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.

Application value of mixed reality in hepatectomy for hepatocellular carcinoma.

BACKGROUND: As a new digital holographic imaging technology, mixed reality (MR) technology has unique advantages in determining the liver anatomy and location of tumor lesions. With the popularization of 5G communication technology, MR shows great potential in preoperative planning and intraoperative navigation, making hepatectomy more accurate and safer. AIM: To evaluate the application value of MR technology in hepatectomy for hepatocellular carcinoma (HCC). METHODS: The clinical data of 95 patients who underwent open hepatectomy surgery for HCC between June 2018 and October 2020 at our hospital were analyzed retrospectively. We selected 95 patients with HCC according to the inclusion criteria and exclusion criteria. In 38 patients, hepatectomy was assisted by MR (Group A), and an additional 57 patients underwent traditional hepatectomy without MR (Group B). The perioperative outcomes of the two groups were collected and compared to evaluate the application value of MR in hepatectomy for patients with HCC. RESULTS: We summarized the technical process of MR-assisted hepatectomy in the treatment of HCC. Compared to traditional hepatectomy in Group B, MR-assisted hepatectomy in Group A yielded a shorter operation time (202.86 ± 46.02 min vs 229.52 ± 57.13 min, P = 0.003), less volume of bleeding (329.29 ± 97.31 mL vs 398.23 ± 159.61 mL, P = 0.028), and shorter obstructive time of the portal vein (17.71 ± 4.16 min vs 21.58 ± 5.24 min, P = 0.019). Group A had lower alanine aminotransferas and higher albumin values on the third day after the operation (119.74 ± 29.08 U/L vs 135.53 ± 36.68 U/L, P = 0.029 and 33.60 ± 3.21 g/L vs 31.80 ± 3.51 g/L, P = 0.014, respectively). The total postoperative complications and hospitalization days in Group A were significantly less than those in Group B [14 (37.84%) vs 35 (60.34%), P = 0.032 and 12.05 ± 4.04 d vs 13.78 ± 4.13 d, P = 0.049, respectively]. CONCLUSION: MR has some application value in three-dimensional visualization of the liver, surgical planning, and intraoperative navigation during hepatectomy, and it significantly improves the perioperative outcomes of hepatectomy for HCC.

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.

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.