[Show abstract][Hide abstract] ABSTRACT: The clinical usefulness of pretreatment imaging techniques for predicting neck control in patients with oropharyngeal or hypopharyngeal squamous cell carcinoma (OHSCC) treated with chemoradiation remains unclear. In this prospective study, we investigated the role of pretreatment dynamic contrast-enhanced perfusion MR imaging (DCE-PWI), diffusion-weighted MR imaging (DWI), and [18F]fluorodeoxyglucose-positron emission tomography (18F-FDG PET)/CT derived imaging markers for the prediction of neck control in OHSCC patients treated with chemoradiation. Patients with untreated OHSCC scheduled for chemoradiation between August, 2010 and July, 2012 were eligible for the study. Clinical variables and the following imaging parameters of metastatic neck lymph nodes were examined in relation to neck control: transfer constant, volume of blood plasma, and volume of extracellular extravascular space (Ve) on DCE-PWI; apparent diffusion coefficient (ADC) on DWI; maximum standardized uptake value, metabolic tumor volume, and total lesion glycolysis on 18F-FDG PET/CT. There were 69 patients (37 with oropharynx SCC and 32 with hypopharynx SCC) with successful pretreatment DCE-PWI and DWI available for analysis. After a median follow-up of 31 months, 25 (36.2%) participants had neck failure. Multivariate analysis identified hemoglobin level <14.3 g/dL (P = 0.019), Ve <0.23 (P = 0.040), and ADC >1.14×10-3 mm2/s (P = 0.003) as independent prognostic factors for 3-year neck control. A prognostic scoring system was formulated by summing up the three significant predictors of neck control. Patients with scores of 2-3 had significantly poorer neck control and overall survival rates than patients with scores of 0-1. We conclude that hemoglobin levels, Ve, and ADC are independent pretreatment prognostic factors for neck control in OHSCC treated with chemoradiation. Their combination may identify a subgroup of patients at high risk of developing neck failure.
PLoS ONE 12/2014; 9(12):e115933. · 3.53 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The question as to whether the regional textural features extracted from PET images predict prognosis in oropharyngeal squamous cell carcinoma (OPSCC) remains open. In this study, we investigated the prognostic impact of regional heterogeneity in patients with T3/T4 OPSCC.
European journal of nuclear medicine and molecular imaging 10/2014; · 5.22 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background
Human papillomaviruses (HPV) seem to be related to distant metastasis (DM) in advanced oral cavity squamous cell carcinoma (OSCC) patients.
This study aimed to investigate whether high-risk HPV viral load may predict DM among OSCC patients and stratify patients for risk-adapted treatment.
Study design: Viral loads of E7 oncogenes for HPV 16/18 were measured by quantitative PCR tests in paraffin-embedded lesional specimens from 312 OSCC of which the HPV genotypes had been determined previously. Multivariable Cox regression analysis was used to identify the independent prognostic factors for 5-year DM and C statistics were further computed.
By multivariable analysis, high HPV 16 E7 viral load (≥15.0 copies/genome); high HPV 18 E7 viral load (≥15.0 copies/genome); pathological N2 status (pN2); tumor depth ≥11 mm; extracapsular spread (ECS); and level IV/V metastases were independent risk factors for DM. We further identified three prognostic groups. In the high-risk group (level IV/V metastases or high HPV 16/18 E7 viral load plus pN2, tumor depth ≥11 mm, or ECS), the 5-year distant metastasis rate was 74%. In the intermediate-risk group (high HPV 16/18 E7 viral load, pN2, tumor depth ≥11 mm, or ECS), the 5-year DM rate was 17%. Finally, the 5-year DM rate was 1% in the low-risk group (no risk factors). The value of the C statistics was 0.78.
Among OSCC patients, high HPV 16/18 E7 viral load identifies a small subgroup of patients at high-risk of 5-year DM and suggest the need for more intensive treatments and follow-up strategies.
Journal of Clinical Virology 10/2014; · 3.47 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: MicroRNA-196 (miR-196), which is highly up-regulated in oral cancer cells, has been reported to be aberrantly expressed in several cancers; however, the significance of miR-196 in oral cancer has not yet been addressed.
Molecular Cancer 09/2014; 13(1):218. · 5.40 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The current American Joint Committee on Cancer (AJCC) staging system for oral cancer demonstrates wide prognostic variability within each primary tumor stage and provides suboptimal staging and prognostic information for some patients.
JAMA otolaryngology-- head & neck surgery. 07/2014;
[Show abstract][Hide abstract] ABSTRACT: Squamous cell carcinoma antigen (SCC-Ag) and C-reactive protein (CRP) levels have been successfully used to stratify risk groups in primary oral squamous cell carcinoma (OSCC) patients; however, related biomarkers have rarely been investigated in recurrent OSCC. The purpose of the present study was to analyze the relationships of SCC-Ag and CRP levels at the time of recurrence with clinical factors and prognosis. We retrospectively recruited patients with recurrence in a cohort of 534 OSCC patients between March 2001 and July 2013. One hundred patients had recurrence. The serum SCC-Ag and CRP levels were measured at the time of cancer diagnosis, 3 to 6 months after treatment with clinical disease-free, and at the time of recurrence. The SCC-Ag levels were significantly lowered after treatment (paired t-test: p = 0.001) and re-elevated at the time of recurrence (paired t-test: p = 0.027). An SCC-Ag level ≥2.0 ng/ml and a CRP level ≥5.0 mg/L at the time of recurrence were significantly associated with recurrent tumor status (P<0.001), recurrent nodal metastasis (χ2 trend test: P = 0.020), distant metastasis (P<0.001), and overall survival (P<0.001). Moreover, the influence of both elevated SCC-Ag and CRP levels on overall survival (P<0.001, H.R. [95% CI]: 5.406 [2.210-13.222]) still existed after adjusting for the recurrent tumor stage and patient age. The present study demonstrates that concurrent high levels of both SCC-Ag and CRP at the diagnosis of recurrence acts as a predictor of recurrent tumor status, recurrent advanced tumor stage, distant metastasis, and survival after the diagnosis of recurrence. This study expands the applicability of these two markers in the risk stratification in recurrent OSCC.
PLoS ONE 07/2014; 9(7):e103265. · 3.53 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: MicroRNAs (miRNAs) have a major impact on regulatory networks in human carcinogenesis. In this study, we sought to investigate the prognostic significance of miRNAs in patients with oral cavity squamous cell carcinoma (OSCC). In a discovery phase, RNA was extracted from 58 OSCC tumor samples and paired normal tissues. MiRNAs expression was evaluated with TaqMan Array Card and TaqMan MicroRNA assays. The prognostic significance of the miRNA signature identified in the discovery phase was validated by qRT-PCR in a replication set consisting of 141 formalin-fixed, paraffin-embedded (FFPE) samples. We identified a miRNA regulatory network centered on the three hub genes (SP1, MYC, and TP53) that predicted distinct clinical endpoints. Three miRNAs (miR-218, miR-125b, and let-7g) and their downstream response genes had a concordant prognostic significance on disease-free survival and disease-specific survival rates. In addition, patients with a reduced expression of miR-218, miR-125b, and let-7g have a higher risk of poor outcomes in presence of specific risk factors (p-stage III-IV, pT3-4, or pN+). Our findings indicate that specific miRNAs have prognostic significance in OSCC patients and may improve prognostic stratification over traditional risk factors.
PLoS ONE 07/2014; 9(7):e102403. · 3.53 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: We sought to investigate whether there is evidence of field cancerization in patients with oral cavity squamous cell carcinoma (OSCC) enrolled in a betel quid chewing area. We also assessed whether betel quid chewing is an independent risk factor for field cancerization in OSCC patients.
[Show abstract][Hide abstract] ABSTRACT: Background: To evaluate the efficacy and adverse events of cisplatin, tegafur, and leucovorin concomitantly with radiotherapy for patients with advanced, non-metastatic squamous cell carcinoma (SCC) of the oropharynx and hypopharynx. Methods: The PTL regimen consisted of cisplatin (P) 50 mg/m 2 on day 1, oral tegafur (T) 800 mg/day plus leucovorin (LV) 60 mg/day on days 1 through 14. It was repeated every 2 weeks through the radiotherapy course. Conventional radiotherapy with 1.8-2.0 Gy/day, 5 days per week, was delivered in a total dose of between 70 and 72 Gy. Results: Sixty-five patients with stage III or IV of SCC of the head and neck were consecutively treated between May 2002 and November 2005. Forty-six (70.7%) patients had complete response after concomitant chemoradiotherapy (CCRT). With a median follow-up of 54.0 months (range 1-103 months), the 5-year locoregional control, progression-free survival, and overall survival rates were 50.6%, 40.7%, and 59.7%, respectively. Three (4.6%) patients had toxic death during treatment. Fifty-one (80.0%) patients experienced grade 3-4 mucositis which occurred in about 35% of the CCRT duration. The functional preservation rate among post-CCRT complete responders was 93.5% (43/46). The median cisplatin accumulated dosage was 150 mg, and the rate of hearing impairment among the survivors was 7.8%. Conclusion: CCRT with outpatient-based PTL for advanced SCC of oropharynx and hypopharynx is feasible and has comparative efficacy and acceptable adverse events.
[Show abstract][Hide abstract] ABSTRACT: There is evidence to suggest that a nodal yield <18 is an independent prognostic factor in patients with clinically node negative (cN0) oral squamous cell carcinoma (SCC) treated with elective neck dissection (END). We sought to evaluate this hypothesis with external validation and to investigate for heterogeneity between institutions.
We analyzed pooled individual data from 1,567 patients treated at nine comprehensive cancer centers worldwide between 1970 and 2011. Nodal yield was assessed with Cox proportional hazard models, stratified by study center, and adjusted for age, sex, pathological T and N stage, margin status, extracapsular nodal spread, time period of primary treatment, and adjuvant therapy. Two-stage random-effects meta-analyses were used to investigate for heterogeneity between institutions.
In multivariable analyses of patients undergoing selective neck dissection, nodal yield <18 was associated with reduced overall survival [hazard ratio (HR) 1.69; 95 % confidence interval (CI) 1.22-2.34; p = 0.002] and disease-specific survival (HR 1.88; 95 % CI 1.21-2.91; p = 0.005), and increased risk of locoregional recurrence (HR 1.53; 95 % CI 1.04-2.26; p = 0.032). Despite significant differences between institutions in terms of patient clinicopathological factors, nodal yield, and outcomes, random-effects meta-analysis demonstrated no evidence of heterogeneity between centers in regards to the impact of nodal yield on disease-specific survival (p = 0.663; I (2) statistic = 0).
Our data confirm that nodal yield is a robust independent prognostic factor in patients undergoing END for cN0 oral SCC, and may be applied irrespective of the underlying patient population and treating institution. A minimum adequate lymphadenectomy in this setting should include at least 18 nodes.
Annals of Surgical Oncology 04/2014; · 3.94 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The fibula osteoseptocutaneous free flap is generally used for segmental mandibular reconstructions following resection of oral cavity squamous cell carcinoma (OSCC). However, less complex reconstructions may be feasible for patients with predicted poor survival. Herein, we sought to identify the main risk factors (RFs) associated with poor prognosis in OSCC patients undergoing segmental mandibulectomy to help decide between fibular and non-fibular reconstructions.
Between 1996 and 2011, we examined the 5-year control, distant metastases, and survival rates in 310 consecutive, previously untreated patients with primary OSCC who underwent segmental mandibulectomy.
Margin status was the only independent RF for 5-year local control. Level IV/V metastases, extracapsular spread, and tumor depth ≥15 mm were independent RFs for poor 5-year survival. In the entire study cohort, 23% of the patients had 2 or 3 adverse RFs; such a high-risk group was characterized by a poor prognosis and may be suitable for non-fibular reconstructions. Overall, 70% of the study patients were cT1-4N0, cT1N2, cT2N1, or had tumor depth <15 mm; less than 5% of patients in this subgroup had 2 or 3 adverse RFs and were thus candidates for fibular reconstructions. Among the remaining 30% of patients who showed both advanced clinical stage (cT2N2, cT3-4N1-2) and tumor depth ≥15 mm, 70% exhibited 2 or 3 adverse RFs.
Level IV/V metastases, extracapsular spread, and tumor depth ≥15 mm were independent predictors of poor prognosis in OSCC patients undergoing segmental mandibulectomy. The preoperative or intraoperative identification of adverse RFs may help decide between fibular and non-fibular mandibular reconstruction. High-risk patients bearing 2 or 3 adverse RFs have poor prognosis and should not be considered as candidates for fibular reconstructions.
PLoS ONE 04/2014; 9(4):e94315. · 3.53 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: To investigate the results of postoperative radiotherapy (PORT) for the treatment of pathologic N2b/c squamous cell carcinoma of the oral cavity (OSCC).
This study reviewed cancer registry data collected in our hospital from 1998 to 2009 with the following inclusion criteria: primary OSCC, treatment with radical surgery, and multiple nodal metastases. Patients who had extracapsular spreading of the lymph node metastases or positive resection margins or who refused to undergo PORT were excluded. The prescribed dose of PORT was 60-66 Gy. Concurrent chemotherapy was optional. Patient characteristics, treatment parameters and clinical outcome were recorded. The primary end point was overall survival, and the secondary endpoint was disease status.
There were 138 eligible cases, and the median follow-up period was 35 months. The 3-year overall survival rate was 56%. Univariate analysis revealed that pathologic T4 status (pT4), bone marrow invasion, and lymphatic invasion were significantly correlated with poor outcome (p<0.05). Multivariate analysis showed that pT4, lymphatic invasion, and the no concurrent chemotherapy were independent poor prognostic factors (p<0.05). Fifty-four patients had tumor recurrence. The 3-year recurrence-free survival rate was 59%. Skin invasion, pT4, and bone marrow invasion were correlated with poor prognosis in the univariate analysis (p<0.05). Only pT4 (p<0.01) and no concurrent chemotherapy (p = 0.03) were independently correlated with poor recurrence-free survival.
For OSCC patients with multiple-node metastases without extracapsular spreading or positive resection margins, PORT without concurrent chemotherapy correlated to inferior outcome. Multiple lymph node metastases might be considered an indication for concurrent chemotherapy.
PLoS ONE 02/2014; 9(2):e86922. · 3.53 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: MicroRNAs (miRNAs), small noncoding RNA molecules can function as oncogenes or tumor suppressors in tumorigenesis. Oral squamous cell carcinoma (OSCC) is one of the most prevalent cancers worldwide with a 5-year survival rate of approximately 50%.
The expression of microRNA-99a (miR-99a) in OSCC tissues and cell lines was investigated using quantitative reverse transcription-polymerase chain reaction (qRT-PCR) analysis. The functions of miR-99a in migration/invasion and lung colonization were determined by transwell and tail vein injection assays, respectively. Specific targets of miR-99a were determined by software prediction, correlation with target protein expression, and luciferase reporter assay. The signaling pathways involved in regulation of miR-99a were investigated using the kinase inhibitors.
We observed reduced levels of miR-99a, identified as one of the most downregulated miRNA in OSCC and all tested OSCC cell lines compared to normal oral keratinocytes. Ectopic miR-99a expression in OSCC cells markedly reduced migration and invasion in vitro as well as lung colonization in vivo. When evaluating the specific targets of miR-99a, we found that ectopic miR-99a expression downregulates insulin-like growth factor 1 receptor (IGF1R) protein and that the expression of miR-99a correlates negatively with IGF1R protein in OSCC cells. Insertion of the 3[prime]UTR of IGF1R mRNA into the 3[prime]UTR of a reporter gene markedly reduced luciferase activity in OSCC cells expressing miR-99a, suggesting that miR-99a reduces luciferase activity by targeting the 3[prime]UTR of IGF1R mRNA. When evaluating the mechanisms of miR-99a downregulation, we observed the upregulation of miR-99a expression in serum-starved conditions and its suppression in response to insulin-like growth factor (IGF1) stimulation. Inhibitors of phosphatidylinositol 3-kinase (PI3K) and mitogen-activated protein kinase (MAPK) kinase inhibited IGF1-induced suppression of miR-99a, suggesting the negative regulation of miR-99a expression by IGF1R signaling.
Overall, results indicate that miR-99a functions as a tumor metastasis suppressor in OSCC cells and mutually regulates IGF1R expression in a reciprocal regulation.
Molecular Cancer 01/2014; 13(1):6. · 5.40 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: To investigate the prognostic value of prepontine cistern invasion (PPCI) in nasopharyngeal carcinoma (NPC) patients treated with intensity-modulated radiotherapy (IMRT).
Five hundred and four non-disseminated NPC patients who underwent magnetic resonance imaging examination before radical IMRT between November 2000 and December 2008 were retrospectively reviewed. The diagnostic criteria for PPCI were tumor invasion through the posterior cortex of clivus and extension into the prepontine cistern.
The median follow-up of the patients in this study was 63.5months. PPCI was found in 44 patients (25% of T4 patients). The 5-year progression-free survival (PFS), local control (LC), distant metastasis-free survival (DMFS), and overall survival (OS) of all patients, with and without PPCI, were 44.3% and 70.5% (p<0.001), 84.4% and 89.1% (p=0.376), 66.6% and 87.3% (p<0.001), and 59.6% and 80.2% (p<0.001), respectively. In T4 patients with PPCI and without PPCI, the 5-year PFS, LC, DMFS, and OS were 44.3% and 62.5% (p=0.023), 84.4% and 84.9% (p=0.946), 66.6% and 83.1% (p=0.022), and 59.6% and 71.0% (p=0.045), respectively. Using multivariate analysis, PPCI was found to be an independent poor prognostic factor for PFS (HR=1.816; p=0.007), DMFS (HR=1.928; p=0.045), and OS (HR=1.798; p=0.016).
Prepontine cistern invasion was an independent prognostic factor for poor DMFS and OS but not LC in NPC patients treated with IMRT, even within T4 patients.
[Show abstract][Hide abstract] ABSTRACT: Background. The quantification of tumor heterogeneity with molecular images, by analyzing the local or global variation in the spatial arrangements of pixel intensity with texture analysis, possesses a great clinical potential for treatment planning and prognosis. To address the lack of available software for computing the tumor heterogeneity on the public domain, we develop a software package, namely, Chang-Gung Image Texture Analysis (CGITA) toolbox, and provide it to the research community as a free, open-source project. Methods. With a user-friendly graphical interface, CGITA provides users with an easy way to compute more than seventy heterogeneity indices. To test and demonstrate the usefulness of CGITA, we used a small cohort of eighteen locally advanced oral cavity (ORC) cancer patients treated with definitive radiotherapies. Results. In our case study of ORC data, we found that more than ten of the current implemented heterogeneity indices outperformed SUVmean for outcome prediction in the ROC analysis with a higher area under curve (AUC). Heterogeneity indices provide a better area under the curve up to 0.9 than the SUVmean and TLG (0.6 and 0.52, resp.). Conclusions. CGITA is a free and open-source software package to quantify tumor heterogeneity from molecular images. CGITA is available for free for academic use at http://code.google.com/p/cgita.
BioMed research international. 01/2014; 2014:248505.
[Show abstract][Hide abstract] ABSTRACT: microRNAs offer tools to identify and treat invasive cancers. Using highly invasive isogenic oral squamous cell carcinoma (OSCC) cells established using in vitro and in vivo selection protocols from poorly invasive parental cell populations, we used microarray expression analysis to identify a relative and specific decrease in miR-491-5p in invasive cells. Lower expression of miR-491-5p correlated with poor overall survival of OSCC patients. miR-491-5p overexpression in invasive OSCC cells suppressed their migratory behavior in vitro and lung metastatic behavior in vivo. We defined the G protein-coupled receptor kinase-interacting protein 1 (GIT1) as a direct target gene for miR-491-5p control. GIT1 overexpression was sufficient to rescue miR-491-5p-mediated inhibition of migration/invasion and lung metastasis. Conversely, GIT1 silencing phenocopied the ability of miR-491-5p to inhibit migration/invasion and metastasis of OSCC cells. Mechanistic investigations indicated that miR-491-5p overexpression or GIT1 attenuation reduced focal adhesions, with a concurrent decrease in steady-state levels of paxillin, phospho-paxillin, phospho-FAK, EGF/EGFR-mediated ERK1/2 activation and MMP2/9 levels and activities. In clinical specimens of OSCC, GIT1 levels were elevated relative to paired normal tissues and were correlated with lymph node metastasis, with expression levels of miR-491-5p and GIT1 correlated inversely in OSCC where they informed tumor grade. Together, our findings identify a functional axis for OSCC invasion that suggests miR-491-5p and GIT1 as biomarkers for prognosis in this cancer.
[Show abstract][Hide abstract] ABSTRACT: Deciphering the causal networks of gene interactions is critical for identifying disease pathways and disease-causing genes. We introduce a method to reconstruct causal networks based on exploring phenotype-specific modules in the human interactome and including the expression quantitative trait loci (eQTLs) that underlie the joint expression variation of each module. Closely associated eQTLs help anchor the orientation of the network. To overcome the inherent computational complexity of causal network reconstruction, we first deduce the local causality of individual subnetworks using the selected eQTLs and module transcripts. These subnetworks are then integrated to infer a global causal network using a random-field ranking method, which was motivated by animal sociology. We demonstrate how effectively the inferred causality restores the regulatory structure of the networks that mediate lymph node metastasis in oral cancer. Network rewiring clearly characterizes the dynamic regulatory systems of distinct disease states. This study is the first to associate an RXRB-causal network with increased risks of nodal metastasis, tumor relapse, distant metastases and poor survival for oral cancer. Thus, identifying crucial upstream drivers of a signal cascade can facilitate the discovery of potential biomarkers and effective therapeutic targets.
Nucleic Acids Research 12/2013; · 8.81 Impact Factor