A novel prognostic index of hepatocellular carcinoma based on immunogenomic landscape analysis.

Changes in immune responses to hepatocellular carcinoma (HCC) are closely related to the occurrence, development, and prognosis of this disease. Exploring the role of immune-related genes (IRGs) in HCC would provide insights into the mechanisms regulating this disease. The Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC) provide a platform for such research, owing to a large number of HCC samples available for comprehensive and systematic immunogenomics analyses. We analyzed the IRGs expression profile and clinical information of patients with HCC based on the TCGA and ICGC database. Potential molecular mechanisms and properties of the screened IRGs were analyzed across multiple databases. And we analyzed the correlation between IRGs, single-nucleotide polymorphisms, and copy number variation. A novel prognostic index, based on IRGs, was developed using the LASSO Cox regression algorithm, followed by univariate and multivariate Cox regression analyses to analyze the prognostic index. Information in the ICGC database was used to verify the reliability of the prognostic index. A total of 54 differentially expressed IRGs were found to be significantly associated with HCC prognosis, and there is a significant correlation between their expression level and copy number variation. Functional enrichment analyses indicated that the genes play active roles in tumor and immune-related signaling pathways. In addition, five potential biomarkers namely IRG, MAPK3, HSP90AA1, HSP90AB1, HSPA4, and CDK4, were identified. Finally, a novel prognostic index, based on IRGs (PSMD14, FABP6, ISG20L2, HGF, BIRC5, IL17D, and STC2), was found useful as an independent prognostic factor, not only for prognosis but also to reflect levels of infiltration in a variety of immune cells. Our team conducted a genomics study of IRGs in HCC and screened several clinically significant IRGs, and our model provides an effective approach for stratification and characterization of patients using IRG-based immunolabeling tools to monitor the prognosis of HCC.

Laparoscopic hepatectomy is associated with a higher incident frequency in hepatolithiasis patients.

PURPOSES: The primary concern regarding laparoscopic hepatectomy in hepatolithiasis patients is surgical safety, which may be high in current practice. METHODS: Hepatolithiasis patients who underwent laparoscopic and laparotomic hepatectomies were retrospectively studies after being matched for age, location of gallstones, liver resection and underlying liver conditions at a ratio of 1:1 (n = 44 in each group). The rates of intraoperative incidents and postoperative complications were examined using validated classification and grading systems. The primary outcome measure was the procedure-related complication/mortality rate. RESULTS: Laparoscopy was converted to open surgery in three patients (6.8 %). The length of the operation for laparoscopic hepatectomy was significantly longer than that for laparotomic hepatectomy (277.5 min [range, 190-410 min] vs. 212.5 min [140-315 min], P < 0.001). The two groups had similar intraoperative blood loss (367.5 mL [150-1200 mL] vs. 392.5 mL [200-1400 mL], P > 0.05) and transfusion frequencies (13.6 vs. 18.2 %, P > 0.05). The laparoscopy group had a higher percentage of patients with at least one intraoperative incident compared with the laparotomy group (22.7 vs. 6.8 %; P < 0.05). Vascular events occurred in nine patients (20.5 %) undergoing laparoscopy and two patients (4.5 %) undergoing laparotomy (OR 5.4 [95 %CI, 1.1-26.7], P < 0.05). CONCLUSIONS: Laparoscopic hepatectomy is associated with a higher risk of intraoperative vascular incidents in hepatolithiasis patients compared wit laparotomy.

[Roles of targeting Ras/Raf/MEK/ERK signaling pathways in the treatment of esophageal carcinoma].

Ras is best known for its ability to regulate cell growth, proliferation and differentiation. Mutations in Ras are associated with the abnormal cell proliferation which can result in incidence of all human cancers. Extracellular signal-regulated kinase (ERK) is a downstream effector of Ras and plays important roles in prognosis of tumors. Recently, evidence has gradually accumulated to demonstrate that there are other effectors between Ras and ERK, these proteins interact each other and constitute the thorough Ras/Raf/MEK/ERK signaling pathway. The pathway has profound effects on incidence of esophageal carcinoma and clinical applications of some chemotherapeutic drugs targeting the pathway. Further understanding of the relevant molecular mechanisms of Ras/Raf/MEK/ERK signaling pathway can be helpful for the development of efficient targeting therapeutic approaches which contribute to the treatment of esophageal cancer. In this article, roles of Ras/Raf/MEK/ERK signaling pathway in esophageal carcinoma as well as pharmacological targeting point in the pathway are reviewed.

Prognostic impact of surgical margin in patients with hepatocellular carcinoma: A meta-analysis.

BACKGROUND: Surgical margin is an important prognostic factor in hepatectomy for patients with hepatocellular carcinoma (HCC). But the extent of surgical margins is still controversial. Our study was designed to systematically evaluate the prognosis of different width of resection margin. METHODS: We conducted comprehensive searches of electronic databases including PubMed, MEDLINE, EMBASE, Cochrane, and the ISI Web of Science for relevant studies. A meta-analysis was performed by RevMan 5.3 software. RESULTS: A total of 7 studies comprising 1932 patients were included. The patients with wider surgical margin were significantly higher than those with narrow surgical margin on 3-year overall survival (odds ratio [OR]: 1.58, 95% confidence interval (95% CI): 1.21-2.06, P = .0008), 5-year overall survival (OR: 1.76, 95% CI: 1.20-2.59, P = .004), 1-year disease-free survival (DFS)/recurrence-free survival (RFS) (OR: 1.43, 95% CI: 1.12-1.82, P = .005), 3-year DFS/RFS (OR: 1.66, 95% CI: 1.35-2.03, P < .00001), and 5-year DFS/RFS (OR: 1.69, 95% CI: 1.37-2.08, P < .00001). There was no significant difference in the 1-year overall survival rate for the 2 groups (OR: 1.24, 95% CI: 0.89-1.72, P = .20). CONCLUSION: In comparison with the narrow surgical margin group (<1 cm), the wide surgical margin (≥1 cm) can significantly improve the prognosis in patients with HCC.

Meta-analysis of the prognostic value of lncRNA ZFAS1 in patients with solid tumors.

Expression of ZFAS1, a newly identified long noncoding RNA (lncRNA), is dysregulated in several types of cancer. Here we assessed the prognostic value of ZFAS1 in solid tumors. A comprehensive literature search was performed by screening the PubMed, EMBASE, MEDLINE, Cochrane Library, CNKI, and Wanfang databases. A total of 874 patients from 10 studies were included. The pooled analysis demonstrated that patients with high ZFAS1 expression had a significantly shorter overall survival (OS) (HR, 1.58; 95% CI, 1.28-1.97; P < 0.001) and recurrence-free survival (RFS) (HR, 1.90; 95% CI, 1.29-2.79; P = 0.001). Moreover, elevated ZFAS1 expression correlated with tumor size, tumor-node-metastasis (TNM) stage, and lymph node metastasis (LNM). These results demonstrate that increased ZFAS1 expression correlates with a poor prognosis in cancer patients, which suggests ZFAS1 might be useful as a potential prognostic biomarker in patients with solid tumors.

Preoperative platelet lymphocyte ratio as independent predictors of prognosis in pancreatic cancer: A systematic review and meta-analysis.

BACKGROUND: Recently, the preoperative platelet to lymphocyte ratio (PLR) has been found reported to predict oncologic outcomes in multiple malignancies. However, its prognostic value in patients with pancreatic cancer (PC) remains controversial. The aim of this study was to assess the prognostic value of preoperative PLR in PC. METHODS: MEDLINE, EMBASE, and Cochrane databases were searched to identify studies evaluating the prognostic significance of preoperative PLR in PC. Pooled hazard ratios (HRs) for overall survival (OS) were calculated using fixed-effects/random-effects models. RESULTS: A total of eight studies comprising 1,904 patients with PC were included in the meta-analysis. The pooled analysis demonstrated that elevated PLR had an association with decreased OS (HR: 1.22, 95% CI: 1.04-1.43, p = 0.02). Subgroup analysis showed that a high PLR significantly predicted poor OS in Asian studies (HR: 1.25, 95% CI: 1.03-1.52, p = 0.02), patients with metastatic disease (HR: 1.34, 95% CI: 1.01-1.77, p = 0.04) and patients with PLR >150 (HR: 1.73, 95% CI: 1.21-2.49, p = 0.003). CONCLUSIONS: The preoperative PLR may be a significant independent prognostic factor in patients with PC.

The pretreatment lymphocyte to monocyte ratio predicts clinical outcome for patients with hepatocellular carcinoma: A meta-analysis.

The lymphocyte-to-monocyte ratio (LMR) has been reported to predict clinical outcomes in multiple malignancies. The aim of this study was to assess the prognostic role of pretreatment LMR in hepatocellular carcinoma (HCC). A total of seven studies comprising 2,738 patients were included in the meta-analysis. Pooled results showed that elevated LMR was significantly associated with increased overall survival (OS) (HR: 0.31, 95% CI: 0.20-0.47, p < 0.001), disease-free survival (DFS)/recurrence-free survival (RFS) (HR: 0.57, 95% CI: 0.49-0.67, p < 0.001). The favorable prognostic impact of high LMR on OS was observed in all subgroup with different sample size, type of publication, NOS score, and the cut-off value of LMR. In addition, low LMR was significantly correlated with TNM stage and BCLC stage. We therefore conclude that elevated pretreatment LMR could be a favorable prognostic factor for clinical outcomes in patients with HCC.

Prognostic role of lncRNA HOTAIR in esophageal squamous cell carcinoma.

BACKGROUND: HOX transcript antisense intergenic RNA (HOTAIR) may be implicated in cancer development and progression. Clinical studies have suggested that HOTAIR may be related to poor prognosis in esophageal squamous cell carcinoma (ESCC). This study was designed to clarify the prognostic role of HOTAIR in ESCC. METHODS: MEDLINE, EMBASE, the Cochrane Central Register of Controlled Trials, and the China National Knowledge Infrastructure (CNKI) databases were searched to identify studies evaluating the prognostic significance of HOTAIR in ESCC. Pooled hazard ratios (HRs) for overall survival (OS), lymph node metastasis (LNM), and cancer stage were calculated using fixed-effects/random-effects models. RESULTS: A total of 510 patients from five studies were included. Meta-analysis revealed that high HOTAIR expression was significantly correlated with poor OS (HR, 2.37; 95% CI, 1.80-3.11; P<0.00001) and positive LNM (RR, 1.96; 95% CI, 1.07-3.60; P=0.03). CONCLUSION: Elevated lncRNA HOTAIR indicated a poor prognosis for patients with ESCC, and it may also have predictive potential for ESCC metastasis.

Prognostic value of the lymphocyte monocyte ratio in patients with colorectal cancer: A meta-analysis.

BACKGROUND: Inflammation plays a critical role in the pathogenesis and progression of cancer. A low lymphocyte-to-monocyte ratio (LMR) is reported be a poor prognostic factor in multiple malignancies. We performed a meta-analysis to evaluate the prognostic role of preoperative LMR in colorectal cancer (CRC). METHODS: Studies investigating the prognostic role of preoperative LMR on survival in patients with CRC were systematically searched for in MEDLINE, EMBASE, Cochrane databases from inception up to August 2016. Pooled hazard ratios (HRs) for overall survival (OS), disease-free survival (DFS), and recurrence-free survival (RFS) were calculated using fixed-effects/random-effects models. RESULTS: A total of nine studies comprising 8626 patients with CRC were included in the meta-analysis. The pooled analysis demonstrated that low LMR was significantly associated with decreased OS (HR: 0.63, 95% CI: 0.56-0.70, P < 0.001) and DFS/RFS (HR: 0.76, 95% CI: 0.68-0.84, P < 0.001). The negative prognostic impact of low LMR on OS was observed in patients with different ethnicity, treatment methods, cut-off values, and across disease stages. CONCLUSIONS: This meta-analysis demonstrates that low preoperative LMR is associated with worse survival in patients with CRC.

The enhanced recovery after surgery (ERAS) program in liver surgery: a meta-analysis of randomized controlled trials.

The enhanced recovery after surgery (ERAS) program aims to attenuate the surgical stress response and decrease postoperative complications. It has increasingly replaced conventional approaches in surgical care. To evaluate the benefits and harms of the ERAS program compared to conventional care in patients undergoing liver surgery. We searched the MEDLINE, PubMed, EMBASE and Cochrane databases. All RCTs that compared the ERAS program with conventional care were selected. Four RCTs were eligible for analysis, which included 634 patients (309 ERAS vs. 325 conventional). Overall morbidity (RR 0.67; 95 % CI 0.48-0.92; p = 0.01), primary length of stay (WMD -2.71; 95 % CI -3.43 to -1.99; p < 0.00001), total length of stay (WMD -2.10; 95 % CI -3.96 to -0.24; p = 0.03), time of functional recovery (WMD -2.30; 95 % CI -3.77 to -0.83; p = 0.002), and time to first flatus (SMD, -0.52; 95 % CI -0.69 to -0.35; p < 0.00001) were significantly shortened in the ERAS group. Quality of life was also better in the ERAS group. However, no significant differences were noted in mortality, readmission rates, operative time and intraoperative blood loss. The ERAS Program for liver surgery significantly reduced overall morbidity rates, accelerated functional recovery, and shortened the primary and total hospital stay without compromising readmission rates. Therefore, ERAS appears to be safe and effective. However, the conclusions are limited because of the low methodological quality of the analyzed studies. Further studies are needed to provide more solid evidence.

Clinicopathological and prognostic significance of platelet-to-lymphocyte ratio in patients with hepatocellular carcinoma.

The platelet-to-lymphocyte ratio (PLR) is reported to be a prognostic factor in multiple malignancies. The aim of this study was to assess its prognostic value in hepatocellular carcinoma (HCC). We performed comprehensive searches of electronic databases for relevant studies. A total of eleven studies comprising 2,507 patients were included. Elevated PLR was significantly associated with poor overall survival (OS) (HR = 1.78; 95% CI = 1.36-2.34; P < 0.001) and disease-free survival (DFS)/recurrence-free survival (RFS) (HR = 1.82; 95% CI = 1.56-2.13; P < 0.001). The findings from most subgroup analyses were consistent with those from the overall analysis. In addition, a high PLR correlated with tumor size > 3 cm, TNM stage, lymph node metastasis, distant metastasis, and vascular invasion. We therefore conclude that elevated pretreatment PLR may be predicative of a poor prognosis in patients with HCC.

[Regulatory effect of clearing-heat secreting-bile regulating-qi flow and activating blood circulation principle on cholecystokinin receptor].

OBJECTIVE: To explore the regulatory effect of clearing-Heat secreting-bile regulating-Qi flow and activating blood circulation (CSRA) principle on cholecystokinin receptor (CCK-R) and its mechanism. METHODS: Cholecystokinin (CCK) in serum of portal venous blood, maximum binding capacity (Bmax) and affinity (Kd) of CCK-R levels in gallbladder of guinea pigs allocated in four groups (control, high cholesterol, natural recovery and treated groups) were determined using radioimmunoassay and radioligand receptor assay (RRA). At the same time, changes of fasting volume (FV) and postprandial volume (PV) of gallbladder, fasting and postprandial bile (FB and PB) in gallbladder, gallbladder contraction rate (GCR) and cholesterol concentration (CC) in bile were observed. RESULTS: Compared with the control group, after two weeks of high cholesterol feeding, increase of FV, FB, PV, PB and CC (P < 0.05), and decrease of GCR (P < 0.01) and Bmax were found in cholesterol group, but with no significant change in Kd and CCK level. The above-mentioned criteria were restored to normal range in the treated group. CONCLUSION: CSRA principle could promote the recovery of gallbladder contraction by regulating CCK-R expression in it, its mechanism is possibly correlated with reduction of cholesterol concentration in bile.

[The impact of initial fluid resuscitation with different ratio of crystalloid-colloid on prognosis of patients with severe acute pancreatitis].

OBJECTIVE: To investigate the impact of fluid resuscitation with different ratio of crystalloid-colloid in early resuscitation stage on prognosis of patients with severe acute pancreatitis (SAP). METHODS: A retrospective analysis was made by reviewing clinical data of 47 patients with SAP from January 2001 to December 2011. According to crystalloid-colloid ratio 1.5 or 3, which was the input volume of crystalloid fluid versus colloid fluid in the first 24 hours, patients were divided into low ratio group (crystalloid-colloid ratio <1.5, n=13), middle ratio group (crystalloid-colloid ratio 1.5-3, n=15) and high ratio group (crystalloid-colloid ratio >3, n=19). Among the patients who had been successfully resuscitated, rate of mechanical ventilation, the oxygenation index, intra-abdominal pressure (IAP), and the amount of fluid retention in the third space within the first 24 hours, as well as the parameters of fluid resuscitation and the survival rate within 2 weeks were collected and analyzed. RESULTS: (1) In the first 24 hours, the rate of mechanical ventilation in the high ratio group was significantly higher than that in the middle ratio group and the low ratio group (68.4% vs. 20.0%, 23.1%, both P<0.05); the oxygenation index was significantly lower than that in the middle ratio group and in the low ratio group (180.7±26.3 mm Hg vs. 280.6±24.8 mm Hg, 260.3±25.7 mm Hg, both P<0.05); the IAP was significantly higher than that in the middle ratio group and the low ratio group (16.8±3.6 cm H(2)O vs. 13.4±3.5 cm H(2)O, 13.1±3.3 cm H(2)O, both P<0.05); the amount of fluid retention in the third space was significant higher than that in the middle ratio group and the low ratio group (2834±631 ml vs. 1887±282 ml, 1865±300 ml, both P<0.05). There was no significant difference in above indexes between middle ratio group and low ratio group (all P>0.05). (2) In the first 24 hours, the volume of crystalloid in high ratio group was significantly larger than that in the middle ratio group and the low ratio group (3611±798 ml vs. 2308±416 ml, 2124±477 ml, both P<0.05); and the volume of colloid in high ratio group and middle ratio group was significantly lower than that in the low ratio group (993±233 ml, 948±140 ml vs. 1506±332 ml, both P<0.05); and the mean crystalloid-colloid rate in the high ratio group was significantly higher than that in the middle ratio group and the low ratio group (3.65±0.13 vs. 2.43±0.13, 1.41±0.08, both P<0.05). The volume of infused fluid during the first 72 hours in the high ratio group was significantly higher than that in the middle and low ratio groups (11 941±1161 ml vs. 9036±982 ml, 9400±1051 ml, both P<0.05). (3) The survival rate in the high ratio group (36.8%) was significantly lower than that in the middle ratio group (86.7%, P<0.05) and the low ratio group (61.5%, P>0.05). CONCLUSIONS: A suitable crystalloid-colloid ratio should be considered in the early stage of resuscitation in patients with severe acute pancreatitis, which would result in a decrease in the fluid retention in the third space as well as an improvement of survival rate in return. It is suggested that the middle ratio of crystalloid-colloid fluid resuscitation should be the optimal strategy.

Metronomic chemotherapy in combination with antiangiogenic treatment induces mosaic vascular reduction and tumor growth inhibition in hepatocellular carcinoma xenografts.

BACKGROUND: In addition to sprouting angiogenesis, other mechanisms, such as mosaic tumor vessel formation, have been recognized to contribute to tumor vascularization. We sought to examine vascular alteration as well as tumor growth inhibition after treatment with antiangiogenic therapy, chemotherapy alone or in combination. METHODS: Hepatocellular carcinoma cells (Hep3B) expressed green fluorescent protein were utilized to establish orthotopic xenograft model in nude mice. The formation and distribution of mosaic vessels was analyzed quantitatively by immunolabeling. Next, changes in tumor microcirculation and therapeutic effects on tumor growth were evaluated in several different treatment groups: control, conventional doxorubicin, metronomic doxorubicin, bevacizumab, bevacizumab plus conventional doxorubicin, and bevacizumab plus metronomic doxorubicin. In addition, we examined the effects of combined regimens on lung metastasis using a highly metastatic human hepatocellular carcinoma (HCCLM3) mouse model. RESULTS: Approximately 62 % of the vessels were present in the central part or near the midsection of the tumor and were mosaic. Only the combined antiangiogenic treatment and chemotherapy (metronomic schedule, P = 0.00; conventional schedule, P = 0.02) had a significant effect on the degree of mosaic vasculature. Metronomic doxorubicin in combination with bevacizumab had an even more profound effect than bevacizumab plus conventional doxorubicin (P < 0.05) on tumor growth inhibition and survival. However, bevacizumab plus metronomic doxorubicin failed to inhibit lung metastasis compared with antiangiogenic monotherapy. CONCLUSIONS: Metronomic chemotherapy in combination with antiangiogenic treatment results in the reduction of mosaic tumor vasculature, inhibition of tumor growth, and enhanced survival of mice. Further investigation of drug scheduling is required to optimize antitumor activity.