A novel fatty acid metabolism-related signature identifies MUC4 as a novel therapy target for esophageal squamous cell carcinoma.

Fatty acid metabolism has been identified as an emerging hallmark of cancer, which was closely associated with cancer prognosis. Whether fatty acid metabolism-related genes (FMGs) signature play a more crucial role in biological behavior of esophageal squamous cell carcinoma (ESCC) prognosis remains unknown. Thus, we aimed to identify a reliable FMGs signature for assisting treatment decisions and prognosis evaluation of ESCC. In the present study, we conducted consensus clustering analysis on 259 publicly available ESCC samples. The clinical information was downloaded from The Cancer Genome Atlas (TCGA, 80 ESCC samples) and Gene Expression Omnibus (GEO) database (GSE53625, 179 ESCC samples). A consensus clustering arithmetic was used to determine the FMGs molecular subtypes, and survival outcomes and immune features were evaluated among the different subtypes. Kaplan-Meier analysis and the receiver operating characteristic (ROC) was applied to evaluate the reliability of the risk model in training cohort, validation cohort and all cohorts. A nomogram to predict patients' 1-year, 3-year and 5-year survival rate was also studied. Finally, CCK-8 assay, wound healing assay, and transwell assay were implemented to evaluate the inherent mechanisms of FMGs for tumorigenesis in ESCC. Two subtypes were identified by consensus clustering, of which cluster 2 is preferentially associated with poor prognosis, lower immune cell infiltration. A fatty acid (FA) metabolism-related risk model containing eight genes (FZD10, TACSTD2, MUC4, PDLIM1, PRSS12, BAALC, DNAJA2 and ALOX12B) was established. High-risk group patients displayed worse survival, higher stromal, immune and ESTIMATE scores than in the low-risk group. Moreover, a nomogram revealed good predictive ability of clinical outcomes in ESCC patients. The results of qRT-PCR analysis revealed that the MUC4 and BAALC had high expression level, and FZD10, PDLIM1, TACSTD2, ALOX12B had low expression level in ESCC cells. In vitro, silencing MUC4 remarkably inhibited ESCC cell proliferation, invasion and migration. Our study fills the gap of FMGs signature in predicting the prognosis of ESCC patients. These findings revealed that cluster subtypes and risk model of FMGs had effects on survival prediction, and were expected to be the potential promising targets for ESCC.

Assessment of Naples prognostic score in predicting survival for small cell lung cancer patients treated with chemoradiotherapy.

BACKGROUNDS: The Naples prognosis score (NPS) is a novel prognostic biomarker-based immune and nutritional status and that can be used to evaluate prognosis. Our study aimed to investigate the prognostic role of NPS in SCLC patients. METHODS: Patients treated with chemoradiotherapy were retrospectively analyzed between June 2012 and August 2017. We divided patients into three groups depending on the NPS: group 0, n = 31; group 1, n = 100; and group 2, n = 48, and associations between clinical characteristics and NPS group were analyzed. The univariable and multivariable Cox analyses were used to evaluate the prognostic value of clinicopathological characteristics and laboratory indicators for overall survival (OS) and progression-free survival (PFS). RESULTS: Data from 179 patients were analyzed. Treatment modality (p < 0.001) and serum CEA (p = 0.03) were significantly different among the NPS groups. The age, sex, smoking status, KPS, Karnofsky performance score (KPS), disease extent, and number of metastatic sites were not correlated with NPS (all p > 0.05). KPS, disease extent, prophylactic cranial irradiation, treatment response and NPS Group were associated with OS. In addition, KPS, disease extent, prophylactic cranial irradiation, treatment response and NPS Group were associated with PFS. Multivariate analysis results showed that NPS was identified as an independent prognostic factor for OS (Group 1: hazard ratio [HR] = 2.704, 95% confidence interval [CI] = 1.403-5.210; p = 0.003; Group 2: HR = 5.154, 95% CI = 2.614-10.166; p < 0.001) and PFS (Group 1: HR = 2.018, 95% CI = 1.014-4.014; p = 0.045; Group 2: HR = 3.339, 95% CI = 1.650-6.756; p = 0.001). CONCLUSIONS: NPS is related to clinical outcomes in patients with SCLC.

Despite the high clinical curative effect to radiation therapy and chemotherapy in SCLC, most patients subsequently experience tumor recurrence or metastasis.Whether NPS has prognostic values in SCLC has not been investigated to date.NPS is related to clinical outcomes in patients with SCLC.NPS as an innovative scoring system, can improves prediction of survival in SCLC patients.

Naples Prognostic Score as an Independent Predictor of Survival Outcomes for Resected Locally Advanced Non-Small Cell Lung Cancer Patients After Neoadjuvant Treatment.

Background: The Naples Prognostic Score (NPS) can reflect patient's nutritional and inflammatory status, which is identified as a prognostic indicator for various malignant tumors. However, its significance in patients with resected locally advanced non-small cell lung cancer (LA-NSCLC) patients who receive neoadjuvant treatment remains unclear so far. Methods: A total of 165 LA-NSCLC patients surgically treated from May 2012 to November 2017 were retrospectively investigated. The LA-NSCLC patients were divided into three groups according to NPS scores. The receiver operating curve (ROC) analysis was performed to reveal the discriminatory ability of NPS and other indicators for predicting the survival. The NPS and clinicopathological variables were further evaluated the prognostic value by univariate and multivariate Cox analysis. Results: The NPS was related to age (P = 0.046), smoking history (P = 0.004), Eastern Cooperative Oncology Group (ECOG) score (P = 0.005), and adjuvant treatment (P = 0.017). Patients with high NPS scores had worse overall survival (OS) (group 1 vs 0, P = 0.006; group 2 vs 0, P < 0.001) and disease-free survival (DFS) (group 1 vs 0, P < 0.001; group 2 vs 0, P < 0.001). The ROC analysis demonstrated that NPS had better predictive ability than other prognostic indicators. Multivariate analysis revealed that NPS was independent prognostic indicator of OS (group 1 vs 0, hazard ratio [HR] =2.591, P = 0.023; group 2 vs 0, HR = 8.744, P = 0.001) and DFS (group 1 vs 0, HR =3.754, P < 0.001; group 2 vs 0, HR = 9.673, P < 0.001). Conclusion: The NPS could be an independent prognostic indicator in patients with resected LA-NSCLC receiving neoadjuvant treatment and more reliable than the other nutritional and inflammatory indicators.

The Value of the Systemic Immune-Inflammation Index in Predicting Survival Outcomes in Patients with Brain Metastases of Non-Small-Cell Lung Cancer Treated with Stereotactic Radiotherapy.

BACKGROUND: As a parameter integrating platelet (P), neutrophil (N), and lymphocyte (L) levels, the systemic immune-inflammation index (SII) has been used as a prognostic marker for patient survival in various types of solid malignant tumors. However, there is no in-depth study in non-small-cell lung cancer (NSCLC) patients with brain metastases after stereotactic radiotherapy. Therefore, we performed a retrospective analysis to determine the clinical and prognostic value of the SII in NSCLC patients with brain metastases who underwent stereotactic radiotherapy. MATERIALS AND METHODS: We enrolled 124 NSCLC patients with brain metastases treated with stereotactic radiotherapy in our hospital between May 2015 and June 2018. We obtained all baseline blood samples within one week prior to stereotactic radiotherapy. The SII was calculated by the following formula: neutrophil counts × platelet counts/lymphocyte counts. The optimal cutoff value of the SII for predicting prognosis was assessed by receiver operating characteristic (ROC) curves with the maximum log-rank values. The discriminative ability of predicting prognosis was calculated and compared using the Kaplan-Meier method and log-rank test. The hazard ratio (HR) and 95% confidence interval (CI) were combined to evaluate the prognostic impact of the blood index on overall survival (OS) and progression-free survival (PFS). Only those parameters that proved to be associated with statistically significant differences in clinical outcomes were compared in multivariate analysis using a multiple Cox proportional hazard regression model to identify independent prognostic factors. RESULTS: Of the total enrolled patients, 53.2% and 46.8% have high SII and low SII, respectively. In this study, Kaplan-Meier curve analysis revealed that the median PFS was 9 months (range: 2-22 months) and the median OS was 18 months (range: 4-37 months). Applying an optimal cutoff of 480 (SII), the median PFS was better in the low SII group patients (11.5 vs. 9 months), and the median OS was significantly longer in the low SII group patients (20 vs. 18 months). A SII > 480 was significantly associated with worse OS (HR: 2.196; 95% CI 1.259-3.832; P = 0.006) and PFS (HR: 2.471; 95% CI 1.488-4.104; P < 0.001) according to univariate analysis. In multivariate analysis, only age (HR: 2.159; 95% CI 1.205-3.869; P = 0.010), KPS (HR: 1.887; 95% CI 1.114-3.198; P = 0.018), and SII (HR: 1.938; 95% CI 1.046-3.589; P = 0.035) were independently correlated with OS, and SII (HR: 2.224; 95% CI 1.298-3.810; P = 0.004) was an independent prognostic predictor of PFS, whereas we found that other inflammation-based indices lost their independent value. CONCLUSIONS: The SII, which is an integrated blood parameter based on platelet, neutrophil, and lymphocyte counts, may be an independent prognostic indicator and may be useful for the identification of NSCLC patients with brain metastases after stereotactic radiotherapy at high risk for recurrence.

Efficacy of bevacizumab combined with temozolomide dose-dense regimen on recurrent glioma.

PURPOSE: To explore the clinical efficacy and safety of bevacizumab combined with temozolomide dose-dense regimen in the treatment of recurrent glioma. METHODS: The clinical data of 102 patients with recurrent glioma after surgery, radiotherapy or chemotherapy treated in our hospital from March 2016 to December 2018 were retrospectively analyzed. There were 51 patients undergoing bevacizumab combined with temozolomide treatment (Bevacizumab group), and the remaining 51 patients received temozolomide treatment alone (Control group). The clinical data of all patients were collected, the short-term efficacy, adverse reactions after treatment and quality of life score were compared between the two groups, and the levels of serum immune factors were recorded. The patients were followed up, and the overall survival (OS) rate and progression-free survival (PFS) rate were recorded. RESULTS: All patients underwent bevacizumab treatment for 2-12 cycles, with an average of 6.3 cycles. The objective response rate (ORR) was 47.1% (24/51) and 23.5% (12/51), and the clinical benefit rate (CBR) was 82.4% (42/51) and 60.8% (31/51), respectively, in the Bevacizumab group and Control group. Both ORR and CBR in the Bevacizumab group were superior to those in the Control group. After treatment, the scores of the SF-36 scale significantly rose in the two groups. After treatment, the levels of serum vascular endothelial growth factor (VEGF), epidermal growth factor (EGF), interleukin-2 (IL-2) and IL-6 obviously declined in the two groups compared with those before treatment, while they were obviously lower in the Bevacizumab group than those in the Control group. The median OS was 9.2 months and 8.7 months, and the median PFS was 4.1 months and 3.3 months, respectively, in the Bevacizumab group and the Control group. Log-rank test revealed that the OS had no statistically significant difference between the two groups, but the PFS in the Bevacizumab group was remarkably better than that in the Control group. CONCLUSIONS: Bevacizumab combined with temozolomide can significantly improve the clinical efficacy, increase the quality of life of patients, and delay the progression of recurrent glioma, with tolerable adverse reactions.

Prognostic significance of negative conversion of high-risk Human Papillomavirus DNA after treatment in Cervical Cancer patients.

Objective: To evaluate the prognostic value of conversion of high-risk human papillomavirus (HR-HPV) status after treatment for cervical cancer. Methods: A total of 112 cervical cancer patients with HR-HPV positivity without distant metastasis treated with surgery or radical concurrent radiochemotherapy were enrolled. HR-HPV status was analyzed before and after treatment and at the time point of recurrence or metastasis. Log-rank tests and Cox proportional hazard models were used to evaluate the association between conversion of HR-HPV status after treatment and survival. Results: Eighty-four (75%) patients had negative conversion HR-HPV (ncHR-HPV) after treatment and twenty-eight (25%) were persistent positive HR-HPV (ppHR-HPV). The negative conversion rate was 75.8% in patients who received surgical treatment and 71.4% in patients who received radical concurrent radiochemotherapy. There was no significant difference between the two groups (χ2=0.000, P=1.000). There was no significant correlation between HR-HPV conversion after treatment with age (χ2=0.616, P=0.252), FIGO stage (χ2=0.051, P=0.823) and pathological type (χ2=0.000, P=1.000). Univariate analysis showed that treatment regimen and ncHR-HPV was closely related to progression-free survival (PFS) and overall survival (OS) of cervical cancer patients. Multivariate COX regression model showed that treatment regimen (HR=3.57, 95% CI: 1.57-8.11, P=0.002) and ncHR-HPV (HR=5.14, 95% CI: 2.32-11.46, P<0.001) were independent prognostic factors for PFS, while only ncHR-HPV (HR=12.56, 95% CI: 3.54-44.65, P<0.001) was an independent prognostic factor for OS. The presence of ppHR-HPV after treatment (χ2=14.827, P<0.001) was associated with recurrence and metastasis. Eleven of the patients with ncHR-HPV after treatment had recurrence or metastasis, and HPV reinfection was not detected in any of them. Conclusion: ncHR-HPV after treatment in cervical cancer patients indicated better PFS and OS, while ppHR-HPV indicated worse prognosis and high risk of recurrence or metastasis. For patients with ncHR-HPV after treatment, continued HPV screening may not predict recurrence or metastasis. This study suggested that HR-HPV monitoring is necessary for ppHR-HPV patients after treatment but may not be for ncHR-HPV patients. However, further large and multi-center prospective studies should be performed to confirm these findings.

The prognostic value of excission repair cross-complementation group one enzyme expression in locally advanced cervical carcinoma patients treated with cisplatin-based treatment: a meta-analysis.

BACKGROUND: Recently, several studies observed that locally advanced cervical carcinoma with negative excision repair crross-complementation group one enzyme expression has better outcomes in cisplatin-based chemotherapy or chemoradiotherapy than carcinoma with positive excission repair cross-complementation group one enzyme expression. In this meta-analysis, we quantitatively evaluated the prognostic value of excission repair cross-complementation group one enzyme expression in locally advanced cervical carcinoma patients receiving platinum-based chemotherapy or chemoradiotherapy. MATERIALS: A systematic search for relevant studies was conducted in the PubMed, Cochrane Library, EMBASE and Medline databases. Fixed- or random-effects models were used for pooled analysis. The endpoints were overall survival and disease-free survival () reported as ORs and 95% CIs. The effects of excission repair cross-complementation group one enzyme expression on the clinicopathological parameters were measured by the pooled ORs and their 95% CIs. RESULTS: Eight studies (612 patients in total) satisfied the inclusion criteria. Negative/low excission repair cross-complementation group one enzyme expression was significantly associated with better overall survival (OR, 1.92; 95% CI, 1.22 to 3.05; P = 0.005) and disease-free survival (OR, 5.77; 95% CI, 1.90 to 17.54; P = 0.002). Additionally, there were significant associations between excission repair cross-complementation group one enzyme expression and lymph node metastasis (OR, 2.57; 95% CI, 1.28 to 5.16; P = 0.008). CONCLUSIONS: This meta-analysis suggested that pretreatment excission repair cross-complementation group one enzyme expression might be a useful biomarker to predict prognoses for locally advanced cervical carcinoma patients receiving platinum-based chemotherapy or chemoradiotherapy.

Combined pretreatment with 18F-FDG PET/CT and Comet assay guides the concurrent chemoradiotherapy of locally advanced cervical cancer: study protocol for a randomized controlled trial.

BACKGROUND: Cisplatin-based chemoradiation is the standard of care for patients with locally advanced cervical cancer. Nevertheless, an increasing number of radio-resistant tumors still recur. METHODS AND DESIGN: Three hundred cervical cancer patients with FIGO stages IB2-IVA and no para-aortic lymphadenopathy (> 10 mm) will be enrolled. All patients will be randomly divided into four arms to receive either (1) intensity modulated radiation therapy (IMRT), (2) RapidArc, (3) positron emission tomography/computed tomography (PET/CT) with F-18 fluorodeoxyglucose (FDG), or (4) Comet assay-guided IMRT, PET/CT, and Comet assay-guided RapidArc. All patients will receive definitive radiotherapy consisting of external beam whole pelvic radiation therapy and high-dose rate intracavitary brachytherapy. Cisplatin 30 mg/m2 weekly will be administered concurrently for five courses. Two to four cycles of TP (Taxol 135 mg/m2, D1, and DDP 75 mg/m2, D1-3) sequential chemotherapy will be performed according to MRI or PET/CT after cisplatin-based chemoradiation. The primary outcome measure is progression-free survival, and the second outcome measures are overall survival and time to progression. DISCUSSION: RapidArc has an obvious advantage in improving the degree of target coverage, improving organs at risk, sparing healthy tissue, and significantly reducing the treatment time. FDG-PET/CT can increase the agreement between biopsies and delineated tumor volume and has the potential to positively impact the course of treatment. The Comet assay is attractive as a potential clinical test of tumor radiosensitivity. During radiotherapy, accurately defining disease areas is critical to avoid the unnecessary irradiation of normal tissue. Based on FDG-PET/CT and Comet assay, higher doses can be safely delivered to accurate tumor volumes, while the doses to the bladder and rectum are relatively low. TRIAL REGISTRATION: ClinicalTrials.gov Protocol Registration and Results System Receipt Release Date: May 21, 2017 - Retrospectively registered. NCT03163979 .

Concurrent weekly single cisplatin vs triweekly cisplatin alone with radiotherapy for treatment of locally advanced cervical cancer: a meta-analysis.

Background: Radiotherapy (RT) concurrent with cisplatin (CDDP) is the standard regimen used for treatment of locally advanced cervical carcinoma. In this meta-analysis, we compared the weekly and triweekly single CDDP concomitant chemoradiation regimens for treatment of cervical cancer with respect to compliance, recurrence, survival, and acute adverse effects. Materials and methods: A systematic search for relevant studies was conducted in PubMed, Cochrane Library, EMBASE, and Medline databases. Fixed- or random-effects model was used for pooled analysis. The end points were overall survival, recurrence, compliance, and acute adverse effect reported as odds ratios (ORs) and 95% CIs. Results: Six randomized trials and two retrospective studies qualified the inclusion criteria. The regimen of triweekly CDDP alone concurrent with RT showed better compliance (OR, 0.49; 95% CI, 0.29-0.83; P=0.009). No significant difference was observed between the 2 arms with respect to recurrence, survival, and acute adverse effects (all P>0.05). However, triweekly CDDP regimen was associated with significantly lower incidence of local recurrence (OR, 1.83; 95% CI: 1.12-3.01; P=0.02), while weekly CDDP regimen was associated with a lower risk of leucopenia (OR, 0.30; 95% CI: 0.10-0.92; P=0.03). Conclusion: Triweekly single platinum chemotherapy plus concurrent RT was superior to weekly CDDP regimen with respect to local recurrence and treatment compliance in patients with locally advanced cervical carcinoma.

Molecular targeting of VEGF/VEGFR signaling by the anti-VEGF monoclonal antibody BD0801 inhibits the growth and induces apoptosis of human hepatocellular carcinoma cells in vitro and in vivo.

Hepatocellular carcinoma (HCC) is the third-leading cause of cancer-related deaths with 750,000 newly diagnosed cases each year. Surgery, radiotherapy, and chemotherapy constitute the main treatment modalities for HCC, but liver cirrhosis and damage often occur. Molecular targeted drugs have been recently developed to treat HCC. Vascular endothelial growth factor (VEGF)/VEGF receptor (VEGFR) autocrine signaling is closely related to the growth, progression, and metastasis of HCC, making the VEGF/VEGFR axis an ideal target for the development of molecular targeted agents. Here, we report the effects of the novel anti-VEGF humanized monoclonal antibody BD0801 on the growth of HCC cells in vitro and in vivo as well as the underlying mechanisms. BD0801 significantly inhibited the proliferation of HepG2, SMMC-7721, and Bel7402 cells in vitro, accompanied with an induction of apoptosis and cell cycle arrest at the G1 phase. BD0801 potently suppressed AKT, Erk1/2, and retinoblastoma (Rb) phosphorylation, while increasing p21 and decreasing cyclin D1 protein levels. BD0801 significantly inhibited growth in mouse tumor xenografts and induced cell apoptosis of HepG2 and SMMC-7721 tumor xenografts. Furthermore, BD0801 effectively reduced the vascular density and tumor tissue microvessel density (MVD). Similarly, BD0801 decreased AKT, Erk1/2, and Rb phosphorylation and cyclin D1 expression whereas it increased p21 protein expression in mouse HCC tumor xenografts. Importantly, BD0801 showed a better effect than Bevacizumab (Bev) on the inhibition of cell growth and induction of apoptosis in HCC cells in vitro and in vivo. These findings suggest that BD0801 is a potent anti-VEGF monoclonal antibody for the treatment of HCC.

Effects of antisense oligonucleotides against C-reactive protein on the development of atherosclerosis in WHHL rabbits.

Increased plasma levels of C-reactive protein (CRP) are closely associated with cardiovascular diseases, but whether CRP is directly involved in the pathogenesis of atherosclerosis is still under debate. Many controversial and contradictory results using transgenic mice and rabbits have been published but it is also unclear whether CRP lowering can be used for the treatment of atherosclerosis. In the current study, we examined the effects of the rabbit CRP antisense oligonucleotides (ASO) on the development of atherosclerosis in WHHL rabbits. CRP ASO treatment led to a significant reduction of plasma CRP levels; however, both aortic and coronary atherosclerotic lesions were not significantly changed compared to those of control WHHL rabbits. These results suggest that inhibition of plasma CRP does not affect the development of atherosclerosis in WHHL rabbits.

Demonstration of vasculogenic mimicry in astrocytomas and effects of Endostar on U251 cells.

Angiogenesis is an important process for the cell growth of normal and tumor tissues. Vasculogenic mimicry (VM) is a newly described vascular network structure that was first described in aggressive melanomas. To find out whether VM also exists in astrocytomas and to examine its clinical significance, we studied 80 malignant astrocytoma samples using immunohistochemistry coupled with periodic acid-Schiff (PAS) staining. To explore the possible therapeutic methods of anti-VM formation, we cultured astrocytoma cells using three-dimensional Matrigel and investigated the effects of Endostar, an endothelial cell growth inhibitor, on astrocytoma cell growth, invasion, and VM formation. VM structures were found in 8 samples of malignant astrocytomas, seven of which were grade IV astrocytomas. Glioblastoma U251 cells cultured in Matrigel formed vessel-like loops and networks, mimicking the features of VM in vivo, whereas such structures were not found in cultured normal astrocytes or well-differentiated astrocytoma SHG44 cells. In addition, treatment with Endostar led to a dose- and time-dependent inhibition of proliferation and invasion of both U251and SHG44 cells, but VM formation by U251 cells in vitro was not prominently affected. In conclusion, VM is frequently detected in aggressive glioblastomas, and the presence of VM may constitute a new predictor for poor prognosis in astrocytoma patients. Although Endostar has broad anti-tumor effects due to anti-angiogenesis and anti-tumor cell mechanisms, its inhibitory effects on VM formation by U251cells in vitro are not remarkable.