Drugs targeting TGF-ß/Notch interaction attenuate hypertrophic scar formation by optic atrophy 1-mediated mitochondrial fusion.

Hypertrophic scar (HS) formation is a cutaneous fibroproliferative disease that occurs after skin injuries and results in severe functional and esthetic disability. To date, few drugs have shown satisfactory outcomes for the treatment of HS formation. Transforming growth factor-beta (TGF-ß)/Notch interaction via small mothers against decapentaplegic 3 (Smad3) could facilitate HS formation; therefore, targeting TGF-ß/ Notch interaction via Smad3 is a potential therapeutic strategy to attenuate HS formation. In addition, optic atrophy 1 (OPA1)-mediated mitochondrial fusion contributes to fibroblast proliferation, and TGF-ß/Smad3 axis and the Notch1 pathway facilitate OPA1-mediated mitochondrial fusion. Thus, the aim of this study was to investigate whether drugs targeting TGF-ß/Notch interaction via Smad3 suppressed fibroblast proliferation to attenuate HS formation through OPA1-mediated mitochondrial fusion. We found that the TGF-ß pathway, Notch pathway, and TGF-ß/Notch interaction via Smad3 were inhibited by pirfenidone, the gamma- secretase inhibitor DAPT, and SIS3 in human keloid fibroblasts (HKF) and an HS rat model, respectively. Protein interaction was detected by co-immunoprecipitation, and mitochondrial morphology was determined by electron microscopy. Our results indicated that pirfenidone, DAPT, and SIS3 suppressed the proliferation of HKFs and attenuated HS formation in the HS rat model by inhibiting TGF-ß/Notch interaction via Smad3. Moreover, pirfenidone, DAPT, and SIS3 hindered OPA1-mediated mitochondrial fusion through inhibiting TGF-ß/Notch interaction, thereby suppressing the proliferation of HS fibroblasts and HS formation. In summary, these findings investigating the effects of drugs targeting TGF-ß/Notch interaction on HS formation might lead to novel drugs for the treatment of HS formation.

Adjuvant transarterial chemoembolization following radical resection for intrahepatic cholangiocarcinoma: A multi-center retrospective study.

Background and Aims: The prognosis of intrahepatic cholangiocarcinoma (ICC) after radical resection is far from satisfactory, but the effect of postoperative transarterial chemoembolization (p-TACE) remains controversial. This multi-center retrospective study was to evaluate the clinical value of p-TACE and identify the selected patients who would benefit from p-TACE. Methods: Data of ICC patients who underwent radical resection with/without p-TACE therapy was obtained from 12 hepatobiliary centers in China between Jan 2014 and Jan 2017. Overall survival (OS) was set as the primary endpoint, which was analyzed by the Kaplan-Meier method before and after propensity score matching (PSM). Subgroup analysis was conducted based on the established staging system and survival risk stratification. Results: A total of 335 patients were enrolled in this study, including 39 patients in the p-TACE group and 296 patients in the non-TACE group. Median OS in the p-TACE group was longer than that in the non-TACE group (63.0 months vs. 18.0 months, P=0.041), which was confirmed after 1:1 PSM (P=0.009). According to the 8th TNM staging system, patients with stage II and stage III stage would be benefited from p-TACE (P=0.021). Subgroup analysis stratified by risk factors showed that p-TACE could only benefit patients with risk factors <2 (P=0.027). Conclusion: Patients with ICC should be recommended to receive p-TACE following radical resection, especially for those with stage II, stage III or risk factors <2. However, the conclusion deserved further validation.

Resectable recurrent colorectal liver metastasis: can radiofrequency ablation replace repeated metastasectomy?

BACKGROUND: Percutaneous radiofrequency ablation (RFA) is used as a first-line treatment for colorectal liver metastases that recur after first liver resection in our institution. We aim to evaluate its therapeutic efficacy compared to repeated surgical resection. METHODS: A retrospective review was performed in 104 patients treated with curative intent for resectable recurrent colorectal liver metastases. RESULTS: Sixty-one patients underwent RFA and 43 patients underwent surgery. The overall recurrence rates were 82% in the RFA group and 65.1% in the resection group (P = 0.05). The local recurrence rate on a lesion-basis was markedly higher after RFA than that after resection (16.7% versus 7.3%, P = 0.04). The difference remained significant in patients with a maximum lesion diameter >3 cm (24.5% versus 7.6%, P = 0.01). RFA treatment was independently associated with recurrence on multivariate analyses (P = 0.01). 69.7% of RFA patients and 42.6% of surgery patients with intrahepatic recurrence were amenable to repeated local treatment (P = 0.05), leading to the equivalent actuarial 3-year progression free survival rates (RFA: 29.1% versus Resection: 33.1%, P = 0.48) and 5-year overall survival rates in the two treatment groups (RFA: 33% versus Resection: 28.4%, P = 0.36). CONCLUSIONS: Surgery remains the treatment of choice for resectable recurrence. RFA may offer similar benefit in selected patients.

A Low Neutrophil to Lymphocyte Ratio Before Preoperative Chemotherapy Predicts Good Outcomes After the Resection of Colorectal Liver Metastases.

BACKGROUND: The neutrophil to lymphocyte ratio (NLR) is a marker of inflammation and is associated with poor outcomes. We aimed to evaluate the role of the pretreatment NLR in predicting the outcomes after preoperative chemotherapy in patients with colorectal liver metastases (CRLM). METHODS: A retrospective review was performed for 183 patients with CRLM. The NLR was measured before chemotherapy, and a receiver operating characteristic (ROC) curve was used to estimate the cutoff value. Logistic regressions were applied to analyze potential predictors of the pathological response. The Cox proportional hazard method was used to analyze survival. RESULTS: The pre-chemotherapy NLR was 2.4 ± 1.1, whereas the post-chemotherapy NLR was 2.1 ± 1.6 (p < 0.001). The pretreatment NLR of 2.3 was a significant predictive marker for the pathological response. The pathological response rates were 67.1% in the patients with an NLR ≤ 2.3 and 48.1% in patients with an NLR > 2.3 (p = 0.01). Multivariate analysis revealed that the factors independently associated with pathological responses were a low pretreatment NLR (p = 0.043), radiological response to chemotherapy (p < 0.001), first-line chemotherapy (p = 0.001), and targeted therapy (p = 0.002). The median overall survival (OS) and recurrence-free survival (RFS) were worse in the increased NLR cohort than in the low NLR cohort (OS: 31.1 vs. 43.1 months, p = 0.012; RFS: 6.5 vs. 9.4 months, p = 0.06). According to multivariate analyses, a high pretreatment NLR was a significant predictor for both worse OS (HR = 2.43, 95%CI = 1.49-3.94, p < 0.001) and RFS (HR = 1.53, 95%CI = 1.08-2.18, p = 0.017). CONCLUSIONS: An increased pretreatment NLR was a significant predictor of a poor pathological response and worse prognosis after preoperative chemotherapy. The NLR is a simple biomarker for assessing chemotherapy efficacy.

Human leukocyte antigen gene polymorphisms are associated with systemic inflammation in hepatitis B virus-related hepatocellular carcinoma.

BACKGROUND: Systemic inflammation (SI) is associated with tumor progression and overall survival (OS) in patients with hepatocellular carcinoma (HCC). The presence of some single nucleotide polymorphisms (SNPs) in the human leukocyte antigen (HLA) region can influence the prognosis of patients with hepatitis B virus (HBV)-related HCC, although the mechanism remains unknown. This study aimed to analyze the correlations between HLA gene polymorphisms and SI. PATIENTS AND METHODS: This study included 330 patients with HCC. The clinical parameters were reviewed, and five SNPs, namely rs2647073, rs3997872, rs3077, rs7453920, and rs7768538, were genotyped using the MassARRAY system. RESULTS: The rs3997872, rs7453920, and rs7768538 genotypes were found to be significantly associated with OS (P<0.05). The rs7453920 genotype was significantly associated with the neutrophil/lymphocyte ratio (NLR; P=0.001), which was used as an SI index with a threshold determined by receiver operating characteristic analysis. An elevated NLR was also an independent predictor of OS according to univariate and multivariate analyses (P<0.001). CONCLUSION: Our data show that HLA gene polymorphisms are associated with SI in patients with HBV-related HCC, and the absence of minor allele A (rs7453920) promotes SI and shortens OS.

Interaction of margin status and tumour burden determines survival after resection of colorectal liver metastases: A retrospective cohort study.

PURPOSE: We sought to determine the impact of surgical margin status on overall survival (OS) and recurrence pattern stratified by tumor burden. MATERIALS AND METHODS: Data were collected from patients undergoing resection for colorectal liver metastases (CRLM). Tumor burden was calculated according to a newly proposed Tumor Burden Score (TBS) system, defined as the distance from the origin on a Cartesian plane that incorporated maximum tumor size and number of liver lesions. Patients were divided into low tumor burden group and high tumor burden group accordingly, and the impact of resection margin on overall survival was examined. RESULTS: A total of 286 patients were available, among which R1 resection was observed in 88 patients. The median TBS for the entire cohort was 3.84. Metastases in the R1 group were characterized by more advanced disease and more complex resections. Compared with a R0 resection, a R1 resection offered an lower 5-year overall survival rate (46.8% vs. 22.1%, p = 0.001). Multivariate analysis identified R1 resection (p = 0.03), high TBS (p = 0.002), lymph nodes metastases (p = 0.003) and lymphovascular invasion (p = 0.03) of the primary colorectal tumor as the factors independently associated with worse survival. The survival benefit associated with negative margins was greater in patients with low TBS (55.7% vs. 21.7%, p = 0.021) than in patients with high TBS (31.8% vs. 24.5%, p = 0.116). R1 resection was associated with an increased true margin recurrence rate in patients with low TBS (32.3% vs. 13.4%; p = 0.014) and an increased risk of new intrahepatic metastases in patients with high TBS (43.9% vs. 26.7%; p = 0.034). CONCLUSIONS: Negative margin is an important determinant of survival. The impact of positive margins is more pronounced in patients with low tumor burden.

A postoperative scoring system for post-hepatectomy early recurrence of colorectal liver metastases.

The aims of this study were to assess early recurrence predictive factors and elucidate the best early recurrence management. 255 patients with colorectal liver metastases (CRLM) who underwent hepatectomy were retrospectively analyzed. A total of 87 patients (34.1%) developed early recurrence, defined as recurrence that occurred within 6 months after resection. Multivariate analysis showed that preoperative carcino-embryonic antigen (CEA) level ≥ 30 ng/ml, primary tumor lymphovascular invasion (LVI), number of metastases ≥ 4, R1 resection and initially unresectable disease were independent predictors of early recurrence. A predictive scoring system for early recurrence was created by incorporating these factors, and this system showed good discrimination (concordance index of 0.78). In early recurrent patients who underwent salvage treatment, those with 0-2 risk factors demonstrated a significantly longer median survival after recurrence than patients with 3-5 risk factors (33.4 months vs. 20.2 months, p = 0.001). For patients who underwent chemotherapy alone, the median survival after recurrence between two groups was comparable (18.3 months vs. 22.6 months, p = 0.926). Multivariate analysis revealed that primary tumor lymph node metastases (HR = 1.96, p = 0.032), early recurrence (HR = 1.67, p = 0.045), salvage treatment for recurrence (HR = 0.47, p = 0.002) and predictive scores for early recurrence (HR = 1.39, p = 0.004) were independent factors for survival in patients with recurrence. In patients with early recurrence, bilobar distribution of metastases (HR = 2.05, p = 0.025) and salvage treatment for recurrence (HR = 0.46, p = 0.019) were independent factors for survival. In conclusion, we developed a predictive model that is a very useful tool for determining both the likelihood of early recurrence and the necessity for salvage treatment.

Non-response to preoperative chemotherapy is a contraindication to hepatectomy plus radiofrequency ablation in patients with colorectal liver metastases.

The long-term outcome of 228 patients with colorectal liver metastases (CRLM) who underwent preoperative chemotherapy followed by hepatectomy ± RFA were retrospectively analyzed. Stratified by chemotherapy response, patients were divided into responding (n=129) and non-responding groups (n=99). Patients who underwent hepatectomy-RFA had a greater number of metastases (median of 4 vs. 2, p=0.000), a higher incidence of bilobar involvement (66.7% vs. 49.1%, p=0.014) and longer chemotherapy cycles (median of 6 vs. 4, p=0.000). In the responding group, the median overall survival (OS) and recurrence free survival (RFS) of hepatectomy-RFA and the hepatectomy alone subgroups were comparable (38.6 months vs. 43.2 months, p=0.824; 8.2 months vs. 11.4 months, p=0.623). In the non-responding group, the median OS and RFS of patients treated with hepatectomy-RFA were significantly shorter (18.5 months vs. 34.2 months, p=0.000; 5.1 months vs. 5.9 months, p=0.002). RFA was identified as the unfavorable independent factor for both OS (HR=3.60, 95%CI=1.81-7.16, p=0.039) and RFS (HR=1.70, 95%CI=1.00-2.86, p=0.048) in non-responsive patients. Local recurrence rate after hepatectomy-RFA was higher in the non-responding group (48.1% vs. 23.6%, p=0.018). Non-response to preoperative chemotherapy may be a contraindication to hepatectomy-RFA in patients with CRLM.

Prognostic Analysis of 102 Patients with Synchronous Colorectal Cancer and Liver Metastases Treated with Simultaneous Resection.

BACKGROUND: The liver is the most common site for colorectal cancer (CRC) metastases. Their removal is a critical and challenging aspect of CRC treatment. We investigated the prognosis and risk factors of patients with CRC and liver metastases (CRCLM) who underwent simultaneous resections for both lesions. METHODS: From January 2009 to August 2016, 102 patients with CRCLM received simultaneous resections of CRCLM at our hospital. We retrospectively analyzed their clinical data and analyzed their outcomes. Overall survival (OS) and disease-free survival (DFS) were examined by Kaplan-Meier and log-rank methods. RESULTS: Median follow-up time was 22.7 months; no perioperative death or serious complications were observed. Median OS was 55.5 months; postoperative OS rates were 1-year: 93.8%, 3-year: 60.7%, and 5-year: 46.4%. Median DFS was 9.0 months; postoperative DFS rates were 1-year: 43.1%, 3-year: 23.0%, and 5-year 21.1%. Independent risk factors found in multivariate analysis included carcinoembryonic antigen ≥100 ng/ml, no adjuvant chemotherapy, tumor thrombus in liver metastases, and bilobar liver metastases for OS; age ≥60 years, no adjuvant chemotherapy, multiple metastases, and largest diameter ≥3 cm for DFS. CONCLUSIONS: Simultaneous surgical resection is a safe and effective treatment for patients with synchronous CRCLM. The main prognostic factors are pathological characteristics of liver metastases and whether standard adjuvant chemotherapy is performed.

Prognostic value of the albumin-bilirubin grade in patients with hepatocellular carcinoma: Validation in a Chinese cohort.

AIM: The prognostic value of the newly raised objective liver function assessment tool, the albumin-bilirubin (ALBI) grade, in patients with hepatocellular carcinoma has not been fully validated. We aimed to compare the performance of ALBI grade with the specific Child-Pugh (C-P) score in predicting prognosis in this study. METHODS: The clinical data of 491 C-P class A patients who underwent liver resection as initial therapy from January 2000 to December 2007 in Cancer Hospital, Chinese Academy of Medical Sciences (Beijing, China) were retrospectively analyzed. The prognostic performances of ALBI and C-P score in predicting the short- and long-term clinical outcomes were compared. RESULTS: The ALBI score gained a significantly larger area under the receiver operating characteristic curve for predicting the occurrence of severe postoperative complications than that of C-P score. With a median follow-up of 57 months, the 1-year, 3-year, and 5-year overall survival rates of the patients were 92.1%, 65.8%, and 45.2%, respectively. Tumor number, tumor size, and ALBI grade were proved to be the independent prognostic factors for overall survival in the multivariate analysis. Prognostic performance was shown to be better for ALBI grade when it was compared to C-P score in terms of both the Akaike information criterion value and χ2 value of likelihood ratio test. CONCLUSIONS: The ALBI grade, which was featured by simplicity and objectivity, gained a superior prognostic value than that of C-P grade in patients with hepatocellular carcinoma who underwent liver resection. Future well-designed studies with larger sample sizes are warranted.

Lactate dehydrogenase is a prognostic indicator in patients with hepatocellular carcinoma treated by sorafenib: results from the real life practice in HBV endemic area.

PURPOSE: Lactate dehydrogenase (LDH), which was an indirect marker of hypoxia, was a potentially prognostic factor in several malignancies. There is a lack of evidence about the prognostic value of serum LDH level in patients with hepatocellular carcinoma (HCC) receiving sorafenib treatment from hepatitis B virus endemic areas. MATERIALS AND METHODS: A total of 119 HBV-related HCC patients treated by sorafenib from a Chinese center were included into the study. They were categorized into 2 groups according to the cut-off value of pre-treatment LDH, which was determined by the time dependent receiver operating characteristics (ROC) curve for the overall survival. The prognostic value of LDH was evaluated. The relationships between LDH and other clinicopathological factors were also assessed. RESULTS: The cut-off value was 221 U/L. With a median follow up of 15 (range, 3-73) months, 91 patients reached the endpoint. Multivariate analysis proved that pre-treatment serum LDH level was an independent prognostic factor for both overall survival (OS) and progression-free survival (PFS). For patients whose pre-treatment LDH ≥ 221 U/L, increased LDH value after 3 months of sorafenib treatment predicted inferior OS and PFS. And patients with elevated pre-treatment LDH level predisposed to be featured with lower serum albumin, presence of macroscopic vascular invasion, advanced Child-Pugh class, advanced T category, higher AFP, and higher serum total bilirubin. CONCLUSIONS: Serum LDH level was a potentially prognostic factor in HCC patients treated by sorafenib in HBV endemic area. More relevant studies with reasonable study design are needed to further strengthen its prognostic value.

Impaction of surgical margin status on the survival outcome after surgical resection of intrahepatic cholangiocarcinoma: a systematic review and meta-analysis.

BACKGROUND: Conflicting results about the prognostic value of surgical margin status in patients with intrahepatic cholangiocarcinoma (ICC) have been reported. We aimed to assess the association between surgical margin status and prognosis in ICC through a meta-analysis. MATERIALS AND METHODS: We conducted a literature search of the articles evaluating the prognostic value of surgical margin status in patients with ICC. The pooled estimation of the hazard ratio (HR) with the 95% confidence interval (CI) was performed to determine the influence of surgical margin status on the survival outcome. RESULTS: A total of 21 studies involving 3201 patients were finally included into the meta-analysis. The percentage of patients with positive surgical margin ranged from 7.2% to 75.9% in the enrolled studies. The pooled estimates showed that patients with positive surgical margin had inferior overall survival (HR: 1.864; 95% CI: 1.542-2.252; P < 0.001) and progression-free survival (HR: 2.033; 95% CI: 1.030-4.011; P = 0.041) than patients with negative ones. The subgroup analyses and sensitivity analyses were consistent with the overall results. CONCLUSIONS: Patients with negative surgical margin had significantly favorable overall survival and progression-free survival after surgical resection for ICC. The notion of achieving the R0 resection should be emphasized.

Prognostic Value of Lymph Node Ratio in Patients Receiving Combined Surgical Resection for Gastric Cancer Liver Metastasis: Results from Two National Centers in China.

The purpose of this study was to evaluate the prognostic value of lymph node ratio (LNR) in patients with gastric cancer liver metastasis (GCLM) who received combined surgical resection. A retrospective analysis of 46 patients from two hospitals was conducted. Patients were dichotomized into two groups (high LNR and low LNR) by the median value of LNR. The overall survival (OS) and recurrence-free survival (RFS) were analyzed by the Kaplan-Meier method with the log-rank test. The Cox proportional hazard model was used to carry out the subsequent multivariate analyses. And the relationship between LNR and clinicopathological characteristics was assessed. The cut-off value defining elevated LNR was 0.347. With a median follow-up of 67.5 months, the median OS and RFS of the patients were 17 and 9.5 months, respectively. Six patients survived for >5 years after surgery. Patients with higher LNR had significantly shorter OS and RFS than those with lower LNR. In the multivariate analyses, higher LNR and multiple liver metastatic tumors were identified as the independent prognostic factors for both OS and RFS. Elevated LNR was significantly associated with advanced pN stage (P <0.001), larger primary tumor size (P = 0.046), the presence of microvascular invasion (P = 0.008), and neoadjuvant chemotherapy (P = 0.004). LNR may be prognostic indicator for patients with GCLM treated by synchronous surgical resection. Patients with lower LNR and single liver metastasis may gain more survival benefits from the surgical resection. Further prospective studies with reasonable study design are warranted.

Excision Repair Cross-complementation Group 1 is a Prognostic Biomarker in Patients with Colorectal Cancer Receiving Chemotherapy.

BACKGROUND: Conflicting results about the association between expression level of excision repair cross-complementation group 1 (ERCC1) and clinical outcome in patients with colorectal cancer (CRC) receiving chemotherapy have been reported. Thus, we searched the available articles and performed the meta-analysis to elucidate the prognostic role of ERCC1 expression in patients with CRC. METHODS: A thorough literature search using PubMed (Medline), Embase, Cochrane Library, Web of Science databases, and Chinese Science Citation Database was conducted to obtain the relevant studies. Pooled hazard ratios (HR s) or odds ratios (OR s) with 95% confidence intervals (CI s) were calculated to estimate the results. RESULTS: A total of 11 studies were finally enrolled in this meta-analysis. Compared with patients with lower ERCC1 expression, patients with higher ERCC1 expression tended to have unfavorable overall survival (OS) (HR = 2.325, 95% CI: 1.720-3.143, P < 0.001), progression-free survival (PFS) (HR = 1.917, 95% CI: 1.366-2.691, P < 0.001) and poor response to chemotherapy (OR = 0.491, 95% CI: 0.243-0.990, P = 0.047). Subgroup analyses by treatment setting, ethnicity, HR extraction, detection methods, survival analysis, and study design demonstrated that our results were robust. CONCLUSIONS: ERCC1 expression may be taken as an effective prognostic factor predicting the response to chemotherapy, OS, and PFS. Further studies with better study design and longer follow-up are warranted in order to gain a deeper understanding of ERCC1's prognostic value.

Total tumor volume predicts survival following liver resection in patients with hepatocellular carcinoma.

Assessing the prognosis of patients with hepatocellular carcinoma (HCC) by the number and size of tumors is sometimes difficult. The main purpose of the study was to evaluate the prognostic value of total tumor volume (TTV), which combines the two factors, in patients with HCC who underwent liver resection. We retrospectively reviewed 521 HCC patients from January 2001 to December 2008 in our center. Patients were categorized using the tertiles of TTV. The prognostic value of TTV was assessed. With a median follow-up of 116 months, the 1-, 3-, and 5-year overall survival (OS) rates of the patients were 93.1 , 69.9, and 46.3 %, respectively. OS was significantly differed by TTV tertile groups, and higher TTV was associated with shorter OS (P < 0.001). Multivariate analysis revealed that TTV was an independent prognostic factor for OS. Larger TTV was significantly associated with higher alpha-fetoprotein level, presence of macrovascular invasion, multiple tumor lesions, larger tumor size, and advanced tumor stages (all P < 0.05). Within the first and second tertiles of TTV (TTV ≤ 73.5 cm(3)), no significant differences in OS were detected in patients within and beyond Milan criteria (P = 0.183). TTV-based Cancer of the Liver Italian Program (CLIP) score gained the lowest Akaike information criterion value, the highest χ (2) value of likelihood ratio test, and the highest C-index among the tested staging systems. Our results suggested that TTV is a good indicator of tumor burden in patients with HCC. Further studies are warranted to validate the prognostic value of TTV.

Prognostic Role of Glasgow Prognostic Score in Patients With Hepatocellular Carcinoma: A Systematic Review and Meta-Analysis.

Conflicting results about the prognostic value of Glasgow Prognostic Score (GPS) in hepatocellular carcinoma (HCC) patients have been reported. We searched the available articles and performed the meta-analysis to clarify the predictive value of GPS in HCC patients' outcome.A systematic literature search was conducted using PubMed (Medline), Embase, Cochrane Library, Web of Science, ChinaInfo, and Chinese National Knowledge Infrastructure for all years up to September 2015. Studies analyzing the relationship of GPS and survival outcome were identified. Hazard ratio (HR) with 95% confidence interval (CI) was calculated to assess the risk.A total of 10 studies were finally enrolled in the meta-analysis. The pooled estimates demonstrated a significant relationship between elevated GPS and inferior overall survival in patients with HCC (HR = 2.156, 95% CI: 1.696-2.740, P < 0.001). Patients with increased GPS had a tendency toward shorter progression-free survival (HR = 1.755, 95% CI: 0.943-3.265, P = 0.076). And elevated GPS was found to be significantly associated with advanced Child-Pugh class (odds ratio = 25.979, 95% CI: 6.159-109.573, P < 0.001). The publication bias analysis revealed that there was publication bias in the meta-analysis.Glasgow Prognostic Score may be an independent prognostic factor in patients with HCC. More well-designed studies with adequate follow-up duration are warranted.

Aberrant expression of peroxiredoxin 1 and its clinical implications in liver cancer.

AIM: To investigate the expression characteristics of peroxiredoxin 1 (PRDX1) mRNA and protein in liver cancer cell lines and tissues. METHODS: The RNA sequencing data from 374 patients with liver cancer were obtained from The Cancer Genome Atlas. The expression and clinical characteristics of PRDX1 mRNA were analyzed in this dataset. The Kaplan-Meier and Cox regression survival analysis was performed to determine the relationship between PRDX1 levels and patient survival. Subcellular fractionation and Western blotting were used to demonstrate the expression of PRDX1 protein in six liver cancer cell lines and 29 paired fresh tissue specimens. After bioinformatics prediction, a putative post-translational modification form of PRDX1 was observed using immunofluorescence under confocal microscopy and immunoprecipitation analysis in liver cancer cells. RESULTS: The mRNA of PRDX1 gene was upregulated about 1.3-fold in tumor tissue compared with the adjacent non-tumor control (P = 0.005). Its abundance was significantly higher in men than women (P < 0.001). High levels of PRDX1 mRNA were associated with a shorter overall survival time (P = 0.04) but not with recurrence-free survival. The Cox regression analysis demonstrated that patients with high PRDX1 mRNA showed about 1.9-fold increase of risk for death (P = 0.03). In liver cancer cells, PRDX1 protein was strongly expressed with multiple different bands. PRDX1 in the cytosol fraction existed near the theoretical molecular weight, whereas two higher molecular weight bands were present in the membrane/organelle and nuclear fractions. Importantly, the theoretical PRDX1 band was increased, whereas the high molecular weight form was decreased in tumor tissues. Subsequent experiments revealed that the high molecular weight bands of PRDX1 might result from the post-translational modification by small ubiquitin-like modifier-1 (SUMO1). CONCLUSION: PRDX1 was overexpressed in the tumor tissues of liver cancer and served as an independent poor prognostic factor for overall survival. PRDX1 can be modified by SUMO to play specific roles in hepatocarcinogenesis.

Prognostic Role of Phospho-STAT3 in Patients with Cancers of the Digestive System: A Systematic Review and Meta-Analysis.

OBJECTIVE: The definite prognostic role of p-STAT3 has not been well defined. We performed a meta-analysis evaluating the prognostic role of p-STAT3 expression in patients with digestive system cancers. METHODS: We searched the available articles reporting the prognostic value of p-STAT3 in patients with cancers of the digestive system, mainly including colorectal cancer, gastric cancer, hepatocellular carcinoma, esophagus cancer and pancreatic cancer. The pooled hazard ratios (HRs) with 95 % confidence intervals (95 % CIs) of overall survival (OS) and disease-free survival (DFS) were used to assess the prognostic role of p-STAT3 expression level in cancer tissues. And the association between p-STAT3 expression and clinicopathological characteristics was evaluated. RESULTS: A total of 22 studies with 3585 patients were finally enrolled in the meta-analysis. The results showed that elevated p-STAT3 expression level predicted inferior OS (HR = 1.809, 95% CI: 1.442-2.270, P < 0.001) and DFS (HR = 1.481, 95% CI: 1.028-2.133, P = 0.035) in patients with malignant cancers of the digestive system. Increased expression of p-STAT3 is significantly related with tumor cell differentiation (Odds ratio (OR) = 1.895, 95% CI: 1.364-2.632, P < 0.001) and lymph node metastases (OR = 2.108, 95% CI: 1.104-4.024, P = 0.024). Sensitivity analysis suggested that the pooled HR was stable and omitting a single study did not change the significance of the pooled HR. Funnel plots and Egger's tests revealed there was no significant publication bias in the meta-analysis. CONCLUSION: Phospho-STAT3 might be a prognostic factor of patients with digestive system cancers. More well designed studies with adequate follow-up are needed to gain a thorough understanding of the prognostic role of p-STAT3.

Evaluation of eight different clinical staging systems associated with overall survival of chinese patients with hepatocellular carcinoma.

BACKGROUND: Hepatocellular carcinoma (HCC) is a common cancer in China, an area of high hepatitis B virus (HBV) infection. Although several staging systems are available, there is no consensus on the best classification to use because multiple factors, such as etiology, clinical treatment and populations could affect the survival of HCC patients. METHODS: This study analyzed 743 HBV-related Chinese HCC patients who received surgery first and evaluated the predictive values of eight different commonly used staging systems in the clinic. RESULTS: The overall 1-, 3-, 5-year survival rates and a median survival were 91.5%, 70.3%, 55.3% and 72 months respectively. Barcelona Clinic Liver Cancer (BCLC) staging systems had the best stratification ability and showed the lowest Akaike information criterion (AIC) values (2896.577), followed by tumor-node-metastasis 7 th (TNM 7 th ) (AIC = 2899.980), TNM 6 th (AIC = 2902.17), Japan integrated staging score (AIC = 2918.085), Tokyo (AIC = 2938.822), Cancer of the Liver Italian Program score (AIC = 2941.950), Chinese University Prognostic Index grade (AIC = 2962.027), and Okuda (AIC = 2979.389). CONCLUSIONS: BCLC staging system is a better staging model for HBV infection patients with HCC in Chinese population among the eight currently used staging systems. These identifications afford a large group of Chinese HCC patients with HBV infection and could be helpful to design a new staging system for a certain population.