Objective:To explore the potential of the novel fibroblast activation protein (FAP)-targeted theranostic agent 68Ga/ 177Lu-1, 4, 7, 10-tetraazacyclododecane-1, 4, 7, 10-tetraacetic acid (DOTA)-2P (FAP inhibitor (FAPI)) 2 in microsatellite stable (MSS) colorectal cancer, and to evaluate the efficacy and underlying mechanism of 177Lu-DOTA-2P(FAPI) 2 in combination with immune checkpoint inhibitors (ICIs). Methods:This study was a randomized, parallel-group design. DOTA-2P(FAPI) 2 was labeled with 68Ga or 177Lu respectively. The binding performance of DOTA-2P(FAPI) 2 to FAP was validated through in vitro cell experiments. FAP-positive CT26-FAP tumor-bearing mouse model was constructed, and microPET imaging and biodistribution were performed. The in vivo antitumor efficacy was assessed for the 177Lu-DOTA-2P(FAPI) 2 monotherapy, α programmed death-ligand 1 (PD-L1) monotherapy, and the combination of 177Lu-DOTA-2P(FAPI) 2 with αPD-L1 therapy groups. Changes in the tumor microenvironment were analyzed using single-cell RNA sequencing to elucidate the mechanism of the combined treatment. Independent-sample t test was used to analyze data. Survival analysis was performed using the log-rank test. Results:The labeling yields of 68Ga/ 177Lu-DOTA-2P(FAPI) 2 were both >90%, with the radiochemical purities both >95%. In vitro cellular uptake and blocking assays showed that FAPI-46 significantly inhibited the binding of 68Ga-DOTA-2P(FAPI) 2 to FAP in CT26-FAP cells, with the cellular uptake values at 60min of (51.5±0.8)% and (1.0±0.3)%, respectively ( t=102.40, P<0.001). MicroPET imaging showed that the tumor uptake of 68Ga-DOTA-2P(FAPI) 2 remained stable even at 4 h post-injection, with a significantly higher uptake value compared to 68Ga-FAPI-46 ((7.3±1.6) vs (3.7±0.2) percentage activity of injection dose per gram of tissue (%ID/g); t=3.87, P=0.018). The biodistribution results indicated significant tumor uptake of 177Lu-DOTA-2P(FAPI) 2 even at 24 h post-injection ((4.30±0.52)%ID/g). The combination of 177Lu-DOTA-2P(FAPI) 2 and αPD-L1 achieved the 30-day survival rate of 100%, which was significantly superior to that of the control group (saline injection; χ2=9.53, P=0.002). Further mechanistic studies revealed that the combination therapy reprogramed the tumor microenvironment, enhanced anti-tumor intercellular communication, and activated signaling pathways such as Fas-FasL between T cells/natural killer (NK) cells and tumor cells, thereby synergistically inhibiting tumor progression. Conclusions:68Ga/ 177Lu-DOTA-2P(FAPI) 2 exhibits theranostic potential for MSS colorectal cancer. The combination of 177Lu-DOTA-2P(FAPI) 2 with ICIs may significantly prolong survival, demonstrating significant potential for clinical translation.

Objective:To evaluate the feasibility of the novel programmed death-ligand 1 (PD-L1)-targeted PET/CT molecular probe for evaluating PD-L1 expression and tumor heterogeneity in patients with non-small cell lung cancer (NSCLC).Methods:From October 2023 to October 2024, 30 patients (21 males, 9 females; age 69(58, 75) years) with newly diagnosed NSCLC at the First Affiliated Hospital of Xiamen University were prospectively enrolled. All patients underwent PET/CT imaging 1 h after intravenous administration of 68Ga-1, 4, 7-triazacyclononane-1, 4, 7-triacetic acid (NOTA)-DK224, and SUV max was calculated. Immunohistochemical staining on biopsy samples of patients were performed and the PD-L1 tumor proportion score (TPS) was calculated. The differences of SUV max between two groups were compared by using Mann-Whitney U test. Results:Of 30 patients, 31 biopsy specimens were obtained including 24 primary lesion biopsies, 1 lymph node lesion biopsy, and 6 metastatic lesion biopsies, with 16 TPS<1%, 9 1%≤TPS<50% and 6 TPS≥50%. PD-L1-positive tumors showed relatively high uptake of 68Ga-NOTA-DK224. The SUV max of TPS≥1% group was significantly higher than that of TPS<1% group (6.9(5.1, 7.7) vs 3.8(3.1, 4.2); Z=-4.47, P<0.001), and SUV max of TPS≥50% group was significantly higher than that of TPS<50% group (8.6(7.3, 12.4) vs 4.2(3.7, 5.3); Z=-3.65, P<0.001). Of 30 patients, 24 had multiple metastatic lesions with 212 lesions in total. The median fold difference was 2.3 (range: 1.4-6.0), and the median CV was 28.3% (range: 11.7%-61.6%). Conclusion:68Ga-NOTA-DK224 PET/CT is able to accurately and comprehensively reflect PD-L1 expression and tumor heterogeneity in primary and metastatic NSCLC.

Objective:To evaluate the feasibility of the novel programmed death-ligand 1 (PD-L1)-targeted PET/CT molecular probe for evaluating PD-L1 expression and tumor heterogeneity in patients with non-small cell lung cancer (NSCLC).Methods:From October 2023 to October 2024, 30 patients (21 males, 9 females; age 69(58, 75) years) with newly diagnosed NSCLC at the First Affiliated Hospital of Xiamen University were prospectively enrolled. All patients underwent PET/CT imaging 1 h after intravenous administration of 68Ga-1, 4, 7-triazacyclononane-1, 4, 7-triacetic acid (NOTA)-DK224, and SUV max was calculated. Immunohistochemical staining on biopsy samples of patients were performed and the PD-L1 tumor proportion score (TPS) was calculated. The differences of SUV max between two groups were compared by using Mann-Whitney U test. Results:Of 30 patients, 31 biopsy specimens were obtained including 24 primary lesion biopsies, 1 lymph node lesion biopsy, and 6 metastatic lesion biopsies, with 16 TPS<1%, 9 1%≤TPS<50% and 6 TPS≥50%. PD-L1-positive tumors showed relatively high uptake of 68Ga-NOTA-DK224. The SUV max of TPS≥1% group was significantly higher than that of TPS<1% group (6.9(5.1, 7.7) vs 3.8(3.1, 4.2); Z=-4.47, P<0.001), and SUV max of TPS≥50% group was significantly higher than that of TPS<50% group (8.6(7.3, 12.4) vs 4.2(3.7, 5.3); Z=-3.65, P<0.001). Of 30 patients, 24 had multiple metastatic lesions with 212 lesions in total. The median fold difference was 2.3 (range: 1.4-6.0), and the median CV was 28.3% (range: 11.7%-61.6%). Conclusion:68Ga-NOTA-DK224 PET/CT is able to accurately and comprehensively reflect PD-L1 expression and tumor heterogeneity in primary and metastatic NSCLC.

Objective:To explore the potential of the novel fibroblast activation protein (FAP)-targeted theranostic agent 68Ga/ 177Lu-1, 4, 7, 10-tetraazacyclododecane-1, 4, 7, 10-tetraacetic acid (DOTA)-2P (FAP inhibitor (FAPI)) 2 in microsatellite stable (MSS) colorectal cancer, and to evaluate the efficacy and underlying mechanism of 177Lu-DOTA-2P(FAPI) 2 in combination with immune checkpoint inhibitors (ICIs). Methods:This study was a randomized, parallel-group design. DOTA-2P(FAPI) 2 was labeled with 68Ga or 177Lu respectively. The binding performance of DOTA-2P(FAPI) 2 to FAP was validated through in vitro cell experiments. FAP-positive CT26-FAP tumor-bearing mouse model was constructed, and microPET imaging and biodistribution were performed. The in vivo antitumor efficacy was assessed for the 177Lu-DOTA-2P(FAPI) 2 monotherapy, α programmed death-ligand 1 (PD-L1) monotherapy, and the combination of 177Lu-DOTA-2P(FAPI) 2 with αPD-L1 therapy groups. Changes in the tumor microenvironment were analyzed using single-cell RNA sequencing to elucidate the mechanism of the combined treatment. Independent-sample t test was used to analyze data. Survival analysis was performed using the log-rank test. Results:The labeling yields of 68Ga/ 177Lu-DOTA-2P(FAPI) 2 were both >90%, with the radiochemical purities both >95%. In vitro cellular uptake and blocking assays showed that FAPI-46 significantly inhibited the binding of 68Ga-DOTA-2P(FAPI) 2 to FAP in CT26-FAP cells, with the cellular uptake values at 60min of (51.5±0.8)% and (1.0±0.3)%, respectively ( t=102.40, P<0.001). MicroPET imaging showed that the tumor uptake of 68Ga-DOTA-2P(FAPI) 2 remained stable even at 4 h post-injection, with a significantly higher uptake value compared to 68Ga-FAPI-46 ((7.3±1.6) vs (3.7±0.2) percentage activity of injection dose per gram of tissue (%ID/g); t=3.87, P=0.018). The biodistribution results indicated significant tumor uptake of 177Lu-DOTA-2P(FAPI) 2 even at 24 h post-injection ((4.30±0.52)%ID/g). The combination of 177Lu-DOTA-2P(FAPI) 2 and αPD-L1 achieved the 30-day survival rate of 100%, which was significantly superior to that of the control group (saline injection; χ2=9.53, P=0.002). Further mechanistic studies revealed that the combination therapy reprogramed the tumor microenvironment, enhanced anti-tumor intercellular communication, and activated signaling pathways such as Fas-FasL between T cells/natural killer (NK) cells and tumor cells, thereby synergistically inhibiting tumor progression. Conclusions:68Ga/ 177Lu-DOTA-2P(FAPI) 2 exhibits theranostic potential for MSS colorectal cancer. The combination of 177Lu-DOTA-2P(FAPI) 2 with ICIs may significantly prolong survival, demonstrating significant potential for clinical translation.

Objective To investigate the clinical efficacy and value of interventional treatment of iatrogenic massive vaginal bleed-ing.Methods Retrospective analysis was performed on 35 patients with postoperative vaginal massive hemorrhage in obstetrics and gynecology who were admitted.Abdominal aorta and bilateral internal iliac arteries angiography and embolization of abnormal vessels were performed under digital subtraction angiography(DS A),and relevant clinical data were recorded and analyzed.Results After interventional treatment,the vaginal bleeding of 33 patients basically stopped within 3 days,and the average interventional operation time was(57.5±17.2)min.The hemoglobin value,hematocrit and blood pressure decreased and the heart rate increased significantly before and after interventional embolization in obstetrics and gynecology,with statistical significance(P＜0.05).There were no sig-nificant changes in hemoglobin value and hematocrit between the completion of interventional embolization and 72 hours after interventional embolization(P＞0.05).The increase of blood pressure and the decrease of heart rate were statistically significant(P＜0.05).Two patients with cesarean section had poor hemostatic effect after interventional embolization,and the bleeding stopped after exploratory laparotomy and hysterectomy.Conclusion Interventional treatment has the advantages of small trauma,simple operation,signifi-cant curative effect,few adverse reactions,and rapid recovery.It plays an important role and clinical value in the diagnosis and treat-ment of iatrogenic vaginal bleeding.

Objective To explore the clinical results after arthroscopy-assisted anatomic coracoclavicu-lar ligament reconstruction(AA-ACCR)using tendon allograft for acute high-grade acromioclavicular joint dislocations.Methods Patients undergoing primary AA-ACCR with tendon allograft for Rockwood type Ⅲ/Ⅴ acromioclavicular joint dislocations between January 2015 and January 2017 were analyzed retrospectively.The coracoclavicular distance(CCD)was obtained on radiographs pre-and post-opera-tively,as well as 6 weeks after the operation and during the final follow-up,and complications were recorded.Moreover,before the operation and during the final follow-up,all patients were evaluated shoulder pain and function using the American Shoulder and Elbow Surgeon score(ASES)and Visual Analogue Scale(VAS).Results In total,21 patients were included for evaluation with a minimum of 6-month follow-up(range,6-18 months).According to preoperative X ray,8 and 13 patients suffered from Rockwood type Ⅲ and V acromioclavicular dislocation,respectively.CCD decreased significantly six weeks postoperatively(8.6±2.6 mm)and at the final follow-up(11.7±3.5 mm)compared with the preoperative value(19.7±4.5 mm,P＜0.01).However,CCD at the latter time points was signifi-cantly higher than right after the operation(7.9±2.5 mm,P＜0.01).Furthermore,CCD increased sig-nificantly at the final follow-up compared with six weeks postoperatively(P＜0.01).At the final follow-up,significant improvement was observed in the average VAS and ASES scores(P＜0.01).Moreover,at the final follow-up,10 out of 21 patients(48％)experienced a loss of reduction,including 3 fail-ures in operation and 7 in later restoration.All patients had both medial and lateral clavicular tunnel widening.However,no fracture of the coracoid/clavicle or other complications were recorded.Conclu-sion AA-ACCR with tendon allograft for acute high-grade acromioclavicular joint dislocations contrib-utes to significant improvement in clinical and radiographic outcomes in the early follow-up.Although the loss of reduction rate is relatively high(48％),it is a safe method without obvious complications.

Objective To explore the clinical results after arthroscopy-assisted anatomic coracoclavicu-lar ligament reconstruction(AA-ACCR)using tendon allograft for acute high-grade acromioclavicular joint dislocations.Methods Patients undergoing primary AA-ACCR with tendon allograft for Rockwood type Ⅲ/Ⅴ acromioclavicular joint dislocations between January 2015 and January 2017 were analyzed retrospectively.The coracoclavicular distance(CCD)was obtained on radiographs pre-and post-opera-tively,as well as 6 weeks after the operation and during the final follow-up,and complications were recorded.Moreover,before the operation and during the final follow-up,all patients were evaluated shoulder pain and function using the American Shoulder and Elbow Surgeon score(ASES)and Visual Analogue Scale(VAS).Results In total,21 patients were included for evaluation with a minimum of 6-month follow-up(range,6-18 months).According to preoperative X ray,8 and 13 patients suffered from Rockwood type Ⅲ and V acromioclavicular dislocation,respectively.CCD decreased significantly six weeks postoperatively(8.6±2.6 mm)and at the final follow-up(11.7±3.5 mm)compared with the preoperative value(19.7±4.5 mm,P＜0.01).However,CCD at the latter time points was signifi-cantly higher than right after the operation(7.9±2.5 mm,P＜0.01).Furthermore,CCD increased sig-nificantly at the final follow-up compared with six weeks postoperatively(P＜0.01).At the final follow-up,significant improvement was observed in the average VAS and ASES scores(P＜0.01).Moreover,at the final follow-up,10 out of 21 patients(48％)experienced a loss of reduction,including 3 fail-ures in operation and 7 in later restoration.All patients had both medial and lateral clavicular tunnel widening.However,no fracture of the coracoid/clavicle or other complications were recorded.Conclu-sion AA-ACCR with tendon allograft for acute high-grade acromioclavicular joint dislocations contrib-utes to significant improvement in clinical and radiographic outcomes in the early follow-up.Although the loss of reduction rate is relatively high(48％),it is a safe method without obvious complications.

Multiple myeloma (MM) lesions are mostly localized in the marrow. Extramedullary disease in multiple myeloma (MM-EMD) is defined as malignant plasma cell infiltration away from the bone marrow or adjacent soft tissue, may occur at the initial diagnosis or during the consultation. MM-EMD may be found at initial diagnosis or during the treatment. MM-EMD has high invasiveness and poor prognosis, with clinical behavior distinct from marrow-restricted myeloma. However, its pathogenesis has not been elucidated. In general, the obstructed homing of myeloma cells, enhanced invasiveness, the degradation of extracellular matrix, and increased angiogenesis capacity may be involved in the occurrence of MM-EMD. Tumor genetic abnormalities and changes in the bone marrow microenvironment play important roles in the above pathogenesis.

Objective:To develop a tetramer probe targeting fibroblast activation protein (FAP), named 1, 4, 7, 10-tetraazacyclododecane-1, 4, 7, 10-tetraacetic acid (DOTA)-4P(FAP inhibitor (FAPI)) 4, evaluate its biodistribution and PET image in FAP-positive-tumor bearing nude mice, and explore its feasibility as a novel radio-regent for treatment of FAP-positive tumor. Methods:FAP tetramer probe was constructed on the FAPI-46 motif with four mini-polyethylene glycol (PEG)(PEG 3) spacers between the four FAPI motifs, denoted as 4P(FAPI) 4. DOTA was used as the chelator for radiolabeling with 68Ga and 177Lu. The FAP binding characteristics were test by in vitro cell competitive binding experiment. Small-animal PET, in vivo biodistribution, and radionuclide targeting therapy were performed in HT-1080-FAP tumor bearing nude mice ( n=39). Independent-sample t test was performed to analyze tumor uptake data, and two-factor repeated measures analysis of variance was utilized to compare tumor volume data in radioactive isotope therapy. Results:Cell experiment showed that FAPI-tetramer and FAPI-monomer had similar half maximal inhibitory concentration values (3.29 and 2.15 nmol/L). 68Ga/ 177Lu radiolabeled FAPI-tetramer had better tumor uptake and retention than FAPI-monomer in small-animal PET and in vivo biodistribution experiment, with the tumor uptake for 177Lu-DOTA-4P(FAPI) 4 and 177Lu-FAPI-46 at 48 h of (18.72±1.32) vs (2.72±1.20) percentage activity of injection dose per gram of tissue (%ID/g) ( t=15.55, P<0.001). 177Lu-DOTA-4P(FAPI) 4 group showed best anti-tumor efficacy compared with 177Lu-FAPI-46 and control group in radionuclide targeting therapy. On the 2nd day after the start of treatment, the tumor volume in the tetramer treatment group was significantly smaller than that in the control group (mean difference 67.19 mm 3, P=0.049); on the 14th day after the start of treatment, the tumor volume in the tetramer treatment group was significantly smaller than that in the monomer treatment group (mean difference 414.33 mm 3, P=0.005). Conclusion:FAPI-tetramer can improve tumor uptake and retention ability compared with FAPI-46, and 177Lu-DOTA-4P(FAPI) 4 can be a promising radio-agent for FAP-positive tumor therapy.

Objective:To analysis the relationship between symptomatic knee osteoarthritis and frailty in older Chinese adults.Methods:In this retrospective study, follow-up data between 2011 and 2015 from the China Health and Retirement Longitudinal Study(CHARLS)were analyzed.Participates over 60 years old were divided into a frailty group, a pre-frailty group, and a normal group, according to the frailty phenotype.Cross-sectional analysis was conducted to examine the relationship between frailty and symptomatic knee osteoarthritis, and the role of symptomatic knee osteoarthritis in the progression of frailty in normal elderly people was further analyzed using a retrospective cohort.Results:In 2011, 5.9% of the elderly were frail and 15.1% of the elderly suffered knee pain.Univariate and multivariate regression analysis indicated that knee pain was a risk factor for frailty( OR: 1.91, 95% CI: 1.37-2.61, P<0.01).After a 4 year-follow-up, 41.7% of the normal elderly participants progressed to the frail or pre-frail state.Multivariate regression analysis suggested that knee pain was a risk factor for normal elderly people to enter the frail or pre-frail state( OR: 1.57, 95% CI: 1.00-2.45, P<0.05). Conclusions:Knee pain is one of the important risk factors for the development of frailty in the elderly.Normal elderly people with knee pain are at an increased risk of frailty or pre-frailty in later years.