Background and purpose:For patients with human epidermal growth factor receptor 2(HER2)-positive metastatic breast cancer,trastuzumab treatment can prolong the overall survival and significantly improve the prognosis of patients.However,the reference original research trastuzumab(Herceptin?)is more expensive.Biosimilars have comparable efficacy and safety profiles while increasing patient access to treatment.This clinical trial aimed to evaluate the efficacy,pharmacokinetics,safety and immunogenicity of the trastuzumab biosimilar AK-HER2 compared to trastuzumab(Herceptin?)in patients with HER2-positive metastatic breast cancer.Methods:This multi-center,randomised,double-blind phase Ⅲ clinical trial was conducted in 43 subcenters in China.This study complied with the research protocol,the ethical principles stated in the Declaration of Helsinki and the quality management standards for drug clinical trials.It was approved by the hospital's medical ethics committee.The clinical trial registration agency is the State Food and Drug Administration(clinical trial approval number:2015L04224;clinical trial registration number:CTR20170516).Written informed consent was obtained from subjects before enrollment.Enrolled patients were randomly assigned to the AK-HER2 group and the control group,respectively receiving AK-HER2 or trastuzumab(initial loading dose 8 mg/kg,maintenance dose 6 mg/kg,every 3 weeks as a treatment cycle,total treatment time is 16 cycles)in combination with docetaxel(75 mg/m2,treatment duration is at least 9 cycles).The primary endpoint of this clinical trial was the objective response rate(ORR9)between the AK-HER2 group and the control group in the 9th cycle.Secondary efficacy endpoints included ORR16,disease control rate(DCR),clinical benefit rate(CBR),progression-free survival(PFS)and 1-year survival rate.In this study,100 subjects(AK-HER2 group to control group=1:1)were randomly selected for blood sample collection after the 6th cycle of medication,The collection time points were 45 minutes after infusion(the end of administration),4,8,24,72,120,168,336,and 504 hours after the end of administration.After collection,blood samples were analyzed by PK parameter set(PKPS).Other evaluation parameters included safety and immunogenicity assessment.Results:A total of 550 patients with HER2-positive metastatic breast cancer were enrolled in this clinical trial between Sep.2017 and Mar.2021.In the AK-HER2 group(n=237),129 subjects in the experimental group achieved complete response(CR)or partial response(PR),and the ORR9 was 54.4%.There were 134 subjects in the control group(n=241)who achieved CR or PR,and the ORR9 was 55.6%.The ORR9 ratio between the AK-HER2 group and the control group was 97.9%[90%confidence interval(CI):85.4%-112.2%,P=0.784],which was not statistically significant.In all secondary efficacy endpoints,no statistically significant differences were observed between the two groups.We conducted a mean ratio analysis of pharmacokinetics(PK)parameters between the AK-HER2 group and the control group,and the results suggested that the pharmacokinetic characteristics of the two drugs are similar.The incidence of treatment emergent adverse event(TEAE)leading to drug reduction or suspension during trastuzumab treatment was 3.6%(10 cases)in the AK-HER2 group and 8.1%(22 cases)in the control group.There was statistically significant difference between the two groups(P=0.027).The incidence rate was significantly lower in the AK-HER2 group than in the control group,and there was no statistically significant difference among the other groups.The differences in the positive rates of anti-drug antibodies(ADA)and neutralizing antibodies(NAB)between groups were of no statistical significance(P=0.385 and P=0.752).Conclusion:In patients with HER2-positive metastatic breast cancer,AK-HER2 was comparable to the trastuzumab(Herceptin?)in terms of drug efficacy,pharmacokinetics,safety and immunogenicity.

Colorectal cancer is currently one of the most common malignant tumors in the world,and its incidence and mortality rates have gradually increased in recent years.As insidious symptoms characterize early colorectal cancer,most of the patients have already developed into late or advanced stages in the primary survey.For stage Ⅳ metastatic colorectal cancer(mCRC),surgery supplemented with chemotherapy or radiotherapy for mCRC patients has a low 5-year survival rate.With the development of immunology in recent years,PD-1/PD-L1 inhibitors have made breakthroughs in treating malignant tumors.They also have improved the therapeutic efficacy of some mCRC patients,especially those with microsatellite instability-high/mismatch repair deficient.The guidelines recommend this approach.However,patients with microsatellite stable/mismatch repair proficiency,which accounts for more than 90%,are poorly treated with PD-1/PD-L1 inhibitors.Fortunately,there are several clinical studies that reported that some of this type of mCRC can gain some benefit.In this review,we examined the anti-tumor mechanism of PD-1/PD-L1 inhibitors and the latest progress of PD-1/PD-L1 inhibitor's clinical application in patients of mCRC with different genotypes.We discussed the prospect of PD-1/PD-L1 inhibitor combination therapy to provide a reference to the benefit of this type of patients and provide information for optimizing the dosing regimen of PD-1/PD-L1 inhibitors in the treatment of mCRC.

Objective To monitor the antifungal resistance of clinical isolates of Candida spp.in the East China region.Methods MALDI-TOF MS or molecular methods were used to re-identify the strains collected from January 2018 to December 2022.Antifungal susceptibility testing was performed using the broth microdilution method.The susceptibility test results were interpreted according to the breakpoints of 2022 Clinical and Laboratory Standards Institute(CLSI)documents M27 M44s-Ed3 and M57s-Ed4.Results A total of 3 026 strains of Candida were collected,65.33％of which were isolated from sterile body sites,mainly from blood(38.86％)and pleural effusion/ascites(10.21％).The predominant species of Candida were Candida albicans(44.51％),followed by Candida parapsilosis complex(19.46％),Candida tropicalis(13.98％),Candida glabrata(10.34％),and other Candida species(0.79％).Candida albicans showed overall high susceptibility rates to the 10 antifungal drugs tested(the lowest rate being 93.62％).Only 2.97％of the strains showed dose-dependent susceptibility(SDD)to fluconazole.Candida parapsilosis complex had a SDD rate of 2.61％and a resistance rate of 9.42％to fluconazole,and susceptibility rates above 90％to other drugs.Candida glabrata had a SDD rate of 92.01％and a resistance rate of 7.99％to fluconazole,resistance rates of 32.27％and 48.24％to posaconazole and voriconazole non-wild-type strains(NWT),respectively,and susceptibility rates above 90％to other drugs.Candida tropicalis had resistance rates of 29.55％and 26.24％to fluconazole and voriconazole,respectively,resistance rates of 76.60％and 21.99％to posaconazole and echinocandins non-wild-type strains(NWT),and a resistance rate of 2.36％to echinocandins.Conclusions The prevalence and species distribution of Candida spp.in the East China region are consistent with previous domestic and international reports.Candida glabrata exhibits certain degree of resistance to fluconazole,while Candida tropicalis demonstrates higher resistance to triazole drugs.Additionally,echinocandins resistance has emerged in Candida albicans,Candida glabrata,Candida tropicalis,and Candida parapsilosis.

Objective:To understand the status of knowledge, attitude and practice of metabolic syndrome(MS) among the elderly in the community and analyze its influencing factors, so as to provide guidance for the prevention and treatment of MS.Methods:From January 2021 to August 2021, permanent residents(residence duration ≥6 months)aged 65 and above with regular health check examination in Fangzhuang Community Health Service Center of Fengtai District, Beijing were investigated using self-designed MS knowledge, attitude and practice questionnaire.After excluding 34 incomplete questionnaires, the 491 valid questionnaires were recycled with questionnaire valid percentage of 93.5%(491/525). The survey results were analyzed by descriptive analysis, Mann-Whitney U test, Kruskal-Wallis H test and multiple linear regression analysis and multiple linear regression.Results:The scores of MS knowledge, attitude and practice of the elderly in the community were 7(5, 10), 9(8, 10)and 19(18, 21)respectively.The correct answer rate of the diagnostic criteria of MS components was less than 50%.The score of knowledge about MS in the elderly was positively correlated with the scores of attitudes( r=0.263)and practice( r=0.134)(all P<0.01). The results of univariate and multiple linear regression analysis showed that gender, attending educational lectures and the prevalence of MS were the influencing factors of MS knowledge score(all P<0.05). Leisure time, attending educational lectures, pre-retirement occupation and regular health check examination were the influencing factors for MS attitude score(all P<0.05); attending educational lectures, leisure time, regular health check examination and pre-retirement occupation were the influencing factors for MS practice score(all P<0.05). Conclusions:The elderly in the community have a low level of knowledge about the components and diagnostic criteria of MS, but have a positive attitude and practice towards the prevention and treatment of MS.The level of knowledge, attitude and practice of MS is affected by health education lectures, occupation, regular health check examination and other factors.Health education on the diagnostic criteria and the awareness of disease prevention for the elderly in the community should be strengthened to improve the levels of the knowledge, attitude and practice of MS.

【Objective】 To analyze the clinical characteristics of patients with primary carcinoma of the gallbladder (PGC) who underwent radical intent resection in our center in the last decade and the therapeutic effects of the operation. 【Methods】 A single-institution database of The First Affiliated Hospital of Xi'an Jiaotong University from January 2008 to December 2017 was queried for patients with PGC who had received surgical treatment. The data were studied retrospectively to assess the trend of total admission, radical resection rate, prognosis and clinicopathological characteristics of PGC in the last decade. 【Results】 A total of 2 159 patients with PGC were treated in our institution from 2008 to 2017. Of them, 1072 were surgically treated and 503 underwent radical intent resection. In the past 5 years (2013-2017), the radical resection rate was 26.5% (319 cases of the operation), which was significantly higher than that in 2008-2012 (19.2%) (P<0.001). The overall survival time of the patients who underwent radical resection was 32 months, and the 1-, 3-, and 5-year survival rate was 68.9%, 48.4% and 41.6%, respectively. Compared with the data of 2008-2012, the proportion of the patients with preoperative jaundice decreased in the past 5 years (7.8% vs. 14.7%, P<0.05), that of the patients who underwent D2 lymphadenectomy (74.0% vs. 26.1%, P<0.001) increased significantly (P<0.001), the total number of lymph nodes obtained from the dissection (8.07±5.18 vs. 5.89±3.14, P<0.001) increased significantly (95.6% vs. 89.7%, P<0.05), and the proportion of R0 resection (95.6%) increased significantly (P<0.05). 【Conclusion】 The diagnosis and treatment of radical intent resection of PGC in our hospital have changed significantly in the last decade, mainly reflected in the extension of lymphadenectomy, increase in R0 resection rate and decrease in patients with preoperative jaundice.

The occurrence and development of tumors is a complex process with multiple factors and multiple steps. Ubiquitination refers to a multi-step cascade of protein modification processes including ubiquitin, ubiquitin-activating enzyme, ubiquitin-binding enzyme, ubiquitin ligase and proteasome, which is important for maintaining eukaryotic homeostasis. mechanism. The E3 ubiquitin ligases family is an important component of the ubiquitin-proteasome system. This family includes many proteins that catalyze the ubiquitination of various protein substrates and promote their degradation by the proteasome system. Up to date, E3 ubiquitin ligases has played an important role in a variety of tumor cell biology processes, including cell proliferation, apoptosis and cycle regulation. HECT-type E3 ubiquitin ligases, one of the earliest studies of E3 ubiquitin ligases, is involved in the ubiquitination of transcriptional regulation of protein translation. This article reviews the recent research progress of HECT-type E3 ubiquitin ligases and its role in tumors.

Objective:To investigate the independent predictors of the long-term clinical outcomes in patients with branch atheromatous disease (BAD) in lenticulostriate artery (LSA) territory.Methods:Patients with LSA-BAD admitted to the Department of Neurology, Zhongnan Hospital of Wuhan University from January 1, 2016 to June 1, 2019 were enrolled retrospectively. Their demography, vascular risk factor, and baseline clinical data were collected. The National Institutes of Health Stroke Scale (NIHSS) was used to evaluate the severity of stroke. The clinical outcomes were evaluated by the modified Rankin Scale at 6 months. 0-2 was defined as good outcome, and >2 was defined as poor outcome. Multivariate logistic regression analysis was used to determine the independent influencing factors of clinical outcomes in patients with LSA-BAD. Results:A total of 81 patients with LSA-BAD were enrolled. Their age 59.20±11.75 years (range, 39-81 years), 53 were male (65.4%), and median baseline NIHSS score was 1.0 (interquartile range, 0-4.0). Forty-one patients (50.6%) received intravenous thrombolysis. At 6-month follow-up after the onset, 63 patients (77.8%) had a good outcome, and 18 (22.2%) had a poor outcome. The baseline NIHSS score of the poor outcome group was significantly higher than that of the good outcome group (6.5 [0-9.0] vs. 1.0 [0-3.0]; Z=2.395, P=0.017), while the proportion of mild stroke (61.6% vs. 98.4%; χ2=17.595, P<0.001) and patients receiving intravenous thrombolysis (38.9% vs. 54.0%; χ2=4.450, P=0.035) were significantly lower than those of the good outcome group. Multivariate logistic regression analysis showed that after adjusting for other confounding factors, venous thrombolysis was independently correlated with the good outcome (odds ratio 0.099, 95% confidence interval 0.011-0.924; P=0.042), while the high baseline NIHSS score was independently associated with the poor outcome (odds ratio 1.736, 95% confidence interval 1.262-2.388; P=0.001). Conclusion:Intravenous thrombolysis is helpful to improve the outcomes of patients with LSA-BAD, and a higher baseline NIHSS score is an independent predictor of the poor outcome.

Objective To investigate the clinical effects and prognostic factors of radical surgery for primary gallbladder cancer (GBC).Methods The retrospective case-control study was conducted.The clinicopathological data of 305 patients with primary GBC who underwent radical Ro resection in the First Affiliated Hospital of Xi'an Jiaotong University from 2013 to 2017 were collected,including 108 males and 197 females,aged from 30 to 88 years,with a median age of 62 years.According to the different tumor staging,patients underwent corresponding operation and adjuvant treatment based on the postoperative indication of chemotherapy.Observation indicators:(1) results of imaging and laboratory examinations;(2) treatment situations:① surgical situations,② postoperative adjuvant treatment;(3) results of postoperative pathological examination;(4) followup;(5) prognostic factors analysis.Follow-up using outpatient examination and telephone interview was performed to detect postoperative survival up to December 5,2018,and death was used as the end point.Measurement data with normal distribution were represented as Mean±SD.Measurement data with skewed distribution were described as M (range).Count data were represented as percentage.The survival curve and survival rate were respectively drawn and calculated using the Kaplan-Meier method.The univariate analysis and multivariate analysis were respectively done using the Log-rank test and COX regression model.Results (1) Results of imaging and laboratory examinations:results of imaging examination showed that diagnostic rates of ultrasound,CT and MRI examination were respectively 84.06％ (174/207),85.71％ (168/196) and 63.11％ (65/103).Results of laboratory examination showed that the positive rates of CA19-9,CA125 and carcinoembryonic antigen (CEA) were respectively 55.34％ (145/262),48.06％ (124/258) and 46.15％ (126/273).(2) Treatment situations:① surgical situations:305 patients underwent radical R0 resection for primary GBC,including 145 undergoing liver wedge resection + D2 lymph node dissection,61 undergoing liver wedge resection + D1 lymph node dissection,55 undergoing liver Ⅳ B and Ⅴ segmentectomy + D2 lymph node dissection,11 undergoing liver Ⅳ B and Ⅴ segrnentectomy + D1 lymph node dissection,9 undergoing right hepatectomy + D2 lymph node dissection,5 undergoing liver wedge resection + D2 lymph node dissection + partial colectomy,4 undergoing pancreaticoduodenectomy,3 undergoing simple cholecystectomy in Tis stage,3 undergoing right hepatectomy + D1 lymph node dissection,2 undergoing liver ⅣB and Ⅴ segmentectomy + D2 lymph node dissection + partial colectomy,1 undergoing liver Ⅳ B and Ⅴ segmentectomy + resection and reconstruction of portal vein + D2 lymph node dissection,1 undergoing liver ⅣB and Ⅴ segmentectomy + D2 lymph node dissection + partial resection of the stomach or duodenum,1 undergoing pancreaticoduodenectomy + resection and reconstruction of portal vein,1 undergoing right hepatectomy + pancreaticoduodenectomy,1 undergoing right hepatic lobectomy + partial gastrectomy + D2 lymph node dissection,1 undergoing right hepatic lobectomy + D1 lymph node dissection and 1 undergoing right hepatic trilobectomy + D2 lymph node dissection.Of 94 patients with unsuspected GBC,78 who were diagnosed in the other hospitals received salvage surgery in the authors' center.Twenty-one patients had postoperative surgery-related complications,including 11 with bile leakage,8 with pulmonary infection and 2 with abdominal bleeding.Two patients died in the perioperative period.② Postoperative adjuvant treatment:26 patients underwent postoperative adjuvant chemotherapy.Chemotherapy regimen:gemcitabine + oxaliplatin were used in 12 patients,gemcitabine + tegafur in 7 patients,gemcitabine + cisplatin in 6 patients,oxaliplatin + tegafur in 1 patient.(3) Results of postoperative pathological examination.The postoperative pathological type of 305 patients:257,23,6,5,4,3,3,2,1 and 1 patients were respectively confirmed as pure adenocarcinoma,adenocarcinoma combined with squamous cell carcinoma,adenocarcinoma combined with neuroendocrine carcinoma,mucinous adenocarcinoma,neuroendocrine carcinoma,adenocarcinoma combined with mucinous carcinoma,squamous cell carcinoma,sarcomatoid carcinoma,adenocarcinoma combined with sarcomatoid carcinoma,adenocarcinoma combined with signet-ring cell carcinoma.Degree of tumor differentiation:highdifferentiated,moderate-differentiated and low-differentiated tumors were detected in 37,130 and 121 patients,respectively,17 with unknown differentiated degree.Of 305 patients,16 and 32 patients had respectively vascular invasion and nerve invasion.The number of lymph node dissected of 305 patients was 8±5,with positive lymph node of 0 (range,0-9),including 121 with lymphatic metastasis (26 with jumping lymphatic metastasis).TNM staging of 305 patients:stage 0,Ⅰ,Ⅱ,ⅢA,ⅢB,ⅣA and ⅣB were detected in 7,18,13,137,57,11 and 62 patients,respectively.(4) Follow-up:245 of 305 patients were followed up for 18.0 months (range,6.0-70.0 months).The survival time,1-and 3-year survival rates were respectively 29.5 months (range,0.5-69.9 months),71.6％ and 45.8％.One hundred and twenty-two patients died during the follow-up.(5) Prognostic factors analysis:the results of univariate analysis showed that preoperative level of bilirubin,pathological type,degree of tumor differentiation,liver invasion,vascular invasion,nerve invasion,T staging,N staging and postoperative chemotherapy were factors affecting prognosis of patients with primary GBC (x2 =10.26,3.96,45.89,34.64,12.75,27.05,35.09,39.44,4.40,P＜0.05).The results of multivariate analysis showed that low-differentiated tumor,liver invasion and N2 staging were independent risk factors affecting prognosis of patients with primary GBC [odds ratio (OR)=1.90,1.71,1.46,95％ confidence interval (CI):1.34-2.70,1.15-2.52,1.17-1.82,P＜0.05],and postoperative chemotherapy was a protective factor affecting prognosis of patients with primary GBC (OR=0.35,95％ CI:0.15-0.82,P＜0.05).Conclusions For patients with primary GBC undergoing radical resection,D2 lymph node dissection should be performed routinely.The low-differentiated tumor,liver invasion and N2 staging are independent risk factors affecting prognosis of patients,and postoperative chemotherapy is a protective factor.

Objective To investigate the relation between the balloon occlusion test ( BOT) and the anatomy of the circle of Willis ( CW) , and to explore the role of balloon occlusion test in the treatment of internal carotid artery permanent occlusion. Methods Selected the clinical data of 49 patients (52 sides) who had BOT in our hospital from October 2009 to June 2015,and analyzed the relationship be-tween the occurrence rate of anterior communicating artery ( AcoA) / posterior communicating artery ( PcoA) and the positive rate of BOT retrospectively. Results The occurrence rate of the AcoA was 97. 9%, and the occurrence rate of PcoA in one side was 82. 7%. Negative rate BOT accounted for 92. 3% and AcoA occurred in all, while the positive rate accounted for 7. 7%, including 2 cases of right superior ar-teria cerebri anterior combined with ipsilateral PcoAs absence, 1 case of left superior arteria cerebri anterior combined with ipsilateral PcoAs absence, and 1 case of AcoA and PcoAs absence. Conclusion Before the permanent occlusion of the internal carotid artery, it’ s necessary to clarify the redistribution of the compensatory way of blood flow in the AcoA-absent cases. Implementing permanent occlusion for cases with complete circle of Willis would cause less ischemic risk.

Objective To investigate the clinical significance of human papillomavirus(HPV )genotype combined with thinprep cytologic test(TCT )in the diagnosis of cervical lesion .Methods A total of 473 patients were checked for 21 subtypes of HPV by diversion hybrid gene chip technology ,TCT and colposcope biopsy were also detected at the same time .The histology was selected as a gold standard to analyze the tested results .Results The over all positive rate of HPV in 473 patients was 35 .7% .The positive rate of high risk HPV(HR‐HPV) was 32 .1% ,the positive rate of TCT was 26 .6% ,the sensibility ,specificity ,false negative rate , positive predictive value and negative predictive value between HR‐HPV detection and TCT detection were no statistical signifi‐cance(χ2 = 3 .444 ,P= 0 .063) .The sensibility ,specificity ,false negative rate ,positive predictive value and negative predictive value of combining test were 95 .8% ,77 .7% ,4 .2% ,52 .3% and 98 .7% ,the sensibility and negative predictive value improved notably , and the omission diagnose rate decreased significantly(P< 0 .05) .Conclusion HPV genotype combined with TCT detection could significantly improve sensibility and negative predictive value and decrease omission diagnose rate in diagnosis of cervical lesion .