Parkin regulates microglial NLRP3 and represses neurodegeneration in Parkinson's disease.

Microglial hyperactivation of the NOD-, LRR-, and pyrin domain-containing 3 (NLRP3) inflammasome contributes to the pathogenesis of Parkinson's disease (PD). Recently, neuronally expressed NLRP3 was demonstrated to be a Parkin polyubiquitination substrate and a driver of neurodegeneration in PD. However, the role of Parkin in NLRP3 inflammasome activation in microglia remains unclear. Thus, we aimed to investigate whether Parkin regulates NLRP3 in microglia. We investigated the role of Parkin in NLRP3 inflammasome activation through the overexpression of Parkin in BV2 microglial cells and knockout of Parkin in primary microglia after lipopolysaccharide (LPS) treatment. Immunoprecipitation experiments were conducted to quantify the ubiquitination levels of NLRP3 under various conditions and to assess the interaction between Parkin and NLRP3. In vivo experiments were conducted by administering intraperitoneal injections of LPS in wild-type and Parkin knockout mice. The Rotarod test, pole test, and open field test were performed to evaluate motor functions. Immunofluorescence was performed for pathological detection of key proteins. Overexpression of Parkin mediated NLRP3 degradation via K48-linked polyubiquitination in microglia. The loss of Parkin activity in LPS-induced mice resulted in excessive microglial NLRP3 inflammasome assembly, facilitating motor impairment, and dopaminergic neuron loss in the substantia nigra. Accelerating Parkin-induced NLRP3 degradation by administration of a heat shock protein (HSP90) inhibitor reduced the inflammatory response. Parkin regulates microglial NLRP3 inflammasome activation through polyubiquitination and alleviates neurodegeneration in PD. These results suggest that targeting Parkin-mediated microglial NLRP3 inflammasome activity could be a potential therapeutic strategy for PD.

Mitochondrial morphology and synaptic structure altered in the retina of parkin-deficient mice.

Mutations in the PRKN gene are the major cause of autosomal recessive Parkinson's disease (PD). However, studies of parkin-/- mice did not show the loss of dopaminergic neurons and motor phenotypes at a young age. Whether pathological changes are associated with nonmotor symptoms of PD remains unclear. Visual impairment is one common nonmotor symptom in patients with PD. This study aimed to examine the effects of parkin-/- on mitochondria and synaptic structures in the retina of 6-month-old mice. Compared with wild-type mice, parkin-/- mice exhibited a slightly thickened retina. Also, the number of normal mitochondria (mito-5 grade) in rod spherules (RSs) significantly decreased (p < 0.01), the average area of mitochondria was significantly larger (p < 0.001), and the number of ribbons in RSs significantly decreased (p = 0.02). The RSs of parkin-/- mice showed severe swelling after flicker stimulation. Our study implicated that parkin-/- led to the impairment of mitochondria and abnormality of the synaptic structure in mouse retina at a young age, which damaged the synaptic transmission between photoreceptors and second-order retinal neurons and resulted in visual impairment.

Quercetin Protects against MPP+/MPTP-Induced Dopaminergic Neuron Death in Parkinson's Disease by Inhibiting Ferroptosis.

Ferroptosis, a novel form of regulated cell death, is caused by accumulation of lipid peroxides and excessive iron deposition. This process has been linked to the death of dopaminergic neurons in substantia nigra compacta (SNc) of Parkinson's disease (PD) patients. Quercetin (QCT), a natural flavonoid, has multiple pharmacological activities. However, it has not been established whether QCT can protect against dopaminergic neuron death by inhibiting ferroptosis. In this study, we investigated the potential antiferroptotic effects of QCT in cellular models established using specific ferroptosis inducers (Erastin and RSL-3) and MPP+. The effects were also explored using MPTP-induced PD mouse models. The cell counting kit-8 (CCK-8) assay was performed to assess cell viability. Variations in mitochondrial morphology were evaluated by transmission electron microscopy (TEM) while the mitochondrial membrane potential, mass, and ROS were measured by fluorescent probes. Lipid peroxidation levels were assayed through measurement of lipid ROS, MDA, GSH, and SOD levels. The effects of QCT on MPTP-induced behavioral disorders were examined by rotarod and open field tests. In vitro and in vivo, QCT significantly inhibited ferroptosis by activating the nuclear factor erythroid 2-related factor 2 (Nrf2) protein. Additionally, QCT ameliorated motor behavioral impairments and protected against the loss of dopaminergic neurons in MPTP-induced PD models. Interestingly, Nrf2 knockdown alleviated the protective effects of QCT against ferroptosis. In conclusion, these results demonstrate that ferroptosis is involved in MPP+/MPTP-induced PD, and QCT inhibits ferroptosis by activating the Nrf2 protein. Therefore, QCT is a potential agent for preventing the loss of dopaminergic neurons by targeting ferroptosis.

Different patterns of exosomal α-synuclein between Parkinson's disease and probable rapid eye movement sleep behavior disorder.

BACKGROUND AND PURPOSE: The insidious onset of Parkinson's disease (PD) makes early diagnosis difficult. Notably, idiopathic rapid eye movement sleep behavior disorder (iRBD) was reported as a prodrome of PD, which may represent a breakthrough for the early diagnosis of PD. However, currently there is no reliable biomarker for PD diagnosis. Considering that α-synuclein (α-Syn) and neuroinflammation are known to develop prior to the onset of clinical symptoms in PD, it was hypothesized that plasma total exosomal α-Syn (t-exo α-Syn), neural-derived exosomal α-Syn (n-exo α-Syn) and exosomal apoptosis-associated speck-like protein containing a caspase activation and recruitment domain (ASC) may be potential biomarkers of PD. METHODS: In this study, 78 PD patients, 153 probable iRBD patients (pRBD) and 63 healthy controls (HCs) were recruited. α-Syn concentrations were measured using a one-step paramagnetic particle-based chemiluminescence immunoassay, and ASC levels were measured using the Ella system. RESULTS: It was found that t-exo α-Syn was significantly increased in the PD group compared to the pRBD and HC groups (p < 0.0001), whilst n-exo α-Syn levels were significantly increased in both the PD and pRBD groups compared to HCs (p < 0.0001). Furthermore, although no difference was found in ASC levels between the PD and pRBD groups, there was a positive correlation between ASC and α-Syn in exosomes. CONCLUSIONS: Our results suggest that both t-exo α-Syn and n-exo α-Syn were elevated in the PD group, whilst only n-exo α-Syn was elevated in the pRBD group. Additionally, the adaptor protein of inflammasome ASC is correlated with α-Syn and may facilitate synucleinopathy.

Cholinergic neurons in the pedunculopontine nucleus guide reversal learning by signaling the changing reward contingency.

Cognitive flexibility enables effective switching between mental processes to generate appropriate responses. Cholinergic neurons (CNs) within the pedunculopontine nucleus (PPN) are associated with many functions, but their contribution to cognitive flexibility remains poorly understood. Here we measure PPN cholinergic activities using calcium indicators during the attentional set-shifting task. We find that PPN CNs exhibit increasing activities correlated with rewards during each stage and error trials in reversal stages, indicating sensitivity to rule switching. Inhibition of PPN cholinergic activity selectively impairs reversal learning, which improves with PPN CN activation. Activation of PPN CNs projecting to the substantia nigra pars compacta, mediodorsal thalamus, and parafascicular nucleus in a time-locked manner with reward improves reversal learning. Therefore, PPN CNs may encode not only reward signals but also the information of changing reward contingency that contributes to guiding reversal learning through output projections to multiple nuclei that participate in flexibility.

Specific immune status in Parkinson's disease at different ages of onset.

Recent evidence suggests that innate and adaptive immunity play a crucial role in Parkinson's disease (PD). However, studies regarding specific immune cell classification in the peripheral blood in PD remain lacking. Therefore, we aimed to explore the different immune status in patients with PD at different ages of onset. We included 22 patients; among them were 10 who had early-onset PD (EOPD) and 12 had late-onset PD (LOPD) and 10 young healthy controls (YHCs) and 8 elder HCs (EHCs). Mass cytometry staining technology was used to perform accurate immunotyping of cell populations in the peripheral blood. Motor symptoms and cognitive function were assessed using the Unified Parkinson's Disease Rating Scale (UPDRS) III score and Mini-mental State Examination (MMSE) score, respectively. T test and ANOVA statistical analysis were performed on the frequency of annotated cell population. Linear regression model was used to analyze the correlation between clusters and clinical symptoms. We characterized 60 cell clusters and discovered that the immune signature of PD consists of cluster changes, including decreased effector CD8+ T cells, lower cytotoxicity natural killer (NK) cells and increased activated monocytes in PD patients. In summary, we found that CD8+ T cells, NK cells, and monocytes were associated with PD. Furthermore, there may be some differences in the immune status of patients with EOPD and LOPD, suggesting differences in the pathogenesis between these groups.

Apolipoprotein E Genotype Contributes to Motor Progression in Parkinson's Disease.

BACKGROUND: Emerging evidence indicates that the apolipoprotein E (APOE) ε4 exacerbates α-synuclein pathology. OBJECTIVE: To determine whether APOE ε4 contributes to motor progression in early Parkinson's disease (PD). METHODS: Longitudinal data were obtained from 384 patients with PD divided into APOE ε4 carriers (n = 85) and noncarriers (n = 299) in the Parkinson's Progression Marker Initiative. Participants underwent yearly motor assessments over a mean follow-up period of 78.9 months. Repeated measures and linear mixed models were used to test the effects of APOE ε4. RESULTS: The motor progression was significantly more rapid in patients with PD carrying APOE ε4 than in noncarriers (ß = 0.283, P = 0.026, 95% confidence interval: 0.033-0.532). Through subgroup analysis, we found that the effect of APOE ε4 was significant only in patients with high amyloid ß burden (ß = 0.761, P < 0.001, 95% confidence interval: 0.0356-1.167). CONCLUSIONS: APOE ε4 may be associated with rapid motor progression in PD. © 2021 International Parkinson and Movement Disorder Society.

Study of the collagen type VI alpha 3 (COL6A3) gene in Parkinson's disease.

BACKGROUND: To date, the genetic contribution to Parkinson's disease (PD) remains unclear. Mutations in the collagen type VI alpha 3 (COL6A3) gene were recently identified as a cause of isolated dystonia. Since PD and dystonia are closely related disorders with shared clinical and genetic characteristics, we explored the association between COL6A3 and PD in a Chinese cohort. METHODS: We performed genetic screening of COL6A3 in a Chinese cohort of 173 patients with sporadic PD and 200 healthy controls. We identified variants that are likely to have pathogenic effects based on: 1) a minor allele frequency of < 0.01; and 2) the variant being recognized as deleterious by at least 15 different in silico predicting tools. Finally, we tested the aggregate burden of COL6A3 on PD via SKAT-O analysis. RESULTS: First, we found compound heterozygous COL6A3 gene mutations in one early-onset PD patients. Then, we explored whether COL6A3 variants contributed to increased risk of developing PD in a Chinese population. We detected 21 rare non-synonymous variants. Pathogenicity predictions identified 7 novel non-synonymous variants as likely to be pathogenic. SKAT-O analysis further revealed that an aggregate burden of variants in COL6A3 contributes to PD (p = 0.038). CONCLUSION: An increased aggregate burden of the COL6A3 gene was detected in patients with PD.

NLRP3 Inflammasomes in Parkinson's disease and their Regulation by Parkin.

Chronic inflammation might correlate with the formation of α-synuclein oligomers, subsequently leading to dopaminergic (DA) neuronal death in Parkinson's disease (PD). As major components of chronic inflammation, NOD-like receptor protein 3 (NLRP3) inflammasomes play a crucial role in PD via caspase 1 activation, primarily induced by mitochondrial damage. NLRP3 binds to apoptosis-associated speck-like protein containing a CARD (PYCARD/ASC), and forms inflammasomes in the brain. Inflammasomes act as a platform for caspase 1 to induce interleukin 1 Beta (IL1ß) maturation, leading to neuronal pyroptosis. Furthermore, alpha-synuclein, whose abnormal aggregation is the main pathogenesis of PD, also activates NLRP3 inflammasomes. Mutations to PRKN (encoding Parkin) are the most common cause of autosomal recessive familial and sporadic early-onset PD. Evidence has confirmed a relationship between Parkin and NLRP3 inflammasomes. In this review, we summarize the current understanding of NLRP3 inflammasomes and their role in PD progression, and discuss their regulation by Parkin.

Prognostic factors for survival after hepatic resection of early hepatocellular carcinoma in HBV-related cirrhotic patients.

OBJECTIVE: The study aimed to identify clinico-pathologic factors that predict survival in early hepatocellular carcinoma (HCC) patients with hepatitis B virus (HBV)-related cirrhosis undergoing liver resection. METHODS: A population-based cohort was investigated to identify cirrhotic patients with confirmed early HCC (tumor size≤5cm and absence of nodal involvement, metastases, or major vascular invasion) after hepatic resection at the Eastern Hepatobiliary Surgery Hospital (Shanghai, China) from April 2005 and November 2010 using the Surveillance, Epidemiology, and End Results (SEER) database. These patients were studied retrospectively in terms of their clinical characteristics and prognostic factors. Predictors for survival were evaluated using Kaplan-Meier methods and Cox proportional hazards models. Besides, a simple prognostic scoring system was proposed to stratify these patients. RESULTS: Of 537 (2.6% of all HCC patients in this period) cirrhotic patients with early HCC identified who had underwent liver resection, 87% were male. Median tumor size was 2.9cm, and 67% of patients had tumors>2cm. Following hepatic resection, overall median and 5-year survival were 75 months and 58%, respectively. Tumor size>2cm (hazard ratio [HR]=1.56), multifocality (HR=1.34), non-anatomic resection (HR=1.44) and vascular invasion (HR=2.03) were associated with worse prognosis (P<0.05). Moreover, these patients could be further stratified into 4 distinct prognostic groups based on the prognostic scoring system developed. CONCLUSION: Tumor size>2cm, multifocality, non-anatomic resection and vascular invasion may be used to stratify HBV-related cirrhotic patients with early HCC after resection. Besides, these data also indicate that pathologic staging is important even in small HCC.

Risk factors and surgical outcomes for spontaneous rupture of BCLC stages A and B hepatocellular carcinoma: a case-control study.

AIM: To investigate the risk factors and surgical outcomes for spontaneous rupture of Barcelona Clinic Liver Cancer (BCLC) stages A and B hepatocellular carcinoma (HCC). METHODS: From April 2002 to November 2006, 92 consecutive patients with spontaneous rupture of BCLC stage A or B HCC undergoing hepatic resection were included in a case group. A control arm of 184 cases (1:2 ratio) was chosen by matching the age, sex, BCLC stage and time of admission among the 2904 consecutive patients with non-ruptured HCC undergoing hepatic resection. Histological confirmation of HCC was available for all patients and ruptured HCC was confirmed by focal discontinuity of the tumor with surrounding perihepatic hematoma observed intraoperatively. Patients with microvascular thrombus in the hepatic vein branches were excluded from the study. Clinical data and survival time were collected and analysed. RESULTS: Sixteen patients were excluded from the study based on exclusion criteria, of whom 3 were in the case group and 13 in the control group. Compared with the control group, more patients in the case group had underlying diseases of hypertension (10.1% vs 3.5%, P = 0.030) and liver cirrhosis (82.0% vs 57.9%, P < 0.001). Tumors in 67 (75.3%) patients in the case group were located in segments II, III and VI, and the figure in the control group was also 67 (39.7%) (P < 0.001). On multivariate analysis, hypertension (HR = 7.38, 95%CI: 1.91-28.58, P = 0.004), liver cirrhosis (HR = 6.04, 95%CI: 2.83-12.88, P < 0.001) and tumor location in segments II, III and VI (HR = 5.03, 95%CI: 2.70-6.37, P < 0.001) were predictive for spontaneous rupture of HCC. In the case group, the median survival time and median disease-free survival time were 12 mo (range: 1-78 mo) and 4 mo (range: 0-78 mo), respectively. The 1-, 3- and 5-year overall survival rates and disease-free survival rates were 66.3%, 23.4% and 10.1%, and 57.0%, 16.8% and 4.5%, respectively. Only radical resection remained predictive for overall survival (HR = 0.32, 95%CI: 0.08-0.61, P = 0.015) and disease-free survival (HR = 0.12, 95%CI: 0.01-0.73, P = 0.002). CONCLUSION: Tumor location, hypertension and liver cirrhosis are associated with spontaneous rupture of HCC. One-stage hepatectomy should be recommended to patients with BCLC stages A and B disease.

Intrahepatic cholangiocarcinoma: a clinicopathologic study of 37 resected cases.

BACKGROUND/AIMS: This study aimed to evaluate prognostic factors for intrahepatic cholangiocarcinoma (ICC) patients who underwent surgical procedure. METHODOLOGY: A total of 37 ICC patients who underwent curative hepatic resection in our department from November 2006 to June 2009 were recruited in this study. Eighteen clinicopathological factors that might influence survival were selected. Survival rates of patients were calculated using the Kaplan-Meier method and the prognostic factors were selected by the Cox proportional hazard model. RESULTS: The overall 1-, 3- and 5- year survival rates were 37.1%, 17.1% and 11.4%, respectively. Univariate analysis showed that tumor thrombus, intrahepatic bile duct dilatation, hepatolithiasis, high serum levels of carbohydrate antigen 19-9 (CA19-9), high serum levels of total bilirubin (TB), low serum levels of prealbumin, high serum levels of γ-glutamyltransferase (γ-GT), high serum levels of alkaline phosphatase (ALP), transfusion, lymph node metastases, advanced UICC stages were significant risk factors for survival. Multivariate analysis identified CA19-9, prealbumin as independent risk factors for postoperative survival. CONCLUSIONS: This study suggested serum prealbumin levels could effectively predict the survival of the ICC patients with the treatment of operation. High serum CA19-9 level was associated with poor survival of ICC patients who underwent operation.

High expression of proline-rich tyrosine kinase 2 is associated with poor survival of hepatocellular carcinoma via regulating phosphatidylinositol 3-kinase/AKT pathway.

BACKGROUND: The peritumoral environment has been implicated to be important in the process of metastasis and recurrence in hepatocellular carcinoma (HCC). Our aims were to assess the prognostic value of proline-rich tyrosine kinase 2 (Pyk2) in HCC and investigate related molecular mechanism. METHODS: Expression of Pyk2 was tested by immunohistochemistry in tissue microarrays containing 141 paired HCC samples. Correlation between Pyk2 and vascular endothelial growth factor (VEGF) expression in clinical samples was analyzed by Spearman rank correlation. Matrigel invasion, anchorage-independent growth assay and immunoblotting were performed to study the effect of Pyk2 on the invasion and progression of HCC cells and phosphoinositide 3-kinase (PI3K)/AKT pathway activation. RESULTS: Higher Pyk2 density in both tumor and peritumor was associated with lower overall survival (P = 0.044; P = 0.041, respectively), serum AFP levels > 1,000 ng/ml (P = 0.013; P = 0.032, respectively) and postoperative distant metastasis (both P < 0.001). However, only higher peritumoral Pyk2 density was related to lower disease-free survival (P = 0.014) and vascular invasion (P = 0.035). A significant correlation between Pyk2 and VEGF density in tumor or peritumoral liver tissue was observed (r = 0. 3133, P = 0.0002; r = 0.5176, P < 0.0001, respectively). Immunoblotting showed that Pyk2 activated PI3K-AKT pathway to upregulate VEGF expression in HL-7702, SMMC-7721 and HepG2 cells. CONCLUSIONS: High Pyk2, especially peritumoral Pyk2 was associated with poor survival, disease recurrence, and metastasis in HCC. PI3K-AKT pathway was involved in Pyk2-mediated VEGF expression during HCC progression and invasion.

Prealbumin is predictive for postoperative liver insufficiency in patients undergoing liver resection.

AIM: To investigate the risk factors for postoperative liver insufficiency in patients with Child-Pugh class A liver function undergoing liver resection. METHODS: A total of 427 consecutive patients undergoing partial hepatectomy from October 2007 to April 2011 at a single center (Department of Hepatic SurgeryI, Eastern Hepatobiliary Surgery Hospital, Shanghai, China) were included in the study. All the patients had preoperative liver function of Child-Pugh class A and were diagnosed as having primary liver cancer by postoperative histopathology. Surgery was performed by the same team and hepatic resection was carried out by a clamp crushing method. A clamp/unclamp time of 15 min/5 min was adopted for hepatic inflow occlusion. Patients' records of demographic variables, intraoperative parameters, pathological findings and laboratory test results were reviewed. Postoperative liver insufficiency and failure were defined as prolonged hyperbilirubinemia unrelated to biliary obstruction or leak, clinically apparent ascites, prolonged coagulopathy requiring frozen fresh plasma, and/or hepatic encephalopathy. The incidence of postoperative liver insufficiency or liver failure was observed and the attributing risk factors were analyzed. A multivariate analysis was conducted to determine the independent predictive factors. RESULTS: Among the 427 patients, there were 362 males and 65 females, with a mean age of 51.1 ± 10.4 years. Most patients (86.4%) had a background of viral hepatitis and 234 (54.8%) patients had liver cirrhosis. Indications for partial hepatectomy included hepatocellular carcinoma (391 patients), intrahepatic cholangiocarcinoma (31 patients) and a combination of both (5 patients). Hepatic resections of ≤ 3 and ≥ 4 liver segments were performed in 358 (83.8%) and 69 (16.2%) patients, respectively. Seventeen (4.0%) patients developed liver insufficiency after hepatectomy, of whom 10 patients manifested as prolonged hyperbilirubinemia unrelated to biliary obstruction or leak, 6 patients had clinically apparent ascites and prolonged coagulopathy, 1 patient had hepatic encephalopathy and died on day 21 after surgery. On univariate analysis, age ≥ 60 years and prealbumin < 170 mg/dL were found to be significantly correlated with postoperative liver insufficiency (P = 0.045 and P = 0.009, respectively). There was no statistical difference in postoperative liver insufficiency between patients with or without hepatitis, liver cirrhosis and esophagogastric varices. Intraoperative parameters (type of resection, inflow blood occlusion time, blood loss and blood transfusion) and laboratory test results were not associated with postoperative liver insufficiency either. Age ≥ 60 years and prealbumin < 170 mg/dL were selected on multivariate analysis, and only prealbumin < 170 mg/dL remained predictive (hazard ratio, 3.192; 95%CI: 1.185-8.601, P = 0.022). CONCLUSION: Prealbumin serum level is a predictive factor for postoperative liver insufficiency in patients with liver function of Child-Pugh class A undergoing hepatectomy. Since prealbumin is a good marker of nutritional status, the improved nutritional status may decrease the incidence of liver insufficiency.

Predictors and clinical outcomes for spontaneous rupture of hepatocellular carcinoma.

AIM: To determine the risk factors for hepatocellular carcinoma (HCC) rupture, and report the management and long-term survival results of patients with spontaneous rupture of HCC. METHODS: Among 4209 patients with HCC who were diagnosed at Eastern Hepatobiliary Surgery Hospital from April 2002 to November 2006, 200 (4.8%) patients with ruptured HCC (case group) were studied retrospectively in term of their clinical characteristics and prognostic factors. The one-stage therapeutic approach to manage ruptured HCC consisted of initial management by conservative treatment, transarterial embolization (TACE) or hepatic resection. Results of various treatments in the case group were evaluated and compared with the control group (202 patients) without ruptured HCC during the same study period. Continuous data were expressed as mean ± SD or median (range) where appropriate and compared using the unpaired t test. Categorical variables were compared using the Chi-square test with Yates correction or the Fisher exact test where appropriate. The overall survival rate in each group was determined using the Kaplan-Meier method and a log-rank test. RESULTS: Compared with the control group, more patients in the case group had underlying diseases of hypertension (7.5% vs 3.0%, P =0.041) and liver cirrhosis (87.5% vs 56.4%, P < 0.001), tumor size >5 cm (83.0% vs 57.4%, P < 0.001), tumor protrusion from the liver surface (66.0% vs 44.6%, P < 0.001), vascular thrombus (30.5% vs 8.9%, P < 0.001) and extrahepatic invasion (36.5% vs 12.4%, P < 0.001). On multivariate logistic regression analysis, underlying diseases of hypertension (P = 0.002) and liver cirrhosis (P < 0.001), tumor size > 5 cm (P < 0.001), vascular thrombus (P = 0.002) and extrahepatic invasion (P < 0.001) were predictive for spontaneous rupture of HCC. Among the 200 patients with spontaneous rupture of HCC, 105 patients underwent hepatic resection, 33 received TACE, and 62 were managed with conservative treatment. The median survival time (MST) of all patients with spontaneous rupture of HCC was 6 mo (range, 1-72 mo), and the overall survival at 1, 3 and 5 years were 32.5%, 10% and 4%, respectively. The MST was 12 mo (range, 1-72 mo) in the surgical group, 4 mo (range, 1-30 mo) in the TACE group and 1 mo (range, 1-19 mo) in the conservative group. Ninety-eight patients in the control group underwent hepatic resection, and the MST and median disease-free survival time were 46 mo (range, 6-93 mo) and 23 mo (range, 3-39 mo) respectively, which were much longer than that of patients with spontaneous rupture of HCC undergoing hepatic resection (P < 0.001). The 1-, 3-, and 5-year overall survival rates and the 1-, 3- and 5-year disease-free survival rates in patients with ruptured HCC undergoing hepatectomy were 57.1%, 19.0% and 7.6%, 27.6%, 14.3% and 3.8%, respectively, compared with those of 77.1%, 59.8% and 41.2%, 57.1%, 40.6% and 32.9% in 98 patients without ruptured HCC undergoing hepatectomy (P < 0.001). CONCLUSION: Prolonged survival can be achieved in selected patients undergoing one-stage hepatectomy, although the survival results were inferior to those of the patients without ruptured HCC.

p28GANK overexpression accelerates hepatocellular carcinoma invasiveness and metastasis via phosphoinositol 3-kinase/AKT/hypoxia-inducible factor-1α pathways.

UNLABELLED: The overall survival of patients with hepatocellular carcinoma (HCC) remains poor, and the molecular mechanisms underlying HCC progression and aggressiveness are unclear. Here, we report that increased expression of p28(GANK) (Gankyrin, PSMD10, or p28) in human HCC predicts poor survival and disease recurrence after surgery. Patients with HCC who have large tumors, with vascular invasion and intrahepatic or distant metastasis, expressed high levels of p28(GANK) . Invasive tumors overexpressing p28(GANK) were featured by active epithelial-mesenchymal transition (EMT), and exhibited increased angiogenesis associated with vascular endothelial growth factor overexpression, whereas silencing p28(GANK) expression attenuated EMT and motility/invasion of tumor cells. The p28(GANK) activates phosphoinositide 3-kinase (PI3K)-V-akt Murine Thymoma Viral Oncogene Homolog (AKT)-hypoxia-inducible factor 1α (HIF-1α) signaling to promote TWIST1, vascular endothelial growth factor, and metalloproteinase 2 expression. Suppression of the PI3K-AKT-HIF-1α pathway interfered with p28(GANK) -mediated EMT and invasion. Consistently, we detected a significant correlation between p28(GANK) expression and p-AKT levels in a cohort of HCC biopsies, and the combination of these two parameters is a more powerful predictor of poor prognosis. CONCLUSION: These results present novel mechanistic insight into a critical role of p28(GANK) in HCC progression and metastasis.

[Exploration of indication of prophylactic transcatheter arterial chemoembolization on postoperative recurrence of hepatocellular carcinoma].

OBJECTIVE: To evaluate the efficacy of prophylactic transcatheter arterial chemoembolization (TACE) on postoperative recurrence of hepatocellular carcinoma. METHODS: A retrospective analysis was performed on clinicopathologic data of 260 hepatocellular carcinoma patients who underwent curative hepatectomy in Eastern Hepatobiliary Surgery Hospital, Second Military Medical University from January 2004 to June 2007. Among the 260 patients, 104 underwent postoperative prophylactic TACE and the other 156 were not. RESULTS: The overall survival rates at 1- and 2-years were 84.1% and 70.5% respectively. The overall disease-free survival rates at 1- and 2-years were 69.2% and 58.4% respectively. Of 260 overall patients, the disease-free survival rates at 1- and 2-years were 72.8% and 54.9% respectively in TACE group, and 66.9% and 59.7% respectively in non-TACE group, statistically significant difference of the cumulative disease-free survival rates at 1- and 2-years between TACE group and non-TACE group were not observed (P = 0.145, P = 0.405). Of 62 patients with tumor size >or= 10 cm, the disease-free survival rates at 1- and 2-years were respectively 66.6% and 48.7% in TACE group, and respectively 44.6% and 31.2% years between TACE group and non-TACE group were observed (P = 0.025, P = 0.025). Of 38 patients with vascular tumor thrombi, the disease-free survival rates at 1- and 2-years were respectively 33.0% and 0 in TACE group, and respectively 26.2% and 21.8% in non-TACE group, statistically significant difference of the cumulative disease-free survival rates at 1-years between TACE group and non-TACE group was observed (P = 0.025), and not at 2-years (P = 0.122). CONCLUSIONS: In non-TACE group, statistically significant difference of the cumulative disease-free survival rates at 1- and 2-Prophylactic TACE is preferred for hepatocellular carcinoma patients with high risk factors for recurrence such as tumor size >or= 10 cm and presented vascular tumor thrombi.

[Treatment strategy for synchronous liver metastasis from colorectal cancer].

BACKGROUND & OBJECTIVE: The patients with synchronous liver metastasis from colorectal cancer might get long-term survival after liver resection. But the optimal timing of surgery is undefined. This study was to explore the treatment strategy for synchronous liver metastasis from colorectal cancer. METHODS: From 1995 to 2005, 83 patients with synchronous liver metastasis from colorectal cancer were treated with operation at Eastern Hepatobiliary Surgery Hospital. Of the 83 patients, 37 received simultaneous liver and colorectal resection, and 46 received staged resection. The occurrence rate of postoperative complications, mortality, blood loss, hospital duration, overall survival rate, median survival time, disease-free survival time and recurrence rate of the 2 groups were compared. RESULTS: The occurrence rates of postoperative complications were 24.3% in simultaneous resection group and 19.6% in staged resection group (P=0.601). No operation-related death occurred. The mean blood losses were 462 mL in simultaneous resection group and 574 mL in staged resection group (P=0.312). The mean hospital duration was 19 days in simultaneous resection group and 36 days in staged resection group (P=0.001). The 1-, 3-and 5-year overall survival rates were 86.5%, 54.1%, and 27.0%, respectively, in simultaneous resection group and 89.1%, 52.2%, and 23.9%, respectively, in staged resection group (P>0.05). The median survival time was 40 months in simultaneous resection group and 37 months in staged resection group (P=0.075)û the median disease-free survival time was 12 and 11 months, respectively (P=0.532). The recurrence rates were 35.1% in simultaneous resection group and 30.4% in staged resection group (P=0.650). CONCLUSION: Synchronous liver and colorectal resection is preferred for synchronous liver metastasis from colorectal cancer.

Precautions in caudate lobe resection: report of 11 cases.

AIM: To find the precautions against the safety in caudate lobe resection. METHODS: The clinical data obtained from 11 cases of primary liver cancer in caudate lobe who received hepatectomy successfully were retrospectively analyzed. Four safe procedures were used in resection of primary liver cancer in caudate lobe: (1) selection of appropriate skin incision to obtain excellent exposure of operative field; (2) adequate mobilization of the liver to allow the liver to be displaced upwards to the left or to the right; (3) preparatory placement of tapes for total hepatic vascular exclusion, so that this procedure could be used to control the fatal bleeding of the liver when necessary; (4) selection of the ideal route for hepatectomy based on the condition of the tumor and the combined removal of multiple lobes if necessary. Among the 11 cases, simple occlusion of vessels of porta hepatis was used in caudate lobectomy for 6 cases, while in the other cases, the vessels were intermittently occluded several times or total hepatic vascular isolation was used in the caudate lobectomy. Combined partial right hepatectomy was done for 3 cases, combined left lateral lobectomy for 2 cases and caudate lobectomy alone for 6 cases. RESULTS: Operation was successful for all the 11 cases. Intermittent inflow occlusion was performed for all patients for 15 min at 5-min intervals. Blockade was performed twice in 3 patients and total hepatic vascular exclusion was performed in one of the three patients. Blockade was performed three times in one patient, including a total hepatic vascular exclusion. Total hepatic vascular exclusion was performed only in one patient. The mean blood loss was 300 mL. Ascites and pleural effusion occurred in 4 patients, jaundice in 1 patient. Six patients died of tumor recurrence in 6, 11, 12, 13, 15, 19 mo after operation, respectively. The other 5 patients have survived more than 16 mo since the operation. CONCLUSION: Caudate lobectomy for liver cancer in candate lobe can be safely performed with the above procedures.