S100P as a novel biomarker of microvascular invasion and portal vein tumor thrombus in hepatocellular carcinoma.

BACKGROUND: Portal vein tumor thrombus (PVTT) and microvascular invasion (MVI) are types of intrahepatic vascular metastasis of hepatocellular carcinoma (HCC) and are highly correlated with poor prognosis. However, the underlying biomarkers of PVTT and MVI are unclear. METHODS: We identified a PVTT/MVI-associated gene S100P by cDNA microarray analysis, and assess the potential value of serum S100P measurement in the differential diagnosis of HCC and prediction of MVI status with large retrospective and perspective cohort studies. RESULTS: The mRNA and protein of S100P was increased in HCCs with PVTT or MVI. High S100P immunostaining in tumors was correlated with inferior tumor-free survival. Serum S100P values discriminated patients with HCCs from those with benign liver tumors, and it showed predictive potential of MVI status in both retrospective and perspective cohorts. S100P may regulate HCC tumorigenicity and invasive ability; S100P also was associated with up-regulation of CD44, which may mediate HCC cell adhesion to form PVTT/MVI. CONCLUSIONS: Serum S100P may be a novel differential diagnostic marker for HCC and a potential predictor of MVI status pre-surgery for HCC patients. S100P overexpression in HCC is highly correlated with the formation of PVTT and MVI, which may make S100P as a potential therapeutic target for HCC metastasis.

Comprehensive circular RNA profiling reveals the regulatory role of circRNA_0007694 in papillary thyroid carcinoma.

PURPOSE: The present study aimed to identify differentially expressed circRNAs in thyroid cancer and verify their potential functions. METHODS: Next-generation sequencing was used to identify differentially expressed circRNAs between papillary thyroid carcinoma (PTC) tissues and paired pericarcinomatous tissues. Polymerase chain reaction and Sanger sequencing methods successfully identified hsa_circ_0007694. A hsa_circ_0007694 over-expression vector was prepared to determine the effect of this circRNA on proliferation, migration, invasion, apoptosis, and the cell cycle in PTC cells. An in vivo animal assay was conducted by injecting PTC cells into the chests of mice. Further, RNA-seq was performed, followed by Gene Ontology and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis, to verify the regulatory mechanism of hsa_circ_0007694. Western blotting was used to verify the genes thought to be involved in the hsa_circ_0007694 regulatory pathways based on KEGG analysis. RESULTS: We identified a circRNA, hsa_circ_0007694 that was down-regulated in PTC tissues compared to pericarcinomatous tissues. Over-expression of hsa_circ_0007694 promoted apoptosis and inhibited proliferation, migration, and invasion in PTC cells in vitro, and decreased tumor growth in vivo. Transcriptome sequence analysis suggested 129 differentially expressed genes between PTC tissue and paired pericarcinomatous tissue. KEGG analysis and western blotting indicated that the PI3K/AKT/mTOR and Wnt signaling networks are most likely to be related to hsa_circ_0007694 in thyroid cancer. CONCLUSION: The circRNA hsa_circ_0007694 is down-regulated in PTC and is therefore a potential therapeutic target.

Comparison of the effect on the prognosis of HCC in terms of different surgical approaches for hepatic inflow occlusion.

BACKGROUND: To investigate the effect of surgical approaches for hepatic inflow occlusion performed during hepatectomy on postoperative tumor-free survival (TFS) in patients treated with R0 resection. METHODS: In total, 343 hepatocellular carcinoma (HCC) patients who underwent hepatectomy (R0) with different surgical approaches for hepatic inflow occlusion were analyzed retrospectively. RESULTS: In total, 68.80% of the patients underwent hepatic inflow occlusion, including 46.65% with a routine Pringle maneuver and 22.16% with selective hemi-hepatic vascular exclusion (SHVE), during surgery. The TFS did not significantly differ among the Pringle group, the SHVE group and the no hepatic inflow occlusion group. After further stratifying the patients according to the Barcelona clinic liver cancer (BCLC) staging system, the patients with BCLC stage A disease in the SHVE group and no hepatic inflow occlusion group displayed better TFS than those in the Pringle maneuver group (P=0.04; P=0.002), but the patients with BCLC stage B-C disease did not show significant differences among the groups. Furthermore, all 214 patients with BCLC stage A disease were classified into two subgroups according to the microvascular invasion (MVI) status. Interestingly, among the patients with MVI, those in the SHVE group and no hepatic inflow occlusion group had significantly longer TFS than those in the Pringle group (P=0.025; P=0.006); however, the patients without MVI did not show differences among the groups. Additionally, the multivariate analysis revealed that a tumor size ≥5 cm, an absent capsule, a low Edmondson grade, MVI positivity and performance of the Pringle maneuver were independent risk factors of the prognosis in patients with BCLC stage A disease. CONCLUSIONS: Hepatic inflow occlusion and the surgical approach used to address this issue may have an impact on HCC prognosis in patients with BCLC stage A disease, especially among those with MVI positivity. No hepatic inflow occlusion or an SHVE approach rather than the Pringle maneuver should be considered first during hepatectomy for patients with BCLC stage A disease.

Effect of KI-67 positive cellular index on prognosis after hepatectomy in Barcelona Clinic Liver Cancer stage A and B hepatocellular carcinoma with microvascular invasion.

OBJECTIVE: This study aimed to explore the relationship between KI-67 positive cellular index and recurrence-free survival (RFS) in Barcelona Clinic Liver Cancer (BCLC) stage A and B hepatocellular carcinoma (HCC) patients, particularly those with microvascular invasion (MVI). METHODS: A total of 333 patients who underwent curative hepatectomy had their immunohistochemistry analyzed retrospectively for KI-67 positive cellular index. RESULTS: In total, 41.1% (137/333) of HCC patients displayed high KI-67 positive cellular index (>35%). Patients with high KI-67 positive cellular index had poorer RFS than those with low index (P<0.0001). Patients were then subdivided into an MVI positivity group (n=192) and an MVI negativity group (n=141). In the MVI positivity group, patients with high KI-67 positive cellular index had a shorter RFS after operation as compared to those with low index (P<0.0001). However, there was no significant difference in RFS between high- and low-index subgroups within the MVI negativity group (P>0.05). Additionally, patients with high KI-67 positive cellular index combined with MVI positivity had the shortest RFS of all those with MVI negativity, regardless of KI-67 cellular index level (P<0.0001). Multivariate analysis showed that node number >1, capsule absence, high KI-67 positive cellular index, and alpha-fetoprotein >400 ng/mL were independent risk factors for a recurrence of HCC with MVI. CONCLUSION: Our results suggested that high KI-67 positive cellular index may represent a poor prognostic factor in BCLC stage A and B HCC patients, especially those with MVI.

Effect of neurological monitoring in postoperative 5-15 days residual thyroidectomy after primary thyroid cancer surgery.

AIM: To explore the application of intraoperative neurological monitoring in residual thyroidectomy 5-15 days after thyroid cancer operation and the influence on postoperative serum thyroglobulin (Tg), recurrent laryngeal nerve and function of parathyroid glands. METHODS: Material of patients receiving thyroid surgery from January 2010 to December 2016 was retrospectively analyzed. Cases meeting with standards were enrolled for analysis and the patients were divided into neurological monitoring group and non-neurological monitoring group in line with the use of neurological monitoring during the operation. Recurrent laryngeal nerve-injured hoarseness, hypoparathyroidism and concentration of serum Tg before and after the surgery were collected and analyzed. RESULTS: Four-hundred and thirty-five patients met with standards, among which 227 from neurological monitoring group and 208 from non-neurological monitoring group. Temporary hoarseness rate of non-neurological monitoring group and neurological monitoring group was 8.67% and 2.2%. Permanent hoarseness rate of non-neurological monitoring group and neurological monitoring group was 1.92% and 0.44%. Temporary hypoparathyroidism rate of non-neurological monitoring group and neurological monitoring group was 18.75% and 7.48%. Permanent hypoparathyroidism rate of non-neurological monitoring group and neurological monitoring group was 1.92% and 0.88%. Average Tg concentration 1 month after the surgery in non-neurological monitoring group and neurological monitoring group was 2.82 and 1.37 ng/mL, respectively. Rate of average Tg concentration less than 1 ng/mL 1 month after the surgery in non-neurological monitoring group and neurological monitoring group was 45.06% and 67.4%. CONCLUSION: Intraoperative neurological monitoring can be adopted in residual thyroidectomy in postoperative 5-15 days after primary thyroid cancer surgery, as to reduce incidence rate of recurrent laryngeal nerve injury and hypoparathyroidism and to enhance thorough removal of thyroid tissues and cancer tissues.

Meta-analysis: Diagnostic Value of N-Terminal Pro-brain Natriuretic Peptide for Kawasaki Disease.

BACKGROUND: Some studies have estimated the diagnostic value of N-terminal pro-brain natriuretic peptide (NTproBNP) for Kawasaki Disease (KD), but the results are not always consistent. The aim of this study was to ascertain the diagnostic value of NT-proBNP for KD. METHODS: EMBSAE and PubMed were searched up to June 30, 2015, to identify eligible studies that evaluated the diagnostic value of NT-proBNP for KD. The quality of the eligible studies was evaluated using the revised Quality Assessment for Studies of Diagnostic Accuracy (QUADAS-2) tools. The overall diagnostic value of NT-proBNP for KD was pooled in a bivariate model. RESULTS: Finally, 7 studies were included for systematic review and meta-analysis. The overall diagnostic sensitivity and specificity were 0.84 (95% CI: 0.78 - 0.89) and 0.79 (95% CI: 0.74 - 0.84), respectively. The area under the summary receiver operating characteristic (sROC) curve (AUC) was 0.87 (95% CI: 0.84 - 0.90). The overall sensitivity and specificity across five studies adopted the threshold of approximately 200 ng/L were 0.85 (95% CI: 0.78 - 0.90) and 0.76 (95% CI: 0.69 - 0.82), respectively. The major design weaknesses of the eligible studies were twogate design and threshold not pre-specified. CONCLUSIONS: We concluded that available studies suggest that NT-proBNP is a useful biomarker for KD. In addition, further well-designed studies are needed to rigorously evaluate the value of NT-proBNP in KD diagnosis.

Expression of chemokine receptor-4 in bone marrow mesenchymal stem cells on experimental rat abdominal aortic aneurysms and the migration of bone marrow mesenchymal stem cells with stromal-derived factor-1.

This study investigated the expression and role of chemokine receptor-4 (CXCR4) in bone marrow mesenchymal stem cells (BMSCs) from experimental rats with abdominal aortic aneurysms (AAA) for migration of BMSCs. Sprague-Dawley rats were divided into an experimental group and control group (n = 18 each). AAA was induced with 0.75 M solution infiltrate for 30 minutes, after which the abdomen was rinsed and closed. Saline was used in place of CaCl2 in the control group. CD34 and CD29 were detected by flow cytometry, the gene and protein expression of CXCR4 were detected by real-time polymerase chain reaction and western blot, respectively. The migration of BMSCs with stromal-derived factor-1 was detected by Transwell chamber. CD34 expression was negative and CD29 expression was positive. The gene and protein expression of CXCR4 were significantly higher in experimental group than them in control group (p < 0.05), the migration ability of BMSCs from the experimental group was significantly higher than that from the control group (p < 0.05). Stromal-derived factor -1/CXCR4 can enhance the migration of BMSCs in vitro in a rat AAA model.

High ALDH1A1 expression correlates with poor survival in papillary thyroid carcinoma.

BACKGROUND: High expression of aldehyde dehydrogenase 1 (ALDH1) has been confirmed in many tumors. This enzyme plays an important role in tumor proliferation, metastasis, and drug resistance. However, in the case of papillary thyroid carcinoma (PTC), the relationship between ALDH1 expression and prognosis remains unknown. METHOD: We used tissue microarrays to evaluate ALDH1A1 expression in 247 surgically resected PTC specimens by immunochemistry, and correlated the findings with the clinicopathological parameters. RESULT: ALDH1A1 levels were significantly higher than in normal thyroid tissues. Moreover, ALDH1A1 overexpression was significantly associated with extrathyroid extension (P = 0.001), pT status (P < 0.001), pN status (P = 0.016) and TNM stage (P < 0.001). The Kaplan-Meier survival analysis suggested that high ALDH1A1 expression reflects a poorer lymph node recurrence-free survival (LN-RFS) and distant recurrence-free survival (DRFS) in PTC patients, as compared with patients having low ALDH1A1 expression. Multivariate analysis confirmed the ALDH1A1 expression was an independent prognostic factor for LN-RFS and DRFS in PTC patients. CONCLUSION: In conclusion, high ALDH1A1 expression correlates with poor survival in PTC patients.

Integration of traditional Chinese medicines and Western medicines for treating diabetes mellitus with coronary heart disease: a systematic review.

PURPOSE: Diabetes mellitus with coronary heart disease (DM with CHD) poses a health challenge to people in China and elsewhere in the world. In Traditional Chinese Medicine (TCM), DM with CHD is classified as a type of disease called Xiaoke and Xiongbi. In Asia, TCM has been used to treat Xiaoke and Xiongbi conditions for centuries, especially in China. In this study, it was evaluated whether integrated strategies incorporating both TCM and Western medicines (iTCWM) could improve the curative efficacy of DM with CHD. METHODS: An extensive search for randomized clinical trials (RCTs) published up to November 2011 in either English or Chinese about iTCWM for DM with CHD was conducted. All listings in PubMed, EMBASE, the Cochrane Library, CBM, CNKI, VIP, and the Wanfang database were included in the literature search. The quality of each trial was assessed using the Cochrane Reviewers' Handbook 5.0. Data analysis was performed by the RevMan 5.0 provided by the Cochrane Collaboration. RESULTS: After an initial selection of 207 articles, 21 RCTs and quasi-RCTs were ultimately included in the analysis for this study. All of these trials were conducted in China and published in Chinese journals. The methodological quality of the trials was low in most studies. Selection bias and measurement bias were common in all of the studies. A meta-analysis was not conducted, due to the poor quality of the available studies. CONCLUSIONS: The current state of the literature regarding the utility of iTCWM for the treatment of DM with CHD is inadequate. The poor quality of the available trials makes it difficult to draw any conclusions regarding the efficacy of iTCWM for the treatment of DM with CHD. This study highlights the paucity of reliable clinical evidence for iTCWM and the need for higher quality RCTs to be conducted in the future.

[Clinical and biopsy-based myopathological features of 5 cases with centronuclear myopathy].

OBJECTIVE: To analyze the clinical and pathological features of the centronuclear myopathy (CNM) in 5 Chinese patients and evaluate their diagnostic and differential diagnostic value. METHODS: A standard series of histochemical and enzymohistochemical investigations were performed on all muscle specimens of CNM cases obtained via biopsy. The clinical manifestations and myopathological features of 5 CNM patients were retrospectively analyzed. RESULTS: The age of onset ranged from 3 to 12 years. All patients primarily presented with limb girdle muscle weakness. In 3 patients extraocular muscles, facial muscles and cervical muscles were affected, respectively. The proximal muscles were affected more seriously than the distal and the lower limbs more seriously than the upper. Tendon reflex was reduced and no evident muscular atrophy was seen. The course of the disease ranged from 4 to 46 years and progressed slowly. The ability of walking could be maintained for many years and the fast movements such as running and jumping were impaired early. The serum creatine kinase (CK) level was normal or elevated slightly. Electromyography showed myopathic pattern in all cases. Two patients (mother and son) were from the same family and the son's two siblings had similar symptoms indicating autosomal dominant inherited pattern. There was mild variation in fiber size and most small fibers were round. Interstitial tissue increase slightly. Fibers with centrally placed nuclei accounted for 23% - 93%. Neither necrotic and regenerated fibers nor infiltration of inflammatory cells were seen. Type I fiber predominance and hypotrophy were present in all patients. Abnormal arrangement of the sarcoplasmic strands in appearance of "spokes of a wheel", increased oxidative enzyme activity around centronuclear and perinuclear halo were observed in 2 patients by NADH-TR staining. CONCLUSIONS: For the patients who had the onset during the childhood and presented with slow progressive limb girdle muscle weakness, disability of fast movements and normal serum CK level, the possibility of benign congenital myopathy should be considered. High percentage of centronuclear fibers as well as type I fiber predominance and hypotrophy in muscle biopsy pathology may provide a morphological evidence for the definite diagnosis of CNM.

[Inhibitory effects of transfection of arresten gene on liver metastasis from colorectal cancer in nude mice].

BACKGROUND & OBJECTIVE: Liver metastasis is the most common cause of death due to colorectal cancer. Above 50% colorecal cancer patients have liver metastasis. This study was to investigate the effect of transfection of arresten gene on liver metastasis from human colorectal cancer (LoVo) xenografts in nude mice. METHODS: The eukaryotic expression plasmid pSecTag2-arresten was transfected into human colorectal cancer cell line LoVo using Lipofectamine 2000. Cells were divided into pSecTag2-arresten group, pSecTag2 group and control group. Expressions of arresten at mRNA and protein levels were detected by RT-PCR and Western blot, respectively. The effect of arresten on proliferation of LoVo cells was measured using MTT assay. LoVo cells transfected with pSecTag2-arresten were implanted into nude mice to investigate the effect of arresten on hepatic metastasis of colorectal cancer. Microvessel density (MVD) of xenograft tumors was assessed using immunohistochemistry with FVIIIRag monoclonal antibody. RESULTS: Arresten was successfully transfected and expressed in LoVo cells. Inhibition of cell proliferation did not differ significantly in all three groups (P > 0.05). The metastastic rate was lower in pSecTag2-arresten group [(25.1+/-2.1)%] than in pSecTag2 group [(87.1+/-1.2)% or control group [(87.1+/-1.5)%] in LoVo cells (P < 0.05). The number of xenograft tumors and MVD were higher in pSecTag2-arresten group [(4.5 +/-0.5) and (15.3+/-3.5)] than in pSecTag2 group [(19.6+/-2.5) and (42.2+/-2.6)] or in control group [(20.4+/-2.5)and (45.6+/-5.1)] in nude mice. CONCLUSION: Arresten can inhibit hepatic metastasis from colorectal cancer, which may be through its inhibition on tumor angiogenesis.

Clinicopathological significance of expression of paxillin, syndecan-1 and EMMPRIN in hepatocellular carcinoma.

AIM: To evaluate the relationship of expression of paxillin, syndecan-1 and EMMPRIN proteins with clinicopathological features in hepatocellular carcinoma (HCC). METHODS: Fifty-one patients who underwent HCC resection were recruited in the study. Paxillin, syndecan-1 and EMMPRIN proteins in HCC tissues were detected with immunohistochemical staining. RESULTS: Of 51 cases of HCC, 23 (45%) exhibited paxillin protein positive expression. Of 42 cases of adjacent non-tumor liver tissues, 24 (57%) exhibited positive expression. Positive paxillin protein expression was associated with low differentiation (r = 0.406, P = 0.004), with the presence of portal vein thrombosis (r = 0.325, P = 0.021), with extra-hepatic metastasis (r = 0.346, P = 0.014). Of 51 cases of HCC, 28 (55%) exhibited syndecan-1 protein positive expression. Of 42 cases of adjacent non-tumor liver tissues, 23 (55%) exhibited positive expression. Positive snydecan-1 protein expression was associated with well differentiation (r = 0.491, P = 0.001), with no extra-hepatic metastasis (r = 0.346, P = 0.014). Of 51 cases of HCC, 28 (55%) exhibited EMMPRIN protein positive expression. Of 42 cases of adjacent non-tumor liver tissues, 21 (50%) exhibited positive expression. Expression of EMMPRIN protein was not associated with serum AFP level, HBsAg status, presence of microsatellite nodule, tumor size, presence of cirrhosis and necrosis, differentiation, presence of portal vein thrombosis, extra-hepatic metastasis, disease-free survival and overall survival (P>0.05). Expression of paxillin protein was correlated conversely with the expression of syndecan-1 protein in HCC (r = -0.366, P = 0.010). CONCLUSION: Expression of paxillin and syndecan-1 proteins in HCC may affect its invasive and metastatic ability of the tumor. There may be a converse correlation between the expression of paxillin and syndecan-1 protein in HCC. Expression of EMMPRIN protein may be detected in HCC, but it may play little role in the invasion and metastasis of HCC.

[The value of Roferon-A combined with hepatic artery chemoembolization and portal vein chemotherapy after radical resection in hepatocellular carcinoma for preventing recurrence].

OBJECTIVE: To explore the change of T cell subsets in patients suffered from hepatocellular carcinoma (HCC) before and after hepatectomy, and study the value of Roferon-A (interferon alpha-2a) combined with hepatic artery chemoembolization (HACE) and portal vein chemotherapy (PVC) after radical resection of HCC for preventing recurrence. METHODS: On 75 HCC patients, PVC and HACE were respectively given at 2 weeks and 4 weeks after radical tumor resection. In 2nd week after surgery, 33 cases of them accepted Roferon-A treatment for 1 week. Seventy-two patients were followed up over 3 years. Effect of Roferon-A combined with HACE and PVC on postoperative recurrence rate was compared with that of HACE and PVC. Changes of T cell subsets in peripheral blood were examined with labeled monoclonal antibodies before and after hepatectomy or using interferon. Forty cholecystolithiasis patients received cholecystectomy were used as the controls. RESULTS: CD(3)(+) and CD(4)(+) cells in peripheral blood were reduced in patients with HCC. After hepatectomy, they declined further with decrease in CD(4)(+)/CD(8)(+) ratio. The results returned to pre-operative level at the end of 4th week after surgery. The CD(3)(+), CD(4)(+) cells and the CD(4)(+)/CD(8)(+) ratio increased remarkably following the use of Roferon-A. The 1-, 2- and 3-year recurrence rates of patients treated with HACE, PVC and Roferon-A in combination were 0%, 6.2% and 15.6%, respectively, while those treated with HACE and PVC were 5.0%, 12.5% and 27.5%, respectively. CONCLUSION: Patients with HCC suffer from marked immuno-suppression which became ever more severe after hepatectomy, combined use of HACE, PVC and Roferon-A is superior to only HACE and PVC by decreasing the recurrence rate.