Fu-Min Fang

Combined-modality therapy for squamous carcinoma of the buccal mucosa: treatment results and prognostic factors.

Reports on locoregional control and survival of squamous cell carcinoma of buccal mucosa are scarce in literature. In this study, a single institutions experience of combined surgery and postoperative radiotherapy (RT) for buccal mucosal malignancy with favorable results was analyzed and presented. The prognostic factors on locoregional control were also discussed.

Fibulin-3 is associated with tumour progression and a poor prognosis in nasopharyngeal carcinomas and inhibits cell migration and invasion via suppressed AKT activity

Nasopharyngeal carcinoma (NPC) is known for its highly metastatic character. Recent advances in diagnosis and treatment have not improved the high mortality rate that is attributable to early metastasis. Although several biomarkers correlate with metastasis and prognosis, the molecular mechanisms of NPC development and progression remain unclear. We demonstrate comprehensively that fibulin‐3 is down‐regulated in NPC. Loss of fibulin‐3 expression is significantly correlated with advanced tumour and lymph node‐metastasis stages, and indicates a poor 5‐year survival rate. Functionally, fibulin‐3 has the ability to suppress cell migration and invasion in NPC cancer cells by decreasing the activity of phospho‐AKT. Conversely, its depletion by fibulin‐3‐mediated siRNAs may elevate phospho‐AKT activity and significantly enhance the ability of NPC cancer cells to migrate and invade. Consistent with this negative association between fibulin‐3 and phospho‐AKT, their expression levels are inversely correlated in NPC specimens by immunohistochemical analysis. Thus, lower fibulin‐3 expression is an important indicator of poor survival. It may also contribute to the development of new therapeutic strategies to block the PI3K/AKT pathway in NPC cancer cells. Copyright

EFFECT OF MEGESTROL ACETATE AND PREPULSID ON NUTRITIONAL IMPROVEMENT IN PATIENTS WITH HEAD AND NECK CANCERS UNDERGOING RADIOTHERAPY

BACKGROUND AND PURPOSEnAnorexia is a common problem in cancer patients who receive radiotherapy. In this current study, we attempt to determine the effect of megestrol acetate and prepulsid on appetite and nutritional improvement in patients with head and neck cancers undergoing radiotherapy.nnnMATERIALS AND METHODSnOne hundred twenty-nine consecutive patients with head and neck cancers treated between July 1993 and June 1994 were prospectively randomized to receive either megestrol acetate, 40 mg qid (megace group), prepulsid, 5 mg tid (cisapride group), or a placebo treatment (control group) during radiotherapy. Before radiotherapy, body weight (kg), appetite score, performance status, biochemical parameters and hematological parameters were evaluated, and the above-noted clinical and biochemical parameters were assessed and recorded every other week. All patients received 6- 10 MV X-rays or Co-60 gamma-ray to head and neck region for a full course of radiotherapy, 61.2-75.6 Gy/7-9 weeks.nnnRESULTSnForty-eight patients were enrolled in the megace group, 41 patients in the cisapride group, and 40 patients in the control group. At the 2nd, 4th, 6th and 8th week, as the radiation dose escalated, the megace group had significantly less body weight loss than did the cisapride and control groups (P = 0.045, 0.024, 0.006, 0.003, respectively). The appetite scores of the megace group were significantly higher than those of the cisapride and control groups (P = 0.0001). However, there were no statistically significant differences in the change of albumin level among these three groups at the 2nd, 4th, 6th and 8th week (P > 0.05, respectively).nnnCONCLUSIONSnMegestrol acetate can significantly decrease the degree of body weight loss, and can prevent the deterioration of appetite in patients with head and neck cancers receiving radiotherapy. However, prepulsid lacks the above-mentioned clinical benefits.

Oncogenic Fibulin-5 Promotes Nasopharyngeal Carcinoma Cell Metastasis through the FLJ10540/AKT Pathway and Correlates with Poor Prognosis

Background Nasopharyngeal carcinoma (NPC) is known for its high metastatic potential and locoregional recurrence, although the molecular alterations that are driving NPC metastasis remain unclear at this time. This study aimed to examine the expression of fibulin-5 in NPC, correlate the results with clinicopathological variables and survival, and to investigate the role of fibulin-5 in human NPC cell lines. Material and Methods Standard semi-quantitative-RT-PCR, quantitative-RT-PCR, immunoblotting, and immunohistochemistry were used to investigate the mRNA and protein expression profiles of fibulin-5 in normal and NPC tissues. Immunohistochemistry of fibulin-5 was correlated with clinicopathological characteristics by univariate analyses. NPC cells overexpressing fibulin-5 or fibulin-5-siRNA cells were generated by stable transfection to characterize the molecular mechanisms of fibulin-5-elicited cell growth and metastasis. Results Our results demonstrated that fibulin-5 overexpression in NPC specimens and significantly correlated with advanced tumor metastasis indicating a poor 5-year overall survival. Fibulin-5 was mainly expressed in the nucleus in human NPC specimens and cell lines. Functionally, fibulin-5 overexpression yielded fast growth in NPC cells. In addition, fibulin-5 promotes cell metastasis in NPC cells through increased FLJ10540 and phosphor-AKT activity. In contrast, siRNA depletion of fibulin-5 suppressed FLJ10540 expression and phosphor-AKT activity. Suppression of either fibulin-5 or FLJ10540 can cause significant inhibition with regards to cell motility in NPC cells. Finally, immunohistochemical analysis of human aggressive NPC specimens showed a significant and positive correlation between fibulin-5 and FLJ10540 expression. Conclusion Higher fibulin-5 expression is not only an important indicator of poor survival, but also contributes to the development of new therapeutic strategies in the FLJ10540/AKT pathway for NPC treatment.

Comprehensive study on the prognostic role of osteopontin expression in oral squamous cell carcinoma

Osteopontin is a tumor-associated protein that promotes tumor development and metastasis. The preoperative blood samples of 94 oral squamous cell carcinoma (OSCC) patients and 28 healthy individuals were analyzed for plasma osteopontin levels, and another 256 paraffin-embedded OSCC specimens were analyzed by osteopontin immunostaining. The patients with advanced tumor (T) stage (T3/T4 vs. T1/T2) and positive nodal (N) status had significantly higher plasma levels of osteopontin (both p<0.001). Positive osteopontin immunostaining also correlated significantly with advanced T stage (p<0.001), positive N status (p<0.001), advanced TNM stage (p<0.001) and male gender (p=0.016). Unfavorable cumulative 5-year overall survival rates correlated significantly with positive osteopontin immunostaining (p<0.001), advanced T stage (p<0.001), positive N status (p<0.001) and advanced TNM stage (p<0.001). However, Cox regression analysis revealed that T stage and N status were independent prognostic factors for survival (both p<0.001) and osteopontin immunostaining was marginally significant for survival (p=0.056). The present study demonstrated that high expression level of osteopontin in either the plasma or the tumor of the patients with OSCC was associated with tumor progression, suggesting that osteopontin expression is an important prognostic factor for OSCC.

FLJ10540 is associated with tumor progression in nasopharyngeal carcinomas and contributes to nasopharyngeal cell proliferation, and metastasis via osteopontin/CD44 pathway

BackgroundNasopharyngeal carcinoma (NPC) is well-known for its highly metastatic characteristics, but little is known of its molecular mechanisms. New biomarkers that predict clinical outcome, in particular the ability of the primary tumor to develop metastatic tumors are urgently needed. The aim of this study is to investigate the role of FLJ10540 in human NPC development.MethodsA bioinformatics approach was used to explore the potentially important regulatory genes involved in the growth/metastasis control of NPC. FLJ10540 was chosen for this study. Two co-expression strategies from NPC microarray were employed to identify the relationship between FLJ10540 and osteopontin. Quantitative-RT-PCR, immunoblotting, and immunohistochemistry analysis were used to investigate the mRNA and protein expression profiles of FLJ10540 and osteopontin in the normal and NPC tissues to confirm microarray results. TW01 and Hone1 NPC cells with overexpression FLJ10540 or siRNA to repress endogenous FLJ10540 were generated by stable transfection to further elucidate the molecular mechanisms of FLJ10540-elicited cell growth and metastasis under osteopontin stimulation.ResultsWe found that osteopontin expression exhibited a positive correlation with FLJ10540 in NPC microarray. We also demonstrated comprehensively that FLJ10540 and osteopontin were not only overexpressed in NPC specimens, but also significantly correlated with advanced tumor and lymph node-metastasis stages, and had a poor 5-year survival rate, respectively. Stimulation of NPC parental cells with osteopontin results in an increase in FLJ10540 mRNA and protein expressions. Functionally, FLJ10540 transfectant alone, or stimulated with osteopontin, exhibited fast growth and increased metastasis as compared to vehicle control with or without osteopontin stimulation. Conversely, knockdown of FLJ10540 by siRNA results in the suppression of NPC cell growth and motility. Treatment with anti-CD44 antibodies in NPC parental cells not only resulted in a decrease of FLJ10540 protein, but also affected the abilities of FLJ10540-elicited cell growth and motility in osteopontin stimulated-NPC cells.ConclusionsThese findings suggest that FLJ10540 may be critical regulator of disease progression in NPC, and the underlying mechanism may involve in the osteopontin/CD44 pathway.

Overexpression of Rap-1A indicates a poor prognosis for oral cavity squamous cell carcinoma and promotes tumor cell invasion via Aurora-A modulation.

The functions of Rap-1A in oral carcinogenesis are largely unexplored. In this study, we examined the expression of Rap-1A at different malignant stages of oral cavity squamous cell carcinoma (OCSCC). Semiquantitative RT-PCR, quantitative RT-PCR, and Western blotting were used to evaluate Rap-1A mRNA and protein expressions, respectively, in paired OCSCC patient specimens. To determine the possible correlation between Rap-1A expression and various clinical characteristics, 256 samples from patients with OCSCC were evaluated by immunohistochemical staining. Strong Rap-1A expression was a significant prognostic marker and predictor of aggressive OCSCC. The overall and disease-specific 5-year survival rates were significantly correlated with strong expression of Rap-1A (P < 0.001). Functionally, overexpressed Rap-1A could promote oral cancer cell migration and invasion by Transwell chambers and wound healing assay. Conversely, the suppression of Rap-1A expression using Rap-1A-mediated siRNA was sufficient to decrease cell motility. Furthermore, our data also illustrated that Aurora-A could not only induce mRNA and protein expressions of Rap-1A for enhancing cancer cell motility but also co-localize and form a complex with Rap-1A in the oral cancer cell line. Finally, immunohistochemical staining, indirect immunofluorescence, and Western blotting analysis of human aggressive OCSCC specimens revealed a significantly positive correlation between Rap-1A and Aurora-A expression. Taken together, our results suggest that the Aurora-A/Rap-1A pathway is associated with survival, tumor progression, and metastasis of OCSCC patients.

Clinical significance of erythropoietin receptor expression in oral squamous cell carcinoma

BackgroundHypoxic tumors are refractory to radiation and chemotherapy. High expression of biomarkers related to hypoxia in head and neck cancer is associated with a poorer prognosis. The present study aimed to evaluate the clinicopathological significance of erythropoietin receptor (EPOR) expression in oral squamous cell carcinoma (OSCC).MethodsThe study included 256 patients who underwent primary surgical resection between October 1996 and August 2005 for treatment of OSCC without previous radiotherapy and/or chemotherapy. Clinicopathological information including gender, age, T classification, N classification, and TNM stage was obtained from clinical records and pathology reports. The mRNA and protein expression levels of EPOR in OSCC specimens were evaluated by Q-RT-PCR, Western blotting and immunohistochemistry assays.ResultsWe found that EPOR were overexpressed in OSCC tissues. The study included 17 women and 239 men with an average age of 50.9u2009years (range, 26–87u2009years). The mean follow-up period was 67u2009months (range, 2–171u2009months). High EPOR expression was significantly correlated with advanced T classification (pu2009<u20090.001), advanced TNM stage (pu2009<u20090.001), and positive N classification (pu2009=u20090.001). Furthermore, the univariate analysis revealed that patients with high tumor EPOR expression had a lower 5-year overall survival rate (pu2009=u20090.0011) and 5-year disease-specific survival rate (pu2009=u20090.0017) than patients who had low tumor levels of EPOR. However, the multivariate analysis using Cox’s regression model revealed that only the T and N classifications were independent prognostic factors for the 5-year overall survival and 5-year disease-specific survival rates.ConclusionsHigh EPOR expression in OSCC is associated with an aggressive tumor behavior and poorer prognosis in the univariate analysis among patients with OSCC. Thus, EPOR expression may serve as a treatment target for OSCC in the future.

Clinical significance of osteopontin expression in T1 and T2 tongue cancers.

Osteopontin (OPN) is considered to be a tumor‐related protein associated with tumor aggressiveness and metastasis.

The expression of activin receptor-like kinase 1 among patients with head and neck cancer.

Objectives We investigated the expression and clinical significance of activin receptor–like kinase 1 (ACVRL1) in patients with head and neck squamous cell carcinoma (HNSCC). Study Design Case series with chart review. Setting Academic Institute of Otolaryngology, Kaohsiung, Taiwan. Subjects and Methods Patients diagnosed with HNSCC (n = 169) underwent surgical resection followed by radiotherapy and/or chemotherapy for aggressive tumors between November 2000 and March 2004. ACVRL1 expression was assessed using quantitative reverse transcription polymerase chain reaction (qRT-PCR) and immunohistochemistry approaches. Results High levels of ACVRL1 expression were significantly correlated with advanced T classification (P < .001), positive N classification (P = .002), advanced TNM stage (P < .001), lymphovascular invasion (P < .001), and extracapsular spread of lymph node metastasis (P = .021). A poor 5-year overall survival rate was correlated with high ACVRL1 expression (P = .0048), advanced T classification (P = .0075), positive N classification (P = .0024), advanced TNM stage (P = .0077), and extracapsular spread of lymph node (P = .0002), but a multivariate analysis using the Cox regression model revealed that the only independent prognostic factors for survival were ACVRL1 expression (P = .043; odds ratio [OR], 1.635; 95% confidence interval [CI], 1.017-2.629) and extracapsular spread of lymph node metastasis (P = .003; OR, 2.052; 95% CI, 1.270-3.315). Conclusion A high level of ACVRL1 expression in tumor tissue is significantly correlated with advanced T classification, positive N classification, advanced TNM stage, and poorer prognosis.