Comparison of Chemoembolization, Radioembolization, and Transarterial Ethanol Ablation for Huge Hepatocellular Carcinoma (≥ 10 cm) in Tumour Response and Long-Term Survival Outcome.

PURPOSE: To compare transarterial chemoembolization (TACE), transarterial radioembolization using Yttrium-90 (TARE), and transarterial ethanol ablation (TEA) for huge hepatocellular carcinoma (HCC) in treatment responses and long-term survival outcomes. MATERIALS AND METHODS: In this retrospective study approved by institutional committee, inclusion criteria were tumour ≥ 10 cm, newly diagnosed, treatment naïve, Child A, Performance Score 0 or 1, no venous invasion or extrahepatic disease on contrast-enhanced CT or MRI. There were 107 patients (Supportive Care [SC] 17, TACE 54, TARE 17, TEA 19). Survival outcomes of SC and TACE were compared (TACE selected as benchmark for transarterial treatments). Tumour response and overall survival (OS) of the three groups were compared. RESULTS: OS of TACE (vs. SC) was significantly longer (9.9 [5.9, 24.1] months versus 2.8 [1.5, 10.2], p = 0.001). Complete response of TEA was significantly better (TEA 10/19 [52.6%] versus TARE 2/17 [12.5%], p = 0.013, versus TACE 9/54 [16.7%], p = 0.002). OS of TEA (vs. TACE) was significantly longer (21.6 [12, 41] months versus 9.9 [5.9, 24.1], p = 0.014, hazard ratio 0.6 (0.3, 1). OS of TEA (vs. TARE) was longer (21.6 [12, 41] months versus 11.9 [7, 28.7], p = 0.082, hazard ratio 0.6 (0.3, 1.3) in favour of TEA). CONCLUSION: In patients with huge HCC, transarterial treatment as represented by TACE had a survival benefit over supportive care. In this retrospective analysis, TEA was associated with better tumour response and survival outcome as compared to TACE or TARE; therefore, transarterial treatment could be useful for prolonging patient survival, and TEA could be a preferred option.

Dynamic Changes of Post-Radiotherapy Plasma Epstein-Barr Virus DNA in a Randomized Trial of Adjuvant Chemotherapy Versus Observation in Nasopharyngeal Cancer.

PURPOSE: To study the dynamic changes in plasma Epstein-Barr virus (pEBV) DNA after radiotherapy in nasopharyngeal cancer (NPC). EXPERIMENTAL DESIGN: We conducted a randomized controlled trial of adjuvant chemotherapy versus observation in patients with NPC who had detectable pEBV DNA at 6 weeks post-radiotherapy. Randomized patients had a second pEBV DNA checked at 6 months post-randomization. The primary endpoint was progression-free survival (PFS). RESULTS: We prospectively enrolled 789 patients. Baseline post-radiotherapy pEBV DNA was undetectable in 573 (72.6%) patients, and detectable in 216 (27.4%) patients, of whom 104 (13.2%) patients were eligible for randomization to adjuvant chemotherapy (n = 52) versus observation (n = 52). The first post-radiotherapy pEBV DNA had a sensitivity of 0.48, specificity of 0.81, area under receiver-operator characteristics curve (AUC) of 0.65, false positive (FP) rate of 13.8%, and false negative (FN) rate of 14.4% for disease progression. The second post-radiotherapy pEBV DNA had improved sensitivity of 0.81, specificity of 0.75, AUC of 0.78, FP rate of 14.3%, and FN rate of 8.1%. Patients with complete clearance of post-radiotherapy pEBV DNA (51%) had survival superior to that of patients without post-radiotherapy pEBV DNA clearance (5-year PFS, 85.5% vs. 23.3%; HR, 9.6; P < 0.0001), comparable with patients with initially undetectable post-radiotherapy pEBV DNA (5-year PFS, 77.1%), irrespective of adjuvant chemotherapy or observation. CONCLUSIONS: Patients with NPC with detectable post-radiotherapy pEBV DNA who experienced subsequent pEBV DNA clearance had superior survival comparable with patients with initially undetectable post-radiotherapy pEBV DNA. Post-radiotherapy pEBV DNA clearance may serve as an early surrogate endpoint for long-term survival in NPC.

Germline Polymorphisms and Length of Survival of Nasopharyngeal Carcinoma: An Exome-Wide Association Study in Multiple Cohorts.

Germline polymorphisms are linked with differential survival outcomes in cancers but are not well studied in nasopharyngeal carcinoma (NPC). Here, a two-phase association study is conducted to discover germline polymorphisms that are associated with the prognosis of NPC. The discovery phase includes two consecutive hospital cohorts of patients with NPC from Southern China. Exome-wide genotypes at 246 173 single nucleotide polymorphisms (SNPs) are determined, followed by survival analysis for each SNP under Cox proportional hazard regression model. Candidate SNP is replicated in another two independent cohorts from Southern China and Singapore. Meta-analysis of all samples (n = 5553) confirms that the presence of rs1131636-T, located in the 3'-UTR of RPA1, confers an inferior overall survival (HR = 1.33, 95% CI = 1.20-1.47, P = 6.31 × 10-8). Bioinformatics and biological assays show that rs1131636 has regulatory effects on upstream RPA1. Functional studies further demonstrate that RPA1 promotes the growth, invasion, migration, and radioresistance of NPC cells. Additionally, miR-1253 is identified as a suppressor for RPA1 expression, likely through regulation of its binding affinity to rs1131636 locus. Collectively, these findings provide a promising biomarker aiding in stratifying patients with poor survival, as well as a potential drug target for NPC.

The emerging data on choice of optimal therapy for locally advanced nasopharyngeal carcinoma.

PURPOSE OF REVIEW: We focus on the emerging data from randomized clinical trials for optimal integration of induction, concurrent, and/or adjuvant chemotherapy with intensity-modulated radiotherapy in locally advanced nasopharyngeal carcinoma (NPC), and the use of plasma Epstein-Barr virus (EBV) DNA for risk stratification. RECENT FINDINGS: Several phase 3 trials have shown that induction chemotherapy followed by concurrent chemoradiation (CRT) improved overall survival or disease-free survival when compared to CRT alone in stage III/IV NPC who is at high risk of distant metastases. The benefit of adjuvant chemotherapy following CRT when compared to CRT alone is uncertain. There are increasing clinical data supporting the use of plasma EBV DNA for risk stratification. There are growing clinical data supporting the integration of immune checkpoint inhibitors into the induction, concurrent, and/or adjuvant/maintenance phase of treatment in locally advanced NPC. SUMMARY: Concurrent chemoradiation remains the standard treatment backbone in locally advanced NPC. There is level 1 evidence for induction chemotherapy followed by CRT in stage III/IV NPC. There is increasing evidence against the indiscriminate use of adjuvant chemotherapy following CRT. With the increasing treatment intensification, future treatment algorithm in NPC should incorporate plasma EBV DNA and other biomarkers for risk stratification and treatment selection.

Ablative Chemoembolization for Hepatocellular Carcinoma: A Prospective Phase I Case-Control Comparison with Conventional Chemoembolization.

Purpose To evaluate the feasibility, safety, and treatment effectiveness of ablative chemoembolization (ACE) in the treatment of hepatocellular carcinoma (HCC) and compare with a similar patient cohort who underwent conventional transarterial chemoembolization (cTACE). Materials and Methods This was a prospective phase I nonrandomized study conducted between March 2013 and October 2016 in accordance to the Declaration of Helsinki and Declaration Good Clinical Practice with written informed consent. There were 36 men and eight women (median age, 64 years [interquartile range, 58-74] and 74.5 years [interquartile range, 70-80], respectively). The primary end points were treatment safety and tumor response. The secondary end points were time to progression, progression-free survival, conversion to partial hepatectomy, and viable HCC within the tumor specimen. The end points of the study group (n = 22) were compared with those of a case-matched control group (n = 22) of patients who underwent conventional cTACE during the same period by using a Pearson χ2 test. Results Treatment with ACE was successfully completed in all patients without adverse effects. The complete response (CR) rates by patient or by tumor were both 100%. The median time to progression and median progression-free survival were significantly longer in the study group than in the control group (both were 28 months vs 10 months, respectively; P < .001). The number of patient conversions to hepatectomy was seven for ACE and three for cTACE. In the tumor specimens, viable tumor was found in two of eight specimens that underwent ACE and three of three that underwent cTACE. Conclusion ACE is a feasible, safe, and well-tolerated treatment for patients with HCC; it is highly effective and may be more effective than cTACE in achieving CR. © RSNA, 2017 Online supplemental material is available for this article.

Surrogate End Points for Overall Survival in Loco-Regionally Advanced Nasopharyngeal Carcinoma: An Individual Patient Data Meta-analysis.

Background: Our objective was to evaluate progression-free survival (PFS) and distant metastasis-free survival (DMFS) as surrogate end points for overall survival (OS) in randomized trials of chemotherapy in loco-regionally advanced nasopharyngeal carcinomas (NPCs). Methods: Individual patient data were obtained from 19 trials of the updated Meta-Analysis of Chemotherapy in Nasopharyngeal Carcinoma (MAC-NPC) plus one additional trial (total = 5144 patients). Surrogacy was evaluated at the individual level using a rank correlation coefficient ρ and at the trial level using a correlation coefficient R2 between treatment effects on the surrogate end point and OS. A sensitivity analysis was performed with two-year PFS/DMFS and five-year OS. Results: PFS was strongly correlated with OS at the individual level (ρ = 0.93, 95% confidence interval [CI] = 0.93 to 0.94) and at the trial level (R2 = 0.95, 95% CI = 0.47 to 1.00). For DMFS, too, the individual-level correlation with OS was strong (ρ = 0.98, 95% CI = 0.98 to 0.98); at trial level, the correlation was high but the regression adjusted for measurement error could not be computed (unadjusted R2 = 0.96, 95% CI = 0.94 to 0.99). In the sensitivity analysis, two-year PFS was highly correlated with five-year OS at the individual level (ρ = 0.89, 95% CI = 0.88 to 0.90) and at the trial level (R2 = 0.85, 95% CI = 0.46 to 1.00); two-year DMFS was highly correlated with five-year OS at the individual level (ρ = 0.95, 95% CI = 0.94 to 0.95) and at the trial level (R2 = 0.78, 95% CI = 0.33 to 1.00). Conclusions: PFS and DMFS are valid surrogate end points for OS to assess treatment effect of chemotherapy in loco-regionally advanced NPC, while PFS can be measured earlier.

Transarterial Ethanol Ablation for Unresectable Hepatocellular Carcinoma: Analysis of Clinical and Tumor Outcomes.

PURPOSE: To evaluate survival, tumor response, and treatment toxicity of transarterial ethanol ablation (TEA) in patients with unresectable hepatocellular carcinoma (HCC). MATERIALS AND METHODS: This prospective study involved 186 patients (146 men and 40 women; median age, 65 y [interquartile range, 57-72.3 y]). Of 186 patients, 146 (78.5%) were hepatitis B virus carriers, 18 (9.7%) were hepatitis C virus carriers, 82 (44.1%) had tumors ≥ 5 cm, and 43 (23.1%) had multifocal tumors. Overall survival (OS), complete response (CR) by European Association for the Study of the Liver criteria, time to progression (TTP), progression-free survival (PFS), and treatment toxicities were evaluated. Univariate and multivariate analyses for prognostic factors of OS were performed. RESULTS: Median OS was 25.7 months (95% confidence interval [CI], 20.9-30.5) and varied significantly between Child-Pugh A and B (28.7 mo vs 13.4 mo, P < .001), and Barcelona Clinic Liver Cancer A and B or C (37.1 mo vs 17.7 mo, P = .001). Prognostic factors for longer OS were solitary tumor, tumor size < 5 cm, > 1 treatments, and CR of all tumors at 6 months. TTP was 9.1 months (95% CI, 6.9-11.3). PFS was 8.4 months (95% CI, 7.1-9.7). CR occurred in 69.1% (159/230) of lesions and 48.9% (88/180) of patients at 6 months. Any one symptom of the postembolization syndrome of grade 2 severity occurred in < 22% (41/186) of patients. No treatment-related hepatitis or death occurred within 30 days. Transient respiratory decompensation occurred in three patients (1.6% [3/186]), and alcoholic intoxication occurred in one patient (0.5% [1/186]). CONCLUSIONS: TEA appears to be safe and effective for local control of HCC.

Preclinical evaluation of PI3K inhibitor BYL719 as a single agent and its synergism in combination with cisplatin or MEK inhibitor in nasopharyngeal carcinoma (NPC).

Nasopharyngeal carcinoma (NPC) is endemic to Southeast Asia and over 40% of NPC tissues harbor PIK3CA amplifications. This study aims to study the preclinical activity of a novel PI3K inhibitor, BYL719, in 6 NPC cell lines: C666-1, CNE-2, HK1, HK1-EBV, HONE-1 and HONE-1-LMP1. Over 70% of growth inhibition was attained when NPC cell lines were exposed to increasing concentrations of BYL719, with IC50 values at the low micro-molar range. Two BYL719-sensitive cell lines that harbor PIK3CA mutations, CNE-2 and HONE-1, were selected for further analysis on the effect of BYL719 on cell cycle progression, apoptosis and PI3K signaling. BYL719 significantly reduced the phosphorylation of Akt, and the Akt-mTOR axis downstream effector S6 in these 2 cell lines, but a feedback activation of MAPK was observed at 72 hours post-treatment. BYL719 induced G0/G1 cell cycle arrest and apoptosis in both cell lines. In 3D cell culture models, the growth of NPC spheroids was significantly inhibited in a dose-depending manner. When BYL719 was combined with a MEK inhibitor (AZD6244) in a 3D cell culture system, strong synergism on NPC cell growth was observed with attenuation of MAPK activation. A synergistic inhibitory effect on growth was observed when BYL719 was combined with higher dose levels of cisplatin. These data suggest that BYL719 has preclinical activity in NPC cell lines especially in those which harbor PIK3CA mutation. Combination with a MEK inhibitor maybe a useful strategy that warrants further investigation.

Chemotherapy and radiotherapy in nasopharyngeal carcinoma: an update of the MAC-NPC meta-analysis.

BACKGROUND: A previous individual patient data meta-analysis by the Meta-Analysis of Chemotherapy in Nasopharynx Carcinoma (MAC-NPC) collaborative group to assess the addition of chemotherapy to radiotherapy showed that it improves overall survival in nasopharyngeal carcinoma. This benefit was restricted to patients receiving concomitant chemotherapy and radiotherapy. The aim of this study was to update the meta-analysis, include recent trials, and to analyse separately the benefit of concomitant plus adjuvant chemotherapy. METHODS: We searched PubMed, Web of Science, Cochrane Controlled Trials meta-register, ClinicalTrials.gov, and meeting proceedings to identify published or unpublished randomised trials assessing radiotherapy with or without chemotherapy in patients with non-metastatic nasopharyngeal carcinoma and obtained updated data for previously analysed studies. The primary endpoint of interest was overall survival. All trial results were combined and analysed using a fixed-effects model. The statistical analysis plan was pre-specified in a protocol. All data were analysed on an intention-to-treat basis. FINDINGS: We analysed data from 19 trials and 4806 patients. Median follow-up was 7·7 years (IQR 6·2-11·9). We found that the addition of chemotherapy to radiotherapy significantly improved overall survival (hazard ratio [HR] 0·79, 95% CI 0·73-0·86, p<0·0001; absolute benefit at 5 years 6·3%, 95% CI 3·5-9·1). The interaction between treatment effect (benefit of chemotherapy) on overall survival and the timing of chemotherapy was significant (p=0·01) in favour of concomitant plus adjuvant chemotherapy (HR 0·65, 0·56-0·76) and concomitant without adjuvant chemotherapy (0·80, 0·70-0·93) but not adjuvant chemotherapy alone (0·87, 0·68-1·12) or induction chemotherapy alone (0·96, 0·80-1·16). The benefit of the addition of chemotherapy was consistent for all endpoints analysed (all p<0·0001): progression-free survival (HR 0·75, 95% CI 0·69-0·81), locoregional control (0·73, 0·64-0·83), distant control (0·67, 0·59-0·75), and cancer mortality (0·76, 0·69-0·84). INTERPRETATION: Our results confirm that the addition of concomitant chemotherapy to radiotherapy significantly improves survival in patients with locoregionally advanced nasopharyngeal carcinoma. To our knowledge, this is the first analysis that examines the effect of concomitant chemotherapy with and without adjuvant chemotherapy as distinct groups. Further studies on the specific benefits of adjuvant chemotherapy after concomitant chemoradiotherapy are needed. FUNDING: French Ministry of Health (Programme d'actions intégrées de recherche VADS), Ligue Nationale Contre le Cancer, and Sanofi-Aventis.

Epstein-Barr virus as a paradigm in nasopharyngeal cancer: from lab to clinic.

Nasopharyngeal carcinoma (NPC) of the undifferentiated subtype remains endemic in southern China, with a peak incidence in this region approaching 30 cases per 100,000 population per year. Despite advances in chemotherapy and radiation delivery techniques in localized disease, distant metastasis is still common and NPC remains the seventh leading cause of cancer death in the region. There is great need for early diagnosis, developing novel therapies, and identifying patients with localized disease at higher risk of future recurrence or metastasis to appropriately tailor their treatment and improve outcomes. Knowledge of the integral involvement of Epstein-Barr virus (EBV) in the pathogenesis of undifferentiated NPC has been of seminal importance in developing strategies to optimize disease management. The close association with EBV is being evaluated in multiple settings including screening of at-risk populations, disease prognostication, development of targeted therapies, optimizing adjuvant treatment, and early recurrence detection. These translational studies are likely to have an enormous effect on management of undifferentiated NPC and significantly improve the landscape of the disease in years to come.

Unresectable hepatocellular carcinoma: randomized controlled trial of transarterial ethanol ablation versus transcatheter arterial chemoembolization.

PURPOSE: To compare effectiveness of transarterial ethanol ablation (TEA) and transcatheter arterial chemoembolization (TACE) for unresectable hepatocellular carcinoma and determine whether TEA leads to better overall survival and tumor response than TACE. MATERIALS AND METHODS: In this institutional review board-approved preregistered randomized controlled trial (n = 200), informed consent was obtained. Primary outcome was overall survival; secondary outcomes were time to progression (TTP), progression-free survival (PFS), tumor response at computed tomography, and treatment-related toxicity. Eligible patients were randomized at a 1:1 ratio. Treatment included transcatheter delivery of ethiodized oil-ethanol mixture (2:1 ratio by volume up to 60 mL) for TEA and cisplatin-ethiodized oil emulsion (0.5 mg cisplatin per milliliter up to 30 mg), followed by 1-mm gelatin-sponge pellets, for TACE. Study was terminated after interim analysis (n = 98); 90 patients were available for analysis. Overall survival, TTP, and PFS were analyzed with Kaplan-Meier method; differences were compared with log-rank test. RESULTS: Study was terminated prematurely after interim analysis, which showed no difference in overall survival; this was unlikely to change with further patient accrual. Median overall survival in TEA and TACE was 24.3 months (95% confidence interval [CI]: 12.8, 32.7) and 20.1 months (95% CI: 9.3, 31.2), respectively (P = .358). Median TTP and PFS for intralesional progression were longer with TEA than TACE (TTP, 34.6 months [95% CI: 28.2, 41] vs 26.05 months [95% CI: 18.7, 33.3]; PFS, 14.8 months [95% CI: 10.2, 19.5] vs 9.3 months [95% CI: 7.1, 11.5]) (P = .028 and 0.029, respectively). Complete response rate on a tumor basis was persistently and significantly higher with TEA at 3 months (62 of 88 [70%] vs 39 of 76 [51%], P = .012), 6 months (64 of 88 [73%] vs 41 of 76 [54%], P = .012), and 12 months (66 of 88 [75%] vs 45 of 76 [59%], P = .031). CONCLUSION: Although there was no significant difference in overall survival, TEA demonstrated better complete tumor response, longer time to intralesional progression, and longer PFS.

Advanced technologies for studying circulating tumor cells at the protein level.

Metastasis is the main cause of cancer death. As the tumor progresses, cells from the primary tumor site are shed into the bloodstream as circulating tumor cells (CTCs). Eventually, these cells colonize other organs and form distant metastases. It is therefore imperative that we gain a better understanding of the biological characteristics of CTCs for development of novel treatment modalities to minimize metastasis-associated cancer deaths. In recent years, rapid developments in technologies for the study of CTCs have taken place. We now have a variety of tools for the isolation and examination of CTCs which were not available before. This review introduces some commonly used protein markers in CTC investigations and summarizes a few advanced technologies which have been successfully applied for studying CTC biology at the protein level.

Phase II study of TAS-106 in patients with platinum-failure recurrent or metastatic head and neck cancer and nasopharyngeal cancer.

TAS-106, a RNA polymerase inhibitor, was studied in solid tumors with potential clinical benefit and reasonable tolerability. We conducted a multicenter, international phase II trial of TAS-106 in salvage metastatic or recurrent head and neck squamous cell cancer (HNSCC) and nasopharyngeal cancer (NPC) patients. TAS-106 monotherapy was given at 6.5 mg/m(2) over 24-h continuous infusion every 3 weeks. Translational studies for blood and tissue were included. Twenty-seven enrolled patients experienced the most common drug-related adverse events of neutropenia, fatigue, non-neutropenic fever, injection site reaction, and skin rash/dermatitis. The greater than or equal to grade 3 adverse events included neutropenia (14.8%), febrile neutropenia (7.4%), pneumonia (7.4%), and peripheral neuropathy (3.7%). The overall response rate was 0% in both subgroups; five HNSCC patients had stable disease (median duration 99 days) and four NPC patients had stable disease (median duration of 92.5 days). Median progression-free survival (PFS) for HNSCC patients was 52 days (95% CI 43.0-99.0 days) and 48 days (95% CI 41.0-83.0 days) for NPC. Median overall survival (OS) for HNSCC patients was 175 days (95% CI 92.0-234.0 days) and 280 days (95% CI 107.0-462.0 days) for NPC. The TAS-106 plasma levels were equivalent between Asian and Caucasian patients. There was no significant correlation of tumor UCK2 protein expression levels to TAS-106 efficacy. TAS-106 was reasonably tolerated in patients with platinum-failure HNSCC and NPC. The administration schedule of 24-h continuous infusion prevented neurologic toxicity, but had myelosuppression as its main toxicity. There was no anti-tumor efficacy seen with TAS-106 monotherapy. Future studies will focus on TAS-106 combinations and mechanisms of drug resistance.

Targeting tumor hypoxia in nasopharyngeal carcinoma.

BACKGROUND: Nasopharyngeal carcinoma (NPC) is an endemic head and neck cancer in Southeast Asia. Although concurrent chemoradiotherapy generally results in good clinical response for early diseases, posttreatment relapse and distant metastasis are major causes for NPC deaths. There is an urgent need for more effective therapies for advanced NPC. Recent studies have demonstrated tumor hypoxia can be a therapeutic target in NPC. METHODS: A Medline review of articles published on clinical and preclinical studies targeting tumor hypoxia was performed. RESULTS: Studies published to date showed that tumor hypoxia is common in NPC and it is associated with disease progression and resistance to therapy. Several mechanisms have been proposed on the role of tumor hypoxia in NPC cell survival, angiogenesis, and metabolism. Studies reported by us and by others have demonstrated the therapeutic potential of targeting tumor hypoxia in NPC. CONCLUSIONS: Cumulative studies indicate that targeting tumor hypoxia could be an effective approach for NPC treatment.

CXCR6 and CCR5 localize T lymphocyte subsets in nasopharyngeal carcinoma.

The substantial T lymphocyte infiltrate found in cases of nasopharyngeal carcinoma (NPC) has been implicated in the promotion of both tumor growth and immune escape. Conversely, because malignant NPC cells harbor the Epstein-Barr virus, this tumor is a candidate for virus-specific T cell-based therapies. Preventing the accumulation of tumor-promoting T cells or enhancing the recruitment of tumor-specific cytotoxic T cells offers therapeutic potential. However, the mechanisms involved in T cell recruitment to this tumor are poorly understood. Comparing memory T cell subsets that have naturally infiltrated NPC tissue with their counterparts from matched blood revealed enrichment of CD8(+), CD4(+), and regulatory T cells expressing the chemokine receptor CXCR6 in tumor tissue. CD8(+) and (nonregulatory) CD4(+) T cells also were more frequently CCR5(+) in tumor than in blood. Ex vivo studies demonstrated that both receptors were functional. CXCL16 and CCL4, unique chemokine ligands for CXCR6 and CCR5, respectively, were expressed by the malignant cells in tumor tissue from the majority of NPC cases, as was another CCR5 ligand, CCL5. The strongest expression of CXCL16 was found on tumor-infiltrating cells. CCL4 was detected on the tumor vasculature in a majority of cases. These findings suggest that CXCR6 and CCR5 play important roles in T cell recruitment and/or retention in NPC and have implications for the pathogenesis and treatment of this tumor.

Prediction of outcome in cancer patients with febrile neutropenia: a prospective validation of the Multinational Association for Supportive Care in Cancer risk index in a Chinese population and comparison with the Talcott model and artificial neural network.

PURPOSE: We aimed to validate the Multinational Association for Supportive Care in Cancer (MASCC) risk index, and compare it with the Talcott model and artificial neural network (ANN) in predicting the outcome of febrile neutropenia in a Chinese population. METHODS: We prospectively enrolled adult cancer patients who developed febrile neutropenia after chemotherapy and risk classified them according to MASCC score and Talcott model. ANN models were constructed and temporally validated in prospectively collected cohorts. RESULTS: From October 2005 to February 2008, 227 consecutive patients were enrolled. Serious medical complications occurred in 22% of patients and 4% died. The positive predictive value of low risk prediction was 86% (95% CI = 81-90%) for MASCC score ≥ 21, 84% (79-89%) for Talcott model, and 85% (78-93%) for the best ANN model. The sensitivity, specificity, negative predictive value, and misclassification rate were 81%, 60%, 52%, and 24%, respectively, for MASCC score ≥ 21; and 50%, 72%, 33%, and 44%, respectively, for Talcott model; and 84%, 60%, 58%, and 22%, respectively, for ANN model. The area under the receiver-operating characteristic curve was 0.808 (95% CI = 0.717-0.899) for MASCC, 0.573 (0.455-0.691) for Talcott, and 0.737 (0.633-0.841) for ANN model. In the low risk group identified by MASCC score ≥ 21 (70% of all patients), 12.5% developed complications and 1.9% died, compared with 43.3%, and 9.0%, respectively, in the high risk group (p < 0.0001). CONCLUSIONS: The MASCC risk index is prospectively validated in a Chinese population. It demonstrates a better overall performance than the Talcott model and is equivalent to ANN model.

Preclinical evaluation of sunitinib as single agent or in combination with chemotherapy in nasopharyngeal carcinoma.

PURPOSE: Sunitinib is a multi-target receptor tyrosine kinase (RTK) inhibitor against vascular endothelial growth factor receptors, platelet-derived growth factor receptors (PDGFR), c-kit and RET. Several of these RTKs are known to be involved in the progression of nasopharyngeal carcinoma (NPC). Here, we evaluated the preclinical activities of sunitinib in NPC. METHOD: We determined the basal level of total and phosphorylated PDGFR, c-kit and RET by immunoblotting in a panel of five NPC cell lines. The effect of sunitinib on NPC cell proliferation was evaluated by MTT assay. We further studied the effect of sunitinib on NPC cell cycle progression and apoptosis. We investigated the in vitro and in vivo activities of sunitinib as single agent and in combination with cisplatin or docetaxel in NPC cell lines and tumor xenografts. RESULTS: Sunitinib exhibited dose-dependent growth inhibition in all NPC cell lines tested with IC(50) between 2-7.5 µM and maximum inhibition of over 97%. Sunitinib induced apoptosis and cell cycle arrest at G(0)/G(1) phase. In vitro, sunitinib moderately enhanced the growth inhibition of cisplatin or docetaxel. Single agent sunitinib demonstrated significant growth inhibition, reduced microvessel density and caused extensive tumor necrosis in a NPC xenograft model. However, concurrent administration of sunitinib and docetaxel induced severe toxicity in mice without enhanced antitumor effect. CONCLUSIONS: Single agent sunitinib demonstrated potent in vitro and in vivo growth inhibition in NPC. When combined with chemotherapy, sequential instead of concurrent administration schedule should be further explored.

STAT3 activation contributes directly to Epstein-Barr virus-mediated invasiveness of nasopharyngeal cancer cells in vitro.

Nasopharyngeal cancer (NPC) is an Epstein-Barr virus (EBV)-associated head and neck cancer prevalent in Asia. Although with reasons not fully understood, the intrinsic invasiveness of NPC is believed to be EBV-linked. Recently, EBV was found to induce STAT3 activation. Constitutive STAT3 activation correlated with advanced clinical staging in NPC. We hypothesized that STAT3 activation by EBV directly contributes to the intrinsic invasiveness of NPC cells. Phospho-STAT3-Tyr705 was detected in high percentage of NPC tumors (7/10 cases). Using a paired NPC cell line model, HONE-1 and the EBV-infected counterpart, HONE-1-EBV, we found that HONE-1-EBV expressed a higher level of phospho-STAT3-Tyr705 and was approximately 11-fold more invasive than HONE-1. In HONE-1-EBV, STAT3 siRNA targeting inhibited both spontaneous and serum-induced invasion, as well as cell growth. Conversely, activation of STAT3 (by expressing an activated STAT3 mutant, namely STAT3C) in the parental HONE-1, mimicking EBV-induced STAT3 activation, significantly enhanced its invasiveness and proliferation, which was accompanied by increased expression of markers of mesenchymal status, proliferation and anti-apoptosis. Our results demonstrated that EBV-induced STAT3 activation is responsible for NPC cell proliferation and invasion. This was further confirmed by a small molecule inhibitor of JAK/STAT3, JSI-124. JSI-124 inhibited STAT3 activation in HONE-1-EBV, with subsequent growth inhibition, induction of PARP cleavage, abrogation of anchorage-independent growth and invasion. We found that EBV-independent activation of STAT3 by a growth factor, EGF, also contributed to NPC invasion. In conclusion, EBV-induced STAT3 activation directly contributes to the intrinsic invasiveness of NPC cells and STAT3 targeting may be beneficial in treating aggressive NPC.

Clinical significance of cytokeratin 20-positive circulating tumor cells detected by a refined immunomagnetic enrichment assay in colorectal cancer patients.

PURPOSE: Current immunomagnetic enrichment method can only detect general epithelial antigens of circulating tumor cells (CTC). Further characterization of the CTCs to provide specific information on the tumor type is not possible. We attempted to overcome this drawback by developing the methodology for using a gastrointestinal-specific anti-cytokeratin (CK) 20 antibody to detect CTCs in colorectal cancer patients' blood. EXPERIMENTAL DESIGN: The protocol was validated using a colorectal cancer SW480 cell line. The clinical significance of findings in colorectal cancer was investigated by detecting CK20-positive CTCs (pCTC) in patients with colorectal cancer, other common cancers, colorectal adenoma, benign colorectal diseases, and normal subjects. Moreover, the malignant nature of CK20 pCTCs was examined by comparing chromosome 17 aberration patterns with those from the corresponding primary tumors. RESULTS: The assay successfully showed CK20-positive SW480 cells. When applied in patient samples, the detection rates were 62% (132 colorectal cancer patients; median number = 11 CTCs), 0% (120 patients with other common cancers), 6% (50 colorectal adenoma patients), 0% (120 patients with benign colorectal diseases), and 0% (40 normal subjects). Furthermore, statistical analysis showed that CK20 pCTC numbers were associated with tumor-node-metastasis stage and lymph node status. Using the median CK20 pCTC numbers as the cutoff points, stratified groups of colorectal cancer patients had significant differences in their recurrence, metastasis, and survival. Finally, chromosome 17 aneusomy in 90% of colorectal cancer patients with CK20 pCTCs matched with those from the primary tumors. CONCLUSIONS: Detection of CK20 pCTCs using the new protocol could generate clinically important information for colorectal cancer patients.