Objective:To investigate the safety and efficacy of FOLFOX (5-fluorouracil + calcium folinate + oxaliplatin) hepatic arterial infusion chemotherapy (FOLFOX-HAIC) combined with immune and targeted therapy as triple combination therapy for patients with single China Liver Cancer Staging (CNLC) Ⅰb hepatocellular carcinoma.Methods:A total of 20 patients with single CNLC Ⅰb hepatocellular carcinoma who received FOLFOX-HAIC combined with immune and targeted therapy as triple combination therapy in the First Affiliated Hospital of Guangxi Medical University from October 2021 to August 2022 were included. The clinical data of all patients was retrospectively analyzed. There were 18 males and 2 females, with the age of (55.1±9.9) years. Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 and Modified Response Evaluation Criteria in Solid Tumors (mRECIST) were used to evaluate the efficacy of FOLFOX-HAIC combined with immune and targeted therapy, and the clinical safety of triple combination therapy was evaluated by common terminology criteria for adverse events 4.0.Results:According to RECIST 1.1, objective response rate of 20 patients was 70.0% (14/20) and disease control rate was 100.0% (20/20) after 2 cycles of treatment (one cycle of FOLFOX-HAIC plus programmed death-1 antibody). According to mRECIST, objective response rate was 90.0% (18/20) and the disease control rate was 100.0% (20/20) after 2 cycles of treatment. Following the treatment, 12 patients (60.0%) received liver tumor resection, and all of them achieved R 0 resection, 2 patients (10.0%) received radiotherapy, 3 patients (15.0%) stopped drug treatment for surgery, 2 patients (10.0%) refused surgery, and 1 patient (5.0%) died of multiple organ failure caused by immune hepatitis. According to pathological results, 3 patients (25.0%, 3/12) achieved pathological complete response, and 4 patients (33.3%, 4/12) achieved major pathological response. In the safety evaluation, the overall incidence of adverse events was 100.0% (20/20). Seven patients (35.0%) had grade 3 adverse events and 1 patient (5.0%) died of multiple organ failure due to immune hepatitis (grade 5). Grade 1-3 adverse events could be relieved after symptomatic treatment. Conclusion:The triple combination therapy of FOLFOX-HAIC combined with immune and targeted therapy is safe and has high objective response rate and disease control rate, which could be a new strategy for the neoadjuvant treatment of hepatocellular carcinoma.

Objective:To evaluate the effect of reactivated ultrasound contrast agent on prevention of ischemia-reperfusion (IR) injury in rat hindlimb ischemia model.Methods:Microbubbles were compressed into nanodroplets (NDs) and the particle size range was determined.In vitro experiments were carried out to observe the acoustic phase transition of nanodroplets in the ultrasound field and the change of dissolved oxygen (DO) concentration in the surrounding solution. Forty-one male Sprague Dawley rats were divided into 5 groups: acoustic nanodroplet vaporization treatment group (NDs+ US group, n=9), saline+ ultrasound treatment group (Saline+ US group, n=8), nanodroplet without ultrasound treatment group (NDs group, n=8), ischemia/reperfusion injury group (IRI group, n=8) and sham operation group (Sham group, n=8). Ultrasound imaging was performed before operation and 12 hours after reperfusion to evaluate the improvement of hemodynamics of criminal artery under different treatments. Tissue injury were evaluated by analyzing immunohistochemistry staining results. Results:The formed NDs ranged in size from approximately 68.0-295.4 nm and the highest concentration in the 100 nm range. In vitro studies, a decrease in DO was measured during the phase transition.In the animal experiment, after ischemia/reperfusion, NDs+ US, Saline+ US, NDs and IRI groups demonstrated a significantly higher resistance index (RI) and pualsatility index (PI) of the right common iliac artery compared with before operation (NDs+ US group: PI 1.79±0.17 vs 1.57±0.23, P=0.014; RI 0.80±0.02 vs 0.75±0.04, P=0.002. Saline+ US group: PI 2.29±0.16 vs 1.57±0.16, P<0.001; RI 0.90±0.06 vs 0.74±0.03, P<0.001. NDs group: PI 2.17±0.14 vs 1.53±0.15, P<0.001; RI 0.91±0.04 vs 0.75±0.04, P<0.001. IRI group: PI 2.12±0.22 vs 1.58±0.20, P<0.001; RI 0.88±0.04 vs 0.75±0.04, P<0.001). The increases of PI and RI (ΔPI, ΔRI) in NDs+ US group were higher than those in sham group (all P<0.05), but significantly lower than those in saline+ US group, NDS group and IRI group (all P<0.05). Immunohistochemical results indicated the percentages malondialdehyde (MDA) positive cells in Saline+ US, NDs and IRI groups were higher than those in NDs+ US and sham groups (all P<0.05). Conclusions:The acoustic phase transition of nanodroplets in the ultrasound field can reduce ischemia/reperfusion injury and improve hemodynamics abnormality after reperfusion.

Objective To understand the incidence and risk factors of warfarin related hemorrhagic events during anticoagulation therapy with warfarin in patients with cirrhosis and portal vein thrombosis (PVT)after transjugular intrahepatic portosystemic shunt (TIPS). Methods The patients with liver cirrhosis who were treated with warfarin after TIPS due to portal hypertension were followed up from January 2012 in Xijing Hospital of Digestive Diseases,Air Force Military Medical University. The data of medical records and follow-up records up to the end of December 2015 in patients undergoing TIPS were collected and retrospectively analyzed. Cumulative incidence of hemorrhagic events related to warfarin treatment was calculated by Kaplan-Meier method. The patients were divided into warfarin-related bleeding group (bleeding group ) and non warfarin-related bleeding group (non-bleeding group ). The risk factors of hemorrhagic events related to warfarin treatment were analyzed using Cox regression model and the hazard ratio (HR)and the 95% confidence interval (CI)were calculated. Results A total of 179 patients were enrolled,including 117 males and 62 females with ages of 25-79 years and average age of (52 ± 12)years;the bleeding group comprised 47 patients (26.3%)and the non-bleeding group comprised 132 patients (73.7%). The follow-up time after discharge ranged 1-74 months and the average time was (28 ± 21) months. The average portal pressure gradient dropped from (25.4 ± 5.2)to (8.7 ± 3.7)mmHg before and after TIPS (P＜0.001). The median dose of oral warfarin in patients in the bleeding group was 2.5 (ranged from 2.5 to 3.75)mg and the median INR was 3.12 (ranged from 2.04 to 9.41);the median dose of oral warfarin in patients in the non-bleeding group was 1.8 (ranged from 0.63 to 2.5)mg and the median INR was 1.85 (ranged from 1.5 to 3.38). Fifty eight cases of hemorrhagic events occurred in 47 patients in the bleeding group,including 24 cases of gingival bleeding,16 cases of epistaxis,8 cases of cutaneous purpura, 4 cases of conjunctival hemorrhage,2 cases of hemorrhage of digestive tract,2 cases of intracranial hemorrhage,1 cases of hematuria,and 1 cases of menorrhagia. Nine of the 47 patients in the bleeding group had bleeding from multiple sites. The results of Kaplan-Meier analysis showed that the 1-,2-,3-,4-,5-and 6-year cumulative incidences of hemorrhagic events related to warfarin treatment after operation were 19%,23%,24%,30%,41%,and 45%,respectively. Warfarin was stopped in 11 patients and given at reduced doses in 36 patients among the 47 patients in the bleeding group. After that,43 patients'hemorrhagic symptoms disappeared and 3 patients' symptoms relieved,and then warfarin treatments were continued,except that 1 patient with a long history of hypertension died of intracranial hemorrhage. Multiple Cox regression analysis showed that the baseline serum creatinine level ＞115 μmol/L was an independent risk factor for hemorrhagic events related to warfarin treatment (HR＝1.82,95%CI:1.01-3.28,P＝0.045). Conclusions It is relatively safe for patients with liver cirrhosis and PVT receiving warfarin anticoagulation therapy after TIPS. Elevated serum creatinine is an independent risk factor for hemorrhagic events related to warfarin treatment.

Objective To understand the incidence and risk factors of warfarin related hemorrhagic events during anticoagulation therapy with warfarin in patients with cirrhosis and portal vein thrombosis (PVT)after transjugular intrahepatic portosystemic shunt (TIPS). Methods The patients with liver cirrhosis who were treated with warfarin after TIPS due to portal hypertension were followed up from January 2012 in Xijing Hospital of Digestive Diseases,Air Force Military Medical University. The data of medical records and follow-up records up to the end of December 2015 in patients undergoing TIPS were collected and retrospectively analyzed. Cumulative incidence of hemorrhagic events related to warfarin treatment was calculated by Kaplan-Meier method. The patients were divided into warfarin-related bleeding group (bleeding group ) and non warfarin-related bleeding group (non-bleeding group ). The risk factors of hemorrhagic events related to warfarin treatment were analyzed using Cox regression model and the hazard ratio (HR)and the 95% confidence interval (CI)were calculated. Results A total of 179 patients were enrolled,including 117 males and 62 females with ages of 25-79 years and average age of (52 ± 12)years;the bleeding group comprised 47 patients (26.3%)and the non-bleeding group comprised 132 patients (73.7%). The follow-up time after discharge ranged 1-74 months and the average time was (28 ± 21) months. The average portal pressure gradient dropped from (25.4 ± 5.2)to (8.7 ± 3.7)mmHg before and after TIPS (P＜0.001). The median dose of oral warfarin in patients in the bleeding group was 2.5 (ranged from 2.5 to 3.75)mg and the median INR was 3.12 (ranged from 2.04 to 9.41);the median dose of oral warfarin in patients in the non-bleeding group was 1.8 (ranged from 0.63 to 2.5)mg and the median INR was 1.85 (ranged from 1.5 to 3.38). Fifty eight cases of hemorrhagic events occurred in 47 patients in the bleeding group,including 24 cases of gingival bleeding,16 cases of epistaxis,8 cases of cutaneous purpura, 4 cases of conjunctival hemorrhage,2 cases of hemorrhage of digestive tract,2 cases of intracranial hemorrhage,1 cases of hematuria,and 1 cases of menorrhagia. Nine of the 47 patients in the bleeding group had bleeding from multiple sites. The results of Kaplan-Meier analysis showed that the 1-,2-,3-,4-,5-and 6-year cumulative incidences of hemorrhagic events related to warfarin treatment after operation were 19%,23%,24%,30%,41%,and 45%,respectively. Warfarin was stopped in 11 patients and given at reduced doses in 36 patients among the 47 patients in the bleeding group. After that,43 patients'hemorrhagic symptoms disappeared and 3 patients' symptoms relieved,and then warfarin treatments were continued,except that 1 patient with a long history of hypertension died of intracranial hemorrhage. Multiple Cox regression analysis showed that the baseline serum creatinine level ＞115 μmol/L was an independent risk factor for hemorrhagic events related to warfarin treatment (HR＝1.82,95%CI:1.01-3.28,P＝0.045). Conclusions It is relatively safe for patients with liver cirrhosis and PVT receiving warfarin anticoagulation therapy after TIPS. Elevated serum creatinine is an independent risk factor for hemorrhagic events related to warfarin treatment.