Objective:To investigate the role of mechanosensor Yes-associated protein 1 (YAP1) in urothelial cells in inducing bladder dysfunction in a partial bladder outlet obstruction (pBOO) model.Methods:Ten female C57BL/6 mice were included in this study and randomly divided into pBOO and sham groups based on body weight using a stratified pairing method, with 5 mice in each group. The pBOO group underwent proximal urethral ligation surgery, while the sham group underwent a sham operation. Two weeks after surgery, the urinary pattern was analyzed using the urine spot test. The significant increase in urine spot numbers indicated the successful establishment of the pBOO model. The mice were then sacrificed, and bladder tissues were weighed and stained with hematoxylin and eosin (HE) to observe morphological changes. The bladder urothelial layer was further isolated, and total cell proteins were extracted to detect the expression levels of YAP1 protein using Western blotting. Mouse immortalized bladder urothelial cells were divided into three experimental groups: the negative control (NC) group, which was treated with YAP1-NC lentivirus; the overexpression (OE) group, which was treated with YAP1-OE lentivirus to induce YAP1 protein overexpression; and the verteporfin treatment (VP) group, which was treated with verteporfin on the basis of the OE group. Real-time quantitative PCR and Western blotting were used to verify the transcription and expression levels of YAP1 protein, the co-transcriptional activator TEAD4 protein, and the phosphorylated protein DRP1-616 (at serine 616) of dynamin-related protein 1 (DRP1). An ATP detection kit was used to measure the ATP release concentration in the NC, OE, and VP groups. The interaction between YAP1 and TEAD4 was investigated using co-immunoprecipitation, and the expression of the mitochondrial marker translocase of the outer mitochondrial membrane 20 (Tom20) was observed using immunofluorescence staining.Results:The results of the urine spot test showed that the number of urine spots on the filter paper in the pBOO group was higher than that in the sham group within 6 hours [(283.0±9.1) spots vs. (3.7±0.3) spots, P<0.01], and the urine spots were scattered. The bladder wet weight in the pBOO group was significantly higher than that in the sham group [(105.70±6.84) mg vs. (22.33±1.20) mg, P<0.01]. Histological observations revealed reduced bladder mucosal folds and increased detrusor muscle thickness in the pBOO group. The expression of YAP1 protein in the bladder urothelial cells of the pBOO group was significantly upregulated compared to the sham group [(1.26±0.08) vs. (0.50±0.04), P<0.01]. In vitro experiments showed that compared to the NC group, the OE group had significantly increased expression of DRP1-616 [(0.94±0.05) vs. (0.33±0.01), P<0.01] and higher ATP release concentration [(24.45±0.16) μmol/mg vs. (19.67±0.42) μmol/mg, P<0.01]. In contrast, the VP group had significantly decreased expression of DRP1-616 [(0.29±0.04) vs. (0.94±0.05), P<0.01] and lower ATP release concentration [(10.55±0.01) μmol/mg vs. (24.45±0.16) μmol/mg, P<0.01] compared to the OE group. Co-immunoprecipitation experiments using YAP1 and TEAD4 antibodies showed that YAP1 and TEAD4 proteins could interact and form a transcriptional complex to regulate ATP release. Immunofluorescence staining revealed increased expression of Tom20 in the OE group compared to the NC group [(104.20±3.28) vs. (74.51±3.87), P<0.01]. Conclusions:In the pBOO-induced bladder dysfunction model, YAP1 is highly expressed in urothelial cells. YAP1 forms a transcriptional complex with TEAD4 to regulate ATP release by promoting mitochondrial fission via DRP1-616 expression, which is a key mechanism underlying pBOO-induced bladder dysfunction.

Objective To explore the roles of the mechanoreceptor Yes-associated protein 1(YAP1)and piezo type mechanosensitive ion channel component 2(PIEZO2)in mechanotransduction in mouse bladder urothelial cells.Methods Mouse bladder urothelial cells were subjected to mechanical stretching using the FX-6000T cell stretching system and treated with the YAP1-specific inhibitor verteporfin(VP).The expressions of PIEZO2,YAP1 and connective tissue growth factor(CTGF)at the mRNA and protein levels,as well as changes in cellular adenosine triphosphatase(ATP)concentration,were detected using reverse transcription quantitative PCR(RT-qPCR)and Western blotting(WB).Results After stretching stimulation,under the fluorescence microscope,it was observed that the diameter length of the stretched cells were longer than that before stretching,and the difference was statistically significant(P＜0.05).The expressions of YAP1,PIEZO2 and CTGF at the mRNA and protein levels were increased in the stretched group compared to those of the non-stretched group(P＜0.05).VP effectively reduced the expressions of YAP1,PIEZO2 and CTGF at the mRNA and protein levels after stretching stimulation(P＜0.05).Stretching stimulation significantly increased the intracellular ATP concentration,while VP was able to inhibit the increase in ATP concentration,with a statistically significant difference(P＜0.000 1).Conclusion Stretching stimulation increased the expressions of YAP1 and PIEZO2 in bladder urothelial cells and promoted the release of ATP;verteporfin inhibited the increase in YAP1 activity and the overexpression of PIEZO2 caused by stretching,thereby reducing the release of ATP.It is suggested that mouse bladder urothelial cells may primarily sense mechanical signals through the YAP1-PIEZO2-ATP pathway.

Objective:To investigate the completion rate of tumor evaluation at initial assessment and after neoadjuvant therapy for mid and low rectal cancer patients in the national multicenter real-world database.Methods:The prospective real-world study was conducted. The clinicopathological data of 1 074 patients who underwent surgical treatment for mid and low rectal cancer in 47 national medical institutions, including Peking Union Medical College Hospital et al, from May 12,2023 to May 11,2024 were collected. Observation indicators: (1) clinical characteristics of patients with mid and low rectal cancer; (2) initial colonoscopy and pathologic evaluation of tumors in patients with mid and low rectal cancer; (3) initial imaging evaluation of patients with mid and low rectal cancer; (4) imaging evaluation after neoadjuvant therapy for patients with mid and low rectal cancer. Measurement data with normal distribution were represented as Mean± SD, and measurement data with skewed distribution were represented as M( Q1, Q3). Count data were described as absoluter numbers and/or percentages. Results:(1) Clinical characteristics of patients with mid and low rectal cancer. Of the 1 074 patients, there were 713 males and 361 females, aged 63(56,70)years. The body mass index of 1 074 patients was 24(21,26)kg/m 2.For American Society of Anesthesiologists classification, there were 147 cases of stage Ⅰ, 641 cases of stage Ⅱ, 157 cases of stage Ⅲ, 2 cases of stage Ⅳ, and there were 127 cases missing data. (2) Initial colonoscopy and pathologic evaluation of tumors in patients with mid and low rectal cancer. Of the 1 074 patients, there were 787 cases (73.28%) undergoing complete colonoscopy, and there were only 197 cases (18.34%) undergoing immunohistochemical evaluation of all four mismatch repair proteins. (3) Initial imaging evaluation of patients with mid and low rectal cancer. Of the 1 074 patients, there were 842(78.40%) patients completing magnetic resonance imaging (MRI) or ultrasound evaluation, and there were 914(85.10%) patients completing chest, abdomen, and pelvis enhanced computed tomography (CT) evaluation. In the 149 patients completing rectal ultrasound evaluation, there were 122 cases (81.88%) comple-ting T staging evaluation, and there were 81 cases (54.36%) completing N staging evaluation. In the 808 patients completing rectal MRI evaluation, there were 708 cases (87.62%) completing T staging evaluation, and there were 590 cases (73.02%) completing N staging evaluation. (4) Imaging evalua-tion after neoadjuvant therapy for patients with mid and low rectal cancer. Of the 388 patients with neoadjuvant therapy, there were 332 patients (85.57%) completing MRI or ultrasound evaluation, and there were 327 patients (84.28%) completing chest, abdomen, and pelvis enhanced CT evalua-tion. In the 70 patients completing rectal ultrasound evaluation, there were 65 cases (92.86%) com-pleting T staging evaluation, and there were 49 cases (70.00%) completing N staging evaluation. In the 327 patients completing rectal MRI evaluation, there were 246 cases (75.23%) completing T staging, and there were 228 cases (69.72%) completing N staging evaluation. Conclusion:The com-pletion rate of tumor imaging evaluation at initial assessment and after neoadjuvant therapy for mid and low rectal cancer patients on a national scale is relatively good.

Objective To explore the roles of the mechanoreceptor Yes-associated protein 1(YAP1)and piezo type mechanosensitive ion channel component 2(PIEZO2)in mechanotransduction in mouse bladder urothelial cells.Methods Mouse bladder urothelial cells were subjected to mechanical stretching using the FX-6000T cell stretching system and treated with the YAP1-specific inhibitor verteporfin(VP).The expressions of PIEZO2,YAP1 and connective tissue growth factor(CTGF)at the mRNA and protein levels,as well as changes in cellular adenosine triphosphatase(ATP)concentration,were detected using reverse transcription quantitative PCR(RT-qPCR)and Western blotting(WB).Results After stretching stimulation,under the fluorescence microscope,it was observed that the diameter length of the stretched cells were longer than that before stretching,and the difference was statistically significant(P＜0.05).The expressions of YAP1,PIEZO2 and CTGF at the mRNA and protein levels were increased in the stretched group compared to those of the non-stretched group(P＜0.05).VP effectively reduced the expressions of YAP1,PIEZO2 and CTGF at the mRNA and protein levels after stretching stimulation(P＜0.05).Stretching stimulation significantly increased the intracellular ATP concentration,while VP was able to inhibit the increase in ATP concentration,with a statistically significant difference(P＜0.000 1).Conclusion Stretching stimulation increased the expressions of YAP1 and PIEZO2 in bladder urothelial cells and promoted the release of ATP;verteporfin inhibited the increase in YAP1 activity and the overexpression of PIEZO2 caused by stretching,thereby reducing the release of ATP.It is suggested that mouse bladder urothelial cells may primarily sense mechanical signals through the YAP1-PIEZO2-ATP pathway.

Objective:To investigate the completion rate of tumor evaluation at initial assessment and after neoadjuvant therapy for mid and low rectal cancer patients in the national multicenter real-world database.Methods:The prospective real-world study was conducted. The clinicopathological data of 1 074 patients who underwent surgical treatment for mid and low rectal cancer in 47 national medical institutions, including Peking Union Medical College Hospital et al, from May 12,2023 to May 11,2024 were collected. Observation indicators: (1) clinical characteristics of patients with mid and low rectal cancer; (2) initial colonoscopy and pathologic evaluation of tumors in patients with mid and low rectal cancer; (3) initial imaging evaluation of patients with mid and low rectal cancer; (4) imaging evaluation after neoadjuvant therapy for patients with mid and low rectal cancer. Measurement data with normal distribution were represented as Mean± SD, and measurement data with skewed distribution were represented as M( Q1, Q3). Count data were described as absoluter numbers and/or percentages. Results:(1) Clinical characteristics of patients with mid and low rectal cancer. Of the 1 074 patients, there were 713 males and 361 females, aged 63(56,70)years. The body mass index of 1 074 patients was 24(21,26)kg/m 2.For American Society of Anesthesiologists classification, there were 147 cases of stage Ⅰ, 641 cases of stage Ⅱ, 157 cases of stage Ⅲ, 2 cases of stage Ⅳ, and there were 127 cases missing data. (2) Initial colonoscopy and pathologic evaluation of tumors in patients with mid and low rectal cancer. Of the 1 074 patients, there were 787 cases (73.28%) undergoing complete colonoscopy, and there were only 197 cases (18.34%) undergoing immunohistochemical evaluation of all four mismatch repair proteins. (3) Initial imaging evaluation of patients with mid and low rectal cancer. Of the 1 074 patients, there were 842(78.40%) patients completing magnetic resonance imaging (MRI) or ultrasound evaluation, and there were 914(85.10%) patients completing chest, abdomen, and pelvis enhanced computed tomography (CT) evaluation. In the 149 patients completing rectal ultrasound evaluation, there were 122 cases (81.88%) comple-ting T staging evaluation, and there were 81 cases (54.36%) completing N staging evaluation. In the 808 patients completing rectal MRI evaluation, there were 708 cases (87.62%) completing T staging evaluation, and there were 590 cases (73.02%) completing N staging evaluation. (4) Imaging evalua-tion after neoadjuvant therapy for patients with mid and low rectal cancer. Of the 388 patients with neoadjuvant therapy, there were 332 patients (85.57%) completing MRI or ultrasound evaluation, and there were 327 patients (84.28%) completing chest, abdomen, and pelvis enhanced CT evalua-tion. In the 70 patients completing rectal ultrasound evaluation, there were 65 cases (92.86%) com-pleting T staging evaluation, and there were 49 cases (70.00%) completing N staging evaluation. In the 327 patients completing rectal MRI evaluation, there were 246 cases (75.23%) completing T staging, and there were 228 cases (69.72%) completing N staging evaluation. Conclusion:The com-pletion rate of tumor imaging evaluation at initial assessment and after neoadjuvant therapy for mid and low rectal cancer patients on a national scale is relatively good.

Objective:To investigate the role of mechanosensor Yes-associated protein 1 (YAP1) in urothelial cells in inducing bladder dysfunction in a partial bladder outlet obstruction (pBOO) model.Methods:Ten female C57BL/6 mice were included in this study and randomly divided into pBOO and sham groups based on body weight using a stratified pairing method, with 5 mice in each group. The pBOO group underwent proximal urethral ligation surgery, while the sham group underwent a sham operation. Two weeks after surgery, the urinary pattern was analyzed using the urine spot test. The significant increase in urine spot numbers indicated the successful establishment of the pBOO model. The mice were then sacrificed, and bladder tissues were weighed and stained with hematoxylin and eosin (HE) to observe morphological changes. The bladder urothelial layer was further isolated, and total cell proteins were extracted to detect the expression levels of YAP1 protein using Western blotting. Mouse immortalized bladder urothelial cells were divided into three experimental groups: the negative control (NC) group, which was treated with YAP1-NC lentivirus; the overexpression (OE) group, which was treated with YAP1-OE lentivirus to induce YAP1 protein overexpression; and the verteporfin treatment (VP) group, which was treated with verteporfin on the basis of the OE group. Real-time quantitative PCR and Western blotting were used to verify the transcription and expression levels of YAP1 protein, the co-transcriptional activator TEAD4 protein, and the phosphorylated protein DRP1-616 (at serine 616) of dynamin-related protein 1 (DRP1). An ATP detection kit was used to measure the ATP release concentration in the NC, OE, and VP groups. The interaction between YAP1 and TEAD4 was investigated using co-immunoprecipitation, and the expression of the mitochondrial marker translocase of the outer mitochondrial membrane 20 (Tom20) was observed using immunofluorescence staining.Results:The results of the urine spot test showed that the number of urine spots on the filter paper in the pBOO group was higher than that in the sham group within 6 hours [(283.0±9.1) spots vs. (3.7±0.3) spots, P<0.01], and the urine spots were scattered. The bladder wet weight in the pBOO group was significantly higher than that in the sham group [(105.70±6.84) mg vs. (22.33±1.20) mg, P<0.01]. Histological observations revealed reduced bladder mucosal folds and increased detrusor muscle thickness in the pBOO group. The expression of YAP1 protein in the bladder urothelial cells of the pBOO group was significantly upregulated compared to the sham group [(1.26±0.08) vs. (0.50±0.04), P<0.01]. In vitro experiments showed that compared to the NC group, the OE group had significantly increased expression of DRP1-616 [(0.94±0.05) vs. (0.33±0.01), P<0.01] and higher ATP release concentration [(24.45±0.16) μmol/mg vs. (19.67±0.42) μmol/mg, P<0.01]. In contrast, the VP group had significantly decreased expression of DRP1-616 [(0.29±0.04) vs. (0.94±0.05), P<0.01] and lower ATP release concentration [(10.55±0.01) μmol/mg vs. (24.45±0.16) μmol/mg, P<0.01] compared to the OE group. Co-immunoprecipitation experiments using YAP1 and TEAD4 antibodies showed that YAP1 and TEAD4 proteins could interact and form a transcriptional complex to regulate ATP release. Immunofluorescence staining revealed increased expression of Tom20 in the OE group compared to the NC group [(104.20±3.28) vs. (74.51±3.87), P<0.01]. Conclusions:In the pBOO-induced bladder dysfunction model, YAP1 is highly expressed in urothelial cells. YAP1 forms a transcriptional complex with TEAD4 to regulate ATP release by promoting mitochondrial fission via DRP1-616 expression, which is a key mechanism underlying pBOO-induced bladder dysfunction.

The incidence of osteoporotic thoracolumbar vertebral fracture (OTLVF) in the elderly is gradually increasing. The kyphotic deformity caused by various factors has become an important characteristic of OTLVF and has received increasing attention. Its clinical manifestations include pain, delayed nerve damage, sagittal imbalance, etc. Currently, the definition and diagnosis of OTLVF with kyphotic deformity in the elderly are still unclear. Although there are many treatment options, they are controversial. Existing guidelines or consensuses pay little attention to this type of fracture with kyphotic deformity. To this end, the Lumbar Education Working Group of the Spine Branch of the Chinese Medicine Education Association and Editorial Committee of Chinese Journal of Trauma organized the experts in the relevant fields to jointly develop Clinical guidelines for the diagnosis and treatment of osteoporotic thoracolumbar vertebral fractures with kyphotic deformity in the elderly ( version 2024), based on evidence-based medical advancements and the principles of scientificity, practicality, and advanced nature, which provided 18 recommendations to standardize the clinical diagnosis and treatment.

Objective:To study the surgical safety and efficacy of preoperative neoadjuvant therapy with immune checkpoint inhibitors combined with anti-angiogenic drugs in patients with China liver cancer staging(CNLC)-Ⅱb and Ⅲa resectable hepatocellular carcinoma.Methods:The data of 129 patients with Ⅱb and Ⅲa hepatocellular carcinoma who underwent surgery at the First Affiliated Hospital of Nanjing Medical University from January 2018 to December 2020 were analyzed. All patients were divided into two groups: the neoadjuvant therapy group( n=14,13 males and 1 female,aged (55.4±12.6)years(range:34 to 75 years)) received immune combined targeted therapy before surgery,immune checkpoint inhibitor camrelizumab was administered intravenously at a dose of 200 mg each time,every 2 weeks for 3 cycles,anti-angiogenesis drug apatinib was taken orally and continuously with a dose of 250 mg for 3 weeks and the conventional surgery group( n=115,103 males and 12 females,aged (55.8±12.0)years(range:21 to 83 years)) did not receive antitumor systemic therapy before surgery. There were 3 patients with CNLC-Ⅱb,11 with CNLC-Ⅲa in the neoadjuvant group;28 patients with CNLC-Ⅱb,87 with CNLC-Ⅲa in the conventional group. Student′s t test or rank-sum test was used to compare the differences between two groups for quantitative data, Fisher′s exact probability method was used to compare the differences of proportions between two groups, and Log-rank test was used to compare survival differences between two groups. Results:The 1-year recurrence rate in the neoadjuvant group was 42.9%,and the 1-year recurrence rate in the conventional group was 64.0%,with a statistically significant difference between the two groups(χ2=3.850, P=0.050);The 1-year survival rate in the neoadjuvant group was 100% and that in the conventional group was 74.2%,with a statistically significant difference between the two groups(χ2=5.170, P=0.023). According to the stratified analysis of the number of tumors,for single tumor,the 1-year recurrence rate in the neoadjuvant group was 25.0%,and that in the conventional surgery group was 71.0%,and the difference between the two groups was statistically significant(χ2=5.280, P=0.022). For multiple tumors, the 1-year recurrence rate in the neoadjuvant group was 66.7%,and the 1-year recurrence rate in the conventional surgery group was 58.9%,with no significant difference between the two groups(χ2=0.110, P=0.736). The operative time,intraoperative blood loss,and postoperative hospital stay in the neoadjuvant group were similar to those in the conventional group,and their differences were not statistically significant. Conclusions:Immune checkpoint inhibitors combined with anti-angiogenic targeted drugs as a neoadjuvant therapy for resectable hepatocellular carcinoma can reduce the 1-year recurrence rate and improve the 1-year survival rate,especially for those with solitary tumor. Limited by the sample size of the neoadjuvant group,the safety of immune combined targeted therapy before surgery cannot be observed more comprehensively,and further studies will be explored.

Objective     To investigate the influence of prior percutaneous coronary intervention (PCI) on the outcome of coronary artery bypass grafting (CABG). Methods     Clinical data of 5 216 patients from Jiangsu Province CABG registry who underwent primary isolated CABG from 2016 to 2019 were retrospectively analyzed. Patients were divided into a PCI group (n=673) and a non-PCI group (n=4 543) according to whether they had received PCI treatment. The PCI group included 491 males and 182 females, aged 62.6±8.2 years, and the non-PCI group included 3 335 males and 1 208 females, aged 63.7±8.7 years. Multivariable logistic regression and propensity score matching (PSM) were used to compare 30-day mortality, incidence of major complications and 1-year follow-up outcomes between the two groups. Results     Both in original cohort and matched cohort, there was no statistical difference in the 30-day mortality [14 (2.1%) vs. 77 (1.7%), P=0.579; 14 (2.1%) vs. 11 (1.6%), P=0.686], or the incidence of major complications (myocardial infarction, stroke, mechanical ventilation≥24 h, dialysis for new-onset renal failure, deep sternal wound infection and atrial fibrillation) (all P>0.05). The rate of reoperation for bleeding in the PCI group was higher than that in the non-PCI group [19 (2.8%) vs. 67 (1.5%), P=0.016; 19 (2.8%) vs. 7 (1.0%), P=0.029]. Both in original cohort and matched cohort, there was no statistical difference in 1-year survival rate between the two groups [613 (93.1%) vs. 4 225 (94.6%), P=0.119; 613 (93.1%) vs. 630 (95.2%), P=0.124], while the re-admission rate in the PCI group was significantly higher than that in the non-PCI group [32 (4.9%) vs. 113 (2.5%), P=0.001; 32 (4.9%) vs. 17 (2.6%), P=0.040]. Conclusion     This study shows that a history of PCI treatment does not significantly increase the perioperative mortality and major complications of CABG, but increases the rate of cardiogenic re-admission 1 year postoperatively.

Objective:To study the surgical safety and efficacy of preoperative neoadjuvant therapy with immune checkpoint inhibitors combined with anti-angiogenic drugs in patients with China liver cancer staging(CNLC)-Ⅱb and Ⅲa resectable hepatocellular carcinoma.Methods:The data of 129 patients with Ⅱb and Ⅲa hepatocellular carcinoma who underwent surgery at the First Affiliated Hospital of Nanjing Medical University from January 2018 to December 2020 were analyzed. All patients were divided into two groups: the neoadjuvant therapy group( n=14,13 males and 1 female,aged (55.4±12.6)years(range:34 to 75 years)) received immune combined targeted therapy before surgery,immune checkpoint inhibitor camrelizumab was administered intravenously at a dose of 200 mg each time,every 2 weeks for 3 cycles,anti-angiogenesis drug apatinib was taken orally and continuously with a dose of 250 mg for 3 weeks and the conventional surgery group( n=115,103 males and 12 females,aged (55.8±12.0)years(range:21 to 83 years)) did not receive antitumor systemic therapy before surgery. There were 3 patients with CNLC-Ⅱb,11 with CNLC-Ⅲa in the neoadjuvant group;28 patients with CNLC-Ⅱb,87 with CNLC-Ⅲa in the conventional group. Student′s t test or rank-sum test was used to compare the differences between two groups for quantitative data, Fisher′s exact probability method was used to compare the differences of proportions between two groups, and Log-rank test was used to compare survival differences between two groups. Results:The 1-year recurrence rate in the neoadjuvant group was 42.9%,and the 1-year recurrence rate in the conventional group was 64.0%,with a statistically significant difference between the two groups(χ2=3.850, P=0.050);The 1-year survival rate in the neoadjuvant group was 100% and that in the conventional group was 74.2%,with a statistically significant difference between the two groups(χ2=5.170, P=0.023). According to the stratified analysis of the number of tumors,for single tumor,the 1-year recurrence rate in the neoadjuvant group was 25.0%,and that in the conventional surgery group was 71.0%,and the difference between the two groups was statistically significant(χ2=5.280, P=0.022). For multiple tumors, the 1-year recurrence rate in the neoadjuvant group was 66.7%,and the 1-year recurrence rate in the conventional surgery group was 58.9%,with no significant difference between the two groups(χ2=0.110, P=0.736). The operative time,intraoperative blood loss,and postoperative hospital stay in the neoadjuvant group were similar to those in the conventional group,and their differences were not statistically significant. Conclusions:Immune checkpoint inhibitors combined with anti-angiogenic targeted drugs as a neoadjuvant therapy for resectable hepatocellular carcinoma can reduce the 1-year recurrence rate and improve the 1-year survival rate,especially for those with solitary tumor. Limited by the sample size of the neoadjuvant group,the safety of immune combined targeted therapy before surgery cannot be observed more comprehensively,and further studies will be explored.