Cheng-Lung Hsu

Staging of untreated nasopharyngeal carcinoma with PET/CT: comparison with conventional imaging work-up

PurposeWe prospectively compared PET/CT and conventional imaging for initial staging of nasopharyngeal carcinoma (NPC).MethodsA total of 111 patients with histologically proven NPC were investigated with PET/CT and conventional imaging (head-and-neck MRI, chest X-ray, abdominal ultrasound, and bone scan) before treatment. The respective findings were reviewed independently and then compared with each other.ResultsWith regard to T staging, PET/CT showed a discrepancy with head-and-neck MRI in 36 (32.4%) of the study subjects. With regard to N staging, PET/CT showed a discrepancy with head-and-neck MRI in 15 (13.5%) patients. Among the discordant cases, MRI was superior in demonstrating tumor involvement in the parapharyngeal space, skull base, intracranial area, sphenoid sinus, and retropharyngeal nodes while PET/CT was superior in demonstrating neck nodal metastasis. PET/CT disclosed 13 of 16 patients with distant malignancy compared with four patients disclosed by conventional imaging work-up. The false-positive rate of PET/CT was 18.8%. PET/CT correctly modified M staging in eight patients (7.2%) and disclosed a second primary lung malignancy in one patient (0.9%).ConclusionIn NPC patients, MRI appears to be superior to PET/CT for the assessment of locoregional invasion and retropharyngeal nodal metastasis. PET/CT is more accurate than MRI for determining cervical nodal metastasis and should be the better reference for the neck status. PET/CT has an acceptable diagnostic yield and a low false-positive rate for the detection of distant malignancy and can replace conventional work-up to this aim. PET/CT and head-and-neck MRI are suggested for the initial staging of NPC patients.

Advantages and pitfalls of 18F-fluoro-2-deoxy-D-glucose positron emission tomography in detecting locally residual or recurrent nasopharyngeal carcinoma: comparison with magnetic resonance imaging

IntroductionThis prospective study was designed to elucidate the advantages and pitfalls of 18F-FDG PET in detecting locally residual/recurrent nasopharyngeal carcinoma (NPC) in comparison with MRI.MethodsWe recruited NPC patients from two ongoing prospective trials. One is being performed to evaluate suspected local recurrence (group A) and the other to assess local treatment response 3 months after therapy (group B). Both groups received 18F-FDG PET and head and neck MRI. The gold standard was histopathology or clinical/imaging follow-up. An optimal cut-off standardised uptake value (SUV) was retrospectively determined.ResultsFrom January 2002 to August 2004, 146 patients were eligible. Thirty-four were from group A and 112 from group B. In all, 26 had locally recurrent/residual tumours. Differences in detection rate between 18F-FDG PET and MRI were not statistically significant in either group. However, 18F-FDG PET showed significantly higher specificity than MRI in detecting residual tumours among patients with initial T4 disease (p=0.04). In contrast, the specificity of 18F-FDG PET for patients with an initial T1–2 tumour treated with intracavitary brachytherapy (ICBT) was significantly lower than that for patients not treated by ICBT (72.2% vs 98.1%, p=0.003). At an SUV cut-off of 4.2, PET showed an equal and a higher accuracy compared with MRI in groups A and B, respectively.Conclusion18F-FDG PET is superior to MRI in identifying locally residual NPC among patients with initial T4 disease but demonstrates limitations in assessing treatment response in patients with initial T1–2 disease after ICBT. A cut-off SUV is a useful index for aiding in the visual detection of locally residual/recurrent NPC.

Complementary serum test of antibodies to Epstein-Barr virus nuclear antigen-1 and early antigen: a possible alternative for primary screening of nasopharyngeal carcinoma.

This hospital-based cohort study evaluated the efficacy of three Epstein-Barr virus (EBV) - associated assays for nasopharyngeal carcinoma (NPC) primary screening and monitoring treatment outcome. Five hundred and seventeen consecutive subjects, including 156 NPC patients, 264 healthy volunteers and 97 patients with head and neck squamous cell carcinoma (HNSCC) were enrolled. The sensitivity and specificity of EBV IgAs to viral capsid antigen (VCA), complementary EBV IgAs to early antigen and nuclear antigen-1 (EA+EBNA-1), and EBV DNA load were examined by immunofluorescent assays, enzyme-linked immunosorbent assays, and quantitative real-time PCR, respectively. After constructing the receiver operating characteristics to demonstrate screening efficacy, EBV EA+EBNA-1 IgA (AUC: 0.952; 95% CI, 0.930-0.974) was proved superior to EBV VCA IgA (AUC: 0.888; 95% CI, 0.854-0.922) or EBV DNA load (AUC: 0.893; 95% CI, 0.854-0.932) in differentiating NPC patients from controls. Comparison of screening efficacy between NPC patients and HNSCC patients revealed EBV EA+EBNA-1 IgA (AUC: 0.964; 95% CI, 0.943-0.985) still outperformed EBV VCA IgA (AUC: 0.884; 95% CI, 0.845-0.923). In subjects with higher serum titer or level equal to or above 1:80 and 6 EU/ml for EBV VCA IgA and EA+EBNA-1 IgA, the specificity reached as high as 99.2% and 95.1%, respectively, in the control groups. However, correlation of these three assays with clinicopathological manifestations of NPC, revealed only EBV DNA load significantly associated with N stage and overall stage in NPC patients. Additionally, EBV DNA load could be used to further raise the specificity of EBV EA+EBNA-1 IgA assays and was also the only assay to be consistently predictive of tumor relapse in post-treatment patients according to serial test results by time frame. Consequently, an EBV EA+EBNA-1 IgA-based protocol is recommended for mass screening, but EBV DNA load should be used solely for post-treatment monitoring for NPC in endemic areas.

Multiplexed immunobead‐based profiling of cytokine markers for detection of nasopharyngeal carcinoma and prognosis of patient survival

The purpose of this study was to examine cytokine profiles of peripheral blood for nasopharyngeal carcinoma (NPC).

Evaluation of Lymphatic and Vascular Invasion in Relation to Clinicopathological Factors and Treatment Outcome in Oral Cavity Squamous Cell Carcinoma

AbstractThis study evaluated the associations between lymphatic and vascular invasion of oral cavity squamous cell carcinoma (OSCC) and clinicopathological manifestations, as well as their impact on patient outcomes after treatment.In total, 571 patients with primary OSCC who underwent surgery with or without adjuvant therapy were enrolled.Lymphatic and vascular invasion were found in 28 (5%) and 16 (3%) patients, respectively. Significant associations were found between lymphatic and vascular invasion and overall stage (Pu200a<u200a0.001 and Pu200a=u200a0.020, respectively), tumor stage (Pu200a=u200a0.009 and Pu200a=u200a0.025, respectively), nodal metastasis (both Pu200a<u200a0.001), extracapsular spread (both Pu200a<u200a0.001), perineural invasion (both Pu200a<u200a0.001), bone invasion (Pu200a=u200a0.004 and Pu200a=u200a0.001, respectively), depth of invasion (Pu200a<u200a0.001 and Pu200a=u200a0.001, respectively), and pathologic differentiation (Pu200a=u200a0.002 and Pu200a<u200a0.001, respectively). In the analysis of adverse events during follow-up, neither lymphatic nor vascular invasion was statistically associated with local recurrence, neck recurrence, and distant metastasis. Although lymphatic invasion exhibited significant associations with poorer overall survival (Pu200a<u200a0.001), disease-specific survival (Pu200a<u200a0.001), and disease-free survival (Pu200a=u200a0.01), it was not demonstrated to be an independent prognostic factor in all multivariate analyses.Although both lymphatic and vascular invasion are associated with many clinicopathological manifestations, neither affects the occurrence of locoregional recurrence and distant metastasis in patients with OSCC after treatment.

Serum CXCL9 Levels Are Associated with Tumor Progression and Treatment Outcome in Patients with Nasopharyngeal Carcinoma

Objectives The aim of this cohort study was to examine the role of the chemokine (C-X-C motif) ligand 9 (CXCL9) on nasopharyngeal carcinoma (NPC). Materials & Methods Sera from 205 NPC patients and 231 healthy individuals, and 86 NPC tumor samples were enrolled. CXCL9 expression in tissue samples was analyzed by quantitative real-time PCR and immunohistochemistry. CXCL9 serum concentrations were measured by enzyme-linked immunosorbent assay. Results CXCL9 expression was significantly higher in tumors than in normal epithelium. CXCL9 serum concentrations were also significantly higher in NPC patients compared to those in healthy individuals (516.8±617.6 vs. 170.7±375.0 pg/mL, P<0.0001). Serum CXCL9 levels were significantly higher in NPC patients with higher tumor stages, nodal stages, and overall stages (P<0.001, Pu200a=u200a0.001, and P<0.001, respectively). We found a statistically significant correlation between the concentrations of CXCL9 and EBV DNA load in the NPC patients (Spearman’s correlation analysis; ru200a=u200a0.473, P<0.001; 95% confidence interval, 0.346–0.582). Moreover, NPC patients with higher CXCL9 levels (>290 pg/mL, median) before treatment had worse prognoses for overall survival and disease-free survival (Pu200a=u200a0.045 and Pu200a=u200a0.008, respectively). Multivariate logistic regression analyses also indicated that higher CXCL9 serum levels were an independent prognostic factor for disease-free survival (Pu200a=u200a0.015). Conclusion Our study demonstrated that CXCL9 is associated with tumor burden and aggressiveness of NPC tumors and the serum level of this ligand may be useful as a prognostic indicator.

Multiparametric imaging using 18 F-FDG PET/CT heterogeneity parameters and functional MRI techniques: prognostic significance in patients with primary advanced oropharyngeal or hypopharyngeal squamous cell carcinoma treated with chemoradiotherapy

BACKGROUNDnIn this study, PET heterogeneity was combined with functional MRI techniques to refine the prediction of prognosis in patients with oropharyngeal or hypopharyngeal squamous cell carcinoma (OHSCC).nnnMETHODSnA total of 124 patients with primary advanced OHSCC who underwent pretreatment 18F-FDG PET/CT, dynamic contrast-enhanced MR imaging (DCE-MRI), and diffusion-weighted MR imaging (DWI) were enrolled. Conventional and heterogeneity parameters from 18F-FDG PET as well as perfusion parameters from DCE-MRI and diffusion parameter from DWI of primary tumors were analyzed in relation to recurrence-free survival (RFS) and overall survival (OS).nnnRESULTSnMultivariate analysis identified hypopharyngeal tumors (P = 0.038), alcohol drinking (P = 0.006), Ktrans ≤ 0.5512 (P = 0.017), and Kep ≤ 0.8872 (P = 0.005) as adverse prognostic factors for RFS. Smoking (p = 0.009), Ktrans ≤ 0.5512 (P = 0.0002), Kep ≤ 0.8872 (P = 0.004), and the PET heterogeneity parameter uniformity ≤ 0.00381 (P = 0.028) were independent predictors of poor OS. The combination of PET uniformity with DCE-MRI parameters and smoking allowed distinguishing four prognostic groups, with 3-year OS rates of 100%, 76.6%, 57.4%, and 7.1%, respectively (P < 0.0001). This prognostic system appeared superior to both the TNM staging system (P = 0.186) and the combination of conventional PET parameters with DCE-MRI (P = 0.004).nnnCONCLUSIONSnMultiparametric imaging based on PET heterogeneity and DCE-MRI parameters combined with clinical risk factors is superior to the concomitant use of functional MRI coupled with conventional PET parameters. This approach may improve the prognostic stratification of OHSCC patients.Background In this study, PET heterogeneity was combined with functional MRI techniques to refine the prediction of prognosis in patients with oropharyngeal or hypopharyngeal squamous cell carcinoma (OHSCC). Methods A total of 124 patients with primary advanced OHSCC who underwent pretreatment 18F-FDG PET/CT, dynamic contrast-enhanced MR imaging (DCE-MRI), and diffusion-weighted MR imaging (DWI) were enrolled. Conventional and heterogeneity parameters from 18F-FDG PET as well as perfusion parameters from DCE-MRI and diffusion parameter from DWI of primary tumors were analyzed in relation to recurrence-free survival (RFS) and overall survival (OS). Results Multivariate analysis identified hypopharyngeal tumors (P = 0.038), alcohol drinking (P = 0.006), Ktrans ≤ 0.5512 (P = 0.017), and Kep ≤ 0.8872 (P = 0.005) as adverse prognostic factors for RFS. Smoking (p = 0.009), Ktrans ≤ 0.5512 (P = 0.0002), Kep ≤ 0.8872 (P = 0.004), and the PET heterogeneity parameter uniformity ≤ 0.00381 (P = 0.028) were independent predictors of poor OS. The combination of PET uniformity with DCE-MRI parameters and smoking allowed distinguishing four prognostic groups, with 3-year OS rates of 100%, 76.6%, 57.4%, and 7.1%, respectively (P < 0.0001). This prognostic system appeared superior to both the TNM staging system (P = 0.186) and the combination of conventional PET parameters with DCE-MRI (P = 0.004). Conclusions Multiparametric imaging based on PET heterogeneity and DCE-MRI parameters combined with clinical risk factors is superior to the concomitant use of functional MRI coupled with conventional PET parameters. This approach may improve the prognostic stratification of OHSCC patients.

Application of a patient-derived xenograft model in cytolytic viral activation therapy for nasopharyngeal carcinoma.

Nasopharyngeal carcinoma (NPC) is an Epstein Barr virus (EBV)-related malignancy in which the tumor microenvironment plays a pivotal role in tumor progression. Here, we developed two patient-derived xenograft (PDX) mouse lines from engrafted NPC metastatic tumors. Positive staining for EBV-encoded small RNAs confirmed that these tumors harbored EBV, and gene expression profile analyses further showed that the PDX was highly similar to the primary parent tumor. In vivo drug screening using the PDX system demonstrated that gemcitabine had the best antitumor effect among the tested drugs. The donor of this PDX also showed excellent responsiveness to gemcitabine treatment. The combination of gemcitabine and valproic acid exerted synergistic antitumor effects. Further addition of ganciclovir to this two-drug combination regimen enhanced cytolytic viral activation, yielding the best antitumor response among tested regimens. Treatment with this three-drug combination regimen decreased plasma EBV-DNA load, tumor viral concentration, and the number of viable tumor cells to a greater extent than the two-drug gemcitabine and valproic acid combination. These results highlight the value of PDX models in the development of EBV-targeted strategies to treat NPC.

Progesterone analogues reduce plasma Epstein–Barr virus DNA load and improve pain control in recurrent/metastatic nasopharyngeal carcinoma patients under supportive care

Background Progesterone analogues, such as megestrol acetate (MA) and medroxyprogesterone (MPA), have been used for the palliative care of cancer cachexia for decades and have proven to increase body weight and improve quality of life and performance status. The objective of this study was to determine the effect of progesterone analogue use on quality of life in terms of pain control, performance status, body weight gain, and Epstein–Barr virus (EBV) DNA load in recurrent/metastatic nasopharyngeal carcinoma (NPC) patients. Methods We retrospectively enrolled 41 patients with locally recurrent or metastatic NPC who received MA or MPA for cachexia management between January 2007 and February 2014. Patients who underwent aggressive treatment with intravenous chemotherapy were excluded. Body weight, performance status, pain score, and plasma EBV DNA load were used to assess quality of life before and after MA/MPA treatment. Results Of the 41 patients, 33 patients (80.5%) experienced body weight gain after progesterone analogue intervention. A significant reduction in plasma EBV DNA load was noted after progesterone analogue use (p < 0.001). In addition, median pain and Karnofsky performance scores were also significantly improved in progesterone analogue responders compared with non-responders (4 vs. 1 and 70 vs. 80, respectively; p = 0.004 and p < 0.001, respectively). Conclusion Progesterone analogues improve quality of life in terms of performance status, pain control, and plasma EBV DNA load in patients with locally recurrent/metastatic NPC under palliative care.

A phase II randomized trial comparing neoadjuvant chemotherapy followed by concurrent chemoradiotherapy versus concurrent chemoradiotherapy alone in advanced squamous cell carcinoma of the pharynx or larynx

Background To clarify the effect of induction chemotherapy (ICT) in patients with advanced pharyngeal and laryngeal squamous cell carcinoma (PLSCC) treated with concurrent chemoradiotherapy (CCRT). Methods Patients with treatment-naïve nonmetastatic advanced PLSCC were stratified according to disease stage (III or IV) and resectability before being randomized to either a ICT/CCRT or CCRT arm. A cisplatin/tegafur-uracil/leucovorin regimen was administered during ICT and CCRT. The primary end point was overall survival (OS). Results We enrolled 151 patients during December 2006 to February 2011. The median follow-up of surviving patients was 54.5 months. The ICT/CCRT arm included more patients with hypopharynx cancer (57.1% vs 40.5%, p = 0.09) and N2 or N3 diseases (85.7% vs 74.4%, p = 0.02). In the ICT/CCRT and CCRT arms, the 5-year OS was 48.1% and 53.2% (p = 0.45); progression-free survival (PFS) was 31.8% and 55.6% (p = 0.015); and locoregional control (LRC) was 37.7% and 56.2% (p = 0.026), respectively. The adverse events and compliance to radiotherapy were similar. However, the proportion of patients receiving a total dose of cisplatin during CCRT <150 mg/m2 was higher in the ICT/CCRT arm (46.8% vs 16.2%; p = 0.000) and independently predicted poorer PFS and LRC in multivariate analysis. Conclusion OS did not vary between the ICT/CCRT and CCRT arms. However, poorer compliance to CCRT and inferior LRC and PFS were observed in the ICT/CCRT arm. Optimizing the therapeutic ratio in both ICT and CCRT settings are necessary for developing a sequential strategy for patients with advanced-stage PLSCC.