Risk of cardiovascular death in patients with hepatocellular carcinoma based on the Fine-Gray model.

BACKGROUND: Hepatocellular carcinoma (HCC) is one of the most common types of cancers worldwide, ranking fifth among men and seventh among women, resulting in more than 7 million deaths annually. With the development of medical technology, the 5-year survival rate of HCC patients can be increased to 70%. However, HCC patients are often at increased risk of cardiovascular disease (CVD) death due to exposure to potentially cardiotoxic treatments compared with non-HCC patients. Moreover, CVD and cancer have become major disease burdens worldwide. Thus, further research is needed to lessen the risk of CVD death in HCC patient survivors. AIM: To determine the independent risk factors for CVD death in HCC patients and predict cardiovascular mortality (CVM) in HCC patients. METHODS: This study was conducted on the basis of the Surveillance, Epidemiology, and End Results database and included HCC patients with a diagnosis period from 2010 to 2015. The independent risk factors were identified using the Fine-Gray model. A nomograph was constructed to predict the CVM in HCC patients. The nomograph performance was measured using Harrell's concordance index (C-index), calibration curve, receiver operating characteristic (ROC) curve, and area under the ROC curve (AUC) value. Moreover, the net benefit was estimated via decision curve analysis (DCA). RESULTS: The study included 21545 HCC patients, of whom 619 died of CVD. Age (< 60) [1.981 (1.573-2.496), P < 0.001], marital status (married) [unmarried: 1.370 (1.076-1.745), P = 0.011], alpha fetoprotein (normal) [0.778 (0.640-0.946), P = 0.012], tumor size (≤ 2 cm) [(2, 5] cm: 1.420 (1.060-1.903), P = 0.019; > 5 cm: 2.090 (1.543-2.830), P < 0.001], surgery (no) [0.376 (0.297-0.476), P < 0.001], and chemotherapy(none/unknown) [0.578 (0.472-0.709), P < 0.001] were independent risk factors for CVD death in HCC patients. The discrimination and calibration of the nomograph were better. The C-index values for the training and validation sets were 0.736 and 0.665, respectively. The AUC values of the ROC curves at 2, 4, and 6 years were 0.702, 0.725, 0.740 in the training set and 0.697, 0.710, 0.744 in the validation set, respectively. The calibration curves showed that the predicted probabilities of the CVM prediction model in the training set vs the validation set were largely consistent with the actual probabilities. DCA demonstrated that the prediction model has a high net benefit. CONCLUSION: Risk factors for CVD death in HCC patients were investigated for the first time. The nomograph served as an important reference tool for relevant clinical management decisions.

Effects of thrombopoietin pre-treatment on peri-liver transplantation thrombocytopenia in a mouse model of cirrhosis with hypersplenism.

BACKGROUND: During cirrhosis, the liver is impaired and unable to synthesize and clear thrombopoietin properly. At the same time, the spleen assumes the function of hemofiltration and storage due to liver dysfunction, resulting in hypersplenism and excessive removal of platelets in the spleen, further reducing platelet count. When liver function is decompensated in cirrhotic patients, the decrease of thrombopoietin (TPO) synthesis is the main reason for the decrease of new platelet production. This change of TPO leads to thrombocytopenia and bleeding tendency in cirrhotic patients with hypersplenism. AIM: To investigate the clinical efficacy of recombinant human TPO (rhTPO) in the treatment of perioperative thrombocytopenia during liver transplantation in cirrhotic mice with hypersplenism. METHODS: C57BL/6J mice and TPO receptor-deficient mice were used to establish models of cirrhosis with hypersplenism. Subsequently, these mice underwent orthotopic liver transplantation (OLT). The mice in the experimental group were given rhTPO treatment for 3 consecutive days before surgery and 5 consecutive days after surgery, while the mice in the control group received the same dose of saline at the same frequency. Differences in liver function and platelet counts were determined between the experimental and control groups. Enzyme-linked immunosorbent assay was used to assess the expression of TPO and TPO receptor (c-Mpl) in the blood. RESULTS: Preoperative administration of rhTPO significantly improved peri-OLT thrombocytopenia in mice with cirrhosis and hypersplenism. Blocking the expression of TPO receptors exacerbated peri-OLT thrombocytopenia. The concentration of TPO decreased while the concentration of c-Mpl increased in compensation in the mouse model of cirrhosis with hypersplenism. TPO pre-treatment significantly increased the postoperative TPO concentration in mice, which in turn led to a decrease in the c-Mpl concentration. TPO pre-treatment also significantly enhanced the Janus kinase (Jak)/signal transducers and activators of transcription pathway protein expressions in bone marrow stem cells of the C57BL/6J mice. Moreover, the administration of TPO, both before and after surgery, regulated the levels of biochemical indicators, such as alanine aminotransferase, alkaline phosphatase, and aspartate aminotransferase in the C57BL/6J mice. CONCLUSION: Pre-treatment with TPO not only exhibited therapeutic effects on perioperative thrombocytopenia in the mice with cirrhosis and hypersplenism, who underwent liver transplantation but also significantly enhanced the perioperative liver function.

Efficacy and safety of sequential therapy with sorafenib and regorafenib for advanced hepatocellular carcinoma: a two-center study in China.

Background: Regorafenib is a standard 2nd-line treatment for patients with advanced hepatocellular carcinoma (HCC), but the efficacy and safety of sequential therapy with sorafenib and regorafenib among advanced HCC patients in China is not clear. Methods: This was a retrospective, two-center, cohort study of advanced HCC patients who received sequential therapy of sorafenib and regorafenib from October 2018 to April 2020 at 2 Chinese institutions. The patients were converted directly to regorafenib after failing to respond to sorafenib monotherapy. The patients underwent evaluations every 4-6 weeks to determine the efficacy and safety of the treatment according to physiological, laboratory, and radiological results. A radiological evaluation using computed tomography or magnetic resonance imaging scans was conducted. The outcomes included overall survival (OS) and progression-free survival (PFS). Results: A total of 43 patients received regorafenib as a 2nd-line treatment after sorafenib progression. Of these patients, 26 (60.5%) and 17 (39.5%) were diagnosed with Barcelona Clinic Liver Cancer (BCLC) stages B and C, respectively. The median PFS was 11.0 [95% confidence interval (CI): 5.8-16.2] months, and the median OS was 17.0 (95% CI: 12.8-21.2) months. Conversely, the most common toxicities were hand-foot skin reaction (48.8%), diarrhea (32.6%), and hypertension (14%). The most common grade 3-4 toxicities were hypoalbuminemia (4.7%), anemia (4.7%), and thrombocytopenia (4.7%). Alpha-fetoprotein (AFP) ≥400, alanine transaminase (ALT) ≥60 IU/L, and aspartate aminotransferase (AST) ≥60 IU/L before 2nd-line treatment were associated with PFS in the univariable analyses. The Cox proportional-hazards regression analysis showed that AFP [hazard ratio (HR) =0.225; 95% CI: 0.073-0.688; P=0.009], ALT (HR =0.195; 95% CI: 0.051-0.741; P=0.016), AST (HR =0.209; 95% CI: 0.063-0.697; P=0.011), and presence of extrahepatic metastasis (HR =0.074; 95% CI: 0.009-0.608; P=0.015) before 2nd-line treatment were independently associated with PFS. Conclusions: The sequential therapy of sorafenib and regorafenib is well-tolerated and effective in advanced HCC patients after sorafenib progression based on our two-center real-world data. Patients with good liver function reserve and a high level of AFP before 2nd-line treatment may benefit from sequential treatment. These results still need further validation.

Pre-treatment with FK506 reduces hepatic ischemia-reperfusion injury in rats.

AIM: The study is aimed to investigate the protective effects and possible mechanism of tacrolimus (FK506) pre-treatment in hepatic ischemia-reperfusion injury in rats. METHODS: The rats were randomly assigned into four groups, which were S, IR, L and H group, and then all groups were subjected to 60min of 70% partial warm liver ischemia, except S group. Rats in the L and H group were pre-treated with two different doses FK506 at 60min before ischemia. The rats of the IR group received an identical volume of normal saline. All animals were sacrificed after 6h of reperfusion. Transaminases were measured by biochemistry analyzer. Elisa kit was used to detect TNF-α, IL-6 and IL-1ß levels in serum. Liver specimens were stained with hematoxylin and eosin (HE) to assess the pathologic changes. The expressions of heme oxygenase-1 (HO-1), hypoxia-inducible factor-1α (HIF-1α), nuclear factor of activated T cells (NFAT3) were measured by real-time quantitative PCR and western blotting and the Bcl-2 and the Bax protein were tested by western blotting. RESULTS: In rats pre-treated with FK506, the levels of transaminases, TNF-α and IL-1ß were reduced significantly and also liver damage was dramatically mitigated compared to those without FK506 pre-treatment. Moreover, the expression of HO-1 at the level of both transcription and translation increased clearly and the activation of the HIF-1α was found in FK506 pre-treated livers. Moreover, NFAT3 protein transportation to the nucleus was reduced and Bax protein expression was decreased, but the expression of Bcl-2 protein was markedly increased after FK506 pre-treatment. CONCLUSION: FK506 pre-treatment could lessen hepatic ischemia-reperfusion injury through up-regulating the expression of HIF-1α and HO-1, and inhibiting nuclear translocation of NFAT3 in liver tissues.

CXC Chemokine Receptor Type 4 Antagonism Ameliorated Allograft Fibrosis in Rat Kidney Transplant Model.

OBJECTIVES: In this study, we evaluated the effects of CXC chemokine receptor type 4 and stromal cell-derived factor 1 signaling in the progression of chronic allograft nephropathy in a rat model. MATERIALS AND METHODS: Experimental rats were divided into 3 groups: Lewis-to-Lewis isograft transplant (group A), Fisher 344 rat-to-Lewis allograft transplant with immunosuppressant cyclosporine (group B), and Fisher 344 rat-to-Lewis allograft transplant treated with cyclosporine and the CXC chemokine receptor type 4 antagonist AMD3100 (1 mg/kg/d) (group C). On day 90 after the operation, renal graft function, proteinuria, and histologic Banff score were measured. The expression levels of transforming growth factor ß1 and collagen IV were determined by quantitative real-time polymerase chain reaction. RESULTS: Renal function and urinary protein were increased in allografts of groups B and C compared with isografts of group A. The Banff score was significantly decreased in the AMD3100-treated animals (group C), with renal fibrosis being reduced. In addition, overexpressed levels of transforming growth factor ß1 and collagen IV in group B allografts were significantly reduced versus that shown with treatment with the CXC chemokine receptor type 4 antagonist in group C. CONCLUSIONS: Together, these data strongly implicate that CXC chemokine receptor type 4 antagonism alleviated renal interstitial fibrosis in long-term surviving allografts by down-regulating expression of transforming growth factor ß1.

Liver tumor boundaries identified intraoperatively using real-time indocyanine green fluorescence imaging.

PURPOSE: Clear delineation between tumors and normal tissues is ideal for real-time surgical navigation imaging. We investigated applying indocyanine green (ICG) fluorescence imaging navigation using an intraoperative administration method in liver resection. METHODS: Fifty patients who underwent liver resection were divided into two groups based on clinical situation and operative purpose. In group I, sizes of superficial liver tumors were determined; tiny tumors were identified. In group II, the liver resection margin was determined; real-time navigation was performed. ICG was injected intravenously at the beginning of the operation; the liver surface was observed with a photodynamic eye (PDE). RESULTS: Liver resection margins were determined using PDE. Fluorescence contrast between normal liver and tumor tissues was obvious in 32 of 35 patients. A boundary for half the liver or specific liver segments was determined in nine patients by examining the portal vein anatomy after ICG injection. Eight small tumors not observed preoperatively were detected; the smallest was 2 mm. CONCLUSIONS: ICG fluorescence imaging navigation is a promising, simple, and safe tool for routine real-time intraoperative imaging during hepatic resection and clinical exploration in hepatocellular carcinoma, enabling high sensibility for identifying liver resection margins and detecting tiny superficial tumors.

Interleukin-22 contributes to liver regeneration in mice with concanavalin A-induced hepatitis after hepatectomy.

AIM: To investigate the therapeutic effects and mechanisms of interleukin (IL)-22 in liver regeneration in mice with concanavalin A (ConA)-induced liver injury following 70% hepatectomy. METHODS: Mice were injected intravenously with ConA at 10 µg/g body weight 4 d before 70% hepatectomy to create a hepatitis model, and recombinant IL-22 was injected at 0.125 µg/g body weight 30 min prior to 70% hepatectomy to create a therapy model. Control animals received an intravenous injection of an identical volume of normal saline. RESULTS: IL-22 treatment prior to 70% hepatectomy performed under general anesthesia resulted in reductions in the biochemical and histological evidence of liver injury, earlier proliferating cell nuclear antigen expression and accelerated recovery of liver mass. IL-22 pretreatment also significantly induced signal transducer and activator of transcription factor 3 (STAT3) activation and increased the expression of a variety of mitogenic proteins, such as Cyclin D1. Furthermore, alpha fetal protein mRNA expression was significantly elevated after IL-22 treatment. CONCLUSION: In this study, we demonstrated that IL-22 is a survival factor for hepatocytes and prevents and repairs liver injury by enhancing pro-growth pathways via STAT3 activation. Treatment with IL-22 protein may represent a novel therapeutic strategy for preventing liver injury in patients with liver disease who have undergone hepatectomy.

Prolonged ischemia elicits acute allograft rejection involved in CXCR3 activation in rat kidney transplants.

BACKGROUND: Acute rejection is a major obstacle in patients with prolonged ischemia in deceased-donor renal transplantation. Chemokines and their receptors play a critical role in leukocyte trafficking, resulting in allograft rejection; therefore, the role of chemokine receptor CXCR3 in acute rejection induced by prolonged ischemia in rat kidney transplantation models was evaluated. METHODS: Syngeneic and allogeneic renal transplantations were performed. For cold ischemia, grafts were stored in 4.0°C University of Wisconsin solution for 12 or 16 h. Serum and renal tissues were harvested 7.0 d after surgery and serum TNF-α, IL-6, and renal function were measured. Graft histology was stained with periodic acid-Schiff and immunohistochemical staining and further evaluated for signs of acute rejection. CXCR3 proteins were quantified by Western blot. The transplanted rats were divided into 4 groups as follows: iso-12-h = isogeneic transplant with 12-h CIT graft; iso-16-h = isogeneic kidney transplant with 16-h CIT graft; allo-12-h = allogeneic renal transplant with 12-h CIT graft; allo-16 h = allogeneic renal transplant with 16-h CIT graft; and 16 h+T = allogeneic 16-h CIT graft received tacrolimus. RESULTS: Prolonged cold ischemia time (CIT; 16 h) enhanced acute glomerular damage, interstitial inflammation, and tubulointerstitial cellular infiltration in allografts with and without immunosuppressant tacrolimus; but it was not apparent in the isografts. The expression of CXCR3 protein and the proportion of CXCR3-positive cells were significantly higher in the allo-16 h and 16 h +T groups than that in the allo-12 h group 7d post-surgery. CONCLUSIONS: CIT triggered acute rejection in allogeneic, but not in isogeneic, kidney transplants, accompanied by an elevation of leukocyte recruitment and damaged graft function. The upregulated expression of chemokine receptor CXCR3 promoted inflammatory infiltration and acute allograft rejection.