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1.  Isolated gastric recurrence from ovarian carcinoma: A case report 
Oncology Letters  2015;9(3):1173-1176.
Although ovarian metastasis secondary to gastric cancer (Krukenberg tumor) has been extensively described in the literature, gastric metastasis from ovarian carcinoma is rare. The present case report describes a patient with gastric metastasis from ovarian carcinoma. A 51-year-old female with previously treated ovarian carcinoma of stage III according to the International Federation of Gynecology and Obstetrics was admitted to the Department of Oncology, First Affiliated Hospital of Nanjing Medical University (Nanjing, China) with high serum carbohydrate antigen-125 levels. Endoscopic ultrasound and 18F-fluorodeoxyglucose positron emission tomography/computed tomography scanning revealed a lesion in the stomach with the typical appearance of a gastrointestinal stromal tumor. The histopathological examination revealed infiltration of the resected specimens by metastatic serous adenocarcinoma and a comparison with the previously resected ovarian specimen confirmed disease recurrence. Although isolated gastric recurrence from ovarian carcinoma is rare, when a patient has a history of ovarian carcinoma (particularly with a high CA-125 level) and when the imaging results show a mass in the stomach wall, metastasis from ovarian carcinoma should be considered.
PMCID: PMC4315010  PMID: 25663876
gastric metastasis; ovarian carcinoma; International Federation of Gynecology and Obstetrics cancer staging; 18F-fluorodeoxyglucose positron emission tomography/computed tomography; recurrent disease; serum carbohydrate antigen-125
2.  Treatment of acute, severe epigastric/chest pain in a patient with stomach cancer following gastrectomy: A case report 
Oncology Letters  2015;9(3):1412-1416.
The treatment of acute chest pain can be a challenge in palliative care. Firstly, because acute chest pain is a symptom of a paucity of diseases, which makes diagnosis difficult and time consuming, while there is also a time constraint, due to the extreme suffering of the patient. Secondly, the condition of a patient with advanced cancer disease and co-morbidities does not always allow for required diagnostic procedures. The present report describes a case of acute, severe epigastric/chest pain in a patient with dynamic disease progression, who was receiving palliative care. This study also demonstrates that the pathophysiology of pain in a terminal patient may determine the treatment strategy. The patient in the present case was a 41-year-old male, who had previously undergone gastrectomy for stomach cancer, followed by postoperative chemotherapy. The patient was treated with palliative chemotherapy for metastases to the lungs, liver and lymph nodes, which led to the development of iatrogenic peripheral neuropathy. The patient was subsequently admitted to the Palliative Medicine In-patient Unit of the University Hospital of Lord’s Transfiguration (Poznan, Poland) with the complaint of acute epigastric and chest pain. An electrocardiogram, echocardiogram, chest and abdomen computerized tomography scan, esophagoduodenoscopy and laboratory analyses were performed to determine the source of the pain. The patient was treated with morphine sulfate, metoclopramide, midazolam, diazepam, acetaminophen, ketamine, hyoscine butylbromide, propofol, dexamethasone and amoxycillin, and received parenteral nutrition. As the source of pain remained unclear, a second esophagoduodenoscopy was performed to determine a diagnosis, resulting in pain relief. Thus, in the present case, esophagoduodenoscopy was diagnostic and therapeutic. Furthermore, although the treatment of acute chest pain may be a challenge in palliative care, the present study indicates that pain treatment should be adjusted to anatomical, pathophysiological and pharmacological factors, and may pose risks due to the unavoidable parenteral co-administration of multiple agents with strong therapeutic effects.
PMCID: PMC4315054  PMID: 25663923
chest pain; epigastric pain; palliative care; stomach cancer
3.  Effect of metformin on insulin-resistant endothelial cell function 
Oncology Letters  2015;9(3):1149-1153.
The aim of the present study was to investigate the effect of metformin on the function of insulin-resistant (IR) endothelial cells. A model of IR endothelial cells was established by incubating cells with 30 mM glucose, 1 μM dexamethasone and various concentrations of insulin. The nitric oxide (NO) content of the endothelial cells was determined by measuring the rate of nitroreductase production; the endothelin (ET) concentration was examined by enzyme-linked immunosorbent assay; and the expression levels of endothelial nitric oxide synthase (eNOS) were detected using western blotting. The optimal conditions for inducing insulin resistance in endothelial cells were a combination treatment of 10−4 mmol/l insulin, 30 mM glucose and 1 μM dexamethasone for 48 h. Notably, metformin administration significantly increased the NO content and reduced the ET-1 concentration in the IR cells compared with the non-treated control cells (P<0.05); furthermore, metformin significantly increased the intracellular eNOS protein expression in IR endothelial cells compared with the non-treated control cells (P<0.05), with an optimal metformin concentration of 10−3 mmol/l. Thus, the present study identified that metformin improves the function of IR endothelial cells, possibly through promoting eNOS protein expression and increasing the NO content.
PMCID: PMC4314968  PMID: 25663871
metformin; insulin resistance; endothelial cells; nitric oxide; endothelial nitric oxide synthase
4.  Link between chronic inflammation and human papillomavirus-induced carcinogenesis (Review) 
Oncology Letters  2015;9(3):1015-1026.
Inflammation is a defense strategy against invading agents and harmful molecules that is activated immediately following a stimulus, and involves the release of cytokines and chemokines, which activate the innate immune response. These mediators act together to increase blood flow and vascular permeability, facilitating recruitment of effector cells to the site of injury. Following resolution of the injury and removal of the stimulus, inflammation is disabled, but if the stimulus persists, inflammation becomes chronic and is strongly associated with cancer. This is likely to be due to the fact that the inflammation leads to a wound that does not heal, requiring a constant renewal of cells, which increases the risk of neoplastic transformation. Debris from phagocytosis, including the reactive species of oxygen and nitrogen that cause damage to DNA already damaged by the leukotrienes and prostaglandins, has an impact on inflammation and various carcinogenic routes. There is an association between chronic inflammation, persistent infection and cancer, where oncogenic action is mediated by autocrine and paracrine signals, causing changes in somatic cells under the influence of the microbial genome or of epigenetic factors. Among the infectious agents associated with cancer, certain genotypes of human papillomavirus (HPV) stand out. HPV is responsible for virtually all cases of cervical cancer and a lower proportion of cancers of the vagina, vulva, anus, penis and a number of extragenital cancers. In the present review, recent advances in the mechanisms involved in the inflammatory response are presented with their participation in the process of carcinogenesis, emphasizing the role of chronic inflammation in the development of HPV-induced cervical cancer.
PMCID: PMC4315066  PMID: 25663851
inflammation; carcinogenesis; human papillomavirus; cervical cancer
5.  FOXP1 regulation via the PI3K/Akt/p70S6K signaling pathway in breast cancer cells 
Oncology Letters  2015;9(3):1482-1488.
Loss of Forkhead box P1 (FOXP1) protein expression confers a poor prognosis in sporadic and familial breast cancer patients, and the FOXP1 gene maps to a tumor suppressor locus at chromosome 3p14. Although correlation studies have indicated that FOXP1 has a role in tumor suppression, determination of the regulatory mechanism of FOXP1 is required to establish its function in breast cancer. It has previously been identified that FOXP1 is regulated by estrogen in breast cancer and that treatment with bisphenol A is effective for regulating the transformation of the normal human breast epithelial cell line, MCF-10F. In addition, FOXO-regulated activation of FOXP1 inhibits the apoptosis of MCF-10F cells following tamoxifen and Akt inhibitor VIII administration. The present study indicates that FOXP1 regulation occurs via a PI3K/Akt/p70S6 kinase (p70S6K) signaling pathway. Following treatment with wortmannin, an inhibitor of phosphatidylinositol 3-kinase (PI3K)/Akt, MCF7 and MDA-MB-231 breast cancer cells demonstrated decreased FOXP1 protein expression levels; this result was also observed in the small interfering (si)RNA silencing of Akt. By contrast, overexpression of Akt resulted in increased FOXP1 protein expression levels in the MDA-MB-231 cells compared with the control cell lysates. Furthermore, treatment with rapamycin, a specific inhibitor of the mammalian target of rapamycin/p70S6K cascade, resulted in decreased FOXP1 expression in the MCF7 cells, but not in the MDA-MB-231 cells, which were resistant to rapamycin-induced inhibition. In addition, silencing of p70S6K using siRNA produced a marked decrease in FOXP1 expression. These data indicate that FOXP1 protein expression is regulated by a PI3K/Akt/p70S6K signaling cascade in breast cancer.
PMCID: PMC4315073  PMID: 25663935
phosphatidylinositol 3-kinase; Akt; p70S6 kinase; Forkhead box P1; breast cancer
6.  Reactive nodular fibrous pseudotumor involving the gastrointestinal tract and mesentery: A case report and review of the literature 
Oncology Letters  2015;9(3):1343-1346.
Reactive nodular fibrous pseudotumor (RNFP) is a tumor-like lesion that is characterized by reactive fibroblast/myofibroblast proliferation within collagenic hyalinized stroma, due to its association with injury or inflammation. The current study describes the case of a 60-year-old female with a history of abdominal surgery and abdominal pain. Upon laparoscopy, multiple nodules attached to the outer layer of the colon and mesentery were identified, and therefore, complete surgical excision was performed. Macroscopically, the nodules were well-circumscribed, firm, tan-white in color and ranged in size between 2.0–10.0 cm at the greatest dimension. Microscopically, the nodules were composed of spindle and stellate cells in a dense collagenic hyalinized background with sparse lymphocytic infiltration. Immunohistochemical analysis demonstrated positive staining for vimentin, smooth muscle actin and cluster of differentiation (CD) 117, and focally-positive keratin staining with AE1/AE3; however, no staining was observed for gastrointestinal stromal tumor 1, CD34, S-100, anaplastic lymphoma kinase or β-catenin. Therefore, it was proposed that the lesion may be most accurately described as an RNFP. The current study reports a rare case of RNFP, emphasizing its histopathological features and differential diagnoses to promote an improved and broader understanding of this poorly understood condition.
PMCID: PMC4315131  PMID: 25663910
reactive nodular fibrous pseudotumor; gastrointestinal tract; mesentery; differential diagnosis
7.  Benign pulmonary metastasizing leiomyoma of the uterus: A case report 
Oncology Letters  2015;9(3):1347-1350.
Pulmonary benign metastasizing leiomyoma (BML), is characterized by multiple pulmonary nodular lesions and is a rare disease. The present study reports the case of a 45-year-old asymptomatic woman who underwent an excision of uterine leiomyoma 11 years previously. Chest computed tomography (CT) revealed multiple bilateral pulmonary nodules five months prior to admission, during a regular check-up. Intravenous levofloxacin (0.5 g/day) was administered for one week, which demonstrated no effect. Positron emission tomography combined with CT (PET/CT) revealed no evident radioactivity concentration. Due to the suspicion of metastasizing leiomyoma, video-assisted thoracoscopic surgery, with a wedge resection of the right pulmonary lesion, was performed. Post-operative pathological examination revealed the lesion to be a pulmonary leiomyoma accompanied by local necrosis. Immunohistochemical staining revealed that the lesion was positive for the expression of smooth muscle actin, desmin, estrogen receptor, progesterone receptor and B-cell lymphoma-2. Cytokeratin and epithelial membrane antigen were not expressed in the tumor cells. Staining for Ki-67 revealed expression of Ki-67 in ~1% of the spindle cells. The overall morphological and immunohistochemical features, accompanied by the remote patient history of primary uterine leiomyoma, supported the diagnosis of pulmonary BML.
PMCID: PMC4314993  PMID: 25663911
lung; leiomyoma; benign lesion; histological origin
8.  Effect of hypoxia on hypoxia inducible factor-1α, insulin-like growth factor I and vascular endothelial growth factor expression in hepatocellular carcinoma HepG2 cells 
Oncology Letters  2015;9(3):1142-1148.
Hypoxic microenvironments and angiogenesis have been a focus of tumor research in previous years. The aim of the the present study was to create a hypoxic model and observe the effect of hypoxia on the expression of hypoxia inducible factor-1α (HIF-1α), insulin-like growth factor I (IGF-1) and vascular endothelial growth factor expression. The hypoxia model was generated using cobalt chloride (CoCl2) and an MTT assay was used to observe the influence of hypoxia on HepG2 cells. Reverse transcription-polymerase chain reaction, western blotting, ELISA and confocal immunofluorescence microscopy were used to detect the expression of HIF-1α, IGF-1 and VEGF in HepG2 cells, in which hypoxia was induced by various concentrations of CoCl2 and for various incubation times. The cell viability worsened with increasing concentrations of CoCl2. The expression of HIF-1α and IGF-1R was observed in hypoxic HepG2 cells, with the exception of HIF-1α mRNA. The expression of IGF-1R and VEGF mRNA and protein was correlated with the concentration of CoCl2 and the time that hypoxia was induced for. The expression of HIF-1α mRNA and protein was positively correlated with the expression of the VEGF mRNA and protein in a dose- and time-dependent manner under hypoxic conditions. Using immunofluorescence, it was observed that IGF-1R and HIF-1α were secreted from the hypoxic HepG2 cells. It was concluded that hypoxia induces the accumulation of IGF-1R and HIF-1α mRNA and protein, which regulates the expression of VEGF mRNA and protein in hypoxic HepG2 cells.
PMCID: PMC4315007  PMID: 25663870
hepatocellular carcinoma; hypoxia; hypoxia inducible factor-1α; insulin-like growth factor I; vascular endothelial growth factor
9.  Cross-talk between endothelial and tumor cells via basic fibroblast growth factor and vascular endothelial growth factor signaling promotes lung cancer growth and angiogenesis 
Oncology Letters  2015;9(3):1089-1094.
The present study aimed to investigate the origin and potential mechanisms of angiogenesis in lung cancer cells. Normal endothelial cells (ECs) were isolated from human umbilical vein ECs (HUVECs) and cultured. The human lung cancer A549 cell line was also used. The cross-talk model between the HUVECs and the A549 cell line was constructed in vitro using a Millicell co-culture system. Cluster of differentiation (CD)31 and CD146 were selected as markers of the HUVECs. CD105 was used as a marker of activated blood vessel ECs in the tumor microenvironment and glucose-regulated protein-78 (GRP-78) was used as a biomarker of the A549 cells. The four markers were detected by immunofluorescence, and the mean optical density was calculated. The growth curves were constructed using the cell proliferation reagent, WST-1. The expression of vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) in the media was measured using an ELISA. The average proliferation rates of the co-cultured HUVECs and A549 cells were significantly higher than those observed in the control groups. The fluorescence intensity of CD105 expression in the co-cultured HUVECs was higher than that in the control group. The fluorescence intensity of GRP-78 in the co-cultured A549 cells was higher than that in the A549 cells cultured alone. The average expression levels of VEGF and bFGF in the co-cultured model were higher than in the control groups. Therefore, it was hypothesized that cancer cells may induce the differentiation of normal ECs into vascular ECs via the secretion of VEGF and bFGF. Furthermore, vascular ECs can affect the proliferation and differentiation of cancer cells.
PMCID: PMC4315052  PMID: 25663861
human umbilical vein endothelial cells; human lung cancer A549 cell line; tumor microenvironment; vascular endothelial growth factor; basic fibroblast growth factor; glucose-regulated protein-78
10.  A novel differential diagnostic model for multiple primary lung cancer: Differentially-expressed gene analysis of multiple primary lung cancer and intrapulmonary metastasis 
Oncology Letters  2015;9(3):1081-1088.
The incidence of synchronous multiple primary lung cancer (MPLC) is increasing. However, present diagnostic methods are unable to satisfy the individualized treatment requirements of patients with MPLC. The present study aimed to establish a quantitative mathematical model and analyze its diagnostic value for distinguishing between MPLC and cases of the histologically similar disease, intrapulmonary metastasis (IPM). The sum value of the differential expression ratios of four proteins, namely p53, p16, p27 and c-erbB2, was evaluated by immunohistochemically-staining specimens of primary cancers, second separate cancers, metastatic lymph nodes and metastatic cancers. The sum value of the differential expression ratio of the four proteins from the primary tumor and the lymph-node metastasis or metastatic cancer was <90 in the 11 patients with a single metastatic cancer and in the 30 patients with lymph-node metastasis, but was >90 in the 14 patients with different histological types of MPLC. Therefore, a quantitative differentially-expressed gene mathematical model was established as follows: Sum of the differential expression ratios = p16T1 − T + p27T1 − T2 + C-erbB2T1 − T2 + p53T1 − T2, where T1 is the primary cancer and T2 is the lymph node metastasis, metastatic cancer or the second separate cancer. The quantitative differentially-expressed gene mathematical model is considered to be a useful tool for distinguishing between MPLC and IPM.
PMCID: PMC4315081  PMID: 25663860
differentially-expressed gene mathematical model; multiple primary lung cancer; intrapulmonary metastasis
11.  microRNA-99a is downregulated and promotes proliferation, migration and invasion in non-small cell lung cancer A549 and H1299 cells 
Oncology Letters  2015;9(3):1128-1134.
There is increasing evidence that microRNAs (miRNAs) are able to play a key role in the diagnosis and therapy of cancer. miRNA-99a (miR-99a), which is downregulated in several human malignancies, has been reported as a potential tumor suppressor. However, to the best of our knowledge, the expression and function of miR-99a has not been investigated in human non-small cell lung cancer (NSCLC) at present. The aim of the current study was to evaluate the association between NSCLC and miR-99a. miR-99a expression was analyzed in 15 pairs of NSCLC and non-cancerous tissue samples by reverse transcription-quantitative polymerase chain reaction. In addition, the NSCLC A549 and H1299 cell lines were transfected with miR-99a mimics, and the effect of miR-99a on the cell cycle, cell proliferation, migration and colony formation of A549 and H1299 cells was investigated. It was found that the level of miR-99a expression was significantly downregulated in NSCLC tissues and that ectopic overexpression of miR-99a significantly inhibited the growth of A549 and H1299 cells. Additionally, ectopic overexpression of miR-99a inhibited A549 and H1299 cell migration and invasion by inhibiting epithelial to mesenchymal transition. The downregulation of insulin-like growth factor 1 receptor (IGF-1R) by miR-99a and knockdown of IGF-1R mediated by siRNA were each found to phenocopy the effect of miR-99a overexpression in NSCLC. To the best of our knowledge, the present study demonstrated for the first time that, in NSCLC, miR-99a is downregulated and thus regulates proliferation, colony formation and migration through the IGF-1R pathway, which indicates that miR-99a is a diagnostic biomarker for NSCLC.
PMCID: PMC4315021  PMID: 25663868
microRNA-99a; insulin-like growth factor 1 receptor; non-small cell lung cancer; diagnosis; epithelial to mesenchymal transition
12.  Involvement of autophagy inhibition in Brucea javanica oil emulsion-induced colon cancer cell death 
Oncology Letters  2015;9(3):1425-1431.
Brucea javanica oil emulsion (BJOE), the petroleum ether extract of B. javanica emulsified by phospholipid, is widely used in China as an anticancer agent. The extracts from B. javanica induce cancer cell death by various mechanisms; however, it is not known whether these mechanisms involve autophagy, which is an important process in cancer development and treatment. Thus, the current study aimed to investigate whether BJOE modulates autophagy in HCT116 human colon cancer cells and whether modulation of autophagy is an anticancer mechanism of BJOE. Immunoblotting was employed to analyze the protein expression levels of microtubule-associated protein light-chain 3 (LC3), a specific protein marker of autophagy, in HCT116 cancer cells following exposure to BJOE. The apoptosis rate of the HCT116 cancer cells was detected by performing an Annexin V-fluorescein isothiocyanate/propidium iodide assay. According to the effect of BJOE administration on autophagy in the HCT116 cancer cells (induction or suppression), a functionally opposite agent (autophagy suppressor or inducer) was applied to counteract this effect, and the apoptosis rate of the cancer cells was detected again. The role of autophagy (pro-survival or pro-death) was demonstrated by comparing the rates of apoptotic cancer cells prior to and following the counteraction. The results revealed that BJOE suppressed the protein expression levels of LC3, including the LC3-I and LC3-II forms, and induced apoptosis in the HCT116 cancer cells with a high level of basal LC3. The apoptosis-inducing activity of BJOE was significantly attenuated when autophagy was induced by the administration of trehalose, an autophagy inducer. The data indicates that autophagy inhibition is involved in BJOE-induced cancer cell death, and that this inhibition may be a potential anticancer mechanism of BJOE.
PMCID: PMC4315055  PMID: 25663926
Brucea javanica oil emulsion; autophagy; apoptosis; colon cancer; light chain 3
13.  Reduced expression levels of let-7c in human breast cancer patients 
Oncology Letters  2015;9(3):1207-1212.
Circulating microRNAs (miRNAs) are important in the diagnosis of a number of diseases, since serum or plasma miRNAs are more stable compared with miRNA isolated from blood samples. The aim of the present study was to investigate the association between the expression levels of serum let-7c miRNA and the clinical diagnosis of breast cancer (BC). The circulating let-7c levels of 90 BC patients and 64 healthy controls were determined by performing a reverse transcription-quantitative polymerase chain reaction assay. The results demonstrated that let-7c expression was downregulated in the BC tissues compared with the paracarcinoma control tissues. In addition, the let-7c expression in the serum of BC patients was significantly lower compared with the healthy controls (P<0.01). Using a cutoff value of 0.374×103 copies/ml, the serum expression levels of let-7c exhibited 87.5% sensitivity and 78.9% specificity for distinguishing BC patients from healthy controls (area under the receiver operating characteristic curve, 0.848; 95% confidence interval, 0.785–0.911). Furthermore, the results demonstrated that the serum expression levels of let-7c were significantly higher in premenopausal compared with postmenopausal patients (P<0.05), supporting the hypothesis that postmenopausal status may affect the serum expression levels of let-7c. However, no statistically significant differences were detected in the serum levels of let-7c between ER (or PR)-positive and -negative patients. Therefore, the current study hypothesized that serum let-7c may be used as a novel and valuable biomarker for the diagnosis of BC.
PMCID: PMC4315068  PMID: 25663883
circulating miRNA; breast cancer; let-7c; predictive factor; receiver operating characteristic analysis
14.  EGFR methylation and outcome of patients with advanced colorectal cancer treated with cetuximab 
Oncology Letters  2015;9(3):1432-1438.
Targeted therapy of metastatic colorectal cancer (mCRC) with monoclonal antibody anti-epidermal growth factor receptor (EGFR) agents, such as cetuximab (CTX) or panitumumab, is the treatment strategy of choice in patients characterised by a wild-type (wt) RAS gene status. However, despite selection based on RAS status, a high proportion of patients do not respond to therapy. EGFR methylation has been reported to have a role in predicting the response to anti-EGFR agents. The present study aimed to evaluate the role of EGFR methylation in association with the clinical outcome of patients with mCRC treated with CTX. In total, 64 patients with mCRC were assessed in the present study. Genomic DNA was extracted from tumoral tissue and EGFR methylation and mutation of the KRAS, BRAF and PIK3CA genes were analysed by pyrosequencing. EGFR expression was assessed by immunohistochemistry. The various alterations were analysed by assessing the objective response rate (ORR), progression free survival (PFS) and overall survival (OS) rates. In total, 42 cases (66%) exhibited >10% EGFR methylation and there was no correlation with EGFR expression. Mean EGFR methylation of 41 and 9% was observed in KRAS-mutated and -wt patients, respectively (P=0.05). Conversely, a high EGFR methylation was observed in BRAF-wt patients with compared with patients possessing the mutated gene (18 vs. 3%, respectively; P=0.07). EGFR methylation was significantly correlated with the OS rate [hazard ratio, 0.98; 95% confidence interval (CI), 0.96–1.00; P=0.019], but not PFS rate. In patients with a methylation rate <10 and >10%, the median OS rate was 7.5 months (95% CI, 4.4–9.4 months) and 12.0 months (95% CI, 8.7–13.9 months), respectively (P=0.034). In conclusion, the present study revealed a correlation between EGFR methylation and improved OS rate in patients treated with CTX-based chemotherapy. The presence of EGFR methylation is inversely correlated with BRAF and PIK3CA mutations, indicating that the prognostic value of gene methylation may be worth verifying in further studies.
PMCID: PMC4315084  PMID: 25663927
methylation; colorectal cancer; epidermal growth factor receptor; cetuximab
15.  Expression of phosphorylated extracellular signal-regulated kinase at the invasive front of hepatic colorectal metastasis 
Oncology Letters  2015;9(3):1261-1265.
Raf-1 kinase inhibitory protein (RKIP), an endogenous inhibitor of the extracellular signal-regulated kinase (ERK) pathway, suppresses metastasis in a number of cancer types, including colorectal carcinoma (CRC); thus, RKIP downregulation significantly contributes to CRC invasiveness and metastatic potential. However, our previous study demonstrated that RKIP-positive tumors in CRC patients are predictive of hepatic colorectal metastases (HCMs). Based on the previous finding that the ERK pathway can be activated independently of RKIP, we hypothesized that RKIP-expressing HCMs may express significant levels of phosphorylated ERK (pERK). Thus, the present study evaluated the expression of RKIP and pERK in 68 HCM tissue samples using immunohistochemistry. RKIP expression was positive in 22 (32.4%) of the 68 samples, seven (31.8%) of which exhibited nuclear pERK immunoreactivity exclusively at the invasive tumor front. Furthermore, pERK expression at the invasive front was significantly associated with recurrent HCM following hepatic resection, and pERK expression observed at the invasive front of RKIP-expressing HCMs indicated that the activation of the ERK pathway may also be involved in the invasive process of these tumors, despite the presence of RKIP. A strong association between pERK expression and the presence of recurrent HCM may indicate that the ERK pathway is important in the metastatic recurrence of RKIP-positive HCM.
PMCID: PMC4315101  PMID: 25663894
extracellular signal-regulated kinase; invasive tumor front; Raf kinase inhibitor protein; colorectal carcinoma; liver; metastasis
16.  Pretreatment platelet count as a predictor for survival and distant metastasis in nasopharyngeal carcinoma patients 
Oncology Letters  2015;9(3):1458-1466.
The aim of the present study was to investigate the prognostic value of different pretreatment platelet (PLT) counts on the treatment outcome in nasopharyngeal carcinoma (NPC) patients receiving concurrent chemoradiotherapy (CCRT) or radiotherapy (RT) alone. A total of 1,501 NPC patients, including 412 receiving CCRT and 1,089 receiving RT, were enrolled in the present study. The PLT count cut-off points for the CCRT and RT groups were 150 and 300×109/l, respectively, and the PLT counts were categorized it into three groups: Low (PLT≤150×109/l), moderate (150×109/l300×109/l). To identify independent predictors of overall survival (OS), the Cox proportional hazards model was used to determine local-regional recurrence-free survival (LRFS) and distant metastasis-free survival (DMFS) rates in the CCRT and RT patients. Furthermore, univariate and multivariate analysis indicated that compared with a moderate PLT count, a low PLT count was an independent unfavorable prognostic factor for OS rate in CCRT patients [hazard ratio (HR), 2.024; 95% confidence interval (CI), 1.165–3.516], and a high PLT count was an independent unfavorable prognostic factor for OS and DMFS rates in CCRT (OS: HR, 1.742; 95% CI, 1.090–2.786; DFMS: HR, 2.110; 95%CI, 1.084–4.108) and RT (OS: HR, 1.740; 95%CI, 1.283–2.362; DMFS: HR, 2.819; 95% CI, 1.766–4.497) patients. Compared with a low PLT count, a high PLT count was significantly and independently associated with a poor DMFS rate in the RT patients (P=0.025; HR, 2.454; 95% CI, 1.121–5.372). Therefore, the present study indicates that low and high PLT counts may be useful indicators of survival and distant metastasis in NPC patients who have undergone radiation treatment.
PMCID: PMC4314978  PMID: 25663931
platelet count; nasopharyngeal carcinoma; radiotherapy; concurrent chemoradiotherapy; predictor; prognosis
17.  Glomangioma of the trachea: A case report and literature review 
Oncology Letters  2015;9(3):1273-1277.
A 44-year-old male presented with progressing cough, dyspnea and hemoptysis due to a tracheal tumor involving the posterior wall of the lower trachea, with severe airway obstruction and coagulopathy. Consequently the patient underwent segmental resection of the trachea with an end-to-end anastomosis. Twenty months after treatment there remained no evidence of endobronchial recurrence at bronchoscopy or imaging studies. The diagnosis was benign tracheal glomus tumor (GT) which is an exceedingly rare mass lesion in the trachea. There are three subtypes: GT proper, glomangioma and glomangiomyoma. The present study describes the clinical and pathological features of glomangioma through a case report and literature review. To the best of our knowledge, this is the fifth report of glomangioma subtype arising from the trachea.
PMCID: PMC4314979  PMID: 25663896
glomus tumor; glomangioma; trachea; segmental resection
18.  Anticancer effects of crocetin in human esophageal squamous cell carcinoma KYSE-150 cells 
Oncology Letters  2015;9(3):1254-1260.
Crocetin is the main pharmacologically-active component of saffron and has been considered as a promising candidate for cancer chemoprevention. The purpose of the present study was to investigate the anticancer effects of crocetin and the possible mechanisms of these properties in the esophageal squamous cell carcinoma cell line KYSE-150. The KYSE-150 cells were cultured in Dulbecco’s modified Eagle’s medium and incubated with 0, 12.5, 25, 50, 100 or 200 μmol/l crocetin for 48 h. Cell proliferation was measured using an MTT assay. Hoechst 33258 staining and observation under fluorescent microscopy were used to analyze the proapoptotic effects of crocetin. The migration rate was assessed by a wound-healing assay. The cell cycle distribution was analyzed using flow cytometry analysis subsequent to propidium iodide staining. The expression of B-cell lymphoma-2-associated X protein (Bax) and cleaved caspase 3 was determined by western blot analysis. It was found that treatment of KYSE-150 cells with crocetin for 48 h significantly inhibited the proliferation of the cells in a concentration-dependent manner, and the inhibition of proliferation was associated with S phase arrest. Crocetin was also found to induce morphological changes and cell apoptosis in a dose-dependent manner through increased expression of proapoptotic Bax and activated caspase 3. In addition, crocetin suppressed the migration of KYSE-150 cells. The present study provides evidence that crocetin exerts a prominent chemopreventive effect against esophageal cancer through the inhibition of cell proliferation, migration and induction of apoptosis. These findings reveal that crocetin may be considered to be a promising future chemotherapeutic agent for esophageal cancer therapy.
PMCID: PMC4315057  PMID: 25663893
esophageal cancer; crocetin; KYSE-150 cells; apoptosis; cell cycle
19.  Successful management of acute myeloid leukemia transformed from chronic myelomonocytic leukemia in the elderly by a combination regimen of decitabine and cytarabine, aclarubicin and granulocyte colony-stimulating factor: A case report 
Oncology Letters  2015;9(3):1217-1220.
Despite advances in the treatment of acute myeloid leukemia (AML) in recent years, the outcome of elderly AML patients with antecedent hematological disorders remains unsatisfactory. The present study describes a case of complete remission in an elderly patient with AML transformed from chronic myelomonocytic leukemia (CMML) and the treatment of the case with decitabine in combination with cytarabine, aclarubicin and granulocyte colony-stimulating factor (CAG). A 70-year-old male was admitted with fever, pruritus and weakness that had been apparent for two weeks, and a two-year history of monocytosis (22.5–27.0%). Further examinations revealed a hemoglobin level of 106 g/l, a white blood cell count of 39.52×109/l, a platelet count of 81×109/l, Y chromosome loss and uniparental disomy on chromosomes 4q, 2q and 19p. The patient was diagnosed with AML transformed from CMML, with cytogenetic anomalies. A combination regimen of decitabine and CAG was administered. Subsequent to one cycle, the patient achieved complete remission. The patient was then followed up with three courses of the same regimen and achieved clinical remission, with no evidence of AML relapse. The present study suggests that a combination of low-dose decitabine and CAG may offer a novel and potentially effective treatment regimen for elderly AML patients.
PMCID: PMC4315126  PMID: 25663885
acute myeloid leukemia; chronic myeloid leukemia; decitabine; cytarabine; aclarubicin and granulocyte colony-stimulating factor; single nucleotide polymorphism
20.  MicroRNA-27b inhibits Spry2 expression and promotes cell invasion in glioma U251 cells 
Oncology Letters  2015;9(3):1393-1397.
MicroRNA (miR)-27b has been reported to participate in glioma. However, a detailed role of miR-27b and the underlying mechanism remain largely unknown. The present study found that the expression of miR-27b was significantly increased in glioma tissues compared with normal adjacent tissues. In addition, miR-27b was also upregulated in the U87, U251 and SHG44 glioma cell lines compared with normal human astrocytes. Sprouty homolog 2 (Spry2), which has been reported to be associated with invasive glioma, was identified as a novel target of miR-27b in U251 glioma cells, and the protein expression of Spry2 was negatively regulated by miR-27b in U251 cells. Additionally, inhibition of miR-27b and upregulation of Spry2 suppressed glioma cell invasion, while downregulation of Spry2 reversed the suppressive effect of miR-27b inhibition on glioma cell invasion. These data suggest that miR-27b may promote glioma cell invasion through direct inhibition of Spry2 expression. The data also suggest that miR-27b may become a promising molecular target for inhibiting the invasion and metastasis of glioma.
PMCID: PMC4314966  PMID: 25663918
glioma; microRNA-27b; sprouty homolog 2; invasion
21.  Symptomatic schwannoma of the abdominal wall: A case report and review of the literature 
Oncology Letters  2015;9(3):1095-1098.
Schwannoma is a rare, benign tumor that arises from the nerve sheath. This tumor usually involves the extremities, but can also be found in the head and neck, trunk, pelvis, retroperitoneum, mediastinum and gastrointestinal tract. In numerous cases, the tumors are asymptomatic and are identified incidentally on physical examination or imaging. Occasionally, schwannoma is symptomatic due to compression of surrounding large nerves. In the present study, a 57-year-old female presented to the surgical outpatient’s department due to a well-localized parietal pain in the left lower quadrant. The onset of the pain occurred three years prior to presentation, without apparent cause and in the absence of other symptoms. Ultrasound and a computed tomography scan revealed a small solid tumor in the anterior abdominal wall, which was dimensionally stable over time, but was not noted in a preliminary analysis by a radiologist. The lesion was surgically removed using an anterior surgical approach. Histopathology revealed the tumor to be benign schwannoma. The painful symptoms completely disappeared. To the best of our knowledge, this is the third case of an abdominal wall benign schwannoma in the medical literature, and the first symptomatic case.
PMCID: PMC4315022  PMID: 25663862
schwannoma; abdominal wall
22.  Culture medium of bone marrow-derived human mesenchymal stem cells effects lymphatic endothelial cells and tumor lymph vessel formation 
Oncology Letters  2015;9(3):1221-1226.
Human bone marrow mesenchymal stem cells (hBM-MSCs) favor tumor growth and metastasis in vivo and in vitro. Neovascularization is involved in several pathological conditions, including tumor growth and metastasis. Previous studies have demonstrated that human bone marrow MSC-derived conditioned medium (hBM-MSC-CM) can promote tumor growth by inducing the expression of vascular epidermal growth factor (VEGF) in tumor cells. However, the effect of BM-MSCs on tumor lymph vessel formation has yet to be elucidated. In the present study, the effect of BM-MSCs on processes involved in lymph vessel formation, including tube formation, migration and proliferation, was investigated in human-derived lymphatic endothelial cells (HDLECs). It was identified that hBM-MSC-CM promoted the tube formation and migration of HDLECs. In addition, tumor cells were revealed to participate in lymph vessel formation. In the present study, the SGC-7901, HGC-27 and GFP-MCF-7 cell lines were treated with hBM-MSC-CM. The results demonstrated that the expression of the lymph-associated markers, prospero homeobox protein 1 and VEGF receptor-3, were increased in the SGC-7901 and HGC-27 cell lines, but not in the GFP-MCF-7 cells. The tube formation assay demonstrated that the HGC-27 cells treated with hBM-MSC-CM for 20 days underwent tube formation. These findings indicate that hBM-MSC-CM can promote tube formation in HDLECs and HGC-27 cells, which may be associated with lymph vessel formation during tumor growth and metastasis.
PMCID: PMC4315037  PMID: 25663886
mesenchymal stem cell; lymph vessel; tumor growth
23.  Partial remission of acute myeloid leukemia complicating multiple myeloma following COAP chemotherapy: A case report 
Oncology Letters  2015;9(3):1303-1306.
A 77-year-old male was admitted to hospital after complaining of fever and a cough for three days. A diagnosis of multiple myeloma was confirmed following M protein identification and a bone marrow biopsy. The patient received chemotherapy regimens of bortezomib plus dexamethasone, cyclophosphamide, thalidomide and dexamethasone, and thalidomide and dexamethasone, and was prescribed thalidomide (100 mg/d) to be taken orally for maintenance therapy. After a further two years the patient was subsequently diagnosed with acute myeloid leukemia. Chemotherapy regimens of cytarabine, aclacinomycin and daunorubicin, homoharringtonine and etoposide, and mitoxantrone and cytarabine resulted in no remission. Partial remission was obtained with a course of ifosfamide, vindesine, cytarabine and prednisone chemotherapy. This therapy may be an alternative treatment for secondary leukemia, particularly in elderly patients.
PMCID: PMC4315064  PMID: 25663902
acute myeloid leukemia; multiple myeloma; partial remission; COAP
24.  Mandibular metastasis as an initial manifestation of hepatocellular carcinoma: A report of two cases 
Oncology Letters  2015;9(3):1213-1216.
The present study reports two cases of mandibular metastasis from hepatocellular carcinoma (HCC), including the clinical presentation, and computed tomography (CT), histopathology and immunohistochemistry results. Space-occupying lesions occurred unilaterally as an initial mandibular manifestation. HCC metastasis was confirmed by post-surgical examination, and the primary tumor was found using CT scans. Hepatitis B virus infection history and positive results of hepatitis B surface antigen, hepatitis B e-antibody, hepatitis B core antibody and hepatitis B virus pre-S1 antigen further supported the pathogenesis of HCC. Based on the clinical findings, the characteristics of the CT scans and the histopathology and immunohistochemistry results, the mechanisms of HCC metastasis and its management are also discussed.
PMCID: PMC4315075  PMID: 25663884
hepatocellular carcinoma; mandible; metastasis
25.  Incidence of tongue carcinoma in Trinidad and Tobago, West Indies 
Oncology Letters  2015;9(3):1417-1419.
The incidence of tongue carcinoma in Trinidad and Tobago and the greater West Indies is unknown; therefore, the present study examines the frequency of tongue carcinoma cases, drawing comparisons to worldwide and regional data. A retrospective analysis of all confirmed cases of tongue carcinoma was conducted using eight years of data from the pathology records at the Port of Spain General Hospital (Port of Spain, Trinidad and Tobago). A total of 26 cases were confirmed, of which 21 were male (81%) and five were female (19%). The age range was 29–86 years, with a mean age of 57 years, and the most common group affected was the 61–70 years age group. In addition, the number of newly diagnosed cases per year ranged between one and seven, with an average of 3.25 new cases per year and a peak incidence of seven new cases in the year of 2009. In the 19 cases where the degree of differentiation was recorded, histological analysis revealed the extent of differentiation as follows: Five cases (26%) were poorly-differentiated squamous cell carcinoma (SCC); eight cases (42%) were moderately-differentiated SCC; and six cases (32%) were well-differentiated SCC. In addition, one case of chronic inflammatory process and one case of mucoepidermoid adenocarcinoma of the tongue in a 57-year-old female were identified. Overall, the incidence of tongue carcinoma in Trinidad and Tobago appears to be low, estimated at 0.46/100,000 individuals/year. The male:female ratio is 4:1 and SCC is the dominant cancer type (96% of cases). The peak age of occurrence is at 61–70 years. These findings are in agreement with previously determined global data, however, additional research of the risk factors and outcomes of surgery as a treatment strategy for tongue carcinoma is required.
PMCID: PMC4315124  PMID: 25663924
tongue carcinoma; West Indies

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