Purpose: To compare the diagnostic performance of two modalities commonly used for detecting distant metastasis in primary nasopharyngeal carcinoma (NPC): 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography/computed tomography (PET/CT) and conventional work-ups (CWUs). Methods: All topic-related studies were comprehensively searched and included. We determined sensitivities and specificities across studies, calculated negative and positive likelihood ratios (LR- and LR+, respectively), and constructed summary receiver operating characteristic curves. Moreover, we compared the diagnostic performance of PET/CT and CWUs by analyzing studies that reported the results of these diagnostic methods on the same patients. Results: The pooled sensitivity and specificity were 85.7% and 98.1% for PET/CT (1474 patients), and 38.0% and 97.6% for CWUs (1329 patients). In the head-to-head comparison of PET/CT and CWUs (1029 patients), PET/CT showed a significantly higher sensitivity (83.7% vs. 40.1%, P < 0.001) and lower LR- (0.169 vs. 0.633, P < 0.001) than CWUs on a per-patient basis; no significant difference was observed in pooled specificity (97.7% vs. 97.8%, P = 0.892) or LR+ (36.416 vs. 16.845, P = 0.149). The superiority of PET/CT over CWUs was due mainly to the better diagnostic performance on bone metastasis. However, suboptimal sensitivity of PET/CT was reported in the aspect of detection of liver metastasis. Sensitivity analyses showed relatively poor sensitivity and LR- of PET/CT compared to the original analysis. Conclusions: PET/CT was superior to CWUs in detecting distant metastasis in primary NPC. However, the efficacy of PET/CT in detecting liver metastasis still requires further optimization.

Dihydromyricetin, the most abundant natural flavonoid isolated from Ampelopsis grossedentata, exhibits broad anti-tumor effects. However, the effects of dihydromyricetin on cholangiocarcinoma remain unclear. This study examined the anti-tumor effects of dihydromyricetin in two human cholangiocarcinoma cell lines HCCC9810 and TFK-1, and the underlying mechanism was also investigated. Our study was the first to show that dihydromyricetin significantly inhibited cell proliferation, migration, invasion and promoted apoptosis in cholangiocarcinoma cells. By analyzing the TCGA dataset, we found that expression of miR-21, an oncogene and a potential target of anticancer drugs for cholangiocarcinoma, was upregulated in cholangiocarcinoma tissues compared to paired control tissues. Moreover, dihydromyricetin significantly reduced the expression of miR-21 in a dose-dependent manner. Overexpression of miR-21 remarkably abolished the inhibitory effects of dihydromyricetin on cell proliferation, migration, invasion and abrogated its effect of promoting cell apoptosis in both HCCC9810 and TFK-1 cells. Dihydromyricetin remarkably increased the expression of PTEN and decreased the expression of phosphorylated Akt, while overexpression of miR-21 abrogated the modulation of PTEN/ Akt pathway by dihydromyricetin. Taken together, our study demonstrates that dihydromyricetin inhibits cell proliferation, migration, invasion and promotes apoptosis in cholangiocarcinoma cells via regulating miR-21.

Purpose: The objective of this study was to confirm the association between pretreatment Epstein-Barr virus (EBV) DNA (pre-DNA) load and survival outcomes after long-term follow-up in patients with locoregionally advanced nasopharyngeal carcinoma (LA-NPC). Materials and Methods: Between November 2009 and February 2012, a total of 1036 patients with LA-NPC were enrolled. There were 762 patients in stage III and 274 in stage IVA-B. All patients were treated with radical radiotherapy with or without chemotherapy, and pre-DNA concentrations were quantified by a polymerase chain reaction assay. Patient outcomes were evaluated. Results: The 5-year overall survival (OS), distant metastasis-free surviva (DMFS), locoregional relapse-free survival (LRFS), and progression-free survival (PFS) rates were 84.7%, 87.0%, 90.2%, and 77.1%, respectively. By using previously defined pre-DNA cutoff value (1500 copies/ml pretreatment), pre-DNA was an independent prognostic predictor for OS, DMFS, and PFS using log-rank test. Multivariate Cox analysis also confirmed these results. Subgroup analysis indicated that the 5-year OS, DMFS, and PFS rates in patients staged IVA-B with pre-DNA < 1500 copies/ml were similar to those patients staged III with pre-DNA ≥ 1500 copies/ml, whereas patients staged IVA-B patients with pre-DNA ≥ 1500 copies/ml predicted worse outcome. Conclusions: In this expanded study, the prognostic significance of pre-DNA was confirmed using predefined cutoff value in an independent patient group, and pre-DNA was identified as an independent prognostic marker for the risk stratification in LA-NPC.

Kinase inhibitors that target Bcr-Abl are highly effective in the treatment of chronic myeloid leukemia (CML). However, these inhibitors are often invalidated due to the drug resistance. Therefore, the discovery and development of novel Bcr-Abl inhibitors is required to overwhelm the drug resistance in the treatment of CML resistant to the currently used first-line Bcr-Abl inhibitors. Herein we have described a newly developed Bcr-Abl inhibitor CT-721, which displayed potent inhibitory effects on wild-type and T315I mutant Bcr-Abl. It functioned as a typically ATP-competitive inhibitor, superior to other existing Bcr-Abl inhibitors. CT-721 also demonstrated time-dependent inhibition of Bcr-Abl activation and the resultant downstream signaling transduction pathways in Bcr-Abl positive cells. Furthermore, CT-721 induced cell apoptosis and cell cycle arrest, and efficaciously inhibited tumor growth in Bcr-Abl-expressed K562 and KU812 xenograft models in a mechanism-based manner. Further PK/PD studies revealed a positive in vivo correlation between the compound concentration and inhibition of Bcr-Abl activity. Taken together, CT-721 is a potent and time-dependent Bcr-Abl kinase inhibitor, and has shown strong in vitro and in vivo anti-CML activities with a favorable pharmacokinetic profile, differentiating it from other Bcr-Abl kinase inhibitors already approved and current in development for the treatment of CML.

Background: To analyze the prognostic value of cervical node necrosis (CNN) observed on pretreatment magnetic resonance imaging (MRI) in patients with nasopharyngeal carcinoma (NPC) treated with intensity-modulated radiotherapy (IMRT). Patients and Methods: The medical records of 1423 NPC patients with cervical node metastasis who underwent IMRT were retrospectively reviewed. Lymph nodes in the axial plane of pretreatment MRI were classified as follows: grade 0 CNN, no hypodense zones; grade 1 CNN, ≤33% areas showing hypodense zones; and grade 2, >33% areas showing hypodense zones. Results: CNN was detectable in 470/1423 (33%) patients. Of these 470 patients, 213 (15%) and 257 (18%) exhibited grade 1 and grade 2 CNN. The grade 0 and grade 1 CNN groups showed significant differences with regard to distant metastasis-free survival (DMFS), but not overall survival (OS), regional relapse-free survival (RRFS), local relapse-free survival (LRFS), and disease-free survival (DFS). Significant differences were observed among the grade 0 and grade 2 CNN groups with regard to OS, RRFS, LRFS, DMFS, and DFS. Moreover, OS, LRFS, RRFS, and DFS were significantly different between the grade 1 and grade 2 CNN groups, whereas DMFS showed no significant differences. Univariate and multivariate analyses revealed CNN on MRI as a significant negative prognostic factor for OS, LRFS, RRFS, DMFS, and DFS in NPC patients. Conclusions: NPC patients with CNN of different grades show various prognosis and failure patterns after IMRT. CNN on MRI can be adopted as a predictive factor for formulating individualized treatment plans for NPC patients.

Background: Besides the well-established risk factors for gastric adenocarcinoma (GaC), many other etiological factors remain largely unexplored. This large comprehensive case-control study aimed to investigate the preventable lifestyle and eating habits associated with GaC. Methods: Consecutive patients with primary microscopically-confirmed GaC diagnosed in 2016-2018 were matched by sex, age, height, and socioeconomic status at a 1:1 ratio with healthy controls. Association of GaC versus control with investigated factors was assessed using the multivariable-adjusted conditional logistic regression for paired samples. Results: Together 302 GaC patients and 302 healthy controls were investigated. Participants receiving higher education and those eating majorly vegetables had less frequently GaC. The majorly frying cooking habit was associated with a higher incidence of GaC. People complaining about poor sleep quality had more often GaC. The more often one smoked, the more often he/she had GaC. A higher frequency for having pickled food was associated with more frequent GaC, while having more frequently vegetables/fruit, beans, or kelps was associated with less often GaC. A greater preference for sour or bitter taste was associated with less frequent GaC. The frequencies of thin liquid intake after meal, swallowing hot food without adequate cooling, doing other things while eating, eating overnight food, and eating midnight snack were all positively associated with GaC, while going to bed regularly was associated with less often GaC. Conclusions: Education level, sleep quality, smoking, the frequencies of use of several foods and seasonings, the preference for specific tastes, and various eating and living habits were associated with GaC. The findings offer important hints for further prospective investigations and for easy effective GaC-preventative strategy-making.

The prognostic value of C-reactive protein/albumin ratio (CRP/Alb), a novel inflammation-based marker, remains unknown in nasopharyngeal carcinoma (NPC).

Cholangiocarcinoma (CCA) leads to poor prognosis due to high aggressiveness and common chemoresistance. Dihydromyricetin (DMY), the main bioactive compound isolated from Ampelopsis grossedentata, exhibits broad anti-tumor effects. This study aimed to investigate the inhibitory effect of DMY on CCA tumor growth and epithelial-mesenchymal transition (EMT) and its underlying mechanism in CCA. DMY treatment significantly inhibited cell proliferation and EMT in CCA cell lines. The expression of ZEB1 and vimentin were down-regulated, while the level of E-cadherin was increased after DMY treatment. By analyzing the TCGA dataset, we found that miR-455 expression was significantly downregulated, while the level of ZEB1 was up-regulated in human CCA tumor tissues compared to normal samples. Mechanistic studies showed that ZEB1 was a direct target of miR-455-3p in CCA. Moreover, DMY treatment potently increased miR-455-3p expression and inhibited ZEB1 expression. Inhibition of miR-455-3p expression abolished DMY's inhibitory effects on tumor growth and EMT in both CCA cells and cell-engrafted nude mice. Finally, DMY significantly suppressed the expressions of p-PI3K and p-AKT, while silencing miR-455-3p remarkably abrogated the inhibitory effect. In conclusion, DMY suppresses tumor growth and EMT through regulating miR-455-3p in human cholangiocarcinoma, suggesting a potential option for CCA treatment.

Background: miR-143 is known to be downregulated in various cancer cells and tumors and generally plays a tumor-suppressor role. miR-143. However, the role of miR-143 in the mediation of the sensitivity of prostate cancer cells to abiraterone acetate remains unrevealed. Methods: The expression levels of miRNAs were determined by miRNA microarray and quantitative real-time PCR (qRT-PCR). The protein levels were assessed by Western blot assay. Cell viability and apoptosis were respectively measured by Cell Counting Kit-8 (CCK-8) assay and flow cytometry. Results: We identified that miR-143 was significantly downregulated in PC3-AbiR cells compared to PC3 cells. Overexpression of miR-143 promoted PC-AbiR sensitivity to abiraterone acetate in vitro and in vivo. We also revealed that miR-143 upregulation inhibited p-JNK (c-Jun N-terminal kinases) and increased p-Bcl2 (B-cell lymphoma 2), contributing to abiraterone acetate-induced apoptosis in PC3-AbiR cells. Finally, we showed that the combination of miR-143 and abiraterone acetate exerted the most profound tumor inhibition effect and prolonged the mice survival rate in PC3-AbiR tumor-bearing mice. Conclusion: Upregulation of miR-143 may serve as a new strategy to enhance the therapeutical effect of abiraterone acetate on prostate cancer patients who are resistant to abiraterone acetate.

The optimal treatment for early-stage nasopharyngeal carcinoma (NPC) remains controversial. Identification of prognostic factors for metastasis and tumor progression is urgently required to improve clinical decision-making for patients with American Joint Committee on Cancer (AJCC) 2009 stage II NPC from the endemic area.

Due to the lack of studies, it remains unclear whether the additional neoadjuvant chemotherapy (NACT) to concurrent chemoradiotherapy (CCRT) is superior to CCRT alone for locoregionally advanced nasopharyngeal carcinoma (NPC). The main objective of this Bayesian network meta-analysis was to determine the efficacy of NACT+CCRT as compared with CCRT alone.

Purpose: To design an alternative workflow for cancer-risk assessment to predict distant metastasis (DM) of nasopharyngeal carcinoma (NPC). Methods: We enrolled 234 patients with non-disseminated NPC and a family history of cancer who underwent intensity-modulated radiotherapy and concurrent chemo-radiotherapy with/without induction chemotherapy in our primary cohort. We conducted univariate and multivariate analyses of the associated prognostic factors, built a nomogram model for distant-metastasis-free survival (DMFS), and confirmed the prognostic value of weight-loss ratio (WTratio). The secondary cohort included 97 patients with available pre-DNA levels who were treated at our cancer center. We performed internal validation with the primary cohort and external validation with the secondary cohort, and compared the new DMFS model with the current 7th TNM staging system. Results: In the primary cohort, 95.9% patients experienced weight loss. The N group (N2-3 vs. N0-1, P = 0.037) and pre-DNA level (P = 0.02) were independent prognostic factors for DMFS in NPC patients. Smoking (P = 0.051) and WTratio (P = 0.052) showed a significant trend for DMFS. WTratio was an independent prognostic factor for DMFS (P = 0.03). Smoking, WTratio, N group, and pre-DNA level were merged to build a risk-score model for DMFS using a nomogram, which could predict survival after internal and external validation. Conclusions: Maintaining body weight during treatment is essential to prevent DM of NPC. Compared with the current 7th TNM staging system, the new DMFS model might better predict DM of NPC. The alternative workflow designed could be applied for prognostic analysis of other cancers.

Background: Anti-epidermal growth factor receptor monoclonal antibodies (anti-EGFR mAbs), such as cetuximab and nimotuzumab have been used in the treatment of nasopharyngeal carcinoma (NPC), yet their efficacy and safety are undetermined. Materials and Methods: We performed two meta-analyses based on systematic searches of PubMed, EMBASE, the Cochrane Library and SinoMed: comparison 1 (standard therapy plus mAbs vs. standard therapy) and comparison 2 (radiotherapy plus concurrent mAbs vs. concurrent chemoradiotherapy) to explore the treatment value of anti-EGFR mAbs in NPC. Primary outcomes were overall survival (OS) and disease-free survival (DFS); secondary outcomes, locoregional recurrence-free survival (LRFS), distant metastasis-free survival (DMFS) and grade 3 and above acute adverse events. Results: Four randomized controlled trials and thirteen observational studies were eligible. Comparison 1 (twelve studies): adding mAbs to standard therapy (radiotherapy or chemoradiotherapy) significantly improved OS (HR, 0.51; 95% CI, 0.39-0.66) and DFS (HR, 0.68; 95% CI, 0.54-0.86), but increased the frequency of skin rashes and mucositis. Comparison 2 (six studies): OS (HR, 1.17; 95% CI, 0.81-1.70) and DFS (HR, 1.16; 95% CI, 0.86-1.57) were not significantly different when mAbs replaced conventional cytotoxic chemotherapy concurrently with radiotherapy, with fewer hematological, gastrointestinal and renal toxicities and more skin rashes in the mAb group. Conclusion: We recommend anti-EGFR mAbs enhance-but should not replace-current treatment paradigms for locoregionally advanced NPC. Further evidence from phase III clinical trials is required.

Purpose: This study aim to explore the effect of down-regulation of PRR11 (proline-rich protein 11) on the proliferation, invasion, migration, Wnt/β-catenin signaling pathway and EMT of osteosarcoma cells. Methods: Immunohistochemical staining, fluorescent quantitative PCR and western blotting were used to detect the expression level of PRR11 in osteosarcoma tissues and osteosarcoma cells. After SiRNA down-regulated the expression level of PRR11, CCK8 was used to detect cell proliferation ability, Transwell chamber to detect cell invasion ability, scratch test to detect cell migration ability, and flow cytometry to detect cell apoptosis. Western blotting was used to detect the expression levels of wnt/β-catenin pathway related proteins and key epithelial-mesenchymal transition proteins. Results: PRR11 is highly expressed in osteosarcoma tissues, and its expression level is related to tumor size, Enneking stage of tumor, lymph node metastasis and patient prognosis. The low expression of PRR11 can inhibit the proliferation, migration and invasion of osteosarcoma cells, and promote apoptosis. Down-regulating the expression of PRR11 will inhibit the expression of Wnt pathway related proteins β-catenin and p-GSK-3β, enhance the expression of p-β-catenin, GSK-3β, and increase the expression of downstream genes CyclinD1 and c-Myc in the Wnt pathway. At the same time, the expression of PRR11 was down-regulated, the epithelial marker E-cadherin was significantly increased, and the expression levels of mesenchymal markers Vimentin and Fibronectin were significantly reduced. Conclusion: Down-regulation of PRR11 can inhibit the proliferation, migration and invasion of osteosarcoma cells, and its mechanism may be related to down-regulation of PRR11 to inhibit the Wnt/β-catenin signaling pathway and thus prevent the EMT process. Therefore, PRR11 may be used as an oncogene to promote the occurrence and development of osteosarcoma, and is a potential prognostic indicator and therapeutic target in osteosarcoma.

The aim of this study is to investigate the prognostic value of neoadjuvant chemotherapy (NCT) in locoregionally advanced nasopharyngeal carcinoma (NPC) with low pre-treatment Epstein-Barr virus (EBV) DNA in the era of intensity-modulated radiotherapy (IMRT).

Background: To explore the value of chemoradiotherapy (CRT) in stage II nasopharyngeal carcinoma (NPC) compared to radiotherapy (RT) alone which includes two-dimensional radiotherapy (2D-RT) and intensity-modulated radiotherapy (IMRT). Methods: All topic-related comparative articles were identified by a comprehensive search of public databases (MEDLINE, EMBASE, Cochrane Library and CBMdisc). The primary outcomes were overall survival (OS), loco-regional relapse-free survival (LRRFS) and distant metastasis-free survival (DMFS). Secondary outcomes were grade 3-4 acute toxicity events. We performed subgroup analysis of CRT versus 2D-RT/IMRT alone to investigate the optimal modality. Sensitivity analysis focused on CRT versus IMRT alone was used to assess stability of the study results. Results: Eleven comparative studies (2138 patients) were eligible. CRT had significantly higher OS (HR = 0.67, 95% CI = 0.45-0.98, P = 0.04) and LRRFS (HR = 0.61, 95% CI = 0.46-0.80, P = 0.0003) than RT alone, but no significant difference was observed in DMFS (HR = 0.83, 95% CI = 0.52-1.31, P = 0.41). Meanwhile, CRT was associated with higher frequencies of grade 3-4 leukopenia, mucositis and nausea (P = 0.005, 0.03, < 0.0001, respectively). Subgroup analysis showed that IMRT alone could achieve equivalent OS, LRRFS and DMFS compared to CRT (P = 0.14, 0.06, 0.89, respectively). Significant value was only observed in LRRFS for CRT compared to 2D-RT alone (P = 0.01). Sensitivity analysis for the comparison of CRT and IMRT alone demonstrated generally stable outcomes, in support of the final conclusions. Conclusions: In the treatment of patients with stage II NPC, CRT was better than 2D-RT alone with significant benefit in LRRFS. IMRT alone was superior to CRT with equivalent survival outcomes and fewer grade 3-4 acute toxicities.

Background: The aim of this study is to evaluate the long-term therapeutic gain of induction chemotherapy (IC) in locoregionally advanced nasopharyngeal carcinoma (NPC) in the era of intensity-modulated radiotherapy (IMRT). Methods: Data on 957 patients with stage T1-2N2-3 or T3-4N1-3 NPC treated with IMRT were retrospectively reviewed. Propensity score matching (PSM) method was adopted to balance influence of various covariates. Patient survival between IC and non-IC groups were compared. Results: For the 318 pairs selected from the original 957 patients by PSM, the median follow-up duration was 57.13 months (range, 1.27-78.1 months). The 5-year overall survival (OS), distant metastasis-free survival (DMFS), disease-free survival (DFS) and locoregional relapse-free survival (LRRFS) rates for IC group vs. non-IC group were 87.2% vs. 80.8% (P = 0.023), 88.1% vs. 83.2% (P = 0.071), 80.7% vs. 71.4% (P = 0.011) and 92.1% vs. 86.7% (P = 0.081), respectively. Multivariate analysis identify IC as an independent prognostic factor for OS (HR, 0.595; 95% CI, 0.397-0.891; P = 0.012) and DFS (HR, 0.627; 95% CI, 0.451-0.872; P = 0.006). After excluding the patients not receiving concurrent chemotherapy, IC was found to be an independent prognostic factor for OS (HR, 0.566; 95% CI, 0.368-0.872; P = 0.01), DMFS (HR, 0.580; 95% CI, 0.367-0.916; P = 0.02) and DFS (HR, 0.633; 95% CI, 0.444-0.903; P = 0.012). Conclusions: IC is an effective treatment modality for patients with stage T1-2N2-3 and T3-4N1-3 NPC, and the incorporation of IC with standard CCRT could achieve the best therapeutic gain.