Peptide-based radiopharmaceuticals targeting integrin α5β1 show promise for precise tumor diagnosis and treatment. However, current peptide-based radioligands that target α5β1 demonstrate inadequate in vivo performance owing to limited tumor retention. The use of PEGylation to enhance the tumor retention of radiopharmaceuticals by prolonging blood circulation time poses a risk of increased blood toxicity. Therefore, a PEGylation strategy that boosts tumor retention while minimizing blood circulation time is urgently needed. Here, we developed a PEGylation-enabled peptide multidisplay platform (PEGibody) for PR_b, an α5β1 targeting peptide. PEGibody generation involved PEGylation and self-assembly. [⁶⁴Cu]QM-2303 PEGibodies displayed spherical nanoparticles ranging from 100 to 200 nm in diameter. Compared with non-PEGylated radioligands, [⁶⁴Cu]QM-2303 demonstrated enhanced tumor retention time due to increased binding affinity and stability. Importantly, the biodistribution analysis confirmed rapid clearance of [⁶⁴Cu]QM-2303 from the bloodstream. Administration of a single dose of [¹⁷⁷Lu]QM-2303 led to robust antitumor efficacy. Furthermore, [⁶⁴Cu]/[¹⁷⁷Lu]QM-2303 exhibited low hematological and organ toxicity in both healthy and tumor-bearing mice. Therefore, this study presents a PEGibody-based radiotheranostic approach that enhances tumor retention time and provides long-lasting antitumor effects without prolonging blood circulation lifetime. The PEGibody-based radiopharmaceutical [⁶⁴Cu]/[¹⁷⁷Lu]QM-2303 shows great potential for positron emission tomography imaging-guided targeted radionuclide therapy for α5β1-overexpressing tumors.

PURPOSE: To assess the relationship between dislocation and functional outcomes in supination-external rotation (SER) ankle fractures. METHODS: A retrospective case series study was performed on patients with ankle fractures treated surgically at a large trauma center from January 2015 to December 2021. The inclusion criteria were young and middle-aged patients of 18 - 65 years with SER ankle fractures that can be classified by Lauge-Hansen classification and underwent surgery at our trauma center. Exclusion criteria were serious life-threatening diseases, open fractures, fractures delayed for more than 3 weeks, fracture sites ≥ 2, etc. Then patients were divided into dislocation and no-dislocation groups. Patient demographics, injury characteristics, surgery-related outcomes, and postoperative functional outcomes were collected and analyzed. The functional outcomes of SER ankle fractures were assessed postoperatively at 1-year face-to-face follow-up using the foot and ankle outcome score (FAOS) and American Orthopedic Foot and Ankle Society ankle hindfoot score and by 2 experienced orthopedic physicians. Relevant data were analyzed using SPSS version 22.0 by Chi-square or t-test. RESULTS: During the study period, there were 371 ankle fractures. Among them, 190 (51.2%) were SER patterns with 69 (36.3%) combined with dislocations. Compared with the no-dislocation group, the dislocation group showed no statistically significant differences in gender, age composition, fracture type, diabetes, or smoking history, preoperative waiting time, operation time, and length of hospital stay (all p > 0.05), but a significantly higher Lauge-Hansen injury grade (p < 0.001) and syndesmotic screw fixation rate (p = 0.033). Moreover, the functional recovery was poorer, revealing a significantly lower FAOS in the sport/rec scale (p < 0.001). Subgroup analysis showed that among SER IV ankle fracture patients, FAOS was much lower in pain (p = 0.042) and sport/rec scales (p < 0.001) for those with dislocations. American Orthopedic Foot and Ankle Society ankle hindfoot score revealed no significant difference between dislocation and no-dislocation patients. CONCLUSION Dislocation in SER ankle fractures suggests more severe injury and negatively affects functional recovery, mainly manifested as more pain and poorer motor function, especially in SER IV ankle cases.
Humans ; Ankle Fractures/physiopathology* ; Male ; Female ; Retrospective Studies ; Adult ; Middle Aged ; Supination ; Aged ; Young Adult ; Rotation ; Joint Dislocations/surgery* ; Fracture Fixation, Internal/methods* ; Adolescent ; Recovery of Function ; Treatment Outcome

The activation proteins released by fibroblasts in the tumor microenvironment regulate tumor growth, migration, and treatment response, thereby influencing tumor progression and therapeutic outcomes. Owing to the proliferation and metastasis of tumors, fibroblast activation protein (FAP) is typically highly expressed in the tumor stroma, whereas it is nearly absent in adult normal tissues and benign lesions, making it an attractive target for precision medicine. Radiolabeled agents targeting FAP have the potential for targeted cancer diagnosis and therapy. This comprehensive review aims to describe the evolution of FAPI-based radiopharmaceuticals and their structural optimization. Within its scope, this review summarizes the advances in the use of radiolabeled small molecule inhibitors for tumor imaging and therapy as well as the modification strategies for FAPIs, combined with insights from structure-activity relationships and clinical studies, providing a valuable perspective for radiopharmaceutical clinical development and application.

Triple-negative breast cancer is therapeutically challenging due to the low expression of tumor markers and 'cold' tumor immunosuppressive microenvironment. Here, we present a dual-targeting peptide-drug conjugate (PDC) for tumor inhibition. Our PDC efficiently and selectively delivers cytotoxic Monomethyl Auristatin E (MMAE) into tumor cells via C-X-C chemokine receptor type 4 (CXCR4) and folate receptor 1 (FOLR1) for synergistic inhibition of growth and metastasis. Our results show that the dual-targeting PDC has potent antitumor activity in cultured human cells and several murine transplanted tumor models without apparent toxicity. The combination of dual-targeting PDC and radiotherapy modulates the tumor immunosuppressive microenvironment by increasing CD8⁺ T cell infiltration and attenuating the proportion of myeloid-derived suppressor and regulatory T cells. Therefore, our dual-targeting PDC represents a promising new strategy for cancer therapy that rebalances the immune system and promotes tumor regression.

Objective:To explore the correlation between metabolic syndrome (MS), serum high-sensitivity C-reactive protein (hs-CRP) levels, their combination and the risk of digestive system malignancies.Methods:A prospective cohort study was conducted in the participants from the Kailuan cohort who took health examination in July 2006. Anthropometric parameters, epidemiological information, and laboratory test results were collected. Incidence and mortality of digestive system malignant tumors were collected through biennial health examinations and questionnaires. The follow-up period ended on December 31, 2021.According to MS status and hs-CRP levels (hs-CRP≤3 or >3 mg/L), the cohort was divided into 4 groups, induding MS -hs-CRP -, MS -hs-CRP +, MS + hs-CRP -, and MS + hs-CRP + group. Chi-squared test, one analysis of variance, and the Kruskal-Wallis H test were used for inter-group comparison among groups. Kaplan-Meier method was used to calculate the cumulative incidence of digestive system malignant tumors, and log-rank test was performed to compare the cumulative incidence among groups. Multivariable Cox proportional hazards regression models were used to evaluate the effects of MS and hs-CRP levels on the overall risk of digestive system malignant tumors, as well as the effects of their combination on the risk of digestive system malignant tumors of different site, and relevant confounding factors were adjusted.A sensitivity analysis was conducted by excluding individuals diagnosed with digestive system malignancies within one year of follow-up, as well as those taking antihypertensive, antidiabetic, or lipid-lowering medications. Results:A total of 92 916 participants were included in this study. Among them, 57 933 cases were in the MS -hs-CRP - group, 10 949 cases in the MS -hs-CRP + group, 18 412 cases in the MS + hs-CRP - group, and 5 622 cases in the MS + hs-CRP + group.The median follow-up period was 15.01 years (14.66 to 15.20 years). By the end of follow-up, these were 1 992 cases of new-onset digestive system malignant tumors. The cumulative incidence rates of digestive system malignant tumors of MS -hs-CRP -, MS -hs-CRP +, MS + hs-CRP -, and MS + hs-CRP + groups were 2.0%(1 164/57 933), 2.3%(249/10 949), 2.4%(440/18 412), and 2.5%(139/5 622), respectively. The difference in the cumulative incidence among the 4 groups was statistically significant ( χ2=14.09, P=0.003).The results of multivariate Cox analysis showed that, after hs-CRP level and other confounding factors were adjusted, the risk of developing digestive system malignant tumors in participants with MS was 21.4% higher than that in those without MS ( HR=1.214 (95% confidence interval (95% CI): 1.086 to 1.340), P<0.001). After MS status and other confounding factors were adjusted, the risk of developing digestive system malignant tumors in participants with high hs-CRP level (>3 mg/L) was 17.2% higher than those with low hs-CRP level (≤3 mg/L) ( HR=1.172 (95% CI: 1.042 to 1.303), P=0.008). After relevant confounding factors were adjusted, the risks of developing digestive system malignant tumors in the MS -hs-CRP +, MS + hs-CRP -, and MS + hs-CRP + groups increased by 17.2%, 21.4%, and 35.9%, respectively, as compared with that of the MS -hs-CRP - group ( HR=1.172 (95% CI: 1.017 to 1.399), P=0.028; HR=1.214 (95% CI: 1.074 to 1.356), P=0.002; HR=1.359 (95% CI: 1.135 to 1.635), P=0.001). Among the 4 groups, the overall risk of developing digestive system malignant tumors of MS + hs-CRP + group was the highest. After relevant confounding factors were adjusted, the risks of colorectal cancer, liver cancer, and pancreatic cancer of the MS + hs-CRP + group increased by 46.2%, 35.7%, and 88.3%, respectively, as compared with those of the MS -hs-CRP - group ( HR=1.462 (95% CI: 1.088 to 1.956), HR=1.357 (95% CI: 1.132 to 2.089), HR=1.883 (95% CI: 1.052 to 3.342)), suggesting that MS combined with high hs-CRP was a significant risk factor for increased incidences of colorectal cancer, liver cancer, and pancreatic cancer ( P=0.012, 0.016 and 0.033). After participants diagnosed with new digestive system malignancies within one year of follow-up and those taking antihypertensive, antidiabetic, or lipid-lowering medications (108 cases, 10 680 cases, 2 344 cases, 906 cases) were excluded, the results of sensitivity analysis indicated the increased risk of digestive system malignant tumors in the MS -hs-CRP +, MS + hs-CRP -, and MS + hs-CRP + groups were 12.1%, 21.4%, 28.7%; 18.2%, 21.4%, 24.8%; 16.4%, 21.4%, 32.2%; 17.3%, 20.4%, 35.8%. Among the 3 groups, the increased risk of developing digestive system malignant tumors of MS + hs-CRP + group was the highest. Conclusion:MS and hs-CRP >3 mg/L are both independent risk factors for developing digestive system malignant tumors, and their combination further increases the risk of developing digestive system malignant tumors.

Objective:To investigate the predictive value of different obesity indicators for colorectal cancer (CRC) risk in different gender populations.Methods:This observational study was conducted within the Kailuan Study (Registration Number: ChiCTR-TNC-11001489). From July 2006 to October 2007, a total of 101,510 employed and retired individuals underwent health examinations, including gastrointestinal disease screening, hematological tests, and questionnaires, at Kailuan General Hospital and its 10 affiliated hospitals. After excluding those with incomplete data, 93,606 participants were included in this study and divided into male (74 852) and female (18 754) groups. CRC incidence was collected through physical examinations and questionnaires every two years. Each participant's follow-up period began at the time of the questionnaire and ended upon CRC diagnosis, death, or December 31, 2021. Body Mass Index (BMI), waist circumference, waist-to-hip ratio (WHR), and waist-to-height ratio (WHtR) were quartiled (Q1, Q2, Q3, Q4), with Q1 serving as the control group. After adjusting for traditional risk factors such as age, total cholesterol, triglycerides, diabetes, hypertension, smoking status, alcohol consumption, and physical exercise, Cox regression models were used to calculate the correlations between BMI, waist circumference, WHR, WHtR, and CRC incidence in both male and female populations.Results:The age of all patients was (51±12) years, BMI was (25.06±3.49) kg/m 2, waist circumference was (86.94±9.97) cm, hip circumference was (97.30±8.81) cm, WHR was 0.89±0.07, and WHtR was 0.52±0.06.Female participants had significantly lower BMI, waist circumference, WHR, and WHtR compared to males, with statistically significant differences (all P<0.05). The mean follow-up duration for all participants was 15.01 (14.10±2.66) years, during which 718 CRC cases were identified, including 626 males (0.83%) and 92 females (0.49%). Cox proportional hazards models for males showed that CRC risk increased with waist circumference from Q3 (HR=1.43, 95%CI: 1.13-1.79, P=0.003) to Q4 (HR=1.45,95%CI: 1.14-1.82, P=0.002). Similarly, CRC risk increased with WHR from Q3 (HR=1.22, 95%CI: 1.01-1.53, P=0.007) to Q4 (HR=1.43, 95%CI: 1.14-1.79, P=0.002) and with WHtR from Q3 (HR=1.37, 95%CI: 1.08-1.74, P=0.009) to Q4 (HR=1.68, 95%CI: 1.33-2.12, P<0.001). For females, CRC risk increased with waist circumference from Q2 (HR=2.37, 95%CI: 1.20-4.67, P=0.012) to Q3 (HR=2.42, 95%CI: 1.21-4.84, P=0.013) but decreased in Q4 ( HR=2.08, 95%CI: 1.02-4.25, P=0.043). CRC risk increased significantly with WHR from Q2 (HR=2.20, 95%CI: 1.11-4.39, P=0.024) to Q3 (HR=2.89, 95%CI: 1.48-5.67, P=0.002) in females but was not statistically significant in Q4 ( P=0.074). Among females, CRC risk also increased significantly with WHtR in Q2 (HR=2.30, 95% CI: 1.16-4.56, P=0.017) and Q4 (HR=2.64, 95%CI: 1.32-5.29, P=0.006). There were no statistically significant differences in CRC risk associated with BMI in either male or female populations (both P>0.05). Conclusion:Waist circumference, WHR, and WHtR were better predictors of CRC risk than BMI in both male and female populations.

Objective:To investigate the influence of diabetes mellitus (DM) and high-sen-sitivity C-reactive protein (Hs-CRP) on the risk of digestive system malignancy.Methods:The pro-spective cohort study was conducted. The clinical data of 93 928 participants who participated health examination in 9 hospitals at Tangshan, including Kailuan General Hospital Affiliated to North China University of Science and Technology et al, in 2006 were selected. According to the presence or absence of DM and the level of Hs-CRP, all participants were divided into 4 groups, including the DM(-)CRP(-) group defined as absence of DM and Hs-CRP ≤3 mg/L, the DM(-)CRP(+) group defined as absence of DM and Hs-CRP>3 mg/L, the DM(+)CRP(-) group defined as presence of DM and Hs-CRP ≤3 mg/L, and the DM(+)CRP(+) group defined as presence of DM and Hs-CRP >3 mg/L. The data of participants were collected by a fixed team of physicians. The first physical examination in 2006 was taken as the starting point for follow-up. The end event of follow-up was defined as the occurrence of digestive system malignancy or death, and the follow-up was up to December 31, 2021. Observation indicators: (1) comparison of clinical data among the 4 groups of participants; (2) the incidence and cumulative incidence rate of digestive system malignancy in participants; (3) influence of DM and Hs-CRP level on the risk of digestive system malignancy; (4) the combined influence of DM and Hs-CRP level on the risk of digestive system malignancy; (5) sensitivity analysis. Comparison of measurement data with normal distribution among multiple groups was conducted using the one-way analysis of variance. For pairwise comparison, least significant difference test was used for homogeneity of variance, and Dunnett′s T3 test was used for heterogeneity of variance. Comparison of measurement data with skewed distribution among multiple groups was conducted using the Kruskal-Wallis rank sum test, and Dunn-Bonferroni test was used for pairwise comparison. Comparison of count data among multiple groups was conducted using the chi-square test, and Bonferroni test was used among multiple comparisons. The Kaplan-Meier method was used to plot cumulative incidence curve, and Log-rank test was used for cumulative incidence rate analysis. The Cox proportional risk model was used for multivariate analysis. All models were adjusted for relevant confounders. Results:(1) Comparison of clinical data among the 4 groups of participants. Of the 93 928 participants, there were 70 743 cases in the DM(-)CRP(-) group, 14 644 cases in the DM(-)CRP(+) group, 6 425 cases in the DM(+)CRP(-) group, and 2 116 cases in the DM(+)CRP(+) group. There were significant differences in gender, age, fasting blood glucose, Hs-CRP, triglyceride, alanine aminotransferase, body mass index, marrital status, smoking, drinking, high school degree or above, physical exercise, high salt diet, high fat diet, positive hepatitis B virus surface antigen, fatty liver, liver cirrhosis, gallstone, taking hypoglycemic drugs, taking lipid-lowering drugs among the 4 groups of participants ( P<0.05). (2) The incidence and cumulative incidence rate of digestive system malignancy in participants. At the end-up of follow-up, 2 008 cases developed digestive system malignancy in the 93 928 participants, including 717 cases of colorectal cancer, 456 cases of liver cancer, 396 cases of gastric cancer, 195 cases of esophageal cancer, 144 cases of pancreatic cancer, 65 cases of gallbladder cancer or extrahepatic cholangiocarcinoma, 35 cases of small bowel cancer. The cumulative incidence rates of digestive system malignancy were 2.19%, 2.42%, 2.86%, 3.59% in participants of the DM(-)CRP(-) group, DM(-)CRP(+) group, DM(+)CRP(-) group, DM(+)CRP(+) group, respectively, showing a significant difference among the 4 groups ( χ2=31.72, P<0.05). (3) Influence of DM and Hs-CRP level on the risk of digestive system malignancy. After adjusting for the confounding factors of the participants, results of multivariate analysis showed that DM and Hs-CRP >3 mg/L were independent influencing factors for the incidence of digestive system malignancy ( hazard ratio=1.32, 1.19, 95% confidence interval as 1.13-1.56, 1.06-1.33, P<0.05). Futher analysis showed that there was a significant difference in interaction between DM and Hs-CRP >3 mg/L ( P<0.05). (4) The combined influence of DM and Hs-CRP level on the risk of digestive system malign-ancy. After adjusting for confounding factors, results of multivariate analysis showed that using the DM(-)CRP(-) group as the control group, the risk of incidence of digestive system malignancy increased in the DM(-)CRP(+) group, DM(+)CRP(-) group, and DM(+)CRP(+) group, respectively ( hazard ratio=1.14, 1.23, 1.79, 95% confidence interval as 1.01-1.29, 1.02-1.48, 1.38-2.31, P<0.05). In the site-specific analysis of digestive system malignancy, using the DM(-)CRP(-) group as the control group, the risk of incidence of liver cancer increased in the DM(-)CRP(+) group ( hazard ratio=1.37, 95% confidence interval as 1.07-1.75, P<0.05), the risk of incidence of liver cancer and pancrea-tic cancer increased in the DM(+)CRP(-) group ( hazard ratio=1.60, 1.74, 95% confidence interval as 1.16-2.21, 1.00-3.02, P<0.05), the risk of incidence of small bowel cancer, pancreatic cancer and colorectal cancer increased in the DM(+)CRP(+) group ( hazard ratio=5.05, 2.31, 2.23, 95% confidence interval as 1.57-16.21, 1.00-5.31, 1.54-3.24, P<0.05). (5) Sensitivity analysis. After adjusting for confounding factors of excluding 3 types of participants (103 cases of digestive system malignancy within 1 year of follow-up, 2 370 cases of taking glucose-lowering drugs, and 915 cases of taking lipid-lowering drugs), results of multivariate analysis showed that using the DM(-)CRP(-) group as the control group, the risk of incidence of digestive system malignancy increased in the DM(+)CRP(-) group, and DM(+)CRP(+) group, respectively ( hazard ratioexcluding cases of digestive system malignancy within 1 year of follow-up=1.26, 1.66, 95% confidence interval as 1.04-1.52, 1.26-2.18, P<0.05; hazard ratioexcluding cases taking glucose-lowering drugs=1.23, 1.75, 95% confidence interval as 1.02-1.49, 1.31-2.33, P<0.05; hazard ratioexcluding cases taking lipid-lowering drugs=1.24, 1.80, 95% confidence interval as 1.03-1.49, 1.39-2.34, P<0.05). Conclusions:DM and Hs-CRP >3 mg/L are independent influencing factors for the incidence of digestive system malignancy. There is an interation and synergistic effect between DM and Hs-CRP to promote the incidence of digestive system malignancy.

Objective:To investigate the predictive value of different obesity indicators for colorectal cancer (CRC) risk in different gender populations.Methods:This observational study was conducted within the Kailuan Study (Registration Number: ChiCTR-TNC-11001489). From July 2006 to October 2007, a total of 101,510 employed and retired individuals underwent health examinations, including gastrointestinal disease screening, hematological tests, and questionnaires, at Kailuan General Hospital and its 10 affiliated hospitals. After excluding those with incomplete data, 93,606 participants were included in this study and divided into male (74 852) and female (18 754) groups. CRC incidence was collected through physical examinations and questionnaires every two years. Each participant's follow-up period began at the time of the questionnaire and ended upon CRC diagnosis, death, or December 31, 2021. Body Mass Index (BMI), waist circumference, waist-to-hip ratio (WHR), and waist-to-height ratio (WHtR) were quartiled (Q1, Q2, Q3, Q4), with Q1 serving as the control group. After adjusting for traditional risk factors such as age, total cholesterol, triglycerides, diabetes, hypertension, smoking status, alcohol consumption, and physical exercise, Cox regression models were used to calculate the correlations between BMI, waist circumference, WHR, WHtR, and CRC incidence in both male and female populations.Results:The age of all patients was (51±12) years, BMI was (25.06±3.49) kg/m 2, waist circumference was (86.94±9.97) cm, hip circumference was (97.30±8.81) cm, WHR was 0.89±0.07, and WHtR was 0.52±0.06.Female participants had significantly lower BMI, waist circumference, WHR, and WHtR compared to males, with statistically significant differences (all P<0.05). The mean follow-up duration for all participants was 15.01 (14.10±2.66) years, during which 718 CRC cases were identified, including 626 males (0.83%) and 92 females (0.49%). Cox proportional hazards models for males showed that CRC risk increased with waist circumference from Q3 (HR=1.43, 95%CI: 1.13-1.79, P=0.003) to Q4 (HR=1.45,95%CI: 1.14-1.82, P=0.002). Similarly, CRC risk increased with WHR from Q3 (HR=1.22, 95%CI: 1.01-1.53, P=0.007) to Q4 (HR=1.43, 95%CI: 1.14-1.79, P=0.002) and with WHtR from Q3 (HR=1.37, 95%CI: 1.08-1.74, P=0.009) to Q4 (HR=1.68, 95%CI: 1.33-2.12, P<0.001). For females, CRC risk increased with waist circumference from Q2 (HR=2.37, 95%CI: 1.20-4.67, P=0.012) to Q3 (HR=2.42, 95%CI: 1.21-4.84, P=0.013) but decreased in Q4 ( HR=2.08, 95%CI: 1.02-4.25, P=0.043). CRC risk increased significantly with WHR from Q2 (HR=2.20, 95%CI: 1.11-4.39, P=0.024) to Q3 (HR=2.89, 95%CI: 1.48-5.67, P=0.002) in females but was not statistically significant in Q4 ( P=0.074). Among females, CRC risk also increased significantly with WHtR in Q2 (HR=2.30, 95% CI: 1.16-4.56, P=0.017) and Q4 (HR=2.64, 95%CI: 1.32-5.29, P=0.006). There were no statistically significant differences in CRC risk associated with BMI in either male or female populations (both P>0.05). Conclusion:Waist circumference, WHR, and WHtR were better predictors of CRC risk than BMI in both male and female populations.

Objective:To investigate the influence of diabetes mellitus (DM) and high-sen-sitivity C-reactive protein (Hs-CRP) on the risk of digestive system malignancy.Methods:The pro-spective cohort study was conducted. The clinical data of 93 928 participants who participated health examination in 9 hospitals at Tangshan, including Kailuan General Hospital Affiliated to North China University of Science and Technology et al, in 2006 were selected. According to the presence or absence of DM and the level of Hs-CRP, all participants were divided into 4 groups, including the DM(-)CRP(-) group defined as absence of DM and Hs-CRP ≤3 mg/L, the DM(-)CRP(+) group defined as absence of DM and Hs-CRP>3 mg/L, the DM(+)CRP(-) group defined as presence of DM and Hs-CRP ≤3 mg/L, and the DM(+)CRP(+) group defined as presence of DM and Hs-CRP >3 mg/L. The data of participants were collected by a fixed team of physicians. The first physical examination in 2006 was taken as the starting point for follow-up. The end event of follow-up was defined as the occurrence of digestive system malignancy or death, and the follow-up was up to December 31, 2021. Observation indicators: (1) comparison of clinical data among the 4 groups of participants; (2) the incidence and cumulative incidence rate of digestive system malignancy in participants; (3) influence of DM and Hs-CRP level on the risk of digestive system malignancy; (4) the combined influence of DM and Hs-CRP level on the risk of digestive system malignancy; (5) sensitivity analysis. Comparison of measurement data with normal distribution among multiple groups was conducted using the one-way analysis of variance. For pairwise comparison, least significant difference test was used for homogeneity of variance, and Dunnett′s T3 test was used for heterogeneity of variance. Comparison of measurement data with skewed distribution among multiple groups was conducted using the Kruskal-Wallis rank sum test, and Dunn-Bonferroni test was used for pairwise comparison. Comparison of count data among multiple groups was conducted using the chi-square test, and Bonferroni test was used among multiple comparisons. The Kaplan-Meier method was used to plot cumulative incidence curve, and Log-rank test was used for cumulative incidence rate analysis. The Cox proportional risk model was used for multivariate analysis. All models were adjusted for relevant confounders. Results:(1) Comparison of clinical data among the 4 groups of participants. Of the 93 928 participants, there were 70 743 cases in the DM(-)CRP(-) group, 14 644 cases in the DM(-)CRP(+) group, 6 425 cases in the DM(+)CRP(-) group, and 2 116 cases in the DM(+)CRP(+) group. There were significant differences in gender, age, fasting blood glucose, Hs-CRP, triglyceride, alanine aminotransferase, body mass index, marrital status, smoking, drinking, high school degree or above, physical exercise, high salt diet, high fat diet, positive hepatitis B virus surface antigen, fatty liver, liver cirrhosis, gallstone, taking hypoglycemic drugs, taking lipid-lowering drugs among the 4 groups of participants ( P<0.05). (2) The incidence and cumulative incidence rate of digestive system malignancy in participants. At the end-up of follow-up, 2 008 cases developed digestive system malignancy in the 93 928 participants, including 717 cases of colorectal cancer, 456 cases of liver cancer, 396 cases of gastric cancer, 195 cases of esophageal cancer, 144 cases of pancreatic cancer, 65 cases of gallbladder cancer or extrahepatic cholangiocarcinoma, 35 cases of small bowel cancer. The cumulative incidence rates of digestive system malignancy were 2.19%, 2.42%, 2.86%, 3.59% in participants of the DM(-)CRP(-) group, DM(-)CRP(+) group, DM(+)CRP(-) group, DM(+)CRP(+) group, respectively, showing a significant difference among the 4 groups ( χ2=31.72, P<0.05). (3) Influence of DM and Hs-CRP level on the risk of digestive system malignancy. After adjusting for the confounding factors of the participants, results of multivariate analysis showed that DM and Hs-CRP >3 mg/L were independent influencing factors for the incidence of digestive system malignancy ( hazard ratio=1.32, 1.19, 95% confidence interval as 1.13-1.56, 1.06-1.33, P<0.05). Futher analysis showed that there was a significant difference in interaction between DM and Hs-CRP >3 mg/L ( P<0.05). (4) The combined influence of DM and Hs-CRP level on the risk of digestive system malign-ancy. After adjusting for confounding factors, results of multivariate analysis showed that using the DM(-)CRP(-) group as the control group, the risk of incidence of digestive system malignancy increased in the DM(-)CRP(+) group, DM(+)CRP(-) group, and DM(+)CRP(+) group, respectively ( hazard ratio=1.14, 1.23, 1.79, 95% confidence interval as 1.01-1.29, 1.02-1.48, 1.38-2.31, P<0.05). In the site-specific analysis of digestive system malignancy, using the DM(-)CRP(-) group as the control group, the risk of incidence of liver cancer increased in the DM(-)CRP(+) group ( hazard ratio=1.37, 95% confidence interval as 1.07-1.75, P<0.05), the risk of incidence of liver cancer and pancrea-tic cancer increased in the DM(+)CRP(-) group ( hazard ratio=1.60, 1.74, 95% confidence interval as 1.16-2.21, 1.00-3.02, P<0.05), the risk of incidence of small bowel cancer, pancreatic cancer and colorectal cancer increased in the DM(+)CRP(+) group ( hazard ratio=5.05, 2.31, 2.23, 95% confidence interval as 1.57-16.21, 1.00-5.31, 1.54-3.24, P<0.05). (5) Sensitivity analysis. After adjusting for confounding factors of excluding 3 types of participants (103 cases of digestive system malignancy within 1 year of follow-up, 2 370 cases of taking glucose-lowering drugs, and 915 cases of taking lipid-lowering drugs), results of multivariate analysis showed that using the DM(-)CRP(-) group as the control group, the risk of incidence of digestive system malignancy increased in the DM(+)CRP(-) group, and DM(+)CRP(+) group, respectively ( hazard ratioexcluding cases of digestive system malignancy within 1 year of follow-up=1.26, 1.66, 95% confidence interval as 1.04-1.52, 1.26-2.18, P<0.05; hazard ratioexcluding cases taking glucose-lowering drugs=1.23, 1.75, 95% confidence interval as 1.02-1.49, 1.31-2.33, P<0.05; hazard ratioexcluding cases taking lipid-lowering drugs=1.24, 1.80, 95% confidence interval as 1.03-1.49, 1.39-2.34, P<0.05). Conclusions:DM and Hs-CRP >3 mg/L are independent influencing factors for the incidence of digestive system malignancy. There is an interation and synergistic effect between DM and Hs-CRP to promote the incidence of digestive system malignancy.

Objective:To explore the correlation between metabolic syndrome (MS), serum high-sensitivity C-reactive protein (hs-CRP) levels, their combination and the risk of digestive system malignancies.Methods:A prospective cohort study was conducted in the participants from the Kailuan cohort who took health examination in July 2006. Anthropometric parameters, epidemiological information, and laboratory test results were collected. Incidence and mortality of digestive system malignant tumors were collected through biennial health examinations and questionnaires. The follow-up period ended on December 31, 2021.According to MS status and hs-CRP levels (hs-CRP≤3 or >3 mg/L), the cohort was divided into 4 groups, induding MS -hs-CRP -, MS -hs-CRP +, MS + hs-CRP -, and MS + hs-CRP + group. Chi-squared test, one analysis of variance, and the Kruskal-Wallis H test were used for inter-group comparison among groups. Kaplan-Meier method was used to calculate the cumulative incidence of digestive system malignant tumors, and log-rank test was performed to compare the cumulative incidence among groups. Multivariable Cox proportional hazards regression models were used to evaluate the effects of MS and hs-CRP levels on the overall risk of digestive system malignant tumors, as well as the effects of their combination on the risk of digestive system malignant tumors of different site, and relevant confounding factors were adjusted.A sensitivity analysis was conducted by excluding individuals diagnosed with digestive system malignancies within one year of follow-up, as well as those taking antihypertensive, antidiabetic, or lipid-lowering medications. Results:A total of 92 916 participants were included in this study. Among them, 57 933 cases were in the MS -hs-CRP - group, 10 949 cases in the MS -hs-CRP + group, 18 412 cases in the MS + hs-CRP - group, and 5 622 cases in the MS + hs-CRP + group.The median follow-up period was 15.01 years (14.66 to 15.20 years). By the end of follow-up, these were 1 992 cases of new-onset digestive system malignant tumors. The cumulative incidence rates of digestive system malignant tumors of MS -hs-CRP -, MS -hs-CRP +, MS + hs-CRP -, and MS + hs-CRP + groups were 2.0%(1 164/57 933), 2.3%(249/10 949), 2.4%(440/18 412), and 2.5%(139/5 622), respectively. The difference in the cumulative incidence among the 4 groups was statistically significant ( χ2=14.09, P=0.003).The results of multivariate Cox analysis showed that, after hs-CRP level and other confounding factors were adjusted, the risk of developing digestive system malignant tumors in participants with MS was 21.4% higher than that in those without MS ( HR=1.214 (95% confidence interval (95% CI): 1.086 to 1.340), P<0.001). After MS status and other confounding factors were adjusted, the risk of developing digestive system malignant tumors in participants with high hs-CRP level (>3 mg/L) was 17.2% higher than those with low hs-CRP level (≤3 mg/L) ( HR=1.172 (95% CI: 1.042 to 1.303), P=0.008). After relevant confounding factors were adjusted, the risks of developing digestive system malignant tumors in the MS -hs-CRP +, MS + hs-CRP -, and MS + hs-CRP + groups increased by 17.2%, 21.4%, and 35.9%, respectively, as compared with that of the MS -hs-CRP - group ( HR=1.172 (95% CI: 1.017 to 1.399), P=0.028; HR=1.214 (95% CI: 1.074 to 1.356), P=0.002; HR=1.359 (95% CI: 1.135 to 1.635), P=0.001). Among the 4 groups, the overall risk of developing digestive system malignant tumors of MS + hs-CRP + group was the highest. After relevant confounding factors were adjusted, the risks of colorectal cancer, liver cancer, and pancreatic cancer of the MS + hs-CRP + group increased by 46.2%, 35.7%, and 88.3%, respectively, as compared with those of the MS -hs-CRP - group ( HR=1.462 (95% CI: 1.088 to 1.956), HR=1.357 (95% CI: 1.132 to 2.089), HR=1.883 (95% CI: 1.052 to 3.342)), suggesting that MS combined with high hs-CRP was a significant risk factor for increased incidences of colorectal cancer, liver cancer, and pancreatic cancer ( P=0.012, 0.016 and 0.033). After participants diagnosed with new digestive system malignancies within one year of follow-up and those taking antihypertensive, antidiabetic, or lipid-lowering medications (108 cases, 10 680 cases, 2 344 cases, 906 cases) were excluded, the results of sensitivity analysis indicated the increased risk of digestive system malignant tumors in the MS -hs-CRP +, MS + hs-CRP -, and MS + hs-CRP + groups were 12.1%, 21.4%, 28.7%; 18.2%, 21.4%, 24.8%; 16.4%, 21.4%, 32.2%; 17.3%, 20.4%, 35.8%. Among the 3 groups, the increased risk of developing digestive system malignant tumors of MS + hs-CRP + group was the highest. Conclusion:MS and hs-CRP >3 mg/L are both independent risk factors for developing digestive system malignant tumors, and their combination further increases the risk of developing digestive system malignant tumors.