the mechanism of the insulin-induced enhancement on 5-FU on growth,a decrease in the level of serum IGF-1 and an increase in serum IGFBP-3 may be important in the chemotherapeutic response.

Efficacy and safety of a novel anti-HER2 therapeutic antibody RC48 in patients with HER2-overexpressing,locally advanced or metastatic gastric or gastroesophageal junction cancer:a single-arm phase II study

Background:Current treatment options for human epidermal growth factor receptor 2(HER2)-overexpressing gastric cancer at third-line have shown limited clinical benefit.Further,there is no specific treatment for HER2 immunohistochemistry(IHC)2+and fluorescence in-situ hybridization-negative patients.Here,we report the efficacy and safety of a novel anti-HER2 antibody RC48 for patients with HER2-overexpressing,advanced gastric or gastroesophageal junction cancer.Methods:Patients with HER2-overexpressing(IHC 2+or 3+),locally advanced or metastatic gastric or gastroesophageal junction cancer who were under at least second-line therapy were eligible and received RC482.5 mg/kg alone every 2 weeks.The primary endpoint was the objective response rate(ORR)assessed by an independent review committee.Secondary endpoints included progressionfree survival(PFS),overall survival(OS),duration of response,time to progression,disease control rate,and safety.Results:Of 179 patients screened,125 were eligible and received RC48 treatment.The ORR was 24.8%(95%confidence interval[CI]:17.5%-33.3%).The median PFS and OS were 4.1 months(95%CI:3.7-4.9 months)and 7.9 months(95%CI:6.7-9.9 months),respectively.The most frequently reported adverse events were decreased white blood cell count(53.6%),asthenia(53.6%),hair loss(53.6%),decreased neutrophil count(52.0%),anemia(49.6%),and increased aspartate aminotransferase level(43.2%).Serious adverse events(SAEs)occurred in 45(36.0%)patients,and RC48-related SAEs were mainly decreased neutrophil count(3.2%).Seven patients had adverse events that led to death were not RC48-related.Conclusions:RC48 showed promising activity with manageable safety,suggesting potential application in patients with HER2-overexpressing,advanced gastric or gastroesophageal junction cancer who have previously received at least two lines of chemotherapy.

Prognostic Significance of Tumor-infiltrating CD8^＋ or CD3^＋ T Lymphocytes and Interleukin-2 Expression in Radically Resected Non-small Cell Lung Cancer

Background：Altered immunoresponse is associated with tumorigenesis and cancer progression.This study assessed the levels of tumor-infiltrating CD3^＋ or CD8^＋ T lymphocytes and interleukin-2 （IL-2） protein in radically resected non-small cell lung cancer （NSCLC） tissues to predict overall survival （OS） of the patients.Methods：Paraffin-embedded tissue specimens from 129 NSCLC patients were retrospectively collected for immunostaining of CD8^＋,CD3^＋,and IL-2 expression.Clinicopathological and survival data were collected and analyzed using the Chi-squared test,Kaplan-Meier curves,and the log-rank test or the Cox regression model.Results：The data showed a significant inverse association between CD8^＋ T lymphocyte levels and IL-2 expression （r =-0.927; P =0.000） and between the levels of CD8^＋ and CD3^＋ T lymphocytes （r =-0.722; P =0.000）,but a positive association between CD3^＋ T lymphocyte levels and IL-2 expression （r =0.781; P =0.000） in NSCLC tissues.Furthermore,the levels of CD3^＋ and CD8^＋ T lymphocytes and IL-2 expression were associated with tumor stage （P =0.023,0.006,and 0.031,respectively） and the level of CD8^＋ T lymphocytes was associated with the patient gender （P =0.024）.In addition,the levels of CD8^＋ T lymphocytes were associated with an unfavorable 5-year OS,whereas patients with high levels of CD3^＋ T lymphocytes in tumor lesions and IL-2-expressing tumors had significantly better 5-year OS rates than patients with low levels.Conclusions：The levels of CD8^＋ T cells in tumor lesions and IL-2 expression were both independent predictors of OS for these NSCLC patients.Thus,the detection of tumor-infiltrating CD3^＋ or CD8^＋ T lymphocytes and IL-2 expression could be useful to predict the prognosis of radically resected NSCLC patients.

Irinotecan plus S-1 versus S-1 in patients with previously treated recurrent or metastatic esophageal cancer(ESWN 01):a prospective randomized,multicenter,open-labeled phase 3 trial

Background:The benefit of systemic treatments in esophageal squamous cell carcinoma(ESCC)which has pro-gressed after chemotherapy is still uncertain and optimal regimens based on randomized trials have not yet been established.We aimed to compare the efficacy of irinotecan plus S-1 with S-1 monotherapy in recurrent or metastatic ESCC patients who had resistance to platinum-or taxane-based chemotherapy.Methods:We conducted a prospective randomized,multicenter,open-label,phase 3 trial in 15 centers across China.Eligible patients were adults with histologically confirmed recurrent or metastatic ESCC,and were randomly assigned(ratio,1:1)to receive either irinotecan plus S-1(intravenous infusion of irinotecan[160 mg/m2]on day 1 and oral S-1[80-120 mg]on days 1-10,repeated every 14 days)or oral S-1 monotherapy(80-120 mg/day on days 1-14,repeated every 21 days)using a central computerized minimization procedure.The primary endpoint was progression-free survival(PFS).Results:Between December 23,2014 and July 25,2016,we screened 148 patients and randomly assigned 123 patients to receive either irinotecan plus S-1 regimen(n=61)or S-1 monotherapy(n=62).After a median follow-up of 29.2 months(95%confidence interval[CI]17.5-40.9 months),the median PFS was significantly longer in the irinotecan plus S-1 group than in the S-1 monotherapy group(3.8 months[95%CI 2.9-4.3 months]vs.1.7 months[95%CI 1.4-2.7 months],hazard ratio=0.58,95%CI 0.38-0.86,P=0.006).The objective response rates were 24.6%in the irinotecan plus S-1 group and 9.7%in the S-1 monotherapy group(P=0.002).The patients in the irinotecan plus S-1 group presented with increased rates of grade 3-4 leukopenia(16.4%vs.0%),neutropenia(14.8%vs.1.6%),and nausea(4.9%vs.0%).No significant difference in grade 3-4 diarrhea and no treatment-related deaths were observed in both groups.Conclusions: The combination of irinotecan with S-1 was similarly tolerable but significantly prolonged PFS compared to S-1 monotherapy as a second- or third-line treatment in patients with recurrent or metastatic ESCC.

Highly stretchable pseudocapacitors based on buckled reticulate hybrid electrodes

以便与高特定的电容和突出的 stretchability 开发优秀 pseudocapacitor 与在便携的未来和 bio-implantable 系统适用的另外的设备匹配，我们在三个重要方面上集中我们的研究：混合电影电极，在不同部件之间的接口，和在基于围单人赛的碳 nanotube/polyaniline (SWCNT/PANI ) 的 supercapacitors 的 stretchability 和电气化学的综合性能的 Stretchability 预先伸长的弹性体上的合成电影。由于中等的孔，弄弯的混合电影避免裂开它发生在常规可拉长的混合电极，和两个 435 F

Optical visualization and polarized light absorption of the single-wall carbon nanotube to verify intrinsic thermal applications

The predicted extraordinary properties of carbon nanotubes(CNTs)from theoretical calculations have great potential for many applications.However,reliable experimental determination of intrinsic properties at the single-tube level is currently a matter of concern,and many challenges remain because of the unhandled and nanoscale size of individual nanotubes.Here,we demonstrated a prototype to detect the intrinsic thermal conductivity of the single-wall carbon nanotube(SWCNT)and verify the significant non-resonant optical absorption behavior on tiny nanotubes by integrating the nanotube and ice into a new core-shell design.In particular,a reversible optical visualization method based on the individual suspended ultra-long SWCNT was first developed by wrapping a nanotube with ice in the cryogenic air environment.The light-induced thermal effect on the hybrid core-shell structure was used tomelt the ice shell,which subsequently acted as a temperature sensor to verify the intrinsic thermal conductivity of the core-like nanotube.More interestingly,we successfully determined for the first time the thermal response phenomenon of the tiny absorption cross section in SWCNT in the vertical-polarization configuration and the significant non-resonant absorption behavior in the parallel-polarization configuration.These investigations will provide a better understanding for the unique optical behaviors of CNT and enable the detection of intrinsic properties of various one-dimensional nanostructures such as nanotubes,nanowires,and nanoribbons.

Effect of blocking Ras signaling pathway with K-Ras siRNA on apoptosis in esophageal squamous carcinoma cells

OBJECTIVE: To study the effect of RNAi silencing of the K-Ras gene on Ras signal pathway activity in EC9706 esophageal cancer cells. METHODS: EC9706 cells were treated in the following six groups: blank group (no transfection), negative control group (transfection no-carrier), transfection group (transfected with pSilencer-siK-ras), taxol chemotherapy group, taxol chemotherapy plus no-carrier group, taxol chemotherapy plus transfection group. Immunocytochemistry, Reverse transcription-polymerase chain reaction and western blotting were used to analyze the expression of MAPK1 (mitogen-activated protein kinases 1) and cyclin D1 in response to siRNA (small interfering RNA) transfection and taxol treatment. RESULTS: K-Ras (K-Ras gene) siRNA transfection of EC9706 esophageal squamous carcinoma cells decreased the expression of K-Ras, MAPK1 and cyclinD1 at the mRNA and protein level. Reverse transcription-polymerase chain reaction indicated that the expression levels of MAPK1 and cyclin D1 mRNAs were significantly lower in the transfection group than in the blank group (P<0.05). Western blotting showed that 72 h after EC9706 cell transfection, the expression levels of MAPK1 and cyclin D1 proteins had decreased in all groups, and the expression levels in the transfection group were significantly inhibited as compared with the blank group. Apoptosis increased significantly in the transfection group or after addition of taxol as compared with the blank group and the no-carrier group. The degree of apoptosis in the taxol plus transfection group was more severe. CONCLUSION: Apoptosis increased significantly in EC9706 esophageal carcinoma cells after siRNA-mediated inhibition of Ras signaling, with the most obvious increase observed in the transfection plus taxol chemotherapy group. Ras knockdown therefore increased cellular sensitivity to the chemotherapeutic agent, taxol. Ras knockdown also down-regulated the expression of the downstream genes, MAPK1 and cyclin D1, thus inhibiting the growth, proliferation and metabolism of esophageal cancer cells.

Paclitaxel and cisplatin with or without cetuximab in metastatic esophageal squamous cell carcinoma:a randomized,multicenter phase II trial

Lack of effective targeted therapy in metastatic esophageal squamous cell carcinoma(ESCC)underscores the urgent need for identifying new treatment approaches for this challenging disease.We sought to assess the addition of cetuximab to paclitaxel-cisplatin chemotherapy for first-line treatment in patients with metastatic ESCC.In this randomized,multicenter,open-label,phase II clinical trial,patients were randomized to receive paclitaxel-cisplatin(TP)(paclitaxel[175 mg/m^(2) intravenously(i.v.)on day 1 of every 3-week cycle]and cisplatin[75 mg/m^(2) i.v.on day 1 of every 3-week cycle])and TP plus cetuximab(CTP)(cetuximab,400 mg/m^(2) i.v.on day 1 of week 1,followed by 250 mg/m^(2) weekly).

CACA guidelines for holistic integrative management of esophageal carcinoma

Esophageal carcinoma(EC)is a common malignant tumor of the upper digestive tract worldwide.An analysis of the latest data from cancer centers in China showed that the incidence of EC and the number of deaths due to EC in China in 2015 were 266,000 and 188,000,respectively,ranking sixth(6.3%)and fourth(8.0%)among all malignant tumors.The early diagnosis and treatment of EC and standardized diagnosis and treatment are important tasks for EC healthcare professionals in various centers across the country.At present,the 8th edition of the EC staging system jointly released by Union for International Cancer Control(UICC)and American Joint Committee on Cancer(AJCC)is the most recent,authoritative and widely used EC staging standard.The EC professional committee of the Chinese Anti-Cancer Association also organizes the"EC Standardization Campaign in China"every year to promote the development of EC diagnostic and treatment norms throughout the country.Since 2011,the EC Committee of the Chinese Anti-Cancer Association has published the Guidelines for Standardized Diagnosis and Treatment of EC.Considering the increasing number of EC clinical studies and the continuous progress in diagnostic and treatment technologies in recent years,the updated Guidelines will include the latest progress in the diagnosis and treatment of EC,with a goal of promoting the forward development of EC diagnosis and treatment in clinical practice.