Thymic carcinoid with multiple bone metastases: A case report.

BACKGROUND: Thymic carcinoid (TC) is a rare entity among anterior mediastinal malignancies. TCs are neuroendocrine carcinomas that constitute approximately 2%-5% of all thymic epithelial tumors. CASE SUMMARY: The study reported a rare TC with multiple bone metastases. A 77-year-old man presented with a 2-month history of lower back pain and weight loss of 5 kg. Magnetic resonance imaging scans revealed damage to the lumbar spine, sacrocaudal vertebrae and iliac crest, suggesting bone metastasis; computed tomography (CT) scan of the thorax showed a calcified anterior mediastinal mass; positron emission tomography-CT demonstrated multiple abnormal bone signals; and laboratory work-up showed no endocrine abnormalities. Fine-needle aspiration biopsy revealed predominantly single small, round to oval cells with scant cytoplasm and some loose clusters, suggesting endocrine manifestations. The pathological diagnosis was atypical carcinoid, which tend to originate from the thymus and was classified as intermediate-highly invasive. The patient underwent anlotinib-targeted therapy. Anlotinib (12 mg) was administered daily for 2 wk, after which the patient was allowed to rest for 21 d. Follow-up CT after one year demonstrated that the tumor had shrunk by approximately 29% after therapy. Treatment has a long stable disease benefit of more than 2.5 years. CONCLUSION: These findings demonstrated that anlotinib is a promising treatment regimen for patients with TC and multiple bone metastases.

Proliferation, Metastasis, and Radiosensitivity of Nasopharyngeal Carcinoma Cells in the Expression and Effect of Kiwifruit Extract through the Regulation of miR-205-5p.

Background: Radix Actinidiae extract (RAE) has been shown to inhibit cancer in many studies, but its potential mechanism in nasopharyngeal cancer (NPC) progression remains unclear. Methods: NPC cells (SUNE1) were treated with different doses of RAE. For transfection, SUNE1 cells were transfected with the microRNA (miR)-205-5p inhibitor (anti-miR-205-5p) or mimic followed by treatment with 200 µg/mL RAE for 24 h. The MTT assay and colony formation assay were used to detect cell proliferation and radiosensitivity. The transwell assay was used to detect cell migration and invasion. The expression of miR-205-5p was detected by quantitative real-time PCR. The protein expression levels of matrix metalloproteinase-2 (MMP2) and matrix metalloproteinase-9 (MMP9) were detected by western blot analysis. Results: RAE inhibited NPC cell proliferation, migration, and invasion, while it enhanced radiosensitivity (P < 0.05). Also, RAE treatment decreased miR-205-5p expression, as well as MMP2 and MMP9 protein levels (P < 0.05). Anti-miR-205-5p transfection enhanced the effects of RAE on NPC cell proliferation, migration, invasion, and radiosensitivity (P < 0.05), while miR-205-5p mimic transfection had an opposite effect (P < 0.05). Conclusion: RAE might decrease miR-205-5p, thereby it inhibited NPC cell proliferation and metastasis and enhanced radiosensitivity.

Artemisinin potentiates apoptosis and triggers cell cycle arrest to attenuate malignant growth of salivary gland tumor cells.

One of the rare malignant tumors developing within the glands of the buccal cavity in human beings is salivary gland tumors (SGTs). The hallmark of SGTs is the fusion of nuclear factor IB (NFIB) and myeloblastosis (MYB) genes developed after the translocation of q22-23; p23-24. Although the aetiology of SGTs is not clear, however, the therapeutic modalities are surgical resection followed by the combination of chemotherapy and radiotherapy if a chance of recurrence seems to develop. Owing to have numerous side effects of chemotherapy, the drug development has been shifted to natural products with minimal side effects. One of the key phytochemical artemisinin derived from wormwood Artemisia annua exhibits various pharmacological activities against various in-vivo and in-vitro cellular models. Here, we evaluated the cytotoxic potential of artemisinin against A-253 cells with possible underlying cell death mechanisms. Our results showed that artemisinin reduces the proliferation of cells in a concentration-dependent manner and displays IC50 value in a range of 10.23, 14.21 µM, and 203.18 µM against A-253/HTB-41 and transformed salivary gland SMIE cells, respectively. Flow cytometry analysis demonstrated that artemisinin promotes a significant amount of apoptotic cellular population and triggers G0/G1 arrest of A-253 cells in a concentration-dependent manner. To verify the mechanism of cell death induced by artemisinin in A-253 cells, we found an increased level of Bax, Bim, Bad, Bak and reduced level of antiapoptotic protein Bcl-2, Bcl-XL with concomitant release of mitochondrial resident protein cytochrome c into the cytoplasm. Additionally, we found that artemisinin augments the production of reactive oxygen species which further leads to the activation of proapoptotic proteins PARP1, and caspase-3, in a concentration-dependent manner thereby triggering apoptosis. In conclusion, artemisinin exhibits promising anticancer therapeutic potential against A-253 cells and needs further validation of in-vitro results in preclinical models.

Regulation of pathophysiological and tissue regenerative functions of MSCs mediated via the WNT signaling pathway (Review).

Tissues have remarkable natural capabilities to regenerate for the purpose of physiological turnover and repair of damage. Adult mesenchymal stem cells (MSCs) are well known for their unique self­renewal ability, pluripotency, homing potential, paracrine effects and immunomodulation. Advanced research of the unique properties of MSCs have opened up new horizons for tissue regenerative therapies. However, certain drawbacks of the application of MSCs, such as the low survival rate of transplanted MSCs, unsatisfactory efficiency and even failure to regenerate under an unbalanced microenvironment, are concerning with regards to their wider therapeutic applications. The activity of stem cells is mainly regulated by the anatomical niche; where they are placed during their clinical and therapeutic applications. Crosstalk between various niche signals maintains MSCs in homeostasis, in which the WNT signaling pathway plays vital roles. Several external or internal stimuli have been reported to interrupt the normal bioactivity of stem cells. The irreversible tissue loss that occurs during infection at the site of tissue grafting suggests an inhibitory effect mediated by microbial infections within MSC niches. In addition, MSC­seeded tissue engineering success is difficult in various tissues, when sites of injury are under the effects of a severe infection despite the immunomodulatory properties of MSCs. In the present review, the current understanding of the way in which WNT signaling regulates MSC activity modification under physiological and pathological conditions was summarized. An effort was also made to illustrate parts of the underlying mechanism, including the inflammatory factors and their interactions with the regulatory WNT signaling pathway, aiming to promote the clinical translation of MSC­based therapy.

MiR-106b-5p regulates the migration and invasion of colorectal cancer cells by targeting FAT4.

MicroRNA-106b-5p (miR-106b-5p) is involved in the development of many cancers including colorectal cancer (CRC), and FAT4 is correlated with regulation of growth and apoptosis of cancer cells. The present study aimed to investigate the relation between FAT4 and miR-106b-5p and the underlying mechanism of the two on the development of CRC. Quantitative real-time PCR (qRT-PCR) assay and Western blot (WB) analysis were performed to detect the expressions of messenger RNAs (mRNAs), microRNAs (miRNAs) and proteins. The viability of CRC cells was detected by cell counting kit-8 (CCK-8). Scratch test and transwell assay were performed to measure the migration and invasion of CRC cell. Tumor angiogenesis was simulated by in vitro angiogenesis experiment. Dual-luciferase reporter assay was performed to verify the targeting relation between miR-106b-5p and FAT4. The study found that the expression of FAT4 was down-regulated and that of miR-106b-5p was up-regulated in CRC tissues. Overexpression of FAT4 resulted in decreased proliferation, migration, invasion and angiogenesis of CRC cells, whereas silencing of FAT4 led to the opposite results. In rescue experiment, miR-106b-5p partially reversed the function of FAT4 in CRC cells, thus playing a carcinogenic role by targeting FAT4 in the CRC cells.

Prognostic value of the tumor volume reduction rate after neoadjuvant chemotherapy in patients with locoregional advanced nasopharyngeal carcinoma.

PURPOSE: Aim of this study was to evaluate the prognostic value of the tumor volume reduction rate (TVRR) of neoadjuvant chemotherapy (NACT) in patients with locoregional advanced nasopharyngeal carcinoma (NPC). METHODS: We collected the clinical data of 263 patients with locoregional advanced NPC receiving NACT and subsequent radiotherapy from two hospitals: a training cohort (n = 130) was obtained from one hospital and a validation cohort was obtained the other hospital (n = 133). By follow-up and calculating the TVRR of all patients, the prognostic value of the TVRR was analyzed though a univariate and multivariate Cox regression model. A cut-off point of the TVRR relating to survival was explored by means of the Youden index, and the prognostic value of the TNM stage plus TVRR was measured by creating receiver operating characteristic (ROC) curves. RESULTS: 12.6%, a cut-off point of TVRR, was found to best predict DFS. Patients with a TVRR > 12.6% had better DFS (hazard ratio, 0.160, 95% confidence interval 0.072-0.354; P < 0.001), LRRFS (0.064, 0.013-0.310; 0.001) and DMFS (0.274, 0.106-0.711; 0.008) than patients with a TVRR ≤ 12.6%. The TVRR was a significant independent prognostic factor for OS, DFS, LRRFS and DMFS. Combining the TVRR and TNM stage enhanced the ability to predict DFS and LRRFS. CONCLUSIONS: The TVRR of NACT is an independent prognostic factor for patients with locoregional advanced NPC receiving radiotherapy. Adding the TVRR to the original TNM staging system improves the prognostic value for locoregional advanced NPC.

Candidate tumor suppressor ZNF154 suppresses invasion and metastasis in NPC by inhibiting the EMT via Wnt/ß-catenin signalling.

BACKGROUND: Nasopharyngeal carcinoma (NPC) is especially prevalent in southeast Asia and southern China, but its molecular mechanisms remain poorly characterized. DNA methylation is associated with initiation and progression of tumors, including NPC. Through a genome-wide DNA methylation screening approach, we discovered ZNF154, but its methylation status and roles in NPC have not been investigated. METHODS: The methylation status of ZNF154 in NPC was detected with Methylation specific-PCR (MSP) and Quantitative Sequenom MassARRAY. The invasion and migration capacities were examined by wound healing and transwell invasion assays. The role of ZNF154 in NPC metastasis was clarified with experimental metastasis assay in vivo. Western blotting analysis was used to investigate protein changes followed by ZNF154 over-expression. Kaplan-Meier analysis was performed to determine the association between ZNF154 methylation and prognosis in NPC. RESULTS: Compared to immortalized nasopharyngeal tissues and cells, ZNF154 expression was frequently downregulated in NPC tissues and cell lines due to promoter methylation. Demethylation treatment with 5-aza-2-deoxycytidine (5-Aza) restored ZNF154 expression in NPC cell lines. Ectopic overexpression of ZNF154 in NPC cells inhibited cell migration and invasion in vitro and lung nodule formation in an in vivo tumor metastasis assay. Mechanistic investigations suggested ZNF154 inhibits Wnt/ß-catenin signalling pathway activation and prevents the EMT in NPC. Furthermore, Kaplan-Meier analysis showed hypermethylation of the ZNF154 promoter was associated with significantly poorer disease-free survival (P = 0.032) and distant metastasis-free survival (P = 0.040) among patients with locoregionally advanced NPC. CONCLUSIONS: Taken together, these findings define a novel role for ZNF154 as a tumor suppressor in NPC.

Matched analysis of induction chemotherapy plus chemoradiotherapy versus induction chemotherapy plus radiotherapy alone in locoregionally advanced nasopharyngeal carcinoma: a multicenter study.

BACKGROUND: The relative efficacy of induction chemotherapy (IC) followed by concurrent chemoradiotherapy (CCRT) versus IC followed by radiotherapy (RT) alone in locoregionally advanced NPC remains unclear. METHODS: A total of 877 patients with locally advanced NPC who underwent IC/CCRT or IC/RT at four institutions in China between January 2004 and December 2010 were retrospectively assessed. IC was cisplatin-based combination chemotherapy; concurrent chemotherapy, single agent cisplatin. Two-dimensional conventional radiotherapy (2DCRT) was the radiotherapy technique. All patients were matched in an equal ratio using a pair-matched method. Overall survival (OS), disease-free survival (DFS), distant metastasis-free survival (DMFS), locoregional relapse-free survival (LRRFS) and toxicities were assessed. RESULTS: Eligible patients were matched (n = 642; 321 patients per arm) based on eight clinicopathological characteristics. Five-year OS, DFS, DMFS, and LRRFS were 76%, 70%, 86%, and 88% for IC/CCRT and 75%, 70%, 90%, and 91% for IC/RT, respectively. There were no statistically significant survival differences between arms (P>0.05), even in subgroup analysis. In multivariate analysis, treatment (IC/CCRT vs. IC/RT) was not an independent prognostic factor for any survival end-point. Grade 3/4 acute gastrointestinal toxicities (vomiting, nausea) and hematological toxicities (leucopenia/neutropenia, thrombocytopenia and anemia) were significantly more common in the IC/CCRT arm than IC/RT arm during RT. CONCLUSION: Overall, IC/CCRT failed to demonstrate any survival advantage but higher acute toxicities over IC/RT in locoregionally advanced NPC.

Prognostic value of phosphorylated Raf kinase inhibitory protein at serine 153 and its predictive effect on the clinical response to radiotherapy in nasopharyngeal carcinoma.

BACKGROUND: Radiation is an effective treatment against nasopharyngeal carcinoma (NPC). However, radioresistance-induced locoregional recurrence remains as a major cause of treatment failure. Therefore, radiosensitivity indicators prior to treatment should be developed to screen radioresistant patients. Previous studies revealed that RKIP (Raf kinase inhibitor protein) is associated with NPC prognosis and radiosensitivity. However, the relationship of p-Ser153 RKIP (RKIP in a phosphorylated form at residue serine153) expression with the effect of radiation and prognosis of NPC patients is not elucidated. Thus, these clinical implication of the phosphorylated RKIP in NPC has yet to be described. METHODS: The effect of p-Ser153 RKIP on locoregional relapse-free survival (LRRFS) was first analyzed in a retrospective cohort of NPC patients without distant metastasis at initial diagnosis. They received radical intensity-modulated radiotherapy alone. Of 180 patients were enrolled in the ongoing matched pair study. The patients were re-classified into radioresistant group or radiosensitive group on the basis of the specified criteria. Patients in the two groups were matched in terms of radiosensitivity-related factors. p-Ser153 RKIP was examined by immunohistochemical staining on a NPC tissue microarray before radiotherapy. The relationship between the expression of p-Ser153 RKIP and the effect of radiotherapy was also analyzed. RESULTS: In this study, a retrospective cohort with 733 cases who received radical radiotherapy alone was established. Using the cohort, we validated that the p-Ser153 RKIP expression observed through immunohistochemical staining in a pretreatment NPC tissue microarray was an independent prognostic factor of LRRFS and OS; we also confirmed that endemic patients with a positive p-Ser153 RKIP expression benefited from irradiation alone in terms of locoregional relapse-free survival. A total of 180 patients were enrolled in a matched pair study. Both groups were well matched in terms of radiosensitivity-related factors. On the basis of the p-Ser153 RKIP expression, we predicted the following data: 80.0 % sensitivity, 73.3 % specificity, 76.7 % accuracy, 75.0 % positive predictive value, and 78.6 % negative predictive value. CONCLUSIONS: Our results revealed for the first time that positive p-Ser153 RKIP expression was a favorable prognostic factor. It was also positively correlated with the radiosensitivity of NPC. p-Ser153 RKIP could also be used as a biomolecular marker with good availability and authenticity to preliminarily screen NPC-related clinical radiosensitivity.

DNA Methylation Biomarkers for Nasopharyngeal Carcinoma: Diagnostic and Prognostic Tools.

Nasopharyngeal carcinoma (NPC) is a common tumor in southern China and south-eastern Asia. Effective strategies for the prevention or screening of NPC are limited. Exploring effective biomarkers for the early diagnosis and prognosis of NPC continues to be a rigorous challenge. Evidence is accumulating that DNA methylation alterations are involved in the initiation and progression of NPC. Over the past few decades, aberrant DNA methylation in single or multiple tumor suppressor genes (TSGs) in various biologic samples have been described in NPC, which potentially represents useful biomarkers. Recently, large-scale DNA methylation analysis by genome-wide methylation platform provides a new way to identify candidate DNA methylated markers of NPC. This review summarizes the published research on the diagnostic and prognostic potential biomarkers of DNA methylation for NPC and discusses the current knowledge on DNA methylation as a biomarker for the early detection and monitoring of progression of NPC.