Transarterial Chemoembolization Combined with Sorafenib in Patients with BCLC Stage C Hepatocellular Carcinoma.

PURPOSE: Transcatheter arterial chemoembolization (TACE) and targeted therapy have become common methods in the treatment of advanced hepatocellular carcinoma (HCC). The purpose of this study was to evaluate the safety and efficacy of TACE combined with sorafenib (TACE-sorafenib) and TACE alone for the treatment of Barcelona clinical stage C HCC. METHODS: The clinical data of 75 patients with BCLC stage C HCC who received TACE-sorafenib or TACE as the initial treatment were retrospectively analyzed. Tumor response, time to progression (TTP), overall survival (OS), and adverse events were compared at 1 month after surgery in the two groups. RESULTS: One month after treatment, the disease control rate in the TACE-sorafenib group was higher than that in the TACE group alone (82.76% and 57.50%, respectively, P = 0.018). The median values of TTP and OS in the TACE-sorafenib group were longer than those in the TACE group (TTP was 7.6 and 3.4 months, respectively, P = 0.002; OS was 13.6 and 6.3 months, respectively, P = 0.041). The cumulative survival time at 3 months, 6 months, and 1 year was higher in the TACE-sorafenib group than in the TACE group (83.5%, 71.2%, 45.7% vs 57.4%, 40.6%, 21.2%). Sorafenib-related side effects such as hypertension, hand-foot syndrome, and oral ulcers were more common than those in the TACE group alone (P<0.05). CONCLUSION: Compared with TACE treatment alone, TACE combined with sorafenib in BCLC-C stage HCC significantly improved disease control rate, TTP, and OS, and no significant increase in adverse reactions was observed.

High Expression of Methylenetetrahydrofolate Dehydrogenase 2 (MTHFD2) in Esophageal Squamous Cell Carcinoma and its Clinical Prognostic Significance.

BACKGROUND Recently, targeted therapy for malignant tumors has developed rapidly, but there is still no effective targeted therapy for advanced esophageal squamous cell carcinoma (ESCC). Methylenetetrahydrofolate dehydrogenase 2 (MTHFD2) is a key enzyme involved in folate metabolism and is closely related to the proliferation in many cancers. However, few studies have explored the expression of MTHFD2 in ESCC and its prognostic significance. MATERIAL AND METHODS The expressions of MTHFD2, ki67, and p53 in ESCC tissues were detected by immunohistochemistry. Further, MTHFD2 expression level in ESCC and its correlations with patients' clinicopathological characteristics and survival prognosis were investigated. RESULTS The enhanced expression of MTHFD2 was observed in ESCC specimens compared with adjacent normal tissue. The increased expression of MTHFD2 was closely related to pathological grading (P=0.020) and tumor TNM stage (P=0.019). In addition, patients with high expression of MTHFD2 had worse survival than those with low MTHFD2 expression (P<0.05). High expression of MTHFD2 in ESCC tissues was often associated with high expression of ki67 and p53 (P<0.05). CONCLUSIONS MTHFD2 had significantly enhanced expression in ESCC tissues and was associated with pathological grading and TNM stage. Taken together, high expression of MTHFD2 was an independent unfavorable prognostic parameter for overall survival (OS) of ESCC patients, suggesting that MTHFD2 might be a potential therapeutic target for ESCC in the future.

Clinical research of individualized therapy in advanced esophageal cancer based on the ERCC1 C8092A genotype.

The present study aimed to explore the role and clinical value of the detection of Excision repair cross-complementing 1(ERCC1) C8092A polymorphisms in individualized therapy of patients with advanced esophageal cancer. A total of 127 patients with advanced esophageal cancer were enrolled between January 2010 and January 2014 in Anhui Provincial Hospital. Patients were randomly assigned in a 1:2 ratio to a standard treatment group or an individualized treatment group, respectively, prior to ERCC1 C8092A assessment. Patients in the standard treatment group were treated with paclitaxel and cisplatin. The DNA was obtained from the peripheral blood of individualized treatment patients, amplified by PCR and sequenced to determine the ERCC1 C8092A polymorphism prior to the administration of chemotherapies. Patients with the ERCC1 C8092A genotype of A/A or A/C received paclitaxel and cisplatin, and those with the genotype of C/C received paclitaxel and fluorouracil. The primary endpoint was response rate (RR). The secondary endpoints included toxicity of chemotherapy, progression-free survival (PFS) and overall survival (OS) times. Differences between the groups were evaluated by χ2 test. Differences in survival were analyzed by Kaplan-Meier survival curves. The survival rate was analyzed by log-rank test. Follow-up data was obtained until December 2015. The RR was obtained for 15 patients (34.8%) in the standard treatment group and 45 patients (53.6%) in the individualized treatment group (χ2=3.095; P=0.046). For adverse events, nausea and vomiting and anemia were significantly decreased in the individualized treatment group compared with the standard treatment group (P=0.001 and P=0.004, respectively). The median progression free survival time was 4.4 months [95% confidence interval (CI)3.8-5.0 months] in the standard treatment group and 6.6 months (95% CI, 5.8-7.4 months) in the individualized treatment group (P=0.018). The median overall survival time was 11.4 months (95% CI, 10.1-12.7 months) in the standard treatment group and 14.2 months (95% CI, 13.2-15.2 months) in the individualized treatment group (P=0.008). The RR, toxicity of chemotherapy, PFS and OS were significantly improved in the individualized treatment group compared with the standard treatment group. Detection of ERCC1 gene polymorphisms maybe performed for patients with advanced esophageal cancer to improve individualized therapy, which requires additional study.

Association between periostin and epithelial-mesenchymal transition in esophageal squamous cell carcinoma and its clinical significance.

The present study aimed to investigate the association between periostin (POSTN), epithelial cadherin (E-cad) and vimentin (Vim) expression levels in esophageal squamous cell carcinoma (ESCC) tissues, and its clinicopathological significance. A total of 58 patients with esophageal cancer were enrolled. Immunohistochemistry was performed to quantify the expression levels of POSTN, E-cad and Vim. E-cad expression was reduced in ESCC tissue, which was associated with severe tumor node metastasis (TNM) stage (P<0.001), lymphatic metastasis (P<0.001) and vascular invasion (P=0.026). Conversely, Vim expression was found to be increased in ESCC tissues, and had associations with TNM stage (P=0.039) and lymphatic metastasis (P=0.039). POSTN overexpression observed in ESCC cells was associated with attenuation of E-cad expression (P<0.001) and elevated expression levels of Vim (P<0.001). Additionally, significant correlations between the overexpression of POSTN in ESCC cells and clinicopathological variables including TNM staging (P=0.009), degree of differentiation (P<0.001), lymphatic metastasis (P=0.009) and vascular invasion (P=0.002) were verified. Multivariate analysis revealed that overexpression of POSTN in ESCC cancer cells is able to predict the poor prognosis of patients independently of overall survival (P=0.022) and disease free survival (P=0.019). The preliminary findings of the present study demonstrate that POSTN is involved in the epithelial-mesenchymal transition of ESCC cells, and may therefore be a predictive factor for tumor invasion and metastasis, as well as an indicator of poor prognosis for patients with ESCC.

Targeting PCDH20 gene by microRNA-122 confers 5-FU resistance in hepatic carcinoma.

Drug resistance is one of the main hurdles for the successful treatment of hepatic carcinoma. However, the detailed mechanisms underlying resistance remain largely unknown and therapeutic approaches are limited. In the present study, we show that miR-122 confers resistance to 5-fluorouracil induced hepatocellular carcinoma cell apoptosis in vitro and reduces the potency of 5-fluorouracil in the inhibition of tumor growth in a mouse xenograft model in vivo. Further studies indicate that miR-122 modulates drug resistance through down-regulation of expression of PCDH20, which belongs to the protocadherin gene family and negatively regulates Akt activation. Knockdown of PCDH20 expression increases Akt phosphorylation, which leads to elevated mTOR activity and enhanced 5-fluorouracil resistance; whereas rescue of PCDH20 expression in miR-122-expressing cells decreases Akt and mTOR phosphorylation, re-sensitizing hepatocellular carcinoma cell to 5-fluorouracil induced apoptosis. Moreover, a specific and potent Akt inhibitor reverses miR-122-conferred 5-fluorouracil resistance. These findings indicate that the miR-122/PCDH20/Akt/mTOR signaling axis has an important role in mediating response to chemotherapy in human hepatocellular carcinoma. A major implication of our study is that inhibition of miR-122 or restoration of PCDH20 expression may have significant therapeutic potential to overcome drug resistance in hepatocellular carcinoma and that the combined use of an Akt inhibitor with 5-fluorouracil may increase efficacy in liver cancer treatment.

Coexpression of periostin and EGFR in patients with esophageal squamous cell carcinoma and their prognostic significance.

BACKGROUND: Both periostin (PN) and epidermal growth factor receptor (EGFR) can predict the prognosis of several carcinomas alone. However, coexpression of PN and EGFR in esophageal squamous cell carcinoma (ESCC) still remains unknown. We aimed to clarify their relationship with clinicopathological factors and prognostic significance of their coexpression in ESCC. PATIENTS AND METHODS: In this single-center retrospective study, immunohistochemistry was performed to evaluate the expression of PN and EGFR in ESCC and paracarcinomatous tissues of 83 patients. The quantitative expression levels of PN and EGFR were examined in two ESCC and tumor-adjacent tissues. The levels of PN and EGFR expression were correlated with clinicopathological parameters by the χ (2) or Kruskal-Wallis method. Spearman's rank correlation test was performed to determine the relationship between PN and EGFR expression levels. Kaplan-Meier and Cox regression analyses were used to detect the prognostic factors of disease-free survival (DFS) and overall survival (OS). RESULTS: The high expression of PN protein in ESCC tissues was significantly associated with tumor length (P=0.044), differentiation grade (P=0.003), venous invasion (P=0.010), invasion depth (P=0.007), lymphatic metastasis (P=0.000), and tumor stage (P=0.000). The high expression of EGFR protein in ESCC tissues was only significantly related to lymphatic metastasis (P=0.000), invasion depth (P=0.022), and tumor stage (P=0.000). Kaplan-Meier analysis showed that high expression of PN was closely correlated to reduced OS (P=0.000) and DFS (P=0.000), which was consistent with EGFR expression. Cox regression analysis identified PN and EGFR as independent poor prognostic factors of OS and DFS in the ESCC patients (P<0.05). Moreover, the risk of death for the ESCC patients with low expression of two biomarkers and high expression of single biomarker was 0.243 times (P=0.000) and 0.503 times (P=0.030), respectively, than that for patients with high expression of two biomarkers. CONCLUSION: PN and EGFR are related to miscellaneous clinicopathologic characteristics. Coexpression of PN and EGFR is more closely to be of predictive value on ESCC development and progression, which may offer a novel and potential target strategy for ESCC treatment in the future.

Clinical features and prognosis-associated factors of non-small cell lung cancer exhibiting symptoms of bone metastasis at the time of diagnosis.

The present study aimed to analyze the clinical characteristics and prognosis-related factors of non-small cell lung cancer (NSCLC) patients with bone metastases at the time of diagnosis. A total of 46 NSCLC patients with skeletal metastases at the time of diagnosis from Anhui Provincial Hospital and Anhui Provincial Cancer Hospital Affiliated to Anhui Medical University (Hefei, China) between February 2010 and February 2012 were investigated retrospectively. The median age was 58 years, with a range of 40-80 years, the ratio of males and females was 2:1, and adenocarcinoma and squamous cell carcinoma accounted for 71.7 and 28.3% of cases, respectively. Furthermore, 84.8% of patients exhibited multiple skeletal metastases at more than two sites and 54.3% of patients experienced skeletal-related events at the time of diagnosis. The median overall survival (OS) time of the patients was 237 days, and Kaplan-Meier analysis demonstrated that patients with adenocarcinoma (P=0.002), single bone metastases (P=0.023), an Eastern Cooperative Oncology Group performance status of 0-1 (P<0.001) or positive expression of estrogen receptor (ER)-ß (P=0.039) exhibited significantly longer survival times. Furthermore, multivariate analysis identified the following independent predictors of OS: Tumor subtype (P=0.022), the number of bone metastases (P=0.016) and an ER-ß-positive tumor (P=0.035). In the cohort of NSCLC patients with bone metastases at the time of diagnosis, adenocarcinoma and multiple skeletal metastases were most common.

Overexpression of AGGF1 is correlated with angiogenesis and poor prognosis of hepatocellular carcinoma.

Angiogenic factor with G-patch and FHA domains 1 (AGGF1) is a factor implicating in vascular differentiation and angiogenesis. Several lines of evidence indicate that aberrant expression of AGGF1 is associated with tumor initiation and progression. The aim of this study was to investigate the expression and prognostic value of AGGF1 in hepatocellular carcinoma (HCC), as well as its relationship with clinicopathological factors and tumor angiogenesis. Immunohistochemistry was performed to evaluate the expression of AGGF1 in HCC and paracarcinomatous tissues collected from 70 patients. Vascular endothelial growth factor (VEGF) and CD34 expression levels were examined in the 70 HCC tissues. Prognostic significance of tumoral AGGF1 expression was determined. Notably, AGGF1 expression was significantly higher in HCC than in surrounding non-tumor tissues (65.7 vs. 25.7 %; P < 0.001). AGGF1 expression was significantly correlated with tumoral VEGF expression and CD34-positive microvessel density. Moreover, AGGF1 expression was significantly associated with tumor size, tumor capsule, vascular invasion, Edmondson grade, alpha-fetoprotein level, and TNM stage. Kaplan-Meier survival analysis showed that high AGGF1 was correlated with reduced overall survival (OS) rate (P = 0.001) and disease-free survival (DFS) rate (P < 0.001). Multivariate analysis identified AGGF1 as an independent poor prognostic factor of OS and DFS in HCC patients (P = 0.043 and P = 0.010, respectively). Taken together, increased AGGF1 expression is associated with tumor angiogenesis and serves as an independent unfavorable prognostic factor for OS and DFS in HCC. AGGF1 may represent a potential therapeutic target for HCC.

Overexpression of periostin is significantly correlated to the tumor angiogenesis and poor prognosis in patients with esophageal squamous cell carcinoma.

Recent studies have found that periostin (PN), as a kind of secreted glycoprotein, is closely related to the metastatic potential and prognosis of many kinds of tumors. This study aimed to examine the expression of PN in patients with esophageal squamous cell carcinoma (ESCC) and explore the relationship of PN expression with clinicopathologic factors, tumor angiogenesis and prognosis. The results showed that increased PN protein expression was prevalent in ESCC and was significantly associated with lymphatic metastasis (P=0.008), tumor differentiation (P=0.04), venous invasion (P=0.014) and TNM stage (P=0.001). Additionally, expression of PN was found to be an independent prognostic factor in ESCC patients. High expression of PN protein is closely correlated to the tumor progression and angiogenesis and poor survival of ESCC. Taken together, PN is a promising biomarker to identify individuals with poor prognostic potential and concludes the possibility of its use as a prognostic marker in patients with ESCC.

Hypoxia-inducible factor 1α in breast cancer prognosis.

BACKGROUND: Recent studies have assessed the relationship between hypoxia-inducible factor 1α (HIF-1α) expression and prognosis in breast cancer patients with inconsistent conclusions. To comprehensively and quantitatively summarize the evidence on the survival of patients with breast cancer, a meta-analysis was performed. METHODS: Systematic literature searching was applied to the databases of PubMed, Embase and Web of science until April 1, 2013. Pooled HR with 95% CI was used to evaluate the association between HIF-1α expression and survival in breast cancer patients. RESULTS: Fourteen papers including 2933 patients were subjected to the final analysis. Of these, 7 provided data on overall survival (OS), 8 on disease-free survival (DFS), 3 on distant metastasis-free survival (DMFS) and 3 on relapse-free survival (RFS). We observed that high expression of HIF-1α in breast cancer patients was an indicator of poor prognosis on OS (HR = 1.46, 95% CI: 1.12-1.92, P = 0.006), DFS (HR = 1.91, 95% CI: 1.43-2.57, P<0.001), DMFS (HR=2.17 95% CI: 1.16-4.05, P=0.015) and RFS (HR=1.33 95% CI: 1.09-1.61, P=0.005). Significant heterogeneity was observed in the analyses of OS and DFS. Subgroup analyses by the cut-off value and antibody for IHC were conducted. CONCLUSION: High expression of HIF-1α indicated a poor prognosis for patients with breast cancer.

A phase II study of paclitaxel and nedaplatin as front-line chemotherapy in Chinese patients with metastatic esophageal squamous cell carcinoma.

AIM: To evaluate the efficacy and safety of paclitaxel-nedaplatin combination as a front-line regimen in Chinese patients with metastatic esophageal squamous cell carcinoma (ESCC). METHODS: A two-center, open-label, single-arm phase II study was designed. Thirty-nine patients were enrolled and included in the intention-to-treat analysis of efficacy and adverse events. Patients received 175 mg/m² of paclitaxel over a 3 h infusion on 1 d, followed by nedaplatin 80 mg/m² in a 1 h infusion on 2 d every 3 wk until the documented disease progression, unacceptable toxicity or patient's refusal. RESULTS: Of the 36 patients assessable for efficacy, there were 2 patients (5.1%) with complete response and 16 patients (41.0%) with partial response, giving an overall response rate of 46.1%. The median progression-free survival and median overall survival for all patients were 7.1 mo (95%CI: 4.6-9.7) and 12.4 mo (95%CI: 9.5-15.3), respectively. Toxicities were moderate and manageable. Grade 3/4 toxicities included neutropenia (15.4%), nausea (10.3%), anemia (7.7%), thrombocytopenia (5.1%), vomiting (5.1%) and neutropenia fever (2.6%). CONCLUSION: The combination of paclitaxel and nedaplatin is active and well tolerated as a first-line therapy for patients with metastatic ESCC.

Association of TNF-α-308 and -238 polymorphisms with risk of cervical cancer: a meta-analysis.

Published data on the associations between tumor necrosis factor-alpha (TNF-α) promoter -308G>A and -238G>A polymorphisms and cervical cancer risk are inconclusive. To derive a more precise estimation of the relationship, a meta-analysis was performed. Data were collected from MEDLINE and PubMed databases. Crude odds ratios (ORs) with 95% confidence intervals (CIs) were calculated in a fixed/random effect model. 13 separate studies including 3294 cases and 3468 controls were involved in the meta-analysis. We found no association between TNF-α-308G>A polymorphism and cervical cancer in overall population. In subgroup analysis, significantly elevated risks were found in Caucasian population (A vs. G: OR=1.43, 95% CI=1.00- 2.03; AA vs. GG: OR=2.09, 95% CI=1.34-3.25; Recessive model: OR=2.09, 95% CI=1.35-3.25) and African population (GA vs. GG: OR=1.53, 95% CI=1.02-2.30). An association of TNF-α-238G>A polymorphism with cervical cancer was found (A vs. G: OR=0.61, 95% CI=0.47-0.78; GA vs. GG: OR=0.59, 95% CI=0.45-0.77; Dominant model: OR=0.59, 95% CI=0.46-0.77). When stratified by ethnicity, similar association was observed in Caucasian population (A vs. G: OR=0.62, 95% CI=0.46-0.84; GA vs. GG: OR=0.59, 95% CI=0.43-0.82; Dominant model: OR=0.60, 95% CI=0.44-0.83). In summary, this meta-analysis suggests that TNF-α-238A allele significantly decreased the cervical cancer risk, and the TNF-α-308G>A polymorphism is associated with the susceptibility to cervical cancer in Caucasian and African population.

Overexpression of cyclooxygenase-2 in noncancerous liver tissue increases the postoperative recurrence of hepatocellular carcinoma in patients with hepatitis B virus-related cirrhosis.

BACKGROUND: Many previous studies have evaluated the histopathological features of tumours as risk factors for postoperative recurrence in hepatitis B virus (HBV)-associated hepatocellular carcinoma (HCC). However, there have been few large studies investigating the relationship between cyclooxygenase-2 (COX-2) expression in noncancerous regions of the liver and postoperative recurrence in the remnant liver, especially in HBV-related HCC. OBJECTIVE: To evaluate the significance of COX-2 expression levels in noncancerous liver regions as a prognostic indicator of HCC in patients with HBV-related cirrhosis. METHODS: A total of 124 patients who underwent curative resection for HCC were reviewed retrospectively. Immunohistochemistry was used to evaluate the expression of COX-2 in noncancerous liver tissue. Clinicopathological variables were compared between patients with high COX-2 expression (n=58 [COX-2-positive group]) and patients with low COX-2 expression (n=66; [COX-2-negative group]). Univariate and multivariate analyses were performed to identify factors that affected disease recurrence. RESULTS: There was a significant correlation between COX-2 expression and alanine aminotransferase levels and vascular invasion. The recurrence-free survival rates in the COX-2-positive group were significantly lower than the rates in the COX-2-negative group. On multivariate analysis, the overexpression of COX-2 in noncancerous liver regions was found to be an unfavourable prognostic indicator for the recurrence of HCC. CONCLUSIONS: The results of the current study suggest that overexpression of COX-2 in noncancerous liver regions is an independent and significant indicator predictive of early recurrence of HCC in patients with HBV-related cirrhosis.

Fatal lactic acidosis and hypoglycemia in a patient with relapsed natural killer/T-cell lymphoma.

Presented here is the first reported case of natural killer (NK)/T-cell lymphoma associated with lactic acidosis (LA) and hypoglycemia. LA and hypoglycemia are rare complications of non-Hodgkin's lymphoma. A 28-year-old male patient with NK/T-cell lymphoma had a relapse after 14 mo of initial remission and was admitted to the hospital because of altered mental status. He developed severe LA (pH, 7.17; lactate, 11.2 mmol/L) and hypoglycemia (42 mg/dL) that was resistant to sodium bicarbonate and glucose infusions. A very brief partial remission was achieved after a cycle of vincristine, dexamethasone, and L-asparaginase was given, but the disease recurred quickly after chemotherapy was discontinued and the patient did not respond to additional chemotherapy. The patient expired at 47 d after relapse. An extensive review of the literature reveals that only 2 of 28 patients have achieved complete remission, and more than 75% of patients died within 1 mo. Furthermore, 90% of previously reported cases had liver involvement. The case described here indicates that non-Hodgkin's lymphoma-induced LA portends a poor prognosis.