Genomic Profiling of Radiation-Induced Sarcomas Reveals the Immunologic Characteristics and Its Response to Immune Checkpoint Blockade.

PURPOSE: Radiation-induced sarcomas (RIS) have a poor prognosis and lack effective treatments. Its genome and tumor microenvironment are not well characterized and need further exploration. EXPERIMENTAL DESIGN: Here, we performed whole-exome sequencing (WES) and mRNA sequencing (mRNA-seq) on patients with RIS and primary sarcomas (WES samples 46 vs. 48, mRNA-seq samples 16 vs. 8, mainly in head and neck), investigated the antitumor effect of programmed cell death protein 1 (PD-1) blockade in RIS patient-derived xenograft models, and analyzed clinical data of patients with RIS treated with chemotherapy alone or combined with an anti-PD-1 antibody. RESULTS: Compared with primary sarcomas, RIS manifested different patterns of copy-number variations, a significantly higher number of predicted strong MHC-binding neoantigens, and significantly increased immune cell infiltration. Clinical data showed that the combinatorial use of chemotherapy and PD-1 blockade achieved a higher objective response rate (36.67% vs. 8.00%; P = 0.003), longer overall survival (31.9 months vs. 14.8 months; P = 0.014), and longer progression-free survival (4.7 months vs. 9.5 months; P = 0.032) in patients with RIS compared with single chemotherapy. CONCLUSIONS: Elevated genomic instability and higher immune cell infiltrations were found in RIS than in primary sarcomas. Moreover, higher efficacy of chemotherapy plus PD-1 blockade was observed in animal experiments and clinical practice. This evidence indicated the promising application of immune checkpoint inhibitors in the treatment of RIS.

Overall Survival Rates Become Similar Between Percutaneous Ablation and Hepatic Resection With Increasing Age Among Elderly Patients With Early Hepatocellular Carcinoma.

Background: This study aimed to investigate the efficacy and safety of percutaneous ablation versus hepatectomy in an elderly population with hepatocellular carcinoma (HCC). Methods: Retrospective data on patients aged ≥ 65 years with very-early/early stages of HCC (≤ 50 mm) were obtained from three centers in China. Inverse probability of treatment weighting analysis was performed after stratifying the patients by age (65 - 69, 70 - 74 and ≥ 75 years). Results: Of the 1,145 patients, 561 and 584 underwent resection and ablation, respectively. For patients aged 65 - 69 and 70 - 74 years, resection resulted in significantly better overall survival (OS) than ablation (age 65 - 69, P < 0.001, hazard ratio (HR) = 0.27; age 70 - 74, P = 0.012, HR = 0.64). However, in patients aged ≥ 75 years, resection and ablation resulted in a similar OS (P = 0.44, HR = 0.84). An interactive effect existed between treatment and age (effect of treatment on OS, age 65 - 69 as the reference, for age 70 - 74, P = 0.039; for age ≥ 75, P = 0.002). The HCC-related death rate was higher in patients aged 65 - 69, and the liver/other cause-related death rate was higher in patients aged > 69. Multivariate analyses showed that the type of treatment, number of tumors, α-fetoprotein level, serum albumin level and associated diabetes mellitus were independent factors associated with OS, but not hypertension or heart diseases. Conclusion: With increasing patient age, the treatment outcomes of ablation become similar to those of resection. A higher liver/other cause-related death rate in very elderly patients may shorten the life expectancy, which may lead to the same OS regardless of whether resection or ablation is chosen.

Investigating Mechanisms of Response or Resistance to Immune Checkpoint Inhibitors by Analyzing Cell-Cell Communications in Tumors Before and After Programmed Cell Death-1 (PD-1) Targeted Therapy: An Integrative Analysis Using Single-cell RNA and Bulk-RNA Sequencing Data.

Currently, a significant proportion of cancer patients do not benefit from programmed cell death-1 (PD-1)-targeted therapy. Overcoming drug resistance remains a challenge. In this study, single-cell RNA sequencing and bulk RNA sequencing data from samples collected before and after anti-PD-1 therapy were analyzed. Cell-cell interaction analyses were performed to determine the differences between pretreatment responders and nonresponders and the relative differences in changes from pretreatment to posttreatment status between responders and nonresponders to ultimately investigate the specific mechanisms underlying response and resistance to anti-PD-1 therapy. Bulk-RNA sequencing data were used to validate our results. Furthermore, we analyzed the evolutionary trajectory of ligands/receptors in specific cell types in responders and nonresponders. Based on pretreatment data from responders and nonresponders, we identified several different cell-cell interactions, like WNT5A-PTPRK, EGFR-AREG, AXL-GAS6 and ACKR3-CXCL12. Furthermore, relative differences in the changes from pretreatment to posttreatment status between responders and nonresponders existed in SELE-PSGL-1, CXCR3-CCL19, CCL4-SLC7A1, CXCL12-CXCR3, EGFR-AREG, THBS1-a3b1 complex, TNF-TNFRSF1A, TNF-FAS and TNFSF10-TNFRSF10D interactions. In trajectory analyses of tumor-specific exhausted CD8 T cells using ligand/receptor genes, we identified a cluster of T cells that presented a distinct pattern of ligand/receptor expression. They highly expressed suppressive genes like HAVCR2 and KLRC1, cytotoxic genes like GZMB and FASLG and the tissue-residence-related gene CCL5. These cells had increased expression of survival-related and tissue-residence-related genes, like heat shock protein genes and the interleukin-7 receptor (IL-7R), CACYBP and IFITM3 genes, after anti-PD-1 therapy. These results reveal the mechanisms underlying anti-PD-1 therapy response and offer abundant clues for potential strategies to improve immunotherapy.

Frequent amplification of HDAC genes and efficacy of HDAC inhibitor chidamide and PD-1 blockade combination in soft tissue sarcoma.

BACKGROUND: The advent of immune checkpoint therapy has been a tremendous advance in cancer treatment. However, the responses are still insufficient in patients with soft tissue sarcoma (STS). We aimed to identify rational combinations to increase the response to immune checkpoint therapy and improve survival. METHODS: Whole-exome sequencing (WES) was performed in 11 patients with liposarcoma. Somatic copy number alterations (SCNAs) were analyzed at the gene level to identify obvious amplification patterns in drug-target genes. The expression and prognostic value of class I histone deacetylases (HDACs) was evaluated in 49 patients with sarcoma in our center and confirmed in 263 sarcoma samples from The Tumor Cancer Genome Atlas (TCGA) database. Q-PCR, flow cytometry and RNA-seq were performed to determine the correlations between class I HDACs, chidamide and PD-L1 in vitro and in vivo. The efficacy of combining chidamide with PD-1 blockade was explored in an immunocompetent murine model and a small cohort of patients with advanced sarcoma. Western blot, ChIP assay and dual luciferase assessment were applied in the mechanistic study. RESULTS: The HDAC gene family was frequently amplified in STS. SCNAs in the HDAC gene family were extensively amplified in 8 of 11 (73%) patients with liposarcoma, based on a drug-target gene set, and we verified amplification in 76.65% (197/257) of cases by analyzing TCGA sarcoma cohort. Class I HDAC expression is associated with a poor prognosis for patients with STS, and its inhibition is responsible for promoting apoptosis and upregulating of programmed cell death ligand 1 (PD-L1). The HDAC class I inhibitor chidamide significantly increases PD-L1 expression, increased the infiltration of CD8+ T cells and reduced the number of MDSCs in the tumor microenvironment. The combination of chidamide with an anti-PD-1 antibody significantly promotes tumor regression and improves survival in a murine model. Moreover, chidamide combined with the anti-PD-1 antibody toripalimab is effective in patients with advanced and metastatic sarcoma, and the side effects are tolerable. Mechanistically, chidamide increases histone acetylation at the PD-L1 gene through the activation of the transcriptional factor STAT1. CONCLUSIONS: The combination of chidamide and anti-programmed cell death 1 (PD-1) therapy represents a potentially important strategy for STS.

Eight key long non-coding RNAs predict hepatitis virus positive hepatocellular carcinoma as prognostic targets.

BACKGROUND: Hepatitis B virus, together with hepatitis C virus, has been recognized as the leading causes of hepatocellular carcinoma (HCC). Long non-coding RNAs (lncRNAs) have been suggested in increasing studies to be the potential prognostic factors for HCC. However, the role of combined application of lncRNAs in estimating overall survival (OS) for hepatitis virus positive HCC (VHCC) is uncertain. AIM: To construct an lncRNA signature related to the OS of VHCC patients to enhance the accuracy of prognosis prediction. METHODS: The expression patterns of lncRNAs, as well as related clinical data were collected from 149 VHCC patients from The Cancer Genome Atlas database. The R package was adopted to obtain the differentially expressed lncRNAs (DElncRNAs). LncRNAs significantly associated with OS were screened by means of univariate Cox regression analysis, so as to construct a least absolute shrinkage and selection operator (LASSO) model. Subsequently, the constructed lncRNA signature was developed and validated. Afterwards, the prognostic nomogram was established, which combined the as-established lncRNA signature as well as the clinical features. Meanwhile, subgroup analysis stratified by the virus type was also performed. Finally, the above-mentioned lncRNAs were enriched to corresponding pathways according to the markedly co-expressed genes. RESULTS: A total of 1420 DElncRNAs were identified, among which 406 were significant in univariate Cox regression analysis. LASSO regression confirmed 8 out of the 406 lncRNAs, including AC005722.2, AC107959.3, AL353803.1, AL589182.1, AP000844.2, AP002478.1, FLJ36000, and NPSR1-AS1. Then, the prognostic risk score was calculated. Our results displayed a significant association between the risk model and the OS of VHCC [hazard ratio = 1.94, 95% confidence interval (CI): 1.61-2.34, log-rank P = 2e-10]. The inference tree suggested that the established lncRNA signature was useful in the risk stratification of VHCC. Furthermore, a nomogram was plotted, and the concordance index of internal validation was 0.763 (95%CI: 0.700-0.826). Moreover, the subgroup analysis regarding etiology confirmed this risk model. In addition, the Wnt signaling pathway, angiogenesis, the p53 pathway, and the PI3 kinase pathway were the remarkably enriched pathways. CONCLUSION: An eight-lncRNA signature has been established to predict the prognosis for VHCC, which contributes to providing a novel foundation for the targeted therapy of VHCC.

Efficacy of treatment regimens for advanced hepatocellular carcinoma: A network meta-analysis of randomized controlled trials.

BACKGROUND: This study aimed to perform a network meta-analysis to evaluate the therapeutic effect and safety of various modalities in treating advanced hepatocellular carcinoma (HCC). Typically, the modalities of interest were comprised of sorafenib, transarterial chemoembolization (TACE), sorafenib combined with TACE, TACE combined with traditional Chinese medicine (TCM), and sorafenib combined with hepatic arterial infusion chemotherapy (HAIC). METHODS: Potentially eligible studies were systemically retrieved from the electronic databases (including PubMed and Cochrane Library) up to September 2018. The overall survival (OS) associated with the 5 modalities of interest enrolled in this study was compared by means of network meta-analysis. Meanwhile, major adverse events (AEs) were also evaluated. RESULTS: The current network meta-analysis enrolled 7 published randomized controlled trials (RCTs), and the pooled results indicated that the TACE-TCM regimen displayed the highest efficacy in treating advanced HCC, followed by HAIC-sorafenib. By contrast, the TACE alone and sorafenib alone regimens had the least efficacy. Relative to other regimens of interest, the TACE-TCM regimen was associated with less incidence of treatment-associated AEs. CONCLUSION: The TACE-TCM regimen was associated with higher treatment responses in advanced HCC patients than those of the other regimens of interest.

Safety and effectiveness of multi-antenna microwave ablation-oriented combined therapy for large hepatocellular carcinoma.

BACKGROUND: In patients with a large, unresectable hepatocellular carcinoma (HCC), the primary recommendation is for transarterial chemoembolization (TACE) but used alone TACE is not typically curative. Combinations of TACE followed in a delayed fashion by single-applicator thermal ablation have also been suboptimal. As an alternative, we investigated the combination of TACE followed within 1-3 days by multi-antenna microwave ablation (MWA) in patients with a large HCC, to determine the feasibility, safety, local control, and short-term survival rates of this approach. METHODS: We retrospectively studied 43 patients with a large HCC (mean diameter, 8.8 cm; SD, 2.8 cm) treated between July 2015 and July 2018, who underwent TACE followed within 3 days by multi-antenna simultaneous MWA. We measured the liver and renal function before and after treatment, recorded complications, used three-dimensional software and imaging to calculate tumor necrosis rates at 1 month after therapy, and calculated overall survival (OS) and progression-free survival (PFS) using the Kaplan-Meier method. RESULTS: Mean follow up was 12.2 (range, 3.5-35.6) months. All patients completed the treatment protocol. At 1 month after combined therapy, tumor necrosis was complete in 16 (37.2%), nearly complete in 19 (44.2%), and partial in 8 (18.6%) patients. The 1- and 2-year OS rates were 64.0% and 46.8%, respectively, with a median OS of 23.0 months; and the 1- and 2-year PFS rates were 19.9% and 4.4%, respectively, with a median PFS of 4.2 months. A transient change in liver function occurred 3 days after MWA but resolved within 1 month. Only two patients had major complications, which were treatable and resolved. CONCLUSION: Multi-antenna MWA-oriented combined therapy is feasible and well tolerated, and it results in satisfactory initial local control and short-term survival in some but not all patients with a large HCC.

Significance of tumor-infiltrating immunocytes for predicting prognosis of hepatitis B virus-related hepatocellular carcinoma.

BACKGROUND: Hepatitis B virus (HBV) has been recognized as a leading cause of hepatocellular carcinoma (HCC). Numerous reports suggest that immune infiltration can predict the prognosis of HCC. Nonetheless, no creditable markers for prognosis of HBV-related HCC have been established by systematically assessing the immune-related markers based on tumor transcriptomes. AIM: To establish an immune-related marker based on the cell compositions of immune infiltrate obtained based on tumor transcriptomes, so as to enhance the prediction accuracy of HBV-related HCC prognosis. METHODS: RNA expression patterns as well as the relevant clinical data of HCC patients were obtained from The Cancer Genome Atlas. Twenty-two immunocyte fraction types were estimated by cell type identification by estimating relative subsets of RNA transcripts. Subsequently, the least absolute shrinkage and selection operator (LASSO) Cox regression model was employed to construct an immunoscore based on the immunocyte fraction types. Afterwards, the receiver operating characteristic (ROC) curve, Kaplan-Meier, and multivariate Cox analyses were performed. Additionally, a nomogram for prognosis that integrated the immunoscore as well as the clinical features was established. Meanwhile, the correlation of immunoscore with immune genes was also detected, and gene set enrichment analysis (GSEA) of the immunoscore was conducted. RESULTS: A total of 22 immunocyte fraction types were predicted and compared among the tumor as well as non-tumor samples. An immunoscore was constructed through adopting the LASSO model, which contained eight immunocyte fraction types. Meanwhile, the areas under the ROC curves for the immunoscore biomarker prognostic model were 0.971, 0.912, and 0.975 for 1-, 3-, and 5-year overall survival (OS), respectively. Difference in OS between the high-immunoscore group and the low-immunoscore group was statistically significant [hazard ratio (HR) = 66.007, 95% confidence interval (CI): 8.361-521.105; P < 0.0001]. Moreover, multivariable analysis showed that the immunoscore was an independent factor for predicting the prognosis (HR = 2.997, 95%CI: 1.737-5.170). A nomogram was established, and the C-index was 0.757 (95%CI: 0.648-0.866). The immunoscore showed a significant negative correlation with the expression of PD-1 (P = 0.024), PD-L1 (P = 0.026), PD-L2 (P = 0.029), and CD27 (P = 0.033). Eight pathways were confirmed by GSEA. CONCLUSION: The established immunoscore can potentially serve as a candidate marker to estimate the OS for HBV-related HCC cases.

TFAP4 Promotes Hepatocellular Carcinoma Invasion and Metastasis via Activating the PI3K/AKT Signaling Pathway.

Transcription factor activating enhancer binding protein 4 (TFAP4) is established as a regulator of human cancer genesis and progression. Overexpression of TFAP4 indicates poor prognosis in various malignancies. The current study was performed to quantify TFAP4 expression as well as to further determine its potential prognostic value and functional role in patients with hepatocellular carcinoma (HCC). We identified that the expression of TFAP4 mRNA in 369 tumor tissues was higher than that in 160 normal liver tissues. Upregulated TFAP4 expressions were discovered in HCC cell lines compared to the healthy liver cell line, and similarly, the levels of TFAP4 were higher in tumor tissues than its expression in paratumor tissues. High mRNA and protein expression of TFAP4 was associated with worse overall survival (OS) and disease-free survival (DFS). Additionally, TFAP4 expression emerged as a risk factor independently affecting both OS and DFS of HCC patients. Functional studies demonstrated that TFAP4 increased HCC cell migration and invasion. Further investigations found that TFAP4 promotes invasion and metastasis by inducing epithelial-mesenchymal transition (EMT) and regulating MMP-9 expression via activating the PI3K/AKT signaling pathway in HCC. In conclusion, our study demonstrated that TFAP4 is a valuable prognostic biomarker in determining the likelihood of tumor metastasis and recurrence, as well as the long-term survival rates of HCC patients. Exploring the regulatory mechanism of TFAP4 will also contribute to the development of new prevention and treatment strategies for HCC.

Examining the key genes and pathways in hepatocellular carcinoma development from hepatitis B virus­positive cirrhosis.

To identify the key genes and pathways in the development of hepatocellular carcinoma (HCC) from hepatitis B virus (HBV)­positive liver cirrhosis, differentially expressed genes (DEGs) between HCC and liver cirrhosis tissue samples from the GSE17548 gene expression profile dataset were screened. A total of 1,845 DEGs were identified, including 1,803 upregulated and 42 downregulated genes. Gene Ontology, Kyoto Encyclopedia of Genes and Genomes (KEGG) and protein­protein interaction (PPI) network analyses were performed. It was identified that the 'cell cycle' and 'progesterone­mediated oocyte maturation' KEGG pathways were significantly enriched in the DEGs. In addition, the high expression of the hub genes from the PPI network (including cyclin dependent kinase 1, cyclin B1, cyclin B2, mitotic arrest deficient 2 like 1, BUB1 mitotic checkpoint serine/threonine kinase and cyclin A2; P=0.00116, 0.00021, 0.04889, 0.00222, 0.00015 and 0.00647, respectively) was associated with a decrease in overall survival for patients with HCC as identified using survival and expression data from The Cancer Genome Atlas. The identified hub genes and pathways may help to elucidate the molecular mechanisms of HCC progression from HBV­positive liver cirrhosis. Additionally, they may be useful as therapeutic targets or serve as novel biomarkers for HCC prognosis prediction.

A Prognostic Score for Nasopharyngeal Carcinoma with Bone Metastasis: Development and Validation from Multicenter.

Background: To establish a prognostic score based on clinical routine factors to stratify nasopharyngeal carcinoma patients with bone metastasis into risk groups with different survival rates. Materials and Methods: Total 276 patients from multicenter were retrospectively analyzed. Kaplan-Meier method and Cox regression were used to confirm independent risk factors, which were checked for internal validity by bootstrapping method. The prognostic score, deriving from the corresponding regression coefficients in Cox model, classified patients into low and high risk groups. Finally, two independent cohorts were used for external validation. Results: In development cohort, six risk factors were identified: age>46 year-old (point=1), N>0 stage (point=2), anemia (point=2), bone metastasis free interval≤12 months (point=1), without radiotherapy to primary sites (point=1), and without radiotherapy to first metastasis sites (point=1). The derived prognostic score divided patients into low (score, 0-4) and high (score, 5-8) risk groups, with highly significant differences of 5-year overall survival rates (high vs. low risk: 24.6% vs. 58.2%, HR 3.47, P<0.001). Two external validations presented congruent results. Conclusion: A feasible and applicative prognostic score was successfully established and validated to discriminate bone metastatic nasopharyngeal carcinoma into low/high risk groups, which will be useful for individual treatment.

Vicious circle of acute radiation toxicities and weight loss predicts poor prognosis for nasopharyngeal carcinoma patients receiving intensity modulated radiotherapy.

Background: Weight loss during radiotherapy has been known as a negative prognostic factor for nasopharyngeal carcinoma (NPC) patients, but the factors related to weight loss during radiotherapy were not fully understood. Methods: A total of 322 newly diagnosed NPC patients receiving intensity modulated radiotherapy (IMRT) in Sun Yat-sen University Cancer Center between June 2002 and August 2006 were enrolled. Kaplan-Meier methods and log-rank test were applied for survival analysis; a multiple regression was used to identify the factors related to weight loss during radiotherapy. Results: The mean and median values of weight loss (%) during radiotherapy were 6.85% and 6.70%. NPC patients with critical weight loss (> 5.4%) have poorer overall survival (OS) and distant metastasis-free survival (DMFS) than the patients without critical weight loss (p = 0.002 and 0.021, respectively). Pre-radiotherapy weight, acute mucosal toxicity, acute pharynx and esophagus toxicity, and acute upper gastrointestinal toxicity were related to the weight loss during radiotherapy independently (p = 0.01, p < 0.001, p < 0.001, and p = 0.009, respectively). Conclusions: Acute radiation toxicities had significant and independent impact on weight loss during radiotherapy. The vicious circle of acute radiation toxicities and weight loss had bad effect on prognosis of NPC patients.

Overweight/obese status associates with favorable outcome in patients with metastatic nasopharyngeal carcinoma: a 10-year retrospective study.

BACKGROUND: Although the prognostic impact of body mass index (BMI) in patients with non-metastatic nasopharyngeal carcinoma (NPC) had been extensively studied, its effect among metastatic NPC patients remains unknown. The purpose of this study was to evaluate the prognostic effect of BMI in patients with metastatic NPC. METHODS: We retrospectively studied 819 patients who were diagnosed with distant metastasis from NPC and received treatment between 1998 and 2007. The patients were divided into three subgroups according to the World Health Organization classifications for Asian populations: underweight (BMI <18.5 kg/m(2)), normal weight (BMI 18.5-22.9 kg/m(2)), and overweight/obese (BMI ≥23.0 kg/m(2)). The associations of BMI with overall survival (OS) and progression-free survival (PFS) were determined by Cox regression analysis. RESULTS: Of the 819 patients, 168 (20.5%) were underweight, 431 (52.6%) were normal weight, and 220 (26.9%) were overweight/obese. Multivariate analysis adjusted for covariates showed that overweight/obese patients had a longer OS than underweight patients [hazard ratio (HR), 0.64; 95% confidence interval (CI), 0.49-0.84] and normal weight patients (HR, 0.72; 95% CI, 0.57-0.90); no significant difference in PFS was observed among these three groups (P = 0.407). Moreover, in stratified analysis, no statistically significant differences in the effect of overweight/obese status among different subgroups were observed. CONCLUSION: For patients with metastatic NPC, overweight/obese status was associated with longer OS but not longer PFS compared with underweight or normal weight status.

Chemolipiodolization with or without embolization in transcatheter arterial chemoembolization combined with radiofrequency ablation for hepatocellular carcinoma-propensity score matching analysis.

To retrospectively compare the outcome of chemolipiodolization with or without embolization in transcatheter arterial chemoembolization (TACE) combined with radiofrequency ablation (RFA) in Patients with hepatocellular carcinoma (HCC) within the Milan criteria. From August 2002 to December 2014, 112 patients (median age, 56.7 years; age range, 22-80 years; 97 men, 15 women) underwent TACE with gelatin sponge particle embolization, and 125 patients (median age, 56.6 years; age range, 23-82 years; 109 men, 16 women) underwent TACE without embolization. RFA was performed within 2 weeks after the TACE. Cumulative overall survival (OS) and disease-free survival (DFS) rates were compared before and after propensity score matching. Before matching, the 1-, 3-, and 5-year OS rate were 96%, 80%, and 62% for embolization group and 94%, 76%, and 59% for non-embolization group . The 1-, 3-, and 5-year DFS rate were 77%, 38%, and 30% for embolization group and 75%, 35%, and 26% for non-embolization group. After matching, the 1-, 3-, and 5-year OS rate were 97%, 82%, and 62% for embolization group and 92%, 74%, and 56% for non-embolization group. The 1-, 3-, and 5-year DFS rate were 79%, 36%, and 30% for embolization group and 74%, 33%, and 26% for non-embolization group. There were no significant difference in OS and DFS rates between the two groups before matching (P =0.999 and P =0.654) and after matching (P =0.951 and P =0.670). In conclusion, embolization in TACE combined with RFA could not improve the survival for patients with HCC within the Milan criteria.

Nomograms for predicting long-term survival in patients with non-metastatic nasopharyngeal carcinoma in an endemic area.

PURPOSE: Nomogram for predicting more than a 5-year survival for non-metastatic nasopharyngeal carcinoma (NPC) was lacking. This study aimed to develop the new nomograms to predict long-term survival in these patients. RESULTS: The median follow-up time for training set and test set was 95.2 months and 133.3 months, respectively. The significant predictors for death were age, gender, body mass index (BMI), T stage, N stage, lactate dehydrogenase (LDH), and radiotherapy techniques. For predicting recurrence, age, gender, T stage, LDH, and radiotherapy techniques were significant predictors, whereas age, gender, BMI, T stage, N stage and LDH were significant predictors for distant metastasis. The calibration curves showed the good agreements between nomogram-predicted and actual survival. The c-indices for predicting death, recurrence, and distant metastases between nomograms and the TNM staging system were 0.767 VS.0.686 (P<0.001), 0.655 VS.0.585 (P<0.001), and 0.881 VS.0.754 (P<0.001), respectively. These results were further confirmed in the test set. METHODS: On the basis of a retrospective study of 1593 patients (training set) who received radiotherapy alone or concurrent chemoradiotherapy from 2000 to 2004, significant predictors were identified and incorporated to build the nomograms. The calibration curves of nomogram-predicted survival versus the actual survival were plotted and reviewed. Bootstrap validation was performed to calculate the concordance index (c-index). These models were further validated in an independent prospective trial (test set, n=400). CONCLUSION: The established nomograms suggest more-accurate long-term prediction for patients with non-metastatic NPC.

Critical weight loss predicts poor prognosis in nasopharyngeal carcinoma.

BACKGROUND: The impacts of weight loss on prognosis in nasopharyngeal carcinoma (NPC) remain unclear. The present study was therefore undertaken to investigate the association between critical weight loss and long-term survival in NPC patients. METHODS: The eligible 2399 NPC patients were reviewed. Weight change was categorized into critical weight loss (CWL) and non-critical weight loss (Non-CWL). The associations of CWL with long-term survival were analyzed by Cox regression in the entire patient and two subsets. Propensity score matching was performed to reduce the effects of confounding factors. RESULTS: CWL was defined as body weight loss of ≥4.6 %. Compared with patients without CWL, patients with CWL had significantly lower 5-year OS (72.4 vs. 79.3 %, P < 0.001), FFS (71.1 vs. 78.4 %, P <0.001), and LR-FFS (78.1 vs. 84.8 %, P <0.001), respectively. After adjustment for potential confounders, CWL remained an independence prognostic factor for OS (HR = 1.352; 95 % CI 1.160-1.576; P < 0.001), FFS (HR = 3.275; 95 % CI 1.101-9.740; P = 0.033), and LR-FFS (HR = 6.620; 95 % CI 2.990-14.658; P < 0.001), respectively. Furthermore, subgroup analysis in the cohort of patients received concurrent chemoradiotherapy or radiotherapy alone confirmed the results in the entire patient even after the propensity-score matching. In IMRT cohort, CWL was also significantly associated with a lower OS (P = 0.04) and FFS (P = 0.04). CONCLUSIONS: CWL has a significant and independent impact on long-term survival in nasopharyngeal carcinoma patients.

The effects of hemoglobin levels and their interactions with cigarette smoking on survival in nasopharyngeal carcinoma patients.

There is very little published information regarding the prognostic value of hemoglobin (Hb) levels combined with smoking on the survival of patients with nasopharyngeal carcinoma (NPC), and the interactions between them remain unclear. A total of 2440 NPC patients were confirmed, and multivariate analysis was performed to identify valuable prognostic Hb levels in the entire population and in the cohort of smokers. The survival differences were compared using log-rank tests. The multiplicative and additive interactions were assessed using Cox regression and a Microsoft Word Excel spreadsheet. Postradiotherapy (RT) Hb was an independent prognostic factor for overall survival (OS) (HR = 0.797; P = 0.006), failure-free survival (FFS) (HR=0.811; P = 0.010), and loco-regional failure-free survival (LR-FFS) (HR = 0.725; P = 0.000). In the cohort of smokers, pack-years was also an independent predictor of OS (HR = 0.673; P < 0.001) and FFS (HR = 0.681; P < 0.001), LR-FFS (HR = 0.663; P = 0.001). A significant positive additive effect was found for the interaction between low post-RT Hb and high SI on OS, with RERI = 5.616, AP = 0.665, and S = 4.078. Stratified analyses demonstrated that heavy smokers with low post-RT Hb had HRs of 2.295 (P < 0.001) for death, 2.222 (P < 0.001) for disease failure, and 2.267 (P < 0.001) loco-regional recurrence compared with light smokers with high post-RT Hb levels, and post-RT Hb level is an important predictor of survival in patients with NPC. The positive interaction between post-RT Hb level and pack-years contributes to the elevated risk of poor survival. Oncologists should devote particular attention to heavy smokers with low post-RT Hb levels in the future.

Alcohol drinking as an unfavorable prognostic factor for male patients with nasopharyngeal carcinoma.

The relationship between alcohol drinking and the prognosis of nasopharyngeal carcinoma (NPC) is unknown. To investigate the prognostic value of alcohol drinking on NPC, this retrospective study was conducted on 1923 male NPC patients. Patients were classified as current, former and non-drinkers according to their drinking status. Furthermore, they were categorized as heavy drinkers and mild/none drinkers based on the intensity and duration of alcohol drinking. Survival outcomes were compared using Kaplan-Meier analysis and Cox proportional hazards model. We found that current drinkers had significantly lower overall survival (OS) rate (5-year OS: 70.2% vs. 76.4%, P < 0.001) and locoregional recurrence-free survival (LRFS) rate (5-year LRFS: 69.3% vs. 77.5%, P < 0.001) compared with non-drinkers. Drinking ≥14 drinks/week, and drinking ≥20 years were both independent unfavorable prognostic factors for OS (hazard ratio [HR] = 1.38, 95% confidence interval [CI] 1.05-1.81, P = 0.022; HR = 1.38, 95% CI 1.09-1.75, P = 0.007). Stratified analyses further revealed that the negative impacts of alcohol were manifested mainly among older patients and among smokers. In conclusion, alcohol drinking is a useful predictor of prognosis in male NPC patients; drinkers, especially heavy drinkers have poorer prognosis.

Subdivision of M category for nasopharyngeal carcinoma with synchronous metastasis: time to expand the M categorization system.

INTRODUCTION: The current metastatic category (M) of nasopharyngeal carcinoma (NPC) is a "catch-all" classification, covering a heterogeneous group of tumors ranging from potentially curable to incurable. The aim of this study was to design an M categorization system that could be applied in planning the treatment of NPC with synchronous metastasis. METHODS: A total of 505 NPC patients diagnosed with synchronous metastasis at Sun Yat-sen University Cancer Center between 2000 and 2009 were involved. The associations of clinical variables, metastatic features, and a proposed M categorization system with overall survival (OS) were determined by using Cox regression model. RESULTS: Multivariate analysis showed that Union for International Cancer Control (UICC) N category (N1-3/N0), number of metastatic lesions (multiple/single), liver involvement (yes/no), radiotherapy to primary tumor (yes/no), and cycles of chemotherapy (>4/≤4) were independent prognostic factors for OS. We defined the following subcategories based on liver involvement and the number of metastatic lesions: M1a, single lesion confined to an isolated organ or location except the liver; M1b, single lesion in the liver and/or multiple lesions in any organs or locations except the liver; and M1c, multiple lesions in the liver. Of the 505 cases, 74 (14.7%) were classified as M1a, 296 (58.6%) as M1b, 134 (26.5%) as M1c, and 1 was not specified. The three M1 subcategories showed significant difference in OS [M1b vs. M1a, hazard ratio (HR) = 1.69, 95% confidence interval (CI) = 1.16-2.48, P = 0.007; M1c vs. M1a, HR = 2.64, 95% CI = 1.75-3.98, P < 0.001]. CONCLUSIONS: We developed an M categorization system based on the independent factors related to the prognosis of patients with metastatic NPC. This system may be helpful to further optimize individualized care for NPC patients.

Pretreatment platelet count improves the prognostic performance of the TNM staging system and aids in planning therapeutic regimens for nasopharyngeal carcinoma: a single-institutional study of 2,626 patients.

INTRODUCTION: Thrombocytosis has been identified as an unfavorable prognostic factor in several types of cancer. This study aimed to evaluate the prognostic value of pretreatment platelet count in association with the TNM staging system and therapeutic regimens in patients with nasopharyngeal carcinoma (NPC). METHODS: A total of 2,626 patients with NPC were retrospectively analyzed. Platelet count >300 × 10(9)/L was defined as thrombocytosis. Matched-pair analysis was performed between patients receiving chemoradiotherapy and radiotherapy. RESULTS: Multivariate analysis showed that platelet count was an independent unfavorable prognostic factor for overall survival (OS) [hazard ratio (HR) = 1.810, 95% confidence interval (CI) = 1.531-2.140, P < 0.001] and distant metastasis-free survival (DMFS) (HR = 1.873, 95% CI = 1.475-2.379, P < 0.001) in the entire patient cohort. Further subgroup analysis revealed that increased platelet count was an independent unfavorable prognostic factor for OS and DMFS in patients with NPC stratified by early and advanced T category, N category, or TNM classification (all P ≤ 0.001). Receiver operating characteristic (ROC) curves verified that the predictive value of TNM classification for OS was improved when combined with pretreatment platelet count (P = 0.030). Matched-pair analysis showed that chemoradiotherapy significantly improved OS only in advanced-stage NPC with thrombocytosis (HR = 0.416, 95% CI = 0.226-0.765, P = 0.005). CONCLUSIONS: Pretreatment platelet count, when combined with TNM classification, is a useful indicator for metastasis and survival in patients with NPC. It may improve the predictive value of the TNM classification and help to identify patients likely to benefit from more aggressive therapeutic regimens.