OBJECTIVE: To identify and validate novel biomarkers for the early diagnosis of sepsis-associated acute kidney injury (SA-AKI) and precise continuous renal replacement therapy (CRRT) using proteomics. METHODS: A prospective multicenter cohort study was conducted. Patients with sepsis admitted to five hospitals in Taizhou City of Zhejiang Province from April 2019 to December 2021 were continuously enrolled, based on the occurrence of acute kidney injury (AKI). Sepsis patients were divided into SA-AKI group and non-SA-AKI group, and healthy individuals who underwent physical examinations during the same period were used as control (NC group). Peripheral blood samples from participants were collected for protein mass spectrometry analysis. Differentially expressed proteins were identified, and functional enrichment analysis was conducted on these proteins. The levels of target proteins were detected by enzyme linked immunosorbent assay (ELISA), and the predictive value of target protein for SA-AKI were evaluated by receiver operator characteristic curve (ROC curve). Additionally, sepsis patients and healthy individuals were selected from one hospital to externally verify the expression level of the target protein and its predictive value for SA-AKI, as well as the accuracy of CRRT treatment. RESULTS: A total of 37 patients with sepsis (including 19 with AKI and 18 without AKI) and 31 healthy individuals were enrolled for proteomic analysis. Seven proteins were identified with significantly differential expression between the SA-AKI group and non-SA-AKI group: namely cystatin C (CST3), β ₂-microglobulin (β ₂M), insulin-like growth factor-binding protein 4 (IGFBP4), complement factor I (CFI), complement factor D (CFD), CD59, and glycoprotein prostaglandin D2 synthase (PTGDS). Functional enrichment analysis revealed that these proteins were involved in immune response, complement activation, coagulation cascade, and neutrophil degranulation. ELISA results demonstrated specific expression of each target protein in the SA-AKI group. Additionally, 65 patients with sepsis (38 with AKI and 27 without AKI) and 20 healthy individuals were selected for external validation of the 7 target proteins. ELISA results showed that there were statistically significant differences in the expression levels of CST3, β ₂M, IGFBP4, CFD, and CD59 between the SA-AKI group and non-SA-AKI group. ROC curve analysis indicated that the area under the curve (AUC) values of CST3, β ₂M, IGFBP4, CFD, and CD59 for predicting SA-AKI were 0.788, 0.723, 0.723, 0.795, and 0.836, respectively, all exceeding 0.7. Further analysis of patients who underwent CRRT or not revealed that IGFBP4 had a good predictive value, with an AUC of 0.84. CONCLUSIONS Based on proteomic analysis, CST3, β ₂M, IGFBP4, CFD, and CD59 may serve as potential biomarkers for the diagnosis of SA-AKI, among which IGFBP4 might be a potential biomarker for predicting the need for CRRT in SA-AKI patients. However, further clinical validation is required.
Humans ; Sepsis/complications* ; Acute Kidney Injury/blood* ; Proteomics ; Prospective Studies ; Biomarkers/blood* ; Male ; Female ; beta 2-Microglobulin/blood* ; Middle Aged ; Cystatin C/blood* ; Aged

Objective:To explore the clinical value of adjuvant therapy in patients with T3 gallbladder cancer (GBC) who have undergone R0 resection.Methods:Clinical and pathological data from 415 patients with T3 GBC who underwent surgical treatment in 7 tertiary centers in China from January 2013 to December 2018 were collected,including 251 males and 164 females,aged (61±11)years (range: 26 to 88 years). Depending on whether to receive adjuvant therapy after radical resection,the patients were divided into the radical resection group alone (group A, n=358) and the radical resection combined with the postoperative adjuvant therapy group (group B, n=57). The general data of the two groups were matched 1∶1 by propensity score matching method,and the caliper value was 0.02.Clinicopathological characteristics,overall survival and disease-free survival of the two groups were compared.The Cox regression model was used for multivariate analysis,and patients with at least one or more independent risk factors were classified as high-risk clinicopathological subtypes. Subgroup analysis was performed to assess the clinical value of adjuvant therapy after radical resection in patients with high-risk clinicopathological subtypes. Results:After the matching,there were 42 patients in each of the two groups. The incidence of gallbladder cancer and the number of dissected lymph nodes in group B after cholecystectomy were higher than those in group A ( χ 2=9.224,2.570,both P<0.05). There were no significant differences in overall survival rate and disease-free survival rate between the two groups before and after matching (all P>0.05). The results of the univariate and multivariate analysis showed that CA19-9>39 U/ml,nerve invasion,tumor location (liver side or bilateral),TNM stage ⅢB to ⅣB ,poorly differentiated tumor were independent prognostic factors of overall survival and disease-free survival of patients with T3 stage gallbladder cancer (all P<0.05).Three hundred and twenty-nine patients(79.3%) had high-risk clinicopathological subtypes,and the median survival time after curative resection with and without adjuvant therapy was 17 months and 34 months respectively,and the 3-year and 5-year overall survival rates were respectively 40.0%,21.3% and 46.0%,46.0% ( χ 2=4.042, P=0.044);the median disease-free survival time was 9 months and 13 months,and the 3-year and 5-year disease-free survival rates were 23.4%,13.6% and 30.2%,18.2% ( χ 2=0.992, P=0.319). Conclusions:Postoperative adjuvant therapy following radical surgery did not yield significant improvements in the overall survival and disease-free survival rates of patients diagnosed with T3 gallbladder cancer. However, it demonstrated a significant extension in the overall survival rate for patients presenting high-risk clinicopathological subtypes.

Objective:To evaluate the prognostic value of sepsis-induced coagulopathy (SIC) in patients with sepsis.Methods:From January 2019 to December 2021, patients with sepsis admitted to the Intensive Care Unit of our hospital were retrospectively classified into the SIC group and non-SIC group according to SIC diagnostic criteria. The baseline clinical data, severity score, total length of hospital stay, length of ICU stay and 28-day survival were compared between the two groups. Kaplan-Meier was used to compare the 28-day survival of patients with sepsis between the two groups. Cox proportional hazard regression model was employed to analyze the risk factors of prognosis in patients with sepsis.Results:Totally 274 patients with sepsis were included in the analysis, including 139 patients in the SIC group and 135 patients in the non-SIC group. The two groups were compared in the perspectives of the Platelet count (PLT), prothrombin time (PT) , procalcitonin (PCT), D dimer, hematocrit, red blood cell distribution width, hemoglobin, acute kidney injury (AKI), the use of continuous renal replacement treatment (CRRT), the use of vasoactive drugs, sequential organ failure assessment (SOFA) score, acute physiology and chronic health evaluation (APACHEⅡ) score were compared between the two groups and the difference were statistically different (all P<0.05). Kaplan-Meier analysis showed that the 28-day mortality rate in the SIC group was significantly higher than that in the non-SIC group (32.4% vs. 14.1%, P<0.05). COX proportional hazard model showed that SIC score ( HR= 2.17, 95% CI: 1.15-3.91, P<0.05), APACHEⅡ score ( HR= 1.13, 95% CI: 1.09-1.17, P<0.05) and the use of vasoactive drugs ( HR=3.66, 95% CI: 1.53-8.75, P<0.05) were independent influencing factors for 28-day death in patients with sepsis. Conclusions:Patients with sepsis and SIC have more severe disease and increased mortality risk. SIC score exhibits good clinical value in predicting the prognosis of patients with sepsis.

Objective:To explore the clinical value of adjuvant therapy in patients with T3 gallbladder cancer (GBC) who have undergone R0 resection.Methods:Clinical and pathological data from 415 patients with T3 GBC who underwent surgical treatment in 7 tertiary centers in China from January 2013 to December 2018 were collected,including 251 males and 164 females,aged (61±11)years (range: 26 to 88 years). Depending on whether to receive adjuvant therapy after radical resection,the patients were divided into the radical resection group alone (group A, n=358) and the radical resection combined with the postoperative adjuvant therapy group (group B, n=57). The general data of the two groups were matched 1∶1 by propensity score matching method,and the caliper value was 0.02.Clinicopathological characteristics,overall survival and disease-free survival of the two groups were compared.The Cox regression model was used for multivariate analysis,and patients with at least one or more independent risk factors were classified as high-risk clinicopathological subtypes. Subgroup analysis was performed to assess the clinical value of adjuvant therapy after radical resection in patients with high-risk clinicopathological subtypes. Results:After the matching,there were 42 patients in each of the two groups. The incidence of gallbladder cancer and the number of dissected lymph nodes in group B after cholecystectomy were higher than those in group A ( χ 2=9.224,2.570,both P<0.05). There were no significant differences in overall survival rate and disease-free survival rate between the two groups before and after matching (all P>0.05). The results of the univariate and multivariate analysis showed that CA19-9>39 U/ml,nerve invasion,tumor location (liver side or bilateral),TNM stage ⅢB to ⅣB ,poorly differentiated tumor were independent prognostic factors of overall survival and disease-free survival of patients with T3 stage gallbladder cancer (all P<0.05).Three hundred and twenty-nine patients(79.3%) had high-risk clinicopathological subtypes,and the median survival time after curative resection with and without adjuvant therapy was 17 months and 34 months respectively,and the 3-year and 5-year overall survival rates were respectively 40.0%,21.3% and 46.0%,46.0% ( χ 2=4.042, P=0.044);the median disease-free survival time was 9 months and 13 months,and the 3-year and 5-year disease-free survival rates were 23.4%,13.6% and 30.2%,18.2% ( χ 2=0.992, P=0.319). Conclusions:Postoperative adjuvant therapy following radical surgery did not yield significant improvements in the overall survival and disease-free survival rates of patients diagnosed with T3 gallbladder cancer. However, it demonstrated a significant extension in the overall survival rate for patients presenting high-risk clinicopathological subtypes.

Objective:To examine a survival prognostic model applicable for patients with intrahepatic cholangiocarcinoma (ICC) based on Bayesian network.Methods:The clinical and pathological data of ICC patients who underwent curative intent resection in ten Chinese hepatobiliary surgery centers from January 2010 to December 2018 were collected.A total of 516 patients were included in the study. There were 266 males and 250 females.The median age( M( Q R)) was 58(14) years.One hundred and sixteen cases (22.5%) with intrahepatic bile duct stones,and 143 cases (27.7%) with chronic viral hepatitis.The Kaplan-Meier method was used for survival analysis.The univariate and multivariate analysis were implemented respectively using the Log-rank test and Cox proportional hazard model.One-year survival prediction models based on tree augmented naive Bayesian (TAN) and na?ve Bayesian algorithm were established by Bayesialab software according to different variables,a nomogram model was also developed based on the independent predictors.The receiver operating characteristic curve and the area under curve (AUC) were used to evaluate the prediction effect of the models. Results:The overall median survival time was 25.0 months,and the 1-,3-and 5-year cumulative survival rates was 76.6%,37.9%,and 21.0%,respectively.Univariate analysis showed that gender,preoperative jaundice,pathological differentiation,vascular invasion,microvascular invasion,liver capsule invasion,T staging,N staging,margin,intrahepatic bile duct stones,carcinoembryonic antigen,and CA19-9 affected the prognosis(χ 2=5.858-54.974, all P<0.05).The Cox multivariate model showed that gender,pathological differentiation,liver capsule invasion, T stage,N stage,intrahepatic bile duct stones,and CA19-9 were the independent predictive factors(all P<0.05). The AUC of the TAN model based on all 19 clinicopathological factors was 74.5%,and the AUC of the TAN model based on the 12 prognostic factors derived from univariate analysis was 74.0%,the AUC of the na?ve Bayesian model based on 7 independent prognostic risk factors was 79.5%,the AUC and C-index of the nomogram survival prediction model based on 7 independent prognostic risk factors were 78.8% and 0.73,respectively. Conclusion:The Bayesian network model may provide a relatively accurate prognostic prediction for ICC patients after curative intent resection and performed superior to the nomogram model.

Objective:To examine a survival prognostic model applicable for patients with intrahepatic cholangiocarcinoma (ICC) based on Bayesian network.Methods:The clinical and pathological data of ICC patients who underwent curative intent resection in ten Chinese hepatobiliary surgery centers from January 2010 to December 2018 were collected.A total of 516 patients were included in the study. There were 266 males and 250 females.The median age( M( Q R)) was 58(14) years.One hundred and sixteen cases (22.5%) with intrahepatic bile duct stones,and 143 cases (27.7%) with chronic viral hepatitis.The Kaplan-Meier method was used for survival analysis.The univariate and multivariate analysis were implemented respectively using the Log-rank test and Cox proportional hazard model.One-year survival prediction models based on tree augmented naive Bayesian (TAN) and na?ve Bayesian algorithm were established by Bayesialab software according to different variables,a nomogram model was also developed based on the independent predictors.The receiver operating characteristic curve and the area under curve (AUC) were used to evaluate the prediction effect of the models. Results:The overall median survival time was 25.0 months,and the 1-,3-and 5-year cumulative survival rates was 76.6%,37.9%,and 21.0%,respectively.Univariate analysis showed that gender,preoperative jaundice,pathological differentiation,vascular invasion,microvascular invasion,liver capsule invasion,T staging,N staging,margin,intrahepatic bile duct stones,carcinoembryonic antigen,and CA19-9 affected the prognosis(χ 2=5.858-54.974, all P<0.05).The Cox multivariate model showed that gender,pathological differentiation,liver capsule invasion, T stage,N stage,intrahepatic bile duct stones,and CA19-9 were the independent predictive factors(all P<0.05). The AUC of the TAN model based on all 19 clinicopathological factors was 74.5%,and the AUC of the TAN model based on the 12 prognostic factors derived from univariate analysis was 74.0%,the AUC of the na?ve Bayesian model based on 7 independent prognostic risk factors was 79.5%,the AUC and C-index of the nomogram survival prediction model based on 7 independent prognostic risk factors were 78.8% and 0.73,respectively. Conclusion:The Bayesian network model may provide a relatively accurate prognostic prediction for ICC patients after curative intent resection and performed superior to the nomogram model.

Objective:To examine the role of the number of lymph nodes examined(NLNE) on the prognosis of patients with curatively resected gallbladder carcinoma(GBC).Methods:The clinicopathological data and prognosis of 401 patients with GBC who underwent radical surgery from six institutions of China from January 2013 to December 2017 were analyzed retrospectively. There were 153 males(38.2%) and 248 females(61.8%), with age of (62.0±10.5) years (range: 30-88 years). Fifty-three patients(22.2%) were accompanied by jaundice. All patients underwent radical resection+regional lymphadenectomy.R0 or R1 resection was confirmed by postoperative pathological examination.The different cut-off values of NLNE were determined by the X-tile software, the optimal cut-off values were identified by analyzing the relationship between different cut-off values of NLNE with survival rate. Kaplan-Meier method was used for survival analysis. Univariate and multivariate analysis were implemented respectively using the Log-rank test and Cox proportional hazard model.Results:Among the 401 patients enrolled, 135 cases (33.6%) had lymphatic metastasis, of which 98 cases were in N1 stage(24.4%) and 37 cases were in N2 stage(9.2%).A total of 2 794 NLNE were retrieved, with a median count of 6 (5).The median positive lymph nodes count was 0 (1), and the median positive lymph nodes ratio was 0 (IQR, 0-0.2). Since the 12 and 15 were determined as the cut-off values by X-tile, all patients were divided into three groups of 1-11, 12-15 and ≥16.The 3-year survival rate of the three groups was 45.2%, 74.5%, 12.0% respectively, with statistically significant difference between three groups (χ 2=10.94, P<0.01). The results of multivariate analysis showed that NLNE was an independent prognostic factor for overall survival ( P<0.05). Further analysis was performed specifically for subgroup of T stages. For T1b patients, the prognosis of the NLNE with 1-7 group was significantly better than that of the ≥8 group(χ 2=4.610, P<0.05). For T2 patients, the prognosis of the TLNE ≥7 group was significantly better than that of 1 -6 group (χ 2=4.287, P<0.05). For T3 and T4 patients, the prognosis of the TLNE with 12 - 15 group was significantly better than that of 1 -11 group (χ 2=5.007, P<0.01) and ≥16 group (χ 2=10.158, P<0.01). Conclusions:The NLNE is an independent factor affecting the prognosis of patients with GBC.For patients with stage T1b,8 lymph nodes should be retrieved; for patients with stage T2,extensive dissection of more than 6 lymph nodes can significantly improve the prognosis.For advanced patients (stages T3 and T4), extensive dissection with 12-15 lymph nodes is recommended. However, it fails to get more survival benefits by dissecting more than 16 lymph nodes.

Objective:To examine the role of the number of lymph nodes examined(NLNE) on the prognosis of patients with curatively resected gallbladder carcinoma(GBC).Methods:The clinicopathological data and prognosis of 401 patients with GBC who underwent radical surgery from six institutions of China from January 2013 to December 2017 were analyzed retrospectively. There were 153 males(38.2%) and 248 females(61.8%), with age of (62.0±10.5) years (range: 30-88 years). Fifty-three patients(22.2%) were accompanied by jaundice. All patients underwent radical resection+regional lymphadenectomy.R0 or R1 resection was confirmed by postoperative pathological examination.The different cut-off values of NLNE were determined by the X-tile software, the optimal cut-off values were identified by analyzing the relationship between different cut-off values of NLNE with survival rate. Kaplan-Meier method was used for survival analysis. Univariate and multivariate analysis were implemented respectively using the Log-rank test and Cox proportional hazard model.Results:Among the 401 patients enrolled, 135 cases (33.6%) had lymphatic metastasis, of which 98 cases were in N1 stage(24.4%) and 37 cases were in N2 stage(9.2%).A total of 2 794 NLNE were retrieved, with a median count of 6 (5).The median positive lymph nodes count was 0 (1), and the median positive lymph nodes ratio was 0 (IQR, 0-0.2). Since the 12 and 15 were determined as the cut-off values by X-tile, all patients were divided into three groups of 1-11, 12-15 and ≥16.The 3-year survival rate of the three groups was 45.2%, 74.5%, 12.0% respectively, with statistically significant difference between three groups (χ 2=10.94, P<0.01). The results of multivariate analysis showed that NLNE was an independent prognostic factor for overall survival ( P<0.05). Further analysis was performed specifically for subgroup of T stages. For T1b patients, the prognosis of the NLNE with 1-7 group was significantly better than that of the ≥8 group(χ 2=4.610, P<0.05). For T2 patients, the prognosis of the TLNE ≥7 group was significantly better than that of 1 -6 group (χ 2=4.287, P<0.05). For T3 and T4 patients, the prognosis of the TLNE with 12 - 15 group was significantly better than that of 1 -11 group (χ 2=5.007, P<0.01) and ≥16 group (χ 2=10.158, P<0.01). Conclusions:The NLNE is an independent factor affecting the prognosis of patients with GBC.For patients with stage T1b,8 lymph nodes should be retrieved; for patients with stage T2,extensive dissection of more than 6 lymph nodes can significantly improve the prognosis.For advanced patients (stages T3 and T4), extensive dissection with 12-15 lymph nodes is recommended. However, it fails to get more survival benefits by dissecting more than 16 lymph nodes.

Objective To discuss the rationality of stage pT3 in the AJCC 8th TNM criteria of gallbladder carcinoma. Methods A retrospective study was performed to analyze the clinical and pathological data of 88 patients with pT3 gallbladder carcinoma admitted to Department of Second Biliary Surgery of Eastern Hepatobiliary Surgery Hospital, affiliated to Naval Medical University from May 2013 to September 2018.pT3 stage tumors were divided into two groups: (1) pT3a stage:tumors had penetrated serosa but not directly invaded liver and/or an adjacent organ or structure;(2) pT3b stage:tumor penetrating serosa and directly invaded liver and/or an adjacent organ or structure. There were 45 patients with pT3a stage, including 15 males and 30 females,aged 36 to 80 years,with a median age of 59 years;43 patients with pT3b, including 24 males and 19 females,aged 41 to 78 years old,median aged 63 years old.Patients with pT3a and pT3b were further divided into two groups respectively: radical resection group and extended radical resection group according to surgical radicalization. Independent sample t?test was used for comparison between two groups with normal distribution measurement data. Wilcoxon rank sum test was used between groups of non?normally distributed measurement data.The comparison of the count data was performed by χ2 test or Fisher exact probability method. Survival analysis was performed using Kaplan?Meier method, and survival rate was compared using Log?rank test.Results (1)Serum total bilirubin(15.6(90.3)mmol/L), albumin(40.2(4.8)mmol/L), and CA19?9(132.90(455.78)U/ml) levels in pT3b patients were higher than that in pT3a patients(10.2(6.8)mmol/L, 41.8(4.9)mmol/L, 14.35(36.27)U/ml), respectively(Z=-3.816,-1.966,-3.739, all P<0.05),postoperative complication rate in pT3b patients(24.4%) was higher than that in pT3a patients(8.9%)(P<0.05),postoperative hospital stay(12(7)days) and overall hospital stay((26±17)days) of pT3b patients were longer than that of pT3a patients((10±5) days and (19±7)days)(P<0.05).(2) The 1?,3?, 5?year survival rates of pT3b and pT3a patients were 53%,22%,22% and 69%, 46%,38%,and the median survival time was 13 months and 26 months, respectively. The difference in survival rates between the two groups was statistically significant(χ2=5.117, P=0.024). (3)The 1?, 3?year survival rates of extended radical resection group(n=19) and radical resection group(n=24) in the pT3b stage were 73%, 36% and 28%, 7%, respectively.The survival time was 20 months and 9 months,respectively,and the difference in survival rates between the two groups was statistically significant(χ2=4.976, P=0.026). Conclusions pT3 gallbladder carcinoma could be further subdivided into pT3a stage and pT3b stage based on the TNM criteria of AJCC 8th gallbladder carcinoma. Extended radical resection for pT3b gallbladder carcinoma should be further considered after comprehensive assessment of the patient′s basic condition and surgical tolerance.

Objective: To compare the efficacy of modified pancreaticojejunostomy with traditional pancreaticojejunostomy following pancreaticoduodenectomy, and to investigate the risk factors of postoperative pancreatic fistula. Methods: Clinical data of 68 patients who underwent pancreaticoduodenectomy between October 2017 and October 2018 at the Second Department of Biliary Tract Surgery, Eastern Hepatobiliary Surgery Hospital was retrospectively collected and analyzed.According to the method of pancreaticojejunostomy, the patients were divided into two groups: modified pancreaticojejunostomy group (34 patients) and traditional pancreaticojejunostomy group (34 patients). There were 18 males and 16 females, aged (60.4±9.6) years of modified pancreaticojejunostomy groups; there were 17 males and 18 females, aged (58.9±10.9) years of traditional pancreaticojejunostomy group. The major postoperative complications such as pancreatic fistula were compared between the two groups, and the risk factors of postoperative pancreatic fistula were analyzed by univariate and multivariate analyses. Results: All of the 68 operations were successfully completed. The overall incidence of postoperative complications was 51.5% (35/68). The incidence of postoperative pancreatic fistula was 13.2% (9/68), of which all were cases of grade B.There were 16 patients (23.5%) occurred with abdominal infection, and 11 patients (16.2%) occurred with delayed gastric emptying, including 1 case of grade A, 1 case of grade B and 9 cases of grade C.And 9 patients (13.2%) occurred with postoperative bleeding was, including 2 cases of mild bleeding, 5 cases of moderate bleeding, and 2 cases of severe bleeding.Biliary leakage occurred in one patient (1.5%) and chylous leakage occurred in two patients (2.9%). The modified pancreaticojejunostomy could significantly reduce the incidence of postoperative bleeding compared with control group (χ²=4.610, P=0.032). And there were no significant differences for other postoperative complications between the two groups (all P>0.05). According to the results of univariate analysis: age, intraoperative bleeding and diameter of pancreatic tube were related factors affecting postoperative pancreatic fistula (P=0.025, 0.019, 0.017, respectively). The results of multivariate analysis showed that intraoperative bleeding>400 ml and diameter of pancreatic tube <3 mm were independent risk factors of pancreatic fistula following pancreaticoduodenectomy (P=0.025, 0.008, respectively). Conclusion The modified pancreaticojejunostomy is feasible with advantages of reducing postoperative bleeding following pancreaticoduodenectomy.