OBJECTIVE To analyze clinical switching patterns and reasons between bevacizumab biosimilar and originator drugs. METHODS The data were collected from 1 175 cancer patients treated with bevacizumab at Ruijin Hospital， Shanghai Jiao Tong University School of Medicine from January 1， 2018， to December 31， 2023. The patients were divided into originator group （n＝250） and biosimilar group （n＝925）. The switching rate， switching type and reasons of the two groups were compared. RESULTS There were no statistically significant differences in the switching rate， switching types， and the number of switches between the two groups （P＞0.05）. Single， one-way switches were the switching type in both groups. The proportion of patients in the biosimilar group who switched due to adverse events was significantly higher than originator group， while the proportion of patients who switched due to treatment costs was significantly lower than originator group （P＜0.05）. There were no statistically significant differences in the proportions of patients who switched due to efficacy and drug accessibility between the two groups （P＞0.05）. CONCLUSIONS The switching between bevacizumab biosimilar and the originator drugs mainly involves single， one- way switches. Treatment costs and drug accessibility are the main factors for the switches among users of originator drugs， while drug accessibility and adverse events are the main factors for the switches among users of biosimilar.

ObjectiveTo investigate the effect of Fuzheng Huayu prescription on hepatocyte extinction and regeneration in fibrotic liver and its mechanism of action in promoting hepatocyte regeneration. MethodsMice were given intraperitoneal injection of CCl₄ for 6 weeks to establish a model of liver cirrhosis， and there were 10 mice in the model group， 10 in the sorafenib group， 10 in the Fuzheng Huayu prescription group， and 9 in the normal control group. Since week 4 of modeling， the mice in the Fuzheng Huayu prescription group and the sorafenib group were given the corresponding drug by gavage at a dose of 4.8 g/kg and 4 mg/kg， respectively， for three consecutive weeks， and those in the normal group and the model group were given an equal volume of sodium carboxymethyl cellulose. Serum liver function parameters were measured； the METAVIR scoring system was used to evaluate liver inflammation and fibrosis stage； Sirius Red staining and hydroxyproline （Hyp） content in liver tissue were used to evaluate collagen deposition； immunohistochemistry was used to measure the protein expression levels of type IV collagen， CD31， CD32b， Ki67， CyclinD1， glutamine synthetase， Wnt2， and HGF， and Western blot was used to measure the expression levels of Wnt2， LRP6， β-catenin， p-β-catenin， and CyclinD1 in liver tissue. A one-way analysis of variance was used for comparison of continuous data between multiple groups， and the least significant difference t-test was used for further comparison between two groups. ResultsCompared with the model group， the Fuzheng Huayu prescription group and the sorafenib group showed the following changes： significant reductions in the serum levels of alanine aminotransferase and aspartate aminotransferase and the content of Hyp in liver tissue （all P<0.01）； a significant reduction in METAVIR score； significant reductions in the expression levels of type Ⅳ collagen and CD31 （all P<0.05） and a significant increase in the expression level of CD32b （P<0.01）； significant reductions in the number of parenchymal extinction lesions and significant increases in the expression levels of Ki67 and CyclinD1 in liver tissue （all P<0.01）； significant increases in the protein expression levels of Wnt2， LRP6， β-catenin， and CyclinD1 and a significant reduction in the protein expression level of p-β-catenin （all P<0.05）； significant increases in the number of cells stained positive for both CD32b and Wnt2. ConclusionFuzheng Huayu prescription can inhibit hepatic sinusoidal capillarization， improve the Wnt2 exocrine function of liver sinusoidal endothelial cells， activate the Wnt/β-catenin signaling pathway associated with hepatocyte regeneration， and finally reverse liver cirrhosis.

Objective:To investigate the influencing factors for early tumor recurrence and the efficacy of adjuvant chemotherapy in gallbladder carcinoma (GBC) patients after curative-intent resection.Methods:The retrospective case-control study was conducted. The clinicopathological data of 506 patients with GBC in 11 medical centers, including The First Affiliated Hospital of Xi'an Jiaotong University et al, from January 2016 to December 2020 were collected. There were 168 males and 338 females, aged (62±11)years. All patients underwent curative-intent resection of GBC, and they were divided into patients with and without early recurrence based on time to postoperative recurrence. Observation indicators: (1) treatment; (2) follow-up and survival of patients; (3) analysis of influencing factors for early tumor recurrence after curative-intent resection of GBC; (4) efficacy of postoperative adjuvant chemotherapy. Measurement data with normal distribution were represented as Mean± SD, and measurement data with skewed distribution were represented as M(range). Count data were described as absolute numbers, and comparison between groups was conducted using the chi-square test. Comparison of ordinal data was conducted using the Mann-Whitney U test. Univariate analysis was conducted using the corresponding statistical methods based on data type. Multivariate analysis was conducted using the Logistic regression model with forward method. The Kaplan-Meier method was used to draw survival curve and calculate survival rate, and Log-Rank test was used for survival analysis. Results:(1) Treatment. Of 506 patients, there were 112 cases with postoperative adjuvant chemotherapy, and 394 cases without postopera-tive adjuvant chemotherapy. They underwent 5(range, 3-9)cycles of postoperative adjuvant chemo-therapy. (2) Follow-up and survival of patients. All 506 patients underwent postoperative follow-up, with the follow-up time of 55(range, 34-93)months. During the follow-up, there were 248 patients with tumor recurrence, including 158 cases of early recurrence and 90 cases of late recurrence, and there were 258 patients without tumor recurrence. Of 506 patients, 275 cases survived, and 231 cases died of multiple organ failure caused by tumor recurrence and metastasis. The postoperative recurr-ence-free survival time, overall survival time were 52(range,1-93)months, 62(range, 2-93)months. The 1-, 3-, 5-year disease-free survival rates and 1-, 3-, 5-year overall survival rates of the 506 pati-ents were 68.8%, 53.8%, 47.9% and 78.3%, 58.7%, 51.6%, respectively. Results of survival analysis showed that the median overall survival time of 158 patients with postoperative early recurrence and 348 patients without postoperative early recurrence (including 90 cases of late recurrence and 258 cases of no tumor recurrence) were 9(range, 2-73)months and unreached, showing a significant difference between them ( χ2=456.15, P<0.05). (3) Analysis of influencing factors for early tumor recurrence after curative-intent resection of GBC. Results of multivariate analysis showed that carcinoembryonic antigen (CEA) >5.0 μg/L, poorly differentiated tumor, liver invasion, and tumor N staging as stage N1-N2 were independent risk factors influencing early tumor recurrence after cura-tive-intent resection of GBC ( odds ratio=2.74, 6.20, 1.81, 2.93, 4.82, 95% confidence interval as 1.62-4.64, 1.82-21.12, 1.15-3.08, 1.68-5.09, 1.91-12.18, P<0.05), while postoperative adjuvant chemo-therapy was an independent protect factor ( odds ratio=0.39, 95% confidence interval as 0.21-0.71, P<0.05). (4) Efficacy of postoperative adjuvant chemotherapy. The median overall survival time of 394 patients without postoperative adjuvant chemotherapy and 112 patients with postoperative adjuvant chemotherapy were 57(range, 2-93)months and unreached, showing a significant differ-ence between them ( χ2=9.38, P<0.05). Of the 158 patients with postoperative early recurrence after curative-intent resection of GBC, 135 cases didn't receive adjuvant chemotherapy and 23 cases received adjuvant chemotherapy, with the overall survival time of 8(range, 2-73)months and 17(range, 8-61)months, respectively, showing a significant difference between them ( χ2=7.68, P<0.05). Conclusions:CEA >5.0 μg/L, poorly differentiated tumor, liver invasion, and tumor N staging as stage N1-N2 are independent risk factors influencing early tumor recurrence after curative-intent resection of GBC, while postoperative adjuvant chemotherapy is an independent protect factor. Postoperative adjuvant chemotherapy can prolong the overall survival time of patients with post-operative tumor early recurrence.

Objective:To investigate the independent and combined effects of maternal smoking during pregnancy and offspring genetic susceptibility on overall cancer mortality.Methods:Based on the United Kingdom Biobank ( n=419 228) data, the Cox proportional hazard regression model was used to estimate the effect of maternal smoking during pregnancy on offspring overall cancer (including 16 cancers in men and 18 in women) mortality and its combined effect and interaction with offspring genetic factors. Results:Maternal smoking during pregnancy was significantly associated with a 13% increased risk of overall cancer mortality in men [hazard ratio( HR)=1.13, 95% CI: 1.06-1.20] and 19% increased risk in women ( HR=1.19, 95% CI: 1.11-1.27). Participants with high genetic risk had the highest overall cancer mortality than those with low genetic risk (men: HR=1.42, 95% CI: 1.30-1.55; women: HR=1.38, 95% CI: 1.25-1.52). Compared with participants without maternal smoking during pregnancy and low genetic risk, those with maternal smoking during pregnancy and high genetic risk were associated with a 56% increased risk of overall cancer mortality in men ( HR=1.56, 95% CI: 1.37-1.77) and 59% in women ( HR=1.59, 95% CI: 1.39-1.83). Conclusion:Maternal smoking during pregnancy may increase offspring overall cancer mortality and more severe harm in individuals with high genetic risk.

Objective:To investigate the clinical effect of proper management of inferior pancreaticoduodenal artery (IPDA) in laparoscopic pancreaticoduodenectomy (LPD).Methods:This is a retrospective case series study. The clinical and pathological data of 70 patients who received LPD due to pancreatic head tumors, periampullary tumors, or distal common bile duct tumors in the Pancreatic Center of the Second Clinical College of Guangzhou University of Chinese Medicine from January to December 2022 were retrospectively collected. There were 47 males(67.1%) and 23 females(32.9%),aged (59.9±12.8)years(range:13 to 87 years).The procedure of IPDA exposure was as follows:a middle approach was utilized to expose the right half of superior mesenteric artery(SMA) and its right branches between the SMA and superior mesenteric vein(SMV) in superior colonic region. In the subcolonic region,SMA trunk exposure via dissection along the jejunal artery from feet to head and identification the association between IPDA and jejunal artery were prior to IPDA root ligation and dissection. The safety and efficacy of intraoperative IPDA handling were assessed based on surgical videos. Follow-up was carried out in outpatient clinic or by telephone, and outpatient follow-up was conducted once every 1 to 3 months after surgery.Results:The percentage of total LPD was 98.6%(69/70),with all patients achieving R0 resection. Nine cases(12.9%) were involved in combined vascular resection and reconstruction,with 1 case (1.4%) requiring additional upper abdominal incision for vascular and gastrointestinal reconstruction,while the remaining eight cases (11.4%) were completed laparoscopically. The operative time was (432.7±115.4)minutes(range:282 to 727 minutes), and the blood loss was (140.0±125.7)ml(range:20 to 800 ml). Only two patients(2.9%) received fresh frozen plasma transfusion,with an average volume of 650 ml. Reliable ligation and safe handling of the IPDA were achieved in 91.4%(64/70) of cases, with 8.6%(6/70) suffering from IPDA injury-related bleeding. No one was converted to opened surgery. Pathologically,the mean tumor size was (3.3±1.6)cm (range:1 to 7 cm),and the mean number of harvested lymph nodes was 17.0±7.3(range:0 to 46). Lymph node metastasis was observed in 13 cases (18.6%). Five cases (13.2%) developed grade B pancreatic fistula,while no grade C pancreatic fistula occurred. Other complications included bile leakage in one case(1.4%),delayed gastric emptying in two cases(2.9%), lymphatic leakage in 2 cases(2.9%),intra-abdominal infection in 9 cases(12.9%),and fat liquefaction of surgical incision in 1 case(1.4%). Two cases(2.9%) experienced postoperative intra-abdominal bleeding,one due to mesangial bleeding of lesser curvature of the stomach and the other due to oozing from the hepatic arterial sheath. These bleeding events were not concerned with IPDA. The average length of postoperative hospital stay was (15.2±4.6)days(range:9 to 28 days).Conclusion:Proper intraoperative management of IPDA in LPD might reduce IPDA-related bleeding during and after surgery and improve the safety of LPD.

Objective:To measure the overall and lobulated volume of the liver with different degrees of liver fibrosis and to further observe pathological changes such as liver microvasculature, hepatocyte apoptosis, and regeneration in order to understand the macroscopic volume changes of the liver during liver fibrosis and its relationship with liver tissue microscopic pathology in patients with chronic liver disease.Methods:53 patients with chronic hepatitis B, alcoholic fatty liver disease, autoimmune liver disease, nonalcoholic fatty liver disease, and drug-induced chronic liver disease who underwent both liver biopsy tissue and abdominal magnetic resonance imaging were collected. Patients were divided into early (F1-2), middle (F3-4), and late (F5-6) in accordance with the Ishak fibrosis stage and Masson stain. The liver and spleen volumes were measured using ITK-SNAP software. CD31 immunohistochemical staining was used to reflect intrahepatic angiogenesis. Ki67 and HNF-4α multiplex immunohistochemical staining were used to reflect hepatocyte regeneration. GS staining was used to determine parenchymal extinction lesions. TUNEL staining was used to observe hepatocyte apoptosis. Spearman correlation analysis was used to analyze the relationship between liver volume changes and liver histopathological changes.Results:As liver fibrosis progressed, the total liver volume and right lobe liver volume gradually decreased ( P<0.05), while the spleen volume gradually increased ( P<0.05). The expression of CD31 and GS gradually increased ( P<0.05), and the expression of Ki67 first increased and then decreased ( P<0.05). The positivity rate of CD31 was negatively correlated with the right lobe liver volume ( r=-0.609, P<0.001) and the total liver volume ( r=-0.363, P=0.017). The positivity rate of Ki67 was positively correlated with the right lobe liver volume ( r=0.423, P=0.018), while the positivity rate of apoptotic cells was significantly negatively correlated with the total liver volume ( r=-0.860, P<0.001). The positivity rate of GS was negatively correlated with the right lobe liver volume ( r=-0.440, P=0.002), and the number of PELs was negatively correlated with RV ( r=-0.476, P=0.013). The CD31 positive staining area was negatively correlated with the Ki67 positive staining area( r=-0.511, P=0.009). Conclusion:As liver fibrosis progresses, patients with chronic liver disease have a depletion in total liver volume and right lobe liver volume, and this is mainly in correlation with fewer liver cells and liver tissue microvasculature disorders.

Objective:To investigate the clinical effect of proper management of inferior pancreaticoduodenal artery (IPDA) in laparoscopic pancreaticoduodenectomy (LPD).Methods:This is a retrospective case series study. The clinical and pathological data of 70 patients who received LPD due to pancreatic head tumors, periampullary tumors, or distal common bile duct tumors in the Pancreatic Center of the Second Clinical College of Guangzhou University of Chinese Medicine from January to December 2022 were retrospectively collected. There were 47 males(67.1%) and 23 females(32.9%),aged (59.9±12.8)years(range:13 to 87 years).The procedure of IPDA exposure was as follows:a middle approach was utilized to expose the right half of superior mesenteric artery(SMA) and its right branches between the SMA and superior mesenteric vein(SMV) in superior colonic region. In the subcolonic region,SMA trunk exposure via dissection along the jejunal artery from feet to head and identification the association between IPDA and jejunal artery were prior to IPDA root ligation and dissection. The safety and efficacy of intraoperative IPDA handling were assessed based on surgical videos. Follow-up was carried out in outpatient clinic or by telephone, and outpatient follow-up was conducted once every 1 to 3 months after surgery.Results:The percentage of total LPD was 98.6%(69/70),with all patients achieving R0 resection. Nine cases(12.9%) were involved in combined vascular resection and reconstruction,with 1 case (1.4%) requiring additional upper abdominal incision for vascular and gastrointestinal reconstruction,while the remaining eight cases (11.4%) were completed laparoscopically. The operative time was (432.7±115.4)minutes(range:282 to 727 minutes), and the blood loss was (140.0±125.7)ml(range:20 to 800 ml). Only two patients(2.9%) received fresh frozen plasma transfusion,with an average volume of 650 ml. Reliable ligation and safe handling of the IPDA were achieved in 91.4%(64/70) of cases, with 8.6%(6/70) suffering from IPDA injury-related bleeding. No one was converted to opened surgery. Pathologically,the mean tumor size was (3.3±1.6)cm (range:1 to 7 cm),and the mean number of harvested lymph nodes was 17.0±7.3(range:0 to 46). Lymph node metastasis was observed in 13 cases (18.6%). Five cases (13.2%) developed grade B pancreatic fistula,while no grade C pancreatic fistula occurred. Other complications included bile leakage in one case(1.4%),delayed gastric emptying in two cases(2.9%), lymphatic leakage in 2 cases(2.9%),intra-abdominal infection in 9 cases(12.9%),and fat liquefaction of surgical incision in 1 case(1.4%). Two cases(2.9%) experienced postoperative intra-abdominal bleeding,one due to mesangial bleeding of lesser curvature of the stomach and the other due to oozing from the hepatic arterial sheath. These bleeding events were not concerned with IPDA. The average length of postoperative hospital stay was (15.2±4.6)days(range:9 to 28 days).Conclusion:Proper intraoperative management of IPDA in LPD might reduce IPDA-related bleeding during and after surgery and improve the safety of LPD.

Objective To establish a method for HPLC fingerprint analysis and determine three main components of Modified Zengye Decoction.Methods The chromatographic column was Shimadzu WondaSil C18 column(250 mm×4.6 mm,5 μm),the mobile phase was acetonitrile-0.3％aqueous phosphoric acid with a gradient elution procedure,the volume flow rate was 1.0 mL/min,the detection wavelengths were 265,203,310 and 290 nm,the column temperature was 25 ℃,and the injection volume was 20 μL.The HPLC fingerprints of the 10 batches of Modified Zengye Decoction were established,and the similarity analysis was performed by using the similarity evaluation system of chromatographic fingerprint of traditional Chinese medicine(version 2012A).The common peaks were identified and assigned,and the contents of the three main components were quantitatively determined.Results There were 17 common peaks in the fingerprints of 10 batches of Modified Zengye Decoction with similarities ranging from 0.872-0.989.The fingerprints recognized peak 9,14 and 17 as ferulic acid,aurantiamarin and harpagoside,respectively.The contents of ferulic acid,aurantiamarin and harpagoside were 0.067 3-0.174 8,0.498 8-1.522 7,0.270 9-0.802 4 mg/g,and the transfer rate were 30.74％-55.63％,11.77％-35.94％,23.15％-68.56％,respectively.Conclusion The established HPLC fingerprint analysis method combined with main components quantitative analysis method can be used for the quality analysis and control of Modified Zengye Decoction with simple analysis method and reliable results.

Humans ; Bradycardia/therapy* ; Tricuspid Valve Insufficiency ; Pacemaker, Artificial/adverse effects* ; Cardiac Pacing, Artificial

Breast cancers that are positive for hormone receptor but negative for human epidermal growth factor receptor 2 (abbreviated as HR+/HER2-) account for approximately 60% of total cases. Targeting estrogen signaling is one of the most important therapeutic strategies for HR+/HER2- breast cancer. However, the management of endocrine-resistant HR+/HER2- breast cancer remains a difficult issue in clinical practice. Previous multi-omic analysis and translational research have identified the mechanisms underlying endocrine-resistance including genomic alteration and abnormal epigenetic modification. To overcome endocrine-resistance, we have established a comprehensive and coherent therapeutic strategy. In addition, several novel therapies have shown promising efficacy in previous clinical trials and will emerge as alternative options for targeting endocrine-resistant HR+/HER2- breast cancer. In this review, we will introduce the mechanisms of endocrine-resistance, explain the current therapeutic strategy for endocrine-resistant HR +/HER2 - breast cancer and discuss the possible targeted therapies in the future.