BACKGROUND:Rheumatoid arthritis is an inflammatory disease.Many studies have shown that wogonin has a good anti-inflammatory effect on rheumatoid arthritis,but its exact efficacy and specific mechanism of action remain to be clarified. OBJECTIVE:To investigate the mechanism of wogonin ameliorating joint inflammation by regulating endoplasmic reticulum stress pathway in rats with collagen-induced arthritis. METHODS:(1)At the animal level:Female Wistar rats were divided into healthy control group,arthritis model group and wogonin treatment group.Rat models of arthritis in the latter two groups were established by subcutaneous injection of bovine type Ⅱ collagen and adjuvant.In the wogonin group,wogonin was given by gavage for 28 consecutive days after modeling.During this period,the rats in each group were weighed,and arthritis score and ankle swelling were measured every 7 days.After the experiment,the pathological changes of the joint were observed,the mRNA and protein levels of endoplasmic reticulum stress pathway GRP78 and CHOP were detected by qRT-PCR,western blot,and immunohistochemistry.(2)At the cellular level,cell counting kit-8 was used to detect the cytotoxic effect of wogonin on fibroblast-like synoviocytes from rats with collagen-induced arthritis.The fibroblast-like synoviocytes induced by thapsigargin were treated with different concentrations of wogonin.The levels of interleukin-1β and tumor necrosis factor-α in the cell supernatant were detected by ELISA,and the intracellular reactive oxygen species in each group were determined by DCFH-DA probe method.The mRNA and protein levels of GRP78,IRE1α,XBP1s and CHOP were detected by qRT-PCR and western blot,respectively. RESULTS AND CONCLUSION:Compared with the healthy control group,arthritis index score and ankle swelling degree in the arthritis model group were increased(P<0.01),synovial hyperplasia,inflammatory cell infiltration,cartilage destruction and bone erosion were observed in pathological sections,and the mRNA and protein expressions of GRP78 and CHOP in the ankle were significantly increased(P<0.01),which were mainly located in synovial tissue and articular surface.Compared with the arthritis model group,the arthritis index score and ankle swelling degree in the wogonin treatment group were decreased(P<0.05),synovial hyperplasia and the number of inflammatory cells were decreased,cartilage destruction and bone erosion were alleviated,the mRNA and protein expression levels of GRP78 and CHOP in the ankle were decreased(P<0.05),particularly in synovial tissue and on the articular surface.There was no significant difference in body mass among the three groups(P>0.05).In the cell experiment,200 μmol/L wogonin significantly reduced the survival rate of fibroblast-like synoviocytes(P<0.01).Compared with the blank control group,the levels of interleukin-1β,tumor necrosis factor-α,content of reactive oxygen species,and mRNA and protein expression of GRP78,IRE1α,XBP1s,and CHOP in the thapsigargin group were significantly increased(P<0.05);compared with the thapsigargin group,50 and 100 μmol/L wogonin significantly reduced the levels of interleukin-1β and tumor necrosis factor-α in the cell supernatant(P<0.05,P<0.01),and 100 μmol/L wogonin significantly reduced the content of reactive oxygen species(P<0.01)and down-regulated the mRNA and protein expression levels of GRP78,IRE1α,XBP1s and CHOP(all P<0.05).These results suggest that wogonin can effectively alleviate joint inflammatory responses in rats with collagen-induced arthritis,and the endoplasmic reticulum stress pathway may be the key target of its intervention.

Objective: To design HBV DNA proficiency testing and system comparison samples with different concentration gradients, analyze their detection results in PCR detection systems, evaluate the nucleic acid detection capabilities of laboratories and differences between detection systems, and put forward suggestions for continuous quality improvement to participating laboratories. Methods: Three groups of randomly numbered proficiency testing samples (with HBV DNA reference concentrations of <2, 7.5, and 30 IU/mL respectively) were taken as the detection objects. Using nucleic acid test data from 11 provincial blood station laboratories as the source, the samples were grouped by detection system and laboratory successively, and statistical analysis was conducted. Results: Statistical analysis of the detection data of the three groups of samples based on detection systems and laboratories showed that from low to high concentration, the coincidence rate between the detection results of different detection systems and laboratories and the expected results showed an increasing trend: 38.89%, 85.90%, and 100.00%; the same system exhibited certain differences in performance among different laboratories. Conclusion: Through this proficiency testing and system comparison, it is found that there are certain differences in the detection capabilities of different laboratories and different nucleic acid test systems. Blood station laboratories should standardize processes, strengthen quality management and data analysis on the basis of being familiar with the detection performance of their detection systems, and at the same time strengthen the control of laboratory interference factors to continuously improve the nucleic acid detection capabilities of blood station laboratories.

Objective:To investigate the impact of the interval period between biopsy and MR examination on tumor detection and extraprostatic extension (EPE) assessment for prostate cancer (PCa) using multi-parametric MRI (mpMRI).Methods:The study was cross-sectional and retrospectively included 130 patients with PCa who underwent RP and preoperative systematic biopsies followed by mpMRI between January 2021 and December 2022 in the First Medical Center of Chinese PLA General Hospital. Patients were divided into 3 groups according to interval following biopsy (group A,<3 weeks, 31 cases; group B, 3-6 weeks, 67 cases; group C,>6 weeks, 32 cases). The percentages of hemorrhage volume in the total prostate were drawn on T 1WI and calculated. The junior, senior and expert radiologists independently localized the index lesions and calculated the accuracy for tumor detection, in addition to assessing the probabilities of EPE according to EPE grade. The correlation between the hemorrhage extent and interval was analyzed using the Spearman correlation coefficient. The accuracy for tumor detection was compared using χ2 test among groups. The diagnostic performance of the radiologists for EPE prediction was assessed using the receiver operating characteristic curve, and the differences between the corresponding area under the curve (AUC) were compared using the DeLong test. Results:The percentage of hemorrhage was correlated with the interval between biopsy and MR examination ( r=-0.325, P<0.001). The detection accuracy of junior radiologist was 83.9% (26/31), 76.1% (51/67), and 78.1% (25/32) in group A, B and C, respectively; no differences were observed in the detection accuracy among three groups ( χ2=0.76, P=0.685). The detection accuracy of senior radiologist was 83.9% (26/31), 80.6% (54/67), and 71.9% (23/32) in 3 groups with no differences ( χ2=1.53, P=0.464). The detection accuracy of expert radiologist was 80.6% (25/31), 77.6% (52/67), and 93.8% (30/32) with no differences ( χ2=3.95, P=0.139). The AUC (95% CI) for predicting EPE were 0.830 (0.652-0.940), 0.704 (0.580-0.809), 0.800 (0.621-0.920) in the group A, B and C for junior radiologist; 0.876 (0.708-0.966), 0.768 (0.659-0.863), 0.896 (0.736-0.975) for senior radiologist; and 0.866 (0.695-0.961), 0.813 (0.699-0.895), 0.852 (0.682-0.952) for expert radiologist, respectively. No differences were observed among the subgroups in each radiologist ( P>0.05). Conclusion:The interval period does not significantly affect the detection accuracy and EPE assessment of PCa using mpMRI. There is probably no necessity for prolonged intervals following systematic biopsy to preserve the clarity of MRI interpretation for PCa.

Objective:To predict the 3-year cancer-specific survival(CSS)of patients with non-meta-static T3a renal cell carcinoma after surgery.Methods:A total of 336 patients with pathologically con-firmed T3a N0-1M0 renal cell carcinoma(RCC)who underwent surgical treatment at the Department of Urology,Peking University Third Hospital from March 2013 to February 2021 were retrospectively collect-ed.The patients were randomly divided into a training cohort of 268 cases and an internal validation co-hort of 68 cases at an 4∶1 ratio.Using two-way Lasso regression,variables were selected to construct a nomogram for predicting the 3-year cancer-specific survival(CSS)of the patients with T3aN0-1M0 RCC.Performance assessment of the nomogram included evaluation of discrimination and calibration ability,as well as clinical utility using measures such as the concordance index(C-index),time-dependent area un-der the receiver operating characteristic curve[time-dependent area under the curve(AUC)],calibra-tion curve,and decision curve analysis(DCA).Risk stratification was determined based on the nomo-gram scores,and Kaplan-Meier survival analysis and Log-rank tests were employed to compare progres-sion-free survival(PFS)and cancer-specific survival(CSS)among the patients in the different risk groups.Results:Based on the Lasso regression screening results,the nomogram was constructed with five variables:tumor maximum diameter,histological grading,sarcomatoid differentiation,T3a feature,and lymph node metastasis.The baseline data of the training and validation sets showed no statistical differences(P＞0.05).The consistency indices of the column diagram were found to be 0.808(0.708-0.907)and 0.903(0.838-0.969)for the training and internal validation sets,respectively.The AUC values for 3-year cancer-specific survival were 0.843(0.725-0.961)and 0.923(0.844-1.002)for the two sets.Calibration curves of both sets demonstrated a high level of consistency between the actual CSS and predicted probability.The decision curve analysis(DCA)curves indicated that the column dia-gram had a favorable net benefit in clinical practice.A total of 336 patients were included in the study,with 35 cancer-specific deaths and 69 postoperative recurrences.According to the line chart,the patients were divided into low-risk group(scoring 0-117)and high-risk group(scoring 119-284).Within the low-risk group,there were 16 tumor-specific deaths out of 282 cases and 36 postoperative recurrences out of 282 cases.In the high-risk group,there were 19 tumor-specific deaths out of 54 cases and 33 post-operative recurrences out of 54 cases.There were significant differences in progression-free survival(PFS)and cancer-specific survival(CSS)between the low-risk and high-risk groups(P＜0.000 1).Conclusion:A nomogram model predicting the 3-year CSS of non-metastatic T3a renal cell carcinoma patients was successfully constructed and validated in this study.This nomogram can assist clinicians in accurately assessing the long-term prognosis of such patients.

Objective To evaluate the stability,safety and immune enhancement and anti-tumor effects of Wilms'tumor gene 1(WT1)peptide combined with AddaVaxTM emulsion vaccine for acute myeloid leukemia.Methods The stability of WT1 peptide in the adjuvant vaccine was evaluated using MALDI-TOF-MS time-of-flight mass spectrometry.Female C57BL/6 mice were randomly divided into PBS group,WT1 peptide group,and WT1 peptide+AddaVaxTMemulsion adjuvant vaccine group.The immunization was performed at a dose of 50 μg/mouse for antigen and 50 μg/mouse for adjuvant,with intramuscular injection on days 0,14,and 28.HE staining was used to assess the toxicity of intramuscular vaccination on mouse organ tissues.Cytokine levels were detected by ELISA,and the number of IFN-γ-secreting splenocytes was measured by ELISpot.Flow cytometry was employed to detect the maturation of bone marrow-derived dendritic cells(BMDCs)promoted by the vaccine in vitro and the promotion for lymphocyte activation,and H-2Db WT1 tetramer was utilized to detect the proportion of specific CD8+T cells.After establishing a mouse leukemia tumor model using the C1498-mWT1 stable cell line,the anti-tumor effects of the vaccine for prevention and treatment were evaluated.Results The WT1 peptide stably existed in the vaccine without causing significant organ tissue changes in mice after intramuscular injection.Compared to the mice immunized with WT1 aqueous solution,the mice after intramuscular injection of the WT1 peptide emulsion adjuvant vaccine showed stronger immune responses of Th1 cells,including IFN-γ and TNF-α,as well as Th17 cells of IL-17A(P＜0.05),and the mice had not only promoted number of IFN-γ secreting splenocytes(P＜0.01)but also enhanced maturation of BMDCs,as indicated by an increase in the proportions of CD40+/CD11c+and CD86+CD80+/CD11c+ cells(P＜0.05).Additionally,there were increases in both the proportion of CD4+/CD3+T and CD69+/CD8+T cells(P＜0.05)and the proportion of specific CD8+T cells(P＜0.05).In the anti-tumor effect study using the C1498-mWT1 mouse model,the median survival time of the WT1+AddaVaxTM group was extended by 6 d compared to the WT1 aqueous solution group.At day 50,the survival rate of mice in the WT1+AddaVaxTM group was still 28.5％,while all mice in the other groups had died(P＜0.05).Conclusion The vaccine with the WT1 peptide and AddaVaxTM emulsion adjuvant exhibits good immunological and anti-tumor effects.

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.

Traditional Chinese medicine can regulate the hypoxia-inducible factor-1α(HIF-1α)signalling pathway and slow down tumour progression mainly by inhibiting tumour angiogenesis,glycolysis,epithelial mesenchymal transition and other pathological processes.This paper,starting from HIF-1α and related factors,reviews its pathological mechanism in tumours and the research of traditional Chinese medicine interventions with the aim of providing theoretical references for the treatment of tumours with traditional Chinese medicine.