OBJECTIVE: To observe the effects of Tongdu Tiaoshen acupuncture (for unblocking the obstruction in the governor vessel and regulating the spirit) on depression-like behavior and the hippocampal Endophilin A1/reactive oxygen species (ROS) pathway in the chronic unpredictable mild stress (CUMS) model rats, and explore the mechanism of this therapy for depression. METHODS: Forty-eight male SD rats of SPF grade were randomly divided into a normal group (n=12) and a modeling group (n=36). In the modeling group, CUMS was performed to establish depression model. The successfully-modeled rats were randomized into a model group, a Tongdu Tiaoshen acupuncture group (referred to as the acupuncture group), and a fluoxetine group, with 12 rats in each group. In the acupuncture group, "Baihui" (GV20), "Shenting" (GV24), "Shuigou" (GV26) and "Dazhui" (GV14) were stimulated with acupuncture. This intervention measure was delivered once a day, continuously for 6 days; it was discontinued on day 7 and was completed in 28 days. In the fluoxetine group, intragastric administration was done with fluoxetine solution (2.1 mg/kg), once a day, and for 28 consecutive days. Before and after modeling, and after intervention completion, the body mass, sucrose preference rate and the total distance of movement and the boxes of horizontal crossing in the open field experiment were observed in each group. After intervention, using HE staining, the hippocampal neuron morphology was observed; using Nissl staining, the hippocampal Nissl body number was counted. The hippocampal mitochondria was observed under transmission electron microscopy. The average fluorescence intensity of ROS in hippocampal was determined using flow cytometry. With Western blot method, the protein expression of Endophilin A1, growth associated protein 43 (GAP-43), and brain-derived neurotrophic factor (BDNF) in hippocampal was detected; and with RT-qPCR method, the mRNA expression of Endophilin A1, GAP-43, and BDNF was recorded. Using the immunofluorescence, the average fluorescence intensity of Endophilin A1, GAP-43, and BDNF in hippocampal tissue was determined. RESULTS: Compared with the normal group, in the model group, the body mass, sucrose preference rate, and the total distance of movement and the boxes of horizontal crossing in the open field experiment decreased (P<0.01); the hippocampal neuronal structure was unclear, the matrix was relatively loose, and the number of Nissl body decreased (P<0.01); mitochondrial structure was disarranged, the outer membrane was ruptured, mitochondrial cristae was irregular or missed; the average fluorescence intensity of ROS in hippocampal tissue, the protein and mRNA expression and the average fluorescence intensity of Endophilin A1 in hippocampal tissue increased (P<0.01), while the protein and mRNA expression of GAP-43 and BDNF and its average fluorescence intensity decreased (P<0.01). Compared with the model group, the acupuncture group and the fluoxetine group showed the increase in body mass, sucrose preference rate, the total distance of movement and the boxes of horizontal crossing in the open field experiment (P<0.05, P<0.01); the hippocampal neuronal structure became relatively clear, the matrix was relatively dense, and the number of Nissl body was elevated (P<0.01); mitochondrial structure got normal and disarranged slightly, the average fluorescence intensity of ROS in hippocampal tissue, the protein and mRNA expression and the average fluorescence intensity of Endophilin A1 in hippocampal tissue were reduced (P<0.01), while the protein and mRNA expression of GAP-43 and BDNF and the average fluorescence intensity rose (P<0.01, P<0.05). Compared with the fluoxetine group, the acupuncture group presented the increase in the average fluorescence intensity of ROS, the protein expression and the average fluorescence intensity of Endophilin A1, the protein expression of GAP-43 and the mRNA expression of BDNF (P<0.01, P<0.05), and the decrease of the protein expression and the average fluorescence intensity of BDNF, the mRNA expression of Endophilin A1, and the average fluorescence intensity of GAP-43 (P<0.01, P<0.05). CONCLUSION Tongdu tiaoshen acupuncture alleviates depression-like behaviors in CUMS model rats and protects hippocampal neurons, which may be related to suppressing Endophilin A1/ROS signaling pathway and attenuating oxidative stress reactions.
Animals ; Male ; Hippocampus/metabolism* ; Acupuncture Therapy ; Rats, Sprague-Dawley ; Rats ; Depression/psychology* ; Humans ; Reactive Oxygen Species/metabolism* ; Disease Models, Animal ; Acupuncture Points

Objective Building a TCM health management and clinical research integration platform for knee osteoarthritis,promoting the integration of traditional Chinese medicine with internet and mobile health technology,driving the digitalization of TCM-enabled knee osteoarthritis health management strategies,and providing a convenient digital platform for the efficient conduct of TCM clinical research on knee osteoarthritis.Methods Using a combination of literature review and market research,a preliminary framework for the platform's functions and services was established.Then,17 patients with knee osteoarthritis were interviewed through a convenient sampling method to identify their needs and preferences,and design the platform's functional modules and service flow.In the development and testing phase,a multidisciplinary team consisting of professional development engineers,data scientists,and clinical experts conducted multiple rounds of discussions to ensure the scientificity,feasibility,and convenience of the platform's function and service development.Results The integrated platform of traditional Chinese medicine health management and clinical research for knee osteoarthritis is built.The traditional Chinese medicine health management module includes features of health education,evaluation and exercise training,etc.The scientific research module includes patient self-report outcome data collection and remote quality control,etc.,which can provide the whole process service integrating health management and remote intelligent clinical trial.Conclusion Building an integrated platform of TCM health management and clinical research will provide more convenient and effective health management solutions for patients with knee osteoarthritis.

Objective:To investigate the efficacy of laparoscopic versus open hepatectomy for intrahepatic bile duct stones based on propensity score matching. Methods:This study used a case-control design to retrospectively analyze 163 patients with intrahepatic bile duct stones who were treated at The Second Hospital of Anhui Medical University between February 2014 and February 2024. Based on the surgical approach, the patients were divided into two groups: the laparoscopic hepatectomy group ( n = 72) and the open hepatectomy group ( n = 91). Using 1:1 PSM, two groups with similar baseline clinical characteristics were created to compare perioperative outcomes, stone residual rates, and recurrence rates. Results:After PSM, a total of 52 matched pairs were successfully obtained. Compared with the laparoscopic hepatectomy group, the open hepatectomy group demonstrated a significantly shorter operative time [233.00 (180.00, 315.00) minutes vs. 313.00 (222.25, 405.75) minutes, Z = 3.41, P = 0.01]. However, no statistically significant differences were observed between the open hepatectomy and laparoscopic hepatectomy groups in terms of pre- to postoperative hemoglobin change [(22.69 ± 14.27) g/L vs. (20.63 ± 14.36) g/L, t = 0.73, P = 0.465], postoperative bile leakage [5.77% (3/52) vs. 11.54% (6/52), χ2 = 1.10, P = 0.25], hypoalbuminemia [82.69% (43/52) vs. 84.62% (44/52), χ2 = 0.07, P = 0.791], pulmonary infection [28.85% (15/52) vs. 40.38% (21/52), χ2 = 1.53, P = 0.216], surgical site infection [5.77% (3/52) vs. 1.92% (1/52), χ2 = 1.04, P = 0.308], intra-abdominal infection [1.92% (1/52) vs. 5.77% (3/52), χ2 = 1.04, P = 0.308], postoperative drainage tube removal time [8.00 (6.00, 11.75) days vs. 8.00 (6.25, 10.00) days, t = 0.05, P = 0.958], postoperative hospital stay [8.00 (9.00, 15.00) days vs. 9.00 (7.00, 12.50) days, t = -1.22, P = 0.222], residual stone rate [11.54% (6/52) vs. 9.62% (5/52), χ2 = 0.10, P = 0.750], and stone recurrence rate [13.46% (7/52) vs. 3.85% (2/52), χ2 = 3.04, P = 0.081]. All differences were statistically significant (all P > 0.05). Conclusions:Laparoscopic hepatectomy and open hepatectomy have comparable efficacy in the treatment of intrahepatic bile duct stones.

Objective Building a TCM health management and clinical research integration platform for knee osteoarthritis,promoting the integration of traditional Chinese medicine with internet and mobile health technology,driving the digitalization of TCM-enabled knee osteoarthritis health management strategies,and providing a convenient digital platform for the efficient conduct of TCM clinical research on knee osteoarthritis.Methods Using a combination of literature review and market research,a preliminary framework for the platform's functions and services was established.Then,17 patients with knee osteoarthritis were interviewed through a convenient sampling method to identify their needs and preferences,and design the platform's functional modules and service flow.In the development and testing phase,a multidisciplinary team consisting of professional development engineers,data scientists,and clinical experts conducted multiple rounds of discussions to ensure the scientificity,feasibility,and convenience of the platform's function and service development.Results The integrated platform of traditional Chinese medicine health management and clinical research for knee osteoarthritis is built.The traditional Chinese medicine health management module includes features of health education,evaluation and exercise training,etc.The scientific research module includes patient self-report outcome data collection and remote quality control,etc.,which can provide the whole process service integrating health management and remote intelligent clinical trial.Conclusion Building an integrated platform of TCM health management and clinical research will provide more convenient and effective health management solutions for patients with knee osteoarthritis.

Objective:To investigate the efficacy of laparoscopic versus open hepatectomy for intrahepatic bile duct stones based on propensity score matching. Methods:This study used a case-control design to retrospectively analyze 163 patients with intrahepatic bile duct stones who were treated at The Second Hospital of Anhui Medical University between February 2014 and February 2024. Based on the surgical approach, the patients were divided into two groups: the laparoscopic hepatectomy group ( n = 72) and the open hepatectomy group ( n = 91). Using 1:1 PSM, two groups with similar baseline clinical characteristics were created to compare perioperative outcomes, stone residual rates, and recurrence rates. Results:After PSM, a total of 52 matched pairs were successfully obtained. Compared with the laparoscopic hepatectomy group, the open hepatectomy group demonstrated a significantly shorter operative time [233.00 (180.00, 315.00) minutes vs. 313.00 (222.25, 405.75) minutes, Z = 3.41, P = 0.01]. However, no statistically significant differences were observed between the open hepatectomy and laparoscopic hepatectomy groups in terms of pre- to postoperative hemoglobin change [(22.69 ± 14.27) g/L vs. (20.63 ± 14.36) g/L, t = 0.73, P = 0.465], postoperative bile leakage [5.77% (3/52) vs. 11.54% (6/52), χ2 = 1.10, P = 0.25], hypoalbuminemia [82.69% (43/52) vs. 84.62% (44/52), χ2 = 0.07, P = 0.791], pulmonary infection [28.85% (15/52) vs. 40.38% (21/52), χ2 = 1.53, P = 0.216], surgical site infection [5.77% (3/52) vs. 1.92% (1/52), χ2 = 1.04, P = 0.308], intra-abdominal infection [1.92% (1/52) vs. 5.77% (3/52), χ2 = 1.04, P = 0.308], postoperative drainage tube removal time [8.00 (6.00, 11.75) days vs. 8.00 (6.25, 10.00) days, t = 0.05, P = 0.958], postoperative hospital stay [8.00 (9.00, 15.00) days vs. 9.00 (7.00, 12.50) days, t = -1.22, P = 0.222], residual stone rate [11.54% (6/52) vs. 9.62% (5/52), χ2 = 0.10, P = 0.750], and stone recurrence rate [13.46% (7/52) vs. 3.85% (2/52), χ2 = 3.04, P = 0.081]. All differences were statistically significant (all P > 0.05). Conclusions:Laparoscopic hepatectomy and open hepatectomy have comparable efficacy in the treatment of intrahepatic bile duct stones.

Objective:To investigate the prognosis and the factors that influence it in patients with non-gastric gastrointestinal stromal tumors (GISTs) who are at low risk of recurrence.Methods:This was a retrospective cohort study. Clinicopathologic and prognostic data from patients with non-gastric GISTs and at low risk of recurrence (i.e., very low-risk or low-risk according to the 2008 version of the Modified NIH Risk Classification), who attended 18 medical centers in China between January 2000 and June 2023, were collected. We excluded patients with a history of prior malignancy, concurrent primary malignancy, multiple GISTs, and those who had received preoperative imatinib. The study cohort comprised 1,571 patients with GISTs, 370 (23.6%) of whom were at very low-risk and 1,201 (76.4%) at low-risk of recurrence. The cohort included 799 (50.9%) men and 772 (49.1%) women of median age 57 (16–93) years. Patients were followed up to July 2024. The prognosis and its influencing factors were analyzed. Receiver operating characteristic curves for tumor diameter and Ki67 were established, and the sensitivity, specificity, area under the curve (AUC) and optimal cut-off value with 95% confidence intervals were calculated. Propensity score matching was implemented using the 1:1 nearest neighbor matching method with a matching tolerance of 0.02.Results:With a median follow-up of 63 (12–267) months, the 5- and 10-year overall survival (OS) rates of the 1,571 patients were 99.5% and 98.0%, respectively, and the 5- and 10-year disease-free survival (DFS) rates were 96.3% and 94.4%, respectively. During postoperative follow-up, 3.8% (60/1,571) patients had disease recurrence or metastasis, comprising 0.8% (3/370) in the very low-risk group and 4.7% (57/1,201) in the low-risk group. In the low-risk group, recurrence or metastasis occurred in 5.5% (25/457) of patients with duodenal GISTs, 3.9% (25/645) of those with small intestinal GISTs, 9.2% (6/65) of those with rectal GISTs, and 10.0% (1/10) of those with colonic GISTs. Among the 60 patients with metastases, 56.7% (34/60) of the metastases were located in the abdominal cavity, 53.3% (32/60) in the liver, and 3.3% (2/60) in bone. During the follow-up period, 13 patients (0.8%) died of disease. Receiver operating characteristic curves were plotted for tumor diameter and Ki67 and assessed using the Jordon index. This showed that the difference in DFS between the two groups was statistically significant when the cutoff value for tumor diameter was 3.5 cm (AUC 0.731, 95% CI: 0.670–0.793, sensitivity 77.7%, specificity 64.1%). Furthermore, the difference in DFS between the two groups was statistically significant when the cutoff value for Ki67 was 5% (AUC 0.693, 95% CI: 0.624–0.762, sensitivity 60.7%, specificity 65.3%). Multifactorial analysis revealed that tumor diameter ≥3.5 cm, Ki67 ≥5%, and R1 resection were independent risk factors for DFS in patients with non-gastric GISTs at low risk of recurrence (all P<0.05). Furthermore, age >57 years, Ki67 ≥5%, and R1 resection were also independent risk factors for OS in patients with non-gastric GISTs at low risk of recurrence (all P<0.05). We also grouped the patients according to whether they had received postoperative adjuvant treatment with imatinib for 1 or 3 years. This yielded 137 patients in the less than 1-year group, 139 in the 1-year plus group; and 44 in both the less than 3 years and 3-years plus group. After propensity score matching for age, tumor diameter, Ki67, and resection status, the differences in survival between the two groups were not statistically significant (all P>0.05). The 10-year DFS and OS were 87.5% and 95.5%, respectively, in the group treated with imatinib for less than 1 year and 88.5% and 97.8%, respectively, in the group treated for more than 1 year. The 10-year DFS and OS were 89.6% and 92.6%, respectively, in the group treated with imatinib for less than 3 years and 88.0% and 100.0%, respectively, in the group treated with imatinib for more than 3 years. Conclusion:The overall prognosis of primary, non-gastric, low recurrence risk GISTs is relatively favorable; however, recurrences and metastases do occur. Age, tumor diameter, Ki67, and R1 resection may affect the prognosis. For some patients with low risk GISTs, administration of adjuvant therapy with imatinib for an appropriate duration may help prevent recurrence and improve survival.

Objective:To investigate the prognosis and safety of ripretinib in the treatment of patients with advanced gastrointestinal mesenchymal stromal tumors (GISTs) and to analyze the relationship between blood concentrations of this drug and prognosis.Methods:In this retrospective study, we investigated the effects of ripretinib in patients with advanced GISTs. The inclusion criteria comprised: (1) daily oral administration of ripretinib scheduled; and (2) uninterrupted treatment for at least 1month, with a stable and relatively fixed daily dosage maintained for a minimum of 2 weeks. Exclusion criteria comprised concurrent use of other tyrosine kinase inhibitors and presence of significant organ dysfunction. We retrospectively identified 79 patients with advanced GISTs who had received ripretinib across seven medical centers, namely Jiangsu Provincial Hospital, Jiangsu Cancer Hospital, Nanjing Drum Tower Hospital Affiliated to Nanjing University, Sir Run Run Shaw Hospital of Zhejiang University, Renji Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, and the General Hospital of the People's Liberation Army, from 1 June 2021 to 31 March 2024. The cohort included 48 men and 31 women, 19 of whom had received ripretinib as second-line, 13 as third-line, and 47 as fourth-line therapy. Two peripheral venous blood samples were obtained from each participant and high-performance liquid chromatography-tandem mass spectrometry used to determine peak (Cmax) and trough (Cmin) concentrations of ripretinib. Machine learning methodologies, specifically the K-nearest neighbor algorithm combined with the Gridsearch CV strategy, were employed to establish the threshold for Cmin. We analyzed adverse reactions, treatment efficacy, median progression-free survival (mPFS), and the relationship between drug blood concentration and selected clinical parameters.Results:In the entire cohort, the Cmin and Cmax of ripretinib were 467 ± 360 μg/L and 986 ± 493 μg/L, respectively. Notably, female patients and individuals in the high-dose group exhibited significantly higher values for both Cmin and Cmax (both P<0.05). However, variations in drug concentrations associated with the line of ripretinib therapy, treatment efficacy, disease progression, and presence of selected specific genetic mutations were not significantly associated with values of Cmin and Cmax ( P>0.05). Among the 79 patients with advanced GISTs receiving ripretinib, reported adverse reactions included alopecia (53, 67.09%), hand–foot syndrome (24, 30.38%), fatigue (22, 27.85%), and myalgia (21, 26.58%). Two patients (2.53%) had grade III complications, both classified as hand–foot syndrome. The correlation between Cmax and adverse reactions was not statistically significant ( P > 0.05). By the time of the latest follow-up, five deaths (6.3%) had occurred within the cohort. The mPFS for the group was 16.3 months, with a mPFS of 14.4 months for those receiving standard dosage and 7.0 months for those receiving escalating dosage. Among the 65 patients treated with standard doses of ripretinib, those with Cmin exceeding a threshold of 450 μg/L exhibited a significantly longer mPFS (18.0 months vs.13.7 months; P < 0.05). Conclusion:In China, patients with advanced GISTs exhibit a notable tolerance to ripretinib, with no evidence for a correlation between adverse reactions and Cmax for the drug. Additionally, a Cmin exceeding 450 μg/L may be associated with an extended mPFS.

Objective:To investigate the prognosis and the factors that influence it in patients with non-gastric gastrointestinal stromal tumors (GISTs) who are at low risk of recurrence.Methods:This was a retrospective cohort study. Clinicopathologic and prognostic data from patients with non-gastric GISTs and at low risk of recurrence (i.e., very low-risk or low-risk according to the 2008 version of the Modified NIH Risk Classification), who attended 18 medical centers in China between January 2000 and June 2023, were collected. We excluded patients with a history of prior malignancy, concurrent primary malignancy, multiple GISTs, and those who had received preoperative imatinib. The study cohort comprised 1,571 patients with GISTs, 370 (23.6%) of whom were at very low-risk and 1,201 (76.4%) at low-risk of recurrence. The cohort included 799 (50.9%) men and 772 (49.1%) women of median age 57 (16–93) years. Patients were followed up to July 2024. The prognosis and its influencing factors were analyzed. Receiver operating characteristic curves for tumor diameter and Ki67 were established, and the sensitivity, specificity, area under the curve (AUC) and optimal cut-off value with 95% confidence intervals were calculated. Propensity score matching was implemented using the 1:1 nearest neighbor matching method with a matching tolerance of 0.02.Results:With a median follow-up of 63 (12–267) months, the 5- and 10-year overall survival (OS) rates of the 1,571 patients were 99.5% and 98.0%, respectively, and the 5- and 10-year disease-free survival (DFS) rates were 96.3% and 94.4%, respectively. During postoperative follow-up, 3.8% (60/1,571) patients had disease recurrence or metastasis, comprising 0.8% (3/370) in the very low-risk group and 4.7% (57/1,201) in the low-risk group. In the low-risk group, recurrence or metastasis occurred in 5.5% (25/457) of patients with duodenal GISTs, 3.9% (25/645) of those with small intestinal GISTs, 9.2% (6/65) of those with rectal GISTs, and 10.0% (1/10) of those with colonic GISTs. Among the 60 patients with metastases, 56.7% (34/60) of the metastases were located in the abdominal cavity, 53.3% (32/60) in the liver, and 3.3% (2/60) in bone. During the follow-up period, 13 patients (0.8%) died of disease. Receiver operating characteristic curves were plotted for tumor diameter and Ki67 and assessed using the Jordon index. This showed that the difference in DFS between the two groups was statistically significant when the cutoff value for tumor diameter was 3.5 cm (AUC 0.731, 95% CI: 0.670–0.793, sensitivity 77.7%, specificity 64.1%). Furthermore, the difference in DFS between the two groups was statistically significant when the cutoff value for Ki67 was 5% (AUC 0.693, 95% CI: 0.624–0.762, sensitivity 60.7%, specificity 65.3%). Multifactorial analysis revealed that tumor diameter ≥3.5 cm, Ki67 ≥5%, and R1 resection were independent risk factors for DFS in patients with non-gastric GISTs at low risk of recurrence (all P<0.05). Furthermore, age >57 years, Ki67 ≥5%, and R1 resection were also independent risk factors for OS in patients with non-gastric GISTs at low risk of recurrence (all P<0.05). We also grouped the patients according to whether they had received postoperative adjuvant treatment with imatinib for 1 or 3 years. This yielded 137 patients in the less than 1-year group, 139 in the 1-year plus group; and 44 in both the less than 3 years and 3-years plus group. After propensity score matching for age, tumor diameter, Ki67, and resection status, the differences in survival between the two groups were not statistically significant (all P>0.05). The 10-year DFS and OS were 87.5% and 95.5%, respectively, in the group treated with imatinib for less than 1 year and 88.5% and 97.8%, respectively, in the group treated for more than 1 year. The 10-year DFS and OS were 89.6% and 92.6%, respectively, in the group treated with imatinib for less than 3 years and 88.0% and 100.0%, respectively, in the group treated with imatinib for more than 3 years. Conclusion:The overall prognosis of primary, non-gastric, low recurrence risk GISTs is relatively favorable; however, recurrences and metastases do occur. Age, tumor diameter, Ki67, and R1 resection may affect the prognosis. For some patients with low risk GISTs, administration of adjuvant therapy with imatinib for an appropriate duration may help prevent recurrence and improve survival.

Objective:To investigate the prognosis and safety of ripretinib in the treatment of patients with advanced gastrointestinal mesenchymal stromal tumors (GISTs) and to analyze the relationship between blood concentrations of this drug and prognosis.Methods:In this retrospective study, we investigated the effects of ripretinib in patients with advanced GISTs. The inclusion criteria comprised: (1) daily oral administration of ripretinib scheduled; and (2) uninterrupted treatment for at least 1month, with a stable and relatively fixed daily dosage maintained for a minimum of 2 weeks. Exclusion criteria comprised concurrent use of other tyrosine kinase inhibitors and presence of significant organ dysfunction. We retrospectively identified 79 patients with advanced GISTs who had received ripretinib across seven medical centers, namely Jiangsu Provincial Hospital, Jiangsu Cancer Hospital, Nanjing Drum Tower Hospital Affiliated to Nanjing University, Sir Run Run Shaw Hospital of Zhejiang University, Renji Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, and the General Hospital of the People's Liberation Army, from 1 June 2021 to 31 March 2024. The cohort included 48 men and 31 women, 19 of whom had received ripretinib as second-line, 13 as third-line, and 47 as fourth-line therapy. Two peripheral venous blood samples were obtained from each participant and high-performance liquid chromatography-tandem mass spectrometry used to determine peak (Cmax) and trough (Cmin) concentrations of ripretinib. Machine learning methodologies, specifically the K-nearest neighbor algorithm combined with the Gridsearch CV strategy, were employed to establish the threshold for Cmin. We analyzed adverse reactions, treatment efficacy, median progression-free survival (mPFS), and the relationship between drug blood concentration and selected clinical parameters.Results:In the entire cohort, the Cmin and Cmax of ripretinib were 467 ± 360 μg/L and 986 ± 493 μg/L, respectively. Notably, female patients and individuals in the high-dose group exhibited significantly higher values for both Cmin and Cmax (both P<0.05). However, variations in drug concentrations associated with the line of ripretinib therapy, treatment efficacy, disease progression, and presence of selected specific genetic mutations were not significantly associated with values of Cmin and Cmax ( P>0.05). Among the 79 patients with advanced GISTs receiving ripretinib, reported adverse reactions included alopecia (53, 67.09%), hand–foot syndrome (24, 30.38%), fatigue (22, 27.85%), and myalgia (21, 26.58%). Two patients (2.53%) had grade III complications, both classified as hand–foot syndrome. The correlation between Cmax and adverse reactions was not statistically significant ( P > 0.05). By the time of the latest follow-up, five deaths (6.3%) had occurred within the cohort. The mPFS for the group was 16.3 months, with a mPFS of 14.4 months for those receiving standard dosage and 7.0 months for those receiving escalating dosage. Among the 65 patients treated with standard doses of ripretinib, those with Cmin exceeding a threshold of 450 μg/L exhibited a significantly longer mPFS (18.0 months vs.13.7 months; P < 0.05). Conclusion:In China, patients with advanced GISTs exhibit a notable tolerance to ripretinib, with no evidence for a correlation between adverse reactions and Cmax for the drug. Additionally, a Cmin exceeding 450 μg/L may be associated with an extended mPFS.

Objective:To evaluate the relationship between preoperative estimated glomerular filtration rate (eGFR) and postoperative delirium (POD) in the patients.Methods:Six hundred and twenty-five patients, aged ≥60 yr, of American Society of Anesthesiologists Physical Status classification Ⅰ-Ⅱ, scheduled for elective total knee and hip arthroplasty under combined spinal-epidural anesthesia, were included. Peripheral blood samples were collected before surgery, and serum creatinine levels were measured by the sarcosine oxidase method, and eGFR was calculated using the MDRD equation. After successful spinal-epidural puncture, cerebrospinal fluid 2 ml was collected for determination of β-amyloid 42 (Aβ42), total tau protein (T-tau) and phosphorylated tau protein (P-tau) by enzyme-linked immunosorbent assay. The patients were divided into POD group and non-POD group (NPOD group) according to the occurrence of POD. The logistic regression analysis was used to identify the risk factors for POD, and the mediating effect of CSF biomarkers was analyzed. The receiver operating characteristic (ROC) curve was drawn to evaluate the accuracy of eGFR and biomarkers in predicting POD.Results:A total of 514 patients were finally enrolled in this study, and the incidence of POD was 16.7%. The logistic regression analysis showed that decreased eGFR and increased levels of P-tau and T-tau in CSF were risk factors for POD, while increased CSF Aβ42 level, Aβ42/P-tau ratio and Aβ42/T-tau ratio were protective factors for POD after adjusting for multiple confounding variables ( P<0.05). Analysis of mediating effet: The direct effect of eGFR on POD was -0.0 005 267, the total effect was 0.0 046 446, T-tau had a partly mediating role and the mediating effect accounted for 11.3% of the total effect. The area under the ROC curve of eGFR and CSF biomarker in predicting POD was 0.812( P<0.001). Conclusions:Preoperative decrease in eGFR is a risk factor for POD, and T-tau in CSF serves as a key mediator in the relationship between eGFR and POD.