Comparison of efficacy, safety, and quality of life between sorafenib and sunitinib as first.line therapy for Chinese patients with metastatic renal cell carcinoma

Background: Sorafenib and sunitinib are widely used as first-line targeted therapy for metastatic renal cell carcinoma(mRCC) in China.This study aimed to compare the efficacy, safety, and quality of life(QoL) in Chinese mRCC patients treated with sorafenib and sunitinib as first-line therapy.Methods: Clinical data of patients with mRCC who received sorafenib(400 mg twice daily; 4 weeks) or sunitinib(50 mg twice daily; on a schedule of 4 weeks on treatment followed by 2 weeks off) were retrieved. Primary outcomes were overall survival(OS), progression-free survival(PFS), adverse events(AEs), and QoL(SF-36 scores), and secondary outcomes were associations of clinical characteristics with QoL.Results: Medical records of 184 patients(110 in the sorafenib group and 74 in the sunitinib group) were reviewed.PFS and OS were comparable between the sorafenib and sunitinib groups(both P > 0.05).The occurrence rates of leukocytopenia, thrombocytopenia, and hypothyroidism were higher in the sunitinib group(36.5% vs. 10.9%,P< 0.001; 40.5% vs. 10.9%, P < 0.001; 17.6% vs. 3.6%, P = 0.001), and that of diarrhea was higher in the sorafenib group(62.7% vs. 35.2%, P < 0.001). There was no significant difference in SF-36 scores between the two groups. Multivariate analysis indicated that role-physical and bodily pain scores were associated with the occurrence rate of grade 3 or 4 AEs(P = 0.017 and 0.005).Conclusions: Sorafenib has comparable efficacy and lower toxicity profile than sunitinib as first-line therapy for mRCC. Both agents showed no significant impact on QoL of patients.

Association of post.treatment hypoalbuminemia and survival in Chinese patients with metastatic renal cell carcinoma

Background:Hypoalbuminemia adversely affects the clinical outcomes of various cancers.The purpose of this study was to estimate the prognostic value of hypoalbuminemia 3-5 weeks after treatment in patients with metastatic renal cell carcinoma(mRCC) who received sorafenib or sunitinib as first-line treatment.Methods:In this single-center,retrospective study,we assessed the progression-free survival(PFS) and overall survival(OS) of 184 mRCC patients who received first-line sorafenib or sunitinib treatment.PFS and OS were compared between patients with post-treatment hypoalbuminemia(post-treatment albumin level <36.4 g/L) and those with normal post-treatment albumin level(albumin level≥36.4 g/L).The Memorial Sloan Kettering Cancer Center(MSKCC)risk model stratified mRCC patients into three risk categories.Prognostic values of all patient characteristics including MSKCC risk category were determined by using univariate and multivariate Cox regression models.Prognostic value was further determined using the Harrell concordance index and receiver operating characteristic curve analysis.Results:The median PFS and OS of the 184 patients were 11 months(95%confidence interval[CI]9-12 months)and 23 months(95%CI 19-33 months),respectively.Patients with post-treatment hypoalbuminemia had significantly shorter median PFS(6 months[95%CI 5-7 months]) and OS(11 months[95%CI 9-15 months]) than patients who had normal post-treatment albumin levels(PFS:12 months[95%CI 11-16 months],P < 0.001;OS:31 months[95%CI24-42 months],P < 0.001),respectively.Multivariate analysis showed that post-treatment hypoalbuminemia was an independent predictor of PFS(hazard ratio[HR],2.113;95%CI 1.390-3.212;P < 0.001) and OS(HR,2.388;95%CI 1.591-3.585;P < 0.001).Post-treatment hypoalbuminemia could also be combined with the MSKCC risk category for better prediction about OS.The model that included post-treatment hypoalbuminemia and MSKCC risk category improved the predictive accuracy for PFS and OS(c-index:0.68 and 0.73,respectively) compared with the basic MSKCC risk model(c-index:0.67 and 0.70,respectively).The prognostic values for PFS and OS of the integrated MSKCC risk model involving post-treatment hypoalbuminemia were significantly more accurate than the basic MSKCC risk model using likelihood ratio analysis(both P < 0.001).Conclusions:Post-treatment hypoalbuminemia can be considered an independent prognostic factor for patients with mRCC who undergo first-line treatment with tyrosine kinase inhibitors.Additionally,integrating post-treatment serum albumin level into the basic MSKCC risk model can improve the accuracy of this model in predicting patient overall survival and progression-free survival.

Modeling and Analysis of Data Dependencies in Business Process for Data-Intensive Services

With the growing popularity of data-intensive services on the Internet, the traditional process-centric model for business process meets challenges due to the lack of abilities to describe data semantics and dependencies, resulting in the inflexibility of the design and implement for the processes. This paper proposes a novel data-aware business process model which is able to describe both explicit control flow and implicit data flow. Data model with dependencies which are formulated by Linear-time Temporal Logic(LTL) is presented, and their satisfiability is validated by an automaton-based model checking algorithm. Data dependencies are fully considered in modeling phase, which helps to improve the efficiency and reliability of programming during developing phase. Finally, a prototype system based on j BPM for data-aware workflow is designed using such model, and has been deployed to Beijing Kingfore heating management system to validate the flexibility, efficacy and convenience of our approach for massive coding and large-scale system management in reality.

索拉非尼与舒尼替尼一线治疗中国转移性肾细胞癌患者的疗效、安全性和生活质量的比较

背景与目的在中国,索拉非尼和舒尼替尼是广泛应用于治疗转移性肾细胞癌(metastatic renal cell carcinoma,mRCC)的一线靶向药物。本研究旨在比较索拉非尼与舒尼替尼一线治疗中国mRCC患者的疗效、安全性和生活质量(quality of life,QoL)。方法收集接受索拉菲尼治疗(400 mg,每天2次;4周)或舒尼替尼(50 mg,每天2次;用药4周后停药2周)治疗的mRCC患者的临床资料。主要指标为总生存(overall survival,OS)、无进展生存(progression-free survival,PFS)、不良事件(adverse events,AEs)和QoL(SF-36评分),次要指标为临床特征与QoL的相关性。结果本研究回顾了184例患者(索拉非尼组110例和舒尼替尼组74例)的病历。索拉非尼和舒尼替尼组的PFS和OS无显著性差异(均P> 0.05)。舒尼替尼组中白细胞减少、血小板减少和甲状腺功能减退的发生率较高(36.5%vs. 10.9%,P <0.001;40.5%vs. 10.9%,P <0.001;17.6%vs. 3.6%,P=0.001),而索拉非尼组腹泻的发生率较高(62.7%vs. 35.2%,P <0.001)。两组的SF-36评分无显著性差异。多因素分析表明,躯体角色和躯体疼痛评分与3或4级AEs的发生率相关(P=0.017和0.005)。结论作为mRCC一线治疗药物的索拉非尼与舒尼替尼相比,疗效相当,毒性较低。两种药物对患者的QoL无显著影响。

中国转移性肾细胞癌患者治疗后低蛋白血症与生存的关系

背景与目的低蛋白血症对多种癌症的临床疗效有不利的影响。本研究旨在评估转移性肾细胞癌(metastatic renal cell carcinoma,mRCC)患者接受索拉非尼或舒尼替尼作为一线治疗3–5周后低蛋白血症的预后价值。方法在这个单中心的回顾性研究中,我们评估了184例接受索拉非尼或舒尼替尼一线治疗的m RCC患者的无进展生存期(progression?free survival,PFS)和总生存期(overall survival,OS)。并对治疗后低蛋白血症患者(治疗后白蛋白水平<36.4 g/L)和治疗后白蛋白水平正常患者(白蛋白水平≥36.4 g/L)的PFS和OS进行了比较。根据纪念斯隆?凯特琳癌症中心(Memorial Sloan Kettering Cancer Center,MSKCC)风险模型将mRCC患者划分为3个风险类别。采用单因素和多因素的Cox回归模型确定包括MSKCC风险类别在内的所有患者特征的预后价值。采用Harrell一致性指数和受试者工作特征曲线分析进一步确定预后价值。结果 184例患者的中位PFS和OS分别为11个月[95%置信区间(confdence interval,CI):9–12个月]和23个月(95%CI:19–33个月)。治疗后低蛋白血症患者的中位PFS[6个月(95%CI:5–7个月)]和OS[11个月(95%CI:9–15个月)]分别显著短于治疗后白蛋白水平正常的患者[PFS:12个月(95%CI:11–16个月),P <0.001;OS:31个月(95%CI:24–42个月),P <0.001]。多因素分析显示,治疗后低蛋白血症是PFS[风险比(hazard ratio,HR)=2.113,95%CI:1.390–3.212,P<0.001]和OS(HR=2.388,95%CI:1.591–3.585,P<0.001)的独立预后因素。治疗后低蛋白血症也可以与MSKCC风险类别相结合以更好地对OS进行预测。应用整合了治疗后低蛋白血症和MSKCC风险类别的模型对PFS和OS的预测准确性(c?指数分别为0.68和0.73)要高于基本MSKCC风险模型(c?指数分别为0.67和0.70)。采用似然比检验,与基本MSKCC风险模型相比,整合了治疗后低蛋白血症的MSKCC风险模型的PFS和OS的预后价值的准确性更高(均P <0.001)。结论治疗后低蛋白血症可作为接受酪氨酸激酶抑制剂一线治疗的mRCC患者的独立预后因素。此外,将治疗后血清白蛋白水平整合到基本MSKCC风险模型中,可以提高该模型在预测患者总生存期和无进展生存期方面的准确性。

MDIG-mediated H3K9me3 demethylation upregulates Myc by activating OTX2 and facilitates liver regeneration

The mineral dust-induced gene(MDIG)comprises a conserved JmjC domain and has the ability to demethylate histone H3 lysine 9 trimethylation(H3K9me3),Previous studies have indicated the significance of MDIG in promoting cell proliferation by modulating cell-cycle transition.However,its involvement in liver regeneration has not been extensively investigated.In this study,we generated mice with liver-specific knockout of MDIG and applied partial hepatectomy or carbon tetrachloride mouse models to investigate the biological contribution of MDIG in liver regeneration.

Epigenome-wide development and validation of a prognostic methylation score in intrahepatic cholangiocarcinoma based on machine learning strategies

Background:Clinical parameter-based nomograms and staging systems provide limited information for the prediction of survival in intrahepatic cholangiocarcinoma(ICC)patients.In this study,we developed a methylation signature that precisely predicts overall survival(OS)after surgery.Methods:An epigenome-wide study of DNA methylation based on whole-genome bisulfite sequencing(WGBS)was conducted for two independent cohorts(discovery cohort,n=164;validation cohort,n=170)from three hepatobiliary centers in China.By referring to differentially methylated regions(DMRs),we proposed the concept of prognostically methylated regions(PMRs),which were composed of consecutive prognostically methylated CpGs(PMCs).Using machine learning strategies(Random Forest and the least absolute shrinkage and selector regression),a prognostic methylation score(PMS)was constructed based on 14 PMRs in the discovery cohort and confirmed in the validation cohort.Results:The C-indices of the PMS for predicting OS in the discovery and validation cohorts were 0.79 and 0.74,respectively.In the whole cohort,the PMS was an independent predictor of OS[hazard ratio(HR)=8.12;95% confidence interval(CI):5.48-12.04;P<0.001],and the C-index(0.78)of the PMS was significantly higher than that of the Johns Hopkins University School of Medicine(JHUSM)nomogram(0.69,P<0.001),the Eastern Hepatobiliary Surgery Hospital(EHBSH)nomogram(0.67,P<0.001),American Joint Committee on Cancer(AJCC)tumor-node-metastasis(TNM)staging system(0.61,P<0.001),and MEGNA prognostic score(0.60,P<0.001).The patients in quartile 4 of PMS could benefit from adjuvant therapy(AT)(HR=0.54;95%CI:0.32-0.91;log-rank P=0.043),whereas those in the quartiles 1-3 could not.However,other nomograms and staging system failed to do so.Further analyses of potential mechanisms showed that the PMS was associated with tumor biological behaviors,pathway activation,and immune microenvironment.Conclusions:The PMS could improve the prognostic accuracy and identify patients who would benefit from AT for ICC patients,and might facilitate decisions in treatment of ICC patients.

LSD1 inhibition suppresses the growth of clear cell renal cell carcinoma via upregulating P21signaling

Histone lysine-specific demethylase 1(LSD1) has been implicated in the disease progression of several types of solid tumors. This study provides the first evidence showing that LSD1 overexpression occurred in 62.6%(224/358) of clear cell renal cell carcinomas(ccRCC). LSD1 expression was associated with the progression of ccRCC, as indicated by TNM stage(P ? 0.006), especially tumor stage(P ? 0.017) and lymph node metastasis(P ? 0.030). High LSD1 expression proved to be an independent prognostic factor for poor overall survival(Po0.001) and recurrence-free survival(Po0.001) of ccRCC patients. We further show that LSD1 inhibition by siRNA knockdown or using the small molecule inhibitor SP2509 suppressed the growth of ccRCC in vitro and in vivo. Mechanistically, inhibition of LSD1 decreased the H3 K4 demethylation at the CDKN1 A gene promoter, which was associated with P21 upregulation and cell cycle arrest at G1/S in ccRCC cells. Our findings provide new mechanistic insights into the role of LSD1 in cc RCC and suggest the therapeutic potential of LSD1 inhibitors in ccRCC treatment.

Neoadjuvant and Adjuvant Therapy in Intrahepatic Cholangiocarcinoma

Intrahepatic cholangiocarcinoma(ICC)is the second most common primary liver cancer and causes major economic and health burdens throughout the world.Although the incidence of ICC is relatively low,an upward trend has been seen over the past few decades.Owing to the lack of specific manifestations and tools for early diagnosis,most ICC patients have relatively advanced disease at diagnosis.Thus,neoadjuvant therapy is necessary to evaluate tumor biology and downstage these patients so that appropriate candidates can be selected for radical liver resection.However,even after radical resection,the recurrence rate is relatively high and is a main cause leading to death after surgery,which makes adjuvant therapy necessary.Because of its low incidence,studies in both neoadjuvant and adjuvant settings of ICC are lagging compared with other types of malignancy.While standard neoadjuvant and adjuvant regimens are not available in the current guidelines due to a lack of high-level evidence,some progress has been achieved in recent years.In this review,the available literature on advances in neoadjuvant and adjuvant strategies in ICC are evaluated,and possible challenges and opportunities for clinical and translational investigations in the near future are discussed.

Comparison of efficacy and safety among axitinib,sunitinib,and sorafenib as neoadjuvant therapy for renal cell carcinoma:a retrospective study

Dear editor,Renal cancer accounts for approximately 2%of all can-cer deaths worldwide,and renal cell carcinoma(RCC)is the predominant subtype[1].Radiotherapy and chemo-therapy have been found to have limited roles in the treatment of RCC.However,the treatment outcomes of metastatic RCC(mRCC)have been improved drastically since the application of molecular targeted therapeutic agents such as tyrosine kinase inhibitors(TKIs).TKIs have been gradually used for the preoperative treatment of RCC.

Clinical outcomes of second-line treatment following first-line VEGFR-TKI failure in patients with metastatic renal cell carcinoma:a comparison of axitinib alone and axitinib plus anti-PD-1 antibody

Dear editor,The prognosis of metastatic renal cell carcinoma(mRCC)has been significantly improvedwith the development and widespread use of vascular endothelial growth factor(VEGF)pathway inhibitors and mammalian target of rapamycin(mTOR)pathway inhibitors[1].For the past decade,the standard of care utilized in the first-line setting was VEGF-targeted therapies.Recently,the mRCC treatment landscape has rapidly changed with the exploration of combinations of immune checkpoint inhibitors(ICIs)and anti-VEGF agents[2,3].

Hierarchical caches in content-centric networks： modeling and analysis

Content-centric network （CCN） is a new Inter- net architecture in which content is treated as the primitive of communication. In CCN, routers are equipped with con- tent stores at the content level, which act as caches for fre- quently requested content. Based on this design, the Internet is available to provide content distribution services without any application-layer support. In addition, as caches are inte- grated into routers, the overall performance of CCN will be deeply affected by the caching efficiency. In this paper, our aim is to gain some insights on how caches should be designed to maintain a high performance in a cost-efficient way. We try to model the two-layer cache hi- erarchy composed of CCN touters using a two-dimensional discrete-time Markov chain, and develop an efficient algo- rithm to calculate the hit ratios of these caches. Simulations validate the accuracy of our modeling method, and convey some meaningful information which can help us better un- derstand the caching mechanism of CCN.

New classification-oriented laparoscopic anatomical hepatectomy strategy for hepatocellular carcinoma invading two or more(sub)segments in the left lobe

With technological advances in laparoscopic hepatectomy and new navigation devices,such as flexible laparoscopic ultrasound probes,indocyanine green(ICG)-fluorescent imaging and three-dimensional imaging,laparoscopic segmentectomy(LS),which maximizes the preservation of the functional hepatic reserve and the possibility for future repeat hepatectomy while ensuring adequate surgical margins,has become a feasible alternative to hemihepatectomy for addressing hepatocellular carcinoma(HCC).