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1.  Management of renal cell carcinoma with solitary metastasis 
Distant metastasis are common in Renal cell carcinoma (RCC) nearly one forth of the patients have metastasis at presentation while another 50% develop metastasis during the follow-up. A small percentage of these are solitary metastasis. We describe survival after surgical excision or radiotherapy of solitary metastatic lesion from renal cell carcinoma
Patients and methods
Between 1988–2001, 43 patients with solitary metastasis to different sites from renal cell carcinoma underwent either surgical excision or radiotherapy were analyzed. The solitary nature of the lesions was confirmed by investigations. All patients have had radical nephrectomy for the primary lesion. Survival analysis was carried out by Kaplan Meier Method.
All solitary metastatic lesions were treated with intent of cure either by excision or radiotherapy. Of these, 13 patients had solitary metastasis at the time of presentation in whom 3-year overall median survival was 26 months. The survival of those who developed solitary metastases during follow-up after nephrectomy for primary was 45 months. The patients with long interval between diagnosis and development of metastasis, early stage and low grade of the primary tumor had better prognosis.
Complete resection of either synchronous or metachronous solitary metastases from renal cell carcinoma is justified and can contribute to a long-term survival in this select group of patients.
PMCID: PMC1185571  PMID: 16029517
2.  Prognostic Value and Staging Classification of Retropharyngeal Lymph Node Metastasis in Nasopharyngeal Carcinoma Patients Treated with Intensity-modulated Radiotherapy 
PLoS ONE  2014;9(10):e108375.
The development of intensity-modulated radiotherapy (IMRT) has revolutionized the management of nasopharyngeal carcinoma (NPC). The purpose of this study was to evaluate the prognostic value and classification of TNM stage system for retropharyngeal lymph node (RLN) metastasis in NPC in the IMRT era.
Material and Methods
We retrospectively reviewed data from 749 patients with biopsy-proven, non-metastatic NPC. All patients received IMRT as the primary treatment. Chemotherapy was administered to 86.2% (424/492) of the patients with stage III or IV disease.
The incidence of RLN metastasis was 64.2% (481/749). Significant differences were observed in the 5-year disease-free survival (DFS; 70.6% vs. 85.4%, P<0.001) and distant metastasis-free survival (DMFS; 79.2% vs. 90.1%, P<0.001) rates of patients with and without RLN metastasis. In multivariate analysis, RLN metastasis was an independent prognostic factor for disease failure and distant failure (P = 0.005 and P = 0.026, respectively), but not for locoregional recurrence. Necrotic RLN metastases have a negative effect on disease failure, distant failure and locoregional recurrence in NPC with RLN metastasis (P = 0.003, P = 0.018 and P = 0.005, respectively). Survival curves demonstrated a significant difference in DFS between patients with N0 disease and N1 disease with only RLN metastasis (P = 0.020), and marginally statistically significant differences in DMFS and DFS between N1 disease with only RLN metastasis and other N1 disease (P = 0.058 and P = 0.091, respectively). In N1 disease, no significant differences in DFS were observed between unilateral and bilateral RLN metastasis (P = 0.994).
In the IMRT era, RLN metastasis remains an independent prognostic factor for DFS and DMFS in NPC. It is still reasonable for RLN metastasis to be classified in the N1 disease, regardless of laterality. However, there is a need to investigate the feasibility of classifying RLN metastasis as N1a disease in future by a larger cohort study.
PMCID: PMC4193733  PMID: 25302611
3.  A Comparison between the Sixth and Seventh Editions of the UICC/AJCC Staging System for Nasopharyngeal Carcinoma in a Chinese Cohort 
PLoS ONE  2014;9(12):e116261.
The International Union Against Cancer/American Joint Committee on Cancer (UICC/AJCC) TNM staging system of nasopharyngeal carcinoma (NPC) is the most important system for survival prediction. The TNM 7th edition UICC/AJCC TNM staging system for NPC was adopted in January 2009, and is now internationally recommended. In comparison with the TNM 6th edition, there were several revisions in the new edition staging system. This study aims to evaluate the prognostic value of the TNM 7th edition for NPC patients in comparison with the TNM 6th edition.
Clinical data of 2,629 NPC patients from the Sun Yat-sen University Cancer Center between January 2006 and December 2010 were retrospectively collected and all the patients were restaged according to the criteria of the TNM 6th edition and TNM 7th edition UICC/AJCC staging manual. Univariate and multivariate COX proportional hazards analyses were applied to evaluate the prognostic values between adjacent stage categories of the TNM 6th edition and TNM 7th edition.
In comparison with the TNM 6th edition, a significant alteration of the distribution of N categories was observed when the TNM 7th edition was applied (χ2 = 20.589, P<0.001), with 119 (119/670, 17.8%) patients up-staging from N0 to N1. With regard to T and overall stage, 37 (37/561, 6.6%) patients were down-staged from T2a with the TNM 6th edition to T1 with the TNM 7th edition, and finally two patients were up-staged to overall stage II (2/118, 1.7%). Moreover, the survival curves were significantly segregated (P<0.05) between T1 and T2 as well as N1 and N2 with the TNM 7th edition.
The TNM 7th edition led to a significant alteration in the distribution of N categories and it is superior to the TNM 6th edition in predicting the frequency of overall survival and distant metastasis-free survival.
PMCID: PMC4275293  PMID: 25536307
4.  A Large Cohort Study Reveals the Association of Elevated Peripheral Blood Lymphocyte-to-Monocyte Ratio with Favorable Prognosis in Nasopharyngeal Carcinoma 
PLoS ONE  2013;8(12):e83069.
Nasopharyngeal carcinoma (NPC) is an endemic neoplasm in southern China. Although NPC sufferers are sensitive to radiotherapy, 20–30% of patients finally progress with recurrence and metastases. Elevated lymphocyte-to-monocyte ratio (LMR) has been reported to be associated with favorable prognosis in some hematology malignancies, but has not been studied in NPC. The aim of this study was to evaluate whether LMR could predict the prognosis of NPC patients.
A retrospective cohort of 1,547 non-metastatic NPC patients was recruited between January 2005 and June 2008. The counts for peripheral lymphocyte and monocyte were retrieved, and the LMR was calculated. Receiver operating characteristic curve analysis, univariate and multivariate COX proportional hazards analyses were applied to evaluate the associations of LMR with overall survival (OS), disease-free survival (DFS), distant metastasis-free survival (DMFS) and loco-regional recurrence-free survival (LRRFS), respectively.
Univariate analysis revealed that higher LMR level (≥5.220) was significantly associated with superior OS, DFS and DMFS (P values <0.001). The higher lymphocyte count (≥2.145×109/L) was significantly associated with better OS (P = 0.002) and DMFS (P = 0.031), respectively, while the lower monocyte count (<0.475×109/L) was associated with better OS (P = 0.012), DFS (P = 0.011) and DMFS (P = 0.003), respectively. Multivariate Cox proportional hazard analysis showed that higher LMR level was a significantly independent predictor for superior OS (hazard ratio or HR  = 0.558, 95% confidence interval or 95% CI  = 0.417–0.748; P<0.001), DFS (HR  = 0.669, 95% CI  = 0.535–0.838; P<0.001) and DMFS (HR = 0.543, 95% CI  = 0.403–0.732; P<0.001), respectively. The advanced T and N stages were also independent indicators for worse OS, DFS, and DMFS, except that T stage showed borderline statistical significance for DFS (P = 0.053) and DMFS (P = 0.080).
The elevated pretreatment peripheral LMR level was a significant favorable factor for NPC prognosis and this easily accessed variable may serve as a potent marker to predict the outcomes of NPC patients.
PMCID: PMC3873908  PMID: 24386144
5.  Elevated expressions of survivin and VEGF protein are strong independent predictors of survival in advanced nasopharyngeal carcinoma 
Nasopharyngeal carcinoma (NPC) is one of the most common malignancies in southern China. The China 1992 TNM staging system has been widely used for prognosis prediction of NPC patients in China. Although NPC patients can be classified according to their clinical stage in this system, their prognosis may vary significantly.
280 cases of NPC with clinical follow-up data were collected and expressions of survivin and VEGF in tumor tissues were investigated by immunohistochemistry (IHC). Apoptosis index (AI) in 100 cases of NPC was detected by the TUNEL method.
Expression of survivin and VEGF were significantly associated with TNM stage, T-stage and metastasis of NPC. The patients with survivin and VEGF over-expression presented lower 5-year survival rate, as compared to those of low-expression (42.32% vs. 70.54%, 40.1% vs. 67.8%, respectively, P < 0.05), especially in advanced stage patients (36.51% vs. 73.41%, 35.03% vs. 65.22%, respectively, P < 0.05). The 5-year survival rate in NPC patients with survivin and VEGF dual over-expression was significantly lower than that of patients with dual low-expression (18.22% vs. 73.54%, respectively; P = 0.0003). Multivariate analysis indicated that both survivin and VEGF over-expression in NPC tumor tissues were strong independent factors of poor prognosis in NPC patients. The mean AI in the 39 survivin low-expression cases was 144.7 ± 39.9, which was significantly higher than that in 61 survivin over-expression cases (111.6 ± 39.8) (T test, P < 0.05).
Survivin and VEGF over-expression are independent prognostic factors for the patients with NPC. These results also suggest that tumor survivin and VEGF expressions are valuable prognostic markers for prognosis prediction in NPC patients.
PMCID: PMC2254380  PMID: 18171482
6.  Metachronous pulmonary metastasis after radical esophagectomy for esophageal cancer: prognosis and outcome 
Few reports discuss the outcome of pulmonary metastasis after radical esophagectomy for esophageal cancer. To clarify the data from such cases, we conducted a retrospective study on the clinical outcome of patients who developed pulmonary metastasis after undergoing radical esophagectomy.
We retrospectively reviewed the prognosis and clinical outcome of 25 patients who developed metachronous pulmonary metastasis after esophagectomy for esophageal cancer.
The site of recurrence was pulmonary without extrapulmonary metastasis in 14 patients and extrapulmonary metastasis was observed in 11. Nineteen patients had multiple pulmonary metastasis and 6 had solitary pulmonary metastasis. Twenty-four of patients underwent systemic chemotherapy during initial treatment for metastatic lesions. Pulmonary metastasectomy was indicated in 5 patients with solitary metastasis. The actual 1-, 2- and 4-year survival rates were 60%, 36% and 27%, respectively. Gender, operative procedure, and postoperative morbidity were not significant prognostic factors. However, pathological staging of primary esophageal cancer was a significant prognostic factor. Survival was significantly worse in patients who did not undergo resection than in those who did. The number of pulmonary metastasis, complicated extrapulmonary metastasis and the time of recurrence were also significant prognostic factors.
Multiple pulmonary metastases or complicated extrapulmonary metastasis were unfavorable prognostic factors for patients with pulmonary metastasis arising from esophageal cancer. Although, surgical intervention is not recommended in such cases, metastasectomy is an acceptable choice of treatment for solitary pulmonary metastasis.
PMCID: PMC3504510  PMID: 23031450
Metachronous pulmonary metastasis; Esophageal cancer; Metastasectomy
7.  Prognostic factors in nasopharyngeal carcinoma with synchronous liver metastasis: a retrospective study for the management of treatment 
To retrospectively analyze the prognosis of patients with nasopharyngeal carcinoma (NPC) initially presenting with liver metastasis, in order to identify independent prognostic factors to facilitate management of treatment.
Eighty-five patients with untreated NPC and synchronous liver metastasis, initially diagnosed between January 2000 and December 2009, were selected for this retrospective study. Seventy-eight received systemic chemotherapy, 32 underwent subsequent radiotherapy of the primary tumor, and 18 received local therapy for metastatic lesions. Clinical features, laboratory parameters and treatment modalities were compared by univariate and multivariate analyses.
The median survival time was 19.0 months and the 3-year overall survival rate was 14.1%. The overall response and disease control rates were 70.4% and 86.4%, respectively. Significant predictors of short survival were KPS ≤ 70 (P = 0.03), serum lactate dehydrogenase levels >245 IU/l (P = 0.01) and poor response to chemotherapy (P < 0.01). In contrast, significantly longer survival rates were achieved by patients having at least six chemotherapy cycles compared to those receiving <6 cycles (3-year OS: 18.3% vs. 7.1%; P < 0.01), and patients receiving radiotherapy of the primary tumor following complete or partial response to chemotherapy (3-year OS: 30.8% vs. 3.8%, P < 0.01).
Five key independent factors were identified and sub-classified as potential prognostic indicators for NPC with liver metastases. Progressive treatments of systemic chemotherapy and radiotherapy at the primary tumor could prolong survival in the subset of patients having fewer negative prognosticators.
PMCID: PMC4225489  PMID: 24252126
Nasopharyngeal carcinoma; Liver metastasis; Prognosis; Response; Lactate dehydrogenase; Local therapy
8.  Familial nasopharyngeal carcinomas possess distinguished clinical characteristics in southern China 
To compare clinical characteristics between familial nasopharyngeal carcinomas (NPCs) and sporadic NPCs in Guangdong province, China, a high-risk area.
Between 1991 and 2001, 993 NPC patients treated at the Cancer Center of Sun Yat-Sen University in Guangdong were randomly selected as probands. Information about NPC among the probands’ relatives and other information were obtained from a retrospective review of the patients’ medical records. The patients were divided into sporadic NPC, low-frequency familial NPC (one NPC patient in addition to the proband in three generations), and high-frequency familial NPC (2 or more additional NPC patients in three generations) groups. Pathological and clinical characteristics were compared among these groups.
Of the 993 patients, 131 (13.2%) had a familial history of NPC. The average age at diagnosis was the lowest in the high-frequency familial NPC group (39 years; P=0.048). Although the overall survival (OS), distant metastasis-free survival (DMFS), and disease-free survival (DFS) rates did not differ between familial and sporadic NPCs, the locoregional recurrence-free survival (LRFS) rate increased in the order sporadic NPCs, low-frequency familial NPCs, and high-frequency familial NPCs (P=0.009), with 5-year rates of 70%, 83%, and 87%, respectively. Multivariate analysis showed that family history of NPC was an independent favorable prognostic factor for LRFS, with adjusted hazard ratio (aHR) of 0.548, 95% CI (0.342-0.878). The high LRFS for familial NPCs was mainly noted among young, advanced-stage patients who received continuous radiation treatment.
Genetic factors may play an important role in the etiology of high-frequency familial NPC and underlie the early age of onset and sensitivity to radiotherapy.
PMCID: PMC4220253  PMID: 25400419
Nasopharyngeal carcinoma (NPC); familial; clinical behavior
9.  Prognosticators and Risk Grouping in Patients with Lung Metastasis from Nasopharyngeal Carcinoma: A more accurate and appropriate assessment of prognosis 
Lung metastases arising from nasopharyngeal carcinomas (NPC) have a relatively favourable prognosis. The purpose of this study was to identify the prognostic factors and to establish a risk grouping in patients with lung metastases from NPC.
A total of 198 patients who developed lung metastases from NPC after primary therapy were retrospectively recruited from January 1982 to December 2000. Univariate and multivariate analyses of clinical variables were performed using Cox proportional hazards regression models. Actuarial survival rates were plotted against time using the Kaplan-Meier method, and log-rank testing was used to compare the differences between the curves.
The median overall survival (OS) period and the lung metastasis survival (LMS) period were 51.5 and 20.9 months, respectively. After univariate and multivariate analyses of the clinical variables, age, T classification, N classification, site of metastases, secondary metastases and disease-free interval (DFI) correlated with OS, whereas age, VCA-IgA titre, number of metastases and secondary metastases were related to LMS. The prognoses of the low- (score 0-1), intermediate- (score 2-3) and high-risk (score 4-8) subsets based on these factors were significantly different. The 3-, 5- and 10-year survival rates of the low-, intermediate- and high-risk subsets, respectively (P < 0.001) were as follows: 77.3%, 60% and 59%; 52.3%, 30% and 27.8%; and 20.5%, 7% and 0%.
In this study, clinical variables provided prognostic indicators of survival in NPC patients with lung metastases. Risk subsets would help in a more accurate assessment of a patient's prognosis in the clinical setting and could facilitate the establishment of patient-tailored medical strategies and supports.
PMCID: PMC3179719  PMID: 21871101
lung metastasis; nasopharyngeal carcinoma; prognosis; risk subset
10.  Experience in hepatic resection for metastatic colorectal cancer: Analysis of clinical and pathologic risk factors 
Surgery  1994;116(4):703-711.
The selection of patients for resective therapy, of hepatic colorectal metastases remains controversial. A number of clinical and pathologic prognostic risk factor have been variably reported to influence survival.
Between January 1981 and December 1991, 204 patients underwent curative hepatic resection for metastatic colorectal cancer. Fourteen clinical and pathologic determinants previously reported to influence outcome were examined retrospectively. This led to a proposed TNM staging system for metastatic colorectal cancer (mTNM).
No operative deaths occurred (death within 1 month). Overall 1-, 3-, and 5-year survivals were 91%, 43%, and 32%, respectively. Gender, Dukes’ classification, site of primary colorectal cancer, histologic differentiation, size of metastatic tumor, and intraoperative blood transfusion requirement were not statistically significant prognostic factors (p > 0.05). Age of 60 years or more, interval of 24 months or less between colorectal and hepatic resection, four or more gross tumors, bilobar involvement, positive resection margin, Lymph node involvement, and direct invasion to adjacent organs were significant poor prognostic factors (p < 0.05). In the absence of nodal disease or direct invasion, patients with unilobar solitary tumor of any size, or unilobar multiple tumors of 2 cm or smaller (stages I and II) had the highest survival rates of 93% at 1 year, 68% at 3 years, and 61% at 5 years. Unilobar disease with multiple lesions greater than 2 cm (stage III) resulted in 1-, 3-, and 5-year survivals of 98%, 45%, and 28%, respectively. Patients with bilobar involvement (multiple tumors, any size, or a single large metastasis) (stage IVA) had survival rates of 88% at 1 year, 28% at 3 years, and 20% at 5 years (p < 0.00001). Patients with nodal involvement or extrahepatic disease (stage IVB) experienced the poorest outcome with 1-, 3-, and 5-year survivals of 80%, 12%, and 0%, respectively (p < 0.00001).
The proposed m TNM staging system appears to be useful in predicting the outcomes after hepatic resection of metastatic colorectal tumors.
PMCID: PMC2967179  PMID: 7940169
11.  Involvement of both Cervical Lymph Nodes and Retropharyngeal Lymph Nodes has prognostic value for N1 patients with Nasopharyngeal Carcinoma 
The N1 definition of 2010 UICC/AJCC staging system for nasopharyngeal carcinoma (NPC) covers quite a large range of nodal pattern. The objective of this research is to investigate prognostic value of lymph nodes related factors including involvement of both cervical lymph nodes (CLNs) and retropharyngeal lymph nodes (RLNs) or not, size and number of cervical lymph nodes (CLNs) in N1 patients with NPC.
142 newly diagnosed non-metastatic N1 patients with NPC, staged according to the 2010 AJCC staging system for NPC were retrospectively enrolled. All patients had undergone contrast-enhanced magnetic resonance imaging (MRI), and received radiotherapy, with or without chemotherapy as their primary treatment.
The median follow-up was 48 months. The 5-year local recurrence-free survival (LFS), nodal recurrence-free survival (NFS), local-regional recurrence-free survival (LRFS), distant metastasis-free survival (DMFS), progression-free survival (PFS), and overall survival (OS) of the whole group were 82.3%, 83.0%, 81.0%, 82.1%, 75.3% and 89.8%, respectively. In univariate analysis, patients with both CLNs and RLNs involvement showed a significant lower DMFS, PFS and LRFS than the rest patients (p = 0.004 p = 0.003 and p = 0.034, respectively). Neither size nor number of CLNs affected the survival. In multivariate analysis, involvement of both CLNs and RLNs was an independent prognostic factor for DMFS and PFS (p = 0.019, p = 0.019), but there was no enough evidence confirming its prognostic value for LRFS (p = 0.051).
For N1 patients with NPC, involvement of both RLNs and CLNs may be a potentially prognostic factor for distant metastasis and disease progression. The N stage for N1 patients with involvement of both cervical lymph nodes and retropharyngeal lymph nodes might need to be deliberated.
PMCID: PMC3996203  PMID: 24393418
Nasopharyngeal carcinoma; Lymph nodes; Prognosis
12.  Quantitative expression analysis and prognostic significance of the BCL2-associated X gene in nasopharyngeal carcinoma: a retrospective cohort study 
BMC Cancer  2013;13:293.
Nasopharyngeal carcinoma (NPC) is a highly metastatic epithelial malignancy showing high prevalence in Southeast Asia and North Africa. The BCL2-associated X (BAX) gene encodes the most important pro-apoptotic member of the BCL2 family. We have recently shown that BCL2 and BCL2L12, two other members of the same apoptosis-related family, possess significant prognostic value in NPC. The objective of the current study was to analyze BAX mRNA expression in nasopharyngeal biopsies of NPC patients, and to assess its prognostic potential in this disease.
Total RNA was isolated from 88 malignant and 9 hyperplastic nasopharyngeal biopsies, resected from Tunisian patients. After cDNA synthesis by reverse transcription of polyadenylated RNA, BAX mRNA expression was analyzed using a highly sensitive quantitative real-time polymerase chain reaction (qRT-PCR) method.
Lower BAX mRNA levels were detected in NPC biopsies than in hyperplastic nasopharyngeal samples. BAX mRNA expression status was associated with low tumor extent, negative regional lymph node status, and absence of distant metastases. Kaplan-Meier survival analysis demonstrated that patients with BAX mRNA-positive NPC have significantly longer disease-free survival (DFS) and overall survival (OS). In accordance with these findings, Cox regression analysis revealed that BAX mRNA expression can be considered as a favorable prognostic indicator of DFS and OS in NPC, independent of their gender, age, tumor histology, tumor extent, and nodal status. Furthermore, NPC patients without distant metastases are less likely to relapse when their primary tumor is BAX mRNA-positive, compared to metastasis-free patients with a BAX-negative nasopharyngeal malignancy.
This is the first study examining the potential clinical utility of BAX as a prognostic tumor biomarker in NPC. We provide evidence that BAX mRNA expression can be considered as an independent favorable prognostic indicator of DFS and OS in NPC.
PMCID: PMC3689087  PMID: 23777485
Head and neck cancer; Nasopharynx; Prognostic tumor biomarkers; Apoptosis; Quantitative real-time PCR
13.  Partial hepatectomy for liver metastases from nasopharyngeal carcinoma: a comparative study and review of the literature 
BMC Cancer  2014;14(1):818.
The management of liver metastases from nasopharyngeal carcinoma (NPC) has not been extensively investigated. This study aimed to compare the long-term outcome of patients with liver metastases from NPC who were treated by a partial hepatectomy or transcatheter hepatic artery chemoembolization (TACE).
Between January 1993 and December 2010, 830 patients were diagnosed with liver metastases from NPC and exhibited a complete response to the primary cancer of the nasopharynx and regional lymph nodes. Fifteen patients with intrahepatic metastasis underwent R0 partial hepatectomy. As a parallel control group, another 15 patients with a resectable liver metastasis who underwent TACE were selected. Prior to the resection and TACE that were performed on patients in these two groups, radical radiotherapy with or without adjuvant chemotherapy was administered. Clinicopathological data and treatment outcomes were compared retrospectively.
No significant differences were observed between the two groups in terms of the clinicopathological features, which include gender ratio, liver function, accompanying cirrhosis, rate of infection with the hepatitis B virus, tumor size, tumor number, pathological type and preoperative comorbidities. The 1-, 3- and 5-year overall survival rates from the time of hepatectomy were 85.7%, 64.2% and 40.2%, respectively, with a median survival of 45.2 months, whereas the 1-, 3- and 5-year overall survival rates were 53.3%, 26.6% and 20.0% for patients in the control group (P = 0.039), respectively, with a median survival of 14.1 months. The actuarial median progression-free survival (PFS) of the patients in the resection group was 21.2 months, and the 1-, 3- and 5-year PFS rates were 70%, 53% and 18%, respectively. In the control group, the 1-, 3- and 5-year PFS rates were 27%, 7% and 0.0% (P = 0.007), respectively, with a median survival of 4.2 months. Thus far, 5 patients have survived for more than 5 years, and the longest survival time is 168.1 months.
For patients with limited liver metastases from NPC, hepatectomy provides a survival advantage over TACE. Due to the limited treatment options for patients with liver metastasis from NPC, hepatectomy should be recommended as an optimal treatment. Moreover, perioperative chemotherapy may be associated with an improved prognosis.
PMCID: PMC4233067  PMID: 25376591
Nasopharyngeal carcinoma; Liver metastasis; Partial hepatectomy; Transarterial chemoembolization
14.  Promising treatment outcomes of intensity-modulated radiation therapy for nasopharyngeal carcinoma patients with N0 disease according to the seventh edition of the AJCC staging system 
BMC Cancer  2012;12:68.
Intensity-modulated radiation therapy (IMRT) provides excellent locoregional control for nasopharyngeal carcinoma (NPC), and has gradually replaced two-dimensional conventional radiotherapy as the first-line radiotherapy technique. Furthermore, in the new seventh edition of the American Joint Committee on Cancer (AJCC) staging system, retropharyngeal lymph nodes were upgraded from N0 to N1 disease as a result of their negative impact on the distant metastasis-free survival (DMFS) rates of NPC. This retrospective study was conducted in order to review the treatment outcomes and patterns of failure in NPC patients with N0 disease after IMRT in order to effectively guide treatment in the future.
We retrospectively reviewed data from 506 biopsy-proven nonmetastatic NPC patients. There were 191 patients with negative cervical lymph node involvement. According to the seventh edition of the American Joint Committee on Cancer (AJCC) staging system, 110 patients (21.7%) were staged with N0 disease, and 81 patients (16.0%) were reclassified with N1 disease due to the presence of RLN metastasis. All patients received IMRT as the primary treatment.
In patients with negative cervical lymph node involvement, distant metastasis-free survival (DMFS) was significantly higher in patients without retropharyngeal lymph node (RLN) metastasis than those with RLN metastasis (95.9% vs. 88.1% respectively, P = 0.04). For N0 disease, the 5-year overall survival (OS), local relapse-free survival (LRFS), nodal relapse-free survival (NRFS) and DMFS rates were 93.8%, 97.1%, 99.1% and 95.9%, respectively. For T1N0, T2N0, T3N0 and T4N0, OS was 97.8%, 100%, 93.8% and 76.9%, LRFS was 100%, 92.9%, 100% and 88.9% and DMFS was 96.6%, 90.9%, 100% and 93.3%, respectively. OS and LRFS were higher in T1-3 N0 patients than T4N0 patients (P < 0.01 and P = 0.01, respectively).
The seventh edition of the AJCC N-staging system improves prognostic accuracy by upgrading RLN metastasis to N1 disease. IMRT produces excellent survival rates in T1-3 N0 disease; however, T4N0 disease remains a challenge and additional improvements are required to achieve a favorable prognosis for these NPC patients.
PMCID: PMC3332280  PMID: 22336097
15.  Induction with mitomycin C, doxorubicin, cisplatin and maintenance with weekly 5-fluorouracil, leucovorin for treatment of metastatic nasopharyngeal carcinoma: a phase II study 
British Journal of Cancer  1999;80(12):1962-1967.
The combination of cisplatin and 5-fluorouracil (5-FU) (PF) is the most popular regimen for treating metastatic nasopharyngeal carcinoma (NPC) but it is limited by severe stomatitis and chronic cisplatin-related toxicity. A novel approach including induction with mitomycin C, doxorubicin and cisplatin (MAP) and subsequent maintenance with weekly 5-FU and leucovorin (FL) were designed with an aim to reduce acute and chronic toxicity of PF. Thirty-two patients of NPC with measurable metastatic lesions in the liver or lung were entered into this phase II trial. Mitomycin C 8 mg m−2, doxorubicin 40 mg m−2 and cisplatin 60 mg m−2 were given on day 1 every 3 weeks as initial induction. After either four courses or remission was achieved, patients received weekly dose of 5-FU 450 mg m−2 and leucovorin 30 mg m−2 for maintenance until disease progression. With 105 courses of MAP given, 5% were accompanied by grade 3 and 0% were accompanied by grade 4 stomatitis. The dose-limiting toxicity of MAP was myelosuppression. Forty per cent of courses had grade 3 and 13% of courses had grade 4 leukopenia. No grade 3 or 4 cisplatin-related toxicity was observed. The overall response rate was 94% (95% confidence interval (CI) 84.9–100%) with a complete response rate (CR) of 6% (95% CI: 0–15.2%) and a good partial response (PR) rate of 28% (95% CI 11.7–44.6%), which was optionally defined as observance of only equivocal lesion identifiable under imaging study. Twenty-seven cases entered weekly FL maintenance phase. The median duration of maintenance with weekly FL was 38 weeks (8–91 weeks). There was no grade 3 or 4 toxicity noted during weekly FL. The median progression-free survival and overall survival were 11.6 ± 0.4 and 18.1 ± 3.6 months respectively. Six patients with a median follow-up of 19.8 months (9.6–41.0 months) were still alive and five of them had disease under control with FL. Good responders (CR and good PR) had better survival than less satisfactory responders (PR and stable disease) (P = 0.05). From Cox’s multivariate regression analysis, the only significant prognostic factor for survival was good response to MAP (P = 0.042). Liver metastasis was the only significant variable in the best subset regression model that predicted good response to MAP (CR and good PR) (P = 0.027). MAP was an effective combination for metastatic NPC with minimal stomatitis and cisplatin-related toxicity but had significant myelosuppression. Weekly FL was a maintenance therapy with minimal side-effects. The response rate and overall survival of MAP-FL were better than series previously reported even when a subset of patients with poor prognosis was selected. MAP-FL's role as neoadjuvant or adjuvant therapy is worthy of further study. © 1999 Cancer Research Campaign
PMCID: PMC2363155  PMID: 10471046
nasopharyngeal carcinoma; metastasis; chemotherapy; mitomycin; cisplatin
16.  Chromodomain helicase/ATPase DNA binding protein 1-like protein expression predicts poor prognosis in nasopharyngeal carcinoma 
Nasopharyngeal carcinoma (NPC) is a malignancy with a high metastatic ability. Recent studies have implicated the role of chromodomain helicase/ATPase DNA binding protein 1-like (CHD1L) gene as a novel oncogene; however, the functional role of CHD1L in NPC remains unknown. The aim of this study was to evaluate the clinical significance of CHD1L positivity in NPC. CHD1L protein expression was examined by performing western blot analysis of 30 fresh NPC tissues and conducting immunohistochemistry tests of 133 NPC samples between December 1, 2005 and December 1, 2009. The correlations of CHD1L expression status with clinicopathological features and prognosis were investigated. Immunohistochemical analysis showed that 88 of 133 (66.2%) paraffin-embedded NPC biopsies exhibited positive expression of CHD1L, but all non-cancerous nasopharyngeal specimens were negative for CHD1L expression. In addition, positive CHD1L expression was strongly associated with an advanced clinical stage (P=0.016), recurrence (P=0.002) and the metastasis status (P=0.031) of NPC. Kaplan-Meier survival analysis demonstrated that patients with CHD1L-positive NPC had significantly shorter overall survival (P<0.001). Furthermore, the multivariate analysis indicated that CHD1L protein expression was an independent prognostic factor for overall survival (hazard ratio, 7.916; 95% confidence interval, 2.067–16.034; P=0.003) in patients with NPC. These results indicate that CHD1L is a prognostic marker for NPC.
PMCID: PMC4217779  PMID: 25371726
nasopharyngeal carcinoma; CHD1L; prognosis; biomarker
17.  Combined upregulation of matrix metalloproteinase-1 and proteinase-activated receptor-1 predicts unfavorable prognosis in human nasopharyngeal carcinoma 
OncoTargets and therapy  2013;6:1139-1146.
The upregulation of matrix metalloproteinase-1 (MMP-1) has been demonstrated to be correlated with lymph node metastasis of nasopharyngeal carcinoma (NPC), while the activation of protease-activated receptor-1 (PAR-1) mediates proliferation and invasion of NPC cells. The present study investigated the clinical significance of the coexpression of MMP-1 and PAR-1 in NPC patients in determining the prognosis.
Immunohistochemistry was performed to detect the expression of MMP-1 and PAR-1 in tumor tissue samples from 266 NPC patients.
Overexpression of MMP-1 and PAR-1 proteins were, respectively, detected in 190 (71.43%) and 182 (68.42%) of the 266 NPC patients. In addition, the combined MMP-1 and PAR-1 expression was significantly associated with advanced T-stage (P = 0.01), advanced clinical stage (P = 0.002), positive recurrence (P = 0.01), and metastatic status (P = 0.01) of NPC. Moreover, the overall survival in NPC patients with MMP-1 and PAR-1 dual overexpression was significantly shorter than in those with dual low expression (P < 0.001). Furthermore, the multivariate analyses indicated that the combined MMP-1 and PAR-1 overexpression was an independent prognostic factor for overall survival (P = 0.001) in NPC patients, but the upregulation of MMP-1 and PAR-1 alone was, in each case, not an independent prognostic factor for this disease.
Our data provide convincing evidence, for the first time, that the activation of the MMP-1 and PAR-1 axis may be involved in the tumorigenesis and progression of NPC. The upregulation of MMP-1 in combination with PAR-1 overexpression is an unfavorable prognostic marker for NPC and might offer the possibility of future therapeutic targets.
PMCID: PMC3754819  PMID: 23986644
MMP-1; PAR-1; nasopharyngeal carcinoma; coexpression; prognosis
18.  Tumor volume is an independent prognostic indicator of local control in nasopharyngeal carcinoma patients treated with intensity-modulated radiotherapy 
To retrospectively analyze whether primary tumor volume and primary nodal volume could be considered independent prognostic factors for nasopharyngeal carcinoma treated with intensity-modulated radiation therapy.
Three hundred sixty-three consecutive nasopharyngeal carcinoma (NPC) patients who were stage I-IVa+b and treated with intensity-modulated radiotherapy (IMRT) in our center from October 2003 to October 2005 were analyzed retrospectively. The predictive ability of gender, age, T and N stage, combined chemotherapy, primary tumor and nodal volume for the 5-year local control (LC), distant-metastasis free survival (DMFS) and overall survival (OS) rate were investigated. Primary tumor and nodal volume were measured based on registration of magnetic resonance imaging (MRI) with contrast-enhanced computed tomography (CT) images. The Kaplan–Meier method was used for survival analysis, the log-rank test was used for univariate analyses and the Cox proportional hazard model was used for multivariate prognostic analyses.
The mean value of primary tumor and nodal volume were 31.5 ml and 9.7 ml. The primary tumor and nodal volume were respectively divided into four groups for analysis (primary tumor volume: TV1≤20 ml, 2040 ml; primay nodal volume: NV1≤5 ml, 520 ml). In univariate analysis, the 5-year LC and DMFS rate for TV4 was significantly decreased compared to the other groups (LC: p<0.001, DMFS: p=0.001), the 5-year OS rate for TV3 and TV4 were significantly decreased compared to other two subgroups (p=0.002) and the 5-year regional control (RC), DMFS and OS rate for NV3 and NV4 were significantly less than NV1 and NV2 (RC: p=0.002, DMFS: p=0.01, OS: p=0.014). Multivariate analysis showed that TV>40 ml was an adverse prognostic factor for the 5-year local regional control (LRC) rate (RR 2.454, p=0.002). Primary nodal volume had no statistical significance in predicting 5-year LRC, DMFS and OS rate in multivariate analysis.
Primary tumor volume could predict LRC rate of NPC patients, and the primary tumor volume of 40 ml may be the cut-off. Primary nodal volume may have predictive significance, but more data are needed. These factors should be considered in the TNM staging system of NPC for better estimates of prognosis.
PMCID: PMC3846569  PMID: 24007375
Primary tumor volume; Primary nodal volume; Nasopharyngeal carcinoma; Prognostic factor
19.  Solitary metachronous gastric metastasis from pulmonary adenocarcinoma: Report of a case 
Gastric metastases from lung adenocarcinoma are rare and usually associated with disseminated disease. The great majority is asymptomatic and in few cases discovered during autopsy studies. Reports of single metachronous metastases during the lifetime are anecdotal. We describe a case of solitary gastric metastasis 5 years after lung surgery.
A 68-year-old male submitted in 2006 to right lobectomy for lung adenocarcinoma was referred at Emergency Room department in 01/2011 because of chronic epigastric pain. Radiologic and endoscopic evaluation showed a bulky lesion inside the stomach, originating from the muscular layer, suspected for GIST. He underwent a subtotal gastrectomy and the pathologic examination revealed an undifferentiated adenocarcinoma, positive for Thyroid Transcriptional Factor-1, Cytokeratin 7, AE 1/3 and CEA, confirming the pulmonary origin.
At the time of diagnosis about 50% of lung cancer are metastatic, with survival rates of 1% at 5-year. Gastric metastasis is very rare; autopsy studies report an incidence of 0.2–0.5%. They develop in the submucosa, usually without any symptom and the diagnosis is incidental during the staging of primary cancer or the follow-up. There are no guidelines about surgical treatment; however few cases of long-term survival following the operation were reported. Pathologic diagnosis is difficult, but the immunohistochemical staining helps to recognize the primary origin.
Solitary metachronous gastric metastasis from pulmonary adenocarcinoma is an exceptional event, but it could happen during the follow-up. It seems that a radical resection, in absence of systemic implants, might provide survival benefits in selected patients.
PMCID: PMC3376723  PMID: 22634567
Lung cancer; Gastric metastasis; Outcome; Immunohistochemical analysis; Surgery
20.  The independent, unfavorable prognostic factors endothelin A receptor and chemokine receptor 4 have a close relationship in promoting the motility of nasopharyngeal carcinoma cells via the activation of AKT and MAPK pathways 
Recent studies have indicated that the expression of endothelin A receptor (ETAR) and chemokine receptor 4 (CXCR4) could be used as an indicator of the metastatic potential of nasopharyngeal carcinoma (NPC). The aim of this study was to determine the prognostic value of ETAR and CXCR4 in NPC patients and to reveal the interplay of the endothelin-1 (ET-1)/ETAR and stromal-derived factor-1(SDF-1)/CXCR4 pathways in promoting NPC cell motility.
Survival analysis was used to analyze the prognostic value of ETAR and CXCR4 expression in 153 cases of NPC. Chemotaxis assays were used to evaluate alterations in the migration ability of non-metastatic 6-10B and metastatic 5-8F NPC cells. Real-time PCR, immunoblotting, and flow cytometric analyses were used to evaluate changes in the expression levels of CXCR4 mRNA and protein induced by ET-1.
The expression levels of ETAR and CXCR4 were closely related to each other and both correlated with a poor prognosis. A multivariate analysis showed that the expression levels of both ETAR and CXCR4 were independent prognostic factors for overall survival (OS), progression-free survival (PFS), and distant metastasis-free survival (DMFS). The migration of 6-10B and 5-8F cells was elevated by ET-1 in combination with SDF-1α. The knockdown of ETAR protein expression by siRNA reduced CXCR4 protein expression in addition to ETAR protein expression, leading to a decrease in the metastatic potential of the 5-8F cells. ET-1 induced CXCR4 mRNA and protein expression in the 6-10B NPC cells in a time- and concentration-dependent fashion and was inhibited by an ETAR antagonist and PI3K/AKT/mTOR and MAPK/ERK1/2 pathway inhibitors.
ETAR and CXCR4 expression levels are potential prognostic biomarkers in NPC patients. ETAR activation partially promoted NPC cell migration via a mechanism that enhanced functional CXCR4 expression.
PMCID: PMC3765987  PMID: 23987636
Nasopharyngeal carcinoma; Prognosis; ETAR; CXCR4; Metastasis
21.  3D-image-guided high-dose-rate intracavitary brachytherapy for salvage treatment of locally persistent nasopharyngeal carcinoma 
To evaluate the therapeutic benefit of 3D-image-guided high-dose-rate intracavitary brachytherapy (3D-image-guided HDR-BT) used as a salvage treatment of intensity modulated radiation therapy (IMRT) in patients with locally persistent nasopharyngeal carcinoma (NPC).
Thirty-two patients with locally persistent NPC after full dose of IMRT were evaluated retrospectively. 3D-image-guided HDR-BT treatment plan was performed on a 3D treatment planning system (PLATO BPS 14.2). The median dose of 16 Gy was delivered to the 100% isodose line of the Gross Tumor Volume.
The whole procedure was well tolerated under local anesthesia. The actuarial 5-y local control rate for 3D-image-guided HDR-BT was 93.8%, patients with early-T stage at initial diagnosis had 100% local control rate. The 5-y actuarial progression-free survival and distant metastasis-free survival rate were 78.1%, 87.5%. One patient developed and died of lung metastases. The 5-y actuarial overall survival rate was 96.9%.
Our results showed that 3D-image-guided HDR-BT would provide excellent local control as a salvage therapeutic modality to IMRT for patients with locally persistent disease at initial diagnosis of early-T stage NPC.
PMCID: PMC3720206  PMID: 23826875
Nasopharyngeal carcinoma; Intensity-modulated radiotherapy; Persistent disease; 3D-image-guided HDR Brachytherapy; Local tumor control
22.  FLJ10540 is associated with tumor progression in nasopharyngeal carcinomas and contributes to nasopharyngeal cell proliferation, and metastasis via osteopontin/CD44 pathway 
Nasopharyngeal 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.
A 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.
We 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.
These findings suggest that FLJ10540 may be critical regulator of disease progression in NPC, and the underlying mechanism may involve in the osteopontin/CD44 pathway.
PMCID: PMC3419101  PMID: 22591637
Nasopharyngeal carcinoma; FLJ10540; Osteopontin; CD44
23.  Radiological, pathological and DNA remission in recurrent metastatic nasopharyngeal carcinoma 
BMC Cancer  2006;6:259.
Circulating plasma Epstein Barr Virus DNA (EBV-DNA) is a sensitive and specific marker of nasopharyngeal carcinoma (NPC). The mainstay of treatment of metastatic NPC is systemic chemotherapy and resection for solitary metastasis. Despite high response rate to chemotherapy, complete remission is uncommonly seen.
Case Presentation
We report a case of recurrent metastatic NPC in a 43-year-old man, who achieved complete remission three times with chemotherapy and surgery. Serial plasma EBV-DNA levels were measured during the course of disease. The patient had three episodes of recurrences of NPC manifested as distant metastasis. Both time, rise in the plasma EBV-DNA level preceded detection of recurrences by imaging. Following systemic chemotherapy, he achieved complete remission each time, of which was confirmed by 18-flourodeoxyglucose positron emission tomography and hepatectomy pathology. The plasma EBV-DNA level dropped to zero copy/ml at the time of each remission.
This case highlights the high chemosensitivity of NPC by illustrating a rare occurrence of complete response of metastatic NPC to chemotherapy. This case also underscores the usefulness of EBV-DNA as a useful tool in monitoring NPC by its ability to detect early recurrence and excellent correlation with treatment response.
PMCID: PMC1634867  PMID: 17076893
24.  HMGA2 is associated with epithelial–mesenchymal transition and can predict poor prognosis in nasopharyngeal carcinoma 
OncoTargets and therapy  2015;8:169-176.
High-mobility group protein 2 (HMGA2) and epithelial–mesenchymal transition (EMT)-associated proteins play key roles in cancer progression and metastasis. However, the clinical significance of HMGA2 and its relationship with EMT markers in nasopharyngeal carcinoma (NPC) is unclear. This study aimed to assess the clinicopathological significance and prognostic value of HMGA2, E-cadherin, and vimentin in NPC.
Using immunohistochemistry, HMGA2, E-cadherin, and vimentin expression levels were evaluated in NPC (n=124) and non-tumoral inflammatory nasopharynx (n=20) tissues. The association of HMGA2 and EMT markers with clinicopathological characteristics and relationships between the protein levels and overall survival were analyzed.
Compared with non-tumorous tissues, HMGA2 and vimentin levels were markedly increased in NPC tissues, whereas decreased E-cadherin levels were observed (P<0.001). Moreover, HMGA2 expression was positively correlated with vimentin levels (r=0.431, P<0.001) and negatively correlated with E-cadherin amounts (r=−0.413, P<0.001) in NPC tissues. The expression of all three proteins correlated significantly with tumor N stage, TNM stage, and 2-year metastasis. Furthermore, significant correlations were found for T stage, N stage, TNM stage, HMGA2, E-cadherin, and vimentin (all P<0.013) with poor prognosis (univariate analysis). However, multivariate analyses showed that only HMGA2 (hazard ratio [HR]: 2.683, 95% confidence interval [CI]: 1.185–6.077, P=0.018) and N stage (HR: 7.892, 95% CI: 2.731–22.807, P<0.001) were independent predictors of poor prognosis.
These results demonstrated that HMGA2, an independent prognostic factor, may promote NPC progression and metastasis, and is significantly associated with EMT proteins. Therefore, HMGA2 may be considered a potential therapeutic target in NPC.
PMCID: PMC4303461  PMID: 25653540
EMT; NPC; high-mobility group protein 2
25.  Upregulation of MiR-155 in Nasopharyngeal Carcinoma is Partly Driven by LMP1 and LMP2A and Downregulates a Negative Prognostic Marker JMJD1A 
PLoS ONE  2011;6(4):e19137.
The role of microRNA-155 (miR-155) has been associated with oncogenesis of several human tumors. However the expression pattern of miR-155 has not been investigated in nasopharyngeal carcinoma (NPC). The present study was to assess miR-155 expression pattern and its possible function in NPC, to identify its targets and evaluate their clinical applications in NPC. MiR-155 was found to be upregulated in two Epstein-Barr virus (EBV) negative NPC derived cell lines CNE1 and TW03, as well as in NPC clinical samples by quantitative Real-time PCR and in situ hybridization detection. EBV encoded LMP1 and LMP2A could further enhance the expression of miR-155 in NPC CNE1 and TW03 cells. JMJD1A and BACH1 were identified as putative targets of miR-155 in a bioinformatics screen. Overexpression of miR-155 downregulated a luciferase transcript fused to the 3′UTR of JMJD1A and BACH1. MiR-155 mimic could downregulate the expression of JMJD1A and BACH1, while miR-155 inhibitor could upregulate JMJD1A expression in NPC cell lines. Moreover, downregulation of JMJD1A was significantly correlated with N stage in TNM classification (p = 0.023), a lower five-year survival rate (p = 0.021), and a lower five-year disease-free survival rate (p = 0.049) of NPC patients. Taken together, up-regulation of miR-155 in NPC is partly driven by LMP1 and LMP2A, and results in downregulation of JMJD1A, which is associated with N stage and poor prognosis of NPC patients. The potential of miR-155 and JMJD1A as therapeutic targets in NPC should be further investigated.
PMCID: PMC3082546  PMID: 21541331

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