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.

Bone organoids can simulate the complex structure and function of the bone tissues, which makes them a frontier technology in organoid researches. Bone organoids show a tremendous potential of applications in bone disease modeling, bone injury repair, and medicine screening. Although advancements have been made so far in constructing bone organoids with functional structures like mineralization, bone marrow, trabecular bone, callus, woven bone, etc, the researches in this field are confronted with numerous challenges such as lack of standardized construction strategies and unified evaluation criteria, which limits their further promotion and application. To standardize researches in bone organoids, the Orthopedic Expert Committee of Geriatric Branch of Chinese Association of Gerontology and Geriatrics, the Youth Osteoporosis Group of Orthopedic Branch of Chinese Medical Association, the Osteoporosis Group of Orthopedic Surgeon Branch of Chinese Medical Doctor Association, and the Osteoporosis Committee of Shanghai Association of Integrated Traditional Chinese and Western Medicine organized related experts to formulate Expert consensus on the construction, evaluation, and application of bone organoids ( version 2024) based on an evidence-based approach. A total of 17 recommendations were put forth, aiming to standardize researches and clinical applications of bone organoids and enhance their value in scientific research and clinical practice.

OBJECTIVE：To establish the f ingerprint of Qinlian runfei decoction，determine the contents of 11 components， and conduct cluster analysis and orthogonal partial least squares discriminant analysis （OPLS-DA）. METHODS ：HPLC method was used. The determination was performed on ZORBAX Eclipse Plus C 18 column with mobile phase consisted of acetonitrile- 0.05％ phosphoric acid solution （gradient elution ）at the flow rate of 1.0 mL/min. The detection wavelength was set at 260 nm， and column temperature was 30 ℃. The sample size was 10 μL. Using wogonoside as reference，HPLC fingerprints of 10 batches of Qinlian runfei decoction were drawn and the similarity evaluation was conducted with Similarity Evaluation System of TCM Chromatographic Fingerprint （2012 edition），the common peaks were also confirmed ；the contents of 11 components in Qinlian runfei decoction were determined by the same method. SPSS 21.0 software was used for clus ter analysis ，and SIMCA 14.0 software was used for OPLS-DA to screen marker components affecting quality. RESULTS ：There were 21 common peaks in 10 batches of Qinlian runfei decoction ，and the similarity with control fingerprint was greater than 0.98. A total of 11 common peaks were identified ， which were rutin ， forsythiaside A ， forsythiaside B ， iris， irigenin， baicalin， forsythiaside， wogonoside， baicalein， irisflorentin and wogonin. The line ar ranges of 11 components were 9.960 0-49.800 0，1.974 0-9.870 0，0.672 0-3.360 0，0.960 0-4.800 0，0.549 0- 2.745 0，5.040 0-25.200 0，1.374 0-6.870 0，0.615 0-3.075 0，0.759 9-3.795 0，0.162 0-0.810 0，0.042 0-0.210 0 μg（all r＞ 0.999）； RSDs of precision ， stability （48 h） and repeatability tests were less than 2％ ； the average recoveries were 95.81％-100.29％ with RSDs of 0.43％-1.73％（n＝6）；the contents were 8.924 4-12.820 8，0.352 2-0.868 7，0.435 6-0.711 2， 0.389 8-1.309 0，0.335 8-0.530 1，1.680 5-4.542 3，0.701 8-1.584 2，2.240 2-5.442 5，2.351 0-5.558 9，0.106 0-0.182 2，0.076 8- 0.128 9 mg/g，respectively. The results of cluster analysis showed that when class spacing was 10，it could be divided into two groups，S1-S3 and S 4-S10；when the class spacing was 5，the second class could be divided into two categories ，S6，S7，S9 were clustered into one category ，and S 4，S5，S8，S10 were clustered into one category. The results of OPLS-DA analysis showed that S6，S7 and S 9 were at the top of the figure ，S4，S5，S8 and S 10 were at the lower left side of the figure ，and S 1-S3 were at the lower right side of the figure ，which was consistent with the cluster analysis results ；VIP values of baicalin ，iris，forsythiaside A ， baicalein and wogonoside were all greater than 1. CONCLUSIONS ：Established fingerprint and content determination methods have high precision and good stability. Combined with multivariate statistical analysis ，it can be used for the quality control of Qinlian runfei decoction. Five components as baicalin are the marker components affecting the quality of Qinlian runfei decoction.

Objective:To evaluate the optimized efficacy of thoracic paravertebral nerve block and subcostal transversus abdominis plane block combined with general anesthesia for elderly patients undergoing thoracic combined with laparoscopic radical resection of esophageal cancer.Methods:Eighty American Society of Anesthesiologists physical status Ⅰ orⅡ patients of both sexes, aged 66-78 yr, weighing 46-80 kg, undergoing elective thoracoscopic combined with laparoscopic radical resection of esophageal cancer, were divided into 2 groups ( n=40 each) using a random number table method: general anesthesia group (group G) and thoracic paravertebral nerve block and subcostal transversus abdominis plane block combined with general anesthesia group (TSG group). Both groups received target-controlled infusion of propofol and remifentanil and intravenous injection of cisatracurium besilate for anesthesia induction and maintenance, with BIS value maintained at 45-60 during operation.Thoracic paravertebral nerve block on the affected side was performed under ultrasound guidance after the end of anesthesia induction, and 0.5% ropivacaine 15 ml was injected in TSG group.The patients were turned to the supine position after the thoracic operation was completed, and the bilateral subcostal approach to the transversus abdominis plane block was performed under ultrasound guidance, and 0.3% ropivacaine 20 ml was injected into each side.Sufentanil was used for patient-controlled intravenous anesthesia (PCIA) after operation.The background infusion rate was 0.05 μg·kg -1·h -1, PCA was 0.04 μg/kg, and the lockout interval was 10 min in group G. The background infusion rate was 0.03 μg·kg -1·h -1, PCA was 0.025 μg/kg, the lockout interval was 10 min in group TSG.Both groups received analgesia until 48 h after operation, and VAS score was maintained ≤3.When VAS score ≥ 4, tramadol 100 mg was intravenously injected for rescue analgesia.At 1 day before operation (T 0), immediately before anesthesia induction (T 1), at 1 h after emergence from anesthesia (T 2), and 4, 8, 12, 24 and 48 h after operation (T 3-7), venous blood samples were collected for determination of serum norepinephrine, epinephrine and cortisol concentrations (by enzyme-linked immunosorbent assay). The intraoperative consumption of remifentanil and occurrence of cardiovascular events were recorded.The pressing times of PCA, consumption of sufentanil and requirement for rescue analgesia within 48 h after operation were recorded.The occurrence of nerve block-related complications (hematoma at the puncture site, infection, local anesthetic poisoning, etc.) and adverse reactions such as nausea and vomiting, respiratory depression and pruritus were recorded within 48 h after the operation. Results:Compared with group G, the concentrations of serum epinephrine, norepinephrine and cortisol were significantly decreased, the consumption of intraoperative remifentanil and postoperative sufentanil and pressing times of PCA were reduced, the rate of rescue analgesia was decreased, scores of satisfaction with analgesia were increased, and the incidence of intraoperative cardiovascular events and postoperative adverse reactions such as nausea and vomiting, pruritus and respiratory depression were decreased in group TSG ( P<0.05). Conclusion:Thoracic paravertebral nerve block and subcostal transversus abdominis plane block combined with general anesthesia can reduce the perioperative consumption of opioids and inhibit perioperative stress responses and postoperative hyperalgesia with fewer adverse reactions when used for the elderly patients undergoing thoracic combined with laparoscopic radical resection of esophageal cancer.

Objective: To investigate the incidence and clinical characteristics of left atrial appendage (LAA) thrombus in patients with hypertrophic cardiomyopathy (HCM) and non-valvular atrial fibrillation (AF) . Methods: Data from 10 440 patients with AF who had undergone transesophageal echocardiography (TEE) before cardioversion or catheter ablation at Beijing Anzhen Hospital from April 2006 to December 2018 were retrospectively screened. Two hundred and five HCM patients were included, 820 AF patients with the same CHA₂DS₂-VASc score over the same period were selected as the control group. HCM patients were divided into two subgroups based on presence or absence of LAA thrombus/sludge. The baseline of clinical information, transthoracic echocardiographic and TEE measures were compared among all the groups. Receiver operating characteristic (ROC) curve was used to evaluate the diagnostic value of left atrial diameter (LAD) for LAA thrombus/sludge. Multivariate logistic regression analysis was applied to analyze the correlative factors of LAA thrombus/sludge in HCM patients. Results: The incidences of LAA thrombus or sludge were higher in HCM group than in control group (10.7% (22/205) vs. 0.7% (6/820); 8.8% (18/205) vs.7.0% (57/820), P<0.001) . In HCM patients, LAD was significantly larger in LAA thrombus/sludge subjects than in those without thrombus/sludge ((48.9±5.1)mm vs. (45.2±6.1) mm, P<0.001). CHA₂DS₂-VASc score was similar between the two subgroups ((2.0±1.4) vs. (1.8±1.4), P>0.05). There was no difference in the rate of patients with a CHA₂DS₂-VASc scores ≥2 between the subgroups(62.5% (25/40) vs. 57.0% (94/165), P=0.525). The incidences of LAA thrombus in HCM and AF patients with CHA₂DS₂-VASc scores of 0, 1 and 2 were 8.8% (3/34) , 9.6% (5/52) , 11.8% (11/119) , respectively; and the rate of LAA sludge were 8.8% (3/52) , 7.7% (4/52) , 9.2% (11/119) , respectively. The cut off value of LAD for the diagnosis of LAA thrombus/sludge was 44.5 mm. Multivariate logistic regression analysis showed that LAD≥44.5 mm (OR=5.134, 95%CI 1.862-14.156, P=0.002) , non-paroxysmal AF (OR=2.782, 95%CI 1.238-6.252, P=0.013) , previous thromboembolism or stroke (OR=1.820, 95%CI 0.774-4.227, P=0.017) were independent determinants of LAA thrombus/sludge. Conclusions The incidence of LAA thrombus/sludge is higher in patients with HCM and AF than in AF patients without HCM. The CHA₂DS₂-VASc score is similar between HCM and AF patients with LAA thrombus/sludge and those without thrombus/sludge. Patients with CHA₂DS₂-VASc score 0-1 are also likely to suffer LAA thrombus/sludge. Left atrial enlargement is associated with LAA thrombus/sludge.

Objective To investigate the incidence and clinical characteristics of left atrial appendage (LAA) thrombus in patients with hypertrophic cardiomyopathy (HCM) and non?valvular atrial fibrillation (AF). Methods Data from 10 440 patients with AF who had undergone transesophageal echocardiography (TEE) before cardioversion or catheter ablation at Beijing Anzhen Hospital from April 2006 to December 2018 were retrospectively screened. Two hundred and five HCM patients were included, 820 AF patients with the same CHA2DS2?VASc score over the same period were selected as the control group. HCM patients were divided into two subgroups based on presence or absence of LAA thrombus/sludge. The baseline of clinical information, transthoracic echocardiographic and TEE measures were compared among all the groups. Receiver operating characteristic (ROC) curve was used to evaluate the diagnostic value of left atrial diameter (LAD) for LAA thrombus/sludge. Multivariate logistic regression analysis was applied to analyze the correlative factors of LAA thrombus/sludge in HCM patients. Results The incidences of LAA thrombus or sludge were higher in HCM group than in control group (10.7% (22/205) vs. 0.7% (6/820); 8.8% (18/205) vs.7.0% (57/820), P<0.001). In HCM patients, LAD was significantly larger in LAA thrombus/sludge subjects than in those without thrombus/sludge ((48.9±5.1)mm vs. (45.2±6.1) mm, P<0.001). CHA2DS2?VASc score was similar between the two subgroups ((2.0 ± 1.4) vs. (1.8 ± 1.4), P>0.05). There was no difference in the rate of patients with a CHA2DS2?VASc scores ≥2 between the subgroups (62.5% (25/40) vs. 57.0% (94/165), P=0.525). The incidences of LAA thrombus in HCM and AF patients with CHA2DS2?VASc scores of 0, 1 and 2 were 8.8% (3/34), 9.6% (5/52), 11.8% (11/119), respectively; and the rate of LAA sludge were 8.8% (3/52), 7.7% (4/52), 9.2% (11/119), respectively. The cut off value of LAD for the diagnosis of LAA thrombus/sludge was 44.5 mm. Multivariate logistic regression analysis showed that LAD≥44.5 mm ( OR=5.134, 95%CI 1.862-14.156, P=0.002), non?paroxysmal AF ( OR＝2.782, 95%CI 1.238-6.252, P=0.013), previous thromboembolism or stroke ( OR＝1.820, 95%CI 0.774-4.227, P=0.017) were independent determinants of LAA thrombus/sludge. Conclusions The incidence of LAA thrombus/sludge is higher in patients with HCM and AF than in AF patients without HCM. The CHA2DS2?VASc score is similar between HCM and AF patients with LAA thrombus/sludge and those without thrombus/sludge. Patients with CHA2DS2?VASc score 0-1 are also likely to suffer LAA thrombus/sludge. Left atrial enlargement is associated with LAA thrombus/sludge.

Objective: To investigate the effect of non-vitamin K antagonist oral anticoagulants (NOAC) on left atrial or atrial appendage (LA/LAA) thrombi in patients with nonvalvular atrial fibrillation (NVAF). Method: Data from 3 042 patients with atrial fibrillation(AF), who underwent transesophageal echocardiography (TEE) examination before cardioversion or catheter ablation for the detection of LA/LAA thrombus in our department from March 2016 to January 2018 were prospectively analyzed. Among these patients, LA/LAA thrombus was detected by TEE in 57 patients. A total of 19 patients who received dabigatran or rivaroxaban for ≥3 weeks and underwent repeated TEE were included, 38 patients were excluded (7 patients with rheumatic heart disease, 1 patient treated with pericardial decortication, 1 patient treated with surgical repair of endocardial cushion defect, 1 patient with LA thrombus associated with the atrial septal occluder device, 14 patients received warfarin therapy, 14 patients did not receive repeated TEE). Results: First repeated TEE results showed that LA/LAA thrombus was not completely resolved in 4 out of 4 patients treated with dabigatran (110 mg bid) for a median time of 119 (47, 258) days, whereas LA/LAA thrombus was completely resolved in 5 out of 11 patients treated with dabigatran (150 mg bid) for a median time of 80 (58, 147) days. Thrombus was completely resolved in 2 out of 2 patients treated with rivaroxaban (15 mg qd) for 110 days and 95 days respectively, and in 1 out of 2 patients treated with rivaroxaban (20 mg qd) for 91 days. Second repeated TEE was performed in 8 patients. Thrombus was resolved completely in 2 out of 3 patients with undissolved thrombus treated by dabigatran (110 mg bid) after increasing the dabigatran dosage (150 mg bid). Thrombus was resolved in 3 (1 patient prolonged treatment with dabigatran 150 mg bid and 2 patients switched to rivaroxaban 20 mg qd) out of 4 patients with undissolved thrombus under the dabigatran 150 mg bid regimen, whereas the thrombus remained unresolved in 1 patient switched to rivaroxaban (15 mg qd). After receiving rivaroxaban 15 mg bid treatment, the thrombus was finally resolved in 1 patient with undissolved thrombus treated by rivaroxaban 20 mg qd. There was no clinical thromboembolism or major bleeding events during the median follow up time of 462 (305, 558) days. Conclusions Our data show that NOAC is an effective therapeutic option for the treatment of LA/LAA thrombi. When eligible, a higher NOAC dosage may be preferred due to the higher efficacy on thrombus resolvement.

The ischemic mitral regurgitation( IMR) is present in 20% to 30% of patients with old myocardial infarction. In patients with heart failure after myocardial infarction , the incidence of IMR is even as high as 50%.IMR has adverse effects on the prognosis of patients and is positively correlated with the degree of reflux , including increased risk of heart failure and mortality of cardiovascular disease.Patients with severe hemodynamic abnormalities, and in the case of have accepted the best drug treatment is still difficult to alleviate symptoms of heart failure , surgical treatment should be implemented.However, the surgical treatment strategy of IMR is still controversial, that is, for the moderate IMR, only the blood transport reconstruction is sufficient to restore the natural form of the valve, whether the valve operation needs to be performed simultaneously ; In the case of severe IMR, simultaneous valvular surgery has been agreed upon.The controversy is that the mitral valve repair(MVP) and mitral valve replacement(MVR) are both superior and inferior.The purpose of this paper is to review the literature on IMR sur-gery in order to help us understand this important question.

Systolic anterior motion of mitral valve ( SAM) is a relatively uncommon complication , but it can result in se-vere left ventricular outflow tract(LVOT) obstruction and/or mitral regurgitation(MR), even can be life-threating.Echocardio-graphy is still the first-line method of SAM diagnosis.Due to LVOT obstruction and MR reducing the long-term prognosis of pa-tients with SAM, it is necessary to carry out surgical treatment for patients with SAM for whom conservative treatment are not ef-fective.Then mitral valve repair(MVREP) is the first choice.Besides, surgical techniques for treatment and prevention of SAM have made great progress which have promoted the popularization of MVREP , and the rate of MVREP in mitral valve oper-ation has been greatly improved .

Objective: To evaluate the efifcacy of modiifed extended Morrow procedure on hypertrophic obstructive cardiomyopathy (HOCM) in adolescent patients. Methods: We retrospectively studied 29 consecutive HOCM patients at the age≤21 years who received modiifed extended Morrow procedure in our hospital from 2011 to 2015 for their clinical conditions to assess surgical efifcacy. Echocardiography was performed to compare left atrial size, left ventricular end diastolic diameter, left ventricular ejection fraction, left ventricular outlfow tract peak pressure, ventricular septal thickness, mitral systolic anterior motion and mitral regurgitation grade before and after operation. Moreover, pre-operative and post-operative plasma NT-proBNP levels were determined. Cardiac function was evaluated by New York Heart Association functional class. Results: There were 17 (58.6%) patients received isolated modiifed extended Morrow procedure and 12 patients had concomitant operation including 8 (27.6%) with coronary artery bypass grafting. Compared with pre-operation, the post-operative thickness of ventricular septum decreased from (24.6 ± 6.8) mm to (16.9 ± 7.1) mm, left ventricular outlfow tract gradient decreased from (68.8 ± 15.7) mmHg to (10.7 ± 4.2) mmHg, bothP<0.001; mitral regurgitation degree reduced from (1.7 ± 1.3) to (0.2 ± 0.4),P<0.01; NYHA classification improved from (3.4 ± 0.8) to (1.4 ± 0.5),P<0.01; plasma level of NT-proBNP reduced from (1957.6 ± 392.5) ng/ml to (458.7 ± 161.0) ng/ml,P<0.01. There was no peri-operative death, the survival rates at 12, 24 and 36 months post-operation were 100%, 86.7% and 86.7% respectively. Conclusion: Modiifed extended Morrow procedure has been a safe and effective method for treating adolescent HOCM patients, adequate exposure is the key point to assure surgical efifcacy.