Concurrent chemoradiotherapy using gemcitabine and nedaplatin in recurrent or locally advanced head and neck squamous cell carcinoma.

BACKGROUND: Patients with recurrent or locally advanced head and neck squamous cell carcinoma (HNSCC) typically have limited treatment options and poor prognosis. AIM: To evaluate the efficacy and safety of two drugs with potent radio-sensitization properties including gemcitabine and nedaplatin as concurrent chemoradiotherapy regimens in treating HNSCC. METHODS: This single-arm prospective study enrolled patients with HNSCC to receive gemcitabine on days 1 and 8 and nedaplatin on days 1 to 3 for 21 days. Intensity-modulated radiation therapy with a conventional fraction was delivered 5 days per week. Objective response rate (ORR), disease control rate, and toxicity were observed as primary endpoints. Overall survival (OS) and progression free survival were recorded and analyzed as secondary endpoints. RESULTS: A total of 24 patients with HNSCC were enrolled. During the median 22.4-mo follow-up, both ORR and disease control rate were 100%. The one-year OS was 75%, and one-year progression-free survival (PFS) was 66.7% (median PFS was 15.1 mo). Recurrent HNSCC patients had a poorer prognosis than the treatment-naïve patients, and patients who achieved complete response had better survival than those in the PR group (all P < 0.05). The most common grade 1-4 (100%) or grade 3-4 toxicities (75%) were hematological, and the most common grade 3-4 non-hematological toxicity was mucositis in 17 (71%) patients. CONCLUSION: Gemcitabine plus nedaplatin with concurrent chemoradiotherapy is a therapeutic option for HNSCC with predictable tolerability. Considering the high adverse event rate, the optimized dose and schedule must be further explored.

A four-miRNA signature identified from genome-wide serum miRNA profiling predicts survival in patients with nasopharyngeal carcinoma.

Recent findings have reported that human serum microRNAs (miRNAs) can be used as prognostic biomarkers in various cancers. We aimed to explore the prognostic value of serum miRNAs in nasopharyngeal carcinoma (NPC) patients. The level of serum miRNA was retrospectively analyzed in 512 NPC patients recruited between January 2001 and December 2006. In the discovery stage, a microarray followed by reverse transcription-quantitative polymerase chain reaction was used to identify differentially altered miRNAs in eight patients with shorter survival and eight patients with longer survival who were well matched by age, sex and clinical stage. The identified serum miRNAs were then validated in all 512 samples, which were randomly divided into a training set and a validation set. Four serum miRNAs (miR-22, miR-572, miR-638 and miR-1234) were found to be differentially altered and were used to construct a miRNA signature. Risk scores were calculated to classify the patients into high- or low-risk groups. Patients with high-risk scores had poorer overall survival [hazard ratio (HR), 2.54; 95% confidence interval (CI), 1.57-4.12; p < 0.001] and distant metastasis-free survival (HR, 3.28; 95% CI, 1.82-5.94; p < 0.001) than those with low-risk scores in the training set; these results were confirmed in the validation and combined sets. The miRNA signature and TNM stage were independent prognostic factors. The combination of the miRNA signature and TNM stage had a better prognostic value than the TNM stage or miRNA signature alone. The four-serum miRNA signature may add prognostic value to the TNM staging system and provide information for personalized therapy in NPC.

Reduced expression of Dicer11 is associated with poor prognosis in patients with nasopharyngeal carcinoma.

Dicer11 plays an important role in generation of microRNA and is dysregulated in a variety of human cancers. The purpose of this study was to evaluate Dicer11 expression and its prognostic value in nasopharyngeal carcinoma (NPC). The protein expression of Dicer1 was examined by immunohistochemistry in 276 NPC specimens, and the mRNA levels of Dicer1 were analyzed by qRT-PCR in 56 NPC and 11 nasopharyngitis tissues. Cox regression analysis was used to identify independent prognostic factors, and a prognostic score model was constructed for survival prediction. Expression of Dicer1 was downregulated in NPC tissues at both the mRNA and the protein levels, and there was a notable positive correlation between the expression levels of Dicer1 mRNA and protein. Low Dicer1 expression was positively correlated with distant metastasis (P < 0.01) and death (P = 0.01). In addition, low expression of Dicer1 was significantly associated with poorer overall survival (HR, 2.32; 95 % CI 1.30-4.14; P < 0.01) and poorer distant metastasis-free survival (HR, 2.56; 95 % CI 1.39-4.74; P < 0.01). Furthermore, multivariate analysis showed that low expression of Dicer1 and tumor-node-metastasis (TNM) stage was independent prognostic indicators for NPC patients. A prognostic score model combining the Dicer1 expression and TNM stage had a better prognostic value than the TNM stage alone model or Dicer1 expression alone model (P < 0.05). Dicer1 was downregulated in NPC tissues at both the mRNA and the protein levels, and low expression of Dicer1 could be served as novel prognostic biomarker for NPC patients.

MiR-29c suppresses invasion and metastasis by targeting TIAM1 in nasopharyngeal carcinoma.

Based on microarray analysis, we previously reported that miR-29c is significantly downregulated in nasopharyngeal carcinoma (NPC). However, little is known about the effect and molecular mechanisms of action of miR-29c deregulation during the development and progression of NPC. Quantitative RT-PCR demonstrated that miR-29c was significantly downregulated in NPC cell lines and clinical specimens. Wound healing, Transwell migration and lung metastasis assays demonstrated that ectopic expression of miR-29c inhibited NPC cell migration and invasion in vitro and suppressed the formation of lung metastases in vivo. T cell lymphoma invasion and metastasis 1 (TIAM1) was confirmed as a miR-29c target gene using luciferase reporter assays, quantitative RT-PCR and Western blotting. Ectopic expression of TIAM1 significantly promoted the migration and invasion of SUNE-1 cell line stably overexpressing miR-29c. The prognostic value of TIAM1 was analyzed in 217 NPC patients using immunohistochemistry. Strikingly, patients with high TIAM1 expression had poorer overall, disease-free and distant metastasis-free survival than patients with low TIAM1 expression. Furthermore, multivariate Cox regression analysis revealed that TIAM1 could serve as an independent prognostic factor in NPC. The newly identified miR-29c/TIAM1 pathway further elucidates the molecular mechanisms regulating invasion and metastasis in NPC, and may provide novel prognostic and treatment strategies for NPC patients.

Low BRMS1 expression promotes nasopharyngeal carcinoma metastasis in vitro and in vivo and is associated with poor patient survival.

BACKGROUND: Breast cancer metastasis suppressor 1 (BRMS1) is a metastasis suppressor gene. This study aimed to investigate the impact of BRMS1 on metastasis in nasopharyngeal carcinoma (NPC) and to evaluate the prognostic significance of BRMS1 in NPC patients. METHODS: BRMS1 expression was examined in NPC cell lines using quantitative reverse transcription-polymerase chain reaction and Western blotting. NPC cells stably expressing BRMS1 were used to perform wound healing and invasion assays in vitro and a murine xenograft assay in vivo. Immunohistochemical staining was performed in 274 paraffin-embedded NPC specimens divided into a training set (n = 120) and a testing set (n = 154). RESULTS: BRMS1 expression was down-regulated in NPC cell lines. Overexpression of BRMS1 significantly reversed the metastatic phenotype of NPC cells in vitro and in vivo. Importantly, low BRMS1 expression was associated with poor distant metastasis-free survival (DMFS, P < 0.001) and poor overall survival (OS, P < 0.001) in the training set; these results were validated in the testing set and overall patient population. Cox regression analysis demonstrated that low BRMS1 expression was an independent prognostic factor for DMFS and OS in NPC. CONCLUSIONS: Low expression of the metastasis suppressor BRMS1 may be an independent prognostic factor for poor prognosis in NPC patients.

Prognostic value of a microRNA signature in nasopharyngeal carcinoma: a microRNA expression analysis.

BACKGROUND: MicroRNAs (miRNAs) can be used as prognostic biomarkers in many types of cancer. We aimed to identify miRNAs that were prognostic in patients with nasopharyngeal carcinoma. METHODS: We retrospectively analysed miRNA expression profiles in 312 paraffin-embedded specimens of nasopharyngeal carcinoma from Sun Yat-sen University Cancer Center (Guangzhou, China) and 18 specimens of non-cancer nasopharyngitis. Using an 873 probe microarray, we assessed associations between miRNA signatures and clinical outcome in a randomly selected 156 samples (training set) and validated findings in the remaining 156 samples (internal validation set). We confirmed the miRNAs signature using quantitative RT-PCR analysis in 156 samples from a second randomisation of the 312 samples, and validated the miRNA signature in 153 samples from the West China Hospital of Sichuan University in Chengdu, China (independent set). We used the Kaplan-Meier method and log-rank tests to estimate correlations of the miRNA signature with disease-free survival (DFS), distant metastasis-free survival (DMFS), and overall survival. FINDINGS: 41 miRNAs were differentially expressed between nasopharyngeal carcinoma and non-cancer nasopharyngitis tissues. A signature of five miRNAs, each significantly associated with DFS, was identified in the training set. We calculated a risk score from the signature and classified patients as high risk or low risk. Compared with patients with low-risk scores, patients with high risk scores in the training set had shorter DFS (hazard ratio [HR] 2·73, 95% CI 1·46-5·11; p=0·0019), DMFS (3·48, 1·57-7·75; p=0·0020), and overall survival (2·48, 1·24-4·96; p=0·010). We noted equivalent findings in the internal validation set for DFS (2·47, 1·32-4·61; p=0·0052), DMFS (2·28, 1·09-4·80; p=0·030), and overall survival (2·87, 1·38-5·96; p=0·0051) and in the independent set for DFS (3·16, 1·65-6·04; p=0·0011), DMFS (2·39, 1·05-5·42; p=0·037), and overall survival (3·07, 1·34-7·01; p=0·0082). The five-miRNA signature was an independent prognostic factor. A combination of this signature and TNM stage had better prognostic value than did TNM stage alone in the training set (area under receiver operating characteristics 0·68 [95% CI 0·60-0·76] vs 0·60 [0·52-0·67]; p=0·013), the internal validation set (0·70 [0·61-0·78] vs 0·61 [0·54-0·68]; p=0·012), and the independent set (0·70 [0·62-0·78] vs 0·63 [0·56-0·69]; p=0·032). INTERPRETATION: Identification of patients with the five-miRNA signature might add prognostic value to the TNM staging system and inform treatment decisions for patients at high risk of progression. FUNDING: Science Foundation of Chinese Ministry of Health, National Natural Science Foundation of China, Pearl River Scholar Funded Scheme, Guangdong Key Scientific and Technological Innovation Program, Guangdong Natural Science Foundation, Fundamental Research Funds for the Central Universities.

Nuclear overexpression of metastasis-associated protein 1 correlates significantly with poor survival in nasopharyngeal carcinoma.

BACKGROUND: Metastasis-associated protein 1 (MTA1) has been associated with poor prognosis in several malignant carcinomas. The purpose of this study was to investigate the expression and prognostic value of MTA1 in nasopharyngeal carcinoma (NPC). METHODS: MTA1 expression was assessed using immunohistochemistry in paraffin-embedded tumor specimens from 208 untreated NPC patients. Cox regression analysis was used to calculate the hazard ratio (HR), 95% confidence interval (CI) and identify independent prognostic factors, and recursive partitioning analysis was used to create a decision tree. RESULTS: Nuclear overexpression of MTA1 was observed in 48.6% (101/208) of the NPC tissues. Nuclear overexpression of MTA1 correlated positively with N classification (P = 0.02), clinical stage (P = 0.04), distant metastasis (P < 0.01) and death (P = 0.01). Additionally, nuclear overexpression of MTA1 correlated significantly with poorer distant metastasis-free survival (DMFS; P <0.01) and poorer overall survival (OS; P < 0.01). MTA1 had prognostic significance in NPC patients with stage II disease, but not stage III or IV disease. Multivariate analysis demonstrated that nuclear overexpression of MTA1 was independently associated with poorer DMFS (HR, 2.05; 95% CI, 1.13-3.72; P = 0.02) and poorer OS (HR, 1.98; 95% CI, 1.09-3.59; P = 0.03). Using recursive partitioning analysis, the NPC patients could be classified with a low, intermediate or high risk of distant metastasis and death, on the basis of clinical stage, age and MTA1 expression. CONCLUSION: The results of this study suggest that nuclear overexpression of MTA1 correlates significantly with poorer DMFS and poorer OS in NPC. MTA1 has potential as a novel prognostic biomarker in NPC.

[Clinical features and treatment of dementia with Lewy bodies].

OBJECTIVE: To investigate the clinical, neuropsychological, neuroimaging features and treatment of dementia with Lewy bodies (DLB). METHODS: The clinical, neuropsychological, neuroimaging and therapeutic features of 33 DLB patients were retrospectively analyzed. RESULTS: There were 25 males and 8 females. The mean course from onset to diagnosis was 3.3 years. Sleep disorder, depression, anxiety and constipation were present at 1 - 10 years prior to DLB onset in 10 patients. Memory impairment (52%) and parkinsonism (21%) were initial symptoms. The mean duration from memory impairment to presence of parkinsonism was 17 months. Pattern of extrapyramidal signs showed bilateral, symmetry and axial muscles bias as postural instability and facial impassivity, tremor was less in DLB. Hallucination (70%), sleep disorder (63%), apathy (56%) and delusion (52%) were the major behavioral and psychological symptoms. Hallucination occurred within a mean of 15 months after presence of initial symptoms. Cognition impairment progressed rapidly in half of patients. Neuropsychological tests of mild patients revealed visuospatial dysfunction and relatively preservation of memory. Severe impairment of all domains of cognition was noticed in moderate-severe patients. MRI (magnetic resonance imaging) revealed the preservation of hippocampal structures. And PET (positron emission tomography) showed hypometabolism of occipital lobe. Cholinesterase inhibitors could improve cognitive impairment and behavioral symptoms in a large majority of patients. CONCLUSION: Neuronal dysfunction may be present at an early stage of DLB. Early presence of hallucination, a high prevalence of sleep disorders, axial rigidity and hypometabolism of occipital lobe on PET may help to distinguish DLB from other types of dementia.

Value of 18F fluoro-2-deoxy-D-glucose positron emission tomography/computed tomography in diagnosis and localization of Cushing's disease / 中国医学科学院学报

<p><b>OBJECTIVE</b>To explore the value of [18F]fluoro-2-deoxy-D-glucose(18 FDG) positron emission tomography and computer tomography (PET/CT) in the qualitative diagnosis and localization of Cushing's disease.</p><p><b>METHODS</b>Totally 12 patients underwent transsphenoidal adenomectomy and were histopathologically proven to be with Cushing's disease. 18FDG PET/CT whole-body and brain scannings were performed preoperatively; meanwhile, magnetic resonance imaging (MRI) and 99mTc-octreotide examination were done in all 12 cases, and inferior petrosal sinus sampling (IPSS) were done in 6 patients.</p><p><b>RESULTS</b>The sensitivity of 18FDG in diagnosing Cushing's disease was 91.6% (11/12), but MRI was 66.7%(8/12). For the 6 patients who performed IPSS, 5 of them was diagnosed to be with Cushing's disease, and only 50% (3/6) were localized correctly in the pituitary gland.</p><p><b>CONCLUSIONS</b>18FDG PET/CT whole-body scan can exclude ectopic adrenocorticotropin-secreting tumors and localize the pituitary lesions with higher accuracy than MRI. Therefore, it is useful for suspected Cushing's disease, especially for patients their MRI and IPSS have negative or paradoxical results.</p>

[18FDG PET in the management of malignant lymphoma].

OBJECTIVE: To study the role and prospect of 18FDG PET imaging in patients with malignant lymphoma. METHODS: Forty-four patients (73 studies) with malignant lymphoma underwent 18FDG PET imaging. Final diagnoses were proved histopathologically. Images obtained were analyzed using visual and semiquantitative analysis (SUV). RESULTS: Either nodal or extranodal tumor foci showed high 18FDG uptake. 18FDG PET led to correct diagnosis in 5 of 6 cases except 1 false negative case. PET imaging changed the staging in 4 of 6 cases pretherapeutically. Of the 16 cases in which either residual tumor mass or suspicious recurrence suggested by other imaging modalities, 18FDG PET confirmed relapse in 5, detected more lesions in 2 and showed no evidence of active tumor mass in 9. For the 3 patients with comparison between pre- or post-treatment PET imaging and 16 patients who only underwent post-treatment PET follow-up studies, therapeutic response was correctly evaluated. CONCLUSIONS: 18FDG PET is a valuable non-invasive metabolic imaging modality in facilitating diagnosis and staging, evaluating therapeutic response, assessing clinical outcome and predicting prognosis in patients with lymphoma.